@article{Lachapelle2024,
abstract = {There remains a clinical need for better approaches to rapid drug susceptibility testing in view of the increasing burden of multidrug resistant tuberculosis. Binary susceptibility phenotypes only capture changes in minimum inhibitory concentration when these cross the critical concentration, even though other changes may be clinically relevant. We developed a machine learning system to predict minimum inhibitory concentration from unassembled whole-genome sequencing data for 13 anti-tuberculosis drugs. We trained, validated and tested the system on 10,859 isolates from the CRyPTIC dataset. Essential agreement rates (predicted MIC within one doubling dilution of observed MIC) were above 92{\%} for first-line drugs, 91{\%} for fluoroquinolones and aminoglycosides, and 90{\%} for new and repurposed drugs, albeit with a significant drop in performance for the very few phenotypically resistant isolates in the latter group. To further validate the model in the absence of external MIC datasets, we predicted MIC and converted values to binary for an external set of 15,239 isolates with binary phenotypes, and compare their performance against a previously validated mutation catalogue, the expected performance of existing molecular assays, and World Health Organization Target Product Profiles. The sensitivity of the model on the external dataset was greater than 90{\%} for all drugs except ethionamide, clofazimine and linezolid. Specificity was greater than 95{\%} for all drugs except ethambutol, ethionamide, bedaquiline, delamanid and clofazimine. The proposed system can provide quantitative susceptibility phenotyping to help guide antimicrobial therapy, although further data collection and validation are required before machine learning can be used clinically for all drugs.},
author = {Lachapelle, Alexander S and Barilar, Ivan and Battaglia, Simone and Borroni, Emanuele and Brandao, Angela P and Brankin, Alice and Cabibbe, Andrea Maurizio and Carter, Joshua and Cirillo, Daniela Maria and Claxton, Pauline and Clifton, David A and Cohen, Ted and Coronel, Jorge and Crook, Derrick W and Dreyer, Viola and Earle, Sarah G and Escuyer, Vincent and Ferrazoli, Lucilaine and Fowler, Philip W and Gao, George Fu and Gardy, Jennifer and Gharbia, Saheer and Ghisi, Kelen T. and Ghodousi, Arash and Cruz, Ana Lu{\'{i}}za Gibertoni and Grandjean, Louis and Grazian, Clara and Groenheit, Ramona and Guthrie, Jennifer L and He, Wencong and Hoffmann, Harald and Hoosdally, Sarah J and Hunt, Martin and Iqbal, Zamin and Ismail, Nazir Ahmed and Jarrett, Lisa and Joseph, Lavania and Jou, Ruwen and Kambli, Priti and Khot, Rukhsar and Knaggs, Jeff and Koch, Anastasia and Kohlerschmidt, Donna and Kouchaki, Samaneh and Lalvani, Ajit and Lapierre, Simon Grandjean and Laurenson, Ian F and Letcher, Brice and Lin, Wan Hsuan and Liu, Chunfa and Liu, Dongxin and Malone, Kerri M and Mandal, Ayan and Mansj{\"{o}}, Mikael and Matias, Daniela and Meintjes, Graeme and Mendes, Fl{\'{a}}via F and Merker, Matthias and Mihalic, Marina and Millard, James and Miotto, Paolo and Mistry, Nerges and Moore, David A J and Musser, Kimberlee A and Ngcamu, Dumisani and Hoang, Nhung N. and Niemann, Stefan and Nilgiriwala, Kayzad Soli and Nimmo, Camus and Okozi, Nana and Oliveira, Rosangela S and Omar, Shaheed Vally and Paton, Nicholas I and Peto, Timothy E A and Pinhata, Juliana M W and Plesnik, Sara and Puyen, Zully M and Rabodoarivelo, Marie Sylvianne and Rakotosamimanana, Niaina and Rancoita, Paola M V and Rathod, Priti and Robinson, Esther and Rodger, Gillian and Rodrigues, Camilla and Rodwell, Timothy C and Roohi, Aysha and Santos-Lazaro, David and Shah, Sanchi and Kohl, Thomas Andreas and Smith, E Grace and Solano, Walter and Spitaleri, Andrea and Supply, Philip and Surve, Utkarsha and Tahseen, Sabira and Thuong, Nguyen Thuy Thuong and Thwaites, Guy and Todt, Katharina and Trovato, Alberto and Utpatel, Christian and {Van Rie}, Annelies and Vijay, Srinivasan and Walker, Timothy M and Walker, A Sarah and Warren, Robin M and Werngren, Jim and Wijkander, Maria and Wilkinson, Robert J and Wilson, Daniel J and Wintringer, Penelope and Xiao, Yu Xin and Yang, Yang and Yanlin, Zhao and Yao, Shen Yuan and Zhu, Baoli and Arandjelovic, Irena and Barbova, Anna and Caws, Maxine and Comas, I{\~{n}}aki and Diel, Roland and Duncan, Carla and Dunstan, Sarah and Farhat, Maha and Fitzgibbon, Margaret M and Furi{\'{o}}, Victoria and Guthrie, Jennifer and Ha, Dang Thi Minh and Holt, Kathryn and Inouye, Michael and Jamieson, Frances B and Kamal, S M Mostofa and Kus, Julianne V and Mathys, Vanessa and Ong, Rick Twee Hee and Qin, Youwen and Rogers, Thomas R and Rossolini, Gian Maria and Roycroft, Emma and Sintchenko, Vitali and Skrahina, Alena and Teo, Yik Ying and Thai, Phan Vuong Khac and van Soolingen, Dick and Wilcox, Mark and Zignol, Matteo},
doi = {10.1371/JOURNAL.PCBI.1012260},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Lachapelle et al. - 2024 - Quantitative drug susceptibility testing for Mycobacterium tuberculosis using unassembled sequencing data and.pdf:pdf},
isbn = {1111111111},
issn = {1553-7358},
journal = {PLOS Computational Biology},
keywords = {Antibiotic resistance,Antibiotics,Catalogs,Consortia,Isoniazid,Machine learning,Mycobacterium tuberculosis,OA,Tuberculosis,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {aug},
number = {8},
pages = {e1012260},
pmid = {39102420},
publisher = {Public Library of Science},
title = {{Quantitative drug susceptibility testing for \textit{Mycobacterium tuberculosis} using unassembled sequencing data and machine learning}},
url = {https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1012260},
volume = {20},
year = {2024}
}

There remains a clinical need for better approaches to rapid drug susceptibility testing in view of the increasing burden of multidrug resistant tuberculosis. Binary susceptibility phenotypes only capture changes in minimum inhibitory concentration when these cross the critical concentration, even though other changes may be clinically relevant. We developed a machine learning system to predict minimum inhibitory concentration from unassembled whole-genome sequencing data for 13 anti-tuberculosis drugs. We trained, validated and tested the system on 10,859 isolates from the CRyPTIC dataset. Essential agreement rates (predicted MIC within one doubling dilution of observed MIC) were above 92% for first-line drugs, 91% for fluoroquinolones and aminoglycosides, and 90% for new and repurposed drugs, albeit with a significant drop in performance for the very few phenotypically resistant isolates in the latter group. To further validate the model in the absence of external MIC datasets, we predicted MIC and converted values to binary for an external set of 15,239 isolates with binary phenotypes, and compare their performance against a previously validated mutation catalogue, the expected performance of existing molecular assays, and World Health Organization Target Product Profiles. The sensitivity of the model on the external dataset was greater than 90% for all drugs except ethionamide, clofazimine and linezolid. Specificity was greater than 95% for all drugs except ethambutol, ethionamide, bedaquiline, delamanid and clofazimine. The proposed system can provide quantitative susceptibility phenotyping to help guide antimicrobial therapy, although further data collection and validation are required before machine learning can be used clinically for all drugs.

@article{Lambarey2024,
abstract = {Summary Background While acute SARS-CoV-2 infection and associated inflammation resulted in substantial morbidity and mortality during the COVID-19 pandemic, particularly in unvaccinated patients, long-term effects of SARS-CoV-2 exposure for reactivation of latent oncogenic herpesviruses, such as KSHV, is unknown. Methods We performed a longitudinal observational cross-sectional study on 407 non-hospitalised adult HIV-infected (CD4 count Findings KSHV seroprevalence was 53.5{\%}; the quarterly SARS-CoV-2 seroprevalence increased from 76.2{\%} (before roll-out of COVID-19 vaccinations) to 94.9{\%}, with 32.2{\%} being self-reportedly vaccinated against COVID-19. Over the course of recruitment, the quarterly percentage of patients with detectable KSHV viral load (VL) in the peripheral blood increased from 3.3{\%} to 69.2{\%}. The presence of KSHV VL was significantly associated with SARS-CoV-2 RBD antibody titers in unvaccinated (median RBD IgG OD 1.24 [IQR 0.82–2.42] in non-reactivated versus 2.83 [IQR 1.08–4.72] in reactivated patients, p = 0.0030) but not in vaccinated patients (median RBD IgG OD 5.13 [IQR 4.11–6.36] in non-reactivated versus 4.53 [IQR 2.90–5.92] in reactivated patients, p = 0.086). Further logistic regression revealed significantly higher odds of KSHV reactivation in unvaccinated, previously SARS-CoV-2 exposed patients (p = 0.015, adjusted OR 1.28 [95{\%} CI: 1.05–1.55]), but not vaccinated patients (p = 0.080, adjusted OR 0.83 [95{\%} CI: 0.67–1.02]). Interestingly, detectable KSHV VL was not associated with increased inflammatory markers such as C-reactive protein and interleukin-6. Interpretation High, and most likely repeated, exposure to SARS-CoV-2 in unvaccinated individuals may have long-term consequences for reactivation of KSHV infection as shown here in the context of HIV-infected patients with impaired immune functions. Post-pandemic prevention and/or monitoring strategies of potential KSHV-associated pathologies in high-risk patients with immunodeficiencies are therefore highly recommended. Funding This research was funded by the EDCTP2 programme (Training and Mobility Action TMA2018SF-2446).},
author = {Lambarey, Humaira and Blumenthal, Melissa J and Chetram, Abeen and Joyimbana, Wendy and Jennings, Lauren and Orrell, Catherine and Sch{\"{a}}fer, Georgia},
doi = {10.1016/J.EBIOM.2024.104986},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Lambarey et al. - 2024 - Reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV) by SARS-CoV-2 in non-hospitalised HIV-infected p.pdf:pdf},
issn = {2352-3964},
journal = {eBioMedicine},
keywords = {ART,Covid-19 vaccination,HIV,KSHV,LMIC,OA,OA{\_}PMC,SARS-CoV-2,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {feb},
pages = {104986},
pmid = {38306893},
publisher = {Elsevier},
title = {{Reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV) by SARS-CoV-2 in non-hospitalised HIV-infected patients}},
url = {http://www.thelancet.com/article/S2352396424000215/fulltext http://www.thelancet.com/article/S2352396424000215/abstract https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(24)00021-5/abstract},
volume = {100},
year = {2024}
}

Summary Background While acute SARS-CoV-2 infection and associated inflammation resulted in substantial morbidity and mortality during the COVID-19 pandemic, particularly in unvaccinated patients, long-term effects of SARS-CoV-2 exposure for reactivation of latent oncogenic herpesviruses, such as KSHV, is unknown. Methods We performed a longitudinal observational cross-sectional study on 407 non-hospitalised adult HIV-infected (CD4 count Findings KSHV seroprevalence was 53.5%; the quarterly SARS-CoV-2 seroprevalence increased from 76.2% (before roll-out of COVID-19 vaccinations) to 94.9%, with 32.2% being self-reportedly vaccinated against COVID-19. Over the course of recruitment, the quarterly percentage of patients with detectable KSHV viral load (VL) in the peripheral blood increased from 3.3% to 69.2%. The presence of KSHV VL was significantly associated with SARS-CoV-2 RBD antibody titers in unvaccinated (median RBD IgG OD 1.24 [IQR 0.82–2.42] in non-reactivated versus 2.83 [IQR 1.08–4.72] in reactivated patients, p = 0.0030) but not in vaccinated patients (median RBD IgG OD 5.13 [IQR 4.11–6.36] in non-reactivated versus 4.53 [IQR 2.90–5.92] in reactivated patients, p = 0.086). Further logistic regression revealed significantly higher odds of KSHV reactivation in unvaccinated, previously SARS-CoV-2 exposed patients (p = 0.015, adjusted OR 1.28 [95% CI: 1.05–1.55]), but not vaccinated patients (p = 0.080, adjusted OR 0.83 [95% CI: 0.67–1.02]). Interestingly, detectable KSHV VL was not associated with increased inflammatory markers such as C-reactive protein and interleukin-6. Interpretation High, and most likely repeated, exposure to SARS-CoV-2 in unvaccinated individuals may have long-term consequences for reactivation of KSHV infection as shown here in the context of HIV-infected patients with impaired immune functions. Post-pandemic prevention and/or monitoring strategies of potential KSHV-associated pathologies in high-risk patients with immunodeficiencies are therefore highly recommended. Funding This research was funded by the EDCTP2 programme (Training and Mobility Action TMA2018SF-2446).

@article{Stewart2024,
abstract = {Background: Tuberculosis (TB) control requires the understanding and disruption of TB transmission. We describe prevalence, incidence and risk factors associated with childhood TB infection in Cape Town. Methods: We report cross-sectional baseline and prospective incidence data from a large trial among primary school children living in high TB-burden communities. Prevalent infection was defined as QuantiFERON-TB Gold Plus (QFT-Plus) positivity as assessed at baseline. Subsequent conversion to QFT-Plus positivity was measured 3 years later among those QFT-Plus-negative at baseline. Multivariable logistic regression models examined factors associated with TB infection. Results: QuantiFERON-positivity at baseline (prevalence: 22.6{\%}, 95{\%} Confidence Interval [CI]: 20.9 - 24.4), was independently associated with increasing age (adjusted odds ratio [aOR] 1.24 per additional year, 95{\%} CI: 1.15 - 1.34) and household exposure to TB during the participant's lifetime (aOR 1.87, 95{\%} CI: 1.46 - 2.40). QFT-Plus conversion at year 3 (12.2{\%}, 95{\%} CI: 10.5-14.0; annual infection rate: 3.95{\%}) was associated with household exposure to an index TB case (aOR 2.74, 95{\%} CI: 1.05 to 7.18). Conclusion: Rates of QFT-diagnosed TB infection remain high in this population. The strong association with household TB exposure reinforces the importance of contact tracing, preventative treatment and early treatment of infectious disease to reduce community transmission. {\#}{\#}{\#} Competing Interest Statement ARM declares receipt of funding in the last 36 months to support vitamin D research from the following companies who manufacture or sell vitamin D supplements: Pharma Nord Ltd, DSM Nutritional Products Ltd, Thornton {\&} Ross Ltd and Hyphens Pharma Ltd. ARM also declares receipt of vitamin D capsules for clinical trial use from Pharma Nord Ltd, Synergy Biologics Ltd and Cytoplan Ltd; support for attending meetings from Pharma Nord Ltd and Abiogen Pharma Ltd; receipt of consultancy fees from DSM Nutritional Products Ltd and Qiagen Ltd; receipt of a speaker fee from the Linus Pauling Institute; participation on Data and Safety Monitoring Boards for the VITALITY trial (Vitamin D for Adolescents with HIV to reduce musculoskeletal morbidity and immunopathology, Pan African Clinical Trials Registry ref PACTR20200989766029) and the Trial of Vitamin D and Zinc Supplementation for Improving Treatment Outcomes Among COVID-19 Patients in India (ClinicalTrials.gov ref [NCT04641195][1]); and unpaid work as a Programme Committee member for the Vitamin D Workshop. All other authors declare that they have no competing interests. {\#}{\#}{\#} Clinical Trial NCT02880982 {\#}{\#}{\#} Funding Statement This research was funded by the UK Medical Research Council (refs MR/R023050/1 and MR/M026639/1, both awarded to ARM). RJW was supported by Wellcome (104803, 203135). He also receives support from the Francis Crick Institute which is funded by Cancer Research UK (FC2112), the UK Medical Research Council (FC2112) and Wellcome (FC2112). {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of University of Cape Town Faculty of Health Sciences gave ethical approval for this work Observational/Interventions Research Ethics committee/IRB of London School of Hygiene and Tropical Medicine gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Anonymised data may be requested from the corresponding author to be shared subject to terms of research ethics committee approval. [1]: /lookup/external-ref?link{\_}type=CLINTRIALGOV{\&}access{\_}num=NCT04641195{\&}atom={\%}2Fmedrxiv{\%}2Fearly{\%}2F2024{\%}2F03{\%}2F13{\%}2F2024.03.11.24304073.atom},
author = {Stewart, Justine and Walker, Neil and Jennings, Karen and Delport, Carmen and Nuttall, James and Coussens, Anna K and Dyers, Robin and Jolliffe, David A and Tang, Jonathan C Y and Fraser, William D and Wilkinson, Robert J and Bekker, Linda-Gail and Martineau, Adrian R and Middelkoop, Keren},
doi = {10.1101/2024.03.11.24304073},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Stewart et al. - 2024 - PREVALENCE, INCIDENCE AND DETERMINANTS OF QUANTIFERON-POSITIVITY IN SOUTH AFRICAN SCHOOLCHILDREN.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {mar},
pages = {2024.03.11.24304073},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Prevalence, incidence and determinants of Quantiferon-positivity in South African schoolchildren}},
url = {https://www.medrxiv.org/content/10.1101/2024.03.11.24304073v1 https://www.medrxiv.org/content/10.1101/2024.03.11.24304073v1.abstract},
year = {2024}
}

Background: Tuberculosis (TB) control requires the understanding and disruption of TB transmission. We describe prevalence, incidence and risk factors associated with childhood TB infection in Cape Town. Methods: We report cross-sectional baseline and prospective incidence data from a large trial among primary school children living in high TB-burden communities. Prevalent infection was defined as QuantiFERON-TB Gold Plus (QFT-Plus) positivity as assessed at baseline. Subsequent conversion to QFT-Plus positivity was measured 3 years later among those QFT-Plus-negative at baseline. Multivariable logistic regression models examined factors associated with TB infection. Results: QuantiFERON-positivity at baseline (prevalence: 22.6%, 95% Confidence Interval [CI]: 20.9 - 24.4), was independently associated with increasing age (adjusted odds ratio [aOR] 1.24 per additional year, 95% CI: 1.15 - 1.34) and household exposure to TB during the participant's lifetime (aOR 1.87, 95% CI: 1.46 - 2.40). QFT-Plus conversion at year 3 (12.2%, 95% CI: 10.5-14.0; annual infection rate: 3.95%) was associated with household exposure to an index TB case (aOR 2.74, 95% CI: 1.05 to 7.18). Conclusion: Rates of QFT-diagnosed TB infection remain high in this population. The strong association with household TB exposure reinforces the importance of contact tracing, preventative treatment and early treatment of infectious disease to reduce community transmission. ### Competing Interest Statement ARM declares receipt of funding in the last 36 months to support vitamin D research from the following companies who manufacture or sell vitamin D supplements: Pharma Nord Ltd, DSM Nutritional Products Ltd, Thornton & Ross Ltd and Hyphens Pharma Ltd. ARM also declares receipt of vitamin D capsules for clinical trial use from Pharma Nord Ltd, Synergy Biologics Ltd and Cytoplan Ltd; support for attending meetings from Pharma Nord Ltd and Abiogen Pharma Ltd; receipt of consultancy fees from DSM Nutritional Products Ltd and Qiagen Ltd; receipt of a speaker fee from the Linus Pauling Institute; participation on Data and Safety Monitoring Boards for the VITALITY trial (Vitamin D for Adolescents with HIV to reduce musculoskeletal morbidity and immunopathology, Pan African Clinical Trials Registry ref PACTR20200989766029) and the Trial of Vitamin D and Zinc Supplementation for Improving Treatment Outcomes Among COVID-19 Patients in India (ClinicalTrials.gov ref [NCT04641195][1]); and unpaid work as a Programme Committee member for the Vitamin D Workshop. All other authors declare that they have no competing interests. ### Clinical Trial NCT02880982 ### Funding Statement This research was funded by the UK Medical Research Council (refs MR/R023050/1 and MR/M026639/1, both awarded to ARM). RJW was supported by Wellcome (104803, 203135). He also receives support from the Francis Crick Institute which is funded by Cancer Research UK (FC2112), the UK Medical Research Council (FC2112) and Wellcome (FC2112). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of University of Cape Town Faculty of Health Sciences gave ethical approval for this work Observational/Interventions Research Ethics committee/IRB of London School of Hygiene and Tropical Medicine gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Anonymised data may be requested from the corresponding author to be shared subject to terms of research ethics committee approval. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04641195&atom=%2Fmedrxiv%2Fearly%2F2024%2F03%2F13%2F2024.03.11.24304073.atom

@article{Hussey2024,
abstract = {In low- and middle-income countries where SARS-CoV-2 testing is limited, seroprevalence studies can help describe and characterise the extent of the pandemic, as well as elucidate protection conferred by prior exposure. We conducted repeated cross-sectional serosurveys (July 2020 –November 2021) using residual samples from patients from Cape Town, South Africa, sent for routine laboratory studies for non-COVID-19 conditions. SARS-CoV-2 anti-nucleocapsid antibodies and linked clinical information were used to investigate: (1) seroprevalence over time and risk factors associated with seropositivity, (2) ecological comparison of seroprevalence between subdistricts, (3) case ascertainment rates, and (4) the relative protection against COVID-19 associated with seropositivity and vaccination statuses. Among the subset sampled, seroprevalence of SARS-CoV-2 in Cape Town increased from 39.19{\%} (95{\%} confidence interval [CI] 37.23–41.19) in July 2020 to 67.8{\%} (95{\%}CI 66.31–69.25) in November 2021. Poorer communities had both higher seroprevalence and COVID-19 mortality. Only 10{\%} of seropositive individuals had a recorded positive SARS-CoV-2 test. Using COVID-19 hospital admission and death data at the Provincial Health Data Centre, antibody positivity before the start of the Omicron BA.1 wave (28 November 2021) was strongly protective for severe disease (adjusted odds ratio [aOR] 0.15; 95{\%}CI 0.05–0.46), with additional benefit in those who were also vaccinated (aOR 0.07, 95{\%}CI 0.01–0.35). The high population seroprevalence in Cape Town was attained at the cost of substantial COVID-19 mortality. At the individual level, seropositivity was highly protective against subsequent infections and severe COVID-19 disease. In low-income communities, where diagnostic testing capacity is often limited, surveillance systems dependent on them will underestimate the true extent of an outbreak. Rapidly conducted seroprevalence studies can play an important role in addressing this.},
author = {Hussey, Hannah and Vreede, Helena and Davies, Mary Ann and Heekes, Alexa and Kalk, Emma and Hardie, Diana and van Zyl, Gert and Naidoo, Michelle and Morden, Erna and Bam, Jamy Lee and Zinyakatira, Nesbert and Centner, Chad M and Maritz, Jean and Opie, Jessica and Chapanduka, Zivanai and Mahomed, Hassan and Smith, Mariette and Cois, Annibale and Pienaar, David and Redd, Andrew D and Preiser, Wolfgang and Wilkinson, Robert J and Boulle, Andrew and Hsiao, Nei Yuan},
doi = {10.1371/JOURNAL.PGPH.0003554},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Hussey et al. - 2024 - SARS-CoV-2 seroepidemiology in Cape Town, South Africa, and implications for future outbreaks in low-income commu.pdf:pdf},
isbn = {1111111111},
issn = {2767-3375},
journal = {PLOS Global Public Health},
keywords = {Antibodies,COVID 19,HIV vaccines,OA,SARS CoV 2,Serodiagnosis,Serology,Vaccination and immunization,Virus testing,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {aug},
number = {8},
pages = {e0003554},
publisher = {Public Library of Science},
title = {{SARS-CoV-2 seroepidemiology in Cape Town, South Africa, and implications for future outbreaks in low-income communities}},
url = {https://journals.plos.org/globalpublichealth/article?id=10.1371/journal.pgph.0003554},
volume = {4},
year = {2024}
}

In low- and middle-income countries where SARS-CoV-2 testing is limited, seroprevalence studies can help describe and characterise the extent of the pandemic, as well as elucidate protection conferred by prior exposure. We conducted repeated cross-sectional serosurveys (July 2020 –November 2021) using residual samples from patients from Cape Town, South Africa, sent for routine laboratory studies for non-COVID-19 conditions. SARS-CoV-2 anti-nucleocapsid antibodies and linked clinical information were used to investigate: (1) seroprevalence over time and risk factors associated with seropositivity, (2) ecological comparison of seroprevalence between subdistricts, (3) case ascertainment rates, and (4) the relative protection against COVID-19 associated with seropositivity and vaccination statuses. Among the subset sampled, seroprevalence of SARS-CoV-2 in Cape Town increased from 39.19% (95% confidence interval [CI] 37.23–41.19) in July 2020 to 67.8% (95%CI 66.31–69.25) in November 2021. Poorer communities had both higher seroprevalence and COVID-19 mortality. Only 10% of seropositive individuals had a recorded positive SARS-CoV-2 test. Using COVID-19 hospital admission and death data at the Provincial Health Data Centre, antibody positivity before the start of the Omicron BA.1 wave (28 November 2021) was strongly protective for severe disease (adjusted odds ratio [aOR] 0.15; 95%CI 0.05–0.46), with additional benefit in those who were also vaccinated (aOR 0.07, 95%CI 0.01–0.35). The high population seroprevalence in Cape Town was attained at the cost of substantial COVID-19 mortality. At the individual level, seropositivity was highly protective against subsequent infections and severe COVID-19 disease. In low-income communities, where diagnostic testing capacity is often limited, surveillance systems dependent on them will underestimate the true extent of an outbreak. Rapidly conducted seroprevalence studies can play an important role in addressing this.

@article{Joseph2024,
abstract = {People with HIV-1 (PWH) on antiretroviral therapy (ART) can maintain undetectable virus levels, but a small pool of infected cells persists. This pool is largely comprised of defective proviruses that may produce HIV-1 proteins but are incapable of making infectious virus, with only a fraction ({\~{}}10{\%}) of these cells harboring intact viral genomes, some of which produce infectious virus following ex vivo stimulation (i.e. inducible intact proviruses). A majority of the inducible proviruses that persist on ART are formed near the time of therapy initiation. Here we compared proviral DNA (assessed here as 3' half genomes amplified from total cellular DNA) and inducible replication competent viruses in the pool of infected cells that persists during ART to determine if the original infection of these cells occurred at comparable times prior to therapy initiation. Overall, the average percent of proviruses that formed late (i.e. around the time of ART initiation, 60{\%}) did not differ from the average percent of replication competent inducible viruses that formed late (69{\%}), and this was also true for proviral DNA that was hypermutated (57{\%}). Further, there was no evidence that entry into the long-lived infected cell pool was impeded by the ability to use the CXCR4 coreceptor, nor was the formation of long-lived infected cells enhanced during primary infection, when viral loads are exceptionally high. We observed that infection of cells that transitioned to be long-lived was enhanced among people with a lower nadir CD4+ T cell count. Together these data suggest that the timing of infection of cells that become long-lived is impacted more by biological processes associated with immunodeficiency before ART than the replication competency and/or cellular tropism of the infecting virus or the intactness of the provirus. Further research is needed to determine the mechanistic link between immunodeficiency and the timing of infected cells transitioning to the long-lived pool, particularly whether this is due to differences in infected cell clearance, turnover rates and/or homeostatic proliferation before and after ART.},
author = {Joseph, Sarah B and Abrahams, Melissa-Rose and Moeser, Matthew and Tyers, Lynn and Archin, Nancie M and Council, Olivia D and Sondgeroth, Amy and Spielvogel, Ean and Emery, Ann and Zhou, Shuntai and Doolabh, Deelan and Ismail, Sherazaan D and Karim, Salim Abdool and Margolis, David M and Pond, Sergei Kosakovsky and Garrett, Nigel and Swanstrom, Ronald and Williamson, Carolyn},
doi = {10.1371/JOURNAL.PPAT.1011974},
editor = {Moore, Penny L.},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Id et al. - 2024 - The timing of HIV-1 infection of cells that persist on therapy is not strongly influenced by replication competency o.pdf:pdf},
isbn = {1111111111},
issn = {1553-7374},
journal = {PLOS Pathogens},
keywords = {Antiretroviral therapy,CCR5 coreceptor,DNA replication,Genomics,HIV-1,OA,Phylogenetic analysis,T helper cells,Viral replication,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {feb},
number = {2},
pages = {e1011974},
publisher = {Public Library of Science},
title = {{The timing of HIV-1 infection of cells that persist on therapy is not strongly influenced by replication competency or cellular tropism of the provirus}},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1011974},
volume = {20},
year = {2024}
}

People with HIV-1 (PWH) on antiretroviral therapy (ART) can maintain undetectable virus levels, but a small pool of infected cells persists. This pool is largely comprised of defective proviruses that may produce HIV-1 proteins but are incapable of making infectious virus, with only a fraction (\ 10%) of these cells harboring intact viral genomes, some of which produce infectious virus following ex vivo stimulation (i.e. inducible intact proviruses). A majority of the inducible proviruses that persist on ART are formed near the time of therapy initiation. Here we compared proviral DNA (assessed here as 3' half genomes amplified from total cellular DNA) and inducible replication competent viruses in the pool of infected cells that persists during ART to determine if the original infection of these cells occurred at comparable times prior to therapy initiation. Overall, the average percent of proviruses that formed late (i.e. around the time of ART initiation, 60%) did not differ from the average percent of replication competent inducible viruses that formed late (69%), and this was also true for proviral DNA that was hypermutated (57%). Further, there was no evidence that entry into the long-lived infected cell pool was impeded by the ability to use the CXCR4 coreceptor, nor was the formation of long-lived infected cells enhanced during primary infection, when viral loads are exceptionally high. We observed that infection of cells that transitioned to be long-lived was enhanced among people with a lower nadir CD4+ T cell count. Together these data suggest that the timing of infection of cells that become long-lived is impacted more by biological processes associated with immunodeficiency before ART than the replication competency and/or cellular tropism of the infecting virus or the intactness of the provirus. Further research is needed to determine the mechanistic link between immunodeficiency and the timing of infected cells transitioning to the long-lived pool, particularly whether this is due to differences in infected cell clearance, turnover rates and/or homeostatic proliferation before and after ART.

@article{Karim2024,
abstract = {SARS-CoV-2 clearance requires adaptive immunity but the contribution of neutralizing antibodies and T cells in different immune states is unclear. Here we ask which adaptive immune responses associate with clearance of long-term SARS-CoV-2 infection in HIV-mediated immunosuppression after suppressive antiretroviral therapy (ART) initiation. We assembled a cohort of SARS-CoV-2 infected people in South Africa (n = 994) including participants with advanced HIV disease characterized by immunosuppression due to T cell depletion. Fifty-four percent of participants with advanced HIV disease had prolonged SARS-CoV-2 infection ({\textgreater}1 month). In the five vaccinated participants with advanced HIV disease tested, SARS-CoV-2 clearance associates with emergence of neutralizing antibodies but not SARS-CoV-2 specific CD8 T cells, while CD4 T cell responses were not determined due to low cell numbers. Further, complete HIV suppression is not required for clearance, although it is necessary for an effective vaccine response. Persistent SARS-CoV-2 infection led to SARS-CoV-2 evolution, including virus with extensive neutralization escape in a Delta variant infected participant. The results provide evidence that neutralizing antibodies are required for SARS-CoV-2 clearance in HIV-mediated immunosuppression recovery, and that suppressive ART is necessary to curtail evolution of co-infecting pathogens to reduce individual health consequences as well as public health risk linked with generation of escape mutants. There is limited data on immune factors contributing to SARS-CoV-2 viral clearance in people living with HIV. Here, the authors show that re-emergence of the neutralizing antibody response may be key to clearing persistent SARS-CoV-2 infection in ART-mediated recovery from immunosuppression in advanced HIV disease.},
author = {Karim, Farina and Riou, Catherine and Bernstein, Mallory and Jule, Zesuliwe and Lustig, Gila and van Graan, Strauss and Keeton, Roanne S. and Upton, Janine Lee and Ganga, Yashica and Khan, Khadija and Reedoy, Kajal and Mazibuko, Matilda and Govender, Katya and Thambu, Kershnee and Ngcobo, Nokuthula and Venter, Elizabeth and Makhado, Zanele and Hanekom, Willem and von Gottberg, Anne and Hoque, Monjurul and Karim, Quarraisha Abdool and {Abdool Karim}, Salim S. and Manickchund, Nithendra and Magula, Nombulelo and Gosnell, Bernadett I. and Lessells, Richard J. and Moore, Penny L. and Burgers, Wendy A. and de Oliveira, Tulio and Moosa, Mahomed Yunus S. and Sigal, Alex},
doi = {10.1038/s41467-024-46673-2},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Karim et al. - 2024 - Clearance of persistent SARS-CoV-2 associates with increased neutralizing antibodies in advanced HIV disease post-.pdf:pdf},
issn = {2041-1723},
journal = {Nature Communications},
keywords = {2,Antibodies,CoV,Evolutionary genetics,HIV infections,Infection,OA,OA{\_}PMC,SARS,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {mar},
number = {1},
pages = {2360},
pmid = {38491050},
publisher = {Nature Publishing Group},
title = {{Clearance of persistent SARS-CoV-2 associates with increased neutralizing antibodies in advanced HIV disease post-ART initiation}},
url = {https://www.nature.com/articles/s41467-024-46673-2},
volume = {15},
year = {2024}
}

SARS-CoV-2 clearance requires adaptive immunity but the contribution of neutralizing antibodies and T cells in different immune states is unclear. Here we ask which adaptive immune responses associate with clearance of long-term SARS-CoV-2 infection in HIV-mediated immunosuppression after suppressive antiretroviral therapy (ART) initiation. We assembled a cohort of SARS-CoV-2 infected people in South Africa (n = 994) including participants with advanced HIV disease characterized by immunosuppression due to T cell depletion. Fifty-four percent of participants with advanced HIV disease had prolonged SARS-CoV-2 infection (\textgreater1 month). In the five vaccinated participants with advanced HIV disease tested, SARS-CoV-2 clearance associates with emergence of neutralizing antibodies but not SARS-CoV-2 specific CD8 T cells, while CD4 T cell responses were not determined due to low cell numbers. Further, complete HIV suppression is not required for clearance, although it is necessary for an effective vaccine response. Persistent SARS-CoV-2 infection led to SARS-CoV-2 evolution, including virus with extensive neutralization escape in a Delta variant infected participant. The results provide evidence that neutralizing antibodies are required for SARS-CoV-2 clearance in HIV-mediated immunosuppression recovery, and that suppressive ART is necessary to curtail evolution of co-infecting pathogens to reduce individual health consequences as well as public health risk linked with generation of escape mutants. There is limited data on immune factors contributing to SARS-CoV-2 viral clearance in people living with HIV. Here, the authors show that re-emergence of the neutralizing antibody response may be key to clearing persistent SARS-CoV-2 infection in ART-mediated recovery from immunosuppression in advanced HIV disease.

@article{Butters2024,
abstract = {Multisystem inflammatory syndrome in children (MIS-C) is a severe, hyperinflammatory disease that occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The underlying immune pathology of MIS-C is incompletely understood, with limited data comparing MIS-C to clinically similar paediatric febrile diseases at presentation. SARS-CoV-2-specific T cell responses have not been compared in these groups to assess whether there is a T cell profile unique to MIS-C. In this study, we measured inflammatory cytokine concentration and SARS-CoV-2-specific humoral immunity and T cell responses in children with fever and suspected MIS-C at presentation (n = 83) where MIS-C was ultimately confirmed (n = 58) or another diagnosis was made (n = 25) and healthy children (n = 91). Children with confirmed MIS-C exhibited distinctly elevated serum IL-10, IL-6, and CRP at presentation. No differences were detected in SARS-CoV-2 spike IgG serum concentration, neutralisation capacity, antibody dependant cellular phagocytosis, antibody dependant cellular cytotoxicity or SARS-CoV-2-specific T cell frequency between the groups. Healthy SARS-CoV-2 seropositive children had a higher proportion of polyfunctional SARS-CoV-2-specific CD4+ T cells compared to children with MIS-C and those with other inflammatory or infectious diagnoses, who both presented a largely monofunctional SARS-CoV-2-specific CD4+ T cell profile. Treatment with steroids and/or intravenous immunoglobulins resulted in rapid reduction of inflammatory cytokines but did not affect the SARS-CoV-2-specific IgG or CD4+ T cell responses in MIS-C. In these data, MIS-C had a unique cytokine profile but not a unique SARS-CoV-2 specific humoral or T cell cytokine response.},
author = {Butters, Claire and Benede, Ntombi and Moyo-Gwete, Thandeka and Richardson, Simone I and Rohlwink, Ursula and Shey, Muki and Ayres, Frances and Manamela, Nelia P and Makhado, Zanele and Balla, Sashkia R and Madzivhandila, Mashudu and Ngomti, Amkele and Baguma, Richard and Facey-Thomas, Heidi and Spracklen, Timothy F and Day, Jonathan and {van der Ross Debbie}, Hamza and Riou, Catherine and Burgers, Wendy A and Scott, Christiaan and Zuhlke, Liesl and Moore, Penny L and Keeton, Roanne S and Webb, Kate},
doi = {10.1016/J.CLIM.2023.109877},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Butters et al. - 2024 - Comparing the immune abnormalities in MIS-C to healthy children and those with inflammatory disease reveals dist.pdf:pdf},
issn = {1521-6616},
journal = {Clinical Immunology},
keywords = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {feb},
pages = {109877},
pmid = {38141746},
publisher = {Academic Press},
title = {{Comparing the immune abnormalities in MIS-C to healthy children and those with inflammatory disease reveals distinct inflammatory cytokine production and a monofunctional T cell response}},
volume = {259},
year = {2024}
}

Multisystem inflammatory syndrome in children (MIS-C) is a severe, hyperinflammatory disease that occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The underlying immune pathology of MIS-C is incompletely understood, with limited data comparing MIS-C to clinically similar paediatric febrile diseases at presentation. SARS-CoV-2-specific T cell responses have not been compared in these groups to assess whether there is a T cell profile unique to MIS-C. In this study, we measured inflammatory cytokine concentration and SARS-CoV-2-specific humoral immunity and T cell responses in children with fever and suspected MIS-C at presentation (n = 83) where MIS-C was ultimately confirmed (n = 58) or another diagnosis was made (n = 25) and healthy children (n = 91). Children with confirmed MIS-C exhibited distinctly elevated serum IL-10, IL-6, and CRP at presentation. No differences were detected in SARS-CoV-2 spike IgG serum concentration, neutralisation capacity, antibody dependant cellular phagocytosis, antibody dependant cellular cytotoxicity or SARS-CoV-2-specific T cell frequency between the groups. Healthy SARS-CoV-2 seropositive children had a higher proportion of polyfunctional SARS-CoV-2-specific CD4+ T cells compared to children with MIS-C and those with other inflammatory or infectious diagnoses, who both presented a largely monofunctional SARS-CoV-2-specific CD4+ T cell profile. Treatment with steroids and/or intravenous immunoglobulins resulted in rapid reduction of inflammatory cytokines but did not affect the SARS-CoV-2-specific IgG or CD4+ T cell responses in MIS-C. In these data, MIS-C had a unique cytokine profile but not a unique SARS-CoV-2 specific humoral or T cell cytokine response.

@article{Gils2024,
abstract = {Background CD4 measurement is pivotal in the management of advanced HIV disease. VISITECT{\textregistered} CD4 Advanced Disease (AccuBio Limited, Alva, UK; VISITECT) is an instrument-free, point-of-care, semi-quantitative test allowing visual identification of a CD4 ≤200 cells/µl, or {\textgreater}200 cells/µl from finger-prick or venous blood. Methods As part of a diagnostic accuracy study of FUJIFILM SILVAMP TB LAM (clinicaltrials.gov: NCT04089423), people living with HIV of ≥18 years old were prospectively recruited in seven countries from outpatient departments if a tuberculosis symptom was present, and from inpatient departments. Participants provided venous blood for CD4 measurement using flow cytometry (reference standard) and finger-prick blood for VISITECT (index text), performed at point-of-care. Sensitivity, specificity, and positive and negative predictive values of VISITECT to determine a CD4 ≤200 cells/µl were evaluated. Results Among 1604 participants, the median flow cytometry CD4 was 367 (IQR 128−626) cells/µl and 521 (32.5{\%}) had a CD4 ≤200 cells/µl. VISITECT sensitivity was 92.7{\%} (483/521, 95{\%} CI 90.1−94.7{\%}) and specificity was 61.4{\%} (665/1083, 95{\%} CI 58.4−64.3{\%}). For participants with a CD4 between 0−100, 101−200, 201−300, 301−500, and {\textgreater}500 cells/µl, VISITECT misclassified 4.5{\%} (95{\%} CI 2.5-7.2{\%}), 12.5 (95{\%} CI 8.0-18.2{\%}), 74.1{\%} (95{\%} CI 67.0-80.5{\%}), 48.0{\%} (95{\%} CI 42.5-53.6{\%}), and 22.6{\%} (95{\%} CI 19.3-26.3{\%}), respectively. Conclusions VISITECT's sensitivity, but not specificity, met the World Health Organization's minimal sensitivity and specificity threshold of 80{\%} for point-of-care CD4 tests. VISITECT's quality needs to be assessed and its accuracy optimized. VISITECT´s utility as CD4 triage test should be investigated.},
author = {Gils, Tinne and Hella, Jerry and Jacobs, Bart K M and Sossen, Bianca and Mukoka, Madalo and Muyoyeta, Monde and Nakabugo, Elizabeth and {Van Nguyen}, Hung and Ubolyam, Sasiwimol and Mac{\'{e}}, Aur{\'{e}}lien and Vermeulen, Marcia and Nyangu, Sarah and Sanjase, Nsala and Sasamalo, Mohamed and Dinh, Huong Thi and Ngo, The Anh and Manosuthi, Weerawat and Jirajariyavej, Supunnee and Denkinger, Claudia M and Nguyen, Nhung Viet and Avihingsanon, Anchalee and Nakiyingi, Lydia and Sz{\'{e}}kely, Rita and Kerkhoff, Andrew D and MacPherson, Peter and Meintjes, Graeme and Reither, Klaus and Ruhwald, Morten},
doi = {10.1093/INFDIS/JIAE374},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Gils et al. - 2024 - A prospective evaluation of the diagnostic accuracy of the point-of-care VISITECT CD4 Advanced Disease test in seve.pdf:pdf},
issn = {0022-1899},
journal = {The Journal of Infectious Diseases},
keywords = {12 FIND,13 Viet Tiep ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯,2000 Antwerpen,Belgium,Geneva,Nationalestraat 155,OA,Switzerland,cell: 0032/49033378,email: tgils@itgbe,fund{\_}ack,original,the global alliance for diagnostics},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jul},
title = {{A prospective evaluation of the diagnostic accuracy of the point-of-care VISITECT CD4 Advanced Disease test in seven countries}},
url = {https://dx.doi.org/10.1093/infdis/jiae374},
year = {2024}
}

Background CD4 measurement is pivotal in the management of advanced HIV disease. VISITECT® CD4 Advanced Disease (AccuBio Limited, Alva, UK; VISITECT) is an instrument-free, point-of-care, semi-quantitative test allowing visual identification of a CD4 ≤200 cells/µl, or \textgreater200 cells/µl from finger-prick or venous blood. Methods As part of a diagnostic accuracy study of FUJIFILM SILVAMP TB LAM (clinicaltrials.gov: NCT04089423), people living with HIV of ≥18 years old were prospectively recruited in seven countries from outpatient departments if a tuberculosis symptom was present, and from inpatient departments. Participants provided venous blood for CD4 measurement using flow cytometry (reference standard) and finger-prick blood for VISITECT (index text), performed at point-of-care. Sensitivity, specificity, and positive and negative predictive values of VISITECT to determine a CD4 ≤200 cells/µl were evaluated. Results Among 1604 participants, the median flow cytometry CD4 was 367 (IQR 128−626) cells/µl and 521 (32.5%) had a CD4 ≤200 cells/µl. VISITECT sensitivity was 92.7% (483/521, 95% CI 90.1−94.7%) and specificity was 61.4% (665/1083, 95% CI 58.4−64.3%). For participants with a CD4 between 0−100, 101−200, 201−300, 301−500, and \textgreater500 cells/µl, VISITECT misclassified 4.5% (95% CI 2.5-7.2%), 12.5 (95% CI 8.0-18.2%), 74.1% (95% CI 67.0-80.5%), 48.0% (95% CI 42.5-53.6%), and 22.6% (95% CI 19.3-26.3%), respectively. Conclusions VISITECT's sensitivity, but not specificity, met the World Health Organization's minimal sensitivity and specificity threshold of 80% for point-of-care CD4 tests. VISITECT's quality needs to be assessed and its accuracy optimized. VISITECT´s utility as CD4 triage test should be investigated.

@article{Dinkele2024,
author = {Dinkele, Ryan and Khan, Palwasha Y and Warner, Digby F},
doi = {10.1016/S1473-3099(24)00154-3},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Dinkele, Khan, Warner - 2024 - Mycobacterium tuberculosis transmission the importance of precision.pdf:pdf},
issn = {1473-3099},
journal = {The Lancet Infectious Diseases},
keywords = {commentary,fund{\_}not{\_}ack},
mendeley-tags = {commentary,fund{\_}not{\_}ack},
month = {mar},
pages = {10.1016/ S1473--3099(24)00154--3},
pmid = {38527472},
publisher = {Elsevier},
title = {{\textit{Mycobacterium tuberculosis} transmission: the importance of precision}},
url = {http://www.thelancet.com/article/S1473309924001543/fulltext http://www.thelancet.com/article/S1473309924001543/abstract https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(24)00154-3/abstract},
year = {2024}
}

@article{Barnacle2024,
abstract = {Tuberculous meningitis (TBM), the most severe form of tuberculosis, causes death in approximately 25{\%} cases despite antibiotic therapy, and half of survivors are left with neurological disability. Mortality and morbidity are contributed to by a dysregulated immune response, and adjunctive host-directed therapies are required to modulate this response and improve outcomes. Developing such therapies relies on improved understanding of the host immune response to TBM. The historical challenges in TBM research of limited in vivo and in vitro models have been partially overcome by recent developments in proteomics, transcriptomics, and metabolomics, and the use of these technologies in nested substudies of large clinical trials. We review the current understanding of the human immune response in TBM. We begin with M. tuberculosis entry into the central nervous system (CNS), microglial infection and blood-brain and other CNS barrier dysfunction. We then outline the innate response, including the early cytokine response, role of canonical and non-canonical inflammasomes, eicosanoids and specialised pro-resolving mediators. Next, we review the adaptive response including T cells, microRNAs and B cells, followed by the role of the glutamate-GABA neurotransmitter cycle and the tryptophan pathway. We discuss host genetic immune factors, differences between adults and children, paradoxical reaction, and the impact of HIV-1 co-infection including immune reconstitution inflammatory syndrome. Promising immunomodulatory therapies, research gaps, ongoing challenges and future paths are discussed.},
author = {Barnacle, James R. and Davis, Angharad G. and Wilkinson, Robert J.},
doi = {10.3389/FIMMU.2023.1326651},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Barnacle, Davis, Wilkinson - 2024 - Recent advances in understanding the human host immune response in tuberculous meningitis.pdf:pdf},
issn = {1664-3224},
journal = {Frontiers in Immunology},
keywords = {Extra-pulmonary tuberculosis (EPTB),Host-directed therapy,Immunity,Mycobacterium tuberculosis,OA,Tuberculosis,Tuberculous meningitis (TBM),fund{\_}ack,immune response,review},
mendeley-tags = {OA,fund{\_}ack,review},
month = {jan},
pages = {1326651},
publisher = {Frontiers},
title = {{Recent advances in understanding the human host immune response in tuberculous meningitis}},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2023.1326651/full},
volume = {14},
year = {2024}
}

Tuberculous meningitis (TBM), the most severe form of tuberculosis, causes death in approximately 25% cases despite antibiotic therapy, and half of survivors are left with neurological disability. Mortality and morbidity are contributed to by a dysregulated immune response, and adjunctive host-directed therapies are required to modulate this response and improve outcomes. Developing such therapies relies on improved understanding of the host immune response to TBM. The historical challenges in TBM research of limited in vivo and in vitro models have been partially overcome by recent developments in proteomics, transcriptomics, and metabolomics, and the use of these technologies in nested substudies of large clinical trials. We review the current understanding of the human immune response in TBM. We begin with M. tuberculosis entry into the central nervous system (CNS), microglial infection and blood-brain and other CNS barrier dysfunction. We then outline the innate response, including the early cytokine response, role of canonical and non-canonical inflammasomes, eicosanoids and specialised pro-resolving mediators. Next, we review the adaptive response including T cells, microRNAs and B cells, followed by the role of the glutamate-GABA neurotransmitter cycle and the tryptophan pathway. We discuss host genetic immune factors, differences between adults and children, paradoxical reaction, and the impact of HIV-1 co-infection including immune reconstitution inflammatory syndrome. Promising immunomodulatory therapies, research gaps, ongoing challenges and future paths are discussed.

@article{Nyakato2024a,
abstract = {Objectives: The objective of this study is to assess the outcomes of children, adolescents and young adults with HIV reported as lost to follow-up, correct mortality estimates for children, adolescents and young adults with HIV for unascertained outcomes in those loss to follow-up (LTFU) based on tracing and linkage data separately using data from the International epidemiology Databases to Evaluate AIDS in Southern Africa. Methods: We included data from two different populations of children, adolescents and young adults with HIV; (1) clinical data from children, adolescents and young adults with HIV aged ≤24 years from Lesotho, Malawi, Mozambique, Zambia and Zimbabwe; (2) clinical data from children, adolescents and young adults with HIV aged ≤14 years from the Western Cape (WC) in South Africa. Outcomes of patients lost to follow-up were available from (1) a tracing study and (2) linkage to a health information exchange. For both populations, we compared six methods for correct- ing mortality estimates for all children, adolescents and young adults with HIV. Results: We found substantial variations of mortality estimates among children, adoles- cents and young adults with HIV reported as lost to follow-up versus those retained in care. Ascertained mortality was higher among lost and traceable children, adolescents and young adults with HIV and lower among lost and linkable than those retained in care (mortality: 13.4{\%} [traced] vs. 12.6{\%} [retained-other Southern Africa countries]; 3.4{\%} [linked] vs. 9.4{\%} [retained-WC]). A high proportion of lost to follow-up children, adolescents and young adults with HIV had self-transferred (21.0{\%} and 47.0{\%}) in the traced and linked samples, respectively. The uncorrected method of non-informative censoring yielded the lowest mortality estimates among all methods for both tracing (6.0{\%}) and linkage (4.0{\%}) approaches at 2 years from ART start. Among corrected methods using ascertained data, multiple imputation, incorporating ascertained data (MI (asc.)) and inverse probability weighting with logistic weights were most robust for the tracing approach. In contrast, for the linkage approach, MI(asc.) was the most robust. Conclusions: Our findings emphasise that lost to follow-up is non-ignorable and both tracing and linkage improved outcome ascertainment: tracing identified substantial mortality in those reported as lost to follow-up, whereas linkage did not identify out- of-facility deaths, but showed that a large proportion of those reported as lost to follow-up were self-transfers.},
author = {Nyakato, Patience and Schomaker, Michael and Boulle, Andrew and Euvrard, Jonathan and Wood, Robin and Eley, Brian and Prozesky, Hans and Christ, Benedikt and Anderegg, Nanina and Ayakaka, Irene and Rafael, Idiovino and Kunzekwenyika, Cordelia and Moore, Carolyn B and van Lettow, Monique and Chimbetete, Cleophas and Mbewe, Safari and Ballif, Marie and Egger, Matthias and Yiannoutsos, Constantin T and Cornell, Morna and Davies, Mary-Ann},
doi = {10.1111/TMI.14030},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Nyakato et al. - 2024 - Correcting mortality estimates among children and youth on antiretroviral therapy in southern Africa A comparati.pdf:pdf},
issn = {1365-3156},
journal = {Tropical Medicine {\&} International Health},
keywords = {OA,children and youth,fund{\_}ack,linkage,loss to follow,mortality,original,self,tracing,transfer,up},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jul},
pages = {10.1111/tmi.14030 RESEARCH},
pmid = {38961819},
publisher = {John Wiley {\&} Sons, Ltd},
title = {{Correcting mortality estimates among children and youth on antiretroviral therapy in southern Africa: a comparative analysis between a multi-country tracing study and linkage to a health information exchange}},
url = {https://onlinelibrary.wiley.com/doi/full/10.1111/tmi.14030 https://onlinelibrary.wiley.com/doi/abs/10.1111/tmi.14030 https://onlinelibrary.wiley.com/doi/10.1111/tmi.14030},
volume = {9},
year = {2024}
}

Objectives: The objective of this study is to assess the outcomes of children, adolescents and young adults with HIV reported as lost to follow-up, correct mortality estimates for children, adolescents and young adults with HIV for unascertained outcomes in those loss to follow-up (LTFU) based on tracing and linkage data separately using data from the International epidemiology Databases to Evaluate AIDS in Southern Africa. Methods: We included data from two different populations of children, adolescents and young adults with HIV; (1) clinical data from children, adolescents and young adults with HIV aged ≤24 years from Lesotho, Malawi, Mozambique, Zambia and Zimbabwe; (2) clinical data from children, adolescents and young adults with HIV aged ≤14 years from the Western Cape (WC) in South Africa. Outcomes of patients lost to follow-up were available from (1) a tracing study and (2) linkage to a health information exchange. For both populations, we compared six methods for correct- ing mortality estimates for all children, adolescents and young adults with HIV. Results: We found substantial variations of mortality estimates among children, adoles- cents and young adults with HIV reported as lost to follow-up versus those retained in care. Ascertained mortality was higher among lost and traceable children, adolescents and young adults with HIV and lower among lost and linkable than those retained in care (mortality: 13.4% [traced] vs. 12.6% [retained-other Southern Africa countries]; 3.4% [linked] vs. 9.4% [retained-WC]). A high proportion of lost to follow-up children, adolescents and young adults with HIV had self-transferred (21.0% and 47.0%) in the traced and linked samples, respectively. The uncorrected method of non-informative censoring yielded the lowest mortality estimates among all methods for both tracing (6.0%) and linkage (4.0%) approaches at 2 years from ART start. Among corrected methods using ascertained data, multiple imputation, incorporating ascertained data (MI (asc.)) and inverse probability weighting with logistic weights were most robust for the tracing approach. In contrast, for the linkage approach, MI(asc.) was the most robust. Conclusions: Our findings emphasise that lost to follow-up is non-ignorable and both tracing and linkage improved outcome ascertainment: tracing identified substantial mortality in those reported as lost to follow-up, whereas linkage did not identify out- of-facility deaths, but showed that a large proportion of those reported as lost to follow-up were self-transfers.

@article{Magodoro2024,
abstract = {Active tuberculosis may heighten the risk of incident cardiovascular morbidity and premature mortality, whereas whether latent TB infection (LTBI) recapitulates these adverse outcomes is unclear. We evaluated the effect of LTBI on all-cause and cardiovascular-specific death among US adults who underwent tuberculin skin testing in 1999-2000 and were followed up to December 31st, 2019. We also examined the impact of co-occurring traditional risk factors on these outcomes. Adjustments were made for socio-economic and demographic factors. LTBI was defined as tuberculin skin induration ≥10mm, and cause of death as cardiovascular if from heart or cerebrovascular diseases, and non-cardiovascular if otherwise. LTBI was associated with increased of overall and non-cardiovascular specific death but not cardiovascular-specific death. Risk of death was highest when LTBI was comorbid LTBI with diabetes. LTBI may increase risk of death by mechanisms other than progression to active TB disease. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Funding Statement RJW is funded by the Francis Crick Institute which is supported by the Medical Research Council (CC2112), Cancer research UK (CC2112) and Wellcome (CC2112). He also receives support from Wellcome (203135). NABN gratefully acknowledges funding from the National Research Foundation, South African Medical Research Council, US National Institutes of Health, Medical Research Council (UK), and the Lily and Ernst Hausmann Trust. For the purposes of open access, the authors have applied a CC-BY public copyright license to any author-accepted manuscript arising from this submission. {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All data used in this study are publicly accessible in a de-identified format at: https://www.cdc.gov/nchs/nhanes/about{\_}nhanes.htm I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced are available online at: https://www.cdc.gov/nchs/nhanes/about{\_}nhanes.htm},
author = {Magodoro, Itai M and Wilkinson, Katalin Andrea and Claggett, Brian and Aluoch, Aloice and Siedner, Mark J and Ntsekhe, Mpiko and Ntusi, Ntobeko AB and Nyirenda, Moffat J. and Wilkinson, Robert J},
doi = {10.1101/2024.03.11.24304070},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Magodoro et al. - 2024 - Latent tuberculosis infection and incident cardiovascular and non-cardiovascular death.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {mar},
pages = {2024.03.11.24304070},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Latent tuberculosis infection and incident cardiovascular and non-cardiovascular death}},
url = {https://www.medrxiv.org/content/10.1101/2024.03.11.24304070v1 https://www.medrxiv.org/content/10.1101/2024.03.11.24304070v1.abstract},
volume = {3935},
year = {2024}
}

Active tuberculosis may heighten the risk of incident cardiovascular morbidity and premature mortality, whereas whether latent TB infection (LTBI) recapitulates these adverse outcomes is unclear. We evaluated the effect of LTBI on all-cause and cardiovascular-specific death among US adults who underwent tuberculin skin testing in 1999-2000 and were followed up to December 31st, 2019. We also examined the impact of co-occurring traditional risk factors on these outcomes. Adjustments were made for socio-economic and demographic factors. LTBI was defined as tuberculin skin induration ≥10mm, and cause of death as cardiovascular if from heart or cerebrovascular diseases, and non-cardiovascular if otherwise. LTBI was associated with increased of overall and non-cardiovascular specific death but not cardiovascular-specific death. Risk of death was highest when LTBI was comorbid LTBI with diabetes. LTBI may increase risk of death by mechanisms other than progression to active TB disease. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement RJW is funded by the Francis Crick Institute which is supported by the Medical Research Council (CC2112), Cancer research UK (CC2112) and Wellcome (CC2112). He also receives support from Wellcome (203135). NABN gratefully acknowledges funding from the National Research Foundation, South African Medical Research Council, US National Institutes of Health, Medical Research Council (UK), and the Lily and Ernst Hausmann Trust. For the purposes of open access, the authors have applied a CC-BY public copyright license to any author-accepted manuscript arising from this submission. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All data used in this study are publicly accessible in a de-identified format at: https://www.cdc.gov/nchs/nhanes/about_nhanes.htm I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced are available online at: https://www.cdc.gov/nchs/nhanes/about_nhanes.htm

@article{Broger2024,
abstract = {Better access to tuberculosis testing is a key priority for fighting tuberculosis, the leading cause of infectious disease deaths in people. Despite the roll-out of molecular WHO-recommended rapid diagnostics to replace sputum smear microscopy over the past decade, a large diagnostic gap remains. Of the estimated 10{\textperiodcentered}6 million people who developed tuberculosis globally in 2022, more than 3{\textperiodcentered}1 million were not diagnosed. An exclusive focus on improving tuberculosis test accuracy alone will not be sufficient to close the diagnostic gap for tuberculosis. Diagnostic yield, which we define as the proportion of people in whom a diagnostic test identifies tuberculosis among all people we attempt to test for tuberculosis, is an important metric not adequately explored. Diagnostic yield is particularly relevant for subpopulations unable to produce sputum such as young children, people living with HIV, and people with subclinical tuberculosis. As more accessible non-sputum specimens (eg, urine, oral swabs, saliva, capillary blood, and breath) are being explored for point-of-care tuberculosis testing, the concept of yield will be of growing importance. Using the example of urine lipoarabinomannan testing, we illustrate how even tests with limited sensitivity can diagnose more people with tuberculosis if they enable increased diagnostic yield. Using tongue swab-based molecular tuberculosis testing as another example, we provide definitions and guidance for the design and conduct of pragmatic studies that assess diagnostic yield. Lastly, we show how diagnostic yield and other important test characteristics, such as cost and implementation feasibility, are essential for increased effective population coverage, which is required for optimal clinical care and transmission impact. We are calling for diagnostic yield to be incorporated into tuberculosis test evaluation processes, including the WHO Grading of Recommendations, Assessment, Development, and Evaluations process, providing a crucial real-life implementation metric that complements traditional accuracy measures.},
author = {Broger, Tobias and Marx, Florian M and Theron, Grant and Marais, Ben J and Nicol, Mark P and Kerkhoff, Andrew D and Nathavitharana, Ruvandhi and Huerga, Helena and Gupta-Wright, Ankur and Kohli, Mikashmi and Nichols, Brooke E and Muyoyeta, Monde and Meintjes, Graeme A and Ruhwald, Morten and Peeling, Rosanna W and Pai, Nitika Pant and Pollock, Nira R and Pai, Madhukar and Cattamanchi, Adithya and Dowdy, David W and Dewan, Puneet and Denkinger, Claudia M},
doi = {10.1016/S2214-109X(24)00148-7},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Broger et al. - 2024 - Diagnostic yield as an important metric for the evaluation of novel tuberculosis tests rationale and guidance for.pdf:pdf},
issn = {2214-109X},
journal = {The Lancet Global Health},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jul},
number = {7},
pages = {e1184--e1191},
pmid = {38876764},
publisher = {Elsevier},
title = {{Diagnostic yield as an important metric for the evaluation of novel tuberculosis tests: rationale and guidance for future research}},
url = {https://linkinghub.elsevier.com/retrieve/pii/S2214109X24001487},
volume = {12},
year = {2024}
}

Better access to tuberculosis testing is a key priority for fighting tuberculosis, the leading cause of infectious disease deaths in people. Despite the roll-out of molecular WHO-recommended rapid diagnostics to replace sputum smear microscopy over the past decade, a large diagnostic gap remains. Of the estimated 10˙6 million people who developed tuberculosis globally in 2022, more than 3˙1 million were not diagnosed. An exclusive focus on improving tuberculosis test accuracy alone will not be sufficient to close the diagnostic gap for tuberculosis. Diagnostic yield, which we define as the proportion of people in whom a diagnostic test identifies tuberculosis among all people we attempt to test for tuberculosis, is an important metric not adequately explored. Diagnostic yield is particularly relevant for subpopulations unable to produce sputum such as young children, people living with HIV, and people with subclinical tuberculosis. As more accessible non-sputum specimens (eg, urine, oral swabs, saliva, capillary blood, and breath) are being explored for point-of-care tuberculosis testing, the concept of yield will be of growing importance. Using the example of urine lipoarabinomannan testing, we illustrate how even tests with limited sensitivity can diagnose more people with tuberculosis if they enable increased diagnostic yield. Using tongue swab-based molecular tuberculosis testing as another example, we provide definitions and guidance for the design and conduct of pragmatic studies that assess diagnostic yield. Lastly, we show how diagnostic yield and other important test characteristics, such as cost and implementation feasibility, are essential for increased effective population coverage, which is required for optimal clinical care and transmission impact. We are calling for diagnostic yield to be incorporated into tuberculosis test evaluation processes, including the WHO Grading of Recommendations, Assessment, Development, and Evaluations process, providing a crucial real-life implementation metric that complements traditional accuracy measures.

@article{Mpofu2024,
abstract = {AIMS Dolutegravir increases serum creatinine by inhibiting its renal tubular secretion and elimination. We investigated determinants of early changes in serum creatinine in a southern African cohort starting first-line dolutegravir-based antiretroviral therapy (ART). METHODS We conducted a secondary analysis of data from participants in a randomized controlled trial of dolutegravir, emtricitabine and tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide fumarate (TAF) (ADVANCE, NCT03122262). We assessed clinical, pharmacokinetic and genetic factors associated with change in serum creatinine from baseline to Week 4 using linear regression models adjusted for age, sex, baseline serum creatinine, HIV-1 RNA concentration, CD4 T-cell count, total body weight and co-trimoxazole use. RESULTS We included 689 participants, of whom 470 had pharmacokinetic data and 315 had genetic data. Mean change in serum creatinine was 11.3 (SD 9.9) $\mu$mol.L-1 . Factors that were positively associated with change in serum creatinine at Week 4 were increased log dolutegravir area under the 24-h concentration-time curve (change in creatinine coefficient [$\beta$] = 2.78 $\mu$mol.L-1 [95{\%} confidence interval (CI) 0.54, 5.01]), TDF use ($\beta$ = 2.30 [0.53, 4.06]), male sex ($\beta$ = 5.20 [2.92, 7.48]), baseline serum creatinine ($\beta$ = -0.22 [-0.31, -0.12]) and UGT1A1 rs929596 A→G polymorphism with a dominant model ($\beta$ = -2.33 [-4.49, -0.17]). The latter did not withstand correction for multiple testing. CONCLUSIONS Multiple clinical and pharmacokinetic factors were associated with early change in serum creatinine in individuals initiating dolutegravir-based ART. UGT1A1 polymorphisms may play a role, but further research on genetic determinants is needed.},
author = {Mpofu, Rephaim and Kawuma, Aida N and Wasmann, Roeland E and Akpomiemie, Godspower and Chandiwana, Nomathemba and Sokhela, Simiso Mandisa and Moorhouse, Michelle and Venter, Willem Daniel Francois and Denti, Paolo and Wiesner, Lubbe and Post, Frank A and Haas, David W and Maartens, Gary and Sinxadi, Phumla},
doi = {10.1111/BCP.16009},
file = {:C$\backslash$:/Users/01462563/OneDrive - University of Cape Town/Documents/CIDRI-Africa papers and outputs/Mpofu et al - 2024 - Determinants of early change in serum creatinine after initiation of.pdf:pdf},
issn = {1365-2125},
journal = {British Journal of Clinical Pharmacology},
keywords = {HIV/AIDS,OA,cytochrome P450 enzymes,drug transporters,fund{\_}ack,original,pharmacodynamic,pharmacogenomics,pharmacokinetic},
mendeley-tags = {OA,fund{\_}ack,original},
month = {feb},
pages = {10.1111/bcp.16009},
pmid = {38332460},
publisher = {John Wiley {\&} Sons, Ltd},
title = {{Determinants of early change in serum creatinine after initiation of dolutegravir-based antiretroviral therapy in South Africa}},
url = {https://onlinelibrary.wiley.com/doi/full/10.1111/bcp.16009 https://onlinelibrary.wiley.com/doi/abs/10.1111/bcp.16009 https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.16009},
year = {2024}
}

AIMS Dolutegravir increases serum creatinine by inhibiting its renal tubular secretion and elimination. We investigated determinants of early changes in serum creatinine in a southern African cohort starting first-line dolutegravir-based antiretroviral therapy (ART). METHODS We conducted a secondary analysis of data from participants in a randomized controlled trial of dolutegravir, emtricitabine and tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide fumarate (TAF) (ADVANCE, NCT03122262). We assessed clinical, pharmacokinetic and genetic factors associated with change in serum creatinine from baseline to Week 4 using linear regression models adjusted for age, sex, baseline serum creatinine, HIV-1 RNA concentration, CD4 T-cell count, total body weight and co-trimoxazole use. RESULTS We included 689 participants, of whom 470 had pharmacokinetic data and 315 had genetic data. Mean change in serum creatinine was 11.3 (SD 9.9) $μ$mol.L-1 . Factors that were positively associated with change in serum creatinine at Week 4 were increased log dolutegravir area under the 24-h concentration-time curve (change in creatinine coefficient [$β$] = 2.78 $μ$mol.L-1 [95% confidence interval (CI) 0.54, 5.01]), TDF use ($β$ = 2.30 [0.53, 4.06]), male sex ($β$ = 5.20 [2.92, 7.48]), baseline serum creatinine ($β$ = -0.22 [-0.31, -0.12]) and UGT1A1 rs929596 A→G polymorphism with a dominant model ($β$ = -2.33 [-4.49, -0.17]). The latter did not withstand correction for multiple testing. CONCLUSIONS Multiple clinical and pharmacokinetic factors were associated with early change in serum creatinine in individuals initiating dolutegravir-based ART. UGT1A1 polymorphisms may play a role, but further research on genetic determinants is needed.

@article{Hunt2024,
abstract = {The SARS-CoV-2 genome occupies a unique place in infection biology -- it is the most highly sequenced genome on earth (making up over 20{\%} of public sequencing datasets) with fine scale information on sampling date and geography, and has been subject to unprecedented intense analysis. As a result, these phylogenetic data are an incredibly valuable resource for science and public health. However, the vast majority of the data was sequenced by tiling amplicons across the full genome, with amplicon schemes that changed over the pandemic as mutations in the viral genome interacted with primer binding sites. In combination with the disparate set of genome assembly workflows and lack of consistent quality control (QC) processes, the current genomes have many systematic errors that have evolved with the virus and amplicon schemes. These errors have significant impacts on the phylogeny, and therefore over the last few years, many thousands of hours of researchers time has been spent in "eyeballing" trees, looking for artefacts, and then patching the tree. Given the huge value of this dataset, we therefore set out to reprocess the complete set of public raw sequence data in a rigorous amplicon-aware manner, and build a cleaner phylogeny. Here we provide a global tree of 3,960,704 samples, built from a consistently assembled set of high quality consensus sequences from all available public data as of March 2023, viewable at https://viridian.taxonium.org. Each genome was constructed using a novel assembly tool called Viridian (https://github.com/iqbal-lab-org/viridian), developed specifically to process amplicon sequence data, eliminating artefactual errors and mask the genome at low quality positions. We provide simulation and empirical validation of the methodology, and quantify the improvement in the phylogeny. Phase 2 of our project will address the fact that the data in the public archives is heavily geographically biased towards the Global North. We therefore have contributed new raw data to ENA/SRA from many countries including Ghana, Thailand, Laos, Sri Lanka, India, Argentina and Singapore. We will incorporate these, along with all public raw data submitted between March 2023 and the current day, into an updated set of assemblies, and phylogeny. We hope the tree, consensus sequences and Viridian will be a valuable resource for researchers. {\#}{\#}{\#} Competing Interest Statement Gavin Screaton sits on the GSK Vaccines Scientific Advisory Board, consults for AstraZeneca, and is a founding member of RQ Biotechnology.},
author = {Hunt, Martin and Hinrichs, Angie S and Anderson, Daniel and Karim, Lily and Dearlove, Bethany L and Knaggs, Jeff and Constantinides, Bede and Fowler, Philip W and Rodger, Gillian and Street, Teresa L and Lumley, Sheila F and Webster, Hermione and Sanderson, Theo and Ruis, Christopher and {De Maio}, Nicola and Amenga-Etego, Lucas N and Amuzu, Dominic SY and Avaro, Martin and Awandare, Gordon A and Ayivor-Djanie, Reuben and Bashton, Matthew and Batty, Elizabeth M and Bediako, Yaw and {De Belder}, Denise and Benedetti, Estefania and Bergthaler, Andreas and Boers, Stefan A and Campos, Josefina and Carr, Rosina Afua Ampomah and Cuba, Facundo and Dattero, Maria Elena and Dejnirattisai, Wanwissa and Dilthey, Alexander T and Duedu, Kwabena Obeng and Endler, Lukas and Engelmann, Ilka and Francisco, Ngiambudulu M and Fuchs, Jonas and Gnimpieba, Etienne Z and Groc, Soraya and Gyamfi, Jones and Heemskerk, Dennis and Houwaart, Torsten and Hsiao, Nei-yuan and Huska, Matthew and Hoelzer, Martin and Iranzadeh, Arash and Jarva, Hanna and Jeewandara, Chandima and Jolly, Bani and Joseph, Rageema and Kant, Ravi and Ki, Karrie Ko Kwan and Kurkela, Satu and Lappalainen, Maija and Lataretu, Marie and Liu, Chang and Malavige, Gathsaurie Neelika and Mashe, Tapfumanei and Mongkolsapaya, Juthathip and Montes, Brigitte and Molina-Mora, Jose Arturo and Morang'a, Collins M and Mvula, Bernard and Nagarajan, Niranjan and Nelson, Andrew and Ngoi, Joyce Mwongeli and da Paixao, Joana Paula and Panning, Marcus and Poklepovich, Tomas and Quashie, Peter Kojo and Ranasinghe, Diyanath and Russo, Mara and San, James E and Sanderson, Nicholas D and Scaria, Vinod and Screaton, Gavin and Sironen, Tarja and Sisay, Abay and Smith, Darren and Smura, Teemu and Supasa, Piyada and Suphavilai, Chayaporn and Swann, Jeremy and Tegally, Houriiyah and Tegomoh, Bryan and Vapalahti, Olli and Walker, Andreas and Wilkinson, Robert J and Williamson, Carolyn and Consortium, IMSSC2 Laboratory Network and de Oliveira, Tulio and Peto, Timothy EA and Crook, Derrick and Corbett-Detig, Russ and Iqbal, Zamin},
doi = {10.1101/2024.04.29.591666},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Hunt et al. - 2024 - Addressing pandemic-wide systematic errors in the SARS-CoV-2 phylogeny.pdf:pdf},
journal = {bioRxiv},
keywords = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {apr},
pages = {2024.04.29.591666},
publisher = {Cold Spring Harbor Laboratory},
title = {{Addressing pandemic-wide systematic errors in the SARS-CoV-2 phylogeny}},
url = {https://www.biorxiv.org/content/10.1101/2024.04.29.591666v1 https://www.biorxiv.org/content/10.1101/2024.04.29.591666v1.abstract},
volume = {15},
year = {2024}
}

The SARS-CoV-2 genome occupies a unique place in infection biology – it is the most highly sequenced genome on earth (making up over 20% of public sequencing datasets) with fine scale information on sampling date and geography, and has been subject to unprecedented intense analysis. As a result, these phylogenetic data are an incredibly valuable resource for science and public health. However, the vast majority of the data was sequenced by tiling amplicons across the full genome, with amplicon schemes that changed over the pandemic as mutations in the viral genome interacted with primer binding sites. In combination with the disparate set of genome assembly workflows and lack of consistent quality control (QC) processes, the current genomes have many systematic errors that have evolved with the virus and amplicon schemes. These errors have significant impacts on the phylogeny, and therefore over the last few years, many thousands of hours of researchers time has been spent in "eyeballing" trees, looking for artefacts, and then patching the tree. Given the huge value of this dataset, we therefore set out to reprocess the complete set of public raw sequence data in a rigorous amplicon-aware manner, and build a cleaner phylogeny. Here we provide a global tree of 3,960,704 samples, built from a consistently assembled set of high quality consensus sequences from all available public data as of March 2023, viewable at https://viridian.taxonium.org. Each genome was constructed using a novel assembly tool called Viridian (https://github.com/iqbal-lab-org/viridian), developed specifically to process amplicon sequence data, eliminating artefactual errors and mask the genome at low quality positions. We provide simulation and empirical validation of the methodology, and quantify the improvement in the phylogeny. Phase 2 of our project will address the fact that the data in the public archives is heavily geographically biased towards the Global North. We therefore have contributed new raw data to ENA/SRA from many countries including Ghana, Thailand, Laos, Sri Lanka, India, Argentina and Singapore. We will incorporate these, along with all public raw data submitted between March 2023 and the current day, into an updated set of assemblies, and phylogeny. We hope the tree, consensus sequences and Viridian will be a valuable resource for researchers. ### Competing Interest Statement Gavin Screaton sits on the GSK Vaccines Scientific Advisory Board, consults for AstraZeneca, and is a founding member of RQ Biotechnology.

@article{Mangu2024,
abstract = {INTRODUCTION Tuberculosis (TB) is an important cause of morbidity and mortality among people living with HIV (PLHIV). Current WHO-recommended strategies for diagnosing TB among hospitalized PLHIV rely on symptom screening and disease severity to assess eligibility for urine lipoarabinomannan lateral flow (LF-LAM) and molecular testing. Despite these recommendations, autopsy studies show a large burden of undiagnosed TB among admitted PLHIV. The EXULTANT trial aims to assess the impact of an expanded screening strategy using three specimens (sputum, stool, and urine) for TB diagnosis among PLHIV admitted to hospitals in two high HIV and TB burden African countries. METHODS This is a multicenter, pragmatic, individually randomized controlled trial conducted across eleven hospitals in Tanzania and Mozambique. Participants in the intervention arm will be tested with Xpert MTB/RIF Ultra{\textregistered} from expectorated sputum, stool, and urine samples, with additional urine LF-LAM testing in the first 24 h after hospital admission, irrespective of the presence of the symptoms. The control arm will implement the WHO standard of care recommendations. Hospitalized adults (≥ 18 years) with a confirmed HIV-diagnosis, irrespective of antiretroviral (ART) therapy status or presence of TB symptoms will be assessed for eligibility at admission. Patients with a pre-existing TB diagnosis, those receiving anti-tuberculosis therapy or tuberculosis preventive treatment in the 6 months prior to enrolment, and those transferred from other hospitals will not be eligible. Also, participants admitted for traumatic reasons such as acute abdomen, maternal conditions, scheduled surgery, having a positive SARS-CoV2 test will be ineligible. The primary endpoint is the proportion of participants with microbiologically confirmed TB starting treatment within 3 days of enrolment. DISCUSSION The EXULTANT trial investigates rapid implementation after admission of a new diagnostic algorithm using Xpert MTB/RIF Ultra{\textregistered} in several non-invasive specimens, in addition to LF-LAM, in hospitalized PLHIV regardless of TB symptoms. This enhanced strategy is anticipated to detect frequently missed TB cases in this population and is being evaluated as an implementable and scalable intervention. TRIAL REGISTRATION Trial reference number: NCT04568967 (ClinicalTrials.gov) registered on 2020-09-29.},
author = {Mangu, Chacha and Cossa, Marta and Ndege, Robert and Khosa, Celso and Leukes, Vinzeigh and de la Torre-P{\'{e}}rez, Laura and Machiana, Antonio and Kivuma, Bernard and Mnzava, Dorcas and Zachariah, Craysophy and Manjate, Patricia and Tagliani, Elisa and Schacht, Claudia and Buech, Julia and Singh, Sunita and Ehrlich, Joanna and Riess, Friedrich and Sanz, Sergi and Kranzer, Katharina and Cox, Helen and Sabi, Issa and Nguenha, Dinis and Meggi, Bindiya and Weisser, Maja and Ntinginya, Nyanda and Schumacher, Samuel and Ruhwald, Morten and Penn-Nicholson, Adam and Garcia-Basteiro, Alberto L and {TB-CAPT Consortium}},
doi = {10.1186/S12879-024-09651-Z/TABLES/1},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Mangu et al. - 2024 - Expanding Xpert MTBRIF Ultra{\textregistered} and LF-LAM testing for diagnosis of tuberculosis among HIV-positive adults admitted.pdf:pdf},
issn = {1471-2334},
journal = {BMC Infectious Diseases},
keywords = {Infectious Diseases,Internal Medicine,Medical Microbiology,OA,Parasitology,Tropical Medicine,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {aug},
number = {1},
pages = {831},
pmid = {39148008},
publisher = {BioMed Central},
title = {{Expanding Xpert MTB/RIF Ultra{\textregistered} and LF-LAM testing for diagnosis of tuberculosis among HIV-positive adults admitted to hospitals in Tanzania and Mozambique: a randomized controlled trial (the EXULTANT trial).}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/39148008 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC11325809},
volume = {24},
year = {2024}
}

INTRODUCTION Tuberculosis (TB) is an important cause of morbidity and mortality among people living with HIV (PLHIV). Current WHO-recommended strategies for diagnosing TB among hospitalized PLHIV rely on symptom screening and disease severity to assess eligibility for urine lipoarabinomannan lateral flow (LF-LAM) and molecular testing. Despite these recommendations, autopsy studies show a large burden of undiagnosed TB among admitted PLHIV. The EXULTANT trial aims to assess the impact of an expanded screening strategy using three specimens (sputum, stool, and urine) for TB diagnosis among PLHIV admitted to hospitals in two high HIV and TB burden African countries. METHODS This is a multicenter, pragmatic, individually randomized controlled trial conducted across eleven hospitals in Tanzania and Mozambique. Participants in the intervention arm will be tested with Xpert MTB/RIF Ultra® from expectorated sputum, stool, and urine samples, with additional urine LF-LAM testing in the first 24 h after hospital admission, irrespective of the presence of the symptoms. The control arm will implement the WHO standard of care recommendations. Hospitalized adults (≥ 18 years) with a confirmed HIV-diagnosis, irrespective of antiretroviral (ART) therapy status or presence of TB symptoms will be assessed for eligibility at admission. Patients with a pre-existing TB diagnosis, those receiving anti-tuberculosis therapy or tuberculosis preventive treatment in the 6 months prior to enrolment, and those transferred from other hospitals will not be eligible. Also, participants admitted for traumatic reasons such as acute abdomen, maternal conditions, scheduled surgery, having a positive SARS-CoV2 test will be ineligible. The primary endpoint is the proportion of participants with microbiologically confirmed TB starting treatment within 3 days of enrolment. DISCUSSION The EXULTANT trial investigates rapid implementation after admission of a new diagnostic algorithm using Xpert MTB/RIF Ultra® in several non-invasive specimens, in addition to LF-LAM, in hospitalized PLHIV regardless of TB symptoms. This enhanced strategy is anticipated to detect frequently missed TB cases in this population and is being evaluated as an implementable and scalable intervention. TRIAL REGISTRATION Trial reference number: NCT04568967 (ClinicalTrials.gov) registered on 2020-09-29.

@article{Waters2024,
abstract = {Aim: T o investigate changes in psychological distress in community dwelling older adults before and during the COID 19 pandemic, and the contribution of frailty transitions and multimorbidity in predicting the psychological distress. Methods: P rospective repeated measures cohort study on a sample of participants aged 60 and over . A tota l of 2, 785 respondents at the baseline ( May 2019 ) were followed during the COVID 19 August 2020 The change s in psychological distress before and during the COVID 19 w ere assessed using generalized estimation equations with adjusting for sex, age, education, economic status, marital status, tea drinking status, smoking status, alcohol drinking status, sedentary time, sleep quality and ADL Results: The psychological distress of older people has significantly increase d i n August 2020 compared with May 2019. Both older adults who remained frail and transitioned into frail state reported more psychological distress during the COVID 19 . Similarly, both pre existing multimorbidity and emerging multimorbidity groups were associated with more psychological distress. The group of frailty progression who reported new emerging multimorbidity showed more increase in psychological distress, in comparison with those remained non frail state who reported no multimorbidity. Conclus ion: P sychological distress has increased among the community dwelling older adults during the COVID 19 pandemic , and s ustained and progressive frail state, as well as multimorbidity were all associated with a greater increase of psychological distress . Th ese findings suggest that future public health measures should take into account the increased psychological distress among older people during the COVID 19 pandemic , and the assessment of frailty and multimorbidity might help in warning of psychological distress.},
author = {Waters, Robyn and Laubscher, Maritz and Dunn, Robert N and Adikary, Nawaal and Coussens, Anna K and Held, Michael},
doi = {10.1093/OFID/OFAD621},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Waters et al. - 2024 - Higher sensitivity of Xpert MTBRIF ultra over tuberculosis culture for the diagnosis of spinal tuberculosis with.pdf:pdf},
issn = {23288957},
journal = {Open Forum Infectious Diseases},
keywords = {Mycobacterium tuberculosis,OA,diagnosis,fund{\_}ack,original,spinal tuberculosis,tuberculosis,tuberculosis diagnosis},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jan},
number = {1},
pages = {ofad621},
publisher = {Oxford Academic},
title = {{Higher sensitivity of Xpert MTB/RIF ultra over tuberculosis culture for the diagnosis of spinal tuberculosis with open or computed tomography–guided biopsies}},
url = {https://dx.doi.org/10.1093/ofid/ofad621},
volume = {11},
year = {2024}
}

Aim: T o investigate changes in psychological distress in community dwelling older adults before and during the COID 19 pandemic, and the contribution of frailty transitions and multimorbidity in predicting the psychological distress. Methods: P rospective repeated measures cohort study on a sample of participants aged 60 and over . A tota l of 2, 785 respondents at the baseline ( May 2019 ) were followed during the COVID 19 August 2020 The change s in psychological distress before and during the COVID 19 w ere assessed using generalized estimation equations with adjusting for sex, age, education, economic status, marital status, tea drinking status, smoking status, alcohol drinking status, sedentary time, sleep quality and ADL Results: The psychological distress of older people has significantly increase d i n August 2020 compared with May 2019. Both older adults who remained frail and transitioned into frail state reported more psychological distress during the COVID 19 . Similarly, both pre existing multimorbidity and emerging multimorbidity groups were associated with more psychological distress. The group of frailty progression who reported new emerging multimorbidity showed more increase in psychological distress, in comparison with those remained non frail state who reported no multimorbidity. Conclus ion: P sychological distress has increased among the community dwelling older adults during the COVID 19 pandemic , and s ustained and progressive frail state, as well as multimorbidity were all associated with a greater increase of psychological distress . Th ese findings suggest that future public health measures should take into account the increased psychological distress among older people during the COVID 19 pandemic , and the assessment of frailty and multimorbidity might help in warning of psychological distress.

@article{Murahwa2024,
abstract = {Background: Human papillomavirus (HPV) vaccination programs are a key intervention in protecting individuals against HPV-related disease. HIV1-infected individuals are at increased risk of HPV-associated cancers. This study was conducted to evaluate the potential role of prophylactic HPV vaccines in preventing new HPV infections among participants with perinatally acquired HIV who received the quadrivalent HPV vaccine at least five years before this study. Methods: This cross-sectional study was conducted at Newlands Clinic, Harare, Zimbabwe. The clinic provided the Gardasil quadrivalent HPV vaccine (4vHPV) to 624 adolescents living with HIV starting in December 2015. Vaginal and penile swabs were collected and tested for HPV types from the study participants who had received the 4vHPV vaccine 5–6 years before enrolment. Results: We present the results of 98 participants (44.6{\%} female) vaccinated at a median age of 15 years (IQR 12–16). The mean amount of time since vaccination was 6 years (SD: ±0.4). The HPV-positive rate amongst the analyzed swabs was 69{\%} (68/98). Among 30/98 (31{\%}) HPV-positive participants, 13/98 (13{\%}) had low-risk HPV types, and 17/98 (17{\%}) had high-risk HPV types. Twelve participants tested positive for HPV18, only one participant tested positive for HPV16, and an additional four (4.3{\%}) tested positive for either type 6 or 11, with respect to vaccine-preventable low-risk HPV types. Conclusion: The Gardasil quadrivalent HPV vaccine (4vHPV) was expected to protect against infection with HPV types 16, 18, 6, and 11. We demonstrated a possible waning of immunity to HPV18 in 17{\%} of the participants, and an associated loss in cross-protection against HPV45. We observed a relatively high prevalence of ‘opportunistic non-vaccine HPV types' or ‘ecological niche occupiers' in this cohort, and suggest further research on the involvement of these types in cervical and other genital cancers. Our study is one of the few, if not the first, to report on HPV vaccine immunoprotection among people living with HIV (PLWH), thereby setting a baseline for further studies on HPV vaccine effectiveness among PLWH.},
author = {Murahwa, Alltalents T. and Mudzviti, Tinashe and Mandishora, Racheal S. Dube and Chatindo, Takudzwa and Chanetsa, Peace and Pascoe, Margaret and Shamu, Tinei and Basera, Wisdom and Luethy, Ruedi and Williamson, Anna-Lise},
doi = {10.3390/V16010162},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Murahwa et al. - 2024 - Vaccine and non-vaccine HPV types presence in adolescents with vertically acquired HIV five years post Gardasil.pdf:pdf},
issn = {1999-4915},
journal = {Viruses},
keywords = {Gardasil quadrivalent vaccine,OA,OA{\_}PMC,fund{\_}ack,human immunodeficiency virus,human papillomavirus,immunoprotection,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,original},
month = {jan},
number = {1},
pages = {162},
pmid = {38275972},
publisher = {Multidisciplinary Digital Publishing Institute},
title = {{Vaccine and non-vaccine HPV types presence in adolescents with vertically acquired HIV five years post Gardasil quadrivalent vaccination: the ZIMGARD cohort}},
url = {https://www.mdpi.com/1999-4915/16/1/162/htm https://www.mdpi.com/1999-4915/16/1/162},
volume = {16},
year = {2024}
}

Background: Human papillomavirus (HPV) vaccination programs are a key intervention in protecting individuals against HPV-related disease. HIV1-infected individuals are at increased risk of HPV-associated cancers. This study was conducted to evaluate the potential role of prophylactic HPV vaccines in preventing new HPV infections among participants with perinatally acquired HIV who received the quadrivalent HPV vaccine at least five years before this study. Methods: This cross-sectional study was conducted at Newlands Clinic, Harare, Zimbabwe. The clinic provided the Gardasil quadrivalent HPV vaccine (4vHPV) to 624 adolescents living with HIV starting in December 2015. Vaginal and penile swabs were collected and tested for HPV types from the study participants who had received the 4vHPV vaccine 5–6 years before enrolment. Results: We present the results of 98 participants (44.6% female) vaccinated at a median age of 15 years (IQR 12–16). The mean amount of time since vaccination was 6 years (SD: ±0.4). The HPV-positive rate amongst the analyzed swabs was 69% (68/98). Among 30/98 (31%) HPV-positive participants, 13/98 (13%) had low-risk HPV types, and 17/98 (17%) had high-risk HPV types. Twelve participants tested positive for HPV18, only one participant tested positive for HPV16, and an additional four (4.3%) tested positive for either type 6 or 11, with respect to vaccine-preventable low-risk HPV types. Conclusion: The Gardasil quadrivalent HPV vaccine (4vHPV) was expected to protect against infection with HPV types 16, 18, 6, and 11. We demonstrated a possible waning of immunity to HPV18 in 17% of the participants, and an associated loss in cross-protection against HPV45. We observed a relatively high prevalence of ‘opportunistic non-vaccine HPV types' or ‘ecological niche occupiers' in this cohort, and suggest further research on the involvement of these types in cervical and other genital cancers. Our study is one of the few, if not the first, to report on HPV vaccine immunoprotection among people living with HIV (PLWH), thereby setting a baseline for further studies on HPV vaccine effectiveness among PLWH.

@article{Kaul2024,
author = {Kaul, Sheetal and Nair, Vivek and Gcanga, Lorna and Lakshmanan, Vairavan and Kalamuddin, M and Anang, Vandana and Rathore, Sumit and Dhawan, Shikha and Alam, Tanvir and Khanna, Vishal and Lohiya, Sheelu and Ali, Shakir and Mannan, Shamim and Rade, Kirankumar and Parihar, Suraj P and Khanna, Ashwani and Malhotra, Pawan and Brombacher, Frank and Dasaradhi, Palakodeti VN and Guler, Reto and Mohmmed, Asif},
doi = {10.1016/J.IJBIOMAC.2024.132714},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Kaul et al. - 2024 - Identifying quantitative sncRNAs signature using global sequencing as a potential biomarker for tuberculosis diagno.pdf:pdf},
issn = {0141-8130},
journal = {International Journal of Biological Macromolecules},
keywords = {fund{\_}ack,original},
mendeley-tags = {fund{\_}ack,original},
month = {jun},
pages = {132714},
publisher = {Elsevier},
title = {{Identifying quantitative sncRNAs signature using global sequencing as a potential biomarker for tuberculosis diagnosis and their role in regulating host response}},
url = {https://linkinghub.elsevier.com/retrieve/pii/S0141813024035190},
volume = {271},
year = {2024}
}

@article{Kuhlin2024,
abstract = {Linezolid treatment has a high risk of toxicity and adverse drug reactions (ADR) are frequent. Few studies have investigated risk factors of major ADRs separately, therefore, we aimed to evaluate major ADRs including peripheral neuropathy in relation to risk factors and drug concentration levels of linezolid in a high-resource setting for multidrug-resistant tuberculosis (MDR-TB). We conducted a retrospective cohort study including participants treated with a linezolid-containing MDR-TB regimen in Sweden 1992-2018. Data was collected from medical records. ADRs were classified according to Common Terminology Criteria for Adverse Events (version 5.0). Of all participants (n=132), 43.2{\%} were female and the median age 28 years. The median linezolid treatment was 6.5 months (IQR 3.0-12.7) with a median daily dose of 9.6 mg/kg/day. Any ADR was seen in 58.3{\%} (n=77) of participants, with 35.6{\%} having peripheral neuropathy (n=47), 27.3{\%} anaemia (n=36), 22.0{\%} leukopenia (n=36) while 6.1{\%} (n=8) had optic neuritis. The median time for peripheral neuropathy was 3.6 months (IQR 2.1-5.9) and 8.3 months (6.2-10.7) for optic neuritis. A {\textgreater}2.0 mg/L trough concentration (n=40) was associated with anaemia (p=0.0038) and thrombocytopenia (p=0.009) but not with peripheral neuropathy. In multivariable analysis, a dose ≥12 mg/kg/day was associated with time to peripheral neuropathy (HR 2.89, 95{\%}CI 1.08-7.74, p=0.035), anaemia (HR 6.62, 95{\%}CI 2.22-19.8, p=0.001) and leukopenia (HR 5.23, 95{\%} CI 1.48-18.5, p=0.010). Linezolid ADRs were frequent in a high-resource setting. Structured, regular follow-up for ADRs and adjusting dosing according to body weight followed-up by monitoring of drug concentrations early may reduce toxicity.},
author = {Kuhlin, Johanna and Forsman, Lina Davies and Osman, Aisha and Skagerberg, Magdalena and Jonsson, Jerker and Groenheit, Ramona and Mansj{\"{o}}, Mikael and Werngren, Jim and Alffenaar, Jan-Willem and Sch{\"{o}}n, Thomas and Bruchfeld, Judith},
doi = {10.1016/J.IJANTIMICAG.2024.107302},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Kuhlin et al. - 2024 - Increased risk of adverse drug reactions by higher linezolid dose per weight in multidrug-resistant tuberculosis.pdf:pdf},
issn = {0924-8579},
journal = {International Journal of Antimicrobial Agents},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {aug},
pages = {107302},
publisher = {Elsevier},
title = {{Increased risk of adverse drug reactions by higher linezolid dose per weight in multidrug-resistant tuberculosis}},
url = {https://linkinghub.elsevier.com/retrieve/pii/S0924857924002188},
year = {2024}
}

Linezolid treatment has a high risk of toxicity and adverse drug reactions (ADR) are frequent. Few studies have investigated risk factors of major ADRs separately, therefore, we aimed to evaluate major ADRs including peripheral neuropathy in relation to risk factors and drug concentration levels of linezolid in a high-resource setting for multidrug-resistant tuberculosis (MDR-TB). We conducted a retrospective cohort study including participants treated with a linezolid-containing MDR-TB regimen in Sweden 1992-2018. Data was collected from medical records. ADRs were classified according to Common Terminology Criteria for Adverse Events (version 5.0). Of all participants (n=132), 43.2% were female and the median age 28 years. The median linezolid treatment was 6.5 months (IQR 3.0-12.7) with a median daily dose of 9.6 mg/kg/day. Any ADR was seen in 58.3% (n=77) of participants, with 35.6% having peripheral neuropathy (n=47), 27.3% anaemia (n=36), 22.0% leukopenia (n=36) while 6.1% (n=8) had optic neuritis. The median time for peripheral neuropathy was 3.6 months (IQR 2.1-5.9) and 8.3 months (6.2-10.7) for optic neuritis. A \textgreater2.0 mg/L trough concentration (n=40) was associated with anaemia (p=0.0038) and thrombocytopenia (p=0.009) but not with peripheral neuropathy. In multivariable analysis, a dose ≥12 mg/kg/day was associated with time to peripheral neuropathy (HR 2.89, 95%CI 1.08-7.74, p=0.035), anaemia (HR 6.62, 95%CI 2.22-19.8, p=0.001) and leukopenia (HR 5.23, 95% CI 1.48-18.5, p=0.010). Linezolid ADRs were frequent in a high-resource setting. Structured, regular follow-up for ADRs and adjusting dosing according to body weight followed-up by monitoring of drug concentrations early may reduce toxicity.

@article{Auld2024,
abstract = {Continued improvements in the treatment of pulmonary infections have paradoxically resulted in a growing challenge of individuals with post-infectious pulmonary complications (PIPCs). PIPCs have be...},
author = {Auld, Sara C and Sheshadri, Ajay and Alexander-Brett, Jennifer and Aschner, Yael and Barczak, Amy K and Basil, Maria and Cohen, Keira A and Cruz, Charles Dela and McGroder, Claire and Restrepo, Marcos and Ridge, Karen and Schnapp, Lynn and Traber, Katrina and Wunderink, Richard and Zhang, David and Ziady, Assem and Attia, Engi and Carter, Jane and Chalmers, James D and Crothers, Kristina and Feldman, Charles and Jones, Barbara and Kaminski, Naftali and Keane, Joseph and Lewinsohn, David and Metersky, Mark and Mizgerd, Joseph P and Morris, Alison and Ramirez, Julio and Samarasinghe, Amali E and Staitieh, Bashar S and Stek, Cari and Sun, Jie and Evans, Scott E},
doi = {10.1513/ANNALSATS.202406-651ST},
issn = {2329-6933},
journal = {Annals of the American Thoracic Society},
keywords = {perspective},
mendeley-tags = {perspective},
month = {jul},
pmid = {39051991},
title = {{Post-infectious pulmonary complications: establishing research priorities to advance the field. An official American Thoracic Society Workshop Report}},
url = {https://www.atsjournals.org/doi/10.1513/AnnalsATS.202406-651ST},
year = {2024}
}

Continued improvements in the treatment of pulmonary infections have paradoxically resulted in a growing challenge of individuals with post-infectious pulmonary complications (PIPCs). PIPCs have be...

@article{Solanki2024,
abstract = {Atherosclerosis is a chronic inflammatory disease in which fats, lipids, cholesterol, calcium, proliferating smooth muscle cells, and immune cells accumulate in the intima of the large arteries, forming atherosclerotic plaques. A complex interplay of various vascular and immune cells takes place during the initiation and progression of atherosclerosis. Multiple reports indicate that tight control of reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive sulfur species (RSS) production is critical for maintaining vascular health. Unre- stricted ROS and RNS generation may lead to activation of various inflammatory signaling pathways, facilitating atherosclerosis. Given these deleterious consequences, it is important to understand how ROS and RNS affect the signaling processes involved in atherogenesis. Conversely, RSS appears to exhibit an atheroprotective potential and can alleviate the deleterious effects of ROS and RNS. Herein, we review the literature describing the effects of ROS, RNS, and RSS on vascular smooth muscle cells, endothelial cells, and macrophages and focus on how changes in their production affect the initiation and progression of atherosclerosis. This review also discusses the contribution of ROS, RNS, and RSS in mediating various post-translational modifications, such as oxidation, nitrosylation, and sulfation, of the molecules involved in inflammatory signaling. 1.},
author = {Solanki, Kundan and Bezsonov, Evgeny and Orekhov, Alexander and Parihar, Suraj P and Vaja, Shivani and White, Fletcher A and Obukhov, Alexander G and Baig, Mirza S},
doi = {10.1016/J.VPH.2024.107282},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Solanki et al. - 2024 - Effect of reactive oxygen, nitrogen, and sulfur species on signaling pathways in atherosclerosis.pdf:pdf},
issn = {1537-1891},
journal = {Vascular Pharmacology},
keywords = {fund{\_}not{\_}ack,original},
mendeley-tags = {fund{\_}not{\_}ack,original},
month = {mar},
pages = {107282},
pmid = {38325566},
publisher = {Elsevier},
title = {{Effect of reactive oxygen, nitrogen, and sulfur species on signaling pathways in atherosclerosis}},
volume = {154},
year = {2024}
}

Atherosclerosis is a chronic inflammatory disease in which fats, lipids, cholesterol, calcium, proliferating smooth muscle cells, and immune cells accumulate in the intima of the large arteries, forming atherosclerotic plaques. A complex interplay of various vascular and immune cells takes place during the initiation and progression of atherosclerosis. Multiple reports indicate that tight control of reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive sulfur species (RSS) production is critical for maintaining vascular health. Unre- stricted ROS and RNS generation may lead to activation of various inflammatory signaling pathways, facilitating atherosclerosis. Given these deleterious consequences, it is important to understand how ROS and RNS affect the signaling processes involved in atherogenesis. Conversely, RSS appears to exhibit an atheroprotective potential and can alleviate the deleterious effects of ROS and RNS. Herein, we review the literature describing the effects of ROS, RNS, and RSS on vascular smooth muscle cells, endothelial cells, and macrophages and focus on how changes in their production affect the initiation and progression of atherosclerosis. This review also discusses the contribution of ROS, RNS, and RSS in mediating various post-translational modifications, such as oxidation, nitrosylation, and sulfation, of the molecules involved in inflammatory signaling. 1.

@article{Ruffieux2024,
abstract = {Background: Several studies have found lower prostate cancer diagnosis rates among men with human immunodeficiency virus (HIV; MWH) than men without HIV but reasons for this finding remain unclear. Methods: We used claims data from a South African private medical insurance scheme (July 2017-July 2020) to assess prostate cancer diagnosis rates among men aged ≥ 18 years with and without HIV. Using flexible parametric survival models, we estimated hazard ratios (HR) for the association between HIV and incident prostate cancer diagnoses. We accounted for potential confounding by age, population group, and sexually transmitted infections (confounder-adjusted model) and additionally for potential mediation by prostatitis diagnoses, prostate-specific antigen testing, and prostate biopsies (fully adjusted model).},
author = {Ruffieux, Yann and {Fern{\'{a}}ndez Villalobos}, Nathalie V and Didden, Christiane and Haas, Andreas D and Chinogurei, Chido and Cornell, Morna and Egger, Matthias and Maartens, Gary and Folb, Naomi and Rohner, Eliane},
doi = {10.1158/1055-9965.EPI-24-0137/3451500/EPI-24-0137.PDF},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Ruffieux et al. - 2024 - Prostate Cancer Diagnosis Rates among Insured Men with and without HIV in South Africa A Cohort Study.pdf:pdf},
issn = {1055-9965},
journal = {Cancer Epidemiology, Biomarkers {\&} Prevention},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jun},
number = {8},
pages = {OF1--OF8},
pmid = {38713162},
publisher = {American Association for Cancer Research (AACR)},
title = {{Prostate cancer diagnosis rates among insured men with and without HIV in South Africa: a cohort study}},
url = {/cebp/article/33/8/1057/746521/Prostate-Cancer-Diagnosis-Rates-among-Insured-Men https://dx.doi.org/10.1158/1055-9965.EPI-24-0137},
volume = {33},
year = {2024}
}

Background: Several studies have found lower prostate cancer diagnosis rates among men with human immunodeficiency virus (HIV; MWH) than men without HIV but reasons for this finding remain unclear. Methods: We used claims data from a South African private medical insurance scheme (July 2017-July 2020) to assess prostate cancer diagnosis rates among men aged ≥ 18 years with and without HIV. Using flexible parametric survival models, we estimated hazard ratios (HR) for the association between HIV and incident prostate cancer diagnoses. We accounted for potential confounding by age, population group, and sexually transmitted infections (confounder-adjusted model) and additionally for potential mediation by prostatitis diagnoses, prostate-specific antigen testing, and prostate biopsies (fully adjusted model).

@article{Doolabh,
abstract = {Introduction: Elucidation of mechanisms that drive HIV latency is essential to identifying cure strategies. While host mechanisms associated with viral persistence on antiretroviral therapy (ART) have been well studied, less is known about the viral properties that influence latency. The viral promoter element, the 5' long terminal repeat (LTR), has been shown to affect the number of latently infected cells shortly after infection. Here we investigated the role of subtype C LTR genotypic variation on the establishment of latency in a dual reporter HIV-1 infection model.The LTR U3 and R regions from 11 women with acute/early subtype C HIV infection were cloned into the dual reporter pRGH plasmid. Latency potential was calculated based on the expression of fluorescent reporter genes in Jurkat E6-1 cells measured by flow cytometry as the proportion of latent (mCherry +ve cells)/proportion of active (eGFP +ve mCherry +ve cells) infection. Reversal of latency was performed using PMA/Ionomycin stimulation 24 hours before fixing of cells. LTR transcriptional capacity, in the presence and absence of a heterologous subtype C Tat, was measured for the same LTRs cloned into a pGL4.10 luciferase expression vector following transfection of HEK293T cells.The majority of proviruses were latent at day 8 post-infection, yet the proportion of latently infected cells varied significantly across participants. We observed a median latent:active infection ratio of 1.97 (range 0.86 -2.83) across LTRs with the hierarchy of latency potential remaining consistent across repeat experiments. The median latent:active infection ratio decreased by a median of 3-fold following PMA/Ionomycin stimulation to 0.55 (range 0.46 -0.78) indicating that a proportion of latently infected cells could produce viral proteins upon activation. Latency potential did not correlate with LTR transcriptional capacity.We found intra-subtype level differences in the latency potential of LTRs from South African women independent of their transcriptional capacity, suggesting that HIV-1 LTRs have intrinsic properties that influence the proportion of latently infected cells shortly after infection. The inability to reactivate viral expression in all latently infected cells supports the complex nature of mechanisms driving latency and the need for continued advancements in methods used to study these mechanisms.},
author = {Doolabh, Deelan Sudhir and Selhorst, Philippe and Williamson, Carolyn and Chopera, Denis and Abrahams, Melissa-Rose},
doi = {10.3389/FVIRO.2024.1393475},
issn = {2673-818X},
journal = {Frontiers in Virology},
keywords = {HIV1,LTR3,OA,genotype5. (Min.5-Max. 8) 2,latency2,original,promoter4},
mendeley-tags = {OA,original},
pages = {1393475},
publisher = {Frontiers},
title = {{HIV latency potential may be influenced by intra-subtype genetic differences in the viral long-terminal repeat}},
volume = {4},
year = {2024}
}

Introduction: Elucidation of mechanisms that drive HIV latency is essential to identifying cure strategies. While host mechanisms associated with viral persistence on antiretroviral therapy (ART) have been well studied, less is known about the viral properties that influence latency. The viral promoter element, the 5' long terminal repeat (LTR), has been shown to affect the number of latently infected cells shortly after infection. Here we investigated the role of subtype C LTR genotypic variation on the establishment of latency in a dual reporter HIV-1 infection model.The LTR U3 and R regions from 11 women with acute/early subtype C HIV infection were cloned into the dual reporter pRGH plasmid. Latency potential was calculated based on the expression of fluorescent reporter genes in Jurkat E6-1 cells measured by flow cytometry as the proportion of latent (mCherry +ve cells)/proportion of active (eGFP +ve mCherry +ve cells) infection. Reversal of latency was performed using PMA/Ionomycin stimulation 24 hours before fixing of cells. LTR transcriptional capacity, in the presence and absence of a heterologous subtype C Tat, was measured for the same LTRs cloned into a pGL4.10 luciferase expression vector following transfection of HEK293T cells.The majority of proviruses were latent at day 8 post-infection, yet the proportion of latently infected cells varied significantly across participants. We observed a median latent:active infection ratio of 1.97 (range 0.86 -2.83) across LTRs with the hierarchy of latency potential remaining consistent across repeat experiments. The median latent:active infection ratio decreased by a median of 3-fold following PMA/Ionomycin stimulation to 0.55 (range 0.46 -0.78) indicating that a proportion of latently infected cells could produce viral proteins upon activation. Latency potential did not correlate with LTR transcriptional capacity.We found intra-subtype level differences in the latency potential of LTRs from South African women independent of their transcriptional capacity, suggesting that HIV-1 LTRs have intrinsic properties that influence the proportion of latently infected cells shortly after infection. The inability to reactivate viral expression in all latently infected cells supports the complex nature of mechanisms driving latency and the need for continued advancements in methods used to study these mechanisms.

@article{Middelkoop2024a,
abstract = {Objective To determine whether vitamin D supplementation influences grip strength, explosive leg power, cardiorespiratory fitness and risk of exercise-induced bronchoconstriciton (EIB) in South African schoolchildren. Methods Sub-study (n=450) in Cape Town schoolchildren aged 8-11 years, nested within a phase 3 randomised placebo-controlled trial (ViDiKids). The intervention was weekly oral doses of 10,000 IU vitamin D3 (n=228) or placebo (n=222) for 3 years. Outcome measures were serum 25-hydroxyvitamin D3 (25[OH]D3) concentrations, grip strength, standing long jump distance, peak oxygen uptake (VO2peak, determined using 20-metre multi-stage shuttle run tests) and the proportion of children with EIB, all measured at end-study. Results 64.7{\%} of participants had serum 25(OH)D3 concentrations {\textless}75 nmol/L at baseline. At 3-year follow-up, children randomised to vitamin D vs. placebo had higher mean serum 25(OH)D3 concentrations (97.6 vs. 58.8 nmol/L respectively; adjusted mean difference [aMD] 39.9 nmol/L, 95{\%} CI 36.1 to 43.6) and long jump distance (128.3 vs. 122.1 cm; aMD 3.6 cm, 95{\%} CI 0.0 to 7.2). No end-study differences in grip strength, VO2peak, or spirometric lung volumes were seen, but administration of vitamin D vs. placebo was associated with a borderline-significant increased risk of EIB (14.5{\%} vs. 8.6{\%}; adjusted odds ratio 1.92, 95{\%} CI 0.99 to 3.73). Conclusion A 3-year course of weekly oral supplementation with 10,000 IU vitamin D3 elevated serum 25(OH)D3 concentrations in South African schoolchildren and induced a small increase in long jump distance, but had no effect on grip strength or VO2 peak. Potential effects of vitamin D on risk of EIB require further research. What is already known on this topic? Observational studies have reported that vitamin D deficiency associates with reduced muscle strength and peak oxygen uptake and increased risk of exercise-induced bronchoconstriction (EIB) in children. Randomised controlled trials (RCT) of vitamin D supplementation to improve children's muscle strength and cardiorespiratory fitness have yielded conflicting results. What this study adds This RCT, conducted in South African schoolchildren aged 8-11 years at baseline, found that a 3-year course of weekly oral supplementation with 10,000 IU vitamin D3 improved vitamin D status and resulted in a small (3.6 cm), borderline-significant increase in long jump distance, but had no effect on grip strength or peak oxygen uptake. Administration of vitamin D was associated with a borderline-significant increased risk of EIB. How this study might affect research, practice or policy Taken together with null results from another Phase 3 randomised controlled trial of vitamin D supplementation conducted in Mongolian children, our findings do not suggest that weekly oral vitamin D supplementation exerts clinically significant effects on muscle strength or peak oxygen uptake in schoolchildren in whom rickets has been excluded. Further research into potential effects of vitamin D supplementation on risk of EIB is needed. {\#}{\#}{\#} Competing Interest Statement ARM declares receipt of funding in the last 36 months to support vitamin D research from the following companies who manufacture or sell vitamin D supplements: Pharma Nord Ltd, DSM Nutritional Products Ltd, Thornton {\&} Ross Ltd and Hyphens Pharma Ltd. ARM also declares receipt of vitamin D capsules for clinical trial use from Pharma Nord Ltd, Synergy Biologics Ltd and Cytoplan Ltd; support for attending meetings from Pharma Nord Ltd and Abiogen Pharma Ltd; receipt of consultancy fees from DSM Nutritional Products Ltd and Qiagen Ltd; receipt of a speaker fee from the Linus Pauling Institute; participation on Data and Safety Monitoring Boards for the VITALITY trial (Vitamin D for Adolescents with HIV to reduce musculoskeletal morbidity and immunopathology, Pan African Clinical Trials Registry ref PACTR20200989766029) and the Trial of Vitamin D and Zinc Supplementation for Improving Treatment Outcomes Among COVID-19 Patients in India (ClinicalTrials.gov ref [NCT04641195][1]); and unpaid work as a Programme Committee member for the Vitamin D Workshop. All other authors declare that they have no competing interests. {\#}{\#}{\#} Clinical Trial NCT02880982 {\#}{\#}{\#} Funding Statement This research was funded by the UK Medical Research Council (refs MR/R023050/1 and MR/M026639/1, both awarded to ARM). RJW was supported by Wellcome (104803, 203135). He also received support from the Francis Crick Institute which is funded by Cancer Research UK (FC2112), the UK Medical Research Council (FC2112) and Wellcome (FC2112). NCH and CC are supported by the UK Medical Research Council [MC$\backslash${\_}PC$\backslash${\_}21003; MC$\backslash${\_}PC$\backslash${\_}21001]. {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The trial was approved by the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee (Ref: 796/2015) and the London School of Hygiene and Tropical Medicine Observational/Interventions Research Ethics Committee (Ref: 7450-2). Participants and their parents/guardians provided written informed assent and consent, respectively, to take part in the trial before any study procedures were conducted. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes [1]: /lookup/external-ref?link{\_}type=CLINTRIALGOV{\&}access{\_}num=NCT04641195{\&}atom={\%}2Fmedrxiv{\%}2Fearly{\%}2F2024{\%}2F03{\%}2F27{\%}2F2024.03.26.24304912.atom},
author = {Middelkoop, Keren and Micklesfield, Lisa K and Hemmings, Stephanie and Walker, Neil and Stewart, Justine and Jolliffe, David A and Mendham, Amy E and Tang, Jonathan C Y and Cooper, Cyrus and Harvey, Nicholas C and Wilkinson, Robert J and Martineau, Adrian R},
doi = {10.1101/2024.03.26.24304912},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Middelkoop et al. - 2024 - Influence of vitamin D supplementation on muscle strength and exercise capacity in South African schoolchildr.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {mar},
pages = {2024.03.26.24304912},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Influence of vitamin D supplementation on muscle strength and exercise capacity in South African schoolchildren: a randomised controlled trial (ViDiKids)}},
url = {https://www.medrxiv.org/content/10.1101/2024.03.26.24304912v1 https://www.medrxiv.org/content/10.1101/2024.03.26.24304912v1.abstract},
year = {2024}
}

Objective To determine whether vitamin D supplementation influences grip strength, explosive leg power, cardiorespiratory fitness and risk of exercise-induced bronchoconstriciton (EIB) in South African schoolchildren. Methods Sub-study (n=450) in Cape Town schoolchildren aged 8-11 years, nested within a phase 3 randomised placebo-controlled trial (ViDiKids). The intervention was weekly oral doses of 10,000 IU vitamin D3 (n=228) or placebo (n=222) for 3 years. Outcome measures were serum 25-hydroxyvitamin D3 (25[OH]D3) concentrations, grip strength, standing long jump distance, peak oxygen uptake (VO2peak, determined using 20-metre multi-stage shuttle run tests) and the proportion of children with EIB, all measured at end-study. Results 64.7% of participants had serum 25(OH)D3 concentrations \textless75 nmol/L at baseline. At 3-year follow-up, children randomised to vitamin D vs. placebo had higher mean serum 25(OH)D3 concentrations (97.6 vs. 58.8 nmol/L respectively; adjusted mean difference [aMD] 39.9 nmol/L, 95% CI 36.1 to 43.6) and long jump distance (128.3 vs. 122.1 cm; aMD 3.6 cm, 95% CI 0.0 to 7.2). No end-study differences in grip strength, VO2peak, or spirometric lung volumes were seen, but administration of vitamin D vs. placebo was associated with a borderline-significant increased risk of EIB (14.5% vs. 8.6%; adjusted odds ratio 1.92, 95% CI 0.99 to 3.73). Conclusion A 3-year course of weekly oral supplementation with 10,000 IU vitamin D3 elevated serum 25(OH)D3 concentrations in South African schoolchildren and induced a small increase in long jump distance, but had no effect on grip strength or VO2 peak. Potential effects of vitamin D on risk of EIB require further research. What is already known on this topic? Observational studies have reported that vitamin D deficiency associates with reduced muscle strength and peak oxygen uptake and increased risk of exercise-induced bronchoconstriction (EIB) in children. Randomised controlled trials (RCT) of vitamin D supplementation to improve children's muscle strength and cardiorespiratory fitness have yielded conflicting results. What this study adds This RCT, conducted in South African schoolchildren aged 8-11 years at baseline, found that a 3-year course of weekly oral supplementation with 10,000 IU vitamin D3 improved vitamin D status and resulted in a small (3.6 cm), borderline-significant increase in long jump distance, but had no effect on grip strength or peak oxygen uptake. Administration of vitamin D was associated with a borderline-significant increased risk of EIB. How this study might affect research, practice or policy Taken together with null results from another Phase 3 randomised controlled trial of vitamin D supplementation conducted in Mongolian children, our findings do not suggest that weekly oral vitamin D supplementation exerts clinically significant effects on muscle strength or peak oxygen uptake in schoolchildren in whom rickets has been excluded. Further research into potential effects of vitamin D supplementation on risk of EIB is needed. ### Competing Interest Statement ARM declares receipt of funding in the last 36 months to support vitamin D research from the following companies who manufacture or sell vitamin D supplements: Pharma Nord Ltd, DSM Nutritional Products Ltd, Thornton & Ross Ltd and Hyphens Pharma Ltd. ARM also declares receipt of vitamin D capsules for clinical trial use from Pharma Nord Ltd, Synergy Biologics Ltd and Cytoplan Ltd; support for attending meetings from Pharma Nord Ltd and Abiogen Pharma Ltd; receipt of consultancy fees from DSM Nutritional Products Ltd and Qiagen Ltd; receipt of a speaker fee from the Linus Pauling Institute; participation on Data and Safety Monitoring Boards for the VITALITY trial (Vitamin D for Adolescents with HIV to reduce musculoskeletal morbidity and immunopathology, Pan African Clinical Trials Registry ref PACTR20200989766029) and the Trial of Vitamin D and Zinc Supplementation for Improving Treatment Outcomes Among COVID-19 Patients in India (ClinicalTrials.gov ref [NCT04641195][1]); and unpaid work as a Programme Committee member for the Vitamin D Workshop. All other authors declare that they have no competing interests. ### Clinical Trial NCT02880982 ### Funding Statement This research was funded by the UK Medical Research Council (refs MR/R023050/1 and MR/M026639/1, both awarded to ARM). RJW was supported by Wellcome (104803, 203135). He also received support from the Francis Crick Institute which is funded by Cancer Research UK (FC2112), the UK Medical Research Council (FC2112) and Wellcome (FC2112). NCH and CC are supported by the UK Medical Research Council [MC$\$_PC$\$_21003; MC$\$_PC$\$_21001]. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The trial was approved by the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee (Ref: 796/2015) and the London School of Hygiene and Tropical Medicine Observational/Interventions Research Ethics Committee (Ref: 7450-2). Participants and their parents/guardians provided written informed assent and consent, respectively, to take part in the trial before any study procedures were conducted. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04641195&atom=%2Fmedrxiv%2Fearly%2F2024%2F03%2F27%2F2024.03.26.24304912.atom

@article{Churchyard2024,
abstract = {Tuberculosis is a leading cause of death from an infectious agent globally. Infectious subclinical tuberculosis accounts for almost half of all tuberculosis cases in national tuberculosis prevalence surveys, and possibly contributes to transmission and might be associated with morbidity. Modelling studies suggest that new tuberculosis vaccines could have substantial health and economic effects, partly based on the assumptions made regarding subclinical tuberculosis. Evaluating the efficacy of prevention of disease tuberculosis vaccines intended for preventing both clinical and subclinical tuberculosis is a priority. Incorporation of subclinical tuberculosis as a composite endpoint in tuberculosis vaccine trials can help to reduce the sample size and duration of follow-up and to evaluate the efficacy of tuberculosis vaccines in preventing clinical and subclinical tuberculosis. Several design options with various benefits, limitations, and ethical considerations are possible in this regard, which would allow for the generation of the evidence needed to estimate the positive global effects of tuberculosis vaccine trials, in addition to informing policy and vaccination strategies.},
author = {Churchyard, Gavin J and Houben, Rein M G J and Fielding, Katherine and Fiore-Gartland, Andrew L and Esmail, Hanif and Grant, Alison D and Rangaka, Molebogeng X and Behr, Marcel and Garcia-Basteiro, Alberto L. and Wong, Emily B and Hatherill, Mark and Mave, Vidya and Dagnew, Alemnew F and Schmidt, Alexander C and Hanekom, Willem A and Cobelens, Frank and White, Richard G},
doi = {10.1016/S2666-5247(24)00127-7},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Churchyard et al. - 2024 - Implications of subclinical tuberculosis for vaccine trial design and global effect.pdf:pdf},
issn = {2666-5247},
journal = {The Lancet Microbe},
keywords = {OA,OA{\_}PMC,fund{\_}not{\_}ack,perspective},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,perspective},
month = {jul},
pages = {10.1016/ S2666--5247(24)00127--7 Aurum},
pmid = {38964359},
publisher = {Elsevier},
title = {{Implications of subclinical tuberculosis for vaccine trial design and global effect}},
year = {2024}
}

Tuberculosis is a leading cause of death from an infectious agent globally. Infectious subclinical tuberculosis accounts for almost half of all tuberculosis cases in national tuberculosis prevalence surveys, and possibly contributes to transmission and might be associated with morbidity. Modelling studies suggest that new tuberculosis vaccines could have substantial health and economic effects, partly based on the assumptions made regarding subclinical tuberculosis. Evaluating the efficacy of prevention of disease tuberculosis vaccines intended for preventing both clinical and subclinical tuberculosis is a priority. Incorporation of subclinical tuberculosis as a composite endpoint in tuberculosis vaccine trials can help to reduce the sample size and duration of follow-up and to evaluate the efficacy of tuberculosis vaccines in preventing clinical and subclinical tuberculosis. Several design options with various benefits, limitations, and ethical considerations are possible in this regard, which would allow for the generation of the evidence needed to estimate the positive global effects of tuberculosis vaccine trials, in addition to informing policy and vaccination strategies.

@article{Macpherson2024,
abstract = {Background WHO Tuberculosis (TB) screening guidelines recommend computer-aided detection (CAD) software for chest radiograph (CXR) interpretation. However, studies evaluating their diagnostic and prognostic accuracy are limited. Methods We conducted a prospective cohort study of household TB contacts in South Africa. Participants all underwent baseline CXR and sputum investigation (routine [single spontaneous] and enhanced [additionally 2-3 induced] sputum investigation and passive and active follow-up for incident TB. CXR were processed comparing 3 CAD softwares (CAD4TBv7.0, qXRv3.0.0, and Lunit INSIGHT CXR 3.1.4.111). We evaluated their performance to detect routine and enhanced prevalent, and incident TB, comparing the performance to blood-based biomarkers (Xpert MTB host-response, Erythrocyte Sedimentation Rate, C-Reactive Protein, QuantiFERON) in a subgroup. Findings 483 participants were followed-up for 4.6 years (median). There were 23 prevalent (7 routinely diagnosed) and 38 incident TB cases. The AUC ROC to identify prevalent TB for CAD4TB, qXR and Lunit INSIGHT CXR were 0.87 (95{\%} CI 0.77-0.96), 0.88 (95{\%} CI 0.79-0.97) and 0.91 (95{\%} CI 0.83-0.99) respectively. {\textgreater}30{\%} with scores above recommended CAD thresholds who were bacteriologically negative on routine baseline sputum were subsequently diagnosed by enhanced baseline sputum investigation or during follow-up. The AUC performance of baseline CAD to identify incident cases ranged between 0.60-0.65. The diagnostic performance of CAD for prevalent TB was superior to blood-based biomarkers. Interpretation Our findings suggest that the potential of CAD-CXR screening for TB is not maximised as a high proportion of those above current thresholds but with a negative routine confirmatory sputum have true TB disease that may benefit intervention. Funding UKRI-MRC Summary We found that the diagnostic accuracy of CAD-CXR to identify prevalent TB cases in household TB contacts was high but {\textgreater}30{\%} with scores above recommended CAD thresholds who were bacteriologically negative on routine testing baseline were subsequently diagnosed suggest that the potential of CAD-CXR screening is not maximised. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Funding Statement This study was supported by an MRC award (Grant Ref: MR/V00476X/1) to HE. HE is partially supported by and MRC unit grant (MC UU 00004/04). AKC is partially supported by the NHMRC (GNT2020750) and WEHI. RJW is supported by the Francis Crick Institute which receives funding from Cancer Research Uk (FC2112), UK Research and Innovation-MRC (CC2112) and Wellcome (CC2112). He also receives funding from Wellcome (203135), South African MRC via its Strategic health Partnerships and the Bill and Melinda Gates Foundation. {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committees of University of Cape Town (449/2014), Boston University (H-35831), Rutgers University (Pro2018001966), NIH (DMID 16-0112) and University College London (19219/001) gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors},
author = {Macpherson, Liana and Kik, Sandra V and Quartagno, Matteo and Lakay, Francisco and Jaftha, Marche and Yende, Nombuso and Galant, Shireen and Aziz, Saalikha and Daroowala, Remy and Court, Richard and Taliep, Arshad and Serole, Keboile and Goliath, Rene T and Davies, Nashreen Omar and Jackson, Amanda and Douglass, Emily and Sossen, Bianca and Mukasa, Sandra and Thienemann, Friedrich and Song, Taeksun and Ruhwald, Morten and Wilkinson, Robert J and Coussens, Anna K and Esmail, Hanif},
doi = {10.1101/2024.06.30.24309731},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Macpherson et al. - 2024 - Diagnostic accuracy of Chest X-Ray Computer Aided Detection software and blood biomarkers for detection of pr.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jul},
pages = {2024.06.30.24309731},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Diagnostic accuracy of chest X-Ray Computer Aided Detection software and blood biomarkers for detection of prevalent and incident tuberculosis in household contacts followed up for 5 years}},
url = {https://www.medrxiv.org/content/10.1101/2024.06.30.24309731v1 https://www.medrxiv.org/content/10.1101/2024.06.30.24309731v1.abstract},
year = {2024}
}

Background WHO Tuberculosis (TB) screening guidelines recommend computer-aided detection (CAD) software for chest radiograph (CXR) interpretation. However, studies evaluating their diagnostic and prognostic accuracy are limited. Methods We conducted a prospective cohort study of household TB contacts in South Africa. Participants all underwent baseline CXR and sputum investigation (routine [single spontaneous] and enhanced [additionally 2-3 induced] sputum investigation and passive and active follow-up for incident TB. CXR were processed comparing 3 CAD softwares (CAD4TBv7.0, qXRv3.0.0, and Lunit INSIGHT CXR 3.1.4.111). We evaluated their performance to detect routine and enhanced prevalent, and incident TB, comparing the performance to blood-based biomarkers (Xpert MTB host-response, Erythrocyte Sedimentation Rate, C-Reactive Protein, QuantiFERON) in a subgroup. Findings 483 participants were followed-up for 4.6 years (median). There were 23 prevalent (7 routinely diagnosed) and 38 incident TB cases. The AUC ROC to identify prevalent TB for CAD4TB, qXR and Lunit INSIGHT CXR were 0.87 (95% CI 0.77-0.96), 0.88 (95% CI 0.79-0.97) and 0.91 (95% CI 0.83-0.99) respectively. \textgreater30% with scores above recommended CAD thresholds who were bacteriologically negative on routine baseline sputum were subsequently diagnosed by enhanced baseline sputum investigation or during follow-up. The AUC performance of baseline CAD to identify incident cases ranged between 0.60-0.65. The diagnostic performance of CAD for prevalent TB was superior to blood-based biomarkers. Interpretation Our findings suggest that the potential of CAD-CXR screening for TB is not maximised as a high proportion of those above current thresholds but with a negative routine confirmatory sputum have true TB disease that may benefit intervention. Funding UKRI-MRC Summary We found that the diagnostic accuracy of CAD-CXR to identify prevalent TB cases in household TB contacts was high but \textgreater30% with scores above recommended CAD thresholds who were bacteriologically negative on routine testing baseline were subsequently diagnosed suggest that the potential of CAD-CXR screening is not maximised. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by an MRC award (Grant Ref: MR/V00476X/1) to HE. HE is partially supported by and MRC unit grant (MC UU 00004/04). AKC is partially supported by the NHMRC (GNT2020750) and WEHI. RJW is supported by the Francis Crick Institute which receives funding from Cancer Research Uk (FC2112), UK Research and Innovation-MRC (CC2112) and Wellcome (CC2112). He also receives funding from Wellcome (203135), South African MRC via its Strategic health Partnerships and the Bill and Melinda Gates Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committees of University of Cape Town (449/2014), Boston University (H-35831), Rutgers University (Pro2018001966), NIH (DMID 16-0112) and University College London (19219/001) gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

@article{Naidoo2024,
abstract = {Drug-resistant tuberculosis (DR-TB) threatens to derail tuberculosis control efforts, particularly in Africa where the disease remains out of control. The dogma that DR-TB epidemics are fueled by unchecked rates of acquired resistance in inadequately treated or non-adherent individuals is no longer valid in most high DR-TB burden settings, where community transmission is now widespread. A large burden of DR-TB in Africa remains undiagnosed due to inadequate access to diagnostic tools that simultaneously detect tuberculosis and screen for resistance. Furthermore, acquisition of drug resistance to new and repurposed drugs, for which diagnostic solutions are not yet available, presents a major challenge for the implementation of novel, all-oral, shortened (6–9 months) treatment. Structural challenges including poverty, stigma, and social distress disrupt engagement in care, promote poor treatment outcomes, and reduce the quality of life for people with DR-TB. We reflect on the lessons learnt from the South African experience in implementing state-of-the-art advances in diagnostic solutions, deploying recent innovations in pharmacotherapeutic approaches for rapid cure, understanding local transmission dynamics and implementing interventions to curtail DR-TB transmission, and in mitigating the catastrophic socioeconomic costs of DR-TB. We also highlight globally relevant and locally responsive research priorities for achieving DR-TB control in South Africa. {\textcopyright} 2024 Elsevier Ltd},
author = {Naidoo, Kogieleum and Perumal, Rubeshan and Cox, Helen and Mathema, Barun and Loveday, Marian and Ismail, Nazir and Omar, Shaheed Vally and Georghiou, Sophia B and Daftary, Amrita and O'Donnell, Max and Ndjeka, Norbert},
doi = {10.1016/S1473-3099(24)00144-0},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Naidoo et al. - 2024 - The epidemiology, transmission, diagnosis, and management of drug-resistant tuberculosis—lessons from the South A.pdf:pdf},
issn = {14744457},
journal = {The Lancet Infectious Diseases},
keywords = {fund{\_}not{\_}ack,review},
mendeley-tags = {fund{\_}not{\_}ack,review},
pages = {10.1016/S1473--3099(24)00144--0},
publisher = {Elsevier Ltd},
title = {{The epidemiology, transmission, diagnosis, and management of drug-resistant tuberculosis—lessons from the South African experience}},
year = {2024}
}

Drug-resistant tuberculosis (DR-TB) threatens to derail tuberculosis control efforts, particularly in Africa where the disease remains out of control. The dogma that DR-TB epidemics are fueled by unchecked rates of acquired resistance in inadequately treated or non-adherent individuals is no longer valid in most high DR-TB burden settings, where community transmission is now widespread. A large burden of DR-TB in Africa remains undiagnosed due to inadequate access to diagnostic tools that simultaneously detect tuberculosis and screen for resistance. Furthermore, acquisition of drug resistance to new and repurposed drugs, for which diagnostic solutions are not yet available, presents a major challenge for the implementation of novel, all-oral, shortened (6–9 months) treatment. Structural challenges including poverty, stigma, and social distress disrupt engagement in care, promote poor treatment outcomes, and reduce the quality of life for people with DR-TB. We reflect on the lessons learnt from the South African experience in implementing state-of-the-art advances in diagnostic solutions, deploying recent innovations in pharmacotherapeutic approaches for rapid cure, understanding local transmission dynamics and implementing interventions to curtail DR-TB transmission, and in mitigating the catastrophic socioeconomic costs of DR-TB. We also highlight globally relevant and locally responsive research priorities for achieving DR-TB control in South Africa. © 2024 Elsevier Ltd

@article{Hamada2024a,
abstract = {Objective: To investigate the prevalence of non-communicable diseases among household contacts of people with tuberculosis. Methods: We conducted a systematic review and individual participant data meta-analysis. We searched Medline, Embase and the Global Index Medicus from inception to 16 May 2023. We included studies that assessed for at least one non-communicable disease among household contacts of people with clinical tuberculosis. We estimated the non-communicable disease prevalence through mixed effects logistic regression for studies providing individual participant data, and compared it with estimates from aggregated data meta-analyses. Furthermore, we compared age and sex-standardised non-communicable disease prevalence with national-level estimates standardised for age and sex. Results: We identified 39 eligible studies, of which 14 provided individual participant data (29,194 contacts). Of the remaining 25 studies, 18 studies reported aggregated data suitable for aggregated data meta-analysis. In individual participant data analysis, the pooled prevalence of diabetes in studies that undertook biochemical testing was 8.8{\%} (95{\%} confidence interval [CI], 5.1{\%}–14.9{\%}, four studies). Age-and sex-standardised prevalence was higher in two studies (10.4{\%} vs. 6.9{\%} and 11.5{\%} vs. 8.4{\%}) than the corresponding national estimates and similar in two studies. Prevalence of diabetes mellitus based on self-report or medical records was 3.4{\%} (95{\%} CI 2.6{\%}–4.6{\%}, 14 studies). Prevalence did not significantly differ compared to estimates from aggregated data meta-analysis. There were limited data for other non-communicable diseases. Conclusion: The prevalence of diabetes mellitus among household contacts was high while that of known diabetes was substantially lower, suggesting the underdiagnosis. tuberculosis household contact investigation offers opportunities to deliver multifaceted interventions to identify tuberculosis infection and disease, screen for non-communicable diseases and address shared risk factors.},
author = {Hamada, Yohhei and Quartagno, Matteo and Malik, Farihah and Ntshamane, Keolebogile and Tisler, Anna and Gaikwad, Sanjay and Acuna-Villaorduna, Carlos and Bhavani, Perumal Kannabiran and Alisjahbana, Bachti and Ronacher, Katharina and Apriani, Lika and Becerra, Mercedes and Chu, Alexander L. and Creswell, Jacob and Diaz, Gustavo and Ferro, Beatriz E. and Galea, Jerome T. and Grandjean, Louis and Grewal, Harleen M.S. and Gupta, Amita and Jones-L{\'{o}}pez, Edward C. and Kleynhans, L{\'{e}}anie and Lecca, Leonid and MacPherson, Peter and Murray, Megan and Mar{\'{i}}n, Diana and Restrepo, Blanca I. and Shivakumar, Shri Vijay Bala Yogendra and Shu, Eileen and Sivakumaran, Dhanasekaran and Vo, Luan Nguyen Quang and Webb, Emily L. and Copas, Andrew and Abubakar, Ibrahim and Rangaka, Molebogeng X.},
doi = {10.1111/TMI.14038},
file = {:C$\backslash$:/Users/01462563/OneDrive - University of Cape Town/Documents/CIDRI-Africa papers and outputs/Hamada et al - 2024 - Prevalence of non‐communicable diseases among household contacts of people with.pdf:pdf},
issn = {1365-3156},
journal = {Tropical Medicine {\&} International Health},
keywords = {OA,chronic diseases,diabetes mellitus,fund{\_}not{\_}ack,review,systematic review,tuberculosis},
mendeley-tags = {OA,fund{\_}not{\_}ack,review},
pmid = {39073229},
publisher = {John Wiley {\&} Sons, Ltd},
title = {{Prevalence of non-communicable diseases among household contacts of people with tuberculosis: A systematic review and individual participant data meta-analysis}},
url = {https://onlinelibrary.wiley.com/doi/full/10.1111/tmi.14038 https://onlinelibrary.wiley.com/doi/abs/10.1111/tmi.14038 https://onlinelibrary.wiley.com/doi/10.1111/tmi.14038},
volume = {30},
year = {2024}
}

Objective: To investigate the prevalence of non-communicable diseases among household contacts of people with tuberculosis. Methods: We conducted a systematic review and individual participant data meta-analysis. We searched Medline, Embase and the Global Index Medicus from inception to 16 May 2023. We included studies that assessed for at least one non-communicable disease among household contacts of people with clinical tuberculosis. We estimated the non-communicable disease prevalence through mixed effects logistic regression for studies providing individual participant data, and compared it with estimates from aggregated data meta-analyses. Furthermore, we compared age and sex-standardised non-communicable disease prevalence with national-level estimates standardised for age and sex. Results: We identified 39 eligible studies, of which 14 provided individual participant data (29,194 contacts). Of the remaining 25 studies, 18 studies reported aggregated data suitable for aggregated data meta-analysis. In individual participant data analysis, the pooled prevalence of diabetes in studies that undertook biochemical testing was 8.8% (95% confidence interval [CI], 5.1%–14.9%, four studies). Age-and sex-standardised prevalence was higher in two studies (10.4% vs. 6.9% and 11.5% vs. 8.4%) than the corresponding national estimates and similar in two studies. Prevalence of diabetes mellitus based on self-report or medical records was 3.4% (95% CI 2.6%–4.6%, 14 studies). Prevalence did not significantly differ compared to estimates from aggregated data meta-analysis. There were limited data for other non-communicable diseases. Conclusion: The prevalence of diabetes mellitus among household contacts was high while that of known diabetes was substantially lower, suggesting the underdiagnosis. tuberculosis household contact investigation offers opportunities to deliver multifaceted interventions to identify tuberculosis infection and disease, screen for non-communicable diseases and address shared risk factors.

@article{Osei-Yeboah2024,
abstract = {In South Africa, PLHIV are eligible for free ART and kidney function screening. Serum creatinine (SCr) laboratory test data from the National Health Laboratory Service are collated at the Provincial Health Data Centre and linked with other routine health data. We analysed SCr and estimated glomerular filtration rate (eGFR) results for PLHIV and HIV-negative healthcare clients aged 18–80 years accessing healthcare in Khayelitsha, South Africa and comorbidity profiles at SCr and eGFR testing. 45 640 individuals aged 18–80 years with at least one renal test accessed Khayelitsha public health facilities in 2016/2017. 22 961 (50.3{\%}) were PLHIV. Median age at first SCr and eGFR test for PLHIV was 33yrs (IQR: 27,41) to 36yrs (IQR: 30,43) compared to 49yrs (IQR: 37,57) and 52yrs (IQR: 44,59) for those without HIV. PLHIV first median SCr results were 66 (IQR: 55,78) $\mu$mol/l compared to 69 (IQR: 58,82) $\mu$mol/l for HIV-negative individuals. Hypertension, diabetes, and CKD at testing were more common in HIV-negative people than PLHIV. HIV, diabetes and tuberculosis (TB) are associated with higher eGFR results; whilst hypertension, being male and older are associated with lower eGFR results. These data reflect testing practices in the Western Cape: younger people without HIV have generally worse kidney function test results; younger PLHIV have generally good test results, and older people with/without HIV have generally similar test results, reflecting regular screening for kidney function in asymptomatic PLHIV whereas young HIV-negative people are tested only when presenting with renal symptoms. Our analysis suggests we cannot infer the future healthcare requirements of younger PLHIV based on the current ageing population, due to changing ART availability for different generations of PLHIV. Instead, routine health data may be used in an agile way to assess ongoing healthcare requirements of ageing PLHIV, and to reflect implementation of treatment guidelines.},
author = {Osei-Yeboah, Richard and Ngwenya, Olina and Tiffin, Nicki},
doi = {10.1371/JOURNAL.PGPH.0002526},
editor = {Robinson, Julia},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Osei et al. - 2024 - Kidney function in healthcare clients in Khayelitsha, South Africa Routine laboratory testing and results reflect d.pdf:pdf},
isbn = {1111111111},
issn = {2767-3375},
journal = {PLOS Global Public Health},
keywords = {Age groups,Chronic kidney disease,Diabetes mellitus,Glomerular filtration rate,HIV,Health care facilities,Kidneys,OA,Virus testing,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {may},
number = {5},
pages = {e0002526},
publisher = {Public Library of Science},
title = {{Kidney function in healthcare clients in Khayelitsha, South Africa: routine laboratory testing and results reflect distinct healthcare experiences by age for healthcare clients with and without HIV}},
url = {https://journals.plos.org/globalpublichealth/article?id=10.1371/journal.pgph.0002526},
volume = {4},
year = {2024}
}

In South Africa, PLHIV are eligible for free ART and kidney function screening. Serum creatinine (SCr) laboratory test data from the National Health Laboratory Service are collated at the Provincial Health Data Centre and linked with other routine health data. We analysed SCr and estimated glomerular filtration rate (eGFR) results for PLHIV and HIV-negative healthcare clients aged 18–80 years accessing healthcare in Khayelitsha, South Africa and comorbidity profiles at SCr and eGFR testing. 45 640 individuals aged 18–80 years with at least one renal test accessed Khayelitsha public health facilities in 2016/2017. 22 961 (50.3%) were PLHIV. Median age at first SCr and eGFR test for PLHIV was 33yrs (IQR: 27,41) to 36yrs (IQR: 30,43) compared to 49yrs (IQR: 37,57) and 52yrs (IQR: 44,59) for those without HIV. PLHIV first median SCr results were 66 (IQR: 55,78) $μ$mol/l compared to 69 (IQR: 58,82) $μ$mol/l for HIV-negative individuals. Hypertension, diabetes, and CKD at testing were more common in HIV-negative people than PLHIV. HIV, diabetes and tuberculosis (TB) are associated with higher eGFR results; whilst hypertension, being male and older are associated with lower eGFR results. These data reflect testing practices in the Western Cape: younger people without HIV have generally worse kidney function test results; younger PLHIV have generally good test results, and older people with/without HIV have generally similar test results, reflecting regular screening for kidney function in asymptomatic PLHIV whereas young HIV-negative people are tested only when presenting with renal symptoms. Our analysis suggests we cannot infer the future healthcare requirements of younger PLHIV based on the current ageing population, due to changing ART availability for different generations of PLHIV. Instead, routine health data may be used in an agile way to assess ongoing healthcare requirements of ageing PLHIV, and to reflect implementation of treatment guidelines.

@article{Naaz2024,
abstract = {Formyl peptide receptors (FPR), part of the G-protein coupled receptor superfamily, are pivotal in directing phagocyte migration towards chemotactic signals from bacteria and host tissues. Although their roles in acute bacterial infections are well-documented, their involvement in immunity against tuberculosis (TB) remains unexplored. This study investigates the functions of Fpr1 and Fpr2 in defense against Mycobacterium tuberculosis (Mtb), the causative agent of TB. Elevated levels of Fpr1 and Fpr2 were found in the lungs of mice, rabbits and peripheral blood of humans infected with Mtb, suggesting a crucial role in the immune response. The effects of Fpr1 and Fpr2 deletion on bacterial load, lung damage, and cellular inflammation were assessed using a TB model of hypervirulent strain of Mtb from the W-Beijing lineage. While Fpr2 deletion showed no impact on disease outcome, Fpr1-deficient mice demonstrated improved bacterial control, especially by macrophages. Bone marrow-derived macrophages from these Fpr1-/- mice exhibited an enhanced ability to contain bacterial growth over time. Contrarily, treating genetically susceptible mice with Fpr1-specific inhibitors caused impaired early bacterial control, corresponding with increased bacterial persistence in necrotic neutrophils. Furthermore, ex vivo assays revealed that Fpr1-/- neutrophils were unable to restrain Mtb growth, indicating a differential function of Fpr1 among myeloid cells. These findings highlight the distinct and complex roles of Fpr1 in myeloid cell-mediated immunity against Mtb infection, underscoring the need for further research into these mechanisms for a better understanding of TB immunity.},
author = {Naaz, Tanvir Noor and Sankar, Poornima and Rousseau, Robert P and Saqib, Mohd and Parihar, Suraj P},
doi = {10.21203/RS.3.RS-4421561/V1},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Naaz et al. - 2024 - Differential requirement of Formyl Peptide Receptor 1 in macrophages and neutrophils in the host defense against My.pdf:pdf},
journal = {Research Square},
keywords = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {may},
pages = {10.21203/rs.3.rs--4421561/v1},
pmid = {38853986},
title = {{Differential requirement of Formyl Peptide Receptor 1 in macrophages and neutrophils in the host defense against Mycobacterium tuberculosis infection}},
url = {https://www.researchsquare.com https://www.researchsquare.com/article/rs-4421561/v1},
year = {2024}
}

Formyl peptide receptors (FPR), part of the G-protein coupled receptor superfamily, are pivotal in directing phagocyte migration towards chemotactic signals from bacteria and host tissues. Although their roles in acute bacterial infections are well-documented, their involvement in immunity against tuberculosis (TB) remains unexplored. This study investigates the functions of Fpr1 and Fpr2 in defense against Mycobacterium tuberculosis (Mtb), the causative agent of TB. Elevated levels of Fpr1 and Fpr2 were found in the lungs of mice, rabbits and peripheral blood of humans infected with Mtb, suggesting a crucial role in the immune response. The effects of Fpr1 and Fpr2 deletion on bacterial load, lung damage, and cellular inflammation were assessed using a TB model of hypervirulent strain of Mtb from the W-Beijing lineage. While Fpr2 deletion showed no impact on disease outcome, Fpr1-deficient mice demonstrated improved bacterial control, especially by macrophages. Bone marrow-derived macrophages from these Fpr1-/- mice exhibited an enhanced ability to contain bacterial growth over time. Contrarily, treating genetically susceptible mice with Fpr1-specific inhibitors caused impaired early bacterial control, corresponding with increased bacterial persistence in necrotic neutrophils. Furthermore, ex vivo assays revealed that Fpr1-/- neutrophils were unable to restrain Mtb growth, indicating a differential function of Fpr1 among myeloid cells. These findings highlight the distinct and complex roles of Fpr1 in myeloid cell-mediated immunity against Mtb infection, underscoring the need for further research into these mechanisms for a better understanding of TB immunity.

@article{Namale2024,
abstract = {Background HIV-associated tuberculosis (TB) contributes disproportionately to global tuberculosis mortality. Patients hospitalized at the time of the diagnosis of HIV-associated disseminated TB are typically severely ill and have a high mortality risk despite initiation of tuberculosis treatment. The objective of the study is to assess the safety and efficacy of both intensified TB treatment (high dose rifampicin plus levofloxacin) and immunomodulation with corticosteroids as interventions to reduce early mortality in hospitalised patients with HIV-associated disseminated TB. Methods This is a phase III randomised controlled superiority trial, evaluating two interventions in a 2x2 factorial design: 1) high dose rifampicin (35mg/kg/day) plus levofloxacin added to standard TB treatment for the first 14 days versus standard tuberculosis treatment; and 2) adjunctive corticosteroids (prednisone 1.5 mg/kg/day) versus identical placebo for the first 14 days of TB treatment. The study population is HIV-positive patients diagnosed with disseminated TB (defined as being positive by at least one of the following assays: urine Alere LAM, urine Xpert MTB/RIF Ultra, or blood Xpert MTB/RIF Ultra) during a hospital admission. The primary endpoint is all-cause mortality at 12 weeks comparing, first, patients receiving intensified TB treatment to standard of care and, second, patients receiving corticosteroids to those receiving placebo. Analysis of the primary endpoint will be by intention to treat. Secondary endpoints include all-cause mortality at 2 and 24 weeks. Safety and tolerability endpoints include hepatoxicity evaluations and corticosteroid-related adverse events. Discussion Disseminated TB is characterised by a high mycobacterial load and patients are often critically ill at presentation, with features of sepsis, which carries a high mortality risk. Interventions that reduce this high mycobacterial load or modulate associated immune activation could potentially reduce mortality. If found to be safe and effective, the interventions being evaluated in this trial could be easily implemented in clinical practice.},
author = {Namale, Phiona E and Boloko, Linda and Vermeulen, Marcia and Haigh, Kate A and Bagula, Fortuna and Maseko, Alexis and Sossen, Bianca and Lee-Jones, Scott and Msomi, Yoliswa and Mclleron, Helen and Crede, Thomas and Szymanski, Patryk and Naude, Jonathan and Ebrahim, Sakeena and Vallie, Yakoob and Moosa, Muhammed S and Bandeker, Ismail and Hoosain, Shakeel and Nicol, Mark P and Samodien, Nazlee and Centner, Chad M and Dowling, Wentzel and Denti, Paolo and Gumedze, Freedom and Little, Francesca and Parker, Arifa and Price, Brendon and Schietekat, Denzil and Simmons, Bryony and Hill, Andrew M and Wilkinson, Robert J and Oliphant, Ida and Hlungulu, Siphokazi and Apolisi, Ivy and Toleni, Monica and Asare, Zimkhitha and Mpalali, Mkanyiseli K and Boshoff, Erica and Prinsloo, Denise and Lakay, Francisco and Bekiswa, Abulele and Jackson, Amanda and Barnes, Ashleigh and Johnson, Ryan and Wasserman, Sean and Maartens, Gary and Barr, David A and Schutz, Charlotte and Meintjes, Graeme A},
doi = {10.21203/RS.3.RS-3869003/V1},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Namale et al. - 2024 - Testing Novel Strategies for Patients Hospitalized with HIV-associated Disseminated Tuberculosis (NewStrat-TB) Pr.pdf:pdf},
journal = {Research Square},
keywords = {OA,fund{\_}ack,protocol},
mendeley-tags = {OA,fund{\_}ack,protocol},
month = {apr},
pages = {https://doi.org/10.21203/rs.3.rs--3869003/v1},
title = {{Testing Novel Strategies for Patients Hospitalized with HIV-associated Disseminated Tuberculosis (NewStrat-TB): protocol for a randomised controlled trial}},
url = {https://www.researchsquare.com https://www.researchsquare.com/article/rs-3869003/v1},
year = {2024}
}

Background HIV-associated tuberculosis (TB) contributes disproportionately to global tuberculosis mortality. Patients hospitalized at the time of the diagnosis of HIV-associated disseminated TB are typically severely ill and have a high mortality risk despite initiation of tuberculosis treatment. The objective of the study is to assess the safety and efficacy of both intensified TB treatment (high dose rifampicin plus levofloxacin) and immunomodulation with corticosteroids as interventions to reduce early mortality in hospitalised patients with HIV-associated disseminated TB. Methods This is a phase III randomised controlled superiority trial, evaluating two interventions in a 2x2 factorial design: 1) high dose rifampicin (35mg/kg/day) plus levofloxacin added to standard TB treatment for the first 14 days versus standard tuberculosis treatment; and 2) adjunctive corticosteroids (prednisone 1.5 mg/kg/day) versus identical placebo for the first 14 days of TB treatment. The study population is HIV-positive patients diagnosed with disseminated TB (defined as being positive by at least one of the following assays: urine Alere LAM, urine Xpert MTB/RIF Ultra, or blood Xpert MTB/RIF Ultra) during a hospital admission. The primary endpoint is all-cause mortality at 12 weeks comparing, first, patients receiving intensified TB treatment to standard of care and, second, patients receiving corticosteroids to those receiving placebo. Analysis of the primary endpoint will be by intention to treat. Secondary endpoints include all-cause mortality at 2 and 24 weeks. Safety and tolerability endpoints include hepatoxicity evaluations and corticosteroid-related adverse events. Discussion Disseminated TB is characterised by a high mycobacterial load and patients are often critically ill at presentation, with features of sepsis, which carries a high mortality risk. Interventions that reduce this high mycobacterial load or modulate associated immune activation could potentially reduce mortality. If found to be safe and effective, the interventions being evaluated in this trial could be easily implemented in clinical practice.

@article{Benede2024,
abstract = {SARS-CoV-2 infection in children typically results in asymptomatic or mild disease. There is a paucity of studies on antiviral immunity in African children. We investigated SARS-CoV-2-specific T cell responses in 71 unvaccinated asymptomatic South African children who were seropositive or seronegative for SARS-CoV-2. SARS-CoV-2-specific CD4+ T cell responses were detectable in 83{\%} of seropositive and 60{\%} of seronegative children. Although the magnitude of the CD4+ T cell response did not differ significantly between the two groups, their functional profiles were distinct, with SARS-CoV-2 seropositive children exhibiting a higher proportion of polyfunctional T cells compared to their seronegative counterparts. The frequency of SARS-CoV-2-specific CD4+ T cells in seronegative children was associated with the endemic human coronavirus (HCoV) HKU1 IgG response. Overall, the presence of SARS-CoV-2-responding T cells in seronegative children may result from cross-reactivity to endemic coronaviruses and could contribute to the relative protection from disease observed in SARS-CoV-2-infected children.},
author = {Benede, Ntombi and Tincho, Marius B and Walters, Avril and Subbiah, Vennesa and Ngomti, Amkele and Baguma, Richard and Butters, Claire and Hahnle, Lina and Mennen, Mathilda and Skelem, Sango and Adriaanse, Marguerite and Facey-Thomas, Heidi and Scott, Christiaan and Day, Jonathan and Spracklen, Timothy F and van Graan, Strauss and Balla, Sashkia R and Moyo-Gwete, Thandeka and Moore, Penny L and MacGinty, Rae and Botha, Maresa and Workman, Lesley and Johnson, Marina and Goldblatt, David and Zar, Heather J and Ntusi, Ntobeko A B and Z{\"{u}}hlke, Liesl and Webb, Kate and Riou, Catherine and Burgers, Wendy A and Keeton, Roanne S},
doi = {10.1016/J.ISCI.2023.108728},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Benede et al. - 2024 - Distinct T cell polyfunctional profile in SARS-CoV-2 seronegative children associated with endemic human coronavi.pdf:pdf},
issn = {2589-0042},
journal = {iScience},
keywords = {OA,OA{\_}PMC,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {jan},
number = {1},
pages = {108728},
pmid = {38235336},
publisher = {Elsevier},
title = {{Distinct T cell polyfunctional profile in SARS-CoV-2 seronegative children associated with endemic human coronavirus cross-reactivity}},
volume = {27},
year = {2024}
}

SARS-CoV-2 infection in children typically results in asymptomatic or mild disease. There is a paucity of studies on antiviral immunity in African children. We investigated SARS-CoV-2-specific T cell responses in 71 unvaccinated asymptomatic South African children who were seropositive or seronegative for SARS-CoV-2. SARS-CoV-2-specific CD4+ T cell responses were detectable in 83% of seropositive and 60% of seronegative children. Although the magnitude of the CD4+ T cell response did not differ significantly between the two groups, their functional profiles were distinct, with SARS-CoV-2 seropositive children exhibiting a higher proportion of polyfunctional T cells compared to their seronegative counterparts. The frequency of SARS-CoV-2-specific CD4+ T cells in seronegative children was associated with the endemic human coronavirus (HCoV) HKU1 IgG response. Overall, the presence of SARS-CoV-2-responding T cells in seronegative children may result from cross-reactivity to endemic coronaviruses and could contribute to the relative protection from disease observed in SARS-CoV-2-infected children.

@article{Waalewijn2024,
abstract = {We characterised population pharmacokinetics in 42 African children receiving once-daily 25 mg (14-{\textless}20 kg) or 50 mg ({\textgreater}20 kg) dolutegravir. Co-administration with emtricitabine and tenofovir alafenamide reduced dolutegravir bioavailability by 19.6{\%} (95{\%}CI: 8.13-30.8{\%}) compared to zidovudine or abacavir with lamivudine. Nevertheless, concentrations remained above efficacy targets, confirming current dosing recommendations.},
author = {Waalewijn, Hylke and Wasmann, Roeland E and Bamford, Alasdair and Gibb, Diana and McIlleron, Helen and Colbers, Angela and Burger, David and Denti, Paolo and Chapas-, The and Team, Trial},
doi = {10.1093/JPIDS/PIAE076},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Waalewijn et al. - 2024 - Population pharmacokinetics of Dolutegravir in African Children results from the CHAPAS-4 trial.pdf:pdf},
issn = {2048-7207},
journal = {Journal of the Pediatric Infectious Diseases Society},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jul},
pmid = {39066509},
title = {{Population pharmacokinetics of Dolutegravir in African Children: results from the CHAPAS-4 trial}},
url = {https://dx.doi.org/10.1093/jpids/piae076},
year = {2024}
}

We characterised population pharmacokinetics in 42 African children receiving once-daily 25 mg (14-\textless20 kg) or 50 mg (\textgreater20 kg) dolutegravir. Co-administration with emtricitabine and tenofovir alafenamide reduced dolutegravir bioavailability by 19.6% (95%CI: 8.13-30.8%) compared to zidovudine or abacavir with lamivudine. Nevertheless, concentrations remained above efficacy targets, confirming current dosing recommendations.

@article{Hamada2024,
abstract = {Tuberculosis (TB) and non-communicable diseases (NCD) share predisposing risk factors. TB-associated NCD might cluster within households affected with TB requiring shared prevention and care strategies. We conducted an individual participant data meta-analysis of national TB prevalence surveys to determine whether NCD cluster in members of households with TB. We identified eligible surveys that reported at least one NCD or NCD risk factor through the archive maintained by the World Health Organization and searching in Medline and Embase from 1 January 2000 to 10 August 2021, which was updated on 23 March 2023. We compared the prevalence of NCD and their risk factors between people who do not have TB living in households with at least one person with TB (members of households with TB), and members of households without TB. We included 16 surveys (n = 740,815) from Asia and Africa. In a multivariable model adjusted for age and gender, the odds of smoking was higher among members of households with TB (adjusted odds ratio (aOR) 1.23; 95{\%} CI: 1.11–1.38), compared with members of households without TB. The analysis did not find a significant difference in the prevalence of alcohol drinking, diabetes, hypertension, or BMI between members of households with and without TB. Studies evaluating household-wide interventions for smoking to reduce its dual impact on TB and NCD may be warranted. Systematically screening for NCD using objective diagnostic methods is needed to understand the actual burden of NCD and inform comprehensive interventions.},
author = {Hamada, Yohhei and Quartagno, Matteo and Law, Irwin and Malik, Farihah and Bonsu, Frank Adae and Adetifa, Ifedayo M O and Adusi-Poku, Yaw and D'Alessandro, Umberto and Bashorun, Adedapo Olufemi and Begum, Vikarunnessa and Lolong, Dina Bisara and Boldoo, Tsolmon and Dlamini, Themba and Donkor, Simon and Dwihardiani, Bintari and Egwaga, Saidi and Farid, Muhammad N and Garfin, Anna Marie Celina G and Gaviola, Donna Mae G and Husain, Mohammad Mushtuq and Ismail, Farzana and Kaggwa, Mugagga and Kamara, Deus V and Kasozi, Samuel and Kaswaswa, Kruger and Kirenga, Bruce and Klinkenberg, Eveline and Kondo, Zuweina and Lawanson, Adebola and Macheque, David and Manhi{\c{c}}a, Ivan and Maama-Maime, Llang Bridget and Mfinanga, Sayoki and Moyo, Sizulu and Mpunga, James and Mthiyane, Thuli and Mustikawati, Dyah Erti and Mvusi, Lindiwe and Nguyen, Hoa Binh and Nguyen, Hai Viet and Pangaribuan, Lamria and Patrobas, Philip and Rahman, Mahmudur and Rahman, Mahbubur and Rahman, Mohammed Sayeedur and Raleting, Thato and Riono, Pandu and Ruswa, Nunurai and Rutebemberwa, Elizeus and Rwabinumi, Mugabe Frank and Senkoro, Mbazi and Sharif, Ahmad Raihan and Sikhondze, Welile and Sismanidis, Charalambos and Sovd, Tugsdelger and Stavia, Turyahabwe and Sultana, Sabera and Suriani, Oster and Thomas, Albertina Martha and Tobing, Kristina and der Walt, Martie Van and Walusimbi, Simon and Zaman, Mohammad Mostafa and Floyd, Katherine and Copas, Andrew and Abubakar, Ibrahim and Rangaka, Molebogeng X},
doi = {10.1371/JOURNAL.PGPH.0002596},
editor = {Banik, Palash Chandra},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Hamada et al. - 2024 - Tobacco smoking clusters in households affected by tuberculosis in an individual participant data meta-analysis o.pdf:pdf},
isbn = {1111111111},
issn = {2767-3375},
journal = {PLOS Global Public Health},
keywords = {Alcohol consumption,Diabetes mellitus,Medical risk factors,Metaanalysis,Noncommunicable diseases,OA,OA{\_}PMC,Systematic reviews,Tuberculosis,Tuberculosis diagnosis and management,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {feb},
number = {2},
pages = {e0002596},
pmid = {38422092},
publisher = {Public Library of Science},
title = {{Tobacco smoking clusters in households affected by tuberculosis in an individual participant data meta-analysis of national tuberculosis prevalence surveys: Time for household-wide interventions?}},
url = {https://journals.plos.org/globalpublichealth/article?id=10.1371/journal.pgph.0002596},
volume = {4},
year = {2024}
}

Tuberculosis (TB) and non-communicable diseases (NCD) share predisposing risk factors. TB-associated NCD might cluster within households affected with TB requiring shared prevention and care strategies. We conducted an individual participant data meta-analysis of national TB prevalence surveys to determine whether NCD cluster in members of households with TB. We identified eligible surveys that reported at least one NCD or NCD risk factor through the archive maintained by the World Health Organization and searching in Medline and Embase from 1 January 2000 to 10 August 2021, which was updated on 23 March 2023. We compared the prevalence of NCD and their risk factors between people who do not have TB living in households with at least one person with TB (members of households with TB), and members of households without TB. We included 16 surveys (n = 740,815) from Asia and Africa. In a multivariable model adjusted for age and gender, the odds of smoking was higher among members of households with TB (adjusted odds ratio (aOR) 1.23; 95% CI: 1.11–1.38), compared with members of households without TB. The analysis did not find a significant difference in the prevalence of alcohol drinking, diabetes, hypertension, or BMI between members of households with and without TB. Studies evaluating household-wide interventions for smoking to reduce its dual impact on TB and NCD may be warranted. Systematically screening for NCD using objective diagnostic methods is needed to understand the actual burden of NCD and inform comprehensive interventions.

@article{Patterson2024,
abstract = {Potential Mycobacterium tuberculosis ( Mtb ) transmission during different pulmonary tuberculosis (TB) disease states is poorly understood. We quantified viable aerosolized Mtb from TB clinic attendees following diagnosis and through six months' follow-up thereafter. Presumptive TB patients (n=102) were classified by laboratory, radiological, and clinical features into Group A: Sputum-Xpert Ultra-positive TB (n=52), Group B: Sputum-Xpert Ultra-negative TB (n=20), or Group C: TB undiagnosed (n=30). All groups were assessed for Mtb bioaerosol release at baseline, and subsequently at 2 wk, 2 mo, and 6 mo. Groups A and B were notified to the national TB program and received standard anti-TB chemotherapy; Mtb was isolated from 92{\%} and 90{\%} at presentation, 87{\%} and 74{\%} at 2 wk, 54{\%} and 44{\%} at 2 mo and 32{\%} and 20{\%} at 6 mo, respectively. Surprisingly, similar numbers were detected in Group C not initiating TB treatment: 93{\%}, 70{\%}, 48{\%} and 22{\%} at the same timepoints. A temporal association was observed between Mtb bioaerosol release and TB symptoms in all three groups. Persistence of Mtb bioaerosol positivity was observed in {\~{}}30{\%} of participants irrespective of TB chemotherapy. Captured Mtb bacilli were predominantly acid-fast stain-negative and poorly culturable; however, three bioaerosol samples yielded sufficient biomass following culture for whole-genome sequencing, revealing two different Mtb lineages. Detection of viable aerosolized Mtb in clinic attendees, independent of TB diagnosis, suggests that unidentified Mtb transmitters might contribute a significant attributable proportion of community exposure. Additional longitudinal studies with sputum culture-positive and -negative control participants are required to investigate this possibility.},
author = {Patterson, Benjamin and Dinkele, Ryan and Gessner, Sophia and Koch, Anastasia and Hoosen, Zeenat and January, Vanessa and Leonard, Bryan and McKerry, Andrea and Seldon, Ronnett and Vazi, Andiswa and Hermans, Sabine and Cobelens, Frank and Warner, Digby F and Wood, Robin},
doi = {10.1073/PNAS.2314813121/SUPPL_FILE/PNAS.2314813121.SAPP.PDF},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Patterson et al. - 2024 - Aerosolization of viable Mycobacterium tuberculosis bacilli by tuberculosis clinic attendees independent of sp.pdf:pdf},
issn = {0027-8424},
journal = {Proceedings of the National Academy of Sciences},
keywords = {OA,aerosol sampling,fund{\_}not{\_}ack,original,subclinical,tuberculosis},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {mar},
number = {12},
pages = {e2314813121},
pmid = {38470917},
publisher = {Proceedings of the National Academy of Sciences},
title = {{Aerosolization of viable \textit{Mycobacterium tuberculosis} bacilli by tuberculosis clinic attendees independent of sputum-Xpert Ultra status}},
url = {https://www.pnas.org/doi/abs/10.1073/pnas.2314813121},
volume = {121},
year = {2024}
}

Potential Mycobacterium tuberculosis ( Mtb ) transmission during different pulmonary tuberculosis (TB) disease states is poorly understood. We quantified viable aerosolized Mtb from TB clinic attendees following diagnosis and through six months' follow-up thereafter. Presumptive TB patients (n=102) were classified by laboratory, radiological, and clinical features into Group A: Sputum-Xpert Ultra-positive TB (n=52), Group B: Sputum-Xpert Ultra-negative TB (n=20), or Group C: TB undiagnosed (n=30). All groups were assessed for Mtb bioaerosol release at baseline, and subsequently at 2 wk, 2 mo, and 6 mo. Groups A and B were notified to the national TB program and received standard anti-TB chemotherapy; Mtb was isolated from 92% and 90% at presentation, 87% and 74% at 2 wk, 54% and 44% at 2 mo and 32% and 20% at 6 mo, respectively. Surprisingly, similar numbers were detected in Group C not initiating TB treatment: 93%, 70%, 48% and 22% at the same timepoints. A temporal association was observed between Mtb bioaerosol release and TB symptoms in all three groups. Persistence of Mtb bioaerosol positivity was observed in \ 30% of participants irrespective of TB chemotherapy. Captured Mtb bacilli were predominantly acid-fast stain-negative and poorly culturable; however, three bioaerosol samples yielded sufficient biomass following culture for whole-genome sequencing, revealing two different Mtb lineages. Detection of viable aerosolized Mtb in clinic attendees, independent of TB diagnosis, suggests that unidentified Mtb transmitters might contribute a significant attributable proportion of community exposure. Additional longitudinal studies with sputum culture-positive and -negative control participants are required to investigate this possibility.

@article{Davies2024,
abstract = {Antibody features vary with tuberculosis (TB) disease state. Whether clinical variables, such as age or sex, influence associations between Mycobacterium tuberculosis-specific antibody responses and disease state is not well explored. Here we profiled Mycobacterium tuberculosis-specific antibody responses in 140 TB-exposed South African individuals from the Adolescent Cohort Study. We identified distinct response features in individuals progressing to active TB from non-progressing, matched controls. A multivariate antibody score differentially associated with progression (SeroScore) identified progressors up to 2 years before TB diagnosis, earlier than that achieved with the RISK6 transcriptional signature of progression. We validated these antibody response features in the Grand Challenges 6–74 cohort. Both the SeroScore and RISK6 correlated better with risk of TB progression in adolescents compared with adults, and in males compared with females. This suggests that age and sex are important, underappreciated modifiers of antibody responses associated with TB progression. Analysis of Mycobacterium tuberculosis-specific antibody responses in previously exposed South African cohorts reveals that profile features associated with progression to active tuberculosis are affected by age and sex.},
author = {Davies, Leela R L and Wang, Chuangqi and Steigler, Pia and Bowman, Kathryn A and Fischinger, Stephanie and Hatherill, Mark and Fisher, Michelle and Mbandi, Stanley Kimbung and Rodo, Miguel and Ottenhoff, Tom H M and Dockrell, Hazel M and Sutherland, Jayne S and Mayanja-Kizza, Harriet and Boom, W Henry and Walzl, Gerhard and Kaufmann, Stefan H E and Nemes, Elisa and Scriba, Thomas J and Lauffenburger, Douglas and Alter, Galit and Fortune, Sarah M},
doi = {10.1038/s41564-024-01678-x},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Davies et al. - 2024 - Age and sex influence antibody profiles associated with tuberculosis progression.pdf:pdf},
issn = {2058-5276},
journal = {Nature Microbiology},
keywords = {Antibodies,OA,Tuberculosis,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {apr},
pages = {https://doi.org/10.1038/s41564--024--01678--x},
pmid = {38658786},
publisher = {Nature Publishing Group},
title = {{Age and sex influence antibody profiles associated with tuberculosis progression}},
url = {https://www.nature.com/articles/s41564-024-01678-x},
year = {2024}
}

Antibody features vary with tuberculosis (TB) disease state. Whether clinical variables, such as age or sex, influence associations between Mycobacterium tuberculosis-specific antibody responses and disease state is not well explored. Here we profiled Mycobacterium tuberculosis-specific antibody responses in 140 TB-exposed South African individuals from the Adolescent Cohort Study. We identified distinct response features in individuals progressing to active TB from non-progressing, matched controls. A multivariate antibody score differentially associated with progression (SeroScore) identified progressors up to 2 years before TB diagnosis, earlier than that achieved with the RISK6 transcriptional signature of progression. We validated these antibody response features in the Grand Challenges 6–74 cohort. Both the SeroScore and RISK6 correlated better with risk of TB progression in adolescents compared with adults, and in males compared with females. This suggests that age and sex are important, underappreciated modifiers of antibody responses associated with TB progression. Analysis of Mycobacterium tuberculosis-specific antibody responses in previously exposed South African cohorts reveals that profile features associated with progression to active tuberculosis are affected by age and sex.

@article{Dinkele2024a,
abstract = {Pioneering studies linking symptomatic disease and cough-mediated release of Mycobacterium tuberculosis (Mtb) established the infectious origin of tuberculosis (TB), simultaneously informing the pervasive notion that pathology is a prerequisite for Mtb transmission. Our prior work has challenged this assumption: by sampling TB clinic attendees, we detected equivalent release of Mtb-containing bioaerosols by confirmed TB patients and individuals not receiving a TB diagnosis, and we demonstrated a time-dependent reduction in Mtb bioaerosol positivity during six-months' follow-up, irrespective of anti-TB chemotherapy. Now, by extending bioaerosol sampling to a randomly selected community cohort, we show that Mtb release is common in a TB-endemic setting: of 89 participants, 79.8{\%} (71/89) produced Mtb bioaerosols independently of QuantiFERON-TB Gold status, a standard test for Mtb infection; moreover, during two-months' longitudinal sampling, only 2{\%} (1/50) were serially Mtb bioaerosol negative. These results necessitate a reframing of the prevailing paradigm of Mtb transmission and infection, and may explain the current inability to elucidate Mtb transmission networks in TB-endemic regions.},
author = {Dinkele, Ryan and Gessner, Sophia and Patterson, Benjamin and McKerry, Andrea and Hoosen, Zeenat and Vazi, Andiswa and Seldon, Ronnett and Koch, Anastasia and Warner, Digby F and Wood, Robin},
doi = {10.1101/2024.04.02.24305196},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Dinkele et al. - 2024 - Persistent Mycobacterium tuberculosis bioaerosol release in a tuberculosis-endemic setting.pdf:pdf},
journal = {medRxiv},
keywords = {MEDLINE,NCBI,NIH,NLM,National Center for Biotechnology Information,National Institutes of Health,National Library of Medicine,OA,OA{\_}PMC,PMC11023659,Preprint,PubMed Abstract,Robin Wood,Ryan Dinkele,Sophia Gessner,doi:10.1101/2024.04.02.24305196,fund{\_}not{\_}ack,original,pmid:38633787},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {apr},
pmid = {38633787},
publisher = {medRxiv},
title = {{Persistent \textit{Mycobacterium tuberculosis} bioaerosol release in a tuberculosis-endemic setting}},
url = {https://pubmed.ncbi.nlm.nih.gov/38633787/ http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC11023659},
year = {2024}
}

Pioneering studies linking symptomatic disease and cough-mediated release of Mycobacterium tuberculosis (Mtb) established the infectious origin of tuberculosis (TB), simultaneously informing the pervasive notion that pathology is a prerequisite for Mtb transmission. Our prior work has challenged this assumption: by sampling TB clinic attendees, we detected equivalent release of Mtb-containing bioaerosols by confirmed TB patients and individuals not receiving a TB diagnosis, and we demonstrated a time-dependent reduction in Mtb bioaerosol positivity during six-months' follow-up, irrespective of anti-TB chemotherapy. Now, by extending bioaerosol sampling to a randomly selected community cohort, we show that Mtb release is common in a TB-endemic setting: of 89 participants, 79.8% (71/89) produced Mtb bioaerosols independently of QuantiFERON-TB Gold status, a standard test for Mtb infection; moreover, during two-months' longitudinal sampling, only 2% (1/50) were serially Mtb bioaerosol negative. These results necessitate a reframing of the prevailing paradigm of Mtb transmission and infection, and may explain the current inability to elucidate Mtb transmission networks in TB-endemic regions.

@article{Nesamari2024,
abstract = {Ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has given rise to recombinant Omicron lineages that dominate globally (XBB.1), as well as the emergence of hypermutated variants (BA.2.86). In this context, durable and cross-reactive T cell immune memory is critical for continued protection against severe COVID-19. We examined T cell responses to SARS-CoV-2 approximately 1.5 years since Omicron first emerged. We describe sustained CD4+ and CD8+ spike-specific T cell memory responses in healthcare workers in South Africa (n = 39) who were vaccinated and experienced at least one SARS-CoV-2 infection. Spike-specific T cells are highly cross-reactive with all Omicron variants tested, including BA.2.86. Abundant nucleocapsid and membrane-specific T cells are detectable in most participants. The bulk of SARS-CoV-2-specific T cell responses have an early-differentiated phenotype, explaining their persistent nature. Overall, hybrid immunity leads to the accumulation of spike and non-spike T cells evident 3.5 years after the start of the pandemic, with preserved recognition of highly mutated SARS-CoV-2 variants.},
author = {Nesamari, Rofhiwa and Omondi, Millicent A and Baguma, Richard and H{\"{o}}ft, Maxine A and Ngomti, Amkele and Nkayi, Anathi A and Besethi, Asiphe S and Magugu, Siyabulela F J and Mosala, Paballo and Walters, Avril and Clark, Gesina M and Mennen, Mathilda and Skelem, Sango and Adriaanse, Marguerite and Grifoni, Alba and Sette, Alessandro and Keeton, Roanne S and Ntusi, Ntobeko A B and Riou, Catherine and Burgers, Wendy A},
doi = {10.1016/J.CHOM.2023.12.003},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Nesamari et al. - 2024 - Post-pandemic memory T cell response to SARS-CoV-2 is durable, broadly targeted, and cross-reactive to the hype.pdf:pdf},
issn = {1931-3128},
journal = {Cell Host {\&} Microbe},
keywords = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {feb},
number = {2},
pages = {162--169},
pmid = {38211583},
publisher = {Cell Press},
title = {{Post-pandemic memory T cell response to SARS-CoV-2 is durable, broadly targeted, and cross-reactive to the hypermutated BA.2.86 variant}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/38211583},
volume = {32},
year = {2024}
}

Ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has given rise to recombinant Omicron lineages that dominate globally (XBB.1), as well as the emergence of hypermutated variants (BA.2.86). In this context, durable and cross-reactive T cell immune memory is critical for continued protection against severe COVID-19. We examined T cell responses to SARS-CoV-2 approximately 1.5 years since Omicron first emerged. We describe sustained CD4+ and CD8+ spike-specific T cell memory responses in healthcare workers in South Africa (n = 39) who were vaccinated and experienced at least one SARS-CoV-2 infection. Spike-specific T cells are highly cross-reactive with all Omicron variants tested, including BA.2.86. Abundant nucleocapsid and membrane-specific T cells are detectable in most participants. The bulk of SARS-CoV-2-specific T cell responses have an early-differentiated phenotype, explaining their persistent nature. Overall, hybrid immunity leads to the accumulation of spike and non-spike T cells evident 3.5 years after the start of the pandemic, with preserved recognition of highly mutated SARS-CoV-2 variants.

@article{Namale2024a,
abstract = {HIV-associated tuberculosis (TB) contributes disproportionately to global tuberculosis mortality. Patients hospitalised at the time of the diagnosis of HIV-associated disseminated TB are typically severely ill and have a high mortality risk despite initiation of tuberculosis treatment. The objective of the study is to assess the safety and efficacy of both intensified TB treatment (high dose rifampicin plus levofloxacin) and immunomodulation with corticosteroids as interventions to reduce early mortality in hospitalised patients with HIV-associated disseminated TB. This is a phase III randomised controlled superiority trial, evaluating two interventions in a 2 × 2 factorial design: (1) high dose rifampicin (35 mg/kg/day) plus levofloxacin added to standard TB treatment for the first 14 days versus standard tuberculosis treatment and (2) adjunctive corticosteroids (prednisone 1.5 mg/kg/day) versus identical placebo for the first 14 days of TB treatment. The study population is HIV-positive patients diagnosed with disseminated TB (defined as being positive by at least one of the following assays: urine Alere LAM, urine Xpert MTB/RIF Ultra or blood Xpert MTB/RIF Ultra) during a hospital admission. The primary endpoint is all-cause mortality at 12 weeks comparing, first, patients receiving intensified TB treatment to standard of care and, second, patients receiving corticosteroids to those receiving placebo. Analysis of the primary endpoint will be by intention to treat. Secondary endpoints include all-cause mortality at 2 and 24 weeks. Safety and tolerability endpoints include hepatoxicity evaluations and corticosteroid-related adverse events. Disseminated TB is characterised by a high mycobacterial load and patients are often critically ill at presentation, with features of sepsis, which carries a high mortality risk. Interventions that reduce this high mycobacterial load or modulate associated immune activation could potentially reduce mortality. If found to be safe and effective, the interventions being evaluated in this trial could be easily implemented in clinical practice. ClinicalTrials.gov NCT04951986. Registered on 7 July 2021 https://clinicaltrials.gov/study/NCT04951986},
author = {Namale, Phiona E and Boloko, Linda and Vermeulen, Marcia and Haigh, Kate A and Bagula, Fortuna and Maseko, Alexis and Sossen, Bianca and Lee-Jones, Scott and Msomi, Yoliswa and McIlleron, Helen and Mnguni, Ayanda Trevor and Crede, Thomas and Szymanski, Patryk and Naude, Jonathan and Ebrahim, Sakeena and Vallie, Yakoob and Moosa, Muhammed Shiraz and Bandeker, Ismail and Hoosain, Shakeel and Nicol, Mark P. and Samodien, Nazlee and Centner, Chad and Dowling, Wentzel and Denti, Paolo and Gumedze, Freedom and Little, Francesca and Parker, Arifa and Price, Brendon and Schietekat, Denzil and Simmons, Bryony and Hill, Andrew and Wilkinson, Robert J and Oliphant, Ida and Hlungulu, Siphokazi and Apolisi, Ivy and Toleni, Monica and Asare, Zimkhitha and Mpalali, Mkanyiseli Kenneth and Boshoff, Erica and Prinsloo, Denise and Lakay, Francisco and Bekiswa, Abulele and Jackson, Amanda and Barnes, Ashleigh and Johnson, Ryan and Wasserman, Sean and Maartens, Gary and Barr, David and Schutz, Charlotte and Meintjes, Graeme A},
doi = {10.1186/S13063-024-08119-4},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Namale et al. - 2024 - Testing novel strategies for patients hospitalised with HIV-associated disseminated tuberculosis (NewStrat-TB) pr.pdf:pdf},
issn = {1745-6215},
journal = {Trials},
keywords = {Biomedicine,Health Sciences,Medicine,Medicine/Public Health,OA,OA{\_}PMC,Statistics for Life Sciences,fund{\_}ack,general,protocol},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,protocol},
month = {may},
number = {1},
pages = {311},
pmid = {38720383},
publisher = {BioMed Central},
title = {{Testing novel strategies for patients hospitalised with HIV-associated disseminated tuberculosis (NewStrat-TB): protocol for a randomised controlled trial}},
url = {https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-024-08119-4 http://creativecom-mons.org/publicdomain/zero/1.0/},
volume = {25},
year = {2024}
}

HIV-associated tuberculosis (TB) contributes disproportionately to global tuberculosis mortality. Patients hospitalised at the time of the diagnosis of HIV-associated disseminated TB are typically severely ill and have a high mortality risk despite initiation of tuberculosis treatment. The objective of the study is to assess the safety and efficacy of both intensified TB treatment (high dose rifampicin plus levofloxacin) and immunomodulation with corticosteroids as interventions to reduce early mortality in hospitalised patients with HIV-associated disseminated TB. This is a phase III randomised controlled superiority trial, evaluating two interventions in a 2 × 2 factorial design: (1) high dose rifampicin (35 mg/kg/day) plus levofloxacin added to standard TB treatment for the first 14 days versus standard tuberculosis treatment and (2) adjunctive corticosteroids (prednisone 1.5 mg/kg/day) versus identical placebo for the first 14 days of TB treatment. The study population is HIV-positive patients diagnosed with disseminated TB (defined as being positive by at least one of the following assays: urine Alere LAM, urine Xpert MTB/RIF Ultra or blood Xpert MTB/RIF Ultra) during a hospital admission. The primary endpoint is all-cause mortality at 12 weeks comparing, first, patients receiving intensified TB treatment to standard of care and, second, patients receiving corticosteroids to those receiving placebo. Analysis of the primary endpoint will be by intention to treat. Secondary endpoints include all-cause mortality at 2 and 24 weeks. Safety and tolerability endpoints include hepatoxicity evaluations and corticosteroid-related adverse events. Disseminated TB is characterised by a high mycobacterial load and patients are often critically ill at presentation, with features of sepsis, which carries a high mortality risk. Interventions that reduce this high mycobacterial load or modulate associated immune activation could potentially reduce mortality. If found to be safe and effective, the interventions being evaluated in this trial could be easily implemented in clinical practice. ClinicalTrials.gov NCT04951986. Registered on 7 July 2021 https://clinicaltrials.gov/study/NCT04951986

@article{Kassanjee2024,
abstract = {Background There are few data on the real-world effectiveness of COVID-19 vaccines and boosting in Africa, which experienced high levels of SARS-CoV-2 infection in a mostly vaccine-na{\"{i}}ve population, and has limited vaccine coverage and competing health service priorities. We assessed the association between vaccination and severe COVID-19 in the Western Cape, South Africa. Methods We performed an observational cohort study of {\textgreater}2 million adults during 2020-2022. We described SARS-CoV-2 testing, COVID-19 outcomes, and vaccine uptake over time. We used multivariable cox models to estimate the association of BNT162b2 and Ad26.COV2.S vaccination with COVID-19-related hospitalisation and death, adjusting for demographic characteristics, underlying health conditions, socioeconomic status proxies and healthcare utilisation. Results By end 2022, only 41{\%} of surviving adults had completed vaccination and 8{\%} a booster dose, despite several waves of severe COVID-19. Recent vaccination was associated with notable reductions in severe COVID-19 during distinct analysis periods dominated by Delta, Omicron BA.1/2 and BA.4/5 (sub)lineages: within 6 months of completing vaccination or boosting, vaccine effectiveness was 46-92{\%} for death (range across periods), 45-92{\%} for admission with severe disease or death, and 25-90{\%} for any admission or death. During the Omicron BA.4/5 wave, within 3 months of vaccination or boosting, BNT162b2 and Ad26.COV2.S were each 84{\%} effective against death (95{\%} CIs: 57-94 and 49-95, respectively). However, there were distinct reductions of VE at larger times post completing or boosting vaccination. Conclusions Continued emphasis on regular COVID-19 vaccination including boosting is important for those at high risk of severe COVID-19 even in settings with widespread infection-induced immunity. {\#}{\#}{\#} Competing Interest Statement MD reports grants from Viiv Healthcare, outside the submitted work. CC reports grants from Sanofi Pasteur, US Centers for Disease Control and Prevention (CDC), Wellcome Trust, South African Medical Research Council (SAMRC) and the Bill {\&} Melinda Gates Foundation. NW reports grants from the Bill and Melinda Gates Foundation and Sanofi. SW reports grants from US CDC and Bill and Melinda Gates Foundation. AvG reports grants from the World Health Organisation Regional Office for Africa (WHO-AFRO), US CDC, SAMRC, Fleming Fund, Africa Centres for Disease Control / African Society for Laboratory Medicine. AB reports grants from the US National Institutes for Health, Bill and Melinda Gates Foundation and the Wellcome Trust. {\#}{\#}{\#} Funding Statement This work was supported by funding from the Western Cape Government Department of Health and Wellness for the Western Cape Provincial Health Data Centre, the US National Institutes for Health [R01 HD080465, U01 AI069924], the Bill and Melinda Gates Foundation [1164272, 1191327], the United States Agency for International Development [72067418CA00023], the European Union [101045989], the Grand Challenges ICODA pilot initiative delivered by Health Data Research UK and funded by the Bill {\&} Melinda Gates and Minderoo Foundations [INV-017293], and the Wellcome Trust [203135/Z/16/Z, 222574]. The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of this report. The opinions, findings and conclusions expressed in this manuscript reflect those of the authors alone. {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Health Research Ethics Committee of the University of Cape Town gave ethical approval for this work (HREC REF 460/2020). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data are not publicly available due to privacy or ethical restrictions. The data that support the findings of this study can be requested from the Western Cape Provincial Health Data Centre (WCPHDC) [{\textless}https://www.westerncape.gov.za/general-publication/provincial-health-data-centre{\textgreater}]; restrictions apply to the availability of these data.},
author = {Kassanjee, Reshma and Davies, Mary-Ann and Heekes, Alexa and Mahomed, Hassan and Hawkridge, Anthony J and Wolmarans, Milani and Morden, Erna and Jacobs, Theuns and Cohen, Cheryl and Moultrie, Harry and Lessells, Richard J and Walt, Nicolette Van Der and Arendse, Juanita O and Goeiman, Hilary and Mudaly, Vanessa and Wolter, Nicole and Walaza, Sibongile and Jassat, Waasila and von Gottberg, Anne and Hannan, Patrick L and Rousseau, Petro and Feikin, Daniel and Cloete, Keith and Boulle, Andrew},
doi = {10.1101/2024.01.24.24301721},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Kassanjee et al. - 2024 - COVID-19 vaccine uptake and effectiveness by time since vaccination in the Western Cape province, South Africa.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {jan},
pages = {2024.01.24.24301721},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{COVID-19 vaccine uptake and effectiveness by time since vaccination in the Western Cape province, South Africa: an observational cohort study during 2020-2022}},
url = {https://www.medrxiv.org/content/10.1101/2024.01.24.24301721v1 https://www.medrxiv.org/content/10.1101/2024.01.24.24301721v1.abstract},
volume = {15},
year = {2024}
}

Background There are few data on the real-world effectiveness of COVID-19 vaccines and boosting in Africa, which experienced high levels of SARS-CoV-2 infection in a mostly vaccine-naïve population, and has limited vaccine coverage and competing health service priorities. We assessed the association between vaccination and severe COVID-19 in the Western Cape, South Africa. Methods We performed an observational cohort study of \textgreater2 million adults during 2020-2022. We described SARS-CoV-2 testing, COVID-19 outcomes, and vaccine uptake over time. We used multivariable cox models to estimate the association of BNT162b2 and Ad26.COV2.S vaccination with COVID-19-related hospitalisation and death, adjusting for demographic characteristics, underlying health conditions, socioeconomic status proxies and healthcare utilisation. Results By end 2022, only 41% of surviving adults had completed vaccination and 8% a booster dose, despite several waves of severe COVID-19. Recent vaccination was associated with notable reductions in severe COVID-19 during distinct analysis periods dominated by Delta, Omicron BA.1/2 and BA.4/5 (sub)lineages: within 6 months of completing vaccination or boosting, vaccine effectiveness was 46-92% for death (range across periods), 45-92% for admission with severe disease or death, and 25-90% for any admission or death. During the Omicron BA.4/5 wave, within 3 months of vaccination or boosting, BNT162b2 and Ad26.COV2.S were each 84% effective against death (95% CIs: 57-94 and 49-95, respectively). However, there were distinct reductions of VE at larger times post completing or boosting vaccination. Conclusions Continued emphasis on regular COVID-19 vaccination including boosting is important for those at high risk of severe COVID-19 even in settings with widespread infection-induced immunity. ### Competing Interest Statement MD reports grants from Viiv Healthcare, outside the submitted work. CC reports grants from Sanofi Pasteur, US Centers for Disease Control and Prevention (CDC), Wellcome Trust, South African Medical Research Council (SAMRC) and the Bill & Melinda Gates Foundation. NW reports grants from the Bill and Melinda Gates Foundation and Sanofi. SW reports grants from US CDC and Bill and Melinda Gates Foundation. AvG reports grants from the World Health Organisation Regional Office for Africa (WHO-AFRO), US CDC, SAMRC, Fleming Fund, Africa Centres for Disease Control / African Society for Laboratory Medicine. AB reports grants from the US National Institutes for Health, Bill and Melinda Gates Foundation and the Wellcome Trust. ### Funding Statement This work was supported by funding from the Western Cape Government Department of Health and Wellness for the Western Cape Provincial Health Data Centre, the US National Institutes for Health [R01 HD080465, U01 AI069924], the Bill and Melinda Gates Foundation [1164272, 1191327], the United States Agency for International Development [72067418CA00023], the European Union [101045989], the Grand Challenges ICODA pilot initiative delivered by Health Data Research UK and funded by the Bill & Melinda Gates and Minderoo Foundations [INV-017293], and the Wellcome Trust [203135/Z/16/Z, 222574]. The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of this report. The opinions, findings and conclusions expressed in this manuscript reflect those of the authors alone. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Health Research Ethics Committee of the University of Cape Town gave ethical approval for this work (HREC REF 460/2020). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data are not publicly available due to privacy or ethical restrictions. The data that support the findings of this study can be requested from the Western Cape Provincial Health Data Centre (WCPHDC) [\textlesshttps://www.westerncape.gov.za/general-publication/provincial-health-data-centre\textgreater]; restrictions apply to the availability of these data.

@article{VanHeerden2024,
abstract = {Background: The prevalence of tuberculosis (TB)-associated pulmonary hypertension (PH) has not previously been quantified, resulting in an underappreciated burden of disease. We aimed to estimate the prevalence of PH in post-TB and active TB populations. Methods: In this systematic review and meta-analysis, we searched PubMed/Medline, Cochrane Library, EBSCOhost, Scopus, African Journals Online and Google Scholar, with no language restriction, for available literature published after 1950. Eligible studies described adult participants (≥16 years), with documented evidence of active or prior TB, diagnosed with PH. Study quality was assessed using a risk of bias tool specifically developed for prevalence studies. Aggregate prevalence estimates with 95{\%} confidence intervals were synthesised using a random-effects meta-analysis model, incorporating the Freeman–Tukey transformation. Subgroup analysis was conducted to ascertain prevalence estimates in specific patient populations. Results: We identified 1452 unique records, of which 34 met our inclusion criteria. 23 studies, with an acceptable risk of bias and where PH was diagnosed at right heart catheterisation or echocardiography, were included in the meta-analysis. In post-TB studies (14/23), the prevalence of PH was 67.0{\%} (95{\%} CI 50.8–81.4) in patients with chronic respiratory failure, 42.4{\%} (95{\%} CI 31.3–54.0) in hospitalised or symptomatic patients and 6.3{\%} (95{\%} CI 2.3–11.8) in nonhealthcare-seeking outpatients (I2=96{\%}). There was a lower estimated prevalence of PH in studies of populations with active TB (9.4{\%}, 95{\%} CI 6.3–13.0), I2=84{\%}). Conclusion: Our results highlight the significant burden of PH in post-TB and active TB populations. We emphasise the need for increased recognition of TB-associated PH and additional high-quality prevalence data. This systematic review and meta-analysis highlights the significant burden of pulmonary hypertension in post-tuberculosis and active tuberculosis populations. An increased recognition of tuberculosis-associated pulmonary hypertension is needed. {\textless}https://bit.ly/47NnTkC{\textgreater}},
author = {van Heerden, Jennifer K and Louw, Elizabeth H and Thienemann, Friedrich and Engel, Mark E and Allwood, Brian W},
doi = {10.1183/16000617.0154-2023},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/van Heerden et al. - 2024 - The prevalence of pulmonary hypertension in post-tuberculosis and active tuberculosis populations a systemat.pdf:pdf},
issn = {0905-9180},
journal = {European Respiratory Review},
keywords = {OA,fund{\_}not{\_}ack,review},
mendeley-tags = {OA,fund{\_}not{\_}ack,review},
month = {jan},
number = {171},
pmid = {38232991},
publisher = {European Respiratory Society},
title = {{The prevalence of pulmonary hypertension in post-tuberculosis and active tuberculosis populations: a systematic review and meta-analysis}},
url = {https://err.ersjournals.com/content/33/171/230154 https://err.ersjournals.com/content/33/171/230154.abstract},
volume = {33},
year = {2024}
}

Background: The prevalence of tuberculosis (TB)-associated pulmonary hypertension (PH) has not previously been quantified, resulting in an underappreciated burden of disease. We aimed to estimate the prevalence of PH in post-TB and active TB populations. Methods: In this systematic review and meta-analysis, we searched PubMed/Medline, Cochrane Library, EBSCOhost, Scopus, African Journals Online and Google Scholar, with no language restriction, for available literature published after 1950. Eligible studies described adult participants (≥16 years), with documented evidence of active or prior TB, diagnosed with PH. Study quality was assessed using a risk of bias tool specifically developed for prevalence studies. Aggregate prevalence estimates with 95% confidence intervals were synthesised using a random-effects meta-analysis model, incorporating the Freeman–Tukey transformation. Subgroup analysis was conducted to ascertain prevalence estimates in specific patient populations. Results: We identified 1452 unique records, of which 34 met our inclusion criteria. 23 studies, with an acceptable risk of bias and where PH was diagnosed at right heart catheterisation or echocardiography, were included in the meta-analysis. In post-TB studies (14/23), the prevalence of PH was 67.0% (95% CI 50.8–81.4) in patients with chronic respiratory failure, 42.4% (95% CI 31.3–54.0) in hospitalised or symptomatic patients and 6.3% (95% CI 2.3–11.8) in nonhealthcare-seeking outpatients (I2=96%). There was a lower estimated prevalence of PH in studies of populations with active TB (9.4%, 95% CI 6.3–13.0), I2=84%). Conclusion: Our results highlight the significant burden of PH in post-TB and active TB populations. We emphasise the need for increased recognition of TB-associated PH and additional high-quality prevalence data. This systematic review and meta-analysis highlights the significant burden of pulmonary hypertension in post-tuberculosis and active tuberculosis populations. An increased recognition of tuberculosis-associated pulmonary hypertension is needed. \textlesshttps://bit.ly/47NnTkC\textgreater

@article{Audley2024,
abstract = {Background. High-flow nasal oxygen (HFNO) is an accepted treatment for severe COVID-19-related acute hypoxaemic respiratory failure (AHRF). Objectives. To determine whether treatment outcomes at Groote Schuur Hospital, Cape Town, South Africa, during the third COVID-19 wave would be affected by increased institutional experience and capacity for HNFO and more restrictive admission criteria for respiratory high-care wards and intensive care units. Methods. We included consecutive patients with COVID-19-related AHRF treated with HFNO during the first and third COVID-19 waves. The primary endpoint was comparison of HFNO failure (composite of the need for intubation or death while on HFNO) between waves. Results. A total of 744 patients were included: 343 in the first COVID-19 wave and 401 in the third. Patients treated with HFNO in the first wave were older (median (interquartile range) age 53 (46 - 61) years v. 47 (40 - 56) years; p{\textless}0.001), and had higher prevalences of diabetes (46.9{\%} v. 36.9{\%}; p=0.006), hypertension (51.0{\%} v. 35.2{\%}; p{\textless}0.001), obesity (33.5{\%} v. 26.2{\%}; p=0.029) and HIV infection (12.5{\%} v. 5.5{\%}; p{\textless}0.001). The partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) ratio at HFNO initiation and the ratio of oxygen saturation/FiO2 to respiratory rate within 6 hours (ROX-6 score) after HFNO commencement were lower in the first wave compared with the third (median 57.9 (47.3 - 74.3) mmHg v. 64.3 (51.2 - 79.0) mmHg; p=0.005 and 3.19 (2.37 - 3.77) v. 3.43 (2.93 - 4.00); p{\textless}0.001, respectively). The likelihood of HFNO failure (57.1{\%} v. 59.6{\%}; p=0.498) and mortality (46.9{\%} v. 52.1{\%}; p=0.159) did not differ significantly between the first and third waves. Conclusion. Despite differences in patient characteristics, circulating viral variant and institutional experience with HFNO, treatment outcomes were very similar in the first and third COVID-19 waves. We conclude that once AHRF is established in COVID-19 pneumonia, the comorbidity profile and HFNO provider experience do not appear to affect outcome.},
author = {Audley, G and Raubenheimer, P and Symons, G and Mendelson, Marc and Meintjes, Graeme A and Ntusi, N A B and Wasserman, Sean and Dlamini, S and Dheda, K and Zyl-Smit, R Van and Calligaro, G},
doi = {10.7196/AJTCCM.2024.V30I1.1151},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Audley et al. - 2024 - High-flow nasal oxygen in resource-constrained, non-intensive, high-care wards for COVID-19 acute hypoxaemic resp.pdf:pdf},
issn = {2617-0205},
journal = {African Journal of Thoracic and Critical Care Medicine},
keywords = {COVID-19,OA,OA{\_}PMC,fund{\_}not{\_}ack,high-flow,original,oxygen},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {apr},
number = {1},
pages = {e1151--e1151},
pmid = {38756391},
title = {{High-flow nasal oxygen in resource-constrained, non-intensive, high-care wards for COVID-19 acute hypoxaemic respiratory failure: comparing outcomes of the first v. third waves at a tertiary centre in South Africa}},
url = {https://samajournals.co.za/index.php/ajtccm/article/view/1151/847 https://samajournals.co.za/index.php/ajtccm/article/view/1151},
volume = {30},
year = {2024}
}

Background. High-flow nasal oxygen (HFNO) is an accepted treatment for severe COVID-19-related acute hypoxaemic respiratory failure (AHRF). Objectives. To determine whether treatment outcomes at Groote Schuur Hospital, Cape Town, South Africa, during the third COVID-19 wave would be affected by increased institutional experience and capacity for HNFO and more restrictive admission criteria for respiratory high-care wards and intensive care units. Methods. We included consecutive patients with COVID-19-related AHRF treated with HFNO during the first and third COVID-19 waves. The primary endpoint was comparison of HFNO failure (composite of the need for intubation or death while on HFNO) between waves. Results. A total of 744 patients were included: 343 in the first COVID-19 wave and 401 in the third. Patients treated with HFNO in the first wave were older (median (interquartile range) age 53 (46 - 61) years v. 47 (40 - 56) years; p\textless0.001), and had higher prevalences of diabetes (46.9% v. 36.9%; p=0.006), hypertension (51.0% v. 35.2%; p\textless0.001), obesity (33.5% v. 26.2%; p=0.029) and HIV infection (12.5% v. 5.5%; p\textless0.001). The partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) ratio at HFNO initiation and the ratio of oxygen saturation/FiO2 to respiratory rate within 6 hours (ROX-6 score) after HFNO commencement were lower in the first wave compared with the third (median 57.9 (47.3 - 74.3) mmHg v. 64.3 (51.2 - 79.0) mmHg; p=0.005 and 3.19 (2.37 - 3.77) v. 3.43 (2.93 - 4.00); p\textless0.001, respectively). The likelihood of HFNO failure (57.1% v. 59.6%; p=0.498) and mortality (46.9% v. 52.1%; p=0.159) did not differ significantly between the first and third waves. Conclusion. Despite differences in patient characteristics, circulating viral variant and institutional experience with HFNO, treatment outcomes were very similar in the first and third COVID-19 waves. We conclude that once AHRF is established in COVID-19 pneumonia, the comorbidity profile and HFNO provider experience do not appear to affect outcome.

@article{Kassanjee2024a,
abstract = {There are few data on the real-world effectiveness of COVID-19 vaccines and boosting in Africa, which experienced widespread SARS-CoV-2 infection before vaccine availability. We assessed the association between vaccination and severe COVID-19 in the Western Cape, South Africa, in an observational cohort study of {\textgreater}2 million adults during 2020–2022. We described SARS-CoV-2 testing, COVID-19 outcomes, and vaccine uptake over time. We used multivariable cox models to estimate the association of BNT162b2 and Ad26.COV2.S vaccination with COVID-19-related hospitalization and death, adjusting for demographic characteristics, underlying health conditions, socioeconomic status proxies, and healthcare utilization. We found that by the end of 2022, 41{\%} of surviving adults had completed vaccination and 8{\%} had received a booster dose. Recent vaccination was associated with notable reductions in severe COVID-19 during periods dominated by Delta, and Omicron BA.1/2 and BA.4/5 (sub)lineages. During the latest Omicron BA.4/5 wave, within 3 months of vaccination or boosting, BNT162b2 and Ad26.COV2.S were each 84{\%} effective against death (95{\%} CIs: 57–94 and 49–95, respectively). However, distinct reductions of effectiveness occurred at longer times post completing or boosting vaccination. Results highlight the importance of continued emphasis on COVID-19 vaccination and boosting for those at high risk of severe COVID-19, even in settings with widespread infection-induced immunity.},
author = {Kassanjee, Reshma and Davies, Mary-Ann and Heekes, Alexa and Mahomed, Hassan and Hawkridge, Anthony and Morden, Erna and Jacobs, Theuns and Cohen, Cheryl and Moultrie, Harry and Lessells, Richard and {Van Der Walt}, Nicolette and Arendse, Juanita and Wolter, Nicole and Walaza, Sibongile and Jassat, Waasila and von Gottberg, Anne and Hannan, Patrick and Feikin, Daniel and Cloete, Keith and Boulle, Andrew},
doi = {10.3390/VACCINES12060628/S1},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Kassanjee et al. - 2024 - COVID-19 Vaccine Uptake and Effectiveness by Time since Vaccination in the Western Cape Province, South Afr(2).pdf:pdf},
issn = {2076393X},
journal = {Vaccines},
keywords = {19,2,COVID,CoV,OA,SARS,South Africa,cohort,fund{\_}ack,genomics{\_}fund{\_}ack,observational,original,vaccine effectiveness},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {jun},
number = {6},
pages = {628},
publisher = {MDPI AG},
title = {{COVID-19 vaccine uptake and effectiveness by time since vaccination in the Western Cape province, South Africa: an observational cohort study during 2020–2022}},
url = {https://www.mdpi.com/2076-393X/12/6/628/htm https://www.mdpi.com/2076-393X/12/6/628},
volume = {12},
year = {2024}
}

There are few data on the real-world effectiveness of COVID-19 vaccines and boosting in Africa, which experienced widespread SARS-CoV-2 infection before vaccine availability. We assessed the association between vaccination and severe COVID-19 in the Western Cape, South Africa, in an observational cohort study of \textgreater2 million adults during 2020–2022. We described SARS-CoV-2 testing, COVID-19 outcomes, and vaccine uptake over time. We used multivariable cox models to estimate the association of BNT162b2 and Ad26.COV2.S vaccination with COVID-19-related hospitalization and death, adjusting for demographic characteristics, underlying health conditions, socioeconomic status proxies, and healthcare utilization. We found that by the end of 2022, 41% of surviving adults had completed vaccination and 8% had received a booster dose. Recent vaccination was associated with notable reductions in severe COVID-19 during periods dominated by Delta, and Omicron BA.1/2 and BA.4/5 (sub)lineages. During the latest Omicron BA.4/5 wave, within 3 months of vaccination or boosting, BNT162b2 and Ad26.COV2.S were each 84% effective against death (95% CIs: 57–94 and 49–95, respectively). However, distinct reductions of effectiveness occurred at longer times post completing or boosting vaccination. Results highlight the importance of continued emphasis on COVID-19 vaccination and boosting for those at high risk of severe COVID-19, even in settings with widespread infection-induced immunity.

@article{Zhao2024,
abstract = {Background: In South African antiretroviral guidelines, selected patients failing second-line protease inhibitor (PI)-based therapy qualify for genotypic resistance testing – those with PI resistance receive darunavir-based third-line regimens; those without PI resistance continue current regimen with adherence support. The Western Cape province, from September 2020, implemented a strategy of tenofovir-lamivudine-dolutegravir (TLD) for patients, provided there was no tenofovir resistance, irrespective of PI resistance. Objectives: To evaluate virologic outcomes with TLD among adults failing second-line PI regimens with no tenofovir resistance. Method: An observational cohort study comparing outcomes in patients switched to TLD with those continuing the same PI or switched to darunavir-based regimens. Follow-up was until virologic suppression (HIV-1 RNA {\textless} 400 copies/mL), or at the point of censoring. Results: One hundred and thirty-three patients switched to TLD, 101 to darunavir-based regimens, and 121 continued with the same PI. By 12 months, among patients with PI resistance, 42/47 (89{\%}) in the TLD group had HIV-1 RNA {\textless} 400 copies/mL compared to 91/99 (92{\%}) in the darunavir group (hazard ratio, 1.11; 95{\%} confidence interval, 0.77–1.60). In patients without PI resistance, 66/86 (77{\%}) in the TLD group had HIV-1 RNA {\textless} 400 copies/mL compared to 42/120 (35{\%}) in those continuing with the same PI (hazard ratio, 4.03; 95{\%} confidence interval, 2.71–5.98). Two patients receiving TLD developed virologic failure with high-level dolutegravir resistance. Conclusion: Amongst patients failing second-line PI with no PI resistance, switching to TLD was associated with higher virologic suppression, likely due to improved adherence. Virologic outcomes were similar in patients with PI resistance switched to darunavir-based regimens or TLD.},
author = {Zhao, Ying and Voget, Jacqueline and Singini, Isaac and Omar, Zaayid and Mudaly, Vanessa and Boulle, Andrew and Maartens, Gary and Meintjes, Graeme A},
doi = {10.4102/SAJHIVMED.V25I1.1567},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Zhao et al. - 2024 - Virologic outcomes with tenofovir-lamivudine-dolutegravir in adults failing PI-based second-line ART.pdf:pdf;:C$\backslash$:/Users/01462563/OneDrive - University of Cape Town/Documents/CIDRI-Africa papers and outputs/Zhao et al - 2024 - Virologic outcomes with tenofovir-lamivudine-dolutegravir in adults failing PI-based second-line ART.pdf:pdf},
issn = {2078-6751},
journal = {Southern African Journal of HIV Medicine},
keywords = {AIDS,Africa,African,HIV,OA,OA{\_}PMC,after,age,analysis,antiretroviral,antiretroviral therapy,associated,based,care,data,disease,dolutegravir,drug,fund{\_}not{\_}ack,group,guidelines,health,healthcare,individuals,infected,infection,line.,model,months,original,patients,people,population,positive,pregnancy,renal,risk,services,study,test,testing,therapy,third,time,treatment,virologic failure,virus,women,workers,years},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {apr},
number = {1},
pages = {a1567},
pmid = {38725705},
title = {{Virologic outcomes with tenofovir-lamivudine-dolutegravir in adults failing PI-based second-line ART}},
url = {https://sajhivmed.org.za/index.php/hivmed/article/view/1567/3249 https://sajhivmed.org.za/index.php/hivmed/article/view/1567/3250 https://sajhivmed.org.za/index.php/hivmed/article/view/1567/3251 https://sajhivmed.org.za/index.php/hivmed/article/view/1567},
volume = {25},
year = {2024}
}

Background: In South African antiretroviral guidelines, selected patients failing second-line protease inhibitor (PI)-based therapy qualify for genotypic resistance testing – those with PI resistance receive darunavir-based third-line regimens; those without PI resistance continue current regimen with adherence support. The Western Cape province, from September 2020, implemented a strategy of tenofovir-lamivudine-dolutegravir (TLD) for patients, provided there was no tenofovir resistance, irrespective of PI resistance. Objectives: To evaluate virologic outcomes with TLD among adults failing second-line PI regimens with no tenofovir resistance. Method: An observational cohort study comparing outcomes in patients switched to TLD with those continuing the same PI or switched to darunavir-based regimens. Follow-up was until virologic suppression (HIV-1 RNA \textless 400 copies/mL), or at the point of censoring. Results: One hundred and thirty-three patients switched to TLD, 101 to darunavir-based regimens, and 121 continued with the same PI. By 12 months, among patients with PI resistance, 42/47 (89%) in the TLD group had HIV-1 RNA \textless 400 copies/mL compared to 91/99 (92%) in the darunavir group (hazard ratio, 1.11; 95% confidence interval, 0.77–1.60). In patients without PI resistance, 66/86 (77%) in the TLD group had HIV-1 RNA \textless 400 copies/mL compared to 42/120 (35%) in those continuing with the same PI (hazard ratio, 4.03; 95% confidence interval, 2.71–5.98). Two patients receiving TLD developed virologic failure with high-level dolutegravir resistance. Conclusion: Amongst patients failing second-line PI with no PI resistance, switching to TLD was associated with higher virologic suppression, likely due to improved adherence. Virologic outcomes were similar in patients with PI resistance switched to darunavir-based regimens or TLD.

@article{Hampton2024,
author = {Hampton, Thomas and Haigh, Kathryn A and Phiri, Mphatso Dennis and Tomeny, Ewan},
doi = {10.1016/J.LANWPC.2024.101008},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Hampton et al. - 2024 - Letter to the editor “Eliciting national and subnational sets of disability weights in mainland China findings f.pdf:pdf},
issn = {2666-6065},
journal = {The Lancet Regional Health - Western Pacific},
keywords = {OA,fund{\_}not{\_}ack,letter},
mendeley-tags = {OA,fund{\_}not{\_}ack,letter},
month = {feb},
pages = {101008},
publisher = {Elsevier},
title = {{Letter to the editor: “Eliciting national and subnational sets of disability weights in mainland China: findings from the Chinese disability weight measurement study”}},
volume = {43},
year = {2024}
}

@article{Wadephul2024,
abstract = {Antibody-based fluorescence analysis of female reproductive tissues in research of sexually transmitted diseases allows for an in-depth understanding of protein localization, interactions, and pathogenesis. However, in many cases, cryosectioning is not compatible with biosafety regulations; at all times, exposure of lab personnel and the public to potentially harmful pathogens from biological infectious material must be avoided; thus, formaldehyde fixation is essential. Due to formaldehyde's cross-linking properties, protein detection with antibodies can be impeded. To allow effective epitope binding during immunofluorescence of formalin-fixed paraffin-embedded vaginal tissue, we investigated two antigen retrieval methods. We tested these methods regarding their suitability for automated image analysis, facilitating reproducible quantitative microscopic data acquisition in sexually transmitted disease research. Heat-based retrieval at 80°C in citrate buffer proved to increase antibody binding to eosinophil protein and HSV-2 visibly and tissue morphology best, and was the most efficient for sample processing and quantitative analysis.},
author = {Wadephul, Lisa Marie and Arndts, Kathrin and Katawa, Gnatoulma and Dietlmeier, Eva and Horsnell, William and Hoerauf, Achim and Ritter, Manuel},
doi = {10.4081/ejh.2024.3929},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Wadephul et al. - 2024 - Walking a thin line between fixation and epitope binding - characterization of antigen retrieval methods suitab.pdf:pdf},
issn = {20388306},
journal = {European Journal of Histochemistry},
keywords = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {apr},
number = {2},
pmid = {38624064},
title = {{Walking a thin line between fixation and epitope binding - characterization of antigen retrieval methods suitable for eosinophil and HSV-2 staining in formalin-fixed female reproductive tissue}},
volume = {68},
year = {2024}
}

Antibody-based fluorescence analysis of female reproductive tissues in research of sexually transmitted diseases allows for an in-depth understanding of protein localization, interactions, and pathogenesis. However, in many cases, cryosectioning is not compatible with biosafety regulations; at all times, exposure of lab personnel and the public to potentially harmful pathogens from biological infectious material must be avoided; thus, formaldehyde fixation is essential. Due to formaldehyde's cross-linking properties, protein detection with antibodies can be impeded. To allow effective epitope binding during immunofluorescence of formalin-fixed paraffin-embedded vaginal tissue, we investigated two antigen retrieval methods. We tested these methods regarding their suitability for automated image analysis, facilitating reproducible quantitative microscopic data acquisition in sexually transmitted disease research. Heat-based retrieval at 80°C in citrate buffer proved to increase antibody binding to eosinophil protein and HSV-2 visibly and tissue morphology best, and was the most efficient for sample processing and quantitative analysis.

@article{Euvrard2024,
abstract = {Background The traditional HIV treatment cascade aims to visualise the journey of each person living with HIV from diagnosis, through initiation on antiretroviral therapy (ART) to treatment success, represented by virological suppression. This representation has been a pivotal tool in highlighting and quantifying sequential gaps along the care continuum. There is longstanding recognition, however, that this may oversimplify the complexity of real-world engagement with HIV services in settings with mature high-burden HIV epidemics. A complementary “cyclical” cascade has been proposed to represent the processes of disengagement at different points on the care continuum, with multiple pathways to re-engagement, although the feasibility of implementing this at scale has been uncertain. This study aimed to populate, refine, and explore the utility of a cyclical representation of the HIV cascade, using routine data from a high-burden HIV setting. Methods and findings This observational cohort study leveraged person-level data on all people living with HIV in the Western Cape (WC), South Africa, who accessed public health services in the 2 years prior to 31 December 2023. Programme data from disease registers were complemented by data from pharmacy and laboratory systems. At study closure, 494 370 people were included, constituting 93{\%} of those of those estimated to be living with HIV in the province, of whom 355 104 were on ART. Substantial disengagement from HIV care was evident at every point on the cascade. Early treatment emerged as a period of higher risk of disengagement, but it did not account for the majority of disengagement. Almost all those currently disengaged had prior experience of treatment. While re-engagement was also common, overall treatment coverage had increased slowly over 5 years. The transition to dolutegravir-based regimens was dramatic with good virological outcomes for those in care, notwithstanding a clearly discernible impact of the Coronavirus Disease 2019 (COVID-19) pandemic on viral load (VL) testing. People currently engaged and disengaged in care are similar with respect to age and gender. Those who died or disengaged recently were previously distributed across a range of cascade statuses, and a substantial proportion of those newly initiating and re-initiating treatment were no longer on treatment 6 months later. The main limitation of this study was incomplete evidence of HIV testing, linkage to HIV-specific services, and out-of-facility mortality. Conclusions Using routine data, it was possible to populate and automate a cyclical cascade of HIV care that continuously captured the nonlinear care journeys of individuals living with HIV. In this generalised mature HIV epidemic, most people are treatment experienced. Disengagement is common and occurs at various points along the cascade, making it challenging to identify high-impact intervention opportunities. While historical HIV cascades remain valuable for target setting and service monitoring, they can be complemented with insights from more detailed cyclical cascades.},
author = {Euvrard, Jonathan and Timmerman, Venessa and Keene, Claire Marriott and Phelanyane, Florence and Heekes, Alexa and Rice, Brian D and Grimsrud, Anna and Ehrenkranz, Peter and Boulle, Andrew},
doi = {10.1371/JOURNAL.PMED.1004407},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Id et al. - 2024 - The cyclical cascade of HIV care Temporal care engagement trends within a population-wide cohort.pdf:pdf},
isbn = {1111111111},
issn = {1549-1676},
journal = {PLOS Medicine},
keywords = {Antiretroviral therapy,COVID 19,HIV,HIV diagnosis and management,HIV epidemiology,OA,Public and occupational health,Viral load,Virus testing,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {may},
number = {5},
pages = {e1004407},
pmid = {38728361},
publisher = {Public Library of Science},
title = {{The cyclical cascade of HIV care: temporal care engagement trends within a population-wide cohort}},
url = {https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004407},
volume = {21},
year = {2024}
}

Background The traditional HIV treatment cascade aims to visualise the journey of each person living with HIV from diagnosis, through initiation on antiretroviral therapy (ART) to treatment success, represented by virological suppression. This representation has been a pivotal tool in highlighting and quantifying sequential gaps along the care continuum. There is longstanding recognition, however, that this may oversimplify the complexity of real-world engagement with HIV services in settings with mature high-burden HIV epidemics. A complementary “cyclical” cascade has been proposed to represent the processes of disengagement at different points on the care continuum, with multiple pathways to re-engagement, although the feasibility of implementing this at scale has been uncertain. This study aimed to populate, refine, and explore the utility of a cyclical representation of the HIV cascade, using routine data from a high-burden HIV setting. Methods and findings This observational cohort study leveraged person-level data on all people living with HIV in the Western Cape (WC), South Africa, who accessed public health services in the 2 years prior to 31 December 2023. Programme data from disease registers were complemented by data from pharmacy and laboratory systems. At study closure, 494 370 people were included, constituting 93% of those of those estimated to be living with HIV in the province, of whom 355 104 were on ART. Substantial disengagement from HIV care was evident at every point on the cascade. Early treatment emerged as a period of higher risk of disengagement, but it did not account for the majority of disengagement. Almost all those currently disengaged had prior experience of treatment. While re-engagement was also common, overall treatment coverage had increased slowly over 5 years. The transition to dolutegravir-based regimens was dramatic with good virological outcomes for those in care, notwithstanding a clearly discernible impact of the Coronavirus Disease 2019 (COVID-19) pandemic on viral load (VL) testing. People currently engaged and disengaged in care are similar with respect to age and gender. Those who died or disengaged recently were previously distributed across a range of cascade statuses, and a substantial proportion of those newly initiating and re-initiating treatment were no longer on treatment 6 months later. The main limitation of this study was incomplete evidence of HIV testing, linkage to HIV-specific services, and out-of-facility mortality. Conclusions Using routine data, it was possible to populate and automate a cyclical cascade of HIV care that continuously captured the nonlinear care journeys of individuals living with HIV. In this generalised mature HIV epidemic, most people are treatment experienced. Disengagement is common and occurs at various points along the cascade, making it challenging to identify high-impact intervention opportunities. While historical HIV cascades remain valuable for target setting and service monitoring, they can be complemented with insights from more detailed cyclical cascades.

@article{LorenzoGuglielmetti2024,
abstract = {Background After a history of poor treatments for rifampin-resistant tuberculosis (RR-TB), recent advances have resulted in shorter, more effective treatments. However, they are not available to everyone and have shortcomings, requiring additional treatment options. Methods endTB is an international, open-label, Phase 3 non-inferiority, randomized, controlled clinical trial to compare five 9-month all-oral regimens including bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C) and pyrazinamide (Z), to the standard (control) for treatment of fluoroquinolone-susceptible RR-TB. Participants were randomized to 9BLMZ, 9BCLLfxZ, 9BDLLfxZ, 9DCLLfxZ, 9DCMZ and control using Bayesian response-adaptive randomization. The primary outcome was favorable outcome at week 73 defined by two negative sputum culture results or by favorable bacteriologic, clinical and radiologic evolution. The non-inferiority margin was 12 percentage points. Results Of 754 randomized patients, 696 and 559 were included in the modified intention to treat (mITT) and per-protocol (PP) analyses, respectively. In mITT, the control had 80.7{\%} favorable outcomes. Regimens 9BCLLfxZ [adjusted risk difference (aRD): 9.5{\%} (95{\%} confidence interval (CI), 0.4 to 18.6)], 9BLMZ [aRD: 8.8{\%} (95{\%}CI, −0.6 to 18.2)], and 9BDLLfxZ [3.9{\%} (95{\%}CI, −5.8 to 13.6)] were non-inferior in mITT and in PP. The proportion of participants experiencing grade 3 or higher adverse events was similar across the regimens. Grade 3 or higher hepatotoxicity occurred in 11.7{\%} of the experimental regimens overall and in 7.1{\%} of the control. Conclusions The endTB trial increases treatment options for RR-TB with three shortened, all-oral regimens that were non-inferior to a current well-performing standard of care. [ClinicalTrials.gov][1]:[NCT02754765][2] {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Clinical Trial NCT02754765 {\#}{\#}{\#} Funding Statement This study was funded by Unitaid. {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Ethics Committees/IRBs of Medecins Sans Frontieres, Harvard Medical School, Institute of Tropical Medicine Antwerp, Interactive Research and Development, and each participating site, gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as [ClinicalTrials.gov][1]. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link{\_}type=CLINTRIALGOV{\&}access{\_}num=NCT02754765{\&}atom={\%}2Fmedrxiv{\%}2Fearly{\%}2F2024{\%}2F01{\%}2F29{\%}2F2024.01.29.24301679.atom},
author = {{Lorenzo Guglielmetti}, Authors and Khan, Uzma and Vel{\'{a}}squez, Gustavo E and Gouillou, Maelenn and Abubakirov, Amanzhan and Baudin, Elisabeth and Berikova, Elmira and Berry, Catherine and Bonnet, Maryline and Cellamare, Matteo and Chavan, Vijay and Cox, Vivian and Dakenova, Zhanna and {Catherine de Jong}, Bouke and Ferlazzo, Gabriella and Karabayev, Aydarkhan and Kirakosyan, Ohanna and Kiria, Nana and Kunda, Mikanda and Lachenal, Nathalie and Lecca, Leonid and McIlleron, Helen and Motta, Ilaria and Mucching-Toscano, Sergio and Mushtaque, Hebah and Nahid, Payam and Oyewusi, Lawrence and Panda, Samiran and Patil, Sandip and Phillips, Patrick and Ruiz, Jimena and Salahuddin, Naseem and Sanchez-Garavito, Epifanio and Seung, Kwonjune J and Ticona, Eduardo and Trippa, Lorenzo and Vargas, Dante and Wasserman, Sean and Rich, Michael L and Varaine, Francis and Mitnick, Carole D and {Francisco GEV}, San and {Nacional Sergio Bernales}, Hospital E},
doi = {10.1101/2024.01.29.24301679},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Lorenzo Guglielmetti et al. - 2024 - Nine-month, all-oral regimens for rifampin-resistant tuberculosis.pdf:pdf},
journal = {medRxiv},
keywords = {Bayesian response-adaptive,MDR-TB,OA,bedaquiline,controlled clinical trial,delamanid,drug resistance,fund{\_}not{\_}ack,original,randomized},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jan},
pages = {2024.01.29.24301679},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Nine-month, all-oral regimens for rifampin-resistant tuberculosis}},
url = {https://www.medrxiv.org/content/10.1101/2024.01.29.24301679v1 https://www.medrxiv.org/content/10.1101/2024.01.29.24301679v1.abstract},
year = {2024}
}

Background After a history of poor treatments for rifampin-resistant tuberculosis (RR-TB), recent advances have resulted in shorter, more effective treatments. However, they are not available to everyone and have shortcomings, requiring additional treatment options. Methods endTB is an international, open-label, Phase 3 non-inferiority, randomized, controlled clinical trial to compare five 9-month all-oral regimens including bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C) and pyrazinamide (Z), to the standard (control) for treatment of fluoroquinolone-susceptible RR-TB. Participants were randomized to 9BLMZ, 9BCLLfxZ, 9BDLLfxZ, 9DCLLfxZ, 9DCMZ and control using Bayesian response-adaptive randomization. The primary outcome was favorable outcome at week 73 defined by two negative sputum culture results or by favorable bacteriologic, clinical and radiologic evolution. The non-inferiority margin was 12 percentage points. Results Of 754 randomized patients, 696 and 559 were included in the modified intention to treat (mITT) and per-protocol (PP) analyses, respectively. In mITT, the control had 80.7% favorable outcomes. Regimens 9BCLLfxZ [adjusted risk difference (aRD): 9.5% (95% confidence interval (CI), 0.4 to 18.6)], 9BLMZ [aRD: 8.8% (95%CI, −0.6 to 18.2)], and 9BDLLfxZ [3.9% (95%CI, −5.8 to 13.6)] were non-inferior in mITT and in PP. The proportion of participants experiencing grade 3 or higher adverse events was similar across the regimens. Grade 3 or higher hepatotoxicity occurred in 11.7% of the experimental regimens overall and in 7.1% of the control. Conclusions The endTB trial increases treatment options for RR-TB with three shortened, all-oral regimens that were non-inferior to a current well-performing standard of care. [ClinicalTrials.gov][1]:[NCT02754765][2] ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT02754765 ### Funding Statement This study was funded by Unitaid. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Ethics Committees/IRBs of Medecins Sans Frontieres, Harvard Medical School, Institute of Tropical Medicine Antwerp, Interactive Research and Development, and each participating site, gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as [ClinicalTrials.gov][1]. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02754765&atom=%2Fmedrxiv%2Fearly%2F2024%2F01%2F29%2F2024.01.29.24301679.atom

@article{Meintjes2024,
author = {Meintjes, Graeme A and Maartens, Gary},
doi = {10.1056/NEJMRA2308181},
editor = {Hardin, C. Corey},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Meintjes, Maartens - 2024 - HIV-Associated Tuberculosis.pdf:pdf},
issn = {0028-4793},
journal = {New England Journal of Medicine},
keywords = {fund{\_}not{\_}ack,review},
mendeley-tags = {fund{\_}not{\_}ack,review},
month = {jul},
number = {4},
pages = {343--355},
title = {{HIV-associated tuberculosis}},
url = {http://www.nejm.org/doi/10.1056/NEJMra2308181},
volume = {391},
year = {2024}
}

@article{Middelkoop2024,
abstract = {Randomized controlled trials (RCTs) to determine the influence of vitamin D on BMC and fracture risk in children of Black African ancestry are lacking. We conducted a sub-study (n = 450) nested within a phase 3 RCT of weekly oral supplementation with 10 000 IU vitamin D3 vs placebo for 3 yr in HIV-uninfected Cape Town schoolchildren aged 6–11 yr. Outcomes were BMC at the whole body less head (WBLH) and LS and serum 25-hydroxyvitamin D3 (25(OH)D3), PTH, alkaline phosphatase, C-terminal telopeptide, and PINP. Incidence of fractures was a secondary outcome of the main trial (n = 1682). At baseline, mean serum 25(OH)D3 concentration was 70.0 nmol/L (SD 13.5), and 5.8{\%} of participants had serum 25(OH)D3 concentrations {\textless}50 nmol/L. Among sub-study participants, end-trial serum 25(OH)D3 concentrations were higher for participants allocated to vitamin D vs placebo (adjusted mean difference [aMD] 39.9 nmol/L, 95{\%} CI, 36.1 to 43.6) and serum PTH concentrations were lower (aMD −0.55 pmol/L, 95{\%} CI, −0.94 to −0.17). However, no interarm differences were seen for WBLH BMC (aMD −8.0 g, 95{\%} CI, −30.7 to 14.7) or LS BMC (aMD −0.3 g, 95{\%} CI, −1.3 to 0.8) or serum concentrations of bone turnover markers. Fractures were rare among participants in the main trial randomized to vitamin D vs placebo (7/755 vs 10/758 attending at least 1 follow-up; adjusted odds ratio 0.70, 95{\%} CI, 0.27 to 1.85). In conclusion, a 3-yr course of weekly oral vitamin D supplementation elevated serum 25(OH)D3 concentrations and suppressed serum PTH concentrations in HIV-uninfected South African schoolchildren of Black African ancestry but did not influence BMC or serum concentrations of bone turnover markers. Fracture incidence was low, limiting power to detect an effect of vitamin D on this outcome.},
author = {Middelkoop, Keren and Micklesfield, Lisa K and Walker, Neil and Stewart, Justine and Delport, Carmen and Jolliffe, David A and Mendham, Amy E and Coussens, Anna K and van Graan, Averalda and Nuttall, James and Tang, Jonathan C Y and Fraser, William D and Cooper, Cyrus and Harvey, Nicholas C and Hooper, Richard L and Wilkinson, Robert J and Bekker, Linda-Gail and Martineau, Adrian R},
doi = {10.1093/JBMR/ZJAE007},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Middelkoop et al. - 2024 - Influence of vitamin D supplementation on bone mineral content, bone turnover markers, and fracture risk in S.pdf:pdf},
issn = {0884-0431},
journal = {Journal of Bone and Mineral Research},
keywords = {OA,bone mineral content,bone turnover markers,cholecalciferol,fracture risk,fund{\_}ack,original,parathyroid hormone},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jan},
pages = {zjae007},
pmid = {38477739},
publisher = {Oxford University Press (OUP)},
title = {{Influence of vitamin D supplementation on bone mineral content, bone turnover markers, and fracture risk in South African schoolchildren: multicenter double-blind randomized placebo-controlled trial (ViDiKids)}},
url = {https://dx.doi.org/10.1093/jbmr/zjae007},
year = {2024}
}

Randomized controlled trials (RCTs) to determine the influence of vitamin D on BMC and fracture risk in children of Black African ancestry are lacking. We conducted a sub-study (n = 450) nested within a phase 3 RCT of weekly oral supplementation with 10 000 IU vitamin D3 vs placebo for 3 yr in HIV-uninfected Cape Town schoolchildren aged 6–11 yr. Outcomes were BMC at the whole body less head (WBLH) and LS and serum 25-hydroxyvitamin D3 (25(OH)D3), PTH, alkaline phosphatase, C-terminal telopeptide, and PINP. Incidence of fractures was a secondary outcome of the main trial (n = 1682). At baseline, mean serum 25(OH)D3 concentration was 70.0 nmol/L (SD 13.5), and 5.8% of participants had serum 25(OH)D3 concentrations \textless50 nmol/L. Among sub-study participants, end-trial serum 25(OH)D3 concentrations were higher for participants allocated to vitamin D vs placebo (adjusted mean difference [aMD] 39.9 nmol/L, 95% CI, 36.1 to 43.6) and serum PTH concentrations were lower (aMD −0.55 pmol/L, 95% CI, −0.94 to −0.17). However, no interarm differences were seen for WBLH BMC (aMD −8.0 g, 95% CI, −30.7 to 14.7) or LS BMC (aMD −0.3 g, 95% CI, −1.3 to 0.8) or serum concentrations of bone turnover markers. Fractures were rare among participants in the main trial randomized to vitamin D vs placebo (7/755 vs 10/758 attending at least 1 follow-up; adjusted odds ratio 0.70, 95% CI, 0.27 to 1.85). In conclusion, a 3-yr course of weekly oral vitamin D supplementation elevated serum 25(OH)D3 concentrations and suppressed serum PTH concentrations in HIV-uninfected South African schoolchildren of Black African ancestry but did not influence BMC or serum concentrations of bone turnover markers. Fracture incidence was low, limiting power to detect an effect of vitamin D on this outcome.

@article{Lemmer2024,
abstract = {In the quest for heightened protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, we engineered a prototype vaccine utilizing the plant expression system of Nicotiana benthamiana, to produce a recombinant SARS-CoV-2 virus-like particle (VLP) vaccine presenting the S-protein from the Beta (B.1.351) variant of concern (VOC). This innovative vaccine, formulated with either a squalene oil-in-water emulsion or a synthetic CpG oligodeoxynucleotide adjuvant, demonstrated efficacy in a golden Syrian Hamster challenge model. The Beta VLP vaccine induced a robust humoral immune response, with serum exhibiting neutralization not only against SARS-CoV-2 Beta but also cross-neutralizing Delta and Omicron pseudoviruses. Protective efficacy was demonstrated, evidenced by reduced viral RNA copies and mitigated weight loss and lung damage compared to controls. This compelling data instills confidence in the creation of a versatile platform for the local manufacturing of potential pan-sarbecovirus vaccines, against evolving viral threats.},
author = {Lemmer, Yolandy and Chapman, Ros and Abolnik, Celia and Smith, Tanja and Sch{\"{a}}fer, Georgia and Hermanus, Tandile and du Preez, Ilse and Goosen, Kruger and Sepotokele, Kamogelo M and Gers, Sophette and Suliman, Tasnim and Preiser, Wolfgang and Shaw, Megan L and Roth, Robyn and Truyts, Alma and Chipangura, John and Magwaza, Martin and Mahanjana, Osborn and Moore, Penny L and O'Kennedy, Martha M},
doi = {10.1016/J.VACCINE.2024.01.036},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Lemmer et al. - 2024 - Protective efficacy of a plant-produced beta variant rSARS-CoV-2 VLP vaccine in golden Syrian hamsters.pdf:pdf},
issn = {0264-410X},
journal = {Vaccine},
keywords = {Efficacy,Immunogenicity,OA,Pan-sarbecovirus,Virus-like particles,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jan},
pmid = {38238112},
publisher = {Elsevier},
title = {{Protective efficacy of a plant-produced beta variant rSARS-CoV-2 VLP vaccine in golden Syrian hamsters}},
year = {2024}
}

In the quest for heightened protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, we engineered a prototype vaccine utilizing the plant expression system of Nicotiana benthamiana, to produce a recombinant SARS-CoV-2 virus-like particle (VLP) vaccine presenting the S-protein from the Beta (B.1.351) variant of concern (VOC). This innovative vaccine, formulated with either a squalene oil-in-water emulsion or a synthetic CpG oligodeoxynucleotide adjuvant, demonstrated efficacy in a golden Syrian Hamster challenge model. The Beta VLP vaccine induced a robust humoral immune response, with serum exhibiting neutralization not only against SARS-CoV-2 Beta but also cross-neutralizing Delta and Omicron pseudoviruses. Protective efficacy was demonstrated, evidenced by reduced viral RNA copies and mitigated weight loss and lung damage compared to controls. This compelling data instills confidence in the creation of a versatile platform for the local manufacturing of potential pan-sarbecovirus vaccines, against evolving viral threats.

@article{Riou2024,
abstract = {We report the safety and immunogenicity of fractional and full dose Ad26.COV2.S and BNT162b2 in an open label phase 2 trial of participants previously vaccinated with a single dose of Ad26.COV2.S, with 91.4{\%} showing evidence of previous SARS-CoV-2 infection. A total of 286 adults (with or without HIV) were enrolled {\textgreater}4 months after an Ad26.COV2.S prime and randomized 1:1:1:1 to receive either a full or half-dose booster of Ad26.COV2.S or BNT162b2 vaccine. B cell responses (binding, neutralization and antibody dependent cellular cytotoxicity-ADCC), and spike-specific T-cell responses were evaluated at baseline, 2, 12 and 24 weeks post-boost. Antibody and T-cell immunity targeting the Ad26 vector was also evaluated. No vaccine-associated serious adverse events were recorded. The full- and half-dose BNT162b2 boosted anti-SARS-CoV-2 binding antibody levels (3.9- and 4.5-fold, respectively) and neutralizing antibody levels (4.4- and 10-fold). Binding and neutralizing antibodies following half-dose Ad26.COV2.S were not significantly boosted. Full-dose Ad26.COV2.S did not boost binding antibodies but slightly enhanced neutralizing antibodies (2.1-fold). ADCC was marginally increased only after a full-dose BNT162b2. T-cell responses followed a similar pattern to neutralizing antibodies. Six months post-boost, antibody and T-cell responses had waned to baseline levels. While we detected strong anti-vector immunity, there was no correlation between anti-vector immunity in Ad26.COV2.S recipients and spike-specific neutralizing antibody or T-cell responses post-Ad26.COV2.S boosting. Overall, in the context of hybrid immunity, boosting with heterologous full- or half-dose BNT162b2 mRNA vaccine demonstrated superior immunogenicity 2 weeks post-vaccination compared to homologous Ad26.COV2.S, though rapid waning occurred by 12 weeks post-boost. Trial Registration: The study has been registered to the South African National Clinical Trial Registry (SANCTR): DOH-27-012022-7841 . The approval letter from SANCTR has been provided in the up-loaded documents.},
author = {Riou, Catherine and Bhiman, Jinal N and Ganga, Yashica and Sawry, Shobna and Ayres, Frances and Baguma, Richard and Balla, Sashkia R and Benede, Ntombi and Bernstein, Mallory and Besethi, Asiphe S and Cele, Sandile and Crowther, Carol and Dhar, Mrinmayee and Geyer, Sohair and Gill, Katherine and Grifoni, Alba and Hermanus, Tandile and Kaldine, Haajira and Keeton, Roanne S and Kgagudi, Prudence and Khan, Khadija and Lazarus, Erica and {Le Roux}, Jean and Lustig, Gila and Madzivhandila, Mashudu and Magugu, Siyabulela F J and Makhado, Zanele and Manamela, Nelia P and Mkhize, Qiniso and Mosala, Paballo and Motlou, Thopisang P and Mutavhatsindi, Hygon and Mzindle, Nonkululeko B and Nana, Anusha and Nesamari, Rofhiwa and Ngomti, Amkele and Nkayi, Anathi A and Nkosi, Thandeka P and Omondi, Millicent A and Panchia, Ravindre and Patel, Faeezah and Sette, Alessandro and Singh, Upasna and van Graan, Strauss and Venter, Elizabeth M and Walters, Avril and Moyo-Gwete, Thandeka and Richardson, Simone I and Garrett, Nigel and Rees, Helen and Bekker, Linda-Gail and Gray, Glenda and Burgers, Wendy A and Sigal, Alex and Moore, Penny L and Fairlie, Lee},
doi = {10.1371/journal.pgph.0002703},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Riou et al. - 2024 - Safety and immunogenicity of booster vaccination and fractional dosing with Ad26.COV2.S or BNT162b2 in Ad26.COV2.S-.pdf:pdf},
journal = {PLOS Global Public Health},
keywords = {Catherine Riou,Jinal N Bhiman,Lee Fairlie,MEDLINE,NCBI,NIH,NLM,National Center for Biotechnology Information,National Institutes of Health,National Library of Medicine,OA,OA{\_}PMC,PMC11008839,PubMed Abstract,doi:10.1371/journal.pgph.0002703,fund{\_}not{\_}ack,original,pmid:38603677},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {apr},
number = {4},
pages = {e0002703},
pmid = {38045321},
publisher = {Public Library of Science (PLoS)},
title = {{Safety and immunogenicity of booster vaccination and fractional dosing with Ad26.COV2.S or BNT162b2 in Ad26.COV2.S-vaccinated participants}},
url = {https://pubmed.ncbi.nlm.nih.gov/38603677/},
volume = {4},
year = {2024}
}

We report the safety and immunogenicity of fractional and full dose Ad26.COV2.S and BNT162b2 in an open label phase 2 trial of participants previously vaccinated with a single dose of Ad26.COV2.S, with 91.4% showing evidence of previous SARS-CoV-2 infection. A total of 286 adults (with or without HIV) were enrolled \textgreater4 months after an Ad26.COV2.S prime and randomized 1:1:1:1 to receive either a full or half-dose booster of Ad26.COV2.S or BNT162b2 vaccine. B cell responses (binding, neutralization and antibody dependent cellular cytotoxicity-ADCC), and spike-specific T-cell responses were evaluated at baseline, 2, 12 and 24 weeks post-boost. Antibody and T-cell immunity targeting the Ad26 vector was also evaluated. No vaccine-associated serious adverse events were recorded. The full- and half-dose BNT162b2 boosted anti-SARS-CoV-2 binding antibody levels (3.9- and 4.5-fold, respectively) and neutralizing antibody levels (4.4- and 10-fold). Binding and neutralizing antibodies following half-dose Ad26.COV2.S were not significantly boosted. Full-dose Ad26.COV2.S did not boost binding antibodies but slightly enhanced neutralizing antibodies (2.1-fold). ADCC was marginally increased only after a full-dose BNT162b2. T-cell responses followed a similar pattern to neutralizing antibodies. Six months post-boost, antibody and T-cell responses had waned to baseline levels. While we detected strong anti-vector immunity, there was no correlation between anti-vector immunity in Ad26.COV2.S recipients and spike-specific neutralizing antibody or T-cell responses post-Ad26.COV2.S boosting. Overall, in the context of hybrid immunity, boosting with heterologous full- or half-dose BNT162b2 mRNA vaccine demonstrated superior immunogenicity 2 weeks post-vaccination compared to homologous Ad26.COV2.S, though rapid waning occurred by 12 weeks post-boost. Trial Registration: The study has been registered to the South African National Clinical Trial Registry (SANCTR): DOH-27-012022-7841 . The approval letter from SANCTR has been provided in the up-loaded documents.

@article{Klc2024,
abstract = {Background: COVID-19 disrupted the TB prevention programme in the UK, especially for TB infection (TBI) care. We explore whether experience of the COVID-19 pandemic impacted on patients' perceptions of TBI and its treatment. Methods: Semi-structured interviews were conducted as part of the Research to Improve Detection and Treatment of TBI (RID-TB) programme, exploring perceptual and practical barriers to TBI treatment. Nineteen people diagnosed with TBI were interviewed between August 2020 and April 2021. Recordings were transcribed and analysed using a constant comparative approach, allowing for a dynamic and iterative exploration of themes. Themes are organised using the Perceptions and Practicalities Approach. Findings: Some participants perceived TBI as a risk factor for increased susceptibility to COVID-19, while some thought that treatment for TBI might protect against COVID-19 or mitigate its effects. Adaptations to TB services (e.g., remote follow-up) and integrated practices during the COVID-19 restrictions (e.g., medication being posted) addressed some practical barriers to TBI treatment. However, we identified beliefs about TBI and COVID-19 that are likely to act as barriers to engagement with TBI treatment, including: interpreting service delays as an indication of TBI not being serious enough for treatment and concerns about contracting COVID-19 in TB clinics. Interpretation: COVID-19 and TBI service delays influence people's perceptions and practical barriers to TBI treatment adherence. Failure to address these beliefs may lead to people's concerns about their treatment not being fully addressed. Utilised service adaptations like remote consultations to address practical barriers may be relevant beyond COVID-19. Funding: NIHR RID-TB Program (RP-PG-0217-20009).},
author = {Kılı{\c{c}}, Ayşenur and Clarke, Amy L and Moon, Zoe and Hamada, Yohhei and Chan, Amy Hai Yan and Rahman, Ananna and Layton, Charlotte and Griffiths, Chris J and Zenner, Dominik and Powell, Ellen and Kunst, Heinke and Lipman, Marc and Mandelbaum, Mike and Papineni, Padmasayee and Tattersall, Tessa and Duong, Trinh and Abubakar, Ibrahim and Rangaka, Molebogeng X and Horne, Robert},
doi = {10.1016/J.DIALOG.2023.100162},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Kılı{\c{c}} et al. - 2024 - Health and illness beliefs in adults with tuberculosis infection during the COVID-19 pandemic in the UK.pdf:pdf},
issn = {2772-6533},
journal = {Dialogues in Health},
keywords = {Covid-19,LTBI,OA,fund{\_}not{\_}ack,health beliefs,original,perceptions,tuberculosis},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jun},
pages = {100162},
pmid = {38516222},
publisher = {Elsevier},
title = {{Health and illness beliefs in adults with tuberculosis infection during the COVID-19 pandemic in the UK}},
volume = {4},
year = {2024}
}

Background: COVID-19 disrupted the TB prevention programme in the UK, especially for TB infection (TBI) care. We explore whether experience of the COVID-19 pandemic impacted on patients' perceptions of TBI and its treatment. Methods: Semi-structured interviews were conducted as part of the Research to Improve Detection and Treatment of TBI (RID-TB) programme, exploring perceptual and practical barriers to TBI treatment. Nineteen people diagnosed with TBI were interviewed between August 2020 and April 2021. Recordings were transcribed and analysed using a constant comparative approach, allowing for a dynamic and iterative exploration of themes. Themes are organised using the Perceptions and Practicalities Approach. Findings: Some participants perceived TBI as a risk factor for increased susceptibility to COVID-19, while some thought that treatment for TBI might protect against COVID-19 or mitigate its effects. Adaptations to TB services (e.g., remote follow-up) and integrated practices during the COVID-19 restrictions (e.g., medication being posted) addressed some practical barriers to TBI treatment. However, we identified beliefs about TBI and COVID-19 that are likely to act as barriers to engagement with TBI treatment, including: interpreting service delays as an indication of TBI not being serious enough for treatment and concerns about contracting COVID-19 in TB clinics. Interpretation: COVID-19 and TBI service delays influence people's perceptions and practical barriers to TBI treatment adherence. Failure to address these beliefs may lead to people's concerns about their treatment not being fully addressed. Utilised service adaptations like remote consultations to address practical barriers may be relevant beyond COVID-19. Funding: NIHR RID-TB Program (RP-PG-0217-20009).

@article{Sinkala2024,
abstract = {In exploring the trans-ancestral genetic nuances of cardiovascular traits, we conducted a multi-trait genome-wide association study focusing on African (AFR) and European (EUR) populations in the UK Biobank. Here, we identify 50 genomic risk loci in the AFR population, among which 43 are novel discoveries associated with four cardiovascular traits. Similarly, we identify 829 loci in the EUR population, with 47 being novel. Also, at these loci, we identify 52 SNPs (45 novel) in the AFR population and 1,856 SNPs (957 novel) in the EUR population, among which 83 are shared, highlighting both the shared and rich diversity of the genetic underpinnings of cardiovascular disease across populations. Furthermore, functional mapping of these SNPs reveals distinct distribution patterns, with the EUR population showing a higher proportion in intronic and untranslated regions. Further, our study unravels population-specific genetic associations, identifying 3,011 genes exclusive to the EUR group and 36 distinct to the AFR group. Additionally, gene enrichment analyses show unique enriched pathways for each population, highlighting the potential influence of genetic ancestry on cardiovascular trait mechanisms and manifestation. Collectively, our results underscore the importance of population-specific approaches in studying the genetic underpinnings of cardiovascular health and further indicate potential avenues for personalised medicine and targeted interventions. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Funding Statement The funding for this project was provided by H3ABioNet, supported by the National Institutes of Health Common Fund under grant number U24HG006941. The content of this publication is solely the authors' responsibility and does not necessarily represent the official views of the National Institutes of Health. {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was reviewed by the UK Biobank Project and was exempt from ethical oversight by local legislation. Information on ethics approval by the UK Biobank can be found here: https://www.ukbiobank.ac.uk/learn-more-about-uk-biobank/about-us/ethics{\#}:{\~{}}:text=UK{\%}20Biobank{\%}20research{\%}20ethics{\%}20approval{\%}20UK{\%}20Biobank{\%}20has,{\%}28MREC{\%}29{\%}20as{\%}20a{\%}20Research{\%}20Tissue{\%}20Bank{\%}20{\%}28RTB{\%}29{\%}20approval. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The datasets that support the results presented in this manuscript are available from: the UK Biobank; {\textless}https://www.ukbiobank.ac.uk{\textgreater}, dbSNP; {\textless}https://www.ncbi.nlm.nih.gov/snp{\textgreater}, and the GWAS Catalog; {\textless}https://www.ebi.ac.uk/gwas{\textgreater}.},
author = {Sinkala, Musalula and Elsheikh, Samar and Mbiyavanga, Mamana and Cullinan, Joshua and Mulder, Nicola},
doi = {10.1101/2022.02.27.22268990},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Sinkala et al. - 2024 - Multitrait genome-wide analysis in the UK biobank reveals novel and distinct variants influencing cardiovascular.pdf:pdf},
journal = {medRxiv},
keywords = {African Population Genetics,Cardiovascular Genetics,Comparative Genetics,European Population Genetics,Genome-Wide Association Studies,Multi-Trait Analyses,OA,Precision Medicine,SNP Discovery,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jan},
pages = {2022.02.27.22268990},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Multitrait genome-wide analysis in the UK biobank reveals novel and distinct variants influencing cardiovascular traits in Africans and Europeans}},
url = {https://www.medrxiv.org/content/10.1101/2022.02.27.22268990v2 https://www.medrxiv.org/content/10.1101/2022.02.27.22268990v2.abstract},
year = {2024}
}

In exploring the trans-ancestral genetic nuances of cardiovascular traits, we conducted a multi-trait genome-wide association study focusing on African (AFR) and European (EUR) populations in the UK Biobank. Here, we identify 50 genomic risk loci in the AFR population, among which 43 are novel discoveries associated with four cardiovascular traits. Similarly, we identify 829 loci in the EUR population, with 47 being novel. Also, at these loci, we identify 52 SNPs (45 novel) in the AFR population and 1,856 SNPs (957 novel) in the EUR population, among which 83 are shared, highlighting both the shared and rich diversity of the genetic underpinnings of cardiovascular disease across populations. Furthermore, functional mapping of these SNPs reveals distinct distribution patterns, with the EUR population showing a higher proportion in intronic and untranslated regions. Further, our study unravels population-specific genetic associations, identifying 3,011 genes exclusive to the EUR group and 36 distinct to the AFR group. Additionally, gene enrichment analyses show unique enriched pathways for each population, highlighting the potential influence of genetic ancestry on cardiovascular trait mechanisms and manifestation. Collectively, our results underscore the importance of population-specific approaches in studying the genetic underpinnings of cardiovascular health and further indicate potential avenues for personalised medicine and targeted interventions. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The funding for this project was provided by H3ABioNet, supported by the National Institutes of Health Common Fund under grant number U24HG006941. The content of this publication is solely the authors' responsibility and does not necessarily represent the official views of the National Institutes of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was reviewed by the UK Biobank Project and was exempt from ethical oversight by local legislation. Information on ethics approval by the UK Biobank can be found here: https://www.ukbiobank.ac.uk/learn-more-about-uk-biobank/about-us/ethics#:\ :text=UK%20Biobank%20research%20ethics%20approval%20UK%20Biobank%20has,%28MREC%29%20as%20a%20Research%20Tissue%20Bank%20%28RTB%29%20approval. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The datasets that support the results presented in this manuscript are available from: the UK Biobank; \textlesshttps://www.ukbiobank.ac.uk\textgreater, dbSNP; \textlesshttps://www.ncbi.nlm.nih.gov/snp\textgreater, and the GWAS Catalog; \textlesshttps://www.ebi.ac.uk/gwas\textgreater.

@article{Ruffieux2024a,
abstract = {Background: Several studies have found lower prostate cancer diagnosis rates among men with human immunodeficiency virus (HIV; MWH) than men without HIV but reasons for this finding remain unclear. Methods: We used claims data from a South African private medical insurance scheme (July 2017-July 2020) to assess prostate cancer diagnosis rates among men aged ≥ 18 years with and without HIV. Using flexible parametric survival models, we estimated hazard ratios (HR) for the association between HIV and incident prostate cancer diagnoses. We accounted for potential confounding by age, population group, and sexually transmitted infections (confounder-adjusted model) and additionally for potential mediation by prostatitis diagnoses, prostate-specific antigen testing, and prostate biopsies (fully adjusted model).},
author = {Ruffieux, Yann and {Fern{\'{a}}ndez Villalobos}, Nathalie V and Didden, Christiane and Haas, Andreas D and Chinogurei, Chido and Cornell, Morna and Egger, Matthias and Maartens, Gary and Folb, Naomi and Rohner, Eliane},
doi = {10.1158/1055-9965.EPI-24-0137/3451500/EPI-24-0137.PDF},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Ruffieux et al. - 2024 - Prostate Cancer Diagnosis Rates among Insured Men with and without HIV in South Africa A Cohort Study(2).pdf:pdf},
issn = {1055-9965},
journal = {Cancer Epidemiology, Biomarkers {\&} Prevention},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jun},
number = {8},
pages = {OF1--OF8},
pmid = {38713162},
publisher = {American Association for Cancer Research (AACR)},
title = {{Prostate cancer diagnosis rates among insured men with and without HIV in South Africa: a cohort study}},
url = {/cebp/article/33/8/1057/746521/Prostate-Cancer-Diagnosis-Rates-among-Insured-Men https://dx.doi.org/10.1158/1055-9965.EPI-24-0137},
volume = {33},
year = {2024}
}

Background: Several studies have found lower prostate cancer diagnosis rates among men with human immunodeficiency virus (HIV; MWH) than men without HIV but reasons for this finding remain unclear. Methods: We used claims data from a South African private medical insurance scheme (July 2017-July 2020) to assess prostate cancer diagnosis rates among men aged ≥ 18 years with and without HIV. Using flexible parametric survival models, we estimated hazard ratios (HR) for the association between HIV and incident prostate cancer diagnoses. We accounted for potential confounding by age, population group, and sexually transmitted infections (confounder-adjusted model) and additionally for potential mediation by prostatitis diagnoses, prostate-specific antigen testing, and prostate biopsies (fully adjusted model).

@article{VanHeerden2024a,
abstract = {Background: Tenofovir diphosphate (TFV-DP) concentration in dried blood spots is a marker of long-term adherence. We investigated the relationship between TFV-DP concentrations and virological outcomes in participants initiating tenofovir–lamivudine–dolutegravir (TLD) as first-line or second-line antiretroviral therapy. Setting: Three primary care clinics in Khayelitsha, Cape Town, South Africa. Methods: We conducted a post hoc analysis of 2 randomized controlled trials of participants initiating TLD. TFV-DP concentrations and viral loads were measured at 12, 24, and 48 weeks. Multivariable logistic regression was performed to assess the association with virological suppression ({\textless}50 copies/mL) per natural logarithm increase in TFV-DP concentration. Generalized estimating equations with logit link were used to assess associations with virological rebound. The Akaike Information Criterion and Quasi-likelihood Information Criteria were used to compare models built on continuous TFV-DP data to 4 previously defined concentration categories. Results: We included 294 participants in the analysis, 188 (64{\%}) of whom initiated TLD as second-line therapy. Adjusted odds ratios (95{\%} CIs) of virological suppression were 2.12 (1.23, 3.75), 3.11 (1.84, 5.65), and 4.69 (2.81, 8.68) per natural logarithm increase in TFV-DP concentration at weeks 12, 24, and 48, respectively. In participants with virological suppression at week 12, the adjusted odds ratio for remaining virologically suppressed was 3.63 (95{\%} CI: 2.21 to 5.69) per natural logarithm increase in TFV-DP concentration. Models using continuous TFV-DP data had lower Akaike Information Criterion and Quasi-likelihood Information Criteria values than those using categorical data for predicting virological outcomes. Conclusion: TFV-DP concentrations in dried blood spots exhibit a dose–response relationship with viral load. Analyzing TFV-DP concentrations as continuous variables rather than conventional categorization may be appropriate.},
author = {van Heerden, Jennifer Kate and Meintjes, Graeme A and Barr, David and Zhao, Ying and Griesel, Rulan and Keene, Claire Marriott and Wiesner, Lubbe and Galileya, Lufina Tsirizani and Denti, Paolo and Maartens, Gary},
doi = {10.1097/QAI.0000000000003341},
file = {:C$\backslash$:/Users/01462563/OneDrive - University of Cape Town/Documents/CIDRI-Africa papers and outputs/van Heerden et al - 2024- relationship{\_}between{\_}tenofovir{\_}diphosphate.7.pdf:pdf},
issn = {1525-4135},
journal = {Journal of Acquired Immune Deficiency Syndromes},
keywords = {fund{\_}ack,original},
mendeley-tags = {fund{\_}ack,original},
month = {mar},
number = {3},
pages = {260--267},
pmid = {38408216},
title = {{Relationship between tenofovir diphosphate concentrations in dried blood spots and virological outcomes after initiating tenofovir–lamivudine–dolutegravir as first-line or second-line antiretroviral therapy}},
url = {https://journals.lww.com/jaids/fulltext/2024/03010/relationship{\_}between{\_}tenofovir{\_}diphosphate.7.aspx},
volume = {95},
year = {2024}
}

Background: Tenofovir diphosphate (TFV-DP) concentration in dried blood spots is a marker of long-term adherence. We investigated the relationship between TFV-DP concentrations and virological outcomes in participants initiating tenofovir–lamivudine–dolutegravir (TLD) as first-line or second-line antiretroviral therapy. Setting: Three primary care clinics in Khayelitsha, Cape Town, South Africa. Methods: We conducted a post hoc analysis of 2 randomized controlled trials of participants initiating TLD. TFV-DP concentrations and viral loads were measured at 12, 24, and 48 weeks. Multivariable logistic regression was performed to assess the association with virological suppression (\textless50 copies/mL) per natural logarithm increase in TFV-DP concentration. Generalized estimating equations with logit link were used to assess associations with virological rebound. The Akaike Information Criterion and Quasi-likelihood Information Criteria were used to compare models built on continuous TFV-DP data to 4 previously defined concentration categories. Results: We included 294 participants in the analysis, 188 (64%) of whom initiated TLD as second-line therapy. Adjusted odds ratios (95% CIs) of virological suppression were 2.12 (1.23, 3.75), 3.11 (1.84, 5.65), and 4.69 (2.81, 8.68) per natural logarithm increase in TFV-DP concentration at weeks 12, 24, and 48, respectively. In participants with virological suppression at week 12, the adjusted odds ratio for remaining virologically suppressed was 3.63 (95% CI: 2.21 to 5.69) per natural logarithm increase in TFV-DP concentration. Models using continuous TFV-DP data had lower Akaike Information Criterion and Quasi-likelihood Information Criteria values than those using categorical data for predicting virological outcomes. Conclusion: TFV-DP concentrations in dried blood spots exhibit a dose–response relationship with viral load. Analyzing TFV-DP concentrations as continuous variables rather than conventional categorization may be appropriate.

@article{Barilar2024,
abstract = {The World Health Organization has a goal of universal drug susceptibility testing for patients with tuberculosis. However, molecular diagnostics to date have focused largely on first-line drugs and predicting susceptibilities in a binary manner (classifying strains as either susceptible or resistant). Here, we used a multivariable linear mixed model alongside whole genome sequencing and a quantitative microtiter plate assay to relate genomic mutations to minimum inhibitory concentration (MIC) in 15,211 Mycobacterium tuberculosis clinical isolates from 23 countries across five continents. We identified 492 unique MIC-elevating variants across 13 drugs, as well as 91 mutations likely linked to hypersensitivity. Our results advance genetics-based diagnostics for tuberculosis and serve as a curated training/testing dataset for development of drug resistance prediction algorithms. Molecular diagnostics for tuberculosis have focused on predicting drug susceptibilities in a binary manner (i.e., strains are either susceptible or resistant). Here, CRyPTIC Consortium researchers use whole genome sequencing and a quantitative assay to identify associations between genomic mutations and minimum inhibitory concentrations in over 15,000 Mycobacterium tuberculosis clinical isolates.},
author = {Barilar, Ivan and Battaglia, Simone and Borroni, Emanuele and Brandao, Angela Pires and Brankin, Alice and Cabibbe, Andrea Maurizio and Carter, Joshua and Chetty, Darren and Cirillo, Daniela Maria and Claxton, Pauline and Clifton, David A and Cohen, Ted and Coronel, Jorge and Crook, Derrick W and Dreyer, Viola and Earle, Sarah G. and Escuyer, Vincent and Ferrazoli, Lucilaine and Fowler, Philip W and Gao, George Fu and Gardy, Jennifer and Gharbia, Saheer and Ghisi, Kelen Teixeira and Ghodousi, Arash and {Gibertoni Cruz}, Ana Lu{\'{i}}za and Grandjean, Louis and Grazian, Clara and Groenheit, Ramona and Guthrie, Jennifer L and He, Wencong and Hoffmann, Harald and Hoosdally, Sarah J and Hunt, Martin and Iqbal, Zamin and Ismail, Nazir Ahmed and Jarrett, Lisa and Joseph, Lavania and Jou, Ruwen and Kambli, Priti and Khot, Rukhsar and Knaggs, Jeff and Koch, Anastasia and Kohlerschmidt, Donna and Kouchaki, Samaneh and Lachapelle, Alexander S and Lalvani, Ajit and Lapierre, Simon Grandjean and Laurenson, Ian F and Letcher, Brice and Lin, Wan-Hsuan and Liu, Chunfa and Liu, Dongxin and Malone, Kerri M and Mandal, Ayan and Mansj{\"{o}}, Mikael and {Calisto Matias}, Daniela Vicente Lucena and Meintjes, Graeme A and {de Freitas Mendes}, Fl{\'{a}}via and Merker, Matthias and Mihalic, Marina and Millard, James and Miotto, Paolo and Mistry, Nerges and Moore, David and Musser, Kimberlee A and Ngcamu, Dumisani and Nhung, Hoang Ngoc and Niemann, Stefan and Nilgiriwala, Kayzad Soli and Nimmo, Camus and O'Donnell, Max and Okozi, Nana and Oliveira, Rosangela Siqueira and Omar, Shaheed Vally and Paton, Nicholas and Peto, Timothy E A and Pinhata, Juliana Maira Watanabe and Plesnik, Sara and Puyen, Zully M and Rabodoarivelo, Marie Sylvianne and Rakotosamimanana, Niaina and Rancoita, Paola M V and Rathod, Priti and Robinson, Esther Rhiannon and Rodger, Gillian and Rodrigues, Camilla and Rodwell, Timothy C and Roohi, Aysha and Santos-Lazaro, David and Shah, Sanchi and Smith, Grace and Kohl, Thomas Andreas and Solano, Walter and Spitaleri, Andrea and Steyn, Adrie J C and Supply, Philip and Surve, Utkarsha and Tahseen, Sabira and Thuong, Nguyen Thuy Thuong and Thwaites, Guy and Todt, Katharina and Trovato, Alberto and Utpatel, Christian and {Van Rie}, Annelies and Vijay, Srinivasan and Walker, A Sarah and Walker, Timothy M and Warren, Robin and Werngren, Jim and Wijkander, Maria and Wilkinson, Robert J and Wilson, Daniel J and Wintringer, Penelope and Xiao, Yu-Xin and Yang, Yang and Yanlin, Zhao and Yao, Shen-Yuan and Zhu, Baoli},
doi = {10.1038/s41467-023-44325-5},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Barilar et al. - 2024 - Quantitative measurement of antibiotic resistance in Mycobacterium tuberculosis reveals genetic determinants of.pdf:pdf},
issn = {2041-1723},
journal = {Nature Communications},
keywords = {Antibiotics,Antimicrobial resistance,Bacterial genes,Infectious,OA,OA{\_}PMC,Pathogens,disease diagnostics,fund{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,original},
month = {jan},
number = {1},
pages = {488},
pmid = {38216576},
publisher = {Nature Publishing Group},
title = {{Quantitative measurement of antibiotic resistance in \textit{Mycobacterium tuberculosis} reveals genetic determinants of resistance and susceptibility in a target gene approach}},
url = {https://www.nature.com/articles/s41467-023-44325-5},
volume = {15},
year = {2024}
}

The World Health Organization has a goal of universal drug susceptibility testing for patients with tuberculosis. However, molecular diagnostics to date have focused largely on first-line drugs and predicting susceptibilities in a binary manner (classifying strains as either susceptible or resistant). Here, we used a multivariable linear mixed model alongside whole genome sequencing and a quantitative microtiter plate assay to relate genomic mutations to minimum inhibitory concentration (MIC) in 15,211 Mycobacterium tuberculosis clinical isolates from 23 countries across five continents. We identified 492 unique MIC-elevating variants across 13 drugs, as well as 91 mutations likely linked to hypersensitivity. Our results advance genetics-based diagnostics for tuberculosis and serve as a curated training/testing dataset for development of drug resistance prediction algorithms. Molecular diagnostics for tuberculosis have focused on predicting drug susceptibilities in a binary manner (i.e., strains are either susceptible or resistant). Here, CRyPTIC Consortium researchers use whole genome sequencing and a quantitative assay to identify associations between genomic mutations and minimum inhibitory concentrations in over 15,000 Mycobacterium tuberculosis clinical isolates.

@article{Juraska2024a,
abstract = {In the Antibody Mediated Prevention (AMP) trials (HVTN 704/HPTN 085 and HVTN 703/HPTN 081), prevention efficacy (PE) of the monoclonal broadly neutralizing antibody (bnAb) VRC01 (vs. placebo) against HIV-1 acquisition diagnosis varied according to the HIV-1 Envelope (Env) neutralization sensitivity to VRC01, as measured by 80{\%} inhibitory concentration (IC80). Here, we performed a genotypic sieve analysis, a complementary approach to gaining insight into correlates of protection that assesses how PE varies with HIV-1 sequence features. We analyzed HIV-1 Env amino acid (AA) sequences from the earliest available HIV-1 RNA-positive plasma samples from AMP participants diagnosed with HIV-1 and identified Env sequence features that associated with PE. The strongest Env AA sequence correlate in both trials was VRC01 epitope distance that quantifies the divergence of the VRC01 epitope in an acquired HIV-1 isolate from the VRC01 epitope of reference HIV-1 strains that were most sensitive to VRC01-mediated neutralization. In HVTN 704/HPTN 085, the Env sequence-based predicted probability that VRC01 IC80 against the acquired isolate exceeded 1 µg/mL also significantly associated with PE. In HVTN 703/HPTN 081, a physicochemical-weighted Hamming distance across 50 VRC01 binding-associated Env AA positions of the acquired isolate from the most VRC01-sensitive HIV-1 strain significantly associated with PE. These results suggest that incorporating mutation scoring by BLOSUM62 and weighting by the strength of interactions at AA positions in the epitope:VRC01 interface can optimize performance of an Env sequence-based biomarker of VRC01 prevention efficacy. Future work could determine whether these results extend to other bnAbs and bnAb combinations.},
author = {Juraska, Michal and Bai, Hongjun and DeCamp, Allan C and Magaret, Craig A and Li, Li and Gillespie, Kevin and Carpp, Lindsay N and Giorgi, Elena E and Ludwig, James and Molitor, Cindy and Hudson, Aaron and Williamson, Brian D and Espy, Nicole and Simpkins, Brian and Rudnicki, Erika and Shao, Danica and Rossenkhan, Raabya and Edlefsen, Paul T and Westfall, Dylan H and Deng, Wenjie and Chen, Lennie and Zhao, Hong and Bhattacharya, Tanmoy and Pankow, Alec and Murrell, Ben and Yssel, Anna and Matten, David and York, Talita and Beaume, Nicolas and Gwashu-Nyangiwe, Asanda and Ndabambi, Nonkululeko and Thebus, Ruwayhida and Karuna, Shelly T and Morris, Lynn and Montefiori, David C and Hural, John A and Cohen, Myron S and Corey, Lawrence and Rolland, Morgane and Gilbert, Peter B and Williamson, Carolyn and Mullins, James I},
doi = {10.1073/PNAS.2308942121/SUPPL_FILE/PNAS.2308942121.SD01.CSV},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Juraska et al. - 2024 - Prevention efficacy of the broadly neutralizing antibody VRC01 depends on HIV-1 envelope sequence features.pdf:pdf},
issn = {10916490},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
keywords = {HIV diversity,Hamming distance,OA,PAR score,epitope,fund{\_}not{\_}ack,original,sieve analysis},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jan},
number = {4},
pages = {e2308942121},
pmid = {38241441},
publisher = {National Academy of Sciences},
title = {{Prevention efficacy of the broadly neutralizing antibody VRC01 depends on HIV-1 envelope sequence features}},
url = {https://www.pnas.org/doi/abs/10.1073/pnas.2308942121},
volume = {121},
year = {2024}
}

In the Antibody Mediated Prevention (AMP) trials (HVTN 704/HPTN 085 and HVTN 703/HPTN 081), prevention efficacy (PE) of the monoclonal broadly neutralizing antibody (bnAb) VRC01 (vs. placebo) against HIV-1 acquisition diagnosis varied according to the HIV-1 Envelope (Env) neutralization sensitivity to VRC01, as measured by 80% inhibitory concentration (IC80). Here, we performed a genotypic sieve analysis, a complementary approach to gaining insight into correlates of protection that assesses how PE varies with HIV-1 sequence features. We analyzed HIV-1 Env amino acid (AA) sequences from the earliest available HIV-1 RNA-positive plasma samples from AMP participants diagnosed with HIV-1 and identified Env sequence features that associated with PE. The strongest Env AA sequence correlate in both trials was VRC01 epitope distance that quantifies the divergence of the VRC01 epitope in an acquired HIV-1 isolate from the VRC01 epitope of reference HIV-1 strains that were most sensitive to VRC01-mediated neutralization. In HVTN 704/HPTN 085, the Env sequence-based predicted probability that VRC01 IC80 against the acquired isolate exceeded 1 µg/mL also significantly associated with PE. In HVTN 703/HPTN 081, a physicochemical-weighted Hamming distance across 50 VRC01 binding-associated Env AA positions of the acquired isolate from the most VRC01-sensitive HIV-1 strain significantly associated with PE. These results suggest that incorporating mutation scoring by BLOSUM62 and weighting by the strength of interactions at AA positions in the epitope:VRC01 interface can optimize performance of an Env sequence-based biomarker of VRC01 prevention efficacy. Future work could determine whether these results extend to other bnAbs and bnAb combinations.

@article{Bekolo2024,
abstract = {Cameroon adopted and started implementing in 2016, the ‘universal test and treat' (UTT) guidelines to fast-track progress towards the 95-95-95 ambitious targets to end the HIV epidemic. Achieving the third 95 (viral load suppression) is the most desirable target in HIV care. We aimed to evaluate the effectiveness of this novel approach on access to viral load testing (VLT), viral suppression (VLS), and viral load rebound (VLR). A retrospective cohort study was conducted at The Nkongsamba Regional Hospital to compare VLT outcomes between the pre-UTT (2002 to 2015) and the post-UTT (2016 to 2020) periods. We used a data extraction form to collect routine data on adult patients living with HIV. We measured uptake levels of the first and serial VLT and compared the incidence rates of VLS (VL{\textless}1000 copies/ml) and viral load rebound (VLR) before and after introducing the UTT approach using Kaplan Meier plots and log-rank tests. Cox regression was used to screen for factors independently associated with VLS and VLR events between the guideline periods. Access to initial VLT increased significantly from 6.11{\%} to 25.56{\%} at 6 months and from 12.00{\%} to 73.75{\%} at 12 months before and after introducing the UTT guidelines respectively. After a total observation time at risk of 17001.63 person-months, the UTT group achieved an incidence rate of 90.36 VLS per 1000 person-months, four-fold higher than the 21.71 VLS per 1000 person-months observed in the pre-UTT group (p{\textless}0.0001). After adjusting for confounding, the VLS rate was about 6-fold higher in the UTT group than in the pre-UTT group (adjusted Hazard Rate (aHR) = 5.81 (95{\%} confidence interval (95{\%}CI): 4.43–7.60). The incidence of VLR increased from 12.60 (95{\%}CI: 9.50–16.72) to 19.11 (95{\%}CI: 14.22–25.67) per 1000 person-months before and after the introduction of UTT guidelines respectively. After adjusting, VLR was more than twice as high in the UTT group than in the pre-UTT group (aHR = 2.32, 95{\%}CI: 1.30–4.13). Increased access to initial VLT and higher rates of VLS have been observed but there are concerns that the suppressed viral load may not be durable since the introduction of the UTT policy in this setting.},
author = {Bekolo, C E and Ndeso, S A and Moifo, L L and Mangala, N and Ateudjieu, J and Kouanfack, C and Dzudie, A and Thienemann, Friedrich and Tendongfor, N and Nsagha, D S and Choukem, S P},
doi = {10.1371/JOURNAL.PGPH.0003042},
editor = {Fatokun, Omotayo},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Bekolo et al. - 2024 - Changes in access to viral load testing, incidence rates of viral load suppression and rebound following the intr.pdf:pdf},
issn = {2767-3375},
journal = {PLOS Global Public Health},
keywords = {C E Bekolo,MEDLINE,NCBI,NIH,NLM,National Center for Biotechnology Information,National Institutes of Health,National Library of Medicine,OA,OA{\_}PMC,PMC11020606,PubMed Abstract,S A Ndeso,S P Choukem,doi:10.1371/journal.pgph.0003042,fund{\_}not{\_}ack,original,pmid:38626049},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {apr},
number = {4},
pages = {e0003042},
pmid = {38626049},
publisher = {PLOS Glob Public Health},
title = {{Changes in access to viral load testing, incidence rates of viral load suppression and rebound following the introduction of the 'universal test and treat' guidelines in Cameroon: A retrospective follow-up analysis}},
url = {https://pubmed.ncbi.nlm.nih.gov/38626049/},
volume = {4},
year = {2024}
}

Cameroon adopted and started implementing in 2016, the ‘universal test and treat' (UTT) guidelines to fast-track progress towards the 95-95-95 ambitious targets to end the HIV epidemic. Achieving the third 95 (viral load suppression) is the most desirable target in HIV care. We aimed to evaluate the effectiveness of this novel approach on access to viral load testing (VLT), viral suppression (VLS), and viral load rebound (VLR). A retrospective cohort study was conducted at The Nkongsamba Regional Hospital to compare VLT outcomes between the pre-UTT (2002 to 2015) and the post-UTT (2016 to 2020) periods. We used a data extraction form to collect routine data on adult patients living with HIV. We measured uptake levels of the first and serial VLT and compared the incidence rates of VLS (VL\textless1000 copies/ml) and viral load rebound (VLR) before and after introducing the UTT approach using Kaplan Meier plots and log-rank tests. Cox regression was used to screen for factors independently associated with VLS and VLR events between the guideline periods. Access to initial VLT increased significantly from 6.11% to 25.56% at 6 months and from 12.00% to 73.75% at 12 months before and after introducing the UTT guidelines respectively. After a total observation time at risk of 17001.63 person-months, the UTT group achieved an incidence rate of 90.36 VLS per 1000 person-months, four-fold higher than the 21.71 VLS per 1000 person-months observed in the pre-UTT group (p\textless0.0001). After adjusting for confounding, the VLS rate was about 6-fold higher in the UTT group than in the pre-UTT group (adjusted Hazard Rate (aHR) = 5.81 (95% confidence interval (95%CI): 4.43–7.60). The incidence of VLR increased from 12.60 (95%CI: 9.50–16.72) to 19.11 (95%CI: 14.22–25.67) per 1000 person-months before and after the introduction of UTT guidelines respectively. After adjusting, VLR was more than twice as high in the UTT group than in the pre-UTT group (aHR = 2.32, 95%CI: 1.30–4.13). Increased access to initial VLT and higher rates of VLS have been observed but there are concerns that the suppressed viral load may not be durable since the introduction of the UTT policy in this setting.

@article{Dale2024,
abstract = {Tuberculosis (TB) is caused by Mycobacterium tuberculosis ( Mtb ). Following infection, immune responses to Mtb antigens can be measured using the tuberculin skin test or an interferon-$\gamma$ release assay. The gain of Mtb immunoreactivity, a change from a negative to a positive tuberculin skin test or interferon-$\gamma$ release assay result, is called conversion and has long been used as a measure of Mtb exposure. However, the loss of immunoreactivity (reversion; a positive followed by a negative result) has often been overlooked. Instead, in clinical and epidemiological circles, Mtb immunoreactivity is commonly considered to persist lifelong and confer a lifetime of disease risk. We present a critical review, describing the evidence for reversion from cohort studies, ecological studies and studies of TB progression risk. We outline the inconsistent reasons why reversion has been dismissed from common understanding and present evidence demonstrating that, just as conversion predominantly indicates prior exposure to Mtb antigens, so its opposite, reversion, suggests the reduction or absence of exposure (endogenous or exogenous). Mtb immunoreactivity is dynamic in both individuals and populations and this is why it is useful for stratifying short-term TB progression risk. The neglect of reversion has shaped TB research and policy at all levels, influencing clinical management and skewing Mtb infection risk estimation and transmission modelling, leading to an underestimation of the contribution of re-exposure to the burden of TB, a serious oversight for an infectious disease. More than a century after it was first demonstrated, it is time to incorporate reversion into our understanding of the natural history of TB. The idea that a positive TST/IGRA “persists” lifelong informs TB clinical care, research and modelling. We present the evidence for the reversion of Mtb immunoreactivity and discuss the reasons why it should be incorporated into our understanding of TB. {\textless}https://bit.ly/4aSbldD{\textgreater}},
author = {Dale, Katie D and Schwalb, Alvaro and Coussens, Anna K and Gibney, Katherine B and Abboud, Alison J and Watts, Krista and Denholm, Justin T},
doi = {10.1183/16000617.0007-2024},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Dale et al. - 2024 - Overlooked, dismissed, and downplayed reversion of Mycobacterium tuberculosis immunoreactivity.pdf:pdf},
issn = {0905-9180},
journal = {European Respiratory Review},
keywords = {OA,fund{\_}not{\_}ack,review},
mendeley-tags = {OA,fund{\_}not{\_}ack,review},
month = {jul},
number = {173},
pages = {240007},
pmid = {39048129},
publisher = {European Respiratory Society},
title = {{Overlooked, dismissed, and downplayed: reversion of \textit{Mycobacterium tuberculosis} immunoreactivity}},
url = {https://err.ersjournals.com/content/33/173/240007 https://err.ersjournals.com/content/33/173/240007.abstract},
volume = {33},
year = {2024}
}

Tuberculosis (TB) is caused by Mycobacterium tuberculosis ( Mtb ). Following infection, immune responses to Mtb antigens can be measured using the tuberculin skin test or an interferon-$γ$ release assay. The gain of Mtb immunoreactivity, a change from a negative to a positive tuberculin skin test or interferon-$γ$ release assay result, is called conversion and has long been used as a measure of Mtb exposure. However, the loss of immunoreactivity (reversion; a positive followed by a negative result) has often been overlooked. Instead, in clinical and epidemiological circles, Mtb immunoreactivity is commonly considered to persist lifelong and confer a lifetime of disease risk. We present a critical review, describing the evidence for reversion from cohort studies, ecological studies and studies of TB progression risk. We outline the inconsistent reasons why reversion has been dismissed from common understanding and present evidence demonstrating that, just as conversion predominantly indicates prior exposure to Mtb antigens, so its opposite, reversion, suggests the reduction or absence of exposure (endogenous or exogenous). Mtb immunoreactivity is dynamic in both individuals and populations and this is why it is useful for stratifying short-term TB progression risk. The neglect of reversion has shaped TB research and policy at all levels, influencing clinical management and skewing Mtb infection risk estimation and transmission modelling, leading to an underestimation of the contribution of re-exposure to the burden of TB, a serious oversight for an infectious disease. More than a century after it was first demonstrated, it is time to incorporate reversion into our understanding of the natural history of TB. The idea that a positive TST/IGRA “persists” lifelong informs TB clinical care, research and modelling. We present the evidence for the reversion of Mtb immunoreactivity and discuss the reasons why it should be incorporated into our understanding of TB. \textlesshttps://bit.ly/4aSbldD\textgreater

@article{Garrett2024,
abstract = {Given limited data on safety and effectiveness of heterologous COVID-19 vaccine boosting in lower income, high-HIV prevalence settings, we evaluated a mRNA-1273 boost after Ad26.COV2.S priming in South Africa. SHERPA was a single-arm, open-label, phase 3 study nested in the Sisonke implementation trial of 500000 healthcare workers (HCWs). Sisonke participants were offered mRNA-1273 boosters between May and November 2022, a period of circulating Omicron sub-lineages. Adverse events (AE) were self-reported, and co-primary endpoints (SARS-CoV-2 infections and COVID-19 hospitalizations or deaths) were collected through national databases. We used Cox regression models with booster status as time-varying covariate to determine the relative vaccine effectiveness (rVE) of the mRNA-1273 booster among SHERPA versus unboosted Sisonke participants. Of 11248 SHERPA participants in the rVE analysis cohort (79.3{\%} female, median age 41), 45.4{\%} had received one and 54.6{\%} two Ad26.COV2.S doses. Self-reported comorbidities included HIV (18.7{\%}), hypertension (12.9{\%}) and diabetes (4.6{\%}). In multivariable analysis including 413161 unboosted Sisonke participants, rVE of the booster was 59{\%} (95{\%}CI 29-76{\%}) against SARS-CoV-2 infection: 77{\%} (95{\%}CI 9–94{\%}) in the one-Ad26.COV2.S dose group and 52{\%} (95{\%}CI 13-73{\%}) in the two-dose group. Severe COVID-19 was identified in 148 unboosted participants, and only one SHERPA participant with severe HIV-related immunosuppression. Of 11798 participants in the safety analysis, 271 (2.3{\%}) reported a reactogenicity event or unsolicited AE, more among those with prior SARS-CoV-2 infections (adjusted odds ratio [aOR] 2.03, 95{\%}CI 1.59-2.59) and less among people living with HIV (PLWH) (aOR 0.49, 95{\%}CI 0.34-0.69). No related serious AEs were reported. In an immunogenicity sub-study, mRNA-1273 increased antibody functions and T-cell responses 4 weeks after boosting regardless of the number of prior Ad26.COV2.S doses, or HIV status, and generated Omicron spike-specific cross-reactive responses. mRNA-1273 boosters after one or two Ad26.COV2.S doses were well-tolerated, safe and effective against Omicron SARS-CoV-2 infections among HCWs and PLWH. Trial Registration The SHERPA study is registered in the Pan African Clinical Trials Registry (PACTR): PACTR202310615330649 and the South African National Clinical Trial Registry (SANCTR): DOH-27-052022-5778. {\#}{\#}{\#} Competing Interest Statement Kate Anteyi, Brett Leav are employees of Moderna, Inc. and may hold stock/stock options in the company. The other authors declare no conflict of interests. {\#}{\#}{\#} Clinical Trial PACTR202310615330649 {\#}{\#}{\#} Funding Statement The SHERPA study was funded by Moderna, Inc. (Cambridge, Massachusetts, US) and the South African Medical Research Council (SAMRC). Moderna provided mRNA-1273 free-of-charge. The Sisonke trial was funded by: The National Department of Health through baseline funding to the SAMRC the Solidarity Response Fund NPC The Michael {\&} Susan Dell Foundation the ELMA Vaccines and Immunization Foundation (21-V0001) and the Bill {\&} Melinda Gates Foundation (INV-030342). Moderna representatives reviewed the study protocol, participated in safety oversight, and contributed as manuscript co-authors, but were not involved in data collection and analysis. {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The SHERPA study received full ethical approval by the following ethics committees in South Africa: Pharma-Ethics, Stellenbosch University Health Research Ethics Committee, University of KwaZulu-Natal Biomedical Research Ethics Committee, University of Cape Town Human Research Ethics Committee, Sefako Makgatho University Research Ethics Committee, The South African Medical Research Council Human Research Ethics Committee and the University of the Witwatersrand Human Research Ethics Committee. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as [ClinicalTrials.gov][1]. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Considering this is a clinical trial, universal access to data may not be possible to protect clinical trial participants. However, SHERPA data will be made available by the authors upon reasonable request. You can access the SHERPA data on the following link: {\textless}https://medat.samrc.ac.za/index.php/catalog/56{\textgreater} {\textless}https://medat.samrc.ac.za/index.php/catalog/56{\textgreater} [1]: http://ClinicalTrials.gov},
author = {Garrett, Nigel and Reddy, Tarylee and Yende-Zuma, Nonhlanhla and Takalani, Azwidhwi and Woeber, Kubashni and Bodenstein, Annie and Jonas, Phumeza and Engelbrecht, Imke and Jassat, Waasila and Moultrie, Harry and Bradshaw, Debbie and Seocharan, Ishen and Odhiambo, Jackline and Khuto, Kentse and Richardson, Simone I and Omondi, Millicent A and Nesamari, Rofhiwa and Keeton, Roanne S and Riou, Catherine and Moyo-Gwete, Thandeka and Innes, Craig and Zwane, Zwelethu and Mngadi, Kathy and Brumskine, William and Naicker, Nivashnee and Potloane, Disebo and Badal-Faesen, Sharlaa and Innes, Steve and Barnabas, Shaun and Lombaard, Johan and Gill, Katherine and Nchabeleng, Maphoshane and Snyman, Elizma and Petrick, Friedrich and Spooner, Elizabeth and Naidoo, Logashvari and Kalonji, Dishiki and Naicker, Vimla and Singh, Nishanta and Maboa, Rebone and Mda, Pamela and Malan, Daniel and Nana, Anusha and Malahleha, Mookho and Kotze, Philip and Allagappen, Jon J and Diacon, Andreas H and Kruger, Gertruida M and Patel, Faeezah and Moore, Penny L and Burgers, Wendy A and Anteyi, Kate and Leav, Brett and Bekker, Linda-Gail and Gray, Glenda E and Goga, Ameena and {the SHERPA study Team}},
doi = {10.1101/2024.06.07.24306760},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Garrett et al. - 2024 - Safety, Effectiveness and Immunogenicity of heterologous mRNA-1273 Boost after Prime with Ad26.COV2.S among Heal.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jun},
pages = {2024.06.07.24306760},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Safety, effectiveness and immunogenicity of heterologous mRNA-1273 boost after prime with Ad26.COV2.S among healthcare workers in South Africa: the single-arm, open-label, Phase 3 SHERPA Study}},
url = {https://www.medrxiv.org/content/10.1101/2024.06.07.24306760v1 https://www.medrxiv.org/content/10.1101/2024.06.07.24306760v1.abstract},
year = {2024}
}

Given limited data on safety and effectiveness of heterologous COVID-19 vaccine boosting in lower income, high-HIV prevalence settings, we evaluated a mRNA-1273 boost after Ad26.COV2.S priming in South Africa. SHERPA was a single-arm, open-label, phase 3 study nested in the Sisonke implementation trial of 500000 healthcare workers (HCWs). Sisonke participants were offered mRNA-1273 boosters between May and November 2022, a period of circulating Omicron sub-lineages. Adverse events (AE) were self-reported, and co-primary endpoints (SARS-CoV-2 infections and COVID-19 hospitalizations or deaths) were collected through national databases. We used Cox regression models with booster status as time-varying covariate to determine the relative vaccine effectiveness (rVE) of the mRNA-1273 booster among SHERPA versus unboosted Sisonke participants. Of 11248 SHERPA participants in the rVE analysis cohort (79.3% female, median age 41), 45.4% had received one and 54.6% two Ad26.COV2.S doses. Self-reported comorbidities included HIV (18.7%), hypertension (12.9%) and diabetes (4.6%). In multivariable analysis including 413161 unboosted Sisonke participants, rVE of the booster was 59% (95%CI 29-76%) against SARS-CoV-2 infection: 77% (95%CI 9–94%) in the one-Ad26.COV2.S dose group and 52% (95%CI 13-73%) in the two-dose group. Severe COVID-19 was identified in 148 unboosted participants, and only one SHERPA participant with severe HIV-related immunosuppression. Of 11798 participants in the safety analysis, 271 (2.3%) reported a reactogenicity event or unsolicited AE, more among those with prior SARS-CoV-2 infections (adjusted odds ratio [aOR] 2.03, 95%CI 1.59-2.59) and less among people living with HIV (PLWH) (aOR 0.49, 95%CI 0.34-0.69). No related serious AEs were reported. In an immunogenicity sub-study, mRNA-1273 increased antibody functions and T-cell responses 4 weeks after boosting regardless of the number of prior Ad26.COV2.S doses, or HIV status, and generated Omicron spike-specific cross-reactive responses. mRNA-1273 boosters after one or two Ad26.COV2.S doses were well-tolerated, safe and effective against Omicron SARS-CoV-2 infections among HCWs and PLWH. Trial Registration The SHERPA study is registered in the Pan African Clinical Trials Registry (PACTR): PACTR202310615330649 and the South African National Clinical Trial Registry (SANCTR): DOH-27-052022-5778. ### Competing Interest Statement Kate Anteyi, Brett Leav are employees of Moderna, Inc. and may hold stock/stock options in the company. The other authors declare no conflict of interests. ### Clinical Trial PACTR202310615330649 ### Funding Statement The SHERPA study was funded by Moderna, Inc. (Cambridge, Massachusetts, US) and the South African Medical Research Council (SAMRC). Moderna provided mRNA-1273 free-of-charge. The Sisonke trial was funded by: The National Department of Health through baseline funding to the SAMRC the Solidarity Response Fund NPC The Michael & Susan Dell Foundation the ELMA Vaccines and Immunization Foundation (21-V0001) and the Bill & Melinda Gates Foundation (INV-030342). Moderna representatives reviewed the study protocol, participated in safety oversight, and contributed as manuscript co-authors, but were not involved in data collection and analysis. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The SHERPA study received full ethical approval by the following ethics committees in South Africa: Pharma-Ethics, Stellenbosch University Health Research Ethics Committee, University of KwaZulu-Natal Biomedical Research Ethics Committee, University of Cape Town Human Research Ethics Committee, Sefako Makgatho University Research Ethics Committee, The South African Medical Research Council Human Research Ethics Committee and the University of the Witwatersrand Human Research Ethics Committee. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as [ClinicalTrials.gov][1]. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Considering this is a clinical trial, universal access to data may not be possible to protect clinical trial participants. However, SHERPA data will be made available by the authors upon reasonable request. You can access the SHERPA data on the following link: \textlesshttps://medat.samrc.ac.za/index.php/catalog/56\textgreater \textlesshttps://medat.samrc.ac.za/index.php/catalog/56\textgreater [1]: http://ClinicalTrials.gov

@article{Schiff2024,
abstract = {Novel biomarkers to identify infectious patients transmitting Mycobacterium tuberculosis are urgently needed to control the global tuberculosis (TB) pandemic. We hypothesized that proteins released into the plasma in active pulmonary TB are clinically useful biomarkers to distinguish TB cases from healthy individuals and patients with other respiratory infections. We applied a highly sensitive non-depletion tandem mass spectrometry discovery approach to investigate plasma protein expression in pulmonary TB cases compared to healthy controls in South African and Peruvian cohorts. Bioinformatic analysis using linear modelling and network correlation analyses identified 118 differentially expressed proteins, significant through three complementary analytical pipelines. Candidate biomarkers were subsequently analysed in two validation cohorts of differing ethnicity using antibody-based proximity extension assays. TB-specific host biomarkers were confirmed. A six-protein diagnostic panel, comprising FETUB, FCGR3B, LRG1, SELL, CD14 and ADA2, differentiated patients with pulmonary TB from healthy controls and patients with other respiratory infections with high sensitivity and specificity in both cohorts. This biomarker panel exceeds the World Health Organisation Target Product Profile specificity criteria for a triage test for TB. The new biomarkers have potential for further development as near-patient TB screening assays, thereby helping to close the case-detection gap that fuels the global pandemic.},
author = {Schiff, Hannah F and Walker, Naomi F and Ugarte-Gil, Cesar and Tebruegge, Marc and Manousopoulou, Antigoni and Garbis, Spiros D and Mansour, Salah and Wong, Pak Ho and Rockett, Gabrielle and Piazza, Paolo and Niranjan, Mahesan and Vallejo, Andres F and Woelk, Christopher H and Wilkinson, Robert J and Tezera, Liku B and Garay-Baquero, Diana and Elkington, Paul},
doi = {10.1172/JCI.INSIGHT.173273},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Schiff et al. - 2024 - Integrated plasma proteomics identifies tuberculosis-specific diagnostic biomarkers.pdf:pdf},
issn = {0021-9738},
journal = {JCI Insight},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {mar},
pages = {10.1172/jci.insight.173273},
publisher = {American Society for Clinical Investigation},
title = {{Integrated plasma proteomics identifies tuberculosis-specific diagnostic biomarkers}},
url = {http://insight.jci.org/articles/view/173273},
year = {2024}
}

Novel biomarkers to identify infectious patients transmitting Mycobacterium tuberculosis are urgently needed to control the global tuberculosis (TB) pandemic. We hypothesized that proteins released into the plasma in active pulmonary TB are clinically useful biomarkers to distinguish TB cases from healthy individuals and patients with other respiratory infections. We applied a highly sensitive non-depletion tandem mass spectrometry discovery approach to investigate plasma protein expression in pulmonary TB cases compared to healthy controls in South African and Peruvian cohorts. Bioinformatic analysis using linear modelling and network correlation analyses identified 118 differentially expressed proteins, significant through three complementary analytical pipelines. Candidate biomarkers were subsequently analysed in two validation cohorts of differing ethnicity using antibody-based proximity extension assays. TB-specific host biomarkers were confirmed. A six-protein diagnostic panel, comprising FETUB, FCGR3B, LRG1, SELL, CD14 and ADA2, differentiated patients with pulmonary TB from healthy controls and patients with other respiratory infections with high sensitivity and specificity in both cohorts. This biomarker panel exceeds the World Health Organisation Target Product Profile specificity criteria for a triage test for TB. The new biomarkers have potential for further development as near-patient TB screening assays, thereby helping to close the case-detection gap that fuels the global pandemic.

@article{Zinyakatira2024,
abstract = {Background: Multi-drug or rifamycin-resistant tuberculosis (MDR/RR-TB) is an important public health concern, including in settings with high HIV prevalence. TB drug resistance can be directly transmitted or arise through resistance acquisition during first-line TB treatment. Limited evidence suggests that people living with HIV (PLHIV) might have an increased risk of acquired rifamycin-resistance (ARR). Methods: To assess HIV as a risk factor for ARR during first-line TB treatment, a systematic review and meta-analysis was conducted. ARR was defined as rifamycin-susceptibility at treatment start with rifamycin-resistance diagnosed during or at the end of treatment, or at recurrence. PubMed/MEDLINE, CINAHL, Cochrane Library, and Google Scholar databases were searched from inception to 23 May 2024 for articles in English; conference abstracts were also searched from 2004 to 2021. The Mantel-Haenszel random-effects model was used to estimate the pooled odds ratio of any association between HIV and ARR among individuals receiving first-line TB treatment. Results: Ten studies that included data collected between 1990 and 2014 were identified: five from the United States, two from South Africa and one each from Uganda, India and Moldova. A total of 97,564 individuals were included across all studies, with 13,359 (13.7{\%}) PLHIV. Overall, 312 (0.32{\%}) acquired rifamycin-resistance, among whom 115 (36.9{\%}) were PLHIV. The weighted odds of ARR were 4.57 (95{\%} CI, 2.01–10.42) times higher among PLHIV compared to HIV-negative individuals receiving first-line TB treatment. Conclusion: The available data, suggest that PLHIV have an increased ARR risk during first-line TB treatment. Further research is needed to clarify specific risk factors, including advanced HIV disease and TB disease severity. Given the introduction of shorter, 4-month rifamycin-based regimens, there is an urgent need for additional data on ARR, particularly for PLHIV. Systematic review registration: PROSPERO CRD42022327337.},
author = {Zinyakatira, Nesbert and Ford, Nathan and Cox, Helen},
doi = {10.1186/S12879-024-09514-7/FIGURES/3},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Zinyakatira, Ford, Cox - 2024 - Association between HIV and acquisition of rifamycin resistance with first-line TB treatment a systemati.pdf:pdf},
issn = {14712334},
journal = {BMC Infectious Diseases},
keywords = {Acquired rifamycin-resistance systematic review,Human immunodeficiency virus,Meta-analysis,OA,Tuberculosis,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {dec},
number = {1},
pages = {1--13},
publisher = {BioMed Central Ltd},
title = {{Association between HIV and acquisition of rifamycin resistance with first-line TB treatment: a systematic review and meta-analysis}},
url = {https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-024-09514-7 http://creativecommons.org/publicdomain/zero/1.0/},
volume = {24},
year = {2024}
}

Background: Multi-drug or rifamycin-resistant tuberculosis (MDR/RR-TB) is an important public health concern, including in settings with high HIV prevalence. TB drug resistance can be directly transmitted or arise through resistance acquisition during first-line TB treatment. Limited evidence suggests that people living with HIV (PLHIV) might have an increased risk of acquired rifamycin-resistance (ARR). Methods: To assess HIV as a risk factor for ARR during first-line TB treatment, a systematic review and meta-analysis was conducted. ARR was defined as rifamycin-susceptibility at treatment start with rifamycin-resistance diagnosed during or at the end of treatment, or at recurrence. PubMed/MEDLINE, CINAHL, Cochrane Library, and Google Scholar databases were searched from inception to 23 May 2024 for articles in English; conference abstracts were also searched from 2004 to 2021. The Mantel-Haenszel random-effects model was used to estimate the pooled odds ratio of any association between HIV and ARR among individuals receiving first-line TB treatment. Results: Ten studies that included data collected between 1990 and 2014 were identified: five from the United States, two from South Africa and one each from Uganda, India and Moldova. A total of 97,564 individuals were included across all studies, with 13,359 (13.7%) PLHIV. Overall, 312 (0.32%) acquired rifamycin-resistance, among whom 115 (36.9%) were PLHIV. The weighted odds of ARR were 4.57 (95% CI, 2.01–10.42) times higher among PLHIV compared to HIV-negative individuals receiving first-line TB treatment. Conclusion: The available data, suggest that PLHIV have an increased ARR risk during first-line TB treatment. Further research is needed to clarify specific risk factors, including advanced HIV disease and TB disease severity. Given the introduction of shorter, 4-month rifamycin-based regimens, there is an urgent need for additional data on ARR, particularly for PLHIV. Systematic review registration: PROSPERO CRD42022327337.

@article{Carse2024,
abstract = {Human papillomavirus (HPV) infection poses a significant health challenge, particularly in low- and middle-income countries (LMIC), where limited healthcare access and awareness hinder vaccine accessibility. To identify alternative HPV targeting interventions, we previously reported on surfactant protein A (SP-A) as a novel molecule capable of recognising HPV16 pseudovirions (HPV16-PsVs) and reducing infection in a murine cervicovaginal HPV challenge model. Building on these findings, our current study aimed to assess SP-A's suitability as a broad-spectrum HPV-targeting molecule and its impact on innate immune responses. We demonstrate SP-A's ability to agglutinate and opsonise multiple oncogenic HPV-PsVs types, enhancing their uptake and clearance by RAW264.7 murine macrophages and THP-1 human-derived immune cells. The SP-A opsonisation of HPV not only led to increased lysosomal accumulation in macrophages and HaCaT keratinocytes but also resulted in a decreased infection of HaCaT cells, which was further decreased when co-cultured with innate immune cells. An analysis of human innate immune cell cytokine profiles revealed a significant inflammatory response upon SP-A exposure, potentially contributing to the overall inhibition of HPV infection. These results highlight the multi-layered impact of SP-A on HPV, innate immune cells and keratinocytes and lay the basis for the development of alternative prophylactic interventions against diverse HPV types.},
author = {Carse, Sinead and Reid, Tim and Madsen, Jens and Clark, Howard and Kirjakulov, Artur and {Bergant Maru{\v{s}}i{\v{c}}}, Martina and Sch{\"{a}}fer, Georgia},
doi = {10.3390/IJMS25147712/S1},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Carse et al. - 2024 - Functional Characterisation of Surfactant Protein A as a Novel Prophylactic Means against Oncogenic HPV Infections.pdf:pdf},
issn = {14220067},
journal = {International Journal of Molecular Sciences},
keywords = {1,A),HPV prophylactic,HaCaT keratinocytes,OA,OA{\_}PMC,RAW264.7 murine macrophages,THP,and middle,cervical cancer,derived immune cells,fund{\_}not{\_}ack,human papillomavirus (HPV),income countries (LMIC),low,original,pseudovirus,surfactant protein A (SP},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {jul},
number = {14},
pages = {7712},
pmid = {39062960},
publisher = {MDPI AG},
title = {{Functional characterisation of surfactant protein A as a novel prophylactic means against oncogenic HPV infections}},
url = {https://www.mdpi.com/1422-0067/25/14/7712/htm https://www.mdpi.com/1422-0067/25/14/7712},
volume = {25},
year = {2024}
}

Human papillomavirus (HPV) infection poses a significant health challenge, particularly in low- and middle-income countries (LMIC), where limited healthcare access and awareness hinder vaccine accessibility. To identify alternative HPV targeting interventions, we previously reported on surfactant protein A (SP-A) as a novel molecule capable of recognising HPV16 pseudovirions (HPV16-PsVs) and reducing infection in a murine cervicovaginal HPV challenge model. Building on these findings, our current study aimed to assess SP-A's suitability as a broad-spectrum HPV-targeting molecule and its impact on innate immune responses. We demonstrate SP-A's ability to agglutinate and opsonise multiple oncogenic HPV-PsVs types, enhancing their uptake and clearance by RAW264.7 murine macrophages and THP-1 human-derived immune cells. The SP-A opsonisation of HPV not only led to increased lysosomal accumulation in macrophages and HaCaT keratinocytes but also resulted in a decreased infection of HaCaT cells, which was further decreased when co-cultured with innate immune cells. An analysis of human innate immune cell cytokine profiles revealed a significant inflammatory response upon SP-A exposure, potentially contributing to the overall inhibition of HPV infection. These results highlight the multi-layered impact of SP-A on HPV, innate immune cells and keratinocytes and lay the basis for the development of alternative prophylactic interventions against diverse HPV types.

@article{Tomasicchio2024,
abstract = {Rationale: In the upper respiratory tract replicating (culturable) SARS-CoV-2 is recoverable for {\~{}} 4 to 8 days after symptom onset, however, there is paucity of data about the frequency or duration of replicating virus in the lower respiratory tract (i.e. the human lung). Objectives: We undertook lung tissue sampling (needle biopsy), shortly after death, in 42 mechanically ventilated decedents during the Beta and Delta waves. An independent group of 18 ambulatory patents served as a control group. Methods: Lung biopsy cores from decedents underwent viral culture, histopathological analysis, electron microscopy, transcriptomic profiling and immunohistochemistry. Results: 38{\%} (16/42) of mechanically ventilated decedents had culturable virus in the lung for a median of 15 days (persisting for up to 4 weeks) after symptom onset. Lung viral culture positivity was not associated with comorbidities or steroid use. Delta but not Beta variant lung culture positivity was associated with accelerated death and secondary bacterial infection (p{\textless}0.05). Nasopharyngeal culture was negative in 23.1{\%} (6/26) of decedents despite lung culture positivity. This, hitherto, undescribed bio-phenotype of lung-specific persisting viral replication was associated with an enhanced transcriptomic pulmonary pro-inflammatory response but with concurrent viral culture positivity. Conclusions: Concurrent, rather than sequential active viral replication continues to drive a heightened pro-inflammatory response in the human lung beyond the second week of illness and was associated with variant-specific increased mortality and morbidity. These findings have potential implications for the design of interventional strategies and clinical management of patients with severe COVID-19 disease.},
author = {Tomasicchio, Michele and Jaumdally, Shameem and Wilson, Lindsay and Kotze, Andrea and Semple, Lynn and Meier, Stuart and Pooran, Anil and Esmail, Aliasgar and Pillay, Komala and Roberts, Riyaadh and Kriel, Raymond and Meldau, Richard and Oelofse, Suzette and Mandviwala, Carley and Burns, Jessica and Londt, Rolanda and Davids, Malika and van der Merwe, Charnay and Roomaney, Aqeedah and K{\"{u}}hn, Loui{\'{e}} and Perumal, Tahlia and Scott, Alex J and Hale, Martin J and Baillie, Vicky and Mahtab, Sana and Williamson, Carolyn and Joseph, Rageema and Sigal, Alex and Joubert, Ivan and Piercy, Jenna and Thomson, David and Fredericks, David L and Miller, Malcolm G A and Nunes, Marta C and Madhi, Shabir A and Dheda, Keertan},
doi = {10.1164/RCCM.202308-1438OC},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Tomasicchio et al. - 2024 - SARS-CoV-2 viral replication persists in the human lung for several weeks after symptom onset.pdf:pdf},
issn = {1073-449X},
journal = {American Journal of Respiratory and Critical Care Medicine},
keywords = {COVID-19,OA,SARS-CoV-2,fund{\_}ack,lower respiratory tract,mechanically ventilated patients,original,virus replication},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jan},
pages = {rccm.202308--1438OC},
pmid = {38226855},
publisher = {AJRCCM Articles in Press. Published},
title = {{SARS-CoV-2 viral replication persists in the human lung for several weeks after symptom onset}},
url = {https://www.atsjournals.org/doi/10.1164/rccm.202308-1438OC},
year = {2024}
}

Rationale: In the upper respiratory tract replicating (culturable) SARS-CoV-2 is recoverable for \  4 to 8 days after symptom onset, however, there is paucity of data about the frequency or duration of replicating virus in the lower respiratory tract (i.e. the human lung). Objectives: We undertook lung tissue sampling (needle biopsy), shortly after death, in 42 mechanically ventilated decedents during the Beta and Delta waves. An independent group of 18 ambulatory patents served as a control group. Methods: Lung biopsy cores from decedents underwent viral culture, histopathological analysis, electron microscopy, transcriptomic profiling and immunohistochemistry. Results: 38% (16/42) of mechanically ventilated decedents had culturable virus in the lung for a median of 15 days (persisting for up to 4 weeks) after symptom onset. Lung viral culture positivity was not associated with comorbidities or steroid use. Delta but not Beta variant lung culture positivity was associated with accelerated death and secondary bacterial infection (p\textless0.05). Nasopharyngeal culture was negative in 23.1% (6/26) of decedents despite lung culture positivity. This, hitherto, undescribed bio-phenotype of lung-specific persisting viral replication was associated with an enhanced transcriptomic pulmonary pro-inflammatory response but with concurrent viral culture positivity. Conclusions: Concurrent, rather than sequential active viral replication continues to drive a heightened pro-inflammatory response in the human lung beyond the second week of illness and was associated with variant-specific increased mortality and morbidity. These findings have potential implications for the design of interventional strategies and clinical management of patients with severe COVID-19 disease.

@article{Nyakato2024,
abstract = {BACKGROUND: Pediatric programs face a high rate of loss to follow-up (LTFU) among children and adolescents living with HIV (CAHIV). We assessed true outcomes and predictors of these among CAHIV who were LTFU using linkage to the Western Cape Provincial Health Data Centre at Western Cape sites of the International epidemiology Databases to Evaluate AIDS-Southern Africa collaboration. METHODS: We examined factors associated with self-transfer, hospital admission and mortality using competing risks regression in a retrospective cohort of CAHIV initiating antiretroviral therapy {\textless}15 years old between 2004 and 2019 and deemed LTFU (no recorded visit at the original facility for ≥180 days from the last visit date before database closure and not known to have officially transferred out or deceased). RESULTS: Of the 1720 CAHIV deemed LTFU, 802 (46.6{\%}) had self-transferred and were receiving care elsewhere within the Western Cape, 463 (26.9{\%}) had been hospitalized and 45 (2.6{\%}) CAHIV had died. The overall rates of self-transfer, hospitalization, mortality and LTFU were 9.4 [95{\%} confidence interval (CI): 8.8-10.1], 5.4 (95{\%} CI: 5.0-6.0), 0.5 (95{\%} CI: 0.4-0.7) and 4.8 (95{\%} CI: 4.4-5.3) per 100 person-years respectively. Increasing duration on antiretroviral therapy before LTFU was associated with self-transfers while male sex, older age at last visit (≥10 years vs. younger) were associated with hospital admission and immune suppression at last visit was associated with 5 times higher mortality. CONCLUSIONS: Nearly half of CAHIV classified as LTFU had self-transferred to another health facility, a quarter had been hospitalized and a small proportion had died.},
author = {Nyakato, Patience and Boulle, Andrew and Wood, Robin and Eley, Brian and Rabie, Helena and Egger, Matthias and Yiannoutsos, Constantin T and Davies, Mary-Ann and Cornell, Morna},
doi = {10.1097/INF.0000000000004281},
file = {:C$\backslash$:/Users/01462563/OneDrive - University of Cape Town/Documents/CIDRI-Africa papers and outputs/Nyakato et al - 2024 - self{\_}transfers,{\_}hospital{\_}admissions{\_}and{\_}mortality.762.pdf:pdf},
issn = {0891-3668},
journal = {Pediatric Infectious Disease Journal},
keywords = {fund{\_}ack,original},
mendeley-tags = {fund{\_}ack,original},
month = {feb},
number = {5},
pages = {430--436},
pmid = {38451913},
title = {{Self-transfers, hospital admissions and mortality among children and adolescents lost to follow-up from antiretroviral therapy programs in the Western Cape, South Africa between 2004 and 2019: linkage to provincial records}},
url = {https://journals.lww.com/pidj/fulltext/9900/self{\_}transfers,{\_}hospital{\_}admissions{\_}and{\_}mortality.762.aspx},
volume = {43},
year = {2024}
}

BACKGROUND: Pediatric programs face a high rate of loss to follow-up (LTFU) among children and adolescents living with HIV (CAHIV). We assessed true outcomes and predictors of these among CAHIV who were LTFU using linkage to the Western Cape Provincial Health Data Centre at Western Cape sites of the International epidemiology Databases to Evaluate AIDS-Southern Africa collaboration. METHODS: We examined factors associated with self-transfer, hospital admission and mortality using competing risks regression in a retrospective cohort of CAHIV initiating antiretroviral therapy \textless15 years old between 2004 and 2019 and deemed LTFU (no recorded visit at the original facility for ≥180 days from the last visit date before database closure and not known to have officially transferred out or deceased). RESULTS: Of the 1720 CAHIV deemed LTFU, 802 (46.6%) had self-transferred and were receiving care elsewhere within the Western Cape, 463 (26.9%) had been hospitalized and 45 (2.6%) CAHIV had died. The overall rates of self-transfer, hospitalization, mortality and LTFU were 9.4 [95% confidence interval (CI): 8.8-10.1], 5.4 (95% CI: 5.0-6.0), 0.5 (95% CI: 0.4-0.7) and 4.8 (95% CI: 4.4-5.3) per 100 person-years respectively. Increasing duration on antiretroviral therapy before LTFU was associated with self-transfers while male sex, older age at last visit (≥10 years vs. younger) were associated with hospital admission and immune suppression at last visit was associated with 5 times higher mortality. CONCLUSIONS: Nearly half of CAHIV classified as LTFU had self-transferred to another health facility, a quarter had been hospitalized and a small proportion had died.

@article{White2024,
author = {White, Richard G and Fiore-Gartland, Andrew J and Hanekom, Willem A and Vekemans, Johan and Garcia-Basteiro, Alberto L and Churchyard, Gavin and Rangaka, Molebogeng X and Frick, Mike and Behr, Marcel A and Hill, Philip C and Mave, Vidya},
doi = {10.1016/S2213-2600(24)00009-2},
issn = {2213-2600},
journal = {The Lancet Respiratory Medicine},
keywords = {fund{\_}not{\_}ack,letter},
mendeley-tags = {fund{\_}not{\_}ack,letter},
month = {jan},
publisher = {Elsevier},
title = {{What is next for BCG revaccination to prevent tuberculosis?}},
url = {https://linkinghub.elsevier.com/retrieve/pii/S2213260024000092},
year = {2024}
}

@article{Jaumdally2024,
abstract = {Airborne transmission of SARS-CoV-2 aerosol remains contentious. Importantly, whether cough or breath-generated bioaerosols can harbor viable and replicating virus remains largely unclarified. We performed size-fractionated aerosol sampling (Andersen cascade impactor) and evaluated viral culturability in human cell lines (infectiousness), viral genetics, and host immunity in ambulatory participants with COVID-19. Sixty-one percent (27/44) and 50{\%} (22/44) of participants emitted variant-specific culture-positive aerosols {\textless}10$\mu$m and {\textless}5$\mu$m, respectively, for up to 9 days after symptom onset. Aerosol culturability is significantly associated with lower neutralizing antibody titers, and suppression of transcriptomic pathways related to innate immunity and the humoral response. A nasopharyngeal Ct {\textless}17 rules-in {\~{}}40{\%} of aerosol culture-positives and identifies those who are probably highly infectious. A parsimonious three transcript blood-based biosignature is highly predictive of infectious aerosol generation (PPV {\textgreater} 95{\%}). There is considerable heterogeneity in potential infectiousness i.e., only 29{\%} of participants were probably highly infectious (produced culture-positive aerosols {\textless}5$\mu$m at {\~{}}6 days after symptom onset). These data, which comprehensively confirm variant-specific culturable SARS-CoV-2 in aerosol, inform the targeting of transmission-related interventions and public health containment strategies emphasizing improved ventilation. SARS-CoV-2 can be spread by aerosols. Here the authors show that between 50-60{\%} of ambulatory COVID-19 patients exhale culturable virus and that this is associated with lower neutralizing antibody titers and suppression of immune related transcriptomic pathways.},
author = {Jaumdally, S and Tomasicchio, M and Pooran, A and Esmail, A and Kotze, A and Meier, S and Wilson, L and Oelofse, S and van der Merwe, C and Roomaney, A and Davids, M and Suliman, T and Joseph, R and Perumal, T and Scott, A and Shaw, M and Preiser, W and Williamson, C and Goga, A and Mayne, E and Gray, G and Moore, P and Sigal, A and Limberis, J and Metcalfe, J and Dheda, K},
doi = {10.1038/s41467-024-45400-1},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Jaumdally et al. - 2024 - Frequency, kinetics and determinants of viable SARS-CoV-2 in bioaerosols from ambulatory COVID-19 patients inf.pdf:pdf},
issn = {2041-1723},
journal = {Nature Communications},
keywords = {2,CoV,Diagnostic markers,Molecular medicine,OA,Respiratory tract diseases,SARS,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {mar},
number = {1},
pages = {2003},
publisher = {Nature Publishing Group},
title = {{Frequency, kinetics and determinants of viable SARS-CoV-2 in bioaerosols from ambulatory COVID-19 patients infected with the Beta, Delta or Omicron variants}},
url = {https://www.nature.com/articles/s41467-024-45400-1},
volume = {15},
year = {2024}
}

Airborne transmission of SARS-CoV-2 aerosol remains contentious. Importantly, whether cough or breath-generated bioaerosols can harbor viable and replicating virus remains largely unclarified. We performed size-fractionated aerosol sampling (Andersen cascade impactor) and evaluated viral culturability in human cell lines (infectiousness), viral genetics, and host immunity in ambulatory participants with COVID-19. Sixty-one percent (27/44) and 50% (22/44) of participants emitted variant-specific culture-positive aerosols \textless10$μ$m and \textless5$μ$m, respectively, for up to 9 days after symptom onset. Aerosol culturability is significantly associated with lower neutralizing antibody titers, and suppression of transcriptomic pathways related to innate immunity and the humoral response. A nasopharyngeal Ct \textless17 rules-in \ 40% of aerosol culture-positives and identifies those who are probably highly infectious. A parsimonious three transcript blood-based biosignature is highly predictive of infectious aerosol generation (PPV \textgreater 95%). There is considerable heterogeneity in potential infectiousness i.e., only 29% of participants were probably highly infectious (produced culture-positive aerosols \textless5$μ$m at \ 6 days after symptom onset). These data, which comprehensively confirm variant-specific culturable SARS-CoV-2 in aerosol, inform the targeting of transmission-related interventions and public health containment strategies emphasizing improved ventilation. SARS-CoV-2 can be spread by aerosols. Here the authors show that between 50-60% of ambulatory COVID-19 patients exhale culturable virus and that this is associated with lower neutralizing antibody titers and suppression of immune related transcriptomic pathways.

@article{Szekely2024,
abstract = {There is an urgent need for rapid, non-sputum point-of-care diagnostics to detect tuberculosis. This prospective trial in seven high tuberculosis burden countries evaluated the diagnostic accuracy of the point-of-care urine-based lipoarabinomannan assay FUJIFILM SILVAMP TB LAM (FujiLAM) among inpatients and outpatients living with HIV. Diagnostic performance of FujiLAM was assessed against a mycobacterial reference standard (sputum culture, blood culture, and Xpert Ultra from urine and sputum at enrollment, and additional sputum culture ≤7 days from enrollment), an extended mycobacterial reference standard (eMRS), and a composite reference standard including clinical evaluation. Of 1637 participants considered for the analysis, 296 (18{\%}) were tuberculosis positive by eMRS. Median age was 40 years, median CD4 cell count was 369 cells/ul, and 52{\%} were female. Overall FujiLAM sensitivity was 54{\textperiodcentered}4{\%} (95{\%} CI: 48{\textperiodcentered}7–60{\textperiodcentered}0), overall specificity was 85{\textperiodcentered}2{\%} (83{\textperiodcentered}2–87{\textperiodcentered}0) against eMRS. Sensitivity and specificity estimates varied between sites, ranging from 26{\textperiodcentered}5{\%} (95{\%} CI: 17{\textperiodcentered}4{\%}–38{\textperiodcentered}0{\%}) to 73{\textperiodcentered}2{\%} (60{\textperiodcentered}4{\%}–83{\textperiodcentered}0{\%}), and 75{\textperiodcentered}0 (65{\textperiodcentered}0{\%}–82{\textperiodcentered}9{\%}) to 96{\textperiodcentered}5 (92{\textperiodcentered}1{\%}–98{\textperiodcentered}5{\%}), respectively. Post-hoc exploratory analysis identified significant variability in the performance of the six FujiLAM lots used in this study. Lot variability limited interpretation of FujiLAM test performance. Although results with the current version of FujiLAM are too variable for clinical decision-making, the lipoarabinomannan biomarker still holds promise for tuberculosis diagnostics. The trial is registered at clinicaltrials.gov (NCT04089423).},
author = {Sz{\'{e}}kely, Rita and Sossen, Bianca and Mukoka, Madalo and Muyoyeta, Monde and Nakabugo, Elizabeth and Hella, Jerry and Nguyen, Hung Van and Ubolyam, Sasiwimol and Chikamatsu, Kinuyo and Mac{\'{e}}, Aur{\'{e}}lien and Vermeulen, Marcia and Centner, Chad M and Nyangu, Sarah and Sanjase, Nsala and Sasamalo, Mohamed and Dinh, Huong Thi and Ngo, The Anh and Manosuthi, Weerawat and Jirajariyavej, Supunnee and Mitarai, Satoshi and Nguyen, Nhung Viet and Avihingsanon, Anchalee and Reither, Klaus and Nakiyingi, Lydia and Kerkhoff, Andrew D. and MacPherson, Peter and Meintjes, Graeme A and Denkinger, Claudia M and Ruhwald, Morten and {FujiLAM Study Consortium}},
doi = {10.1371/JOURNAL.PONE.0303846},
editor = {Pham, Minh Duc},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Sz{\'{e}}kely et al. - 2024 - Prospective multicentre accuracy evaluation of the FUJIFILM SILVAMP TB LAM test for the diagnosis of tuberculosi.pdf:pdf},
isbn = {1111111111},
issn = {1932-6203},
journal = {PLOS ONE},
keywords = {HIV diagnosis and management,Mycobacterium tuberculosis,Nontuberculous mycobacteria,OA,OA{\_}PMC,Sputum,Tuberculosis,Tuberculosis diagnosis and management,Urine,Virus testing,fund{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,original},
month = {may},
number = {5},
pages = {e0303846},
pmid = {38820372},
publisher = {Public Library of Science},
title = {{Prospective multicentre accuracy evaluation of the FUJIFILM SILVAMP TB LAM test for the diagnosis of tuberculosis in people living with HIV demonstrates lot-to-lot variability}},
url = {https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0303846},
volume = {19},
year = {2024}
}

There is an urgent need for rapid, non-sputum point-of-care diagnostics to detect tuberculosis. This prospective trial in seven high tuberculosis burden countries evaluated the diagnostic accuracy of the point-of-care urine-based lipoarabinomannan assay FUJIFILM SILVAMP TB LAM (FujiLAM) among inpatients and outpatients living with HIV. Diagnostic performance of FujiLAM was assessed against a mycobacterial reference standard (sputum culture, blood culture, and Xpert Ultra from urine and sputum at enrollment, and additional sputum culture ≤7 days from enrollment), an extended mycobacterial reference standard (eMRS), and a composite reference standard including clinical evaluation. Of 1637 participants considered for the analysis, 296 (18%) were tuberculosis positive by eMRS. Median age was 40 years, median CD4 cell count was 369 cells/ul, and 52% were female. Overall FujiLAM sensitivity was 54˙4% (95% CI: 48˙7–60˙0), overall specificity was 85˙2% (83˙2–87˙0) against eMRS. Sensitivity and specificity estimates varied between sites, ranging from 26˙5% (95% CI: 17˙4%–38˙0%) to 73˙2% (60˙4%–83˙0%), and 75˙0 (65˙0%–82˙9%) to 96˙5 (92˙1%–98˙5%), respectively. Post-hoc exploratory analysis identified significant variability in the performance of the six FujiLAM lots used in this study. Lot variability limited interpretation of FujiLAM test performance. Although results with the current version of FujiLAM are too variable for clinical decision-making, the lipoarabinomannan biomarker still holds promise for tuberculosis diagnostics. The trial is registered at clinicaltrials.gov (NCT04089423).

@article{Shaw2024,
abstract = {Summary Tuberculosis drug development has stagnated for decades, so the recent availability of bedaquiline is welcome. Bedaquiline-containing regimens, now the first-line therapy recommended by WHO, have transformed the treatment of drug-resistant tuberculosis, offering safer and more effective oral treatment options. However, key obstacles need to be overcome to ensure global access and prevent the rapid development of resistance against this promising class of drugs. In this Personal View, building on an international workshop held in 2023, we evaluate the current evidence and suggest possible ways forward, recognising the tension between increasing use and slowing the rise of resistance. We also discuss problems in accessing bedaquiline-containing regimens, the potential widening of their use beyond drug-resistant tuberculosis, and lessons for utilising new drugs as they are developed.},
author = {Shaw, Emily S and Stoker, Neil G and Potter, Jessica L and Claassen, Helgard and Leslie, Alasdair and Tweed, Conor D and Chiang, Chen-Yuan and Conradie, Francesca and Esmail, Hanif and Lange, Christoph and Pinto, Lancelot and Rucsineanu, Oxana and Sloan, Derek J and Theron, Grant and Tisile, Phumeza and Voo, Teck Chuan and Warren, Robin M and Lebina, Limakatso and Lipman, Marc},
doi = {10.1016/S2666-5247(24)00149-6},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Shaw et al. - 2024 - Bedaquiline what might the future hold.pdf:pdf},
issn = {2666-5247},
journal = {The Lancet Microbe},
keywords = {OA,fund{\_}not{\_}ack,perspective},
mendeley-tags = {OA,fund{\_}not{\_}ack,perspective},
month = {jul},
pages = {100909},
pmid = {39074472},
publisher = {Elsevier},
title = {{Bedaquiline: what might the future hold?}},
url = {http://www.thelancet.com/article/S2666524724001496/fulltext http://www.thelancet.com/article/S2666524724001496/abstract https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(24)00149-6/abstract},
year = {2024}
}

Summary Tuberculosis drug development has stagnated for decades, so the recent availability of bedaquiline is welcome. Bedaquiline-containing regimens, now the first-line therapy recommended by WHO, have transformed the treatment of drug-resistant tuberculosis, offering safer and more effective oral treatment options. However, key obstacles need to be overcome to ensure global access and prevent the rapid development of resistance against this promising class of drugs. In this Personal View, building on an international workshop held in 2023, we evaluate the current evidence and suggest possible ways forward, recognising the tension between increasing use and slowing the rise of resistance. We also discuss problems in accessing bedaquiline-containing regimens, the potential widening of their use beyond drug-resistant tuberculosis, and lessons for utilising new drugs as they are developed.

@article{Porter2024,
author = {Porter, Mireille and Smith, R and Teixeira, N and Thwala, B and Choshi, Puthi and Phillips, E J and Meintjes, Graeme A and Dlamini, S and Peter, J. and Lehloenya, R.},
doi = {10.1016/J.JAIP.2024.05.045},
file = {:C$\backslash$:/Users/01462563/OneDrive - University of Cape Town/Documents/CIDRI-Africa papers and outputs/Porter et al - 2024 - First-line anti-TB drug challenge reactions in DRESS in an HIV endemic setting.pdf:pdf;:C$\backslash$:/Users/01462563/OneDrive - University of Cape Town/Documents/CIDRI-Africa papers and outputs/Porter et al - 2024 - First-line anti-TB drug challenge reactions in DRESS in an HIV endemic setting{\_}final.pdf:pdf},
issn = {2213-2198},
journal = {The Journal of Allergy and Clinical Immunology: In Practice},
keywords = {fund{\_}ack,original},
mendeley-tags = {fund{\_}ack,original},
month = {jun},
pages = {10.1016/j.jaip.2024.05.045},
pmid = {38852619},
publisher = {Elsevier},
title = {{First-line anti-tuberculosis drug challenge reactions in DRESS in an HIV endemic setting.}},
year = {2024}
}

@article{Griesel2024,
abstract = {Background Dolutegravir exposure is reduced after switching from efavirenz, which could select for dolutegravir resistance if switching occurs during virologic failure. Methods We measured serial dolutegravir trough concentrations after switching from efavirenz in a clinical trial, which randomised some participants to a supplemental dolutegravir dose or placebo for the first 14 days. Changes in dolutegravir trough concentrations between days 3, 7, 14 and 28 were evaluated. The primary outcome was the geometric mean ratio (GMR) of dolutegravir trough concentrations on day 7 versus day 28. Results Twenty-four participants received double-dose dolutegravir (50 mg twice daily) and 11 standard-dose for the first 14 days. Baseline characteristics were: 77{\%} female, median age 36 years, CD4 cell count 254 cells/mm3 , and HIV-1 RNA 4.0 log10 copies/mL. The GMR (90{\%} CI) of dolutegravir trough concentrations on day 7 versus day 28 were: 0.637 (0.485 to 0.837) in the standard-dose group and 1.654 (1.404 to 1.948) in the double-dose group. There was a prolonged induction effect at day 28 in participants with efavirenz slow metaboliser genotypes. One participant in the double-dose group had a dolutegravir trough concentration below the protein-binding adjusted concentration needed to inhibit 90{\%} of HIV-1 (PA-IC90) at day 3. Conclusions No participants on standard-dose dolutegravir had dolutegravir trough concentrations below the PA-IC90. Slow efavirenz metaboliser genotypes had higher baseline efavirenz concentrations and more pronounced and longer period of induction post-switch. These findings suggest that a 14-day lead-in supplemental dolutegravir dose may not be necessary when switching from a failing efavirenz-based first-line regimen.},
author = {Griesel, Rulan and Banda, Clifford G and Zhao, Ying and Omar, Zaayid and Wiesner, Lubbe and Meintjes, Graeme and Sinxadi, Phumla and Maartens, Gary},
doi = {10.1097/QAI.0000000000003402},
file = {:C$\backslash$:/Users/01462563/OneDrive - University of Cape Town/Documents/CIDRI-Africa papers and outputs/Griesel et al - 2024 - pharmacokinetics{\_}of{\_}single{\_}versus{\_}double{\_}dose.385.pdf:pdf},
issn = {1525-4135},
journal = {Journal of Acquired Immune Deficiency Syndromes},
keywords = {fund{\_}ack,original},
mendeley-tags = {fund{\_}ack,original},
month = {feb},
number = {1},
pages = {85--91},
pmid = {38372621},
title = {{Pharmacokinetics of single-dose versus double-dose dolutegravir after switching from a failing efavirenz-based regimen}},
url = {https://journals.lww.com/jaids/fulltext/9900/pharmacokinetics{\_}of{\_}single{\_}versus{\_}double{\_}dose.385.aspx},
volume = {96},
year = {2024}
}

Background Dolutegravir exposure is reduced after switching from efavirenz, which could select for dolutegravir resistance if switching occurs during virologic failure. Methods We measured serial dolutegravir trough concentrations after switching from efavirenz in a clinical trial, which randomised some participants to a supplemental dolutegravir dose or placebo for the first 14 days. Changes in dolutegravir trough concentrations between days 3, 7, 14 and 28 were evaluated. The primary outcome was the geometric mean ratio (GMR) of dolutegravir trough concentrations on day 7 versus day 28. Results Twenty-four participants received double-dose dolutegravir (50 mg twice daily) and 11 standard-dose for the first 14 days. Baseline characteristics were: 77% female, median age 36 years, CD4 cell count 254 cells/mm3 , and HIV-1 RNA 4.0 log10 copies/mL. The GMR (90% CI) of dolutegravir trough concentrations on day 7 versus day 28 were: 0.637 (0.485 to 0.837) in the standard-dose group and 1.654 (1.404 to 1.948) in the double-dose group. There was a prolonged induction effect at day 28 in participants with efavirenz slow metaboliser genotypes. One participant in the double-dose group had a dolutegravir trough concentration below the protein-binding adjusted concentration needed to inhibit 90% of HIV-1 (PA-IC90) at day 3. Conclusions No participants on standard-dose dolutegravir had dolutegravir trough concentrations below the PA-IC90. Slow efavirenz metaboliser genotypes had higher baseline efavirenz concentrations and more pronounced and longer period of induction post-switch. These findings suggest that a 14-day lead-in supplemental dolutegravir dose may not be necessary when switching from a failing efavirenz-based first-line regimen.

@article{Coussens2024,
abstract = {Summary The current active–latent paradigm of tuberculosis largely neglects the documented spectrum of disease. Inconsistency with regard to definitions, terminology, and diagnostic criteria for different tuberculosis states has limited the progress in research and product development that are needed to achieve tuberculosis elimination. We aimed to develop a new framework of classification for tuberculosis that accommodates key disease states but is sufficiently simple to support pragmatic research and implementation. Through an international Delphi exercise that involved 71 participants representing a wide range of disciplines, sectors, income settings, and geographies, consensus was reached on a set of conceptual states, related terminology, and research gaps. The International Consensus for Early TB (ICE-TB) framework distinguishes disease from infection by the presence of macroscopic pathology and defines two subclinical and two clinical tuberculosis states on the basis of reported symptoms or signs of tuberculosis, further differentiated by likely infectiousness. The presence of viable Mycobacterium tuberculosis and an associated host response are prerequisites for all states of infection and disease. Our framework provides a clear direction for tuberculosis research, which will, in time, improve tuberculosis clinical care and elimination policies.},
author = {Coussens, Anna K and Zaidi, Syed M A and Allwood, Brian W and Dewan, Puneet K and Gray, Glenda and Kohli, Mikashmi and Kredo, Tamara and Marais, Ben J and Marks, Guy B and Martinez, Leo and Ruhwald, Morten and Scriba, Thomas J and Seddon, James A and Tisile, Phumeza and Warner, Digby F and Wilkinson, Robert J and Esmail, Hanif and Houben, Rein M G J and Alland, David and Behr, Marcel A and Beko, Busisiwe B and Burhan, Erlina and Churchyard, Gavin and Cobelens, Frank and Denholm, Justin T and Dinkele, Ryan and Ellner, Jerrold J and Fatima, Razia and Haigh, Kate A and Hatherill, Mark and Horton, Katherine C and Kendall, Emily A and Khan, Palwasha Y and MacPherson, Peter and Malherbe, Stephanus T and Mave, Vidya and Mendelsohn, Simon C and Musvosvi, Munyaradzi and Nemes, Elisa and Penn-Nicholson, Adam and Ramamurthy, Dharanidharan and Rangaka, Molebogeng X and Sahu, Suvanand and Schwalb, Alvaro and Shah, Divya K and Sheerin, Dylan and Simon, Donald and Steyn, Adrie J C and Anh, Nguyen Thu and Walzl, Gerhard and Weller, Charlotte L and Williams, Caroline ML and Wong, Emily B and Wood, Robin and Xie, Yingda L and Yi, Siyan},
doi = {10.1016/S2213-2600(24)00028-6},
file = {:C$\backslash$:/Users/01462563/OneDrive - University of Cape Town/Documents/CIDRI-Africa papers and outputs/Coussens et al - 2024 - ICE-TB position paper.pdf:pdf},
issn = {2213-2600},
journal = {The Lancet Respiratory Medicine},
keywords = {fund{\_}ack,perspective},
mendeley-tags = {fund{\_}ack,perspective},
month = {mar},
pages = {10.1016/S2213--2600(24)00028--6},
publisher = {Elsevier},
title = {{Classification of early tuberculosis states to guide research for improved care and prevention: an international Delphi consensus exercise}},
url = {http://www.thelancet.com/article/S2213260024000286/fulltext http://www.thelancet.com/article/S2213260024000286/abstract https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(24)00028-6/abstract},
year = {2024}
}

Summary The current active–latent paradigm of tuberculosis largely neglects the documented spectrum of disease. Inconsistency with regard to definitions, terminology, and diagnostic criteria for different tuberculosis states has limited the progress in research and product development that are needed to achieve tuberculosis elimination. We aimed to develop a new framework of classification for tuberculosis that accommodates key disease states but is sufficiently simple to support pragmatic research and implementation. Through an international Delphi exercise that involved 71 participants representing a wide range of disciplines, sectors, income settings, and geographies, consensus was reached on a set of conceptual states, related terminology, and research gaps. The International Consensus for Early TB (ICE-TB) framework distinguishes disease from infection by the presence of macroscopic pathology and defines two subclinical and two clinical tuberculosis states on the basis of reported symptoms or signs of tuberculosis, further differentiated by likely infectiousness. The presence of viable Mycobacterium tuberculosis and an associated host response are prerequisites for all states of infection and disease. Our framework provides a clear direction for tuberculosis research, which will, in time, improve tuberculosis clinical care and elimination policies.

@article{Madlala2024,
abstract = {Background: Postpartum weight (PPW) contributes to long-term obesity, a growing concern in persons with HIV (PWHs). We investigated whether inflammatory markers in pregnancy may be involved in postpartum (PP) obesity in PWHs. Setting: A total of 57 pregnant PWHs enrolled at ≤14 weeks gestation (T1) in Gugulethu antenatal care clinic in Cape Town and followed through 48 weeks PP were included. Methods: Plasma soluble (s) CD14, sCD163, leptin, tumor necrosis factor receptor 1, resistin, adiponectin, and interleukin-6 (IL-6) were assayed in duplicate using the Luminex platform. We considered each inflammatory marker at T1 (n = 57) and T3 (29–36 weeks gestation, n = 31) as a separate exposure of interest. Linear mixed-effects models were fit to examine whether each exposure was associated with average PPW and PPW trajectories; linear regression was used for associations with PPW change between T1 and 48 weeks. Results: The median age was 32 years (interquartile range [IQR], 29–35), 98{\%} were multigravida, and 49{\%} had a BMI ≥30 kg/m2. Higher T1 sCD14 levels were associated with higher average weight through 48 weeks PP ({\ss} = 0.002, P = 0.04) and T3 sCD14 with higher PPW gain ({\ss} = 0.007, P = 0.04). Leptin ({\ss} = 0.414, P {\textless} 0.01), tumor necrosis factor receptor 1 ({\ss} = 11.048, P {\textless} 0.01), and resistin ({\ss} = 0.714, P = 0.01) at T3 were associated with higher average PPW and IL-6 ({\ss} = 2.266, P = 0.02) with PPW gain. Conclusions: These findings suggest that low-grade inflammation in pregnancy may play a role in PP obesity, pointing to potential mechanisms with implications for long-term cardiometabolic health in PWH.},
author = {Madlala, Hlengiwe P and Myer, Landon and Geffen, Hayli and Rusch, Jody and Shey, Muki S and Meyer, Demi and Goedecke, Julia H and Malaba, Thokozile R and Gray, Clive M and Newell, Marie-Louise and Jao, Jennifer},
doi = {10.1097/QAI.0000000000003406},
issn = {1525-4135},
journal = {Journal of Acquired Immune Deficiency Syndromes},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jun},
number = {2},
pages = {161--165},
pmid = {38465914},
publisher = {Ovid Technologies (Wolters Kluwer Health)},
title = {{Inflammatory markers in pregnancy are associated with postpartum weight in South African women living with HIV on antiretroviral therapy}},
url = {https://journals.lww.com/jaids/fulltext/2024/06010/brief{\_}report{\_}{\_}inflammatory{\_}markers{\_}in{\_}pregnancy.9.aspx},
volume = {96},
year = {2024}
}

Background: Postpartum weight (PPW) contributes to long-term obesity, a growing concern in persons with HIV (PWHs). We investigated whether inflammatory markers in pregnancy may be involved in postpartum (PP) obesity in PWHs. Setting: A total of 57 pregnant PWHs enrolled at ≤14 weeks gestation (T1) in Gugulethu antenatal care clinic in Cape Town and followed through 48 weeks PP were included. Methods: Plasma soluble (s) CD14, sCD163, leptin, tumor necrosis factor receptor 1, resistin, adiponectin, and interleukin-6 (IL-6) were assayed in duplicate using the Luminex platform. We considered each inflammatory marker at T1 (n = 57) and T3 (29–36 weeks gestation, n = 31) as a separate exposure of interest. Linear mixed-effects models were fit to examine whether each exposure was associated with average PPW and PPW trajectories; linear regression was used for associations with PPW change between T1 and 48 weeks. Results: The median age was 32 years (interquartile range [IQR], 29–35), 98% were multigravida, and 49% had a BMI ≥30 kg/m2. Higher T1 sCD14 levels were associated with higher average weight through 48 weeks PP (ß = 0.002, P = 0.04) and T3 sCD14 with higher PPW gain (ß = 0.007, P = 0.04). Leptin (ß = 0.414, P \textless 0.01), tumor necrosis factor receptor 1 (ß = 11.048, P \textless 0.01), and resistin (ß = 0.714, P = 0.01) at T3 were associated with higher average PPW and IL-6 (ß = 2.266, P = 0.02) with PPW gain. Conclusions: These findings suggest that low-grade inflammation in pregnancy may play a role in PP obesity, pointing to potential mechanisms with implications for long-term cardiometabolic health in PWH.

@article{Broger2023,
abstract = {Summary Background Sputum is the most widely used sample to diagnose active tuberculosis, but many people living with HIV are unable to produce sputum. Urine, in contrast, is readily available. We hypothesised that sample availability influences the diagnostic yield of various tuberculosis tests. Methods In this systematic review and meta-analysis of individual participant data, we compared the diagnostic yield of point-of-care urine-based lipoarabinomannan tests with that of sputum-based nucleic acid amplification tests (NAATs) and sputum smear microscopy (SSM). We used microbiologically confirmed tuberculosis based on positive culture or NAAT from any body site as the denominator and accounted for sample provision. We searched PubMed, Web of Science, Embase, African Journals Online, and clinicaltrials.gov from database inception to Feb 24, 2022 for randomised controlled trials, cross-sectional studies, and cohort studies that assessed urine lipoarabinomannan point-of-care tests and sputum NAATs for active tuberculosis detection in participants irrespective of tuberculosis symptoms, HIV status, CD4 cell count, or study setting. We excluded studies in which recruitment was not consecutive, systematic, or random; provision of sputum or urine was an inclusion criterion; less than 30 participants were diagnosed with tuberculosis; early research assays without clearly defined cutoffs were tested; and humans were not studied. We extracted study-level data, and authors of eligible studies were invited to contribute deidentified individual participant data. The main outcomes were the tuberculosis diagnostic yields of urine lipoarabinomannan tests, sputum NAATs, and SSM. Diagnostic yields were predicted using Bayesian random-effects and mixed-effects meta-analyses. This study is registered with PROSPERO, CRD42021230337. Findings We identified 844 records, from which 20 datasets and 10 202 participants (4561 [45{\%}] male participants and 5641 [55{\%}] female participants) were included in the meta-analysis. All studies assessed sputum Xpert (MTB/RIF or Ultra, Cepheid, Sunnyvale, CA, USA) and urine Alere Determine TB LAM (AlereLAM, Abbott, Chicago, IL, USA) in people living with HIV aged 15 years or older. Nearly all (9957 [98{\%}] of 10 202) participants provided urine, and 82{\%} (8360 of 10 202) provided sputum within 2 days. In studies that enrolled unselected inpatients irrespective of tuberculosis symptoms, only 54{\%} (1084 of 1993) of participants provided sputum, whereas 99{\%} (1966 of 1993) provided urine. Diagnostic yield was 41{\%} (95{\%} credible interval [CrI] 15–66) for AlereLAM, 61{\%} (95{\%} Crl 25–88) for Xpert, and 32{\%} (95{\%} Crl 10–55) for SSM. Heterogeneity existed across studies in the diagnostic yield, influenced by CD4 cell count, tuberculosis symptoms, and clinical setting. In predefined subgroup analyses, all tests had higher yields in symptomatic participants, and AlereLAM yield was higher in those with low CD4 counts and inpatients. AlereLAM and Xpert yields were similar among inpatients in studies enrolling unselected participants who were not assessed for tuberculosis symptoms (51{\%} vs 47{\%}). AlereLAM and Xpert together had a yield of 71{\%} in unselected inpatients, supporting the implementation of combined testing strategies. Interpretation AlereLAM, with its rapid turnaround time and simplicity, should be prioritised to inform tuberculosis therapy among inpatients who are HIV-positive, regardless of symptoms or CD4 cell count. The yield of sputum-based tuberculosis tests is undermined by people living with HIV who cannot produce sputum, whereas nearly all participants are able to provide urine. The strengths of this meta-analysis are its large size, the carefully harmonised denominator, and the use of Bayesian random-effects and mixed-effects models to predict yields; however, data were geographically restricted, clinically diagnosed tuberculosis was not considered in the denominator, and little information exists on strategies for obtaining sputum samples. Funding FIND, the Global Alliance for Diagnostics.},
author = {Broger, Tobias and Koeppel, Lisa and Huerga, Helena and Miller, Poppy and Gupta-Wright, Ankur and Blanc, Fran{\c{c}}ois-Xavier and Esmail, Aliasgar and Reeve, Byron W P and Floridia, Marco and Kerkhoff, Andrew D and Ciccacci, Fausto and Kasaro, Margaret P and Thit, Swe Swe and Bastard, Mathieu and Ferlazzo, Gabriella and Yoon, Christina and Hoving, Dani{\"{e}}l J Van and Sossen, Bianca and Garc{\'{i}}a, Juan Ignacio and Cummings, Matthew J and Wake, Rachel M and Hanson, Josh and Cattamanchi, Adithya and Meintjes, Graeme and Maartens, Gary and Wood, Robin and Theron, Grant and Dheda, Keertan and Olaru, Ioana Diana and Denkinger, Claudia M and Oelofse, Suzette and Laureillard, Didier and Andreotti, Mauro and Chilyabanyama, Obvious Nchimunya and Welu, Benjamin and Molfino, Lucas and R{\"{u}}cker, Sekai Chenai Mathabire and Szumilin, Elisabeth and Cossa, Loide and Mel{\'{e}}ndez, Johanna and Mbuthini, Linda and O'Donnell, Max and Jarvis, Joseph N and Ndlangalavu, Gcobisa and Fielding, Katherine},
doi = {10.1016/S2214-109X(23)00135-3},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Broger et al. - 2023 - Diagnostic yield of urine lipoarabinomannan and sputum tuberculosis tests in people living with HIV a systematic.pdf:pdf},
issn = {2214-109X},
journal = {The Lancet Global Health},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jun},
number = {6},
pages = {e903--e916},
publisher = {Elsevier},
title = {{Diagnostic yield of urine lipoarabinomannan and sputum tuberculosis tests in people living with HIV: a systematic review and meta-analysis of individual participant data}},
url = {http://www.thelancet.com/article/S2214109X23001353/fulltext http://www.thelancet.com/article/S2214109X23001353/abstract https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(23)00135-3/abstract},
volume = {11},
year = {2023}
}

Summary Background Sputum is the most widely used sample to diagnose active tuberculosis, but many people living with HIV are unable to produce sputum. Urine, in contrast, is readily available. We hypothesised that sample availability influences the diagnostic yield of various tuberculosis tests. Methods In this systematic review and meta-analysis of individual participant data, we compared the diagnostic yield of point-of-care urine-based lipoarabinomannan tests with that of sputum-based nucleic acid amplification tests (NAATs) and sputum smear microscopy (SSM). We used microbiologically confirmed tuberculosis based on positive culture or NAAT from any body site as the denominator and accounted for sample provision. We searched PubMed, Web of Science, Embase, African Journals Online, and clinicaltrials.gov from database inception to Feb 24, 2022 for randomised controlled trials, cross-sectional studies, and cohort studies that assessed urine lipoarabinomannan point-of-care tests and sputum NAATs for active tuberculosis detection in participants irrespective of tuberculosis symptoms, HIV status, CD4 cell count, or study setting. We excluded studies in which recruitment was not consecutive, systematic, or random; provision of sputum or urine was an inclusion criterion; less than 30 participants were diagnosed with tuberculosis; early research assays without clearly defined cutoffs were tested; and humans were not studied. We extracted study-level data, and authors of eligible studies were invited to contribute deidentified individual participant data. The main outcomes were the tuberculosis diagnostic yields of urine lipoarabinomannan tests, sputum NAATs, and SSM. Diagnostic yields were predicted using Bayesian random-effects and mixed-effects meta-analyses. This study is registered with PROSPERO, CRD42021230337. Findings We identified 844 records, from which 20 datasets and 10 202 participants (4561 [45%] male participants and 5641 [55%] female participants) were included in the meta-analysis. All studies assessed sputum Xpert (MTB/RIF or Ultra, Cepheid, Sunnyvale, CA, USA) and urine Alere Determine TB LAM (AlereLAM, Abbott, Chicago, IL, USA) in people living with HIV aged 15 years or older. Nearly all (9957 [98%] of 10 202) participants provided urine, and 82% (8360 of 10 202) provided sputum within 2 days. In studies that enrolled unselected inpatients irrespective of tuberculosis symptoms, only 54% (1084 of 1993) of participants provided sputum, whereas 99% (1966 of 1993) provided urine. Diagnostic yield was 41% (95% credible interval [CrI] 15–66) for AlereLAM, 61% (95% Crl 25–88) for Xpert, and 32% (95% Crl 10–55) for SSM. Heterogeneity existed across studies in the diagnostic yield, influenced by CD4 cell count, tuberculosis symptoms, and clinical setting. In predefined subgroup analyses, all tests had higher yields in symptomatic participants, and AlereLAM yield was higher in those with low CD4 counts and inpatients. AlereLAM and Xpert yields were similar among inpatients in studies enrolling unselected participants who were not assessed for tuberculosis symptoms (51% vs 47%). AlereLAM and Xpert together had a yield of 71% in unselected inpatients, supporting the implementation of combined testing strategies. Interpretation AlereLAM, with its rapid turnaround time and simplicity, should be prioritised to inform tuberculosis therapy among inpatients who are HIV-positive, regardless of symptoms or CD4 cell count. The yield of sputum-based tuberculosis tests is undermined by people living with HIV who cannot produce sputum, whereas nearly all participants are able to provide urine. The strengths of this meta-analysis are its large size, the carefully harmonised denominator, and the use of Bayesian random-effects and mixed-effects models to predict yields; however, data were geographically restricted, clinically diagnosed tuberculosis was not considered in the denominator, and little information exists on strategies for obtaining sputum samples. Funding FIND, the Global Alliance for Diagnostics.

@article{Moyo-Gwete2023a,
abstract = {The impact of previous SARS-CoV-2 infection on the durability of Ad26.COV2.S vaccine-elicited responses, and the effect of homologous boosting has not been well explored. We followed a cohort of healthcare workers for 6 months after receiving the Ad26.COV2.S vaccine and a further one month after they received an Ad26.COV2.S booster dose. We assessed longitudinal spike-specific antibody and T cell responses in individuals who had never had SARS-CoV-2 infection, compared to those who were infected with either the D614G or Beta variants prior to vaccination. Antibody and T cell responses elicited by the primary dose were durable against several variants of concern over the 6 month follow-up period, regardless of infection history. However, at 6 months after first vaccination, antibody binding, neutralization and ADCC were as much as 59-fold higher in individuals with hybrid immunity compared to those with no prior infection. Antibody cross-reactivity profiles of the previously infected groups were similar at 6 months, unlike at earlier time points, suggesting that the effect of immune imprinting diminishes by 6 months. Importantly, an Ad26.COV2.S booster dose increased the magnitude of the antibody response in individuals with no prior infection to similar levels as those with previous infection. The magnitude of spike T cell responses and proportion of T cell responders remained stable after homologous boosting, concomitant with a significant increase in long-lived early differentiated CD4 memory T cells. Thus, these data highlight that multiple antigen exposures, whether through infection and vaccination or vaccination alone, result in similar boosts after Ad26.COV2.S vaccination.},
author = {Moyo-Gwete, Thandeka and Richardson, Simone I. and Keeton, Roanne and Hermanus, Tandile and Spencer, Holly and Manamela, Nelia P. and Ayres, Frances and Makhado, Zanele and Motlou, Thopisang and Tincho, Marius B. and Benede, Ntombi and Ngomti, Amkele and Baguma, Richard and Chauke, Masego V. and Mennen, Mathilda and Adriaanse, Marguerite and Skelem, Sango and Goga, Ameena and Garrett, Nigel and Bekker, Linda-Gail and Gray, Glenda and Ntusi, Ntobeko A. B. and Riou, Catherine and Burgers, Wendy A. and Moore, Penny L.},
doi = {10.1371/JOURNAL.PPAT.1011772},
editor = {Silvestri, Guido},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Moyo-Gwete et al. - 2023 - Homologous Ad26.COV2.S vaccination results in reduced boosting of humoral responses in hybrid immunity, bu(2).pdf:pdf},
isbn = {1111111111},
issn = {1553-7374},
journal = {PLOS Pathogens},
keywords = {Antibodies,Antibody response,Booster doses,Cell differentiation,Cytotoxic T cells,Immune response,OA,OA{\_}PMC,SARS CoV 2,Vaccination and immunization,fund{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,original},
month = {nov},
number = {11},
pages = {e1011772},
pmid = {37943890},
publisher = {Public Library of Science},
title = {{Homologous Ad26.COV2.S vaccination results in reduced boosting of humoral responses in hybrid immunity, but elicits antibodies of similar magnitude regardless of prior infection}},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1011772},
volume = {19},
year = {2023}
}

The impact of previous SARS-CoV-2 infection on the durability of Ad26.COV2.S vaccine-elicited responses, and the effect of homologous boosting has not been well explored. We followed a cohort of healthcare workers for 6 months after receiving the Ad26.COV2.S vaccine and a further one month after they received an Ad26.COV2.S booster dose. We assessed longitudinal spike-specific antibody and T cell responses in individuals who had never had SARS-CoV-2 infection, compared to those who were infected with either the D614G or Beta variants prior to vaccination. Antibody and T cell responses elicited by the primary dose were durable against several variants of concern over the 6 month follow-up period, regardless of infection history. However, at 6 months after first vaccination, antibody binding, neutralization and ADCC were as much as 59-fold higher in individuals with hybrid immunity compared to those with no prior infection. Antibody cross-reactivity profiles of the previously infected groups were similar at 6 months, unlike at earlier time points, suggesting that the effect of immune imprinting diminishes by 6 months. Importantly, an Ad26.COV2.S booster dose increased the magnitude of the antibody response in individuals with no prior infection to similar levels as those with previous infection. The magnitude of spike T cell responses and proportion of T cell responders remained stable after homologous boosting, concomitant with a significant increase in long-lived early differentiated CD4 memory T cells. Thus, these data highlight that multiple antigen exposures, whether through infection and vaccination or vaccination alone, result in similar boosts after Ad26.COV2.S vaccination.

@article{Tomasicchio2023,
abstract = {Rationale: In the upper respiratory tract replicating (culturable) SARS-CoV-2 is recoverable for {\~{}} 4 to 8 days after symptom onset, however, there is paucity of data about the frequency or duration of replicating virus in the lower respiratory tract (i.e. the human lung). Objectives: We undertook lung tissue sampling (needle biopsy), shortly after death, in 42 mechanically ventilated decedents during the Beta and Delta waves. An independent group of 18 ambulatory patents served as a control group. Methods: Lung biopsy cores from decedents underwent viral culture, histopathological analysis, electron microscopy, transcriptomic profiling and immunohistochemistry. Results: 38{\%} (16/42) of mechanically ventilated decedents had culturable virus in the lung for a median of 15 days (persisting for up to 4 weeks) after symptom onset. Lung viral culture positivity was not associated with comorbidities or steroid use. Delta but not Beta variant lung culture positivity was associated with accelerated death and secondary bacterial infection (p{\&}lt;0.05). Nasopharyngeal culture was negative in 23.1{\%} (6/26) of decedents despite lung culture positivity. This, hitherto, undescribed bio-phenotype of lung-specific persisting viral replication was associated with an enhanced transcriptomic pulmonary pro-inflammatory response but with concurrent viral culture positivity. Conclusions: Concurrent, rather than sequential active viral replication continues to drive a heightened pro-inflammatory response in the human lung beyond the second week of illness and was associated with variant-specific increased mortality and morbidity. These findings have potential implications for the design of interventional strategies and clinical management of patients with severe COVID-19 disease.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThe study was funded by the South African Medical Research Council.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethical approval was obtained from the Human Research Ethics Committee (HREC) of the University of Cape Town (HREC approval number 866/2020) and University of Witwatersrand (HREC approval number M200313). Biosafety approvals were obtained from the Faculty Biosafety Committee of the University of Cape Town (IBC008-2021).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesIndividual participant data will be made available to researchers who provide a protocol that is approved by their respective human research ethics committee. All protocols will be reviewed and approved by the MITS consortium trial steering committee up to five years following publication. A data sharing agreement (DTA) will need to be concluded between the representatives of the requesting institution and the University of Cape Town Lung Institute. Data sharing requests should be directed to keertan.dheda@uct.ac.za},
author = {Tomasicchio, Michele and Jaumdally, Shameem and Pooran, Anil and Esmail, Aliasgar and Wilson, Lindsay and Kotze, Andrea and Semple, Lynn and Meier, Stuart and Pillay, Komala and Roberts, Riyaadh and Kriel, Raymond and Meldau, Richard and Oelofse, Suzette and Mandviwala, Carley and Burns, Jessica and Londt, Rolanda and Davids, Malika and van der Merwe, Charnay and Roomaney, Aqeedah and Kuhn, Louie and Perumal, Tahlia and Scott, Alex and Hale, Martin and Baillie, Vicky and Mahtab, Sana and Williamson, Carolyn and Joseph, Rageema and Sigal, Alex and Joubert, Ivan and Piercy, Jenna and Thomson, David and Fredericks, David and Miller, Malcolm and Nunes, Marta and Madhi, Shabir and Dheda, Keertan},
doi = {10.1101/2023.03.06.23286834},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Tomasicchio et al. - 2023 - SARS-CoV-2 viral replication persists in the human lung for several weeks after symptom onset.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jan},
pages = {2023.03.06.23286834},
title = {{SARS-CoV-2 viral replication persists in the human lung for several weeks after symptom onset}},
url = {http://medrxiv.org/content/early/2023/08/23/2023.03.06.23286834.abstract},
year = {2023}
}

Rationale: In the upper respiratory tract replicating (culturable) SARS-CoV-2 is recoverable for \  4 to 8 days after symptom onset, however, there is paucity of data about the frequency or duration of replicating virus in the lower respiratory tract (i.e. the human lung). Objectives: We undertook lung tissue sampling (needle biopsy), shortly after death, in 42 mechanically ventilated decedents during the Beta and Delta waves. An independent group of 18 ambulatory patents served as a control group. Methods: Lung biopsy cores from decedents underwent viral culture, histopathological analysis, electron microscopy, transcriptomic profiling and immunohistochemistry. Results: 38% (16/42) of mechanically ventilated decedents had culturable virus in the lung for a median of 15 days (persisting for up to 4 weeks) after symptom onset. Lung viral culture positivity was not associated with comorbidities or steroid use. Delta but not Beta variant lung culture positivity was associated with accelerated death and secondary bacterial infection (p<0.05). Nasopharyngeal culture was negative in 23.1% (6/26) of decedents despite lung culture positivity. This, hitherto, undescribed bio-phenotype of lung-specific persisting viral replication was associated with an enhanced transcriptomic pulmonary pro-inflammatory response but with concurrent viral culture positivity. Conclusions: Concurrent, rather than sequential active viral replication continues to drive a heightened pro-inflammatory response in the human lung beyond the second week of illness and was associated with variant-specific increased mortality and morbidity. These findings have potential implications for the design of interventional strategies and clinical management of patients with severe COVID-19 disease.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThe study was funded by the South African Medical Research Council.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethical approval was obtained from the Human Research Ethics Committee (HREC) of the University of Cape Town (HREC approval number 866/2020) and University of Witwatersrand (HREC approval number M200313). Biosafety approvals were obtained from the Faculty Biosafety Committee of the University of Cape Town (IBC008-2021).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesIndividual participant data will be made available to researchers who provide a protocol that is approved by their respective human research ethics committee. All protocols will be reviewed and approved by the MITS consortium trial steering committee up to five years following publication. A data sharing agreement (DTA) will need to be concluded between the representatives of the requesting institution and the University of Cape Town Lung Institute. Data sharing requests should be directed to keertan.dheda@uct.ac.za

@article{Davis2022a,
abstract = {BACKGROUND: Cognitive impairment is reported as a common complication in adult tuberculous meningitis (TBM), yet few studies have systematically assessed the frequency and nature of impairment. Moreover, the impact of impairment on functioning and medication adherence has not been described. METHODS: A cognitive test battery (10 measures assessing 7 cognitive domains) was administered to 34 participants with human immunodeficiency virus (HIV)-associated TBM 6 months after diagnosis. Cognitive performance was compared with that a comparator group of 66 people with HIV without a history of tuberculosis. A secondary comparison was made between participants with TBM and 26 participants with HIV 6 months after diagnosis of tuberculosis outside the central nervous system (CNS). Impact on functioning was evaluated, including through assessment of medication adherence. RESULTS: Of 34 participants with TBM, 16 (47{\%}) had low performance on cognitive testing. Cognition was impaired across all domains. Global cognitive performance was significantly lower in participants with TBM than in people with HIV (mean T score, 41 vs 48, respectively; P {\textless} .001). These participants also had lower global cognition scores than those with non-CNS tuberculosis (mean global T score, 41 vs 46; P = .02). Functional outcomes were not significantly correlated with cognitive performance in the subgroup of participants in whom this was assessed (n = 19). CONCLUSIONS: Low cognitive performance following HIV-associated TBM is common. This effect is independent of, and additional to, effects of HIV and non-CNS tuberculosis disease. Further studies are needed to understand longer-term outcomes, clarify the association with treatment adherence, a key predictor of outcome in TBM, and develop context-specific tools to identify individuals with cognitive difficulties in order to improve outcomes in TBM.},
author = {Davis, Angharad G and Dreyer, Anna J and Albertyn, Christine and Maxebengula, Mpumi and Stek, Cari and Wasserman, Sean and Marais, Suzaan and Bateman, Kathleen and Solms, Mark and Joska, John and Wilkinson, Robert J and Nightingale, Sam},
doi = {10.1093/CID/CIAC831},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Davis et al. - 2023 - Cognitive impairment in tuberculous meningitis.pdf:pdf;:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Davis et al. - 2023 - Cognitive impairment in tuberculous meningitis(2).pdf:pdf},
issn = {1058-4838},
journal = {Clinical Infectious Diseases},
keywords = {OA,OA{\_}PMC,fund{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,original},
month = {oct},
number = {5},
pages = {842--849},
pmid = {36262054},
title = {{Cognitive impairment in tuberculous meningitis}},
url = {https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac831/6763738},
volume = {76},
year = {2023}
}

BACKGROUND: Cognitive impairment is reported as a common complication in adult tuberculous meningitis (TBM), yet few studies have systematically assessed the frequency and nature of impairment. Moreover, the impact of impairment on functioning and medication adherence has not been described. METHODS: A cognitive test battery (10 measures assessing 7 cognitive domains) was administered to 34 participants with human immunodeficiency virus (HIV)-associated TBM 6 months after diagnosis. Cognitive performance was compared with that a comparator group of 66 people with HIV without a history of tuberculosis. A secondary comparison was made between participants with TBM and 26 participants with HIV 6 months after diagnosis of tuberculosis outside the central nervous system (CNS). Impact on functioning was evaluated, including through assessment of medication adherence. RESULTS: Of 34 participants with TBM, 16 (47%) had low performance on cognitive testing. Cognition was impaired across all domains. Global cognitive performance was significantly lower in participants with TBM than in people with HIV (mean T score, 41 vs 48, respectively; P \textless .001). These participants also had lower global cognition scores than those with non-CNS tuberculosis (mean global T score, 41 vs 46; P = .02). Functional outcomes were not significantly correlated with cognitive performance in the subgroup of participants in whom this was assessed (n = 19). CONCLUSIONS: Low cognitive performance following HIV-associated TBM is common. This effect is independent of, and additional to, effects of HIV and non-CNS tuberculosis disease. Further studies are needed to understand longer-term outcomes, clarify the association with treatment adherence, a key predictor of outcome in TBM, and develop context-specific tools to identify individuals with cognitive difficulties in order to improve outcomes in TBM.

@article{Patel2023,
author = {Patel, Kashyap and Sikder, Omaike and Nair, Nikhil and Wasserman, Sean and Eikelboom, John W},
doi = {10.1055/a-2110-5884},
edition = {2023/06/14},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Patel et al. - 2023 - Venous thromboembolism in patients with HIV.pdf:pdf},
issn = {2512-9465},
journal = {TH Open},
keywords = {OA,OA{\_}PMC,fund{\_}not{\_}ack,letter},
language = {EN},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,letter},
month = {jun},
pages = {10.1055/ a--2110--5884},
pmid = {37497427},
publisher = {Georg Thieme Verlag KG},
title = {{Venous thromboembolism in patients with HIV}},
url = {http://www.thieme-connect.de/products/ejournals/abstract/10.1055/a-2110-5884 http://www.thieme-connect.de/DOI/DOI?10.1055/a-2110-5884},
year = {2023}
}

@article{Amaral2023,
abstract = {Oxidative stress triggers ferroptosis, a form of cellular necrosis characterized by iron-dependent lipid peroxidation, and has been implicated in Mycobacterium tuberculosis (Mtb) pathogenesis. We investigated whether Bach1, a transcription factor that represses multiple antioxidant genes, regulates host resistance to Mtb. We found that BACH1 expression is associated clinically with active pulmonary tuberculosis. Bach1 deletion in Mtb-infected mice increased glutathione levels and Gpx4 expression that inhibit lipid peroxidation. Bach1−/− macrophages exhibited increased resistance to Mtb-induced cell death, while Mtb-infected Bach1-deficient mice displayed reduced bacterial loads, pulmonary necrosis and lipid peroxidation concurrent with increased survival. Single-cell RNA-seq analysis of lungs from Mtb-infected Bach1−/− mice revealed an enrichment of genes associated with ferroptosis suppression. Bach1 depletion in Mtb-infected B6.Sst1S mice that display human-like necrotic lung pathology also markedly reduced necrosis and increased host resistance. These findings identify Bach1 as a key regulator of cellular and tissue necrosis and host resistance in Mtb infection. The host transcription factor, Bach1, promotes Mycobacterium tuberculosis pathogenesis by inhibiting protective glutathione metabolism and antioxidant responses that prevent ferroptosis.},
author = {Amaral, Eduardo P. and Namasivayam, Sivaranjani and Queiroz, Artur T.L. and Fukutani, Eduardo and Hilligan, Kerry L. and Aberman, Kate and Fisher, Logan and Bomfim, Caio Cesar B. and Kauffman, Keith and Buchanan, Jay and Santuo, Leslie and Gazzinelli-Guimaraes, Pedro Henrique and Costa, Diego L. and Teixeira, Mariane Araujo and Barreto-Duarte, Beatriz and Rocha, Clarissa Gurgel and Santana, Monique Freire and Cordeiro-Santos, Marcelo and Barber, Daniel L. and Wilkinson, Robert J. and Kramnik, Igor and Igarashi, Kazuhiko and Scriba, Thomas and Mayer-Barber, Katrin D. and Andrade, Bruno B. and Sher, Alan},
doi = {10.1038/s41564-023-01523-7},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Amaral et al. - 2023 - BACH1 promotes tissue necrosis and Mycobacterium tuberculosis susceptibility.pdf:pdf},
issn = {2058-5276},
journal = {Nature Microbiology 2023},
keywords = {Cell death,Cell death and immune response,OA,Tuberculosis,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {dec},
pages = {10.1038/s41564--023--01523--7},
publisher = {Nature Publishing Group},
title = {{BACH1 promotes tissue necrosis and \textit{Mycobacterium tuberculosis} susceptibility}},
url = {https://www.nature.com/articles/s41564-023-01523-7},
volume = {13},
year = {2023}
}

Oxidative stress triggers ferroptosis, a form of cellular necrosis characterized by iron-dependent lipid peroxidation, and has been implicated in Mycobacterium tuberculosis (Mtb) pathogenesis. We investigated whether Bach1, a transcription factor that represses multiple antioxidant genes, regulates host resistance to Mtb. We found that BACH1 expression is associated clinically with active pulmonary tuberculosis. Bach1 deletion in Mtb-infected mice increased glutathione levels and Gpx4 expression that inhibit lipid peroxidation. Bach1−/− macrophages exhibited increased resistance to Mtb-induced cell death, while Mtb-infected Bach1-deficient mice displayed reduced bacterial loads, pulmonary necrosis and lipid peroxidation concurrent with increased survival. Single-cell RNA-seq analysis of lungs from Mtb-infected Bach1−/− mice revealed an enrichment of genes associated with ferroptosis suppression. Bach1 depletion in Mtb-infected B6.Sst1S mice that display human-like necrotic lung pathology also markedly reduced necrosis and increased host resistance. These findings identify Bach1 as a key regulator of cellular and tissue necrosis and host resistance in Mtb infection. The host transcription factor, Bach1, promotes Mycobacterium tuberculosis pathogenesis by inhibiting protective glutathione metabolism and antioxidant responses that prevent ferroptosis.

@article{Reiche2023,
abstract = {The Africa Microscopy Initiative (AMI) aims to promote the use of microscopy in biomedical research through facilitated access to instruments and expertise, and via training and networking opportunities. By coupling technology dissemination with expertise and training, AMI is designed to serve as a crucible for the sustainable development of imaging expertise across Africa.},
author = {Reiche, Michael Anton and Jacobs, Caron Adrienne and Aaron, Jesse Scott and Mizrahi, Valerie and Warner, Digby F and Chew, Teng-Leong},
doi = {10.1038/s41556-023-01221-w},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Reiche et al. - 2023 - A comprehensive strategy to strengthen bioimaging in Africa through the Africa Microscopy Initiative.pdf:pdf},
issn = {1476-4679},
journal = {Nature Cell Biology},
keywords = {Imaging,Microscopy,commentary,fund{\_}not{\_}ack},
mendeley-tags = {commentary,fund{\_}not{\_}ack},
month = {oct},
number = {10},
pages = {1387--1393},
publisher = {Nature Publishing Group},
title = {{A comprehensive strategy to strengthen bioimaging in Africa through the Africa Microscopy Initiative}},
url = {https://www.nature.com/articles/s41556-023-01221-w},
volume = {25},
year = {2023}
}

The Africa Microscopy Initiative (AMI) aims to promote the use of microscopy in biomedical research through facilitated access to instruments and expertise, and via training and networking opportunities. By coupling technology dissemination with expertise and training, AMI is designed to serve as a crucible for the sustainable development of imaging expertise across Africa.

@article{Arnab2023,
abstract = {Background: Efavirenz (EFV) is associated with neuropsychiatric symptoms. Severe neurotoxicity has been reported but the clinical phenotype and risk factors are poorly defined. Objectives: To characterise clinical presentations, risk factors and outcomes to help clinicians recognise severe neurotoxicity earlier. Method: The authors retrospectively identified adults with supratherapeutic EFV concentrations ({\textgreater} 4 mg/L) obtained during routine clinical care in Cape Town, South Africa. Clinical and laboratory data at the time of EFV quantification were extracted from medical records. Logistic regression was performed to identify associations with neuropsychiatric symptoms, and with severe neurotoxicity. Results: Eighty one patients were included; 62 with neuropsychiatric manifestations (most frequently ataxia [ n = 20] and psychomotor slowing [ n = 24]); and 19 with hepatotoxicity. Overall, 28 (34.6{\%}) were male, 49 (60.5{\%}) had concomitant isoniazid exposure, and median EFV concentration was 12.1 mg/L (interquartile range [IQR]: 6.6–20.0). Neuropsychiatric symptoms were associated with longer duration of EFV therapy, adjusted odds ratio (aOR) 1.3/180-day increment (95{\%} confidence interval [CI]: 1.0–1.7); higher EFV concentrations, aOR 1.2/1 mg/L increase (95{\%} CI: 1.0–1.4) and isoniazid exposure, aOR 8.2 (95{\%} CI: 2.5–26.7). Severe neuropsychiatric symptoms occurred in 47 (75{\%}) patients at a median of 5.9 months (IQR: 2.1–40.8) after EFV initiation. Severe symptoms odds were 1.2-fold higher (95{\%} CI: 1.1–1.4) per 1 mg/L increase in EFV concentration. Symptoms resolved completely within 1 month in 25 (76{\%}) patients with severe neurotoxicity who discontinued EFV. Conclusion: A concentration–effect relationship for severe neurotoxicity exists, which occurred late and resolved in most patients after EFV discontinuation. Contribution: The authors highlighted clinical heterogeneity and morbidity of EFV-associated neurotoxicity.},
author = {Arnab, Priyadarshini and Croxford, Roland and Scott, Janet and Peruma, Sameshan and Mohammed, Zahraa and Wiesner, Lubbe and Cohen, Karen and Wasserman, Sean},
doi = {https://doi.org/10.4102/sajid.v38i1.522},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Arnab et al. - 2023 - Severe efavirenz associated neurotoxicity a retrospective cohort study.pdf:pdf},
journal = {Southern African Journal of Infectious Diseases},
keywords = {Cape Town,OA,cerebellar,efavirenz,fund{\_}ack,isoniazid,neurotoxicity,original,risk factors},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jul},
number = {1},
pages = {a522},
title = {{Severe efavirenz associated neurotoxicity: a retrospective cohort study}},
url = {https://sajid.co.za/index.php/sajid/article/view/522},
volume = {38},
year = {2023}
}

Background: Efavirenz (EFV) is associated with neuropsychiatric symptoms. Severe neurotoxicity has been reported but the clinical phenotype and risk factors are poorly defined. Objectives: To characterise clinical presentations, risk factors and outcomes to help clinicians recognise severe neurotoxicity earlier. Method: The authors retrospectively identified adults with supratherapeutic EFV concentrations (\textgreater 4 mg/L) obtained during routine clinical care in Cape Town, South Africa. Clinical and laboratory data at the time of EFV quantification were extracted from medical records. Logistic regression was performed to identify associations with neuropsychiatric symptoms, and with severe neurotoxicity. Results: Eighty one patients were included; 62 with neuropsychiatric manifestations (most frequently ataxia [ n = 20] and psychomotor slowing [ n = 24]); and 19 with hepatotoxicity. Overall, 28 (34.6%) were male, 49 (60.5%) had concomitant isoniazid exposure, and median EFV concentration was 12.1 mg/L (interquartile range [IQR]: 6.6–20.0). Neuropsychiatric symptoms were associated with longer duration of EFV therapy, adjusted odds ratio (aOR) 1.3/180-day increment (95% confidence interval [CI]: 1.0–1.7); higher EFV concentrations, aOR 1.2/1 mg/L increase (95% CI: 1.0–1.4) and isoniazid exposure, aOR 8.2 (95% CI: 2.5–26.7). Severe neuropsychiatric symptoms occurred in 47 (75%) patients at a median of 5.9 months (IQR: 2.1–40.8) after EFV initiation. Severe symptoms odds were 1.2-fold higher (95% CI: 1.1–1.4) per 1 mg/L increase in EFV concentration. Symptoms resolved completely within 1 month in 25 (76%) patients with severe neurotoxicity who discontinued EFV. Conclusion: A concentration–effect relationship for severe neurotoxicity exists, which occurred late and resolved in most patients after EFV discontinuation. Contribution: The authors highlighted clinical heterogeneity and morbidity of EFV-associated neurotoxicity.

@article{Richardson2023,
abstract = {The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.4 and BA.5 variants caused major waves of infections. Here, we assess the sensitivity of BA.4 to binding, neutralization, and antibody-dependent cellular cytotoxicity (ADCC) potential, measured by Fc$\gamma$RIIIa signaling, in convalescent donors infected with four previous variants of SARS-CoV-2, as well as in post-vaccination breakthrough infections (BTIs) caused by Delta or BA.1. We confirm that BA.4 shows high-level neutralization resistance regardless of the infecting variant. However, BTIs retain activity against BA.4, albeit at reduced titers. BA.4 sensitivity to ADCC is reduced compared with other variants but with smaller fold losses compared with neutralization and similar patterns of cross-reactivity. Overall, the high neutralization resistance of BA.4, even to antibodies from BA.1 infection, provides an immunological mechanism for the rapid spread of BA.4 immediately after a BA.1-dominated wave. Furthermore, although ADCC potential against BA.4 is reduced, residual activity may contribute to observed protection from severe disease.},
author = {Richardson, Simone I and Kgagudi, Prudence and Manamela, Nelia P and Kaldine, Haajira and Venter, Elizabeth M and Pillay, Thanusha and Lambson, Bronwen E and van der Mescht, Mieke A and Hermanus, Tandile and Balla, Sashkia R and de Beer, Zelda and de Villiers, Talita R and Bodenstein, Annie and van den Berg, Gretha and du Pisanie, Marizane and Burgers, Wendy A and Ntusi, Ntobeko A B and Abdullah, Fareed and Ueckermann, Veronica and Rossouw, Theresa M and Boswell, Michael T and Moore, Penny L},
doi = {10.1016/j.xcrm.2022.100910},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Richardson et al. - 2023 - Antibody-dependent cellular cytotoxicity against SARS-CoV-2 Omicron sub-lineages is reduced in convalescent s.pdf:pdf},
issn = {26663791},
journal = {Cell Reports Medicine},
keywords = {COVID-19,Fc effector function,OA,Omicron BA.4,SARS-CoV-2,VOC,antibody-dependent cellular cytotoxicity,breakthrough infection,fund{\_}not{\_}ack,neutralization,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jan},
number = {1},
pages = {100910},
publisher = {Cell Press},
title = {{Antibody-dependent cellular cytotoxicity against SARS-CoV-2 Omicron sub-lineages is reduced in convalescent sera regardless of infecting variant}},
url = {http://www.cell.com/article/S266637912200489X/fulltext http://www.cell.com/article/S266637912200489X/abstract https://www.cell.com/cell-reports-medicine/abstract/S2666-3791(22)00489-X},
volume = {4},
year = {2023}
}

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.4 and BA.5 variants caused major waves of infections. Here, we assess the sensitivity of BA.4 to binding, neutralization, and antibody-dependent cellular cytotoxicity (ADCC) potential, measured by Fc$γ$RIIIa signaling, in convalescent donors infected with four previous variants of SARS-CoV-2, as well as in post-vaccination breakthrough infections (BTIs) caused by Delta or BA.1. We confirm that BA.4 shows high-level neutralization resistance regardless of the infecting variant. However, BTIs retain activity against BA.4, albeit at reduced titers. BA.4 sensitivity to ADCC is reduced compared with other variants but with smaller fold losses compared with neutralization and similar patterns of cross-reactivity. Overall, the high neutralization resistance of BA.4, even to antibodies from BA.1 infection, provides an immunological mechanism for the rapid spread of BA.4 immediately after a BA.1-dominated wave. Furthermore, although ADCC potential against BA.4 is reduced, residual activity may contribute to observed protection from severe disease.

@incollection{Broger2023a,
abstract = {Background Tuberculosis (TB) is the most common cause of death in people living with HIV (PLHIV), yet TB often goes undiagnosed since many patients are not able to produce a sputum specimen, and traditional diagnostics are costly or unavailable. A novel, rapid lateral flow assay, Fujifilm SILVAMP TB LAM (SILVAMP-LAM), detects the presence of TB lipoarabinomannan (LAM) in urine, and is substantially more sensitive for diagnosing TB in PLHIV than an earlier LAM assay (Alere Determine TB LAM lateral flow assay [LF-LAM]). Here, we present an individual participant data meta-analysis of the diagnostic accuracy of SILVAMP-LAM in adult PLHIV, including both published and unpublished data. Methods and findings Adult PLHIV ({\textgreater}=18 years) were assessed in 5 prospective cohort studies in South Africa (3 cohorts), Vietnam, and Ghana, carried out during 2012 to 2017. Of the 1,595 PLHIV who met eligibility criteria, the majority (61{\%}) were inpatients, median age was 37 years (IQR 30-43), 43{\%} had a CD4 count . 100 cells/il, and 35{\%} were receiving antiretroviral therapy. Most participants (94{\%}) had a positive WHO symptom screen for TB on enrollment, and 45{\%} were diagnosed with microbiologically confirmed TB, using mycobacterial culture or Xpert MTB/RIF testing of sputum, urine, or blood. Previously published data from inpatients were combined with unpublished data from outpatients. Biobanked urine samples were tested, using blinded double reading, with SILVAMP-LAM and LF-LAM. Applying a microbiological reference standard for assessment of sensitivity, the overall sensitivity for TB detection was 70.7{\%} (95{\%} CI 59.0{\%}-80.8{\%}) for SILVAMP-LAM compared to 34.9{\%} (95{\%} CI 19.5{\%}-50.9{\%}) for LF-LAM. Using a composite reference standard (which included patients with both microbiologically confirmed as well as clinically diagnosed TB), SILVAMP-LAM sensitivity was 65.8{\%} (95{\%} CI 55.9{\%}-74.6{\%}), and that of LF-LAM 31.4{\%} (95{\%} CI 19.1{\%}-43.7{\%}). In patients with CD4 count . 100 cells/il, SILVAMP-LAM sensitivity was 87.1{\%} (95{\%} CI 79.3{\%}-93.6{\%}), compared to 56.0{\%} (95{\%} CI 43.9{\%}-64.9{\%}) for LF-LAM. In patients with CD4 count 101-200 cells/il, SILVAMP-LAM sensitivity was 62.7{\%} (95{\%} CI 52.4{\%}-71.9{\%}), compared to 25.3{\%} (95{\%} CI 15.8{\%}-34.9{\%}) for LF-LAM. In those with CD4 count {\textgreater} 200 cells/il, SILVAMP-LAM sensitivity was 43.9{\%} (95{\%} CI 34.3{\%}-53.9{\%}), compared to 10.9{\%} (95{\%} CI 5.2{\%}-18.4{\%}) for LF-LAM. Using a microbiological reference standard, the specificity of SILVAMP-LAM was 90.9{\%} (95{\%} CI 87.2{\%}-93.7{\%}), and that of LFLAM 95.3{\%} (95{\%} CI 92.2{\%}-97.7{\%}). Limitations of this study include the use of biobanked, rather than fresh urine samples, and testing by skilled laboratory technicians in research laboratories, rather than at the point of care. Conclusions In this study, we found that SILVAMP-LAM identified a substantially higher proportion of TB patients in PLHIV than LF-LAM. The sensitivity of SILVAMP-LAM was highest in patients with CD4 count {\textless}= 100 cells/il. Further work is needed to demonstrate accuracy when implemented as a point-of-care test.Copyright {\textcopyright} 2020 Public Library of Science. All rights reserved.},
author = {Broger, Tobias and Nicol, Mark P and Sz{\'{e}}kely, Rita and Bjerrum, Stephanie and Sossen, Bianca and Schutz, Charlotte and Opintan, Japheth A and Johansen, Isik S and Mitarai, Satoshi and Chikamatsu, Kinuyo and Kerkhoff, Andrew D and Mac{\'{e}}, Aur{\'{e}}lien and Ongarello, Stefano and Meintjes, Graeme A and Denkinger, Claudia M and Schumacher, Samuel G},
booktitle = {Advances in Medical Imaging, Detection, and Diagnosis},
doi = {10.1201/9781003298038-33/DIAGNOSTIC-ACCURACY-NOVEL-TUBERCULOSIS-POINT-CARE-URINE-LIPOARABINOMANNAN-ASSAY-PEOPLE-LIVING-HIV-META-ANALYSIS-INDIVIDUAL-OUTPATIENT-DATA-TOBIAS-BROGER-MARK-NICOL-RITA-SZ},
isbn = {9781000602043},
keywords = {book{\_}chap,original},
mendeley-tags = {book{\_}chap,original},
month = {sep},
pages = {955--972},
publisher = {Jenny Stanford Publishing},
title = {{Diagnostic accuracy of a novel tuberculosis point-of-care urine lipoarabinomannan assay for people living with HIV: a meta-analysis of individual in- and outpatient Data}},
url = {https://www.taylorfrancis.com/chapters/edit/10.1201/9781003298038-33/diagnostic-accuracy-novel-tuberculosis-point-care-urine-lipoarabinomannan-assay-people-living-hiv-meta-analysis-individual-outpatient-data-tobias-broger-mark-nicol-rita-sz{\'{e}}kely-stephanie},
year = {2023}
}

Background Tuberculosis (TB) is the most common cause of death in people living with HIV (PLHIV), yet TB often goes undiagnosed since many patients are not able to produce a sputum specimen, and traditional diagnostics are costly or unavailable. A novel, rapid lateral flow assay, Fujifilm SILVAMP TB LAM (SILVAMP-LAM), detects the presence of TB lipoarabinomannan (LAM) in urine, and is substantially more sensitive for diagnosing TB in PLHIV than an earlier LAM assay (Alere Determine TB LAM lateral flow assay [LF-LAM]). Here, we present an individual participant data meta-analysis of the diagnostic accuracy of SILVAMP-LAM in adult PLHIV, including both published and unpublished data. Methods and findings Adult PLHIV (\textgreater=18 years) were assessed in 5 prospective cohort studies in South Africa (3 cohorts), Vietnam, and Ghana, carried out during 2012 to 2017. Of the 1,595 PLHIV who met eligibility criteria, the majority (61%) were inpatients, median age was 37 years (IQR 30-43), 43% had a CD4 count . 100 cells/il, and 35% were receiving antiretroviral therapy. Most participants (94%) had a positive WHO symptom screen for TB on enrollment, and 45% were diagnosed with microbiologically confirmed TB, using mycobacterial culture or Xpert MTB/RIF testing of sputum, urine, or blood. Previously published data from inpatients were combined with unpublished data from outpatients. Biobanked urine samples were tested, using blinded double reading, with SILVAMP-LAM and LF-LAM. Applying a microbiological reference standard for assessment of sensitivity, the overall sensitivity for TB detection was 70.7% (95% CI 59.0%-80.8%) for SILVAMP-LAM compared to 34.9% (95% CI 19.5%-50.9%) for LF-LAM. Using a composite reference standard (which included patients with both microbiologically confirmed as well as clinically diagnosed TB), SILVAMP-LAM sensitivity was 65.8% (95% CI 55.9%-74.6%), and that of LF-LAM 31.4% (95% CI 19.1%-43.7%). In patients with CD4 count . 100 cells/il, SILVAMP-LAM sensitivity was 87.1% (95% CI 79.3%-93.6%), compared to 56.0% (95% CI 43.9%-64.9%) for LF-LAM. In patients with CD4 count 101-200 cells/il, SILVAMP-LAM sensitivity was 62.7% (95% CI 52.4%-71.9%), compared to 25.3% (95% CI 15.8%-34.9%) for LF-LAM. In those with CD4 count \textgreater 200 cells/il, SILVAMP-LAM sensitivity was 43.9% (95% CI 34.3%-53.9%), compared to 10.9% (95% CI 5.2%-18.4%) for LF-LAM. Using a microbiological reference standard, the specificity of SILVAMP-LAM was 90.9% (95% CI 87.2%-93.7%), and that of LFLAM 95.3% (95% CI 92.2%-97.7%). Limitations of this study include the use of biobanked, rather than fresh urine samples, and testing by skilled laboratory technicians in research laboratories, rather than at the point of care. Conclusions In this study, we found that SILVAMP-LAM identified a substantially higher proportion of TB patients in PLHIV than LF-LAM. The sensitivity of SILVAMP-LAM was highest in patients with CD4 count \textless= 100 cells/il. Further work is needed to demonstrate accuracy when implemented as a point-of-care test.Copyright © 2020 Public Library of Science. All rights reserved.

@article{Mutemaringa2023,
abstract = {IntroductionThe Patient Master Index (PMI) plays an important role in management of patient information and epidemiological research, and the availability of unique patient identifiers improves the accuracy when linking patient records across disparate datasets. In our environment, however, a unique identifier is seldom present in all datasets containing patient information. Quasi identifiers are used to attempt to link patient records but sometimes present higher risk of over-linking. Data quality and completeness thus affect the ability to make correct linkages. AimThis paper describes the record linkage system that is currently implemented at the Provincial Health Data Centre (PHDC) in the Western Cape, South Africa, and assesses its output to date. MethodsWe apply a stepwise deterministic record linkage approach to link patient data that are routinely collected from health information systems in the Western Cape province of South Africa. Variables used in the linkage process include South African National Identity number (RSA ID), date of birth, year of birth, month of birth, day of birth, residential address and contact information. Descriptive analyses are used to estimate the level and extent of duplication in the provincial PMI. ResultsThe percentage of duplicates in the provincial PMI lies between 10{\%} and 20{\%}. Duplicates mainly arise from spelling errors, and surname and first names carry most of the errors, with the first names and surname being different for the same individual in approximately 22{\%} of duplicates. The RSA ID is the variable mostly affected by poor completeness with less than 30{\%} of the records having an RSA ID. The current linkage algorithm requires refinement as it makes use of algorithms that have been developed and validated on anglicised names which might not work well for local names. Linkage is also affected by data quality-related issues that are associated with the routine nature of the data which often make it difficult to validate and enforce integrity at the point of data capture.},
author = {Mutemaringa, Themba and Heekes, Alexa and Smith, Mariette and Boulle, Andrew and Tiffin, Nicki},
doi = {10.23889/IJPDS.V8I1.1771},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Mutemaringa et al. - 2023 - Record linkage for routinely collected health data in an African health information exchange.pdf:pdf},
issn = {23994908},
journal = {International Journal of Population Data Science},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {mar},
number = {1},
pages = {07},
publisher = {Swansea University},
title = {{Record linkage for routinely collected health data in an African health information exchange}},
volume = {8},
year = {2023}
}

IntroductionThe Patient Master Index (PMI) plays an important role in management of patient information and epidemiological research, and the availability of unique patient identifiers improves the accuracy when linking patient records across disparate datasets. In our environment, however, a unique identifier is seldom present in all datasets containing patient information. Quasi identifiers are used to attempt to link patient records but sometimes present higher risk of over-linking. Data quality and completeness thus affect the ability to make correct linkages. AimThis paper describes the record linkage system that is currently implemented at the Provincial Health Data Centre (PHDC) in the Western Cape, South Africa, and assesses its output to date. MethodsWe apply a stepwise deterministic record linkage approach to link patient data that are routinely collected from health information systems in the Western Cape province of South Africa. Variables used in the linkage process include South African National Identity number (RSA ID), date of birth, year of birth, month of birth, day of birth, residential address and contact information. Descriptive analyses are used to estimate the level and extent of duplication in the provincial PMI. ResultsThe percentage of duplicates in the provincial PMI lies between 10% and 20%. Duplicates mainly arise from spelling errors, and surname and first names carry most of the errors, with the first names and surname being different for the same individual in approximately 22% of duplicates. The RSA ID is the variable mostly affected by poor completeness with less than 30% of the records having an RSA ID. The current linkage algorithm requires refinement as it makes use of algorithms that have been developed and validated on anglicised names which might not work well for local names. Linkage is also affected by data quality-related issues that are associated with the routine nature of the data which often make it difficult to validate and enforce integrity at the point of data capture.

@article{Chirehwa2023,
abstract = {Moxifloxacin is included in some treatment regimens for drug-sensitive tuberculosis (TB) and multidrug-resistant TB (MDR-TB). Aiming to optimize dosing, we described moxifloxacin pharmacokinetic an...},
author = {Chirehwa, M T and Resendiz-Galvan, J E and Court, R and {De Kock}, M and Wiesner, L and de Vries, N and Harding, J and Gumbo, T and Warren, R and Maartens, G and Denti, P and McIlleron, H},
doi = {10.1128/AAC.01426-22},
issn = {0066-4804},
journal = {Antimicrobial Agents and Chemotherapy},
keywords = {MDR-TB,efavirenz,moxifloxacin,multidrug resistance,original,pharmacometrics,population pharmacokinetics},
mendeley-tags = {original},
month = {feb},
pages = {10.1128/aac.01426--22},
pmid = {36744891},
publisher = {American Society for Microbiology 1752 N St., N.W., Washington, DC},
title = {{Optimizing moxifloxacin dose in MDR-TB participants with or without efavirenz coadministration using population pharmacokinetic modeling}},
url = {https://journals.asm.org/doi/10.1128/aac.01426-22},
year = {2023}
}

Moxifloxacin is included in some treatment regimens for drug-sensitive tuberculosis (TB) and multidrug-resistant TB (MDR-TB). Aiming to optimize dosing, we described moxifloxacin pharmacokinetic an...

@article{Moyo-Gwete2023,
abstract = {The impact of previous SARS-CoV-2 infection on the durability of Ad26.COV2.S vaccine-elicited responses, and the effect of homologous boosting has not been well explored. We followed a cohort of healthcare workers for 6 months after receiving the Ad26.COV2.S vaccine and a further one month after they received an Ad26.COV2.S booster dose. We assessed longitudinal spike-specific antibody and T cell responses in individuals who had never had SARS-CoV-2 infection, compared to those who were infected with either the D614G or Beta variants prior to vaccination. Antibody and T cell responses elicited by the primary dose were durable against several variants of concern over the 6 month follow-up period, regardless of infection history. However, at 6 months after first vaccination, antibody binding, neutralization and ADCC were as much as 33-fold higher in individuals with hybrid immunity compared to those with no prior infection. Antibody cross-reactivity profiles of the previously infected groups were similar at 6 months, unlike at earlier time points suggesting that the effect of immune imprinting diminishes by 6 months. Importantly, an Ad26.COV2.S booster dose increased the magnitude of the antibody response in individuals with no prior infection to similar levels as those with previous infection. The magnitude of spike T cell responses and proportion of T cell responders remained stable after homologous boosting, concomitant with a significant increase in long-lived early differentiated CD4 memory T cells. Thus, these data highlight that multiple antigen exposures, whether through infection and vaccination or vaccination alone, result in similar boosts after Ad26.COV2.S vaccination. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Funding Statement Research reported in this publication was supported by the South African Medical Research Council (SA MRC) with funds received from the South African Department of Science and Innovation (DSI), including grants 96825, SHIPNCD 76756 and DST/CON 0250/2012. This work was also supported by the Poliomyelitis Research Foundation (21/65) and the Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), which is supported by core funding from Wellcome Trust (203135/Z/16/Z and 222574). We acknowledge funding from the Bill and Melinda Gates Foundation, through the Global Immunology and Immune Sequencing for Epidemic Response (GIISER) program. PLM is supported by the South African Research Chairs Initiative of the Department of Science and Innovation and National Research Foundation of South Africa (NRF 9834), the SA Medical Research Council SHIP program, the Centre for the AIDS Programme of Research in South Africa (CAPRISA). TMG is funded by a South African Medical Research Council Self-Initiated Research Grant. SIR is funded by the Poliomyelitis Research Foundation. WAB and CR are supported by the EDCTP2 programme of the European Union Horizon 2020 programme (TMA2017SF-1951-TB-SPEC to C.R. and TMA2016SF-1535-CaTCH-22 to WAB) and the Wellcome Trust (226137/Z/22/ Z). CR is supported by the National Institutes of Health (NIH) (R21AI148027). NABN acknowledges funding from the SA MRC, MRC UK, NRF and the Lily and Ernst Hausmann Trust. {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the University of Cape Town Human Research Ethics Committee (Ethics number: HREC 190/2020 and 209/2020) and the University of the Witwatersrand Human Research Medical Ethics Committee (Ethics number: M210429). Written informed consent was obtained from all participants. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data are readily available upon request to the corresponding authors.},
author = {Moyo-Gwete, Thandeka and Richardson, Simone I and Keeton, Roanne and Hermanus, Tandile and Spencer, Holly and Manamela, Nelia P and Ayres, Frances and Makhado, Zanele and Motlou, Thopisang and Tincho, Marius B and Benede, Ntombi and Ngomti, Amkele and Baguma, Richard and Chauke, Masego V and Mennen, Mathilda and Adriaanse, Marguerite and Skelem, Sango and Goga, Ameena and Garrett, Nigel and Bekker, Linda-Gail and Gray, Glenda and Ntusi, Ntobeko A B and Riou, Catherine and Burgers, Wendy A and Moore, Penny L},
doi = {10.1101/2023.03.15.23287288},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Moyo-Gwete et al. - 2023 - Homologous Ad26.COV2.S vaccination results in reduced boosting of humoral responses in hybrid immunity, but e.pdf:pdf},
journal = {medRxiv},
keywords = {ADCC,Ad26COV2S vaccine,OA,SARS-CoV-2,T cells,antibodies,fund{\_}ack,genomics{\_}fund{\_}ack,hybrid immunity,memory differentiation,neutralization,original},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {mar},
pages = {2023.03.15.23287288},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Homologous Ad26.COV2.S vaccination results in reduced boosting of humoral responses in hybrid immunity, but elicits antibodies of similar magnitude regardless of prior infection}},
url = {https://www.medrxiv.org/content/10.1101/2023.03.15.23287288v1 https://www.medrxiv.org/content/10.1101/2023.03.15.23287288v1.abstract},
volume = {10},
year = {2023}
}

The impact of previous SARS-CoV-2 infection on the durability of Ad26.COV2.S vaccine-elicited responses, and the effect of homologous boosting has not been well explored. We followed a cohort of healthcare workers for 6 months after receiving the Ad26.COV2.S vaccine and a further one month after they received an Ad26.COV2.S booster dose. We assessed longitudinal spike-specific antibody and T cell responses in individuals who had never had SARS-CoV-2 infection, compared to those who were infected with either the D614G or Beta variants prior to vaccination. Antibody and T cell responses elicited by the primary dose were durable against several variants of concern over the 6 month follow-up period, regardless of infection history. However, at 6 months after first vaccination, antibody binding, neutralization and ADCC were as much as 33-fold higher in individuals with hybrid immunity compared to those with no prior infection. Antibody cross-reactivity profiles of the previously infected groups were similar at 6 months, unlike at earlier time points suggesting that the effect of immune imprinting diminishes by 6 months. Importantly, an Ad26.COV2.S booster dose increased the magnitude of the antibody response in individuals with no prior infection to similar levels as those with previous infection. The magnitude of spike T cell responses and proportion of T cell responders remained stable after homologous boosting, concomitant with a significant increase in long-lived early differentiated CD4 memory T cells. Thus, these data highlight that multiple antigen exposures, whether through infection and vaccination or vaccination alone, result in similar boosts after Ad26.COV2.S vaccination. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Research reported in this publication was supported by the South African Medical Research Council (SA MRC) with funds received from the South African Department of Science and Innovation (DSI), including grants 96825, SHIPNCD 76756 and DST/CON 0250/2012. This work was also supported by the Poliomyelitis Research Foundation (21/65) and the Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), which is supported by core funding from Wellcome Trust (203135/Z/16/Z and 222574). We acknowledge funding from the Bill and Melinda Gates Foundation, through the Global Immunology and Immune Sequencing for Epidemic Response (GIISER) program. PLM is supported by the South African Research Chairs Initiative of the Department of Science and Innovation and National Research Foundation of South Africa (NRF 9834), the SA Medical Research Council SHIP program, the Centre for the AIDS Programme of Research in South Africa (CAPRISA). TMG is funded by a South African Medical Research Council Self-Initiated Research Grant. SIR is funded by the Poliomyelitis Research Foundation. WAB and CR are supported by the EDCTP2 programme of the European Union Horizon 2020 programme (TMA2017SF-1951-TB-SPEC to C.R. and TMA2016SF-1535-CaTCH-22 to WAB) and the Wellcome Trust (226137/Z/22/ Z). CR is supported by the National Institutes of Health (NIH) (R21AI148027). NABN acknowledges funding from the SA MRC, MRC UK, NRF and the Lily and Ernst Hausmann Trust. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the University of Cape Town Human Research Ethics Committee (Ethics number: HREC 190/2020 and 209/2020) and the University of the Witwatersrand Human Research Medical Ethics Committee (Ethics number: M210429). Written informed consent was obtained from all participants. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data are readily available upon request to the corresponding authors.

@article{Chetty2023,
abstract = {Helminth-induced eosinophils accumulate around the parasite at the site of infection, or in parasite-damaged tissues well after the helminth has left the site. The role of helminth-elicited eosinophils in mediating parasite control is complex. While they may contribute to direct parasite-killing and tissue repair, their involvement in long-term immunopathogenesis is a concern. In allergic Siglec-FhiCD101hi, eosinophils are associated with pathology. Research has not shown if equivalent subpopulations of eosinophils are a feature of helminth infection. In this study, we demonstrate that lung migration of rodent hookworm Nippostrongylus brasiliensis (Nb) results in a long-term expansion of distinct Siglec-FhiCD101hi eosinophil subpopulations. Nb-elevated eosinophil populations in the bone marrow and circulation did not present this phenotype. Siglec-FhiCD101hi lung eosinophils exhibited an activated morphology including nuclei hyper-segmentation and cytoplasm degranulation. Recruitment of ST2+ ILC2s and not CD4+ T cells to the lungs was associated with the expansion of Siglec-FhiCD101hi eosinophils. This data identifies a morphologically distinct and persistent subset of Siglec-FhiCD101hi lung eosinophils induced following Nb infection. These eosinophils may contribute to long-term pathology following helminth infection.},
author = {Chetty, Alisha and Darby, Matthew G. and Pillaye, Jamie and Taliep, A'ishah and Cunningham, Adam F. and O'Shea, Matthew K. and Katawa, Gnatoulma and Layland, Laura E. and Ritter, Manuel and Horsnell, William G.C.},
doi = {10.3389/FIMMU.2023.1170807/BIBTEX},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Chetty et al. - 2023 - Induction of Siglec-FhiCD101hi eosinophils in the lungs following murine hookworm Nippostrongylus brasiliensis in.pdf:pdf},
issn = {16643224},
journal = {Frontiers in Immunology},
keywords = {CD101,ILC2s,Nippostrongylus brasilienis,OA,OA{\_}PMC,Siglec-F,eosinophils,fund{\_}ack,helminths,lung,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,original},
month = {may},
pages = {2082},
pmid = {37251384},
publisher = {Frontiers Media S.A.},
title = {{Induction of Siglec-FhiCD101hi eosinophils in the lungs following murine hookworm \textit{Nippostrongylus brasiliensis} infection}},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2023.1170807/full},
volume = {14},
year = {2023}
}

Helminth-induced eosinophils accumulate around the parasite at the site of infection, or in parasite-damaged tissues well after the helminth has left the site. The role of helminth-elicited eosinophils in mediating parasite control is complex. While they may contribute to direct parasite-killing and tissue repair, their involvement in long-term immunopathogenesis is a concern. In allergic Siglec-FhiCD101hi, eosinophils are associated with pathology. Research has not shown if equivalent subpopulations of eosinophils are a feature of helminth infection. In this study, we demonstrate that lung migration of rodent hookworm Nippostrongylus brasiliensis (Nb) results in a long-term expansion of distinct Siglec-FhiCD101hi eosinophil subpopulations. Nb-elevated eosinophil populations in the bone marrow and circulation did not present this phenotype. Siglec-FhiCD101hi lung eosinophils exhibited an activated morphology including nuclei hyper-segmentation and cytoplasm degranulation. Recruitment of ST2+ ILC2s and not CD4+ T cells to the lungs was associated with the expansion of Siglec-FhiCD101hi eosinophils. This data identifies a morphologically distinct and persistent subset of Siglec-FhiCD101hi lung eosinophils induced following Nb infection. These eosinophils may contribute to long-term pathology following helminth infection.

@article{Parsons2023,
abstract = {The epidemiology of human parainfluenza viruses (HPIV), particularly its role as a cause of acute respiratory infection (ARI) in infants, has not been formally studied in South Africa. We evaluated HPIV prevalence in diagnostic samples from hospitalized children from public sector hospitals in the Western Cape between 2014 and 2022. HPIV infection was detected in 2–10{\%} of patients, with the majority of infections detected in children less than 1 year of age. Prior to 2020, HPIV 4 (40{\%}) and HPIV 3 (34{\%}) were the most prevalent types, with seasonal peaks in late winter/spring for HPIV 3 and autumn/winter for HPIV 4. HPIV 4A and 4B co-circulated during the seasonal activity between 2014 and 2017. Pandemic restrictions in 2020 had a profound effect on HPIV circulation and the rebound was dominated by waves of HPIV 3, accounting for 66{\%} of detections and a sustained decline in the circulation of HPIV 1, 2 and 4. An immunity gap could account for the surge in HPIV 3 infections, but the decline in prior HPIV 4 dominance is unexplained and requires further study.},
author = {Parsons, Jane and Korsman, Stephen and Smuts, Heidi and Hsiao, Nei-Yuan and Valley-Omar, Ziyaad and Gelderbloem, Tathym and Hardie, Diana},
doi = {10.3390/diagnostics13152576},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Parsons et al. - 2023 - Human Parainfluenza Virus (HPIV) detection in hospitalized children with acute respiratory tract infection in th.pdf:pdf},
isbn = {2075-4418},
issn = {2075-4418},
journal = {Diagnostics},
keywords = {OA,OA{\_}PMC,South Africa,acute respiratory infection,children,epidemiology,fund{\_}ack,genomics{\_}fund{\_}ack,human parainfluenza virus,multiplex real-time PCR,original,pneumonia},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {aug},
number = {15},
pages = {2576},
pmid = {37568938},
title = {{Human Parainfluenza Virus (HPIV) detection in hospitalized children with acute respiratory tract infection in the Western Cape, South Africa during 2014–2022 reveals a shift in dominance of HPIV 3 and 4 infections}},
url = {https://www.mdpi.com/2075-4418/13/15/2576},
volume = {13},
year = {2023}
}

The epidemiology of human parainfluenza viruses (HPIV), particularly its role as a cause of acute respiratory infection (ARI) in infants, has not been formally studied in South Africa. We evaluated HPIV prevalence in diagnostic samples from hospitalized children from public sector hospitals in the Western Cape between 2014 and 2022. HPIV infection was detected in 2–10% of patients, with the majority of infections detected in children less than 1 year of age. Prior to 2020, HPIV 4 (40%) and HPIV 3 (34%) were the most prevalent types, with seasonal peaks in late winter/spring for HPIV 3 and autumn/winter for HPIV 4. HPIV 4A and 4B co-circulated during the seasonal activity between 2014 and 2017. Pandemic restrictions in 2020 had a profound effect on HPIV circulation and the rebound was dominated by waves of HPIV 3, accounting for 66% of detections and a sustained decline in the circulation of HPIV 1, 2 and 4. An immunity gap could account for the surge in HPIV 3 infections, but the decline in prior HPIV 4 dominance is unexplained and requires further study.

@article{Nesamari2023,
abstract = {The COVID-19 post-pandemic period is characterised by infection waves of uncertain size (due to low rates of SARS-CoV-2 testing and notification), as well as limited uptake or global access to updated variant vaccines. Ongoing SARS-CoV-2 evolution has given rise to recombinant Omicron lineages that dominate globally (XBB.1), as well as the emergence of hypermutated variants (BA.2.86). In this context, durable and cross-reactive T-cell immune memory is critical for continued protection against severe COVID-19. We examined T-cell responses to SARS-CoV-2 approximately 1.5 years since Omicron first emerged. We describe sustained CD4+ and CD8+ spike-specific T-cell memory responses in healthcare workers in South Africa (n=39), most of whom had received 2 doses of Ad26.CoV2.S (Johnson {\&} Johnson/Janssen) vaccine and experienced at least one SARS-CoV-2 infection. Spike-specific T cells were highly cross-reactive with all Omicron variants tested, including BA.2.86. Abundant non-spike (nucleocapsid and membrane)-specific T cells were detectable in most participants, augmenting the total T-cell resources available for protection. The bulk of SARS-CoV-2-specific T-cell responses had an early-differentiated phenotype, explaining their persistent nature. Thus, hybrid immunity leads to the accumulation of spike and non-spike T cells evident 3.5 years after the start of the pandemic, with preserved recognition of highly mutated SARS-CoV-2 variants. Long-term T-cell immune memory is likely to provide continued protection against severe outcomes of COVID-19. {\#}{\#}{\#} Competing Interest Statement Alex Sette is a consultant for AstraZeneca Pharmaceuticals, Calyptus Pharmaceuticals, Inc, Darwin Health, EmerVax, EUROIMMUN, F. Hoffman-La Roche Ltd, Fortress Biotech, Gilead Sciences, Granite bio., Gritstone Oncology, Guggenheim Securities, Moderna, Pfizer, RiverVest Venture Partners, and Turnstone Biologics. Alba Grifoni is a consultant for Pfizer. LJI has filed for patent protection for various aspects of T cell epitope and vaccine design work. All other authors declare no competing interests. {\#}{\#}{\#} Funding Statement Wellcome Trust (226137/Z/22/Z) South African Medical Research Council (SA-MRC) with funds received from the South African Department of Science and Innovation (DSI) Bill and Melinda Gates Foundation (INV-046743) Poliomyelitis Research Foundation (21/65) Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa) which is supported by core funding from the Wellcome Trust (203135/Z/16/Z and 222754) W.A.B. and C.R. are supported by the EDCTP2 program of the European Unions Horizon 2020 program (TMA2016SF-1535-CaTCH-22 to W.A.B and TMA2017SF-1951-TB-SPEC to C.R.) R.N. is supported by the Harry Crossley Foundation N.A.B.N. acknowledges funding from the SA-MRC, MRC UK, NRF, and the Lily and Ernst Hausmann Trust This project has been funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. 75N93021C00016 to A.G. and Contract No. 75N93019C00065 to A.S. {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the University of Cape Town Human Research Ethics Committee (HREC 190/2020 and 291/2020), and written informed consent was obtained from all participants. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data reported in this paper will be shared by the lead contacts upon request. This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contacts upon request.},
author = {Nesamari, Rofhiwa and Omondi, Millicent A and H{\"{o}}ft, Maxine A and Ngomti, Amkele and Baguma, Richard and Nkayi, Anathi A and Besethi, Asiphe S and Magugu, Siyabulela F J and Mosala, Paballo and Walters, Avril and Clark, Gesina M and Mennen, Mathilda and Skelem, Sango and Adriaanse, Marguerite and Grifoni, Alba and Sette, Alessandro and Keeton, Roanne S and Ntusi, Ntobeko A B and Riou, Catherine and Burgers, Wendy A},
doi = {10.1101/2023.10.28.23297714},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Nesamari et al. - 2023 - Post-pandemic memory T-cell response to SARS-CoV-2 is durable, broadly targeted and cross-reactive to hypermuta.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {oct},
pages = {2023.10.28.23297714},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Post-pandemic memory T-cell response to SARS-CoV-2 is durable, broadly targeted and cross-reactive to hypermutated BA.2.86}},
url = {https://www.medrxiv.org/content/10.1101/2023.10.28.23297714v1 https://www.medrxiv.org/content/10.1101/2023.10.28.23297714v1.abstract},
year = {2023}
}

The COVID-19 post-pandemic period is characterised by infection waves of uncertain size (due to low rates of SARS-CoV-2 testing and notification), as well as limited uptake or global access to updated variant vaccines. Ongoing SARS-CoV-2 evolution has given rise to recombinant Omicron lineages that dominate globally (XBB.1), as well as the emergence of hypermutated variants (BA.2.86). In this context, durable and cross-reactive T-cell immune memory is critical for continued protection against severe COVID-19. We examined T-cell responses to SARS-CoV-2 approximately 1.5 years since Omicron first emerged. We describe sustained CD4+ and CD8+ spike-specific T-cell memory responses in healthcare workers in South Africa (n=39), most of whom had received 2 doses of Ad26.CoV2.S (Johnson & Johnson/Janssen) vaccine and experienced at least one SARS-CoV-2 infection. Spike-specific T cells were highly cross-reactive with all Omicron variants tested, including BA.2.86. Abundant non-spike (nucleocapsid and membrane)-specific T cells were detectable in most participants, augmenting the total T-cell resources available for protection. The bulk of SARS-CoV-2-specific T-cell responses had an early-differentiated phenotype, explaining their persistent nature. Thus, hybrid immunity leads to the accumulation of spike and non-spike T cells evident 3.5 years after the start of the pandemic, with preserved recognition of highly mutated SARS-CoV-2 variants. Long-term T-cell immune memory is likely to provide continued protection against severe outcomes of COVID-19. ### Competing Interest Statement Alex Sette is a consultant for AstraZeneca Pharmaceuticals, Calyptus Pharmaceuticals, Inc, Darwin Health, EmerVax, EUROIMMUN, F. Hoffman-La Roche Ltd, Fortress Biotech, Gilead Sciences, Granite bio., Gritstone Oncology, Guggenheim Securities, Moderna, Pfizer, RiverVest Venture Partners, and Turnstone Biologics. Alba Grifoni is a consultant for Pfizer. LJI has filed for patent protection for various aspects of T cell epitope and vaccine design work. All other authors declare no competing interests. ### Funding Statement Wellcome Trust (226137/Z/22/Z) South African Medical Research Council (SA-MRC) with funds received from the South African Department of Science and Innovation (DSI) Bill and Melinda Gates Foundation (INV-046743) Poliomyelitis Research Foundation (21/65) Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa) which is supported by core funding from the Wellcome Trust (203135/Z/16/Z and 222754) W.A.B. and C.R. are supported by the EDCTP2 program of the European Unions Horizon 2020 program (TMA2016SF-1535-CaTCH-22 to W.A.B and TMA2017SF-1951-TB-SPEC to C.R.) R.N. is supported by the Harry Crossley Foundation N.A.B.N. acknowledges funding from the SA-MRC, MRC UK, NRF, and the Lily and Ernst Hausmann Trust This project has been funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. 75N93021C00016 to A.G. and Contract No. 75N93019C00065 to A.S. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the University of Cape Town Human Research Ethics Committee (HREC 190/2020 and 291/2020), and written informed consent was obtained from all participants. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data reported in this paper will be shared by the lead contacts upon request. This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contacts upon request.

@article{Zass2023,
abstract = {Modern biomedical research is characterised by its high-throughput and interdisciplinary nature. Multiproject and consortium-based collaborations requiring meaningful analysis of multiple heterogeneous phenotypic datasets have become the norm; however, such analysis remains a challenge in many regions across the world. An increasing number of data harmonisation efforts are being undertaken by multistudy collaborations through either prospective standardised phenotype data collection or retrospective phenotype harmonisation. In this regard, the Phenotype Harmonisation Working Group (PHWG) of the Human Heredity and Health in Africa (H3Africa) consortium aimed to facilitate phenotype standardisation by both promoting the use of existing data collection standards (hosted by PhenX), adapting existing data collection standards for appropriate use in low- and middle-income regions such as Africa, and developing novel data collection standards where relevant gaps were identified. Ultimately, the PHWG produced 11 data collection kits, consisting of 82 protocols, 38 of which were existing protocols, 17 were adapted, and 27 were novel protocols. The data collection kits will facilitate phenotype standardisation and harmonisation not only in Africa but also across the larger research community. In addition, the PHWG aims to feed back adapted and novel protocols to existing reference platforms such as PhenX.},
author = {Zass, Lyndon and Johnston, Katherine and Benkahla, Alia and Chaouch, Melek and Kumuthini, Judit and Radouani, Fouzia and Mwita, Liberata Alexander and Alsayed, Nihad and Allie, Taryn and Sathan, Dassen and Masamu, Upendo and {Seuneu Tchamga}, Milaine Sergine and Tamuhla, Tsaone and Samtal, Chaimae and Nembaware, Victoria and Gill, Zoe and Ahmed, Samah and Hamdi, Yosr and Fadlelmola, Faisal and Tiffin, Nicki and Mulder, Nicola},
doi = {10.1155/2023/6693323},
editor = {Mboowa, Gerald},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Zass et al. - 2023 - Developing clinical phenotype data collection standards for research in Africa.pdf:pdf},
issn = {2054-4200},
journal = {Global Health, Epidemiology and Genomics},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
pages = {6693323},
publisher = {Hindawi},
title = {{Developing clinical phenotype data collection standards for research in Africa}},
url = {https://doi.org/10.1155/2023/6693323},
volume = {2023},
year = {2023}
}

Modern biomedical research is characterised by its high-throughput and interdisciplinary nature. Multiproject and consortium-based collaborations requiring meaningful analysis of multiple heterogeneous phenotypic datasets have become the norm; however, such analysis remains a challenge in many regions across the world. An increasing number of data harmonisation efforts are being undertaken by multistudy collaborations through either prospective standardised phenotype data collection or retrospective phenotype harmonisation. In this regard, the Phenotype Harmonisation Working Group (PHWG) of the Human Heredity and Health in Africa (H3Africa) consortium aimed to facilitate phenotype standardisation by both promoting the use of existing data collection standards (hosted by PhenX), adapting existing data collection standards for appropriate use in low- and middle-income regions such as Africa, and developing novel data collection standards where relevant gaps were identified. Ultimately, the PHWG produced 11 data collection kits, consisting of 82 protocols, 38 of which were existing protocols, 17 were adapted, and 27 were novel protocols. The data collection kits will facilitate phenotype standardisation and harmonisation not only in Africa but also across the larger research community. In addition, the PHWG aims to feed back adapted and novel protocols to existing reference platforms such as PhenX.

@article{Stek2023,
abstract = {The development of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) and its prevention using prednisone may potentially be mediated by the LTA4H genotype. We assessed this hypothesis in a clinical trial evaluating prednisone to prevent TB-IRIS. We did not find an association between LTA4H genotype and TB-IRIS incidence or prednisone efficacy.},
author = {Stek, Cari and Shey, Muki and Mnika, Khuthala and Schutz, Charlotte and Thienemann, Friedrich and Wilkinson, Robert J and Lynen, Lutgarde and Meintjes, Graeme},
doi = {10.1093/OFID/OFAD379},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Stek et al. - 2023 - Relationship between LTA4H promotor polymorphism and tuberculosis-associated immune reconstitution inflammatory syn.pdf:pdf},
issn = {23288957},
journal = {Open Forum Infectious Diseases},
keywords = {IRIS,LTA4H genotype,OA,OA{\_}PMC,corticosteroids,fund{\_}ack,immune reconstitution inflammatory syndrome,original,tuberculosis},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,original},
month = {jul},
number = {7},
pages = {ofad379},
pmid = {37520416},
publisher = {Oxford Academic},
title = {{Relationship between LTA4H promotor polymorphism and tuberculosis-associated immune reconstitution inflammatory syndrome and its prevention with prednisone}},
url = {https://dx.doi.org/10.1093/ofid/ofad379},
volume = {10},
year = {2023}
}

The development of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) and its prevention using prednisone may potentially be mediated by the LTA4H genotype. We assessed this hypothesis in a clinical trial evaluating prednisone to prevent TB-IRIS. We did not find an association between LTA4H genotype and TB-IRIS incidence or prednisone efficacy.

@article{Kroon2023,
abstract = {Persons living with HIV (PLWH) have an increased risk for tuberculosis (TB). After prolonged and repeated exposure, some PLWH never develop TB and test persistently negative in tests of immune sensitization tuberculin skin test (TST) and interferon gamma release assays (IGRA) for Mycobacterium tuberculosis (Mtb). This group has been identified and defined as HIV+ persistently TB, tuberculin and IGRA negative (HITTIN). To investigate potential innate mechanisms unique to individuals with the HITTIN phenotype we compared their neutrophil Mtb infection response to that of PLWH, with no TB history, but who test persistently IGRA positive, and tuberculin positive (HIT). Neutrophil samples from 17 HITTIN (PMNHITTIN) and 11 HIT (PMNHIT) were isolated and infected with Mtb H37Rv for 1h and 6h. RNA was extracted and used for RNAseq analysis. At 1h of Mtb infection, PMNHITTIN displayed 151 significantly upregulated and 40 significantly downregulated differentially expressed genes (DEGs) and PMNHIT 98 significantly upregulated and 11 significantly downregulated DEGs. At the 6h timepoint, PMNHITTIN displayed 3106 significantly upregulated and 3548 significantly downregulated DEGs while PMNHIT had 3816 significantly up- and 3794 significantly downregulated DEGs. There was no significant differential transcriptional response at 1h between infected PMNHITTIN and PMNHIT. However, when contrasting the log2FC 6h infection response to Mtb from PMNHITTIN against PMNHIT, 2285 genes showed significant differential response between the two groups. Apoptosis and NETosis were key pathways linked to the enrichment of genes in PMNHITTIN when contrasted to PMNHIT after 6h infection with Mtb. Fluorescence microscopy revealed relatively lower neutrophil extracellular trap formation and cell loss in PMNHITTIN compared to PMNHIT, showing that PMNHITTIN have a distinct response to Mtb. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest.},
author = {Kroon, Elouise Elizabeth and de Macedo, Wilian Correa and Evans, Rachel and Seeger, Allison and Engelbrecht, Lize and Kriel, Jurgen and Loos, Ben and Okugbeni, Naomi and Orlova, Marianna Olegovna and Cassart, Pauline and Kinnear, Craig and Tromp, Gerard and Moller, Marlo and Wilkinson, Robert J and Coussens, Anna K},
doi = {10.1101/2023.04.19.537498},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Kroon et al. - 2023 - Altered neutrophil extracellular traps in response to iMycobacterium tuberculosisi in persons living with HIV with.pdf:pdf},
journal = {bioRxiv},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {apr},
pages = {2023.04.19.537498},
publisher = {Cold Spring Harbor Laboratory},
title = {{Altered neutrophil extracellular traps in response to \textit{Mycobacterium tuberculosis} in persons living with HIV with no previous TB and negative TST and IGRA}},
url = {https://www.biorxiv.org/content/10.1101/2023.04.19.537498v1 https://www.biorxiv.org/content/10.1101/2023.04.19.537498v1.abstract},
year = {2023}
}

Persons living with HIV (PLWH) have an increased risk for tuberculosis (TB). After prolonged and repeated exposure, some PLWH never develop TB and test persistently negative in tests of immune sensitization tuberculin skin test (TST) and interferon gamma release assays (IGRA) for Mycobacterium tuberculosis (Mtb). This group has been identified and defined as HIV+ persistently TB, tuberculin and IGRA negative (HITTIN). To investigate potential innate mechanisms unique to individuals with the HITTIN phenotype we compared their neutrophil Mtb infection response to that of PLWH, with no TB history, but who test persistently IGRA positive, and tuberculin positive (HIT). Neutrophil samples from 17 HITTIN (PMNHITTIN) and 11 HIT (PMNHIT) were isolated and infected with Mtb H37Rv for 1h and 6h. RNA was extracted and used for RNAseq analysis. At 1h of Mtb infection, PMNHITTIN displayed 151 significantly upregulated and 40 significantly downregulated differentially expressed genes (DEGs) and PMNHIT 98 significantly upregulated and 11 significantly downregulated DEGs. At the 6h timepoint, PMNHITTIN displayed 3106 significantly upregulated and 3548 significantly downregulated DEGs while PMNHIT had 3816 significantly up- and 3794 significantly downregulated DEGs. There was no significant differential transcriptional response at 1h between infected PMNHITTIN and PMNHIT. However, when contrasting the log2FC 6h infection response to Mtb from PMNHITTIN against PMNHIT, 2285 genes showed significant differential response between the two groups. Apoptosis and NETosis were key pathways linked to the enrichment of genes in PMNHITTIN when contrasted to PMNHIT after 6h infection with Mtb. Fluorescence microscopy revealed relatively lower neutrophil extracellular trap formation and cell loss in PMNHITTIN compared to PMNHIT, showing that PMNHITTIN have a distinct response to Mtb. ### Competing Interest Statement The authors have declared no competing interest.

@article{Shey2023,
abstract = {Background: Currently, diagnosis of latent TB infection (LTBI) is based on the secretion of IFN-$\gamma$ in response to Mycobacterium tuberculosis (Mtb) antigens, the absence of which is regarded as no infection. Some individuals appear to resist Mtb infection despite sustained exposure (resisters). In this study, we aimed to assess cytokines, chemokines and antibodies that may be associated with resistance to Mtb infection. We hypothesized that there may be an alternative immune response to Mtb exposure in the absence of IFN-$\gamma$ in resisters. Methods: We enrolled HIV-uninfected healthcare workers who had worked in high TB-exposure environments for 5 years or longer. We screened them for LTBI using the tuberculin skin test and the QuantiFERON-TB Gold Plus assay. We performed multiplex Luminex to measure concentrations of T cell-associated cytokines and chemokines as well as total antibodies in plasma collected from unstimulated fresh whole blood and supernatants from QuantiFERON-TB Gold Plus tubes following incubation of whole blood for 16-24 hours with ESAT6/CFP10 peptides. Results: Samples from 78 individuals were analyzed: 33 resisters (TST{\textless}10mm; IGRA{\textless}0.35 IU/mL), 33 with LTBI (TST≥10mm and IGRA≥0.35 IU/mL) and 12 discordant (TST=0mm; IGRA≥1.0 IU/mL). There were no differences in concentrations of cytokines and chemokines in plasma between the different groups. Resisters had significantly lower concentrations of IFN-$\gamma$, IL-2, TNF-$\alpha$, MIP-1$\alpha$, MIP-1$\beta$, ITAC, IL-13 and GM-CSF in supernatants compared with LTBI group. There were no significant differences in the concentrations in supernatants of IL-10, IL-1$\beta$, IL-17A, IL-21, IL-23, MIP-3$\alpha$, IL-4, IL-5, IL-6, IL-7, IL-8, Fractalkine and IL-12p70 between the groups. We observed that resisters had similar concentrations of total antibodies (IgG1, IgG2, IgG3, IgG4, IgA, and IgM) in plasma and supernatants compared to the LTBI and discordant groups. Conclusion: Resistance to Mtb infection despite sustained exposure is associated with lower Mtb-specific secretion of Th1-associated cytokines and chemokines. However, resisters showed secreted concentrations after Mtb stimulation of total antibodies and cytokines/chemokines associated with innate and Th17 immune responses similar to those with Mtb infection. This suggests an ability to mount non-IFN-$\gamma$ immune responses to Mtb in apparent resisters.},
author = {Shey, Muki S and Balfour, Avuyonke and Masina, Nomawethu and Bekiswa, Abulele and Schutz, Charlotte and Goliath, Rene and Dielle, Rachel and Katoto, Patrick Dmc and Wilkinson, Katalin A and Lewinsohn, David and Lewinsohn, Deborah A and Meintjes, Graeme A},
doi = {10.3389/FIMMU.2023.1176615/BIBTEX},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Shey et al. - 2023 - Mycobacterial-specific secretion of cytokines and chemokines in healthcare workers with apparent resistance to infe.pdf:pdf},
issn = {16643224},
journal = {Frontiers in Immunology},
keywords = {Mycobacterium tuberculosis,OA,antibodies,chemokines,cytokines,fund{\_}ack,latent TB infection (LTBI),original,resister},
mendeley-tags = {OA,fund{\_}ack,original},
month = {may},
pages = {1176615},
pmid = {37275871},
publisher = {NLM (Medline)},
title = {{Mycobacterial-specific secretion of cytokines and chemokines in healthcare workers with apparent resistance to infection with Mycobacterium tuberculosis}},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2023.1176615/full},
volume = {14},
year = {2023}
}

Background: Currently, diagnosis of latent TB infection (LTBI) is based on the secretion of IFN-$γ$ in response to Mycobacterium tuberculosis (Mtb) antigens, the absence of which is regarded as no infection. Some individuals appear to resist Mtb infection despite sustained exposure (resisters). In this study, we aimed to assess cytokines, chemokines and antibodies that may be associated with resistance to Mtb infection. We hypothesized that there may be an alternative immune response to Mtb exposure in the absence of IFN-$γ$ in resisters. Methods: We enrolled HIV-uninfected healthcare workers who had worked in high TB-exposure environments for 5 years or longer. We screened them for LTBI using the tuberculin skin test and the QuantiFERON-TB Gold Plus assay. We performed multiplex Luminex to measure concentrations of T cell-associated cytokines and chemokines as well as total antibodies in plasma collected from unstimulated fresh whole blood and supernatants from QuantiFERON-TB Gold Plus tubes following incubation of whole blood for 16-24 hours with ESAT6/CFP10 peptides. Results: Samples from 78 individuals were analyzed: 33 resisters (TST\textless10mm; IGRA\textless0.35 IU/mL), 33 with LTBI (TST≥10mm and IGRA≥0.35 IU/mL) and 12 discordant (TST=0mm; IGRA≥1.0 IU/mL). There were no differences in concentrations of cytokines and chemokines in plasma between the different groups. Resisters had significantly lower concentrations of IFN-$γ$, IL-2, TNF-$α$, MIP-1$α$, MIP-1$β$, ITAC, IL-13 and GM-CSF in supernatants compared with LTBI group. There were no significant differences in the concentrations in supernatants of IL-10, IL-1$β$, IL-17A, IL-21, IL-23, MIP-3$α$, IL-4, IL-5, IL-6, IL-7, IL-8, Fractalkine and IL-12p70 between the groups. We observed that resisters had similar concentrations of total antibodies (IgG1, IgG2, IgG3, IgG4, IgA, and IgM) in plasma and supernatants compared to the LTBI and discordant groups. Conclusion: Resistance to Mtb infection despite sustained exposure is associated with lower Mtb-specific secretion of Th1-associated cytokines and chemokines. However, resisters showed secreted concentrations after Mtb stimulation of total antibodies and cytokines/chemokines associated with innate and Th17 immune responses similar to those with Mtb infection. This suggests an ability to mount non-IFN-$γ$ immune responses to Mtb in apparent resisters.

@article{Malahleha2023,
abstract = {In South Africa, HIV acquisition risk has been studied less in people assigned male at birth. We studied the associations between risk behaviors, clinical features and HIV incidence amongst males in two South African HIV preventive vaccine efficacy trials. We used Cox proportional hazards models to test for associations between demographics, sexual behaviors, clinical variables and HIV acquisition among males followed in the HVTN 503 (n = 219) and HVTN 702 (n = 1611) trials. Most males reported no male sexual partners (99.09{\%} in HVTN 503) or identified as heterosexual (88.08{\%} in HVTN 702). Annual HIV incidence was 1.39{\%} in HVTN 503 (95{\%} CI 0.76–2.32{\%}) and 1.33{\%} in HVTN 702 (95{\%} CI 0.80–2.07{\%}). Increased HIV acquisition was significantly associated with anal sex (HR 6.32, 95{\%} CI 3.44–11.62), transactional sex (HR 3.42, 95{\%} CI 1.80–6.50), and non-heterosexual identity (HR 16.23, 95{\%}CI 8.13–32.41) in univariate analyses and non-heterosexual identity (HR 14.99, 95{\%} CI 4.99–45.04; p {\textless} 0.01) in multivariate analysis. It is appropriate that prevention efforts in South Africa, although focused on the severe epidemic in young women, also encompass key male populations, including men who have sex with men, but also men who engage in anal or transactional sex.},
author = {Malahleha, Mookho and Laher, Fatima and Dilraj, Athmanundh and Smith, Philip and Gray, Glenda E and Grove, Doug and Odhiambo, Jackline A and Andrasik, Michele P and Grunenberg, Nicole A and Moodie, Zoe and Huang, Yunda and Borate, Bhavesh R and Gillespie, Kevin M and Allen, Mary and Atujuna, Millicent and Singh, Nishanta and Kalonji, Dishiki and Meintjes, Graeme and Kotze, Phillip and Bekker, Linda-Gail and Janes, Holly},
doi = {10.1007/S10461-023-04025-Z},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Malahleha et al. - 2023 - Risk factors associated with HIV acquisition in males participating in HIV vaccine efficacy trials in South(2).pdf:pdf},
issn = {1573-3254},
journal = {AIDS and Behavior},
keywords = {Health Psychology,Infectious Diseases,OA,Public Health,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {mar},
pages = {1--11},
publisher = {Springer},
title = {{Risk factors associated with HIV acquisition in males participating in HIV vaccine efficacy trials in South Africa}},
url = {https://link.springer.com/article/10.1007/s10461-023-04025-z},
year = {2023}
}

In South Africa, HIV acquisition risk has been studied less in people assigned male at birth. We studied the associations between risk behaviors, clinical features and HIV incidence amongst males in two South African HIV preventive vaccine efficacy trials. We used Cox proportional hazards models to test for associations between demographics, sexual behaviors, clinical variables and HIV acquisition among males followed in the HVTN 503 (n = 219) and HVTN 702 (n = 1611) trials. Most males reported no male sexual partners (99.09% in HVTN 503) or identified as heterosexual (88.08% in HVTN 702). Annual HIV incidence was 1.39% in HVTN 503 (95% CI 0.76–2.32%) and 1.33% in HVTN 702 (95% CI 0.80–2.07%). Increased HIV acquisition was significantly associated with anal sex (HR 6.32, 95% CI 3.44–11.62), transactional sex (HR 3.42, 95% CI 1.80–6.50), and non-heterosexual identity (HR 16.23, 95%CI 8.13–32.41) in univariate analyses and non-heterosexual identity (HR 14.99, 95% CI 4.99–45.04; p \textless 0.01) in multivariate analysis. It is appropriate that prevention efforts in South Africa, although focused on the severe epidemic in young women, also encompass key male populations, including men who have sex with men, but also men who engage in anal or transactional sex.

@article{Gonzalez-Rodriguez2023,
abstract = {The emergence of a polybasic cleavage motif for the protease furin in SARS-CoV-2 spike has been established as a major factor for human viral transmission. The region N-terminal to that motif is extensively mutated in variants of concern (VOCs). Besides furin, spikes from these variants appear to rely on other proteases for maturation, including TMPRSS2. Glycans near the cleavage site have raised questions about proteolytic processing and the consequences of variant-borne mutations. Here, we identify that sialic acid-containing O-linked glycans on Thr678 of SARS-CoV-2 spike influence furin and TMPRSS2 cleavage and posit O-linked glycosylation as a likely driving force for the emergence ofVOC mutations. We provide direct evidence that the glycosyltransferase GalNAc-T1 primes glycosylation at Thr678 in the living cell, an event that is suppressed by mutations in the VOCs Alpha, Delta, and Omicron. We found that the sole incorporation of N-acetylgalactosamine did not impact furin activity in synthetic O-glycopeptides, but the presence of sialic acid reduced the furin rate by up to 65{\%}. Similarly, O-glycosylation with a sialylated trisaccharide had a negative impact on TMPRSS2 cleavage. With a chemistry-centered approach, we substantiate O-glycosylation as a major determinant of spike maturation and propose disruption of O-glycosylation as a substantial driving force for VOC evolution.},
author = {Gonzalez-Rodriguez, Edgar and Zol-Hanlon, Mia and Bineva-Todd, Ganka and Marchesi, Andrea and Skehel, Mark and Mahoney, Keira E and Roustan, Chlo{\"{e}} and Borg, Annabel and Vagno, Lucia Di and Kj{\ae}r, Svend and Wrobel, Antoni G and Benton, Donald J and Nawrath, Philipp and Flitsch, Sabine L and Joshi, Dhira and Gonz{\'{a}}lez-Ram{\'{i}}rez, Andr{\'{e}}s Manuel and Wilkinson, Katalin A and Wilkinson, Robert J and Wall, Emma C and Hurtado-Guerrero, Ram{\'{o}}n and Malaker, Stacy A and Schumann, Benjamin},
doi = {10.1021/ACSCENTSCI.2C01349},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Gonzalez-Rodriguez et al. - 2023 - O-Linked sialoglycans modulate the proteolysis of SARS-CoV-2 spike and likely contribute to the mutat.pdf:pdf},
issn = {2374-7943},
journal = {ACS Central Science},
keywords = {OA,OA{\_}PMC,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {feb},
pages = {10.1021/acscentsci.2c01349},
pmid = {36968546},
publisher = {American Chemical Society},
title = {{O-Linked sialoglycans modulate the proteolysis of SARS-CoV-2 spike and likely contribute to the mutational trajectory in variants of concern}},
url = {https://pubs.acs.org/doi/full/10.1021/acscentsci.2c01349},
year = {2023}
}

The emergence of a polybasic cleavage motif for the protease furin in SARS-CoV-2 spike has been established as a major factor for human viral transmission. The region N-terminal to that motif is extensively mutated in variants of concern (VOCs). Besides furin, spikes from these variants appear to rely on other proteases for maturation, including TMPRSS2. Glycans near the cleavage site have raised questions about proteolytic processing and the consequences of variant-borne mutations. Here, we identify that sialic acid-containing O-linked glycans on Thr678 of SARS-CoV-2 spike influence furin and TMPRSS2 cleavage and posit O-linked glycosylation as a likely driving force for the emergence ofVOC mutations. We provide direct evidence that the glycosyltransferase GalNAc-T1 primes glycosylation at Thr678 in the living cell, an event that is suppressed by mutations in the VOCs Alpha, Delta, and Omicron. We found that the sole incorporation of N-acetylgalactosamine did not impact furin activity in synthetic O-glycopeptides, but the presence of sialic acid reduced the furin rate by up to 65%. Similarly, O-glycosylation with a sialylated trisaccharide had a negative impact on TMPRSS2 cleavage. With a chemistry-centered approach, we substantiate O-glycosylation as a major determinant of spike maturation and propose disruption of O-glycosylation as a substantial driving force for VOC evolution.

@article{Abdelgawad2023,
abstract = {Limited knowledge is available on the pharmacokinetics of rifampicin in children with tuberculous meningitis (TBM) and its penetration into brain tissue, which is the site of infection. In this ana...},
author = {Abdelgawad, Noha and Tshavhungwe, Mvuwo (Phophi) and Rohlwink, Ursula and McIlleron, Helen and Abdelwahab, Mahmoud T and Wiesner, Lubbe and Castel, Sandra and Steele, Chanel and Enslin, Johannes (Nico) and Thango, Nqobile Sindiswa and Denti, Paolo and Figaji, Anthony},
doi = {10.1128/AAC.01474-22},
issn = {0066-4804},
journal = {Antimicrobial Agents and Chemotherapy},
keywords = {WHO,brain extracellular fluid,cerebrospinal fluid,children,meningitis,microdialysis,original,population pharmacokinetics,rifampicin,tuberculosis},
mendeley-tags = {original},
month = {feb},
number = {3},
pages = {e0147422},
pmid = {36815838},
publisher = {American Society for Microbiology 1752 N St., N.W., Washington, DC},
title = {{Population pharmacokinetic analysis of rifampicin in plasma, cerebrospinal fluid, and brain extracellular fluid in South African children with tuberculous meningitis}},
url = {https://journals.asm.org/doi/10.1128/aac.01474-22},
volume = {67},
year = {2023}
}

Limited knowledge is available on the pharmacokinetics of rifampicin in children with tuberculous meningitis (TBM) and its penetration into brain tissue, which is the site of infection. In this ana...

@article{Omollo2023,
abstract = {Tuberculosis (TB) imposes a major burden on global public health which is exacerbated by the escalating number of multidrug-resistant (MDR)-TB cases. There is consequently an urgent need for new anti-TB drugs and combination regimens. We have investigated the natural product antibiotic fusidic acid (FA) for repurposing against Mycobacterium tuberculosis , the causative agent of TB. Here, we report the results of synergy screens combining FA with a panel of approved anti-TB agents. Checkerboard and time-kill kinetics assays identified seven compounds from different chemical classes that synergized with FA in inhibiting the growth of M. tuberculosis in vitro : rifampicin (RIF), a rifamycin and frontline anti-TB drug; the macrolides, erythromycin (ERY), clarithromycin (CLR), and roxythromycin (ROX); the oxazolidinone, linezolid (LZD); the aminoglycoside, streptomycin (STR); and the aminocyclitol, spectinomycin (SPC). Among these, the strongest synergies were observed where FA was combined with SPC and ERY. Moreover, the FA-RIF combination was cidal, while all other FA combinations were bacteriostatic. These results provide in vitro evidence of the potential utility of FA-containing combinations against M. tuberculosis .},
author = {Omollo, Charles and Moosa, Atica and Chibale, Kelly and Warner, Digby F},
doi = {10.1101/2023.01.19.524834},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Omollo et al. - 2023 - Fusidic acid-based drug combinations exhibit enhanced activity against Mycobacterium tuberculosis.pdf:pdf},
journal = {bioRxiv},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jan},
pages = {2023.01.19.524834},
publisher = {Cold Spring Harbor Laboratory},
title = {{Fusidic acid-based drug combinations exhibit enhanced activity against \textit{Mycobacterium tuberculosis}}},
url = {https://www.biorxiv.org/content/10.1101/2023.01.19.524834v1 https://www.biorxiv.org/content/10.1101/2023.01.19.524834v1.abstract},
year = {2023}
}

Tuberculosis (TB) imposes a major burden on global public health which is exacerbated by the escalating number of multidrug-resistant (MDR)-TB cases. There is consequently an urgent need for new anti-TB drugs and combination regimens. We have investigated the natural product antibiotic fusidic acid (FA) for repurposing against Mycobacterium tuberculosis , the causative agent of TB. Here, we report the results of synergy screens combining FA with a panel of approved anti-TB agents. Checkerboard and time-kill kinetics assays identified seven compounds from different chemical classes that synergized with FA in inhibiting the growth of M. tuberculosis in vitro : rifampicin (RIF), a rifamycin and frontline anti-TB drug; the macrolides, erythromycin (ERY), clarithromycin (CLR), and roxythromycin (ROX); the oxazolidinone, linezolid (LZD); the aminoglycoside, streptomycin (STR); and the aminocyclitol, spectinomycin (SPC). Among these, the strongest synergies were observed where FA was combined with SPC and ERY. Moreover, the FA-RIF combination was cidal, while all other FA combinations were bacteriostatic. These results provide in vitro evidence of the potential utility of FA-containing combinations against M. tuberculosis .

@article{Zaidi2023,
abstract = {Summary There is growing recognition that tuberculosis (TB) infection and disease exists as a spectrum of states beyond the current binary classification of latent and active TB. Our aim was to systematically map and synthesize published conceptual frameworks for TB states. We searched MEDLINE, Embase and EMcare for review articles from 1946 to September 2023. We included 40 articles that explicitly described greater than two states for TB. We identified that terminology, definitions and diagnostic criteria for additional TB states within these articles were inconsistent. Eight broad conceptual themes were identified that were used to categorize TB states: State 0: Mycobacterium tuberculosis (Mtb) elimination with innate immune response (n = 25/40, 63{\%}); State I: Mtb elimination by acquired immune response (n = 31/40, 78{\%}); State II: Mtb infection not eliminated but controlled (n = 37/40, 93{\%}); State III: Mtb infection not controlled (n = 24/40, 60{\%}); State IV: bacteriologically positive without symptoms (n = 26/40, 65{\%}); State V: signs or symptoms associated with TB (n = 39/40, 98{\%}); State VI: severe or disseminated TB disease (n = 11/40, 28{\%}); and State VII: previous history of TB (n = 5/40, 13{\%}). Consensus on a non-binary framework that includes additional TB states is required to standardize scientific communication and to inform advancements in research, clinical and public health practice.},
author = {Zaidi, Syed M A and Coussens, Anna K and Seddon, James A and Kredo, Tamara and Warner, Digby F and Houben, Rein M G J and Esmail, Hanif},
doi = {10.1016/J.ECLINM.2023.102332},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Zaidi et al. - 2023 - Beyond latent and active tuberculosis a scoping review of conceptual frameworks.pdf:pdf},
issn = {2589-5370},
journal = {eClinicalMedicine},
keywords = {Conceptual framework,Incipient tuberculosis,Latent tuberculosis,OA,Spectrum,Subclinical tuberculosis,Tuberculosis,fund{\_}not{\_}ack,review},
mendeley-tags = {OA,fund{\_}not{\_}ack,review},
month = {nov},
pages = {102332},
publisher = {Elsevier},
title = {{Beyond latent and active tuberculosis: a scoping review of conceptual frameworks}},
url = {http://www.thelancet.com/article/S2589537023005096/fulltext http://www.thelancet.com/article/S2589537023005096/abstract https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00509-6/abstract},
year = {2023}
}

Summary There is growing recognition that tuberculosis (TB) infection and disease exists as a spectrum of states beyond the current binary classification of latent and active TB. Our aim was to systematically map and synthesize published conceptual frameworks for TB states. We searched MEDLINE, Embase and EMcare for review articles from 1946 to September 2023. We included 40 articles that explicitly described greater than two states for TB. We identified that terminology, definitions and diagnostic criteria for additional TB states within these articles were inconsistent. Eight broad conceptual themes were identified that were used to categorize TB states: State 0: Mycobacterium tuberculosis (Mtb) elimination with innate immune response (n = 25/40, 63%); State I: Mtb elimination by acquired immune response (n = 31/40, 78%); State II: Mtb infection not eliminated but controlled (n = 37/40, 93%); State III: Mtb infection not controlled (n = 24/40, 60%); State IV: bacteriologically positive without symptoms (n = 26/40, 65%); State V: signs or symptoms associated with TB (n = 39/40, 98%); State VI: severe or disseminated TB disease (n = 11/40, 28%); and State VII: previous history of TB (n = 5/40, 13%). Consensus on a non-binary framework that includes additional TB states is required to standardize scientific communication and to inform advancements in research, clinical and public health practice.

@article{Achar2023,
abstract = {With recent expansion in the use of bedaquiline and limited access to accurate drug susceptibility testing (DST), we read with concern of examples of the high prevalence of bedaquiline resistance detected in Mycobacterium tuberculosis isolates [1]. Choosing the most effective regimen for treatment of drug-resistant tuberculosis (TB) is crucially important [2] and requires accurate and timely DST. In the past decade, there has been wide roll-out of rapid molecular tests that can identify M. tuberculosis and mutations conferring rifampicin resistance (RR). However, for potent second-line drugs, such as fluoroquinolones [3], bedaquiline, pretomanid and linezolid, DST is either unavailable, has poor coverage or generates delayed results. To support clinicians, policymakers must provide pragmatic treatment recommendations for situations where a patient is diagnosed with RR-TB, but where additional DST results for second-line drugs are delayed or unavailable. Second-line drug susceptibility test results are frequently unavailable for people with TB. A method is proposed for comparing risks and benefits of different treatment regimens for rifampicin-resistant TB when accurate results are unavailable. https://bit.ly/46KHyl0},
author = {Achar, Jay and Seddon, James A and Knight, Gwenan M and Dodd, Peter J and Esmail, Hanif and Hughes, Jennifer and McQuaid, C Finn},
doi = {10.1183/13993003.00969-2023},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Achar et al. - 2023 - Guiding pragmatic treatment choices for rifampicin-resistant tuberculosis in the absence of second-line drug susce.pdf:pdf},
issn = {0903-1936},
journal = {European Respiratory Journal},
keywords = {OA,fund{\_}not{\_}ack,letter},
mendeley-tags = {OA,fund{\_}not{\_}ack,letter},
month = {nov},
number = {5},
pages = {2300969},
pmid = {37945035},
publisher = {European Respiratory Society},
title = {{Guiding pragmatic treatment choices for rifampicin-resistant tuberculosis in the absence of second-line drug susceptibility testing}},
url = {https://erj.ersjournals.com/content/62/5/2300969 https://erj.ersjournals.com/content/62/5/2300969.abstract},
volume = {62},
year = {2023}
}

With recent expansion in the use of bedaquiline and limited access to accurate drug susceptibility testing (DST), we read with concern of examples of the high prevalence of bedaquiline resistance detected in Mycobacterium tuberculosis isolates [1]. Choosing the most effective regimen for treatment of drug-resistant tuberculosis (TB) is crucially important [2] and requires accurate and timely DST. In the past decade, there has been wide roll-out of rapid molecular tests that can identify M. tuberculosis and mutations conferring rifampicin resistance (RR). However, for potent second-line drugs, such as fluoroquinolones [3], bedaquiline, pretomanid and linezolid, DST is either unavailable, has poor coverage or generates delayed results. To support clinicians, policymakers must provide pragmatic treatment recommendations for situations where a patient is diagnosed with RR-TB, but where additional DST results for second-line drugs are delayed or unavailable. Second-line drug susceptibility test results are frequently unavailable for people with TB. A method is proposed for comparing risks and benefits of different treatment regimens for rifampicin-resistant TB when accurate results are unavailable. https://bit.ly/46KHyl0

@article{Sossen2023,
author = {Sossen, Bianca and Meintjes, Graeme A},
doi = {10.1016/S2214-109X(22)00513-7},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Sossen, Meintjes - 2023 - Development of accurate non-sputum-based diagnostic tests for tuberculosis an ongoing challenge.pdf:pdf},
issn = {2214-109X},
journal = {The Lancet Global Health},
keywords = {OA,commentary,fund{\_}ack},
mendeley-tags = {OA,commentary,fund{\_}ack},
month = {jan},
number = {1},
pages = {e16--e17},
pmid = {36521945},
publisher = {Elsevier},
title = {{Development of accurate non-sputum-based diagnostic tests for tuberculosis: an ongoing challenge}},
volume = {11},
year = {2023}
}

@article{Zwyer2023,
abstract = {In settings with high tuberculosis (TB) endemicity, distinct genotypes of the Mycobacterium tuberculosis complex (MTBC) often differ in prevalence. However, the factors leading to these differences remain poorly understood. Here we studied the MTBC population in Dar es Salaam, Tanzania over a six-year period, using 1,082 unique patient-derived MTBC whole-genome sequences (WGS) and associated clinical data. We show that the TB epidemic in Dar es Salaam is dominated by multiple MTBC genotypes introduced to Tanzania from different parts of the world during the last 300 years. The most common MTBC genotypes deriving from these introductions exhibited differences in transmission rates and in the duration of the infectious period, but little differences in overall fitness, as measured by the effective reproductive number. Moreover, measures of disease severity and bacterial load indicated no differences in virulence between these genotypes during active TB. Instead, the combination of an early introduction and a high transmission rate accounted for the high prevalence of L3.1.1, the most dominant MTBC genotype in this setting. Yet, a longer co-existence with the host population did not always result in a higher transmission rate, suggesting that distinct life-history traits have evolved in the different MTBC genotypes. Taken together, our results point to bacterial factors as important determinants of the TB epidemic in Dar es Salaam.},
author = {Zwyer, Michaela and Rutaihwa, Liliana K and Windels, Etthel and Hella, Jerry and Menardo, Fabrizio and Sasamalo, Mohamed and Sommer, Gregor and Schm{\"{u}}lling, Lena and Borrell, Sonia and Reinhard, Miriam and D{\"{o}}tsch, Anna and Hiza, Hellen and Stritt, Christoph and Sikalengo, George and Fenner, Lukas and {De Jong}, Bouke C and Kato-Maeda, Midori and Jugheli, Levan and Ernst, Joel D. and Niemann, Stefan and Jeljeli, Leila and Ballif, Marie and Egger, Matthias and Rakotosamimanana, Niaina and Yeboah-Manu, Dorothy and Asare, Prince and Malla, Bijaya and Dou, Horng Yunn and Zetola, Nicolas and Wilkinson, Robert J and Cox, Helen and Carter, E Jane and Gnokoro, Joachim and Yotebieng, Marcel and Gotuzzo, Eduardo and Abimiku, Alash'le and Avihingsanon, Anchalee and Xu, Zhi Ming and Fellay, Jacques and Portevin, Damien and Reither, Klaus and Stadler, Tanja and Gagneux, Sebastien and Brites, Daniela},
doi = {10.1371/JOURNAL.PPAT.1010893},
editor = {Boshoff, Helena Ingrid},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Zwyer et al. - 2023 - Back-to-Africa introductions of iMycobacterium tuberculosisi as the main cause of tuberculosis in Dar es Salaam, T.pdf:pdf},
isbn = {1111111111},
issn = {1553-7374},
journal = {PLOS Pathogens},
keywords = {Africa,Asia,Genomics,Mycobacterium tuberculosis,OA,Phylogenetic analysis,Phylogeography,Tanzania,Tuberculosis,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {apr},
number = {4},
pages = {e1010893},
pmid = {37014917},
publisher = {Public Library of Science},
title = {{Back-to-Africa introductions of \textit{Mycobacterium tuberculosis} as the main cause of tuberculosis in Dar es Salaam, Tanzania}},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1010893},
volume = {19},
year = {2023}
}

In settings with high tuberculosis (TB) endemicity, distinct genotypes of the Mycobacterium tuberculosis complex (MTBC) often differ in prevalence. However, the factors leading to these differences remain poorly understood. Here we studied the MTBC population in Dar es Salaam, Tanzania over a six-year period, using 1,082 unique patient-derived MTBC whole-genome sequences (WGS) and associated clinical data. We show that the TB epidemic in Dar es Salaam is dominated by multiple MTBC genotypes introduced to Tanzania from different parts of the world during the last 300 years. The most common MTBC genotypes deriving from these introductions exhibited differences in transmission rates and in the duration of the infectious period, but little differences in overall fitness, as measured by the effective reproductive number. Moreover, measures of disease severity and bacterial load indicated no differences in virulence between these genotypes during active TB. Instead, the combination of an early introduction and a high transmission rate accounted for the high prevalence of L3.1.1, the most dominant MTBC genotype in this setting. Yet, a longer co-existence with the host population did not always result in a higher transmission rate, suggesting that distinct life-history traits have evolved in the different MTBC genotypes. Taken together, our results point to bacterial factors as important determinants of the TB epidemic in Dar es Salaam.

@article{VanHeerden2023,
abstract = {Cutaneous tuberculosis is an infrequent form of extra-pulmonary tuberculosis, even in high-prevalence settings. We present the case of a patient living with advanced HIV who developed extensive cutaneous tuberculosis. The polymorphic skin lesions were the most striking clinical manifestation of underlying disseminated tuberculosis. Contribution: This case report highlights an unusual presentation of tuberculosis. Cutaneous tuberculosis has a wide spectrum of clinical presentations and may be under-recognised by clinicians. We recommend early biopsy for microbiological diagnosis.},
author = {{Van Heerden}, Jennifer K and Broadhurst, Alistair G B and {De Jager}, Ruan S and {Du Plessis}, Wesley and Ebrahim, Nabilah and Mnguni, Ayanda T and Schietekat, Denzil and Meintjes, Graeme A and {Van Heerden}, Jennifer},
doi = {10.4102/SAJID.V38I1.526},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Van Heerden et al. - 2023 - Cutaneous tuberculosis an infrequent manifestation of a common pathogen in South Africa.pdf:pdf},
issn = {2313-1810},
journal = {Southern African Journal of Infectious Diseases},
keywords = {HIV,Infectious diseases,OA,OA{\_}PMC,South Africa,TB,bacterial,clinical,communicable,cutaneous tuberculosis,diagnosis,epidemiology,fund{\_}not{\_}ack,fungal,human immunodeficiency virus,laboratory,original,parasitic,treatment,tuberculosis,viral},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {jun},
number = {1},
pages = {a526},
pmid = {37435117},
title = {{Cutaneous tuberculosis: an infrequent manifestation of a common pathogen in South Africa}},
url = {https://sajid.co.za/index.php/sajid/article/view/526/1222 https://sajid.co.za/index.php/sajid/article/view/526/1223 https://sajid.co.za/index.php/sajid/article/view/526/1224 https://sajid.co.za/index.php/sajid/article/view/526},
volume = {38},
year = {2023}
}

Cutaneous tuberculosis is an infrequent form of extra-pulmonary tuberculosis, even in high-prevalence settings. We present the case of a patient living with advanced HIV who developed extensive cutaneous tuberculosis. The polymorphic skin lesions were the most striking clinical manifestation of underlying disseminated tuberculosis. Contribution: This case report highlights an unusual presentation of tuberculosis. Cutaneous tuberculosis has a wide spectrum of clinical presentations and may be under-recognised by clinicians. We recommend early biopsy for microbiological diagnosis.

@incollection{Sawhney2023,
abstract = {Medicinal plants have been with mankind since their existence on Earth. Till date, the prior art is filled with the use and significance of a repertoire of a variety of medicinal plants from different geographical regions around the world. Building immunity was a...},
address = {Singapore},
author = {Sawhney, Gifty and Navgire, Gauri Sanjay and Parihar, Suraj and Farooq, Umer and Ansari, Mohammad Javed},
booktitle = {Immunity Boosting Medicinal Plants of the Western Himalayas},
doi = {10.1007/978-981-19-9501-9_1},
keywords = {book{\_}chap,fund{\_}not{\_}ack},
mendeley-tags = {book{\_}chap,fund{\_}not{\_}ack},
pages = {1--27},
publisher = {Springer, Singapore},
title = {{Introduction to plants of western Himalayas}},
url = {https://link.springer.com/chapter/10.1007/978-981-19-9501-9{\_}1},
year = {2023}
}

Medicinal plants have been with mankind since their existence on Earth. Till date, the prior art is filled with the use and significance of a repertoire of a variety of medicinal plants from different geographical regions around the world. Building immunity was a...

@article{Opperman2023,
author = {Opperman, C J and Singh, S and Davids, T and Cox, H and Warren, R and Goosen, W},
doi = {10.7196/SAMJ.2022.V113I6.16771},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Opperman et al. - 2023 - Identifying non-tuberculosis mycobacteria Is it time to introduce new molecular assays.pdf:pdf},
issn = {20785135},
journal = {South African Medical Journal},
keywords = {OA,fund{\_}not{\_}ack,letter},
mendeley-tags = {OA,fund{\_}not{\_}ack,letter},
month = {may},
number = {6},
pages = {4--5},
pmid = {37278260},
publisher = {NLM (Medline)},
title = {{Identifying non-tuberculosis mycobacteria: Is it time to introduce new molecular assays?}},
volume = {113},
year = {2023}
}

@article{Sharaf2023,
abstract = {The Open Institute of the African BioGenome Project empowers African scientists and institutions with the skill sets, capacity and infrastructure to advance scientific knowledge and innovation and drive economic growth.},
author = {Sharaf, Abdoallah and Ndiribe, Charlotte C. and Omotoriogun, Taiwo Crossby and Abueg, Linelle and Badaoui, Bouabid and {Badiane Markey}, Fatu J. and Beedessee, Girish and Diouf, Diaga and Duru, Vincent C. and Ebuzome, Chukwuike and Eziuzor, Samuel C. and {Jaufeerally Fakim}, Yasmina and Formenti, Giulio and Ghanmi, Nidhal and Guerfali, Fatma Zahra and Houaga, Isidore and Ideozu, Justin Eze and Katee, Sally Mueni and Khayi, Slimane and Kuja, Josiah O. and Kwon-Ndung, Emmanuel Hala and Marks, Rose A. and Moila, Acclaim M. and Mungloo-Dilmohamud, Zahra and Muzemil, Sadik and Nigussie, Helen and Osuji, Julian O. and Ras, Verena and Tchiechoua, Yves H. and Zoclanclounon, Yedomon Ange Bovys and Tolley, Krystal A. and Ziyomo, Cathrine and Mapholi, Ntanganedzeni and Muigai, Anne W.T. and Djikeng, Appolinaire and Ebenezer, Thank God Echezona},
doi = {10.1038/s41587-023-01933-2},
issn = {1546-1696},
journal = {Nature Biotechnology 2023 41:9},
keywords = {Agricultural genetics,Communication and replication,Developing world,Education,Plant genetics,fund{\_}not{\_}ack,perspective},
mendeley-tags = {fund{\_}not{\_}ack,perspective},
month = {sep},
number = {9},
pages = {1348--1354},
pmid = {37699986},
publisher = {Nature Publishing Group},
title = {{Bridging the gap in African biodiversity genomics and bioinformatics}},
url = {https://www.nature.com/articles/s41587-023-01933-2},
volume = {41},
year = {2023}
}

The Open Institute of the African BioGenome Project empowers African scientists and institutions with the skill sets, capacity and infrastructure to advance scientific knowledge and innovation and drive economic growth.

@article{Patil2023,
abstract = {Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients. endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80{\%} power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12{\%}, against the control in both modified intention-to-treat and per-protocol populations. This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen. ClinicalTrials.Gov NCT03896685. Registered on 1 April 2018; the record was last updated for study protocol version 4.3 on 17 March 2023.},
author = {Patil, S B and Tamirat, M and Khazhidinov, K and Ardizzoni, E and Atger, M and Austin, A and Baudin, E and Bekhit, M. and Bektasov, S. and Berikova, E. and Bonnet, M. and Caboclo, R. and Chaudhry, M. and Chavan, V. and Cloez, S. and Coit, J. and Coutisson, S. and Dakenova, Z. and {De Jong}, B. C. and Delifer, C. and Demaisons, S. and Do, J. M. and {Dos Santos Tozzi}, D. and Ducher, V. and Ferlazzo, G. and Gouillou, M. and Khan, U. and Kunda, M. and Lachenal, N. and LaHood, A. N. and Lecca, L. and Mazmanian, M. and McIlleron, H. and Moreau, M. and Moschioni, M. and Nahid, P. and Osso, E. and Oyewusi, L. and Panda, S. and P{\^{a}}quet, A. and {Thuong Huu}, P. and Pichon, L. and Rich, M. L. and Rupasinghe, P. and Salahuddin, N. and {Sanchez Garavito}, E. and Seung, K. J. and Vel{\'{a}}squez, G. E. and Vallet, M. and Varaine, F. and Yuya-Septoh, F. J. and Mitnick, C. D. and Guglielmetti, L.},
doi = {10.1186/S13063-023-07701-6},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Patil et al. - 2023 - Evaluating newly approved drugs in combination regimens for multidrug-resistant tuberculosis with fluoroquinolone.pdf:pdf},
issn = {1745-6215},
journal = {Trials},
keywords = {Biomedicine,Health Sciences,Medicine,Medicine/Public Health,OA,OA{\_}PMC,Statistics for Life Sciences,fund{\_}not{\_}ack,general,protocol},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,protocol},
month = {nov},
number = {1},
pages = {773},
pmid = {38037119},
publisher = {BioMed Central},
title = {{Evaluating newly approved drugs in combination regimens for multidrug-resistant tuberculosis with fluoroquinolone resistance (endTB-Q): study protocol for a multi-country randomized controlled trial}},
url = {https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-023-07701-6 http://creativecom-mons.org/publicdomain/zero/1.0/},
volume = {24},
year = {2023}
}

Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients. endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80% power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per-protocol populations. This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen. ClinicalTrials.Gov NCT03896685. Registered on 1 April 2018; the record was last updated for study protocol version 4.3 on 17 March 2023.

@article{Proust2023,
abstract = {Although mainly causing a respiratory syndrome, numerous neurological symptoms have been identified following of SARS-CoV-2 infection. However, how the virus affects the brain and how the mutations carried by the different variants modulate those neurological symptoms remain unclear.},
author = {Proust, Aliz{\'{e}} and Queval, Christophe J and Harvey, Ruth and Adams, Lorin and Bennett, Michael and Wilkinson, Robert J},
doi = {10.1186/s12974-023-02861-3},
issn = {1742-2094},
journal = {Journal of Neuroinflammation},
keywords = {OA,OA{\_}PMC,fund{\_}not{\_}ack},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack},
number = {1},
pages = {184},
pmid = {37537664},
title = {{Differential effects of SARS-CoV-2 variants on central nervous system cells and blood–brain barrier functions}},
url = {https://doi.org/10.1186/s12974-023-02861-3},
volume = {20},
year = {2023}
}

Although mainly causing a respiratory syndrome, numerous neurological symptoms have been identified following of SARS-CoV-2 infection. However, how the virus affects the brain and how the mutations carried by the different variants modulate those neurological symptoms remain unclear.

@article{Wadhonkar2023,
abstract = {Colorectal cancer is one of the leading causes of death worldwide. Its incidence and mortality have significantly increased during the past few years. Colorectal cancer cells cross-talk with other ...},
author = {Wadhonkar, Khandu and Singh, Neha and {Heralde Iii}, Francisco M and Parihar, Suraj P and Hirani, Nik and Mirza, {\&} and Baig, S},
doi = {10.2217/CRC-2022-0012},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Wadhonkar et al. - 2023 - Exosome-derived miRNAs regulate macrophage-colorectal cancer cell cross-talk during aggressive tumor developme.pdf:pdf},
issn = {1758-194X},
journal = {Colorectal Cancer},
keywords = {OA,colorectal cancer (CRC),exosome,fund{\_}not{\_}ack,metastasis,microRNAs (miRNAs),review,tumor microenvironment (TME),tumor-associated macrophages (TAM)},
mendeley-tags = {OA,fund{\_}not{\_}ack,review},
month = {mar},
number = {1},
pages = {CRC40},
publisher = {Future Medicine Ltd London, UK},
title = {{Exosome-derived miRNAs regulate macrophage-colorectal cancer cell cross-talk during aggressive tumor development}},
url = {https://www.futuremedicine.com/doi/10.2217/crc-2022-0012},
volume = {12},
year = {2023}
}

Colorectal cancer is one of the leading causes of death worldwide. Its incidence and mortality have significantly increased during the past few years. Colorectal cancer cells cross-talk with other ...

@article{Scheier2023a,
abstract = {The World Health Organization (WHO) recommends an evidence-based package of care to reduce mortality and morbidity among people with advanced HIV disease (AHD). Adoption of these recommendations by national guidelines in sub-Saharan Africa is poorly documented. We aimed to review national guidelines for AHD management across six selected countries in sub-Saharan Africa for benchmarking against the 2021 WHO recommendations. We reviewed national guidelines from six countries participating in an ongoing randomized controlled trial recruiting people with AHD. We extracted information addressing 18 items of AHD diagnosis and management across the following domains: [1] Definition of AHD, [2] Screening, [3] Prophylaxis, [4] Supportive care, and [5] HIV treatment. Data from national guideline documents were compared to the 2021 WHO consolidated guidelines on HIV and an agreement score was produced to evaluate extent of guideline adoption. The distribution of categories of agreement varied for the national documents. Four of the six countries addressed all 18 items (Malawi, Nigeria, Sierra Leone, Uganda). Overall agreement with the WHO 2021 guidelines ranged from 9 to 15.5 out of 18 possible points: Malawi 15.5 points, Nigeria, and Sierra Leone 14.5 points, South Africa 13.5 points, Uganda 13.0 points and Botswana with 9.0 points. Most inconsistencies were reported for the delay of antiretroviral therapy (ART) in presence of opportunistic diseases. None of the six national guidelines aligned with WHO recommendations around ART timing in patients with tuberculosis. Agreement correlated with the year of publication of the national guideline. National guidelines addressing the care of advanced HIV disease in sub-Saharan Africa are available. Besides optimal timing for start of ART in presence of tuberculosis, most national recommendations are in line with the 2021 WHO standards.},
author = {Scheier, Thomas C. and Youssouf, Nabila and Mosepele, Mosepele and Kanyama, Cecilia and Adekanmbi, Olukemi and Lakoh, Sulaiman and Muzoora, Conrad K. and Meintjes, Graeme and Mertz, Dominik and Eikelboom, John W. and Wasserman, Sean},
doi = {10.1186/S12981-023-00581-5},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Scheier et al. - 2023 - Standard of care in advanced HIV disease review of HIV treatment guidelines in six sub-Saharan African countries.pdf:pdf},
issn = {1742-6405},
journal = {AIDS Research and Therapy},
keywords = {Infectious Diseases,OA,Standard of care,Sub-Saharan Africa,Virology,WHO,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {nov},
number = {1},
pages = {83},
publisher = {BioMed Central},
title = {{Standard of care in advanced HIV disease: review of HIV treatment guidelines in six sub-Saharan African countries}},
url = {https://aidsrestherapy.biomedcentral.com/articles/10.1186/s12981-023-00581-5 http://creativecommons.org/publicdomain/zero/1.0/},
volume = {20},
year = {2023}
}

The World Health Organization (WHO) recommends an evidence-based package of care to reduce mortality and morbidity among people with advanced HIV disease (AHD). Adoption of these recommendations by national guidelines in sub-Saharan Africa is poorly documented. We aimed to review national guidelines for AHD management across six selected countries in sub-Saharan Africa for benchmarking against the 2021 WHO recommendations. We reviewed national guidelines from six countries participating in an ongoing randomized controlled trial recruiting people with AHD. We extracted information addressing 18 items of AHD diagnosis and management across the following domains: [1] Definition of AHD, [2] Screening, [3] Prophylaxis, [4] Supportive care, and [5] HIV treatment. Data from national guideline documents were compared to the 2021 WHO consolidated guidelines on HIV and an agreement score was produced to evaluate extent of guideline adoption. The distribution of categories of agreement varied for the national documents. Four of the six countries addressed all 18 items (Malawi, Nigeria, Sierra Leone, Uganda). Overall agreement with the WHO 2021 guidelines ranged from 9 to 15.5 out of 18 possible points: Malawi 15.5 points, Nigeria, and Sierra Leone 14.5 points, South Africa 13.5 points, Uganda 13.0 points and Botswana with 9.0 points. Most inconsistencies were reported for the delay of antiretroviral therapy (ART) in presence of opportunistic diseases. None of the six national guidelines aligned with WHO recommendations around ART timing in patients with tuberculosis. Agreement correlated with the year of publication of the national guideline. National guidelines addressing the care of advanced HIV disease in sub-Saharan Africa are available. Besides optimal timing for start of ART in presence of tuberculosis, most national recommendations are in line with the 2021 WHO standards.

@article{Waalewijn2023,
abstract = {Background There are few pharmacokinetic data of tenofovir alafenamide fumarate (TAF) in children. We evaluated the pharmacokinetics of TAF and tenofovir in a subset of African children enrolled in the CHAPAS-4-trial (ISRCTN22964075). Methods Children with HIV infection aged 3-15 years failing first-line antiretroviral therapy (ART) were randomised to emtricitabine/TAF versus standard-of-care nucleoside reverse transcriptase inhibitor combination, plus dolutegravir, atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. Daily emtricitabine/TAF was dosed according to WHO-recommended weight bands: 120/15mg in children weighing 14-{\textless}-25kg and 200/25mg in those ≥25kg, regardless of anchor drug in the combination.At steady state, 8-9 blood samples were taken to construct pharmacokinetic curves. Geometric mean (GM) area under the concentration-time curve (AUC) and the maximum concentration (Cmax) were calculated for TAF and tenofovir and compared to reference exposures in adults taking 25mg TAF with/without a boosted PI. Results Pharmacokinetic results from 104 children taking TAF were analysed. GM(CV{\%}) TAF AUClast when combined with dolutegravir (n=18), darunavir/ritonavir (n=34) or lopinavir/ritonavir (n=20) were 284.5(79), 232.0(61), and 210.2(98) ng*h/mL, respectively, and were comparable to adult reference values. When combined with atazanavir/ritonavir (n=32), TAF AUClast increased to 511.4(68) ng*h/mL. For each combination, tenofovir GM(CV{\%}) AUCtau and Cmax remained below reference values in adults taking 25mg TAF with a boosted PI. Conclusions In children, TAF combined with boosted PIs or dolutegravir and dosed according to WHO-recommended weight bands provides TAF and tenofovir concentrations previously demonstrated to be well tolerated and effective in adults. These data provide the first evidence for use of these combinations in African children.},
author = {Waalewijn, Hylke and Szubert, Alexander J and Wasmann, Roeland E and Wiesner, Lubbe and Chabala, Chishala and Bwakura-Dangarembizi, Mutsa and Makumbi, Shafic and Nangiya, Joan and Mumbiro, Vivian and Mulenga, Veronica and Musiime, Victor and Monkiewicz, Lara N and Griffiths, Anna L and Bamford, Alasdair and Doerholt, Katja and Denti, Paolo and Burger, David M and Gibb, Diana M and McIlleron, Helen M and Colbers, Angela and trial Team, the CHAPAS-4 and {Di Gibb}, Di Gibb and Walker, Sarah and Turkova, Anna and Shakeshaft, Clare and Spyer, Moira and Thomason, Margaret and Griffiths, Anna and Monkiewicz, Lara and Massingham, Sue and Szubert, Alex and Bamford, Alasdair and Doerholt, Katja and Bigault, Amanda and Dudakia, Nimisha and South, Annabelle and {Van Looy}, Nadine and Au, Carly and Sweeney, Hannah and Kityo, Cissy M and Musiime, Victor and Natukunda, Eva and Nambi, Esether and Antonia, Diana Rutebarika and Nazzinda, Rashida and Namyalo, Imelda and Nangiya, Joan and Nabeeta, Lilian and Nakalyango, Aidah and Kobusingye, Lilian and Otike, Caroline and Namala, Winnie and Ampaire, Phionah and Edgar, Ayesiga and Nasaazi, Claire and Ndigendawani, Milly and Ociti, Paul and Kyobutungi, Priscilla and Mbabazi, Ritah and Rubondo, Phyllis Mwesigwa and Ankunda, Juliet and Naabalamba, Mariam and Nannungi, Mary and Musiime, Alex and Mbasani, Faith and Louis, Babu Enoch and Namusanje, Josephine and Odoch, Denis and Bagirigomwa, Edward and Rubanga, Eddie and Mulima, Disan and Oronon, Paul and Williams, Eram David and Baliruno, David and Kobusingye, Josephine and Uyungrwoth, Agnes and Mukanza, Barbara and Okello, Jimmy and Ninsiima, Emily and Ezra, Lutaro and Nambi, Christine and Mangadalen, Nansaigi and Sharif, Musumba and Serunjogi, Nobert B and Thomas, Otim and Lugemwa, Abbas and Makumbi, Shafic and Musumba, Sharif and Mawejje, Edward and Yawe, Ibrahim and Kyomuhendo, Linda Jovia and Kasozi, Mariam and Ankunda, Rogers and Kariisa, Samson and Inyakuwa, Christine and Ninsiima, Emily and Atwine, Lorna and Tumusiime, Beatrice and Ahuura, John and Tukwasibwe, Deogracious and Nagasha, Violet and Kukundakwe, Judith and Nakisekka, Mariam Zahara and Nambejja, Ritah Winnie and Tukamushaba, Mercy and Baker, Rubinga and Keminyeto, Edridah and Ainebyoona, Barbara and Myalo, Sula and Acen, Juliet and Wangwe, Nicholas Jinta and Natuhurira, Ian and Natukunatsa, Gershom Kananura and Mulenga, Veronica and Chabala, Chishala and Lungu, Joyce Chipili and Kapasa, Monica and Zyambo, Khonzya and Zimba, Kevin and Zangata, Dorothy and Shingalili, Ellen and Mumba, Naomi and Kaonga, Nayunda and Kabesha, Mukumbi and Mwenechanya, Oliver and Chipoya, Terrence and Manakalanga, Friday and Malama, Stephen and Chola, Daniel and Nduna, Bwendo and Mwamabazi, Mwate and Banda, Kabwe and Kabamba, Beatrice and Inambao, Muleya and Mukandila, Pauline Mahy and Nachamba, Mwizukanji and Himabala, Stella and Ngosa, Shadrick and Sondashi, Davies and Banda, Collins and Munyangabe, Mark and Ngoma, Grace Mbewe and Chimfwembe, Sarah and Malasha, Mercy Lukonde and Kajimalwendo, Mumba and Musukwa, Henry and Mumba, Shadrick and Hakim, James and Bwakura-Dangarembizi, Mutsa and Nathoo, Kusum and Kamuzungu, Taneal and Chidziva, Ennie and Bhiri, Joyline and Choga, Joshua and Mujuru, Hilda Angela and Musoro, Godfrey and Mumbiro, Vivian and Chitsamatanga, Moses and Mutata, Constantine and Zimunhu, Rudo and Mudzingwa, Shepherd and Gondo, Secrecy and Moyo, Columbus and Nhema, Ruth and Boyd, Kathryn and Matimba, Farai and Kouamou, Vinie and Matarise, Richard and Tangwena, Zorodzai and Mudzviti, Taona and Matubu, Allen and Kateta, Alfred and Chinembiri, Victor and Mukura, Dorinda and Chimanzi, Joy and Murungu, Dorothy and Mapfumo, Wendy and Ngwaru, Pia and Chivere, Lynette and Dube, Prosper and Mukanganiki, Trust and Weza, Sibusisiwe and Gwenzi, Tsitsi and Mutsai, Shirley and Phiri, Misheck and Ndlovu, Makhosonke and Gwaze, Tapiwa and Chitongo, Stuart and Njaravani, Winisayi and Musarurwa, Sandra and Langa, Cleopatra and Tafeni, Sue and Ishemunyoro, Wilbert and Mudzimirema, Nathalie and Ndebele, Wedu and Nyathi, Mary and Siziba, Grace and Tawodzera, Getrude and Makuchete, Tracey and Chidarura, Takudzwa and Murangandi, Shingaidzo and Mafaro, Lawrence and Chivima, Owen and Dumani, Sifiso and Mampondo, Beaullar and Maphosa, Constance and Mwale, Debra and Dhlamini, Rangarirai and Sibanda, Thabani and Madubeko, Nobukhosi and Nyathi, Silibaziso and Matiwaza, Zibusiso and Nabukenya, Sylvia and Tibakabikoba, Harriet and Nakalanzi, Sarah and Williams, Cynthia and Chandiwana, Precious and Gozhora, Winnie and Dube, Benedictor and Mulambo, Sylvia and Mwanyungwi, Hope and Burger, David and Colbers, Angela and Waalewijn, Hylke and Bevers, Lisanne and Mohsenian-Naghani, Shaghayegh and McIlleron, Helen and Norman, Jennifer and Wiesner, Lubbe and Wasmann, Roeland and Denti, Paolo and Galileya, Lufina Tsirizani and Natukunda, Eva and Musiime, Victor and Musoke, Phillipa and Revill, Paul and Walker, Simon and Kekitiinwa, Adeodata and Mushavi, Angela and Kawamya, Febby Banda and Tindyebwa, Denis and Lyall, Hermione and Weller, Ian and Peto, Tim and Musoke, Philippa and Siwale, Margaret and Kambarami, Rose and Roth, Johanna and Beattie, Pauline},
doi = {10.1093/CID/CIAD267},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Waalewijn et al. - 2023 - First pharmacokinetic data of tenofovir alafenamide fumarate and tenofovir with dolutegravir or boosted protea.pdf:pdf},
journal = {Clinical Infectious Diseases},
keywords = {Children,Drug-interaction,HIV,OA,OA{\_}PMC,Pharmacokinetics,TAF,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
number = {6},
pages = {875--882},
pmid = {37315296},
title = {{First pharmacokinetic data of tenofovir alafenamide fumarate and tenofovir with dolutegravir or boosted protease inhibitors in African children: a substudy of the CHAPAS-4 trial}},
url = {https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciad267/7158422},
volume = {77},
year = {2023}
}

Background There are few pharmacokinetic data of tenofovir alafenamide fumarate (TAF) in children. We evaluated the pharmacokinetics of TAF and tenofovir in a subset of African children enrolled in the CHAPAS-4-trial (ISRCTN22964075). Methods Children with HIV infection aged 3-15 years failing first-line antiretroviral therapy (ART) were randomised to emtricitabine/TAF versus standard-of-care nucleoside reverse transcriptase inhibitor combination, plus dolutegravir, atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. Daily emtricitabine/TAF was dosed according to WHO-recommended weight bands: 120/15mg in children weighing 14-\textless-25kg and 200/25mg in those ≥25kg, regardless of anchor drug in the combination.At steady state, 8-9 blood samples were taken to construct pharmacokinetic curves. Geometric mean (GM) area under the concentration-time curve (AUC) and the maximum concentration (Cmax) were calculated for TAF and tenofovir and compared to reference exposures in adults taking 25mg TAF with/without a boosted PI. Results Pharmacokinetic results from 104 children taking TAF were analysed. GM(CV%) TAF AUClast when combined with dolutegravir (n=18), darunavir/ritonavir (n=34) or lopinavir/ritonavir (n=20) were 284.5(79), 232.0(61), and 210.2(98) ng*h/mL, respectively, and were comparable to adult reference values. When combined with atazanavir/ritonavir (n=32), TAF AUClast increased to 511.4(68) ng*h/mL. For each combination, tenofovir GM(CV%) AUCtau and Cmax remained below reference values in adults taking 25mg TAF with a boosted PI. Conclusions In children, TAF combined with boosted PIs or dolutegravir and dosed according to WHO-recommended weight bands provides TAF and tenofovir concentrations previously demonstrated to be well tolerated and effective in adults. These data provide the first evidence for use of these combinations in African children.

@article{Hill2023,
abstract = {A new tuberculosis (TB) vaccine is a high priority. However, the classical development pathway is a major deterrent. Most TB cases arise within two years after M. tuberculosis exposure, suggesting a three-year trial period should be possible if sample size is large to maximise the number of early exposures. Increased sample size could be facilitated by working alongside optimised routine services for case ascertainment, with strategies for enhanced case detection and safety monitoring. Shortening enrolment could be achieved by simplifying screening criteria and procedures and strengthening site capacity. Together, these measures could enable radically shortened phase 3 TB vaccine trials.},
author = {Hill, Philip C and Cobelens, Frank and Martinez, Leonardo and Behr, Marcel A and Churchyard, Gavin and Evans, Tom and Fiore-Gartland, Andrew J and Garcia-Basteiro, Alberto L and Hanekom, Willem and Rangaka, Molebogeng X and Vekemans, Johan and White, Richard G},
doi = {10.1093/INFDIS/JIAD356},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Hill et al. - 2023 - An aspiration to radically shorten phase 3 TB vaccine trials.pdf:pdf},
issn = {0022-1899},
journal = {The Journal of Infectious Diseases},
keywords = {OA,fund{\_}not{\_}ack,perspective},
mendeley-tags = {OA,fund{\_}not{\_}ack,perspective},
month = {aug},
pages = {jiad356},
pmid = {37607272},
title = {{An aspiration to radically shorten phase 3 TB vaccine trials}},
url = {https://dx.doi.org/10.1093/infdis/jiad356},
year = {2023}
}

A new tuberculosis (TB) vaccine is a high priority. However, the classical development pathway is a major deterrent. Most TB cases arise within two years after M. tuberculosis exposure, suggesting a three-year trial period should be possible if sample size is large to maximise the number of early exposures. Increased sample size could be facilitated by working alongside optimised routine services for case ascertainment, with strategies for enhanced case detection and safety monitoring. Shortening enrolment could be achieved by simplifying screening criteria and procedures and strengthening site capacity. Together, these measures could enable radically shortened phase 3 TB vaccine trials.

@article{Parker2023,
abstract = {Background. Obesity is now well recognised as a risk factor for severe COVID‐19, but the true prevalence of obesity in hospitalised adults with COVID‐19 remains unclear because formal body mass indices (BMIs) are not routinely measured on admission. Objectives. To describe the true prevalence of obesity measured by the BMI, and associated comorbidities, in patients hospitalised with severe COVID‐19, including people with HIV (PWH). Methods. We conducted a point‐prevalence study of measured BMI in consecutive patients with severe COVID‐19 admitted to the medical COVID‐19 wards in a tertiary academic hospital in Cape Town, South Africa (SA). Patients were enrolled over a 2‐week period during the peak of the first COVID‐19 wave in SA. Results. We were able to measure the BMI in 122 of the 146 patients admitted during the study period. The prevalence of HIV was 20{\%} (n=24/122). Most of the participants were overweight or obese (n=104; 85{\%}), and 84 (68.9{\%}) met criteria for obesity. The mean (standard deviation) BMI was 33 (7.5), and 34.5 (9.1) in PWH. Of PWH, 83{\%} (n=20/24) were overweight or obese and 75{\%} (n=18) met criteria for obesity. Multimorbidity was present in 22 (92{\%}) of PWH. Conclusion. We found that most patients, including PWH, met criteria for being overweight or obese. The high prevalence of obesity in PWH and severe COVID‐19 reinforces the need for targeted management of non‐communicable diseases, including obesity, in PWH.},
author = {Parker, A and Broadhurst, A G B and Moolla, M S and Amien, L and Ahmed, R and Taljaard, J J and Meintjes, G and Nyasulu, P and Koegelenberg, C F N},
doi = {10.7196/AJTCCM.2023.V29I3.660},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Parker et al. - 2023 - A point-prevalence study of body mass indices in HIV-positive and HIV-negative patients admitted to hospital with.pdf:pdf},
issn = {2617-0205},
journal = {African Journal of Thoracic and Critical Care Medicine},
keywords = {19,COVID,HIV,OA,fund{\_}ack,multimorbidity,obesity,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {aug},
number = {3},
pages = {127--130},
title = {{A point-prevalence study of body mass indices in HIV-positive and HIV-negative patients admitted to hospital with COVID-19 in South Africa}},
url = {https://samajournals.co.za/index.php/ajtccm/article/view/660},
volume = {29},
year = {2023}
}

Background. Obesity is now well recognised as a risk factor for severe COVID‐19, but the true prevalence of obesity in hospitalised adults with COVID‐19 remains unclear because formal body mass indices (BMIs) are not routinely measured on admission. Objectives. To describe the true prevalence of obesity measured by the BMI, and associated comorbidities, in patients hospitalised with severe COVID‐19, including people with HIV (PWH). Methods. We conducted a point‐prevalence study of measured BMI in consecutive patients with severe COVID‐19 admitted to the medical COVID‐19 wards in a tertiary academic hospital in Cape Town, South Africa (SA). Patients were enrolled over a 2‐week period during the peak of the first COVID‐19 wave in SA. Results. We were able to measure the BMI in 122 of the 146 patients admitted during the study period. The prevalence of HIV was 20% (n=24/122). Most of the participants were overweight or obese (n=104; 85%), and 84 (68.9%) met criteria for obesity. The mean (standard deviation) BMI was 33 (7.5), and 34.5 (9.1) in PWH. Of PWH, 83% (n=20/24) were overweight or obese and 75% (n=18) met criteria for obesity. Multimorbidity was present in 22 (92%) of PWH. Conclusion. We found that most patients, including PWH, met criteria for being overweight or obese. The high prevalence of obesity in PWH and severe COVID‐19 reinforces the need for targeted management of non‐communicable diseases, including obesity, in PWH.

@article{Savulescu2023,
abstract = {Macrophages provide a first line of defense against invading pathogens, including the leading cause of bac- terial mortality, Mycobacterium tuberculosis (Mtb). A challenge for quantitative characterization of host-path- ogen processes in differentially polarized primary human monocyte-derived macrophages (MDMs) is their heterogeneous morphology. Here, we describe the use of microfabricated patterns that constrain the size and shape of cells, mimicking the physiological spatial confinement cells experience in tissues, to quantita- tively characterize interactions during and after phagocytosis at the single-cell level at high resolution. Comparing pro-inflammatory (M1) and anti-inflammatory (M2) MDMs, we find interferon-g stimulation in- creases the phagocytic contraction, while contraction and bacterial uptake decrease following silencing of phagocytosis regulator NHLRC2 or bacterial surface lipid removal. We identify host organelle position alter- ations within infected MDMs and differences in Mtb subcellular localization in line with M1 and M2 cellular polarity. Our approach can be adapted to study other host-pathogen interactions and coupled with down- stream automated analytical approaches.},
author = {Savulescu, Anca F and Peton, Nashied and Oosthuizen, Delia and Hazra, Rudranil and Rousseau, Robert P and Mhlanga, Musa M and Coussens, Anna K},
doi = {10.1016/J.CRMETH.2023.100640},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Savulescu et al. - 2023 - Quantifying spatial dynamics of iMycobacterium tuberculosisi infection of human macrophages using microfabrica.pdf:pdf},
issn = {2667-2375},
journal = {Cell Reports Methods},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {nov},
number = {11},
pages = {100640},
pmid = {37963461},
publisher = {Cell Press},
title = {{Quantifying spatial dynamics of \textit{Mycobacterium tuberculosis} infection of human macrophages using microfabricated patterns}},
volume = {3},
year = {2023}
}

Macrophages provide a first line of defense against invading pathogens, including the leading cause of bac- terial mortality, Mycobacterium tuberculosis (Mtb). A challenge for quantitative characterization of host-path- ogen processes in differentially polarized primary human monocyte-derived macrophages (MDMs) is their heterogeneous morphology. Here, we describe the use of microfabricated patterns that constrain the size and shape of cells, mimicking the physiological spatial confinement cells experience in tissues, to quantita- tively characterize interactions during and after phagocytosis at the single-cell level at high resolution. Comparing pro-inflammatory (M1) and anti-inflammatory (M2) MDMs, we find interferon-g stimulation in- creases the phagocytic contraction, while contraction and bacterial uptake decrease following silencing of phagocytosis regulator NHLRC2 or bacterial surface lipid removal. We identify host organelle position alter- ations within infected MDMs and differences in Mtb subcellular localization in line with M1 and M2 cellular polarity. Our approach can be adapted to study other host-pathogen interactions and coupled with down- stream automated analytical approaches.

@article{Dhana2023,
abstract = {Background: The World Health Organization (WHO) recommends that outpatient people living with HIV (PLHIV) undergo tuberculosis screening with the WHO four-symptom screen (W4SS) or C-reactive protein (CRP) (5 mg{\textperiodcentered}L−1 cut-off) followed by confirmatory testing if screen positive. We conducted an individual participant data meta-analysis to determine the performance of WHO-recommended screening tools and two newly developed clinical prediction models (CPMs). Methods: Following a systematic review, we identified studies that recruited adult outpatient PLHIV irrespective of tuberculosis signs and symptoms or with a positive W4SS, evaluated CRP and collected sputum for culture. We used logistic regression to develop an extended CPM (which included CRP and other predictors) and a CRP-only CPM. We used internal–external cross-validation to evaluate performance. Results: We pooled data from eight cohorts (n=4315 participants). The extended CPM had excellent discrimination (C-statistic 0.81); the CRP-only CPM had similar discrimination. The C-statistics for WHO-recommended tools were lower. Both CPMs had equivalent or higher net benefit compared with the WHO-recommended tools. Compared with both CPMs, CRP (5 mg{\textperiodcentered}L−1 cut-off) had equivalent net benefit across a clinically useful range of threshold probabilities, while the W4SS had a lower net benefit. The W4SS would capture 91{\%} of tuberculosis cases and require confirmatory testing for 78{\%} of participants. CRP (5 mg{\textperiodcentered}L−1 cut-off), the extended CPM (4.2{\%} threshold) and the CRP-only CPM (3.6{\%} threshold) would capture similar percentages of cases but reduce confirmatory tests required by 24, 27 and 36{\%}, respectively. Conclusions: CRP sets the standard for tuberculosis screening among outpatient PLHIV. The choice between using CRP at 5 mg{\textperiodcentered}L−1 cut-off or in a CPM depends on available resources. C-reactive protein at a 5 mg cut-off and two newly developed clinical prediction models from this study show clinical utility for TB screening among outpatient PLHIV, while the WHO-recommended four-symptom screen showed suboptimal clinical utility {\textless}https://bit.ly/3yShJ3m{\textgreater}},
author = {Dhana, Ashar and Gupta, Rishi K and Hamada, Yohhei and Kengne, Andre P and Kerkhoff, Andrew D and Yoon, Christina and Cattamanchi, Adithya and Reeve, Byron W P and Theron, Grant and Ndlangalavu, Gcobisa and Wood, Robin and Drain, Paul K and Calderwood, Claire J and Noursadeghi, Mahdad and Boyles, Tom and Meintjes, Graeme A and Maartens, Gary and Barr, David A},
doi = {10.1183/16000617.0021-2023},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Dhana et al. - 2023 - Clinical utility of WHO-recommended screening tools and development and validation of novel clinical prediction mo.pdf:pdf},
issn = {0905-9180},
journal = {European Respiratory Review},
keywords = {OA,OA{\_}PMC,fund{\_}ack,review},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,review},
month = {jun},
number = {168},
pages = {230021},
pmid = {37286216},
publisher = {European Respiratory Society},
title = {{Clinical utility of WHO-recommended screening tools and development and validation of novel clinical prediction models for pulmonary tuberculosis screening among outpatients living with HIV: an individual participant data meta-analysis}},
url = {https://err.ersjournals.com/content/32/168/230021 https://err.ersjournals.com/content/32/168/230021.abstract},
volume = {32},
year = {2023}
}

Background: The World Health Organization (WHO) recommends that outpatient people living with HIV (PLHIV) undergo tuberculosis screening with the WHO four-symptom screen (W4SS) or C-reactive protein (CRP) (5 mg˙L−1 cut-off) followed by confirmatory testing if screen positive. We conducted an individual participant data meta-analysis to determine the performance of WHO-recommended screening tools and two newly developed clinical prediction models (CPMs). Methods: Following a systematic review, we identified studies that recruited adult outpatient PLHIV irrespective of tuberculosis signs and symptoms or with a positive W4SS, evaluated CRP and collected sputum for culture. We used logistic regression to develop an extended CPM (which included CRP and other predictors) and a CRP-only CPM. We used internal–external cross-validation to evaluate performance. Results: We pooled data from eight cohorts (n=4315 participants). The extended CPM had excellent discrimination (C-statistic 0.81); the CRP-only CPM had similar discrimination. The C-statistics for WHO-recommended tools were lower. Both CPMs had equivalent or higher net benefit compared with the WHO-recommended tools. Compared with both CPMs, CRP (5 mg˙L−1 cut-off) had equivalent net benefit across a clinically useful range of threshold probabilities, while the W4SS had a lower net benefit. The W4SS would capture 91% of tuberculosis cases and require confirmatory testing for 78% of participants. CRP (5 mg˙L−1 cut-off), the extended CPM (4.2% threshold) and the CRP-only CPM (3.6% threshold) would capture similar percentages of cases but reduce confirmatory tests required by 24, 27 and 36%, respectively. Conclusions: CRP sets the standard for tuberculosis screening among outpatient PLHIV. The choice between using CRP at 5 mg˙L−1 cut-off or in a CPM depends on available resources. C-reactive protein at a 5 mg cut-off and two newly developed clinical prediction models from this study show clinical utility for TB screening among outpatient PLHIV, while the WHO-recommended four-symptom screen showed suboptimal clinical utility \textlesshttps://bit.ly/3yShJ3m\textgreater

@article{ThorburnGray2023,
abstract = {Background People with radiographic evidence for pulmonary tuberculosis (TB), but negative sputum cultures, have increased risk of developing culture-positive TB. Recent expansion of X-ray screening is leading to increased identification of this group. We set out to synthesise the evidence for treatment to prevent progression to culture-positive disease. Methods We conducted a systematic review and meta-analysis. We searched for prospective trials evaluating the efficacy of TB regimens against placebo, observation, or alternative regimens, for the treatment of adults and children with radiographic evidence of TB but culture-negative respiratory samples. Databases were searched up to 18 Oct 2022. Study quality was assessed using ROB 2{\textperiodcentered}0 and ROBINS-I. The primary outcome was progression to culture-positive TB. Meta-analysis with a random effects model was conducted to estimate pooled efficacy. This study was registered with PROSPERO (CRD42021248486). Findings We included 13 trials (32,568 individuals) conducted between 1955 and 2018. Radiographic and bacteriological criteria for inclusion varied. 19{\textperiodcentered}1{\%} to 57{\textperiodcentered}9{\%} of participants with active x-ray changes and no treatment progressed to culture-positive disease. Progression was reduced with any treatment (6 studies, risk ratio [RR] 0{\textperiodcentered}27, 95{\%}CI 0{\textperiodcentered}13–0{\textperiodcentered}56), although multi-drug TB treatment (RR 0{\textperiodcentered}11, 95{\%}CI 0{\textperiodcentered}05–0{\textperiodcentered}23) was significantly more effective than isoniazid treatment (RR 0{\textperiodcentered}63, 95{\%}CI 0{\textperiodcentered}35–1{\textperiodcentered}13) (p = 0{\textperiodcentered}0002). Interpretation Multi-drug regimens were associated with significantly reduced risk of progression to TB disease for individuals with radiographically apparent, but culture-negative TB. However, most studies were old, conducted prior to the HIV epidemic and with outdated regimens. New clinical trials are required to identify the optimal treatment approach.},
author = {{Thorburn Gray}, Adam and Macpherson, Liana and Carlin, Ffion and Sossen, Bianca and Richards, Alexandra S and Kik, Sandra V and Houben, Rein M G J and MacPherson, Peter and Quartagno, Matteo and Rogozi{\'{n}}ska, Ewelina and Esmail, Hanif},
doi = {10.1371/JOURNAL.PONE.0293535},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Thorburn Gray et al. - 2023 - Treatment for radiographically active, sputum culture-negative pulmonary tuberculosis a systematic review.pdf:pdf},
isbn = {1111111111},
issn = {1932-6203},
journal = {PLOS ONE},
keywords = {Bacterial pathogens,Diagnostic radiology,Isoniazid,Medical risk factors,Metaanalysis,OA,OA{\_}PMC,Sputum,Tuberculosis,Tuberculosis diagnosis and management,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {nov},
number = {11},
pages = {e0293535},
pmid = {37972202},
publisher = {Public Library of Science},
title = {{Treatment for radiographically active, sputum culture-negative pulmonary tuberculosis: a systematic review and meta-analysis}},
url = {https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0293535},
volume = {18},
year = {2023}
}

Background People with radiographic evidence for pulmonary tuberculosis (TB), but negative sputum cultures, have increased risk of developing culture-positive TB. Recent expansion of X-ray screening is leading to increased identification of this group. We set out to synthesise the evidence for treatment to prevent progression to culture-positive disease. Methods We conducted a systematic review and meta-analysis. We searched for prospective trials evaluating the efficacy of TB regimens against placebo, observation, or alternative regimens, for the treatment of adults and children with radiographic evidence of TB but culture-negative respiratory samples. Databases were searched up to 18 Oct 2022. Study quality was assessed using ROB 2˙0 and ROBINS-I. The primary outcome was progression to culture-positive TB. Meta-analysis with a random effects model was conducted to estimate pooled efficacy. This study was registered with PROSPERO (CRD42021248486). Findings We included 13 trials (32,568 individuals) conducted between 1955 and 2018. Radiographic and bacteriological criteria for inclusion varied. 19˙1% to 57˙9% of participants with active x-ray changes and no treatment progressed to culture-positive disease. Progression was reduced with any treatment (6 studies, risk ratio [RR] 0˙27, 95%CI 0˙13–0˙56), although multi-drug TB treatment (RR 0˙11, 95%CI 0˙05–0˙23) was significantly more effective than isoniazid treatment (RR 0˙63, 95%CI 0˙35–1˙13) (p = 0˙0002). Interpretation Multi-drug regimens were associated with significantly reduced risk of progression to TB disease for individuals with radiographically apparent, but culture-negative TB. However, most studies were old, conducted prior to the HIV epidemic and with outdated regimens. New clinical trials are required to identify the optimal treatment approach.

@article{Keene2023,
abstract = {Background: Recycling tenofovir and lamivudine/emtricitabine with dolutegravir (TLD) after failure of non-nucleoside transcriptase inhibitor (NNRTI) first-line antiretroviral therapy (ART) is more tolerable and scalable than dolutegravir plus optimized nucleoside reverse transcriptase inhibitors. Studies have demonstrated TLD's efficacy as second-line, but long term follow-up is limited. Methods: ARTIST is a single arm, prospective, interventional study conducted in Khayelitsha, South Africa, which switched 62 adults with two viral loads (VL) {\textgreater}1000 copies/mL from tenofovir, lamivudine/emtricitabine and an NNRTI to TLD. We report efficacy to 72 weeks and, in a post hoc analysis, evaluated VL trajectories of individuals with viraemic episodes. Results: Virologic suppression was 86{\%} (95{\%} Confidence Interval (CI) 74-93), 74{\%} (95{\%} CI 61-84) and 75{\%} (95{\%} CI 63-86) {\textless}50 copies/mL, and 95{\%}, 84{\%} and 77{\%} {\textless}400 copies/mL at week 24, 48 and 72 respectively, with 89{\%} (50/56) resistant (Stanford score ≥15) to tenofovir and/or lamivudine pre-switch. No participants developed integrase-inhibitor resistance. Of the 20 participants not suppressed at week 24 and/or 48, two developed virologic failure, one switched regimen (adverse event), two were lost to follow-up, one missed the visit, one transferred out, nine resuppressed {\textless}50 copies/mL with enhanced adherence counselling and four remained viraemic (three with {\textless}200 copies/mL) at week 72. Conclusions: Recycling NRTIs with dolutegravir was effective for most participants to 72 weeks. Most with viraemia did not develop virologic failure and subsequently suppressed with enhanced adherence counselling or continued to have low-level viraemia. No integrase-inhibitor resistance was detected despite low-level viraemia in a minority of participants. Copyright {\textcopyright} 2023 Wolters Kluwer Health, Inc. All rights reserved.},
author = {Keene, Claire M and Cassidy, Tali and Zhao, Ying and Griesel, Rulan and Jackson, Amanda and Sayed, Kaneez and Omar, Zaayid and Hill, Andrew and Ngwenya, Olina and {Van Zyl}, Gert and Flowers, Tracy and Goemaere, Eric and Maartens, Gary and Meintjes, Graeme},
issn = {1525-4135},
journal = {JAIDS},
keywords = {TLD,dolutegravir,fund{\_}ack,low-level viraemia,original,recycling-NRTIs,second-line antiretroviral therapy},
mendeley-tags = {fund{\_}ack,original},
number = {5},
pages = {422--429},
pmid = {36706364},
title = {{Recycling tenofovir in second-line antiretroviral treatment with dolutegravir: outcomes and viral load trajectories to 72 weeks}},
url = {https://journals.lww.com/jaids/Fulltext/9900/Recycling{\_}tenofovir{\_}in{\_}second{\_}line{\_}antiretroviral.176.aspx},
volume = {92},
year = {2023}
}

Background: Recycling tenofovir and lamivudine/emtricitabine with dolutegravir (TLD) after failure of non-nucleoside transcriptase inhibitor (NNRTI) first-line antiretroviral therapy (ART) is more tolerable and scalable than dolutegravir plus optimized nucleoside reverse transcriptase inhibitors. Studies have demonstrated TLD's efficacy as second-line, but long term follow-up is limited. Methods: ARTIST is a single arm, prospective, interventional study conducted in Khayelitsha, South Africa, which switched 62 adults with two viral loads (VL) \textgreater1000 copies/mL from tenofovir, lamivudine/emtricitabine and an NNRTI to TLD. We report efficacy to 72 weeks and, in a post hoc analysis, evaluated VL trajectories of individuals with viraemic episodes. Results: Virologic suppression was 86% (95% Confidence Interval (CI) 74-93), 74% (95% CI 61-84) and 75% (95% CI 63-86) \textless50 copies/mL, and 95%, 84% and 77% \textless400 copies/mL at week 24, 48 and 72 respectively, with 89% (50/56) resistant (Stanford score ≥15) to tenofovir and/or lamivudine pre-switch. No participants developed integrase-inhibitor resistance. Of the 20 participants not suppressed at week 24 and/or 48, two developed virologic failure, one switched regimen (adverse event), two were lost to follow-up, one missed the visit, one transferred out, nine resuppressed \textless50 copies/mL with enhanced adherence counselling and four remained viraemic (three with \textless200 copies/mL) at week 72. Conclusions: Recycling NRTIs with dolutegravir was effective for most participants to 72 weeks. Most with viraemia did not develop virologic failure and subsequently suppressed with enhanced adherence counselling or continued to have low-level viraemia. No integrase-inhibitor resistance was detected despite low-level viraemia in a minority of participants. Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.

@article{Galileya2023,
abstract = {Background The current World Health Organization (WHO) pediatric tuberculosis dosing guidelines lead to suboptimal drug exposures. Identifying factors altering the exposure of these drugs in children is essential for dose optimization. Pediatric pharmacokinetic studies are usually small, leading to high variability and uncertainty in pharmacokinetic results between studies. We pooled data from large pharmacokinetic studies to identify key covariates influencing drug exposure to optimize tuberculosis dosing in children. Methods and findings We used nonlinear mixed-effects modeling to characterize the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide, and investigated the association of human immunodeficiency virus (HIV), antiretroviral therapy (ART), drug formulation, age, and body size with their pharmacokinetics. Data from 387 children from South Africa, Zambia, Malawi, and India were available for analysis; 47{\%} were female and 39{\%} living with HIV (95{\%} on ART). Median (range) age was 2.2 (0.2 to 15.0) years and weight 10.9 (3.2 to 59.3) kg. Body size (allometry) was used to scale clearance and volume of distribution of all 3 drugs. Age affected the bioavailability of rifampicin and isoniazid; at birth, children had 48.9{\%} (95{\%} confidence interval (CI) [36.0{\%}, 61.8{\%}]; p {\textless} 0.001) and 64.5{\%} (95{\%} CI [52.1{\%}, 78.9{\%}]; p {\textless} 0.001) of adult rifampicin and isoniazid bioavailability, respectively, and reached full adult bioavailability after 2 years of age for both drugs. Age also affected the clearance of all drugs (maturation), children reached 50{\%} adult drug clearing capacity at around 3 months after birth and neared full maturation around 3 years of age. While HIV per se did not affect the pharmacokinetics of first-line tuberculosis drugs, rifampicin clearance was 22{\%} lower (95{\%} CI [13{\%}, 28{\%}]; p {\textless} 0.001) and pyrazinamide clearance was 49{\%} higher (95{\%} CI [39{\%}, 57{\%}]; p {\textless} 0.001) in children on lopinavir/ritonavir; isoniazid bioavailability was reduced by 39{\%} (95{\%} CI [32{\%}, 45{\%}]; p {\textless} 0.001) when simultaneously coadministered with lopinavir/ritonavir and was 37{\%} lower (95{\%} CI [22{\%}, 52{\%}]; p {\textless} 0.001) in children on efavirenz. Simulations of 2010 WHO-recommended pediatric tuberculosis doses revealed that, compared to adult values, rifampicin exposures are lower in most children, except those younger than 3 months, who experience relatively higher exposure for all drugs, due to immature clearance. Increasing the rifampicin doses in children older than 3 months by 75 mg for children weighing {\textless}25 kg and 150 mg for children weighing {\textgreater}25 kg could improve rifampicin exposures. Our analysis was limited by the differences in availability of covariates among the pooled studies. Conclusions Children older than 3 months have lower rifampicin exposures than adults and increasing their dose by 75 or 150 mg could improve therapy. Altered exposures in children with HIV is most likely caused by concomitant ART and not HIV per se. The importance of the drug–drug interactions with lopinavir/ritonavir and efavirenz should be evaluated further and considered in future dosing guidance. Trial registration ClinicalTrials.gov registration numbers; NCT02348177, NCT01637558, ISRCTN63579542},
author = {Galileya, Tsirizani Lufina and Wasmann, Roeland E and Chabala, Chishala and Rabie, Helena and Lee, Janice and Mukui, Irene Njahira and Hesseling, Anneke and Zar, Heather and Aarnoutse, Rob and Turkova, Anna and Gibb, Diana and Cotton, Mark F and McIlleron, Helen and Denti, Paolo},
doi = {10.1371/JOURNAL.PMED.1004303},
editor = {Newell, Marie-Louise},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Galileya et al. - 2023 - Evaluating pediatric tuberculosis dosing guidelines a model-based individual data pooled analysis.pdf:pdf},
isbn = {1111111111},
issn = {1549-1676},
journal = {PLOS Medicine},
keywords = {Antiretroviral therapy,Body weight,Drug administration,HIV,Isoniazid,OA,OA{\_}PMC,Pediatrics,Pharmacokinetics,Tuberculosis,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
number = {11},
pages = {e1004303},
pmid = {37988391},
publisher = {Public Library of Science},
title = {{Evaluating pediatric tuberculosis dosing guidelines: a model-based individual data pooled analysis}},
url = {https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004303},
volume = {20},
year = {2023}
}

Background The current World Health Organization (WHO) pediatric tuberculosis dosing guidelines lead to suboptimal drug exposures. Identifying factors altering the exposure of these drugs in children is essential for dose optimization. Pediatric pharmacokinetic studies are usually small, leading to high variability and uncertainty in pharmacokinetic results between studies. We pooled data from large pharmacokinetic studies to identify key covariates influencing drug exposure to optimize tuberculosis dosing in children. Methods and findings We used nonlinear mixed-effects modeling to characterize the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide, and investigated the association of human immunodeficiency virus (HIV), antiretroviral therapy (ART), drug formulation, age, and body size with their pharmacokinetics. Data from 387 children from South Africa, Zambia, Malawi, and India were available for analysis; 47% were female and 39% living with HIV (95% on ART). Median (range) age was 2.2 (0.2 to 15.0) years and weight 10.9 (3.2 to 59.3) kg. Body size (allometry) was used to scale clearance and volume of distribution of all 3 drugs. Age affected the bioavailability of rifampicin and isoniazid; at birth, children had 48.9% (95% confidence interval (CI) [36.0%, 61.8%]; p \textless 0.001) and 64.5% (95% CI [52.1%, 78.9%]; p \textless 0.001) of adult rifampicin and isoniazid bioavailability, respectively, and reached full adult bioavailability after 2 years of age for both drugs. Age also affected the clearance of all drugs (maturation), children reached 50% adult drug clearing capacity at around 3 months after birth and neared full maturation around 3 years of age. While HIV per se did not affect the pharmacokinetics of first-line tuberculosis drugs, rifampicin clearance was 22% lower (95% CI [13%, 28%]; p \textless 0.001) and pyrazinamide clearance was 49% higher (95% CI [39%, 57%]; p \textless 0.001) in children on lopinavir/ritonavir; isoniazid bioavailability was reduced by 39% (95% CI [32%, 45%]; p \textless 0.001) when simultaneously coadministered with lopinavir/ritonavir and was 37% lower (95% CI [22%, 52%]; p \textless 0.001) in children on efavirenz. Simulations of 2010 WHO-recommended pediatric tuberculosis doses revealed that, compared to adult values, rifampicin exposures are lower in most children, except those younger than 3 months, who experience relatively higher exposure for all drugs, due to immature clearance. Increasing the rifampicin doses in children older than 3 months by 75 mg for children weighing \textless25 kg and 150 mg for children weighing \textgreater25 kg could improve rifampicin exposures. Our analysis was limited by the differences in availability of covariates among the pooled studies. Conclusions Children older than 3 months have lower rifampicin exposures than adults and increasing their dose by 75 or 150 mg could improve therapy. Altered exposures in children with HIV is most likely caused by concomitant ART and not HIV per se. The importance of the drug–drug interactions with lopinavir/ritonavir and efavirenz should be evaluated further and considered in future dosing guidance. Trial registration ClinicalTrials.gov registration numbers; NCT02348177, NCT01637558, ISRCTN63579542

@article{Peterson2023,
abstract = {Background: Despite treatment with combination antiretroviral therapy (cART), persons living with HIV (PLWH) are at higher risk of cardiac structural abnormalities that may presage clinical heart failure, including myocardial fibrosis. This study assessed whether circulating cellular and soluble protein markers of immune activation cross-sectionally associate with myocardial fibrosis among cART-treated PLWH in South Africa. Methods: Participants were enrolled in Khayelitsha township near Cape Town, SA. Cardiac magnetic resonance imaging was performed. Plasma protein biomarkers were measured using enzyme-linked immunoassays and monocyte phenotypes were evaluated using flow cytometry. Associations were assessed using multivariable linear and logistic regression. Results: Among 69 cART-treated PLWH, mean (SD) age was 48 (10) years, 71{\%} were female, and time since HIV diagnosis was 9 (6) years. Evidence of left ventricular fibrosis by late gadolinium enhancement was present in 74{\%} of participants and mean (SD) extracellular volume fraction (ECV) was 30.9 (5.9){\%}. Degree of myocardial fibrosis/inflammation measured by ECV was positively associated with percentages of circulating non-classical and intermediate monocyte phenotypes reflecting inflammation and tissue injury. Conclusion: These data generate hypotheses on possible immune mechanisms of HIV-associated non-ischemic myocardial disease, specifically among cART-treated PLWH in sub-Saharan Africa, where the majority of the HIV burden exists globally.},
author = {Peterson, Tess E and Shey, Muki and Masina, Nomawethu and Wong, Lye Yeng and Shuldiner, Scott R and Wolfson, Julian and Jermy, Stephen and Saad, Hadil and Lumbamba, Mbalabu A J and Singh, Achita and Meintjes, Graeme and Ntusi, Ntobeko A B and Ntsekhe, Mpiko and Baker, Jason V},
doi = {10.1016/J.IJCARD.2023.131332},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Peterson et al. - 2023 - Myocardial extracellular volume fraction is positively associated with activated monocyte subsets among cART-tr.pdf:pdf},
issn = {0167-5273},
journal = {International Journal of Cardiology},
keywords = {Extracellular volume fraction,HIV infection,Monocyte activation,Monocyte phenotype,Myocardial fibrosis,fund{\_}ack,original},
mendeley-tags = {fund{\_}ack,original},
month = {sep},
pages = {doi.org/10.1016/j.ijcard.2023.131332},
pmid = {37673402},
publisher = {Elsevier},
title = {{Myocardial extracellular volume fraction is positively associated with activated monocyte subsets among cART-treated persons living with HIV in South Africa}},
year = {2023}
}

Background: Despite treatment with combination antiretroviral therapy (cART), persons living with HIV (PLWH) are at higher risk of cardiac structural abnormalities that may presage clinical heart failure, including myocardial fibrosis. This study assessed whether circulating cellular and soluble protein markers of immune activation cross-sectionally associate with myocardial fibrosis among cART-treated PLWH in South Africa. Methods: Participants were enrolled in Khayelitsha township near Cape Town, SA. Cardiac magnetic resonance imaging was performed. Plasma protein biomarkers were measured using enzyme-linked immunoassays and monocyte phenotypes were evaluated using flow cytometry. Associations were assessed using multivariable linear and logistic regression. Results: Among 69 cART-treated PLWH, mean (SD) age was 48 (10) years, 71% were female, and time since HIV diagnosis was 9 (6) years. Evidence of left ventricular fibrosis by late gadolinium enhancement was present in 74% of participants and mean (SD) extracellular volume fraction (ECV) was 30.9 (5.9)%. Degree of myocardial fibrosis/inflammation measured by ECV was positively associated with percentages of circulating non-classical and intermediate monocyte phenotypes reflecting inflammation and tissue injury. Conclusion: These data generate hypotheses on possible immune mechanisms of HIV-associated non-ischemic myocardial disease, specifically among cART-treated PLWH in sub-Saharan Africa, where the majority of the HIV burden exists globally.

@article{Wilkinson2023,
author = {Wilkinson, Robert J and Donovan, Joseph and Thwaites, Guy E and van Crevel, Reinout and Wasserman, Sean},
doi = {10.1016/J.TUBE.2023.102361},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Wilkinson et al. - 2023 - Treatment of tuberculous meningitis overdue for concerted action.pdf:pdf},
issn = {1472-9792},
journal = {Tuberculosis},
keywords = {fund{\_}ack,perspective},
mendeley-tags = {fund{\_}ack,perspective},
month = {sep},
pages = {102361},
pmid = {37394302},
publisher = {Churchill Livingstone},
title = {{Treatment of tuberculous meningitis: overdue for concerted action}},
volume = {142},
year = {2023}
}

@article{Gafar2022,
abstract = {Background Suboptimal exposure to antituberculosis drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line antituberculosis drug pharmacokinetics in children and adolescents at a global level. Methods We systematically searched MEDLINE, Embase, and Web of Science (1990–2021) for pharmacokinetic studies of first-line antituberculosis drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve (AUC0–24) and peak plasma concentration (Cmax) were assessed with random-effects models, normalised with current WHO-recommended paediatric doses. Determinants of AUC0–24 and Cmax were assessed with linear mixed-effects models. Results Of 55 eligible studies, individual patient data were available for 39 (71{\%}), including 1628 participants from 12 countries. Geometric means (95{\%} CIs) of steady-state AUC0–24 were summarised for isoniazid (18.7 [15.5−22.6] h{\textperiodcentered}mg{\textperiodcentered}L−1), rifampicin (34.4 [29.4−40.3] h{\textperiodcentered}mg{\textperiodcentered}L−1), pyrazinamide (375.0 [339.9−413.7] h{\textperiodcentered}mg{\textperiodcentered}L−1), and ethambutol (8.0 [6.4−10.0] h{\textperiodcentered}mg{\textperiodcentered}L−1). Our multivariate models indicated that younger age (especially {\textless}2 years) and HIV-positive status were associated with lower AUC0–24 for all antituberculosis drugs, while severe malnutrition was associated with lower AUC0–24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0–24 and slow acetylators had higher isoniazid AUC0–24 than intermediate acetylators. Determinants of Cmax were generally similar to those for AUC0–24. Conclusion This study provides the most comprehensive estimates of plasma exposures to first-line antituberculosis drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: HSS reports grants from the NIH/IMPAACT; and honoraria from Ann Lake publications − sponsored by Johnson {\&} Johnson − for an educational publication on the management of MDR-TB in children. Conflict of interest: AB reports grants from IMPAACT, UNITAID; lecture honoraria from Sandoz; support for attending PENTA PIM meeting; and received generic LPV/r, 3TC and ABC for the PETITE study. Conflict of interest: DJB reports support for attending a meeting from ViiV pharmaceuticals; and attendance fees for an Advisory board meeting from ViiV pharmaceuticals. Conflict of interest: LC reports grants from the UKRI MRC DfID Wellcome NIHR Joint Global Health Trials, TB Alliance Support for trial drug purchase, and UKRI COVID-19 Grant Extension Allocation Award. Conflict of interest: PD reports a grant for WHO expert review for TB drugs in children. Conflict of interest: SMG reports participation on a Data Safety Monitoring Board for the TB CHAMP trial; and leadership roles as a co-chair for Guidelines Development Committee of the WHO updated recommendations and consolidated guidelines on child and adolescents TB, and as a core member for the WHO Child and Adolescent TB Working Group. Conflict of interest: SKH reports grants from the NIH, DANIDA, and EDTCP; royalties or licenses from UpToDate; and honoraria for lectures from Henry Stewart Talks. Conflict of interest: AK reports a grant from the NIH/NICHD. Conflict of interest: VM reports grants from the NIH and CDC. Conflict of interest: CAP reports a grant from the NIH. Conflict of interest: VR reports a grant from the Delhi State TB Association; and leadership roles as a member of the Delhi State TB Association and the MAMC TB Committee. Conflict of interest: EMS reports grants from the NWO personal Veni, IMI UNITE4TB consortium, TB Alliance, UNITAID BenefitKids consortium, WHO expert review, NIH support for IMPAACT studies, Blueprint, Probex, ACTG study Clo-FAST, Janssen pharmaceuticals, EDCTP suport PanTB-HM, and Legochem; and leadership of fiduciary roles in ISOP DI{\&}E committee and BenNeLux PMX organizing committee. Conflict of interest: UT reports participation on a Data Safety Monitoring Board for an ICMR TB trial. Conflict of interest: TAT reports grants from the NIH and the University of Virginia. Conflict of interest: DJT reports a grant from Chiesi; consulting fees from Pure IMS and Sanguin; and participation on a Data Safety Monitoring Board for the FORMAT trial. Conflict of interest: AT reports grants from the UKRI MRC DfID Wellcome NIHR Joint Global Health Trials and the MRC Grants for core funding of the Medical Research Council Clinical Trials Unit at the UCL; and TB Alliance Support for SHINE trial drug purchase. Conflict of interest: All of this work was declared by the authors to be outside the submitted work. Conflict of interest: All other authors declare no competing interests.},
author = {Gafar, Fajri and Wasmann, Roeland E and McIlleron, Helen M and Aarnoutse, Rob E and Schaaf, H Simon and Marais, Ben J and Agarwal, Dipti and Antwi, Sampson and Bang, Nguyen D and Bekker, Adrie and Bell, David J and Chabala, Chishala and Choo, Louise and Davies, Geraint R and Day, Jeremy N and Dayal, Rajeshwar and Denti, Paolo and Donald, Peter R and Engidawork, Ephrem and Garcia-Prats, Anthony J and Gibb, Diana and Graham, Stephen M and Hesseling, Anneke C and Heysell, Scott K and Idris, Misgana I and Kabra, Sushil K and Kinikar, Aarti and Kumar, Agibothu K Hemanth and Kwara, Awewura and Lodha, Rakesh and Magis-Escurra, Cecile and Martinez, Nilza and Mathew, Binu S and Mave, Vidya and Mduma, Estomih and Mlotha-Mitole, Rachel and Mpagama, Stellah G and Mukherjee, Aparna and Nataprawira, Heda M and Peloquin, Charles A and Pouplin, Thomas and Ramachandran, Geetha and Ranjalkar, Jaya and Roy, Vandana and Ruslami, Rovina and Shah, Ira and Singh, Yatish and Sturkenboom, Marieke G G and Svensson, Elin M and Swaminathan, Soumya and Thatte, Urmila and Thee, Stephanie and Thomas, Tania A and Tikiso, Tjokosela and Touw, Daan J and Turkova, Anna and Velpandian, Thirumurthy and Verhagen, Lilly M and Winckler, Jana L and Yang, Hongmei and Yunivita, Vycke and Taxis, Katja and Stevens, Jasper and Alffenaar, Jan-Willem C and Drugs, for the Global Collaborative Group for Meta-Analysis of Paediatric Individual Patient Data in Pharmacokinetics of Anti-TB},
doi = {10.1183/13993003.01596-2022},
issn = {0903-1936},
journal = {European Respiratory Journal},
keywords = {OA,OA{\_}PMC,fund{\_}not{\_}ack,review},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,review},
month = {nov},
number = {3},
pages = {2201596},
pmid = {36328357},
publisher = {European Respiratory Society},
title = {{Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis}},
url = {https://erj.ersjournals.com/content/early/2022/10/13/13993003.01596-2022 https://erj.ersjournals.com/content/early/2022/10/13/13993003.01596-2022.abstract},
volume = {61},
year = {2023}
}

Background Suboptimal exposure to antituberculosis drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line antituberculosis drug pharmacokinetics in children and adolescents at a global level. Methods We systematically searched MEDLINE, Embase, and Web of Science (1990–2021) for pharmacokinetic studies of first-line antituberculosis drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve (AUC0–24) and peak plasma concentration (Cmax) were assessed with random-effects models, normalised with current WHO-recommended paediatric doses. Determinants of AUC0–24 and Cmax were assessed with linear mixed-effects models. Results Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means (95% CIs) of steady-state AUC0–24 were summarised for isoniazid (18.7 [15.5−22.6] h˙mg˙L−1), rifampicin (34.4 [29.4−40.3] h˙mg˙L−1), pyrazinamide (375.0 [339.9−413.7] h˙mg˙L−1), and ethambutol (8.0 [6.4−10.0] h˙mg˙L−1). Our multivariate models indicated that younger age (especially \textless2 years) and HIV-positive status were associated with lower AUC0–24 for all antituberculosis drugs, while severe malnutrition was associated with lower AUC0–24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0–24 and slow acetylators had higher isoniazid AUC0–24 than intermediate acetylators. Determinants of Cmax were generally similar to those for AUC0–24. Conclusion This study provides the most comprehensive estimates of plasma exposures to first-line antituberculosis drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: HSS reports grants from the NIH/IMPAACT; and honoraria from Ann Lake publications − sponsored by Johnson & Johnson − for an educational publication on the management of MDR-TB in children. Conflict of interest: AB reports grants from IMPAACT, UNITAID; lecture honoraria from Sandoz; support for attending PENTA PIM meeting; and received generic LPV/r, 3TC and ABC for the PETITE study. Conflict of interest: DJB reports support for attending a meeting from ViiV pharmaceuticals; and attendance fees for an Advisory board meeting from ViiV pharmaceuticals. Conflict of interest: LC reports grants from the UKRI MRC DfID Wellcome NIHR Joint Global Health Trials, TB Alliance Support for trial drug purchase, and UKRI COVID-19 Grant Extension Allocation Award. Conflict of interest: PD reports a grant for WHO expert review for TB drugs in children. Conflict of interest: SMG reports participation on a Data Safety Monitoring Board for the TB CHAMP trial; and leadership roles as a co-chair for Guidelines Development Committee of the WHO updated recommendations and consolidated guidelines on child and adolescents TB, and as a core member for the WHO Child and Adolescent TB Working Group. Conflict of interest: SKH reports grants from the NIH, DANIDA, and EDTCP; royalties or licenses from UpToDate; and honoraria for lectures from Henry Stewart Talks. Conflict of interest: AK reports a grant from the NIH/NICHD. Conflict of interest: VM reports grants from the NIH and CDC. Conflict of interest: CAP reports a grant from the NIH. Conflict of interest: VR reports a grant from the Delhi State TB Association; and leadership roles as a member of the Delhi State TB Association and the MAMC TB Committee. Conflict of interest: EMS reports grants from the NWO personal Veni, IMI UNITE4TB consortium, TB Alliance, UNITAID BenefitKids consortium, WHO expert review, NIH support for IMPAACT studies, Blueprint, Probex, ACTG study Clo-FAST, Janssen pharmaceuticals, EDCTP suport PanTB-HM, and Legochem; and leadership of fiduciary roles in ISOP DI&E committee and BenNeLux PMX organizing committee. Conflict of interest: UT reports participation on a Data Safety Monitoring Board for an ICMR TB trial. Conflict of interest: TAT reports grants from the NIH and the University of Virginia. Conflict of interest: DJT reports a grant from Chiesi; consulting fees from Pure IMS and Sanguin; and participation on a Data Safety Monitoring Board for the FORMAT trial. Conflict of interest: AT reports grants from the UKRI MRC DfID Wellcome NIHR Joint Global Health Trials and the MRC Grants for core funding of the Medical Research Council Clinical Trials Unit at the UCL; and TB Alliance Support for SHINE trial drug purchase. Conflict of interest: All of this work was declared by the authors to be outside the submitted work. Conflict of interest: All other authors declare no competing interests.

@article{Griesel2023,
abstract = {Summary Background The drug–drug interaction between rifampicin and dolutegravir can be overcome by supplemental dolutegravir dosing, which is difficult to implement in high-burden settings. We aimed to test whether virological outcomes with standard-dose dolutegravir-based antiretroviral therapy (ART) are acceptable in people with HIV on rifampicin-based antituberculosis therapy. Methods RADIANT-TB was a phase 2b, randomised, double-blind, non-comparative, placebo-controlled trial at a single site in Khayelitsha, Cape Town, South Africa. Participants were older than 18 years of age, with plasma HIV-1 RNA greater than 1000 copies per mL, CD4 count greater than 100 cells per $\mu$L, ART-naive or first-line ART interrupted, and on rifampicin-based antituberculosis therapy for less than 3 months. By use of permuted block (block size of 6) randomisation, participants were assigned (1:1) to receive either tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus supplemental 50 mg dolutegravir 12 h later or tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus matched placebo 12 h later. Participants received standard antituberculosis therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol for the first 2 months followed by isoniazid and rifampicin for 4 months). The primary outcome was the proportion of participants with virological suppression (HIV-1 RNA Findings Between Nov 28, 2019, and July 23, 2021, 108 participants (38 female, median age 35 years [IQR 31–40]) were randomly assigned to supplemental dolutegravir (n=53) or placebo (n=55). Median baseline CD4 count was 188 cells per $\mu$L (IQR 145–316) and median HIV-1 RNA was 5{\textperiodcentered}2 log10 copies per mL (4{\textperiodcentered}6–5{\textperiodcentered}7). At week 24, 43 (83{\%}, 95{\%} CI 70–92) of 52 participants in the supplemental dolutegravir arm and 44 (83{\%}, 95{\%} CI 70–92) of 53 participants in the placebo arm had virological suppression. No treatment-emergent dolutegravir resistance mutations were detected up to week 48 in the 19 participants with study-defined virological failure. Grade 3 and 4 adverse events were similarly distributed between the study arms. The most frequent grade 3 and 4 adverse events were weight loss (4/108 [4{\%}]), insomnia (3/108 [3{\%}]), and pneumonia (3/108 [3{\%}]). Interpretation Our findings suggest that twice-daily dolutegravir might be unnecessary in people with HIV-associated tuberculosis. Funding Wellcome Trust.},
author = {Griesel, Rulan and Zhao, Ying and Simmons, Bryony and Omar, Zaayid and Wiesner, Lubbe and Keene, Claire M and Hill, Andrew M and Meintjes, Graeme A and Maartens, Gary},
doi = {10.1016/S2352-3018(23)00081-4},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Griesel et al. - 2023 - Standard-dose versus double-dose dolutegravir in HIV-associated tuberculosis in South Africa (RADIANT-TB) a phas.pdf:pdf},
issn = {2352-3018},
journal = {The Lancet HIV},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {may},
number = {7},
pages = {e433--e441},
pmid = {37230101},
publisher = {Elsevier},
title = {{Standard-dose versus double-dose dolutegravir in HIV-associated tuberculosis in South Africa (RADIANT-TB): a phase 2, non-comparative, randomised controlled trial}},
url = {http://www.thelancet.com/article/S2352301823000814/fulltext http://www.thelancet.com/article/S2352301823000814/abstract https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(23)00081-4/abstract},
volume = {10},
year = {2023}
}

Summary Background The drug–drug interaction between rifampicin and dolutegravir can be overcome by supplemental dolutegravir dosing, which is difficult to implement in high-burden settings. We aimed to test whether virological outcomes with standard-dose dolutegravir-based antiretroviral therapy (ART) are acceptable in people with HIV on rifampicin-based antituberculosis therapy. Methods RADIANT-TB was a phase 2b, randomised, double-blind, non-comparative, placebo-controlled trial at a single site in Khayelitsha, Cape Town, South Africa. Participants were older than 18 years of age, with plasma HIV-1 RNA greater than 1000 copies per mL, CD4 count greater than 100 cells per $μ$L, ART-naive or first-line ART interrupted, and on rifampicin-based antituberculosis therapy for less than 3 months. By use of permuted block (block size of 6) randomisation, participants were assigned (1:1) to receive either tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus supplemental 50 mg dolutegravir 12 h later or tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus matched placebo 12 h later. Participants received standard antituberculosis therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol for the first 2 months followed by isoniazid and rifampicin for 4 months). The primary outcome was the proportion of participants with virological suppression (HIV-1 RNA Findings Between Nov 28, 2019, and July 23, 2021, 108 participants (38 female, median age 35 years [IQR 31–40]) were randomly assigned to supplemental dolutegravir (n=53) or placebo (n=55). Median baseline CD4 count was 188 cells per $μ$L (IQR 145–316) and median HIV-1 RNA was 5˙2 log10 copies per mL (4˙6–5˙7). At week 24, 43 (83%, 95% CI 70–92) of 52 participants in the supplemental dolutegravir arm and 44 (83%, 95% CI 70–92) of 53 participants in the placebo arm had virological suppression. No treatment-emergent dolutegravir resistance mutations were detected up to week 48 in the 19 participants with study-defined virological failure. Grade 3 and 4 adverse events were similarly distributed between the study arms. The most frequent grade 3 and 4 adverse events were weight loss (4/108 [4%]), insomnia (3/108 [3%]), and pneumonia (3/108 [3%]). Interpretation Our findings suggest that twice-daily dolutegravir might be unnecessary in people with HIV-associated tuberculosis. Funding Wellcome Trust.

@article{Buchanan2023,
abstract = {Propionic acid (PPA) is used to study the role of mitochondrial dysfunction in neurodevelopmental conditions like autism spectrum disorders. PPA is known to disrupt mitochondrial biogenesis, metabolism, and turnover. However, the effect of PPA on mitochondrial dynamics, fission, and fusion remains challenging to study due to the complex temporal nature of these mechanisms. Here, we use complementary quantitative visualization techniques to examine how PPA influences mitochondrial ultrastructure, morphology, and dynamics in neuronal-like SH-SY5Y cells. PPA (5 mM) induced a significant decrease in mitochondrial area (p {\textless} 0.01), Feret's diameter and perimeter (p {\textless} 0.05), and in area2 (p {\textless} 0.01). Mitochondrial event localiser analysis demonstrated a significant increase in fission and fusion events (p {\textless} 0.05) that preserved mitochondrial network integrity under stress. Moreover, mRNA expression of cMYC (p {\textless} 0.0001), NRF1 (p {\textless} 0.01), TFAM (p {\textless} 0.05), STOML2 (p {\textless} 0.0001), and OPA1 (p {\textless} 0.01) was significantly decreased. This illustrates a remodeling of mitochondrial morphology, biogenesis, and dynamics to preserve function under stress. Our data provide new insights into the influence of PPA on mitochondrial dynamics and highlight the utility of visualization techniques to study the complex regulatory mechanisms involved in the mitochondrial stress response.},
author = {Buchanan, Erin and Mahony, Caitlyn and Bam, Sophia and Jaffer, Mohamed and Macleod, Sarah and Mangali, Asandile and van der Watt, Mignon and de Wet, Sholto and Theart, Rensu and Jacobs, Caron and Loos, Ben and O'Ryan, Colleen},
doi = {10.1038/s41598-023-40130-8},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Buchanan et al. - 2023 - Propionic acid induces alterations in mitochondrial morphology and dynamics in SH-SY5Y cells.pdf:pdf},
isbn = {0123456789},
issn = {2045-2322},
journal = {Scientific Reports},
keywords = {Cellular imaging,Cellular neuroscience,Gene expression,OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {aug},
pages = {13248},
pmid = {37582965},
publisher = {Nature Publishing Group},
title = {{Propionic acid induces alterations in mitochondrial morphology and dynamics in SH-SY5Y cells}},
url = {https://www.nature.com/articles/s41598-023-40130-8},
volume = {13},
year = {2023}
}

Propionic acid (PPA) is used to study the role of mitochondrial dysfunction in neurodevelopmental conditions like autism spectrum disorders. PPA is known to disrupt mitochondrial biogenesis, metabolism, and turnover. However, the effect of PPA on mitochondrial dynamics, fission, and fusion remains challenging to study due to the complex temporal nature of these mechanisms. Here, we use complementary quantitative visualization techniques to examine how PPA influences mitochondrial ultrastructure, morphology, and dynamics in neuronal-like SH-SY5Y cells. PPA (5 mM) induced a significant decrease in mitochondrial area (p \textless 0.01), Feret's diameter and perimeter (p \textless 0.05), and in area2 (p \textless 0.01). Mitochondrial event localiser analysis demonstrated a significant increase in fission and fusion events (p \textless 0.05) that preserved mitochondrial network integrity under stress. Moreover, mRNA expression of cMYC (p \textless 0.0001), NRF1 (p \textless 0.01), TFAM (p \textless 0.05), STOML2 (p \textless 0.0001), and OPA1 (p \textless 0.01) was significantly decreased. This illustrates a remodeling of mitochondrial morphology, biogenesis, and dynamics to preserve function under stress. Our data provide new insights into the influence of PPA on mitochondrial dynamics and highlight the utility of visualization techniques to study the complex regulatory mechanisms involved in the mitochondrial stress response.

@article{Boyd2023,
abstract = {Chronic schistosomiasis affects either the genitourinary or gastrointestinal tract. Rarely, schistosomes cause ectopic disease, such as in the case of a South African woman from a non-endemic province, who presented with suspected pericardial tamponade because of tuberculosis. However, histology and polymerase chain reaction from pericardial biopsy confirmed Schistosoma haematobium. A finding of mediastinal non-Hodgkin lymphoma came to light when our patient's clinical condition unexpectedly deteriorated. Contribution: This case highlights an unusual manifestation of schistosomiasis.},
author = {Boyd, Michael J and Mendelson, Marc and Dlamini, Sipho K and Wasserman, Sean and Fakier, Ghaalied and Roberts, Riyaadh and Papavarnavas, Nectarios S},
doi = {10.4102/SAJID.V38I1.524},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Boyd et al. - 2023 - A case of pericardial schistosomiasis and non-Hodgkin high grade B-cell lymphoma.pdf:pdf},
issn = {2313-1810},
journal = {Southern African Journal of Infectious Diseases},
keywords = {Hodgkin lymphoma,Infectious diseases,OA,Schistosoma haematobium,bacterial,clinical,communicable,diagnosis,epidemiology,fund{\_}not{\_}ack,fungal,laboratory,non,original,parasitic,pericardial effusion,pericardial schistosomiasis,schistosomiasis,treatment,viral},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {sep},
number = {1},
pages = {4},
title = {{A case of pericardial schistosomiasis and non-Hodgkin high grade B-cell lymphoma}},
url = {https://sajid.co.za/index.php/sajid/article/view/524/1262 https://sajid.co.za/index.php/sajid/article/view/524/1263 https://sajid.co.za/index.php/sajid/article/view/524/1264 https://sajid.co.za/index.php/sajid/article/view/524},
volume = {38},
year = {2023}
}

Chronic schistosomiasis affects either the genitourinary or gastrointestinal tract. Rarely, schistosomes cause ectopic disease, such as in the case of a South African woman from a non-endemic province, who presented with suspected pericardial tamponade because of tuberculosis. However, histology and polymerase chain reaction from pericardial biopsy confirmed Schistosoma haematobium. A finding of mediastinal non-Hodgkin lymphoma came to light when our patient's clinical condition unexpectedly deteriorated. Contribution: This case highlights an unusual manifestation of schistosomiasis.

@article{Boshoff2023,
author = {Boshoff, Helena I M and Warner, Digby F and Gold, Ben},
doi = {10.3389/FCIMB.2023.1215294/BIBTEX},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Boshoff, Warner, Gold - 2023 - Drug-resistant Mycobacterium tuberculosis.pdf:pdf},
issn = {22352988},
journal = {Frontiers in Cellular and Infection Microbiology},
keywords = {Mycobacterium tuberculosis,OA,antimicrobial resistance (AMR),drug discovery,drug resistance,drug synergy,drug tolerance,editorial,fund{\_}not{\_}ack,phenotypic resistance,tuberculosis},
mendeley-tags = {OA,editorial,fund{\_}not{\_}ack},
month = {may},
pages = {1215294},
pmid = {37274311},
publisher = {NLM (Medline)},
title = {{Drug-resistant \textit{Mycobacterium tuberculosis}}},
volume = {13},
year = {2023}
}

@article{Hermans2023,
abstract = {Background: The emergence of genetic variants of SARS-CoV-2 was associated with changing epidemiological characteristics throughout coronavirus disease 2019 (COVID-19) pandemic in population-based studies. Individual-level data on the clinical characteristics of infection with different SARS-CoV-2 variants in African countries is less well documented. Objectives: To describe the evolving clinical differences observed with the various SARS-CoV-2 variants of concern and compare the Omicron-driven wave in infections to the previous Delta-driven wave. Method: We performed a retrospective observational cohort study among patients admitted to a South African referral hospital with COVID-19 pneumonia. Patients were stratified by epidemiological wave period, and in a subset, the variants associated with each wave were confirmed by genomic sequencing. Outcomes were analysed by Cox proportional hazard models. Results: We included 1689 patients were included, representing infection waves driven predominantly by ancestral, Beta, Delta and Omicron BA1/BA2 {\&} BA4/BA5 variants. Crude 28-day mortality was 25.8{\%} (34/133) in the Omicron wave period versus 37.1{\%} (138/374) in the Delta wave period (hazard ratio [HR] 0.68 [95{\%} CI 0.47–1.00] p = 0.049); this effect persisted after adjustment for age, gender, HIV status and presence of cardiovascular disease (adjusted HR [aHR] 0.43 [95{\%} CI 0.28–0.67] p {\textless} 0.001). Hospital-wide SARS-CoV-2 admissions and deaths were highest during the Delta wave period, with a decoupling of SARS-CoV-2 deaths and overall deaths thereafter. Conclusion: There was lower in-hospital mortality during Omicron-driven waves compared with the prior Delta wave, despite patients admitted during the Omicron wave being at higher risk. Contribution: This study summarises clinical characteristics associated with SARS-CoV-2 variants during the COVID-19 pandemic at a South African tertiary hospital, demonstrating a waning impact of COVID-19 on healthcare services over time despite epidemic waves driven by new variants. Findings suggest the absence of increasing virulence from later variants and protection from population and individual-level immunity.},
author = {Hermans, Lucas E and Booysen, Petro and Boloko, Linda and Adriaanse, Marguerite and de Wet, Timothy J and Lifson, Aimee R and Wadee, Naweed and Papavarnavas, Nectarios and Marais, Gert and Hsiao, Nei-yuan and Rosslee, Michael-Jon and Symons, Gregory and Calligaro, Gregory L and Iranzadeh, Arash and Wilkinson, Robert J and Ntusi, Ntobeko A B and Williamson, Carolyn and Davies, Mary-Ann and Meintjes, Graeme A and Wasserman, Sean},
doi = {10.4102/SAJID.V38I1.550},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Hermans et al. - 2023 - Changing character and waning impact of COVID-19 at a tertiary centre in Cape Town, South Africa.pdf:pdf},
issn = {2313-1810},
journal = {Southern African Journal of Infectious Diseases},
keywords = {19,2,COVID,CoV,Delta,Infectious diseases,OA,Omicron,SARS,bacterial,clinical,clinical characteristics,communicable,diagnosis,epidemiology,fund{\_}ack,fungal,genomics{\_}fund{\_}ack,laboratory,observational study,original,parasitic,treatment,viral},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {dec},
number = {1},
pages = {a550},
pmid = {38223432},
publisher = {AOSIS},
title = {{Changing character and waning impact of COVID-19 at a tertiary centre in Cape Town, South Africa}},
url = {https://sajid.co.za/index.php/sajid/article/view/550/1329 https://sajid.co.za/index.php/sajid/article/view/550/1330 https://sajid.co.za/index.php/sajid/article/view/550/1331 https://sajid.co.za/index.php/sajid/article/view/550},
volume = {38},
year = {2023}
}

Background: The emergence of genetic variants of SARS-CoV-2 was associated with changing epidemiological characteristics throughout coronavirus disease 2019 (COVID-19) pandemic in population-based studies. Individual-level data on the clinical characteristics of infection with different SARS-CoV-2 variants in African countries is less well documented. Objectives: To describe the evolving clinical differences observed with the various SARS-CoV-2 variants of concern and compare the Omicron-driven wave in infections to the previous Delta-driven wave. Method: We performed a retrospective observational cohort study among patients admitted to a South African referral hospital with COVID-19 pneumonia. Patients were stratified by epidemiological wave period, and in a subset, the variants associated with each wave were confirmed by genomic sequencing. Outcomes were analysed by Cox proportional hazard models. Results: We included 1689 patients were included, representing infection waves driven predominantly by ancestral, Beta, Delta and Omicron BA1/BA2 & BA4/BA5 variants. Crude 28-day mortality was 25.8% (34/133) in the Omicron wave period versus 37.1% (138/374) in the Delta wave period (hazard ratio [HR] 0.68 [95% CI 0.47–1.00] p = 0.049); this effect persisted after adjustment for age, gender, HIV status and presence of cardiovascular disease (adjusted HR [aHR] 0.43 [95% CI 0.28–0.67] p \textless 0.001). Hospital-wide SARS-CoV-2 admissions and deaths were highest during the Delta wave period, with a decoupling of SARS-CoV-2 deaths and overall deaths thereafter. Conclusion: There was lower in-hospital mortality during Omicron-driven waves compared with the prior Delta wave, despite patients admitted during the Omicron wave being at higher risk. Contribution: This study summarises clinical characteristics associated with SARS-CoV-2 variants during the COVID-19 pandemic at a South African tertiary hospital, demonstrating a waning impact of COVID-19 on healthcare services over time despite epidemic waves driven by new variants. Findings suggest the absence of increasing virulence from later variants and protection from population and individual-level immunity.

@article{Sisay2023,
abstract = {Ethiopia is the second most populous country in Africa and the sixth most affected by COVID-19 on the continent. Despite having experienced five infection waves, {\textgreater}499,000 cases, and {\~{}}7500 COVID-19-related deaths as of January 2023, there is still no detailed genomic epidemiological report on the introduction and spread of SARS-CoV-2 in Ethiopia. In this study, we reconstructed and elucidated the COVID-19 epidemic dynamics. Specifically, we investigated the introduction, local transmission, ongoing evolution, and spread of SARS-CoV-2 during the first four infection waves using 353 high-quality near-whole genomes sampled in Ethiopia. Our results show that whereas viral introductions seeded the first wave, subsequent waves were seeded by local transmission. The B.1.480 lineage emerged in the first wave and notably remained in circulation even after the emergence of the Alpha variant. The B.1.480 was outcompeted by the Delta variant. Notably, Ethiopia{\&}rsquo;s lack of local sequencing capacity was further limited by sporadic, uneven, and insufficient sampling that limited the incorporation of genomic epidemiology in the epidemic public health response in Ethiopia. These results highlight Ethiopia{\&}rsquo;s role in SARS-CoV-2 dissemination and the urgent need for balanced, near-real-time genomic sequencing.},
author = {Sisay, Abay and Tshiabuila, Derek and van Wyk, Stephanie and Tesfaye, Abraham and Mboowa, Gerald and Oyola, Samuel O and Tesema, Sofonias Kifle and Baxter, Cheryl and Martin, Darren and Lessells, Richard and Tegally, Houriiyah and Moir, Monika and Giandhari, Jennifer and Pillay, Sureshnee and Singh, Lavanya and Ramphal, Yajna and Maharaj, Arisha and Pillay, Yusasha and Maharaj, Akhil and Naidoo, Yeshnee and Ramphal, Upasana and Chabuka, Lucious and Wilkinson, Eduan and de Oliveira, Tulio and Desta, Adey Feleke and San, James E},
doi = {10.3390/GENES14030705},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Sisay et al. - 2023 - Molecular epidemiology and diversity of SARS-CoV-2 in Ethiopia, 2020-2022.pdf:pdf},
isbn = {3070900100},
issn = {2073-4425},
journal = {Genes},
keywords = {19,2,COVID,CoV,Ethiopia,OA,OA{\_}PMC,SARS,fund{\_}not{\_}ack,molecular epidemiology,original,whole genome sequence},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {mar},
number = {3},
pages = {705},
pmid = {36980977},
publisher = {Multidisciplinary Digital Publishing Institute},
title = {{Molecular epidemiology and diversity of SARS-CoV-2 in Ethiopia, 2020-2022}},
url = {https://www.mdpi.com/2073-4425/14/3/705/htm https://www.mdpi.com/2073-4425/14/3/705},
volume = {14},
year = {2023}
}

Ethiopia is the second most populous country in Africa and the sixth most affected by COVID-19 on the continent. Despite having experienced five infection waves, \textgreater499,000 cases, and \ 7500 COVID-19-related deaths as of January 2023, there is still no detailed genomic epidemiological report on the introduction and spread of SARS-CoV-2 in Ethiopia. In this study, we reconstructed and elucidated the COVID-19 epidemic dynamics. Specifically, we investigated the introduction, local transmission, ongoing evolution, and spread of SARS-CoV-2 during the first four infection waves using 353 high-quality near-whole genomes sampled in Ethiopia. Our results show that whereas viral introductions seeded the first wave, subsequent waves were seeded by local transmission. The B.1.480 lineage emerged in the first wave and notably remained in circulation even after the emergence of the Alpha variant. The B.1.480 was outcompeted by the Delta variant. Notably, Ethiopia’s lack of local sequencing capacity was further limited by sporadic, uneven, and insufficient sampling that limited the incorporation of genomic epidemiology in the epidemic public health response in Ethiopia. These results highlight Ethiopia’s role in SARS-CoV-2 dissemination and the urgent need for balanced, near-real-time genomic sequencing.

@article{Zemanay2023,
author = {Zemanay, Widaad and Cox, Helen},
doi = {10.1016/S1473-3099(23)00550-9},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Zemanay, Cox - 2023 - Minimising the threat of bedaquiline-resistant tuberculosis better diagnosis as prevention.pdf:pdf},
issn = {1473-3099},
journal = {The Lancet Infectious Diseases},
keywords = {commentary,fund{\_}not{\_}ack},
mendeley-tags = {commentary,fund{\_}not{\_}ack},
month = {nov},
pages = {10.1016/S1473--3099(23)00550--9},
publisher = {Elsevier},
title = {{Minimising the threat of bedaquiline-resistant tuberculosis: better diagnosis as prevention}},
year = {2023}
}

@article{Sheerin2023,
abstract = {When profiling blood samples by RNA-sequencing (RNA-seq), RNA from haemoglobin (Hgb) can account for up to 70{\%} of the transcriptome. Due to considerations of sequencing depth and power to detect biological variation, Hgb RNA is typically depleted prior to sequencing by hybridisation-based methods; an alternative approach is to deplete reads arising from Hgb RNA bioinformatically. In the present study, we compared the impact of these two approaches on the outcome of differential gene expression analysis performed using RNA-seq data from 58 human tuberculosis (TB) patient or contact whole blood samples–29 globin kit-depleted and 29 matched non-depleted—a subset of which were taken at TB diagnosis and at six months post-TB treatment from the same patient. Bioinformatic depletion of Hgb genes from the non-depleted samples (bioinformatic-depleted) substantially reduced library sizes (median = 57.24{\%}) and fewer long non-coding, micro, small nuclear and small nucleolar RNAs were captured in these libraries. Profiling published TB gene signatures across all samples revealed inferior correlation between kit-depleted and bioinformatic-depleted pairs when the proportion of reads mapping to Hgb genes was higher in the non-depleted sample, particularly at the TB diagnosis time point. A set of putative “globin-fingerprint” genes were identified by directly comparing kit-depleted and bioinformatic-depleted samples at each timepoint. Two TB treatment response signatures were also shown to have decreased differential performance when comparing samples at TB diagnosis to six months post-TB treatment when profiled on the bioinformatic-depleted samples compared with their kit-depleted counterparts. These results demonstrate that failure to deplete Hgb RNA prior to sequencing has a negative impact on the sensitivity to detect disease-relevant gene expression changes even when bioinformatic removal is performed.},
author = {Sheerin, Dylan and Lakay, Francisco and Esmail, Hanif and Kinnear, Craig and Sansom, Bianca and Glanzmann, Brigitte and Wilkinson, Robert J and Ritchie, Matthew E and Coussens, Anna K},
doi = {10.1038/s41598-023-28218-7},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Sheerin et al. - 2023 - Identification and control for the effects of bioinformatic globin depletion on human RNA-seq differential expre.pdf:pdf},
isbn = {0123456789},
issn = {2045-2322},
journal = {Scientific Reports},
keywords = {Data processing,OA,OA{\_}PMC,Quality control,Statistical methods,Tuberculosis,fund{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,original},
month = {feb},
pages = {1859},
pmid = {36725870},
publisher = {Nature Publishing Group},
title = {{Identification and control for the effects of bioinformatic globin depletion on human RNA-seq differential expression analysis}},
url = {https://www.nature.com/articles/s41598-023-28218-7},
volume = {13},
year = {2023}
}

When profiling blood samples by RNA-sequencing (RNA-seq), RNA from haemoglobin (Hgb) can account for up to 70% of the transcriptome. Due to considerations of sequencing depth and power to detect biological variation, Hgb RNA is typically depleted prior to sequencing by hybridisation-based methods; an alternative approach is to deplete reads arising from Hgb RNA bioinformatically. In the present study, we compared the impact of these two approaches on the outcome of differential gene expression analysis performed using RNA-seq data from 58 human tuberculosis (TB) patient or contact whole blood samples–29 globin kit-depleted and 29 matched non-depleted—a subset of which were taken at TB diagnosis and at six months post-TB treatment from the same patient. Bioinformatic depletion of Hgb genes from the non-depleted samples (bioinformatic-depleted) substantially reduced library sizes (median = 57.24%) and fewer long non-coding, micro, small nuclear and small nucleolar RNAs were captured in these libraries. Profiling published TB gene signatures across all samples revealed inferior correlation between kit-depleted and bioinformatic-depleted pairs when the proportion of reads mapping to Hgb genes was higher in the non-depleted sample, particularly at the TB diagnosis time point. A set of putative “globin-fingerprint” genes were identified by directly comparing kit-depleted and bioinformatic-depleted samples at each timepoint. Two TB treatment response signatures were also shown to have decreased differential performance when comparing samples at TB diagnosis to six months post-TB treatment when profiled on the bioinformatic-depleted samples compared with their kit-depleted counterparts. These results demonstrate that failure to deplete Hgb RNA prior to sequencing has a negative impact on the sensitivity to detect disease-relevant gene expression changes even when bioinformatic removal is performed.

@article{Margolin2023,
abstract = {Molecular farming of vaccines has been heralded as a cheap, safe and scalable production platform. In reality, however, differences in the plant biosynthetic machinery, compared to mammalian cells, can complicate the production of viral glycoproteins. Remodelling the secretory pathway presents an opportunity to support key post-translational modifications, and to tailor aspects of glycosylation and glycosylation-directed folding. In this study, we applied an integrated host and glyco-engineering approach, NXS/T Generation™, to produce a SARS-CoV-2 prefusion spike trimer in Nicotiana benthamiana as a model antigen from an emerging virus. The size exclusion-purified protein exhibited a characteristic prefusion structure when viewed by transmission electron microscopy, and this was indistinguishable from the equivalent mammalian cell-produced antigen. The plant-produced protein was decorated with under-processed oligomannose N-glycans and exhibited a site occupancy that was comparable to the equivalent protein produced in mammalian cell culture. Complex-type glycans were almost entirely absent from the plant-derived material, which contrasted against the predominantly mature, complex glycans that were observed on the mammalian cell culture-derived protein. The plant-derived antigen elicited neutralizing antibodies against both the matched Wuhan and heterologous Delta SARS-CoV-2 variants in immunized hamsters, although titres were lower than those induced by the comparator mammalian antigen. Animals vaccinated with the plant-derived antigen exhibited reduced viral loads following challenge, as well as significant protection from SARS-CoV-2 disease as evidenced by reduced lung pathology, lower viral loads and protection from weight loss. Nonetheless, animals immunized with the mammalian cell-culture-derived protein were better protected in this challenge model suggesting that more faithfully reproducing the native glycoprotein structure and associated glycosylation of the antigen may be desirable.},
author = {Margolin, Emmanuel and Sch{\"{a}}fer, Georgia and Allen, Joel D. and Gers, Sophette and Woodward, Jeremy and Sutherland, Andrew D. and Blumenthal, Melissa and Meyers, Ann and Shaw, Megan L. and Preiser, Wolfgang and Strasser, Richard and Crispin, Max and Williamson, Anna-Lise and Rybicki, Edward P. and Chapman, Ros},
doi = {10.3389/FPLS.2023.1146234/BIBTEX},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Margolin et al. - 2023 - A plant-produced SARS-CoV-2 spike protein elicits heterologous immunity in hamsters.pdf:pdf},
issn = {1664462X},
journal = {Frontiers in Plant Science},
keywords = {Glycosylation,Immunogenicity,OA,SARS-CoV-2,Vaccine,challenge,fund{\_}ack,glycoprotein,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {mar},
pages = {734},
publisher = {Frontiers Media SA},
title = {{A plant-produced SARS-CoV-2 spike protein elicits heterologous immunity in hamsters}},
volume = {14},
year = {2023}
}

Molecular farming of vaccines has been heralded as a cheap, safe and scalable production platform. In reality, however, differences in the plant biosynthetic machinery, compared to mammalian cells, can complicate the production of viral glycoproteins. Remodelling the secretory pathway presents an opportunity to support key post-translational modifications, and to tailor aspects of glycosylation and glycosylation-directed folding. In this study, we applied an integrated host and glyco-engineering approach, NXS/T Generation™, to produce a SARS-CoV-2 prefusion spike trimer in Nicotiana benthamiana as a model antigen from an emerging virus. The size exclusion-purified protein exhibited a characteristic prefusion structure when viewed by transmission electron microscopy, and this was indistinguishable from the equivalent mammalian cell-produced antigen. The plant-produced protein was decorated with under-processed oligomannose N-glycans and exhibited a site occupancy that was comparable to the equivalent protein produced in mammalian cell culture. Complex-type glycans were almost entirely absent from the plant-derived material, which contrasted against the predominantly mature, complex glycans that were observed on the mammalian cell culture-derived protein. The plant-derived antigen elicited neutralizing antibodies against both the matched Wuhan and heterologous Delta SARS-CoV-2 variants in immunized hamsters, although titres were lower than those induced by the comparator mammalian antigen. Animals vaccinated with the plant-derived antigen exhibited reduced viral loads following challenge, as well as significant protection from SARS-CoV-2 disease as evidenced by reduced lung pathology, lower viral loads and protection from weight loss. Nonetheless, animals immunized with the mammalian cell-culture-derived protein were better protected in this challenge model suggesting that more faithfully reproducing the native glycoprotein structure and associated glycosylation of the antigen may be desirable.

@article{Krause2023,
abstract = {Neutralizing antibodies strongly correlate with protection for COVID-19 vaccines, but the corresponding memory B cells that form to protect against future infection are relatively understudied. Here we examine the effect of prior SARS-CoV-2 infection on the magnitude and phenotype of the memory B cell response to single dose Johnson and Johnson (Ad26.COV2.S) vaccination in South African health care workers. Participants were either na{\"{i}}ve to SARS-CoV-2 or had been infected before vaccination. SARS-CoV-2-specific memory B-cells expand in response to Ad26.COV2.S and are maintained for the study duration (84 days) in all individuals. However, prior infection is associated with a greater frequency of these cells, a significant reduction in expression of the germinal center chemokine receptor CXCR5, and increased class switching. These B cell features correlated with neutralization and antibody-dependent cytotoxicity (ADCC) activity, and with the frequency of SARS-CoV-2 specific circulating T follicular helper cells (cTfh). Vaccination-induced effective neutralization of the D614G variant in both infected and na{\"{i}}ve participants but boosted neutralizing antibodies against the Beta and Omicron variants only in participants with prior infection. In addition, the SARS-CoV-2 specific CD8+ T cell response correlated with increased memory B cell expression of the lung-homing receptor CXCR3, which was sustained in the previously infected group. Finally, although vaccination achieved equivalent B cell activation regardless of infection history, it was negatively impacted by age. These data show that phenotyping the response to vaccination can provide insight into the impact of prior infection on memory B cell homing, CSM, cTfh, and neutralization activity. These data can provide early signals to inform studies of vaccine boosting, durability, and co-morbidities.},
author = {Krause, Robert G E and Moyo-Gwete, Thandeka and Richardson, Simone I and Makhado, Zanele and Manamela, Nelia P and Hermanus, Tandile and Mkhize, Nonhlanhla N and Keeton, Roanne and Benede, Ntombi and Mennen, Mathilda and Skelem, Sango and Karim, Farina and Khan, Khadija and Riou, Catherine and Ntusi, Ntobeko A B and Goga, Ameena and Gray, Glenda and Hanekom, Willem and Garrett, Nigel and Bekker, Linda-Gail and Groll, Andreas and Sigal, Alex and Moore, Penny L and Burgers, Wendy A and Leslie, Alasdair},
doi = {10.1038/s41541-023-00724-9},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Krause et al. - 2023 - Infection pre-Ad26.COV2.S-vaccination primes greater class switching and reduced CXCR5 expression by SARS-CoV-2-s.pdf:pdf},
issn = {2059-0105},
journal = {npj Vaccines},
keywords = {DNA vaccines,OA,OA{\_}PMC,Viral infection,fund{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,original},
month = {aug},
number = {1},
pages = {119},
pmid = {37573434},
publisher = {Nature Publishing Group},
title = {{Infection pre-Ad26.COV2.S-vaccination primes greater class switching and reduced CXCR5 expression by SARS-CoV-2-specific memory B cells}},
url = {https://www.nature.com/articles/s41541-023-00724-9},
volume = {8},
year = {2023}
}

Neutralizing antibodies strongly correlate with protection for COVID-19 vaccines, but the corresponding memory B cells that form to protect against future infection are relatively understudied. Here we examine the effect of prior SARS-CoV-2 infection on the magnitude and phenotype of the memory B cell response to single dose Johnson and Johnson (Ad26.COV2.S) vaccination in South African health care workers. Participants were either naïve to SARS-CoV-2 or had been infected before vaccination. SARS-CoV-2-specific memory B-cells expand in response to Ad26.COV2.S and are maintained for the study duration (84 days) in all individuals. However, prior infection is associated with a greater frequency of these cells, a significant reduction in expression of the germinal center chemokine receptor CXCR5, and increased class switching. These B cell features correlated with neutralization and antibody-dependent cytotoxicity (ADCC) activity, and with the frequency of SARS-CoV-2 specific circulating T follicular helper cells (cTfh). Vaccination-induced effective neutralization of the D614G variant in both infected and naïve participants but boosted neutralizing antibodies against the Beta and Omicron variants only in participants with prior infection. In addition, the SARS-CoV-2 specific CD8+ T cell response correlated with increased memory B cell expression of the lung-homing receptor CXCR3, which was sustained in the previously infected group. Finally, although vaccination achieved equivalent B cell activation regardless of infection history, it was negatively impacted by age. These data show that phenotyping the response to vaccination can provide insight into the impact of prior infection on memory B cell homing, CSM, cTfh, and neutralization activity. These data can provide early signals to inform studies of vaccine boosting, durability, and co-morbidities.

@article{Riou2023,
abstract = {Efforts to curb the tuberculosis (TB) pandemic remain hindered by a lack of objective measures to quantify disease severity and track treatment success that are valid in both HIV-1-infected and -uninfected TB patients. Ralph et al. [1] developed a promising radiographic scoring system, with baseline scores being predictive of sputum smear conversion at 2 months, but it is reliant on skilled readers and has not been systematically validated in predominantly HIV-infected study populations with varying CD4 counts. Superior to conventional chest radiography, high-resolution computed tomography (HRCT) is a highly sensitive tool to track endobronchial TB disease extent [2]. A high-resolution CT based, semi-automated radiographic score correlates with Mycobacterium tuberculosis (Mtb) bacterial burden, peripheral monocyte count and the phenotypic profile of Mtb-specific CD4 T-cells, irrespective of HIV status {\textless}https://bit.ly/44do4V6{\textgreater} We would like to thank all the study participants as well as Lorraine Brydon and her dedicated team of radiographers at Morton and Partners at Vincent Pallotti Hospital, Cape Town, South Africa.},
author = {Riou, Catherine and du Bruyn, Elsa and Kim, Grace Hyun J and da Costa, Irene and Lee, Jihey and Sher, Alan and Wilkinson, Robert J and Allwood, Brian W and Goldin, Jonathan},
doi = {10.1183/13993003.00600-2023},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Riou et al. - 2023 - Derivation of a high-resolution CT-based, semi-automated radiographic score in tuberculosis and its relationship to.pdf:pdf},
issn = {0903-1936},
journal = {European Respiratory Journal},
keywords = {OA,fund{\_}ack,letter},
mendeley-tags = {OA,fund{\_}ack,letter},
month = {sep},
number = {3},
pages = {2300600},
pmid = {37678952},
publisher = {European Respiratory Society},
title = {{Derivation of a high-resolution CT-based, semi-automated radiographic score in tuberculosis and its relationship to bacillary load and antitubercular therapy}},
url = {https://erj.ersjournals.com/content/62/3/2300600 https://erj.ersjournals.com/content/62/3/2300600.abstract},
volume = {62},
year = {2023}
}

Efforts to curb the tuberculosis (TB) pandemic remain hindered by a lack of objective measures to quantify disease severity and track treatment success that are valid in both HIV-1-infected and -uninfected TB patients. Ralph et al. [1] developed a promising radiographic scoring system, with baseline scores being predictive of sputum smear conversion at 2 months, but it is reliant on skilled readers and has not been systematically validated in predominantly HIV-infected study populations with varying CD4 counts. Superior to conventional chest radiography, high-resolution computed tomography (HRCT) is a highly sensitive tool to track endobronchial TB disease extent [2]. A high-resolution CT based, semi-automated radiographic score correlates with Mycobacterium tuberculosis (Mtb) bacterial burden, peripheral monocyte count and the phenotypic profile of Mtb-specific CD4 T-cells, irrespective of HIV status \textlesshttps://bit.ly/44do4V6\textgreater We would like to thank all the study participants as well as Lorraine Brydon and her dedicated team of radiographers at Morton and Partners at Vincent Pallotti Hospital, Cape Town, South Africa.

@article{DuBruyn2023,
abstract = {Few studies from Africa have described the clinical impact of co-infections on SARS-CoV-2 infection. Here, we investigate the presentation and outcome of SARS-CoV-2 infection in an African setting of high HIV-1 and tuberculosis prevalence by an observational case cohort of SARS-CoV-2 patients. A comparator group of non SARS-CoV-2 participants is included. The study includes 104 adults with SARS-CoV-2 infection of whom 29.8{\%} are HIV-1 co-infected. Two or more co-morbidities are present in 57.7{\%} of participants, including HIV-1 (30{\%}) and active tuberculosis (14{\%}). Amongst patients dually infected by tuberculosis and SARS-CoV-2, clinical features can be typical of either SARS-CoV-2 or tuberculosis: lymphopenia is exacerbated, and some markers of inflammation (D-dimer and ferritin) are further elevated (p {\textless} 0.05). Amongst HIV-1 co-infected participants those with low CD4 percentage strata exhibit reduced total, but not neutralising, anti-SARS-CoV-2 antibodies. SARS-CoV-2 specific CD8 T cell responses are present in 35.8{\%} participants overall but undetectable in combined HIV-1 and tuberculosis. Death occurred in 30/104 (29{\%}) of all COVID-19 patients and in 6/15 (40{\%}) of patients with coincident SARS-CoV-2 and tuberculosis. This shows that in a high incidence setting, tuberculosis is a common co-morbidity in patients admitted to hospital with COVID-19. The immune response to SARS-CoV-2 is adversely affected by co-existent HIV-1 and tuberculosis. Here the authors describe outcomes of SARS-CoV-2 infection in an African setting of high HIV-1 and tuberculosis prevalence. They find that tuberculosis is a common co-morbidity in patients admitted to hospital with COVID-19 and that the immune response to SARS-CoV-2 is adversely affected by co-existent HIV-1 and tuberculosis.},
author = {{Du Bruyn}, Elsa and Stek, Cari and Daroowala, Remi and Said-Hartley, Qonita and Hsiao, Marvin and Schafer, Georgia and Goliath, Rene T and Abrahams, Fatima and Jackson, Amanda and Wasserman, Sean and Allwood, Brian W and Davis, Angharad G. and Lai, Rachel P.-J. and Coussens, Anna K and Wilkinson, Katalin A and de Vries, Jantina and Tiffin, Nicki and Cerrone, Maddalena and Ntusi, Ntobeko A B and HIATUS consortium and Riou, Catherine and Wilkinson, Robert J},
doi = {10.1038/s41467-022-35689-1},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Du Bruyn et al. - 2023 - Effects of tuberculosis andor HIV-1 infection on COVID-19 presentation and immune response in Africa.pdf:pdf},
issn = {2041-1723},
journal = {Nature Communications},
keywords = {Medical research,OA,OA{\_}PMC,Pathogenesis,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {jan},
number = {1},
pages = {188},
pmid = {36635274},
publisher = {Nature Publishing Group},
title = {{Effects of tuberculosis and/or HIV-1 infection on COVID-19 presentation and immune response in Africa}},
url = {https://www.nature.com/articles/s41467-022-35689-1},
volume = {14},
year = {2023}
}

Few studies from Africa have described the clinical impact of co-infections on SARS-CoV-2 infection. Here, we investigate the presentation and outcome of SARS-CoV-2 infection in an African setting of high HIV-1 and tuberculosis prevalence by an observational case cohort of SARS-CoV-2 patients. A comparator group of non SARS-CoV-2 participants is included. The study includes 104 adults with SARS-CoV-2 infection of whom 29.8% are HIV-1 co-infected. Two or more co-morbidities are present in 57.7% of participants, including HIV-1 (30%) and active tuberculosis (14%). Amongst patients dually infected by tuberculosis and SARS-CoV-2, clinical features can be typical of either SARS-CoV-2 or tuberculosis: lymphopenia is exacerbated, and some markers of inflammation (D-dimer and ferritin) are further elevated (p \textless 0.05). Amongst HIV-1 co-infected participants those with low CD4 percentage strata exhibit reduced total, but not neutralising, anti-SARS-CoV-2 antibodies. SARS-CoV-2 specific CD8 T cell responses are present in 35.8% participants overall but undetectable in combined HIV-1 and tuberculosis. Death occurred in 30/104 (29%) of all COVID-19 patients and in 6/15 (40%) of patients with coincident SARS-CoV-2 and tuberculosis. This shows that in a high incidence setting, tuberculosis is a common co-morbidity in patients admitted to hospital with COVID-19. The immune response to SARS-CoV-2 is adversely affected by co-existent HIV-1 and tuberculosis. Here the authors describe outcomes of SARS-CoV-2 infection in an African setting of high HIV-1 and tuberculosis prevalence. They find that tuberculosis is a common co-morbidity in patients admitted to hospital with COVID-19 and that the immune response to SARS-CoV-2 is adversely affected by co-existent HIV-1 and tuberculosis.

@article{Gunther2023,
abstract = {Post-tuberculosis (TB) radiological changes and symptoms can mimic TB. PCR-based diagnostic tests can show positive results, suggesting the presence of Mycobacterium tuberculosis DNA in the absence of viable bacteria. We present a case with two episodes of previous TB. Despite workup including trace to low positive PCR results, after performing sputum analysis, bronchoalveolar lavage analysis, cyto-brush and 18F-FDG PET/CT guided transthoracic biopsy, no culturable mycobacteria were detected. 18F-FDG PET/CT showed a high metabolic activity of the biopsied lesions. More accurate strategies and tools in patients with previous TB and positive PCR results are required to make appropriate treatment decisions.},
author = {G{\"{u}}nther, Gunar and {Abu- Hussain}, Nebal and Keller, Peter M and Guler, Reto and Mukasa, Sandra L and Wolmarans, Karen and Thienemann, Friedrich},
doi = {10.1016/J.RMCR.2023.101932},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/G{\"{u}}nther et al. - 2023 - To treat or not to treat tuberculosis –clinical decision making in patients with previous pulmonary tuberculosis.pdf:pdf},
issn = {2213-0071},
journal = {Respiratory Medicine Case Reports},
keywords = {18F-FDG PET/CT,False-positive,OA,OA{\_}PMC,Tuberculosis,fund{\_}not{\_}ack,original,recurrent},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {jan},
pages = {101932},
pmid = {38025249},
publisher = {Elsevier},
title = {{To treat or not to treat tuberculosis –clinical decision making in patients with previous pulmonary tuberculosis using 18F-FDG PET/CT}},
volume = {46},
year = {2023}
}

Post-tuberculosis (TB) radiological changes and symptoms can mimic TB. PCR-based diagnostic tests can show positive results, suggesting the presence of Mycobacterium tuberculosis DNA in the absence of viable bacteria. We present a case with two episodes of previous TB. Despite workup including trace to low positive PCR results, after performing sputum analysis, bronchoalveolar lavage analysis, cyto-brush and 18F-FDG PET/CT guided transthoracic biopsy, no culturable mycobacteria were detected. 18F-FDG PET/CT showed a high metabolic activity of the biopsied lesions. More accurate strategies and tools in patients with previous TB and positive PCR results are required to make appropriate treatment decisions.

@article{Maartens2023,
author = {Maartens, Gary and Griesel, Rulan},
doi = {10.1016/S2352-3018(23)00230-8},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Maartens, Griesel - 2023 - Dolutegravir dosing with rifampicin – Authors' reply.pdf:pdf},
issn = {2352-3018},
journal = {The Lancet HIV},
keywords = {fund{\_}not{\_}ack,letter},
mendeley-tags = {fund{\_}not{\_}ack,letter},
month = {sep},
pages = {10.1016/ S2352--3018(23)00230--8 1},
pmid = {37717590},
publisher = {Elsevier},
title = {{Dolutegravir dosing with rifampicin – Authors' reply}},
url = {http://www.thelancet.com/article/S2352301823002308/fulltext http://www.thelancet.com/article/S2352301823002308/abstract https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(23)00230-8/abstract},
year = {2023}
}

@article{DuBruyn2023a,
abstract = {In the published article, there was an error in the author list, and author Maddalena Cerrone was erroneously excluded. The corrected author list appears above. The author has also been included in the Author Contributions section shown below. Author contributions CR, EB, DB, KM-B, MN, BM and RW designed the study. PH, MC, AJ and EB recruited the study participants. SR, EB, MC, and CR performed the whole blood and PCF assay. EB and CR performed the flow experiments. CR analysed and interpreted the data. ASe and CLA provided critical reagents. RW, ASh and CR obtained funding to support the project. CR and EB wrote the manuscript with all authors contributing to providing critical feedback. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.},
author = {{Du Bruyn}, Elsa and Ruzive, Sheena and Howlett, Patrick and Cerrone, Maddalena and Jacobs, Ashley J. and {Lindestam Arlehamn}, Cecilia S. and Sette, Alessandro and Sher, Alan and Mayer-Barber, Katrin D. and Barber, Daniel L. and Mayosi, Bongani and Ntsekhe, Mpiko and Wilkinson, Robert J. and Riou, Catherine},
doi = {10.3389/FIMMU.2023.1141704},
issn = {1664-3224},
journal = {Frontiers in Immunology},
keywords = {CD4 response,OA,Pericardial fluid,Pericardial tuberculosis,site of disease,treatment response,whole blood},
mendeley-tags = {OA},
month = {feb},
pages = {217},
publisher = {Frontiers},
title = {{Corrigendum: Comparison of the frequency and phenotypic profile of \textit{Mycobacterium tuberculosis}-specific CD4 T cells between the site of disease and blood in pericardial tuberculosis}},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2023.1141704/full},
volume = {14},
year = {2023}
}

In the published article, there was an error in the author list, and author Maddalena Cerrone was erroneously excluded. The corrected author list appears above. The author has also been included in the Author Contributions section shown below. Author contributions CR, EB, DB, KM-B, MN, BM and RW designed the study. PH, MC, AJ and EB recruited the study participants. SR, EB, MC, and CR performed the whole blood and PCF assay. EB and CR performed the flow experiments. CR analysed and interpreted the data. ASe and CLA provided critical reagents. RW, ASh and CR obtained funding to support the project. CR and EB wrote the manuscript with all authors contributing to providing critical feedback. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.

@article{Middelkoop2023a,
abstract = {Objective To determine whether weekly oral vitamin D supplementation influences growth, body composition, pubertal development or spirometric outcomes in South African schoolchildren. Design Phase 3 double-blind randomised placebo-controlled trial ([clinicaltrials.gov][1] registration no. [NCT02880982][2]). Setting Socio-economically disadvantaged peri-urban district of Cape Town, South Africa Participants 1682 children of Black African ancestry attending government primary schools and aged 6-11 years at baseline. Interventions Oral vitamin D3 (10,000 IU/week) vs. placebo for 3 years Main outcome measures height-for-age and body mass index-for-age, measured in all participants); Tanner scores for pubertal development, spirometric lung volumes and body composition, measured in a subset of 450 children who additionally took part in a nested sub-study. Results Mean serum 25-hydroxyvitamin D3 concentration at 3-year follow-up was higher among children randomised to receive vitamin D vs. placebo (104.3 vs. 64.7 nmol/L, respectively; mean difference [MD] 39.7 nmol/L, 95{\%} CI 37.6 to 41.9 nmol/L). No statistically significant differences in height-for-age z-score (adjusted MD [aMD] −0.08, 95{\%} CI −0.19 to 0.03) or body mass index-for-age z-score (aMD −0.04, 95{\%} CI −0.16 to 0.07) were seen between vitamin D vs. placebo groups at follow-up. Among sub-study participants, allocation to vitamin D vs. placebo did not influence pubertal development scores, {\%} predicted forced expiratory volume in 1 second (FEV1), {\%} predicted forced vital capacity (FVC), {\%} predicted FEV1/FVC, fat mass or fat-free mass. Conclusions Weekly oral administration of 10,000 IU vitamin D3 boosted vitamin D status but did not influence growth, body composition, pubertal development or spirometric outcomes in South African schoolchildren. What is already known on this topic? What this study adds How this study might affect research, practice or policy {\#}{\#}{\#} Competing Interest Statement ARM declares receipt of funding in the last 36 months to support vitamin D research from the following companies who manufacture or sell vitamin D supplements: Pharma Nord Ltd, DSM Nutritional Products Ltd, Thornton {\&} Ross Ltd and Hyphens Pharma Ltd. ARM also declares receipt of vitamin D capsules for clinical trial use from Pharma Nord Ltd, Synergy Biologics Ltd and Cytoplan Ltd; support for attending meetings from Pharma Nord Ltd and Abiogen Pharma Ltd; receipt of consultancy fees from DSM Nutritional Products Ltd and Qiagen Ltd; receipt of a speaker fee from the Linus Pauling Institute; participation on Data and Safety Monitoring Boards for the VITALITY trial (Vitamin D for Adolescents with HIV to reduce musculoskeletal morbidity and immunopathology, Pan African Clinical Trials Registry ref PACTR20200989766029) and the Trial of Vitamin D and Zinc Supplementation for Improving Treatment Outcomes Among COVID-19 Patients in India (ClinicalTrials.gov ref [NCT04641195][3]); and unpaid work as a Programme Committee member for the Vitamin D Workshop. All other authors declare that they have no competing interests. {\#}{\#}{\#} Clinical Trial NCT02880982 {\#}{\#}{\#} Funding Statement This study was funded by the UK Medical Research Council (refs MR/R023050/1 and MR/M026639/1, both awarded to ARM). {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The trial was approved by the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee (Ref: 796/2015) and the London School of Hygiene and Tropical Medicine Observational/Interventions Research Ethics Committee (Ref: 7450-2). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Anonymised data may be requested from the corresponding author to be shared subject to terms of research ethics committee approval. [1]: http://clinicaltrials.gov [2]: /lookup/external-ref?link{\_}type=CLINTRIALGOV{\&}access{\_}num=NCT02880982{\&}atom={\%}2Fmedrxiv{\%}2Fearly{\%}2F2023{\%}2F11{\%}2F30{\%}2F2023.11.29.23299226.atom [3]: /lookup/external-ref?link{\_}type=CLINTRIALGOV{\&}access{\_}num=NCT04641195{\&}atom={\%}2Fmedrxiv{\%}2Fearly{\%}2F2023{\%}2F11{\%}2F30{\%}2F2023.11.29.23299226.atom},
author = {Middelkoop, Keren and Micklesfield, Lisa K and Stewart, Justine and Walker, Neil and Jolliffe, David A and Mendham, Amy E and Coussens, Anna K and Nuttall, James and Tang, Jonathan C Y and Fraser, William D and Momand, Waheedullah and Cooper, Cyrus and Harvey, Nicholas C and Wilkinson, Robert J and Bekker, Linda-Gail and Martineau, Adrian R},
doi = {10.1101/2023.11.29.23299226},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Middelkoop et al. - 2023 - Influence of vitamin D supplementation on growth, body composition, pubertal development and spirometry in So.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {nov},
pages = {2023.11.29.23299226},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Influence of vitamin D supplementation on growth, body composition, pubertal development and spirometry in South African schoolchildren: a randomised controlled trial (ViDiKids)}},
url = {https://www.medrxiv.org/content/10.1101/2023.11.29.23299226v1 https://www.medrxiv.org/content/10.1101/2023.11.29.23299226v1.abstract},
year = {2023}
}

Objective To determine whether weekly oral vitamin D supplementation influences growth, body composition, pubertal development or spirometric outcomes in South African schoolchildren. Design Phase 3 double-blind randomised placebo-controlled trial ([clinicaltrials.gov][1] registration no. [NCT02880982][2]). Setting Socio-economically disadvantaged peri-urban district of Cape Town, South Africa Participants 1682 children of Black African ancestry attending government primary schools and aged 6-11 years at baseline. Interventions Oral vitamin D3 (10,000 IU/week) vs. placebo for 3 years Main outcome measures height-for-age and body mass index-for-age, measured in all participants); Tanner scores for pubertal development, spirometric lung volumes and body composition, measured in a subset of 450 children who additionally took part in a nested sub-study. Results Mean serum 25-hydroxyvitamin D3 concentration at 3-year follow-up was higher among children randomised to receive vitamin D vs. placebo (104.3 vs. 64.7 nmol/L, respectively; mean difference [MD] 39.7 nmol/L, 95% CI 37.6 to 41.9 nmol/L). No statistically significant differences in height-for-age z-score (adjusted MD [aMD] −0.08, 95% CI −0.19 to 0.03) or body mass index-for-age z-score (aMD −0.04, 95% CI −0.16 to 0.07) were seen between vitamin D vs. placebo groups at follow-up. Among sub-study participants, allocation to vitamin D vs. placebo did not influence pubertal development scores, % predicted forced expiratory volume in 1 second (FEV1), % predicted forced vital capacity (FVC), % predicted FEV1/FVC, fat mass or fat-free mass. Conclusions Weekly oral administration of 10,000 IU vitamin D3 boosted vitamin D status but did not influence growth, body composition, pubertal development or spirometric outcomes in South African schoolchildren. What is already known on this topic? What this study adds How this study might affect research, practice or policy ### Competing Interest Statement ARM declares receipt of funding in the last 36 months to support vitamin D research from the following companies who manufacture or sell vitamin D supplements: Pharma Nord Ltd, DSM Nutritional Products Ltd, Thornton & Ross Ltd and Hyphens Pharma Ltd. ARM also declares receipt of vitamin D capsules for clinical trial use from Pharma Nord Ltd, Synergy Biologics Ltd and Cytoplan Ltd; support for attending meetings from Pharma Nord Ltd and Abiogen Pharma Ltd; receipt of consultancy fees from DSM Nutritional Products Ltd and Qiagen Ltd; receipt of a speaker fee from the Linus Pauling Institute; participation on Data and Safety Monitoring Boards for the VITALITY trial (Vitamin D for Adolescents with HIV to reduce musculoskeletal morbidity and immunopathology, Pan African Clinical Trials Registry ref PACTR20200989766029) and the Trial of Vitamin D and Zinc Supplementation for Improving Treatment Outcomes Among COVID-19 Patients in India (ClinicalTrials.gov ref [NCT04641195][3]); and unpaid work as a Programme Committee member for the Vitamin D Workshop. All other authors declare that they have no competing interests. ### Clinical Trial NCT02880982 ### Funding Statement This study was funded by the UK Medical Research Council (refs MR/R023050/1 and MR/M026639/1, both awarded to ARM). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The trial was approved by the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee (Ref: 796/2015) and the London School of Hygiene and Tropical Medicine Observational/Interventions Research Ethics Committee (Ref: 7450-2). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Anonymised data may be requested from the corresponding author to be shared subject to terms of research ethics committee approval. [1]: http://clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02880982&atom=%2Fmedrxiv%2Fearly%2F2023%2F11%2F30%2F2023.11.29.23299226.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04641195&atom=%2Fmedrxiv%2Fearly%2F2023%2F11%2F30%2F2023.11.29.23299226.atom

@article{Hoft2023,
abstract = {This review examines the intersection of the HIV and SARS-CoV-2 pandemics. People with HIV (PWH) are a heterogeneous group that differ in their degree of immune suppression, immune reconstitution, and viral control. While COVID-19 in those with well-controlled HIV infection poses no greater risk than that for HIV-uninfected individuals, people with advanced HIV disease are more vulnerable to poor COVID-19 outcomes. COVID-19 vaccines are effective and well tolerated in the majority of PWH, though reduced vaccine efficacy, breakthrough infections and faster waning of vaccine effectiveness have been demonstrated in PWH. This is likely a result of suboptimal humoral and cellular immune responses after vaccination. People with advanced HIV may also experience prolonged infection that may give rise to new epidemiologically significant variants, but initiation or resumption of antiretroviral therapy (ART) can effectively clear persistent infection. COVID-19 vaccine guidelines reflect these increased risks and recommend prioritization for vaccination and additional booster doses for PWH who are moderately to severely immunocompromised. We recommend continued research and monitoring of PWH with SARS-CoV-2 infection, especially in areas with a high HIV burden.},
author = {H{\"{o}}ft, Maxine A and Burgers, Wendy A and Riou, Catherine},
doi = {10.1038/s41423-023-01087-w},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/H{\"{o}}ft, Burgers, Riou - 2023 - The immune response to SARS-CoV-2 in people with HIV.pdf:pdf},
issn = {2042-0226},
journal = {Cellular {\&} Molecular Immunology},
keywords = {Cellular immunity,Humoral immunity,OA,Prolonged infection,SARS-CoV-2,Vaccine efficacy,Viral infection,fund{\_}not{\_}ack,review},
mendeley-tags = {OA,fund{\_}not{\_}ack,review},
month = {oct},
pages = {1--13},
pmid = {37821620},
publisher = {Nature Publishing Group},
title = {{The immune response to SARS-CoV-2 in people with HIV}},
url = {https://www.nature.com/articles/s41423-023-01087-w},
year = {2023}
}

This review examines the intersection of the HIV and SARS-CoV-2 pandemics. People with HIV (PWH) are a heterogeneous group that differ in their degree of immune suppression, immune reconstitution, and viral control. While COVID-19 in those with well-controlled HIV infection poses no greater risk than that for HIV-uninfected individuals, people with advanced HIV disease are more vulnerable to poor COVID-19 outcomes. COVID-19 vaccines are effective and well tolerated in the majority of PWH, though reduced vaccine efficacy, breakthrough infections and faster waning of vaccine effectiveness have been demonstrated in PWH. This is likely a result of suboptimal humoral and cellular immune responses after vaccination. People with advanced HIV may also experience prolonged infection that may give rise to new epidemiologically significant variants, but initiation or resumption of antiretroviral therapy (ART) can effectively clear persistent infection. COVID-19 vaccine guidelines reflect these increased risks and recommend prioritization for vaccination and additional booster doses for PWH who are moderately to severely immunocompromised. We recommend continued research and monitoring of PWH with SARS-CoV-2 infection, especially in areas with a high HIV burden.

@article{Benede2023,
abstract = {SUMMARY SARS-CoV-2 infection in children typically results in asymptomatic or mild disease. There is a paucity of studies on antiviral immunity in African children. We investigated SARS-CoV-2-specific T cell responses in 71 unvaccinated asymptomatic South African children who were seropositive or seronegative for SARS-CoV-2. SARS-CoV-2-specific CD4+ T cell responses were detectable in 83{\%} of seropositive and 60{\%} of seronegative children. Although the magnitude of the CD4+ T cell response did not differ significantly between the two groups, their functional profiles were distinct, with SARS-CoV-2 seropositive children exhibiting a higher proportion of polyfunctional T cells compared to their seronegative counterparts. The frequency of SARS-CoV-2-specific CD4+ T cells in seronegative children was associated with the endemic human coronavirus (HCoV) HKU1 IgG response. Overall, the presence of SARS-CoV-2-responding T cells in seronegative children may result from cross-reactivity to endemic coronaviruses and could contribute to the relative protection from disease observed in SARS-CoV-2-infected children. Key words: SARS-CoV-2, Children, IgG responses, T cell response, Polyfunctional profile, endemic HCoV {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Funding Statement This work is supported by the South African Medical Research Council (SA-MRC) with funds received from the South African Department of Science and Innovation (DSI), (grants 96825, SHIPNCD 76756, and DST/CON 0250/2012), the Poliomyelitis Research Foundation (21/65) and the Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), which is supported by core funding from the Wellcome Trust (203135/Z/16/Z and 222754). SA-MRC to R.S.K. UK NIHR GECO award (GEC111 to H.J.Z), the Bill {\&} Melinda Gates Foundation, USA (grants OPP1017641, OPP1017579 to H.J.Z). P.L.M. is supported by the South African Research Chairs Initiative of the Department of Science and Innovation and National Research Foundation of South Africa (NRF 9834), the SA Medical Research Council SHIP programme and the Centre for the AIDS Programme of Research in South Africa (CAPRISA). C.R. is supported by the EDCTP2 program of the European Unions Horizon 2020 programme (TMA2017SF-1951-TB-SPEC), the Wellcome Trust (226137/Z/22/Z) and the National Institutes of Health (NIH) (R21AI148027). W.A.B. is supported by the EDCTP2 program of the European Unions Horizon 2020 programme (TMA2016SF-1535-CaTCH-22), the Wellcome Trust (226137/Z/22/Z) and the EU-Africa Concerted Action on SARS-CoV-2 Virus Variant and Immunological Surveillance (COVICIS), funded through the EUs Horizon Europe Research and Innovation Programme (101046041). H.J.Z is supported by the SA-MRC. L.J.Z. is funded by the South African Medical Research Council (SAMRC) through its Division of Research Capacity Development under the Mid-Career Scientist Programme from funding received from the South African National Treasury. The content hereof is the sole responsibility of the authors and do not necessarily represent the official views of the SAMRC. L.J.Z also receives support from the National Research Foundation of South Africa (NRFSA), as well as the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement, via the African Research Leader Award (MR/S005242/1). {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The University of Cape Town Human Ethics Committee gave ethical approval for this work (HREC 599/2020, 401/2009, 190/2020 and 209/2020). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors},
author = {Benede, Ntombi S.B. and Tincho, Marius B and Walters, Avril and Subbiah, Vennesa and Ngomti, Amkele and Baguma, Richard and Butters, Claire and Mennen, Mathilda and Skelem, Sango and Adriaanse, Marguerite and van Graan, Strauss and Balla, Sashkia R. and Moyo-Gwete, Thandeka and Moore, Penny L. and Botha, Maresa and Workman, Lesley and Zar, Heather J. and Ntusi, Ntobeko A. B. and Z{\"{u}}hlke, Liesl and Webb, Kate and Riou, Catherine and Burgers, Wendy A and Keeton, Roanne S},
doi = {10.1101/2023.05.16.23290059},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Benede et al. - 2023 - Distinct T cell functional profiles in SARS-CoV-2 seropositive and seronegative children associated with endemic.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {may},
pages = {2023.05.16.23290059},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Distinct T cell functional profiles in SARS-CoV-2 seropositive and seronegative children associated with endemic human coronavirus cross-reactivity}},
url = {https://www.medrxiv.org/content/10.1101/2023.05.16.23290059v1 https://www.medrxiv.org/content/10.1101/2023.05.16.23290059v1.abstract},
year = {2023}
}

SUMMARY SARS-CoV-2 infection in children typically results in asymptomatic or mild disease. There is a paucity of studies on antiviral immunity in African children. We investigated SARS-CoV-2-specific T cell responses in 71 unvaccinated asymptomatic South African children who were seropositive or seronegative for SARS-CoV-2. SARS-CoV-2-specific CD4+ T cell responses were detectable in 83% of seropositive and 60% of seronegative children. Although the magnitude of the CD4+ T cell response did not differ significantly between the two groups, their functional profiles were distinct, with SARS-CoV-2 seropositive children exhibiting a higher proportion of polyfunctional T cells compared to their seronegative counterparts. The frequency of SARS-CoV-2-specific CD4+ T cells in seronegative children was associated with the endemic human coronavirus (HCoV) HKU1 IgG response. Overall, the presence of SARS-CoV-2-responding T cells in seronegative children may result from cross-reactivity to endemic coronaviruses and could contribute to the relative protection from disease observed in SARS-CoV-2-infected children. Key words: SARS-CoV-2, Children, IgG responses, T cell response, Polyfunctional profile, endemic HCoV ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work is supported by the South African Medical Research Council (SA-MRC) with funds received from the South African Department of Science and Innovation (DSI), (grants 96825, SHIPNCD 76756, and DST/CON 0250/2012), the Poliomyelitis Research Foundation (21/65) and the Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), which is supported by core funding from the Wellcome Trust (203135/Z/16/Z and 222754). SA-MRC to R.S.K. UK NIHR GECO award (GEC111 to H.J.Z), the Bill & Melinda Gates Foundation, USA (grants OPP1017641, OPP1017579 to H.J.Z). P.L.M. is supported by the South African Research Chairs Initiative of the Department of Science and Innovation and National Research Foundation of South Africa (NRF 9834), the SA Medical Research Council SHIP programme and the Centre for the AIDS Programme of Research in South Africa (CAPRISA). C.R. is supported by the EDCTP2 program of the European Unions Horizon 2020 programme (TMA2017SF-1951-TB-SPEC), the Wellcome Trust (226137/Z/22/Z) and the National Institutes of Health (NIH) (R21AI148027). W.A.B. is supported by the EDCTP2 program of the European Unions Horizon 2020 programme (TMA2016SF-1535-CaTCH-22), the Wellcome Trust (226137/Z/22/Z) and the EU-Africa Concerted Action on SARS-CoV-2 Virus Variant and Immunological Surveillance (COVICIS), funded through the EUs Horizon Europe Research and Innovation Programme (101046041). H.J.Z is supported by the SA-MRC. L.J.Z. is funded by the South African Medical Research Council (SAMRC) through its Division of Research Capacity Development under the Mid-Career Scientist Programme from funding received from the South African National Treasury. The content hereof is the sole responsibility of the authors and do not necessarily represent the official views of the SAMRC. L.J.Z also receives support from the National Research Foundation of South Africa (NRFSA), as well as the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement, via the African Research Leader Award (MR/S005242/1). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The University of Cape Town Human Ethics Committee gave ethical approval for this work (HREC 599/2020, 401/2009, 190/2020 and 209/2020). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

@article{Gray2023,
abstract = {INTRODUCTION People with radiographic evidence for pulmonary tuberculosis (TB), but negative sputum cultures, have increased risk of developing culture-positive TB. Recent expansion of X-ray screening is leading to increased identification of this group. We set out to synthesise the evidence for treatment to prevent progression to culture-positive disease. METHODS We searched for prospective trials evaluating the efficacy of TB regimens against placebo, observation, or alternative regimens, for the treatment of adults and children with radiographic evidence of TB but culture-negative respiratory samples. Databases were searched up to 18 Oct 2022. Study quality was assessed using ROB 2.0 and ROBINS-I. The primary outcome was progression to culture-positive TB. Meta-analysis with a random effects model was conducted to estimate pooled efficacy. RESULTS We included 13 trials (32,568 individuals) conducted between 1955 and 2018. Radiographic and bacteriological criteria for inclusion varied. 19.1{\%} to 57.9{\%} of participants with active x-ray changes and no treatment progressed to culture-positive disease. Progression was reduced with any treatment (6 studies, risk ratio [RR] 0.27, 95{\%}CI 0.13-0.56); multi-drug TB treatment (RR 0.11, 95{\%}CI 0.05 - 0.23), was significantly more effective than isoniazid treatment (RR 0.63, 95{\%}CI 0.35-1.13) (p=0.0002). DISCUSSION Multi-drug regimens were associated with significantly reduced risk of progression to TB disease for individuals with radiographically apparent, but culture-negative TB. However, most studies were old, conducted prior to the HIV epidemic and with outdated regimens. New clinical trials are required to identify the optimal treatment approach. STUDY REGISTRATION CRD42021248486Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was funded by an MRC grant (MR/V00476X/1) awarded to HE. HE, ER and MQ are partially supported through MRC unit grants (MC UU 00004/04, MC UU 00004/06, MC UU 00004/07, and MC UU 00004/09). RMGJH and ASR were funded by the European Research Council (Action number 757699). ASR was also supported by the UK FCDO (Leaving no-one behind: transforming gendered pathways to health for TB). This research has been partially funded by UK aid from the UK government (to ASR), however the views expressed do not necessarily reflect the UK governments official policies. SVK is affiliated with FIND. FIND conducts multiple clinical research projects to evaluate new diagnostic tests against published target product profiles that have been defined through consensus processes. These include studies of diagnostic products developed by private sector companies who provide access to know-how, equipment/reagents, and may contribute through unrestricted donations according to FIND policies and in line with guidance from the organisations external scientific advisory council. PM is funded by Wellcome (206575/Z/17/Z).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesI confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors},
author = {Gray, Adam Thorburn and Macpherson, Liana and Carlin, Ffion and Sossen, Bianca and Richards, Alexandra and Kik, Sandra Vivian and Houben, Rein M G J and MacPherson, Peter and Quartagno, Matteo and Rogozinska, Ewelina and Esmail, Hanif},
doi = {10.1101/2023.01.27.23285085},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Gray et al. - 2023 - Treatment for radiographically active, sputum culture-negative pulmonary tuberculosis a systematic review and meta-.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}not{\_}ack,review},
mendeley-tags = {OA,fund{\_}not{\_}ack,review},
month = {jan},
pages = {2023.01.27.23285085},
title = {{Treatment for radiographically active, sputum culture-negative pulmonary tuberculosis: a systematic review and meta-analysis}},
url = {http://medrxiv.org/content/early/2023/01/28/2023.01.27.23285085.abstract},
year = {2023}
}

INTRODUCTION People with radiographic evidence for pulmonary tuberculosis (TB), but negative sputum cultures, have increased risk of developing culture-positive TB. Recent expansion of X-ray screening is leading to increased identification of this group. We set out to synthesise the evidence for treatment to prevent progression to culture-positive disease. METHODS We searched for prospective trials evaluating the efficacy of TB regimens against placebo, observation, or alternative regimens, for the treatment of adults and children with radiographic evidence of TB but culture-negative respiratory samples. Databases were searched up to 18 Oct 2022. Study quality was assessed using ROB 2.0 and ROBINS-I. The primary outcome was progression to culture-positive TB. Meta-analysis with a random effects model was conducted to estimate pooled efficacy. RESULTS We included 13 trials (32,568 individuals) conducted between 1955 and 2018. Radiographic and bacteriological criteria for inclusion varied. 19.1% to 57.9% of participants with active x-ray changes and no treatment progressed to culture-positive disease. Progression was reduced with any treatment (6 studies, risk ratio [RR] 0.27, 95%CI 0.13-0.56); multi-drug TB treatment (RR 0.11, 95%CI 0.05 - 0.23), was significantly more effective than isoniazid treatment (RR 0.63, 95%CI 0.35-1.13) (p=0.0002). DISCUSSION Multi-drug regimens were associated with significantly reduced risk of progression to TB disease for individuals with radiographically apparent, but culture-negative TB. However, most studies were old, conducted prior to the HIV epidemic and with outdated regimens. New clinical trials are required to identify the optimal treatment approach. STUDY REGISTRATION CRD42021248486Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis work was funded by an MRC grant (MR/V00476X/1) awarded to HE. HE, ER and MQ are partially supported through MRC unit grants (MC UU 00004/04, MC UU 00004/06, MC UU 00004/07, and MC UU 00004/09). RMGJH and ASR were funded by the European Research Council (Action number 757699). ASR was also supported by the UK FCDO (Leaving no-one behind: transforming gendered pathways to health for TB). This research has been partially funded by UK aid from the UK government (to ASR), however the views expressed do not necessarily reflect the UK governments official policies. SVK is affiliated with FIND. FIND conducts multiple clinical research projects to evaluate new diagnostic tests against published target product profiles that have been defined through consensus processes. These include studies of diagnostic products developed by private sector companies who provide access to know-how, equipment/reagents, and may contribute through unrestricted donations according to FIND policies and in line with guidance from the organisations external scientific advisory council. PM is funded by Wellcome (206575/Z/17/Z).Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesI confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors

@article{Allwood2023,
abstract = {Background. Pulmonary hypertension (PH) after tuberculosis (TB) is typically not included among the chronic lung diseases causing PH (group 3 PH), with few data available to support the inclusion. Objectives. To determine the prevalence of PH in an adult population completing TB treatment. Methods. This single-centre, cross-sectional study only included patients with their first documented episode of TB, and who were in the second half of treatment or had recently completed treatment. PH was assessed using transthoracic echocardiography. Questionnaires were also completed and spirometry and a 6-minute walk test were performed. Results. One hundred patients were enrolled, with a mean age of 37.1 years, of whom 58{\%} were male and 46{\%} HIV positive. The median time since initiation of TB treatment was 22 weeks. The mean (standard deviation) measured right ventricular systolic pressure (RVSP) was 23.6 (6.24) mmHg. One participant had PH (defined as RVSP ≥40 mmHg; 95{\%} confidence interval (CI) 0.0 - 3.0) and a further 3 had possible PH (RVSP ≥35 and {\textless}40 mmHg), with a combined PH prevalence of 4{\%} (95{\%} CI 0.2 - 7.8). Airflow obstruction on spirometry was found in 13.3{\%} of 98 patients, while 25.5{\%} had a reduced forced vital capacity. There was no association between RVSP or PH/possible PH and sex, age, HIV status, systemic hypertension, spirometry measurements or 6-minute walking distance. Smoking status was associated with RVSP, but not with the presence of PH/possible PH. Conclusion. There was a significant prevalence of PH in this preliminary study of predominantly young patients completing treatment for a first episode of TB. Larger and more detailed studies are warranted.},
author = {Allwood, B W and Manie, S and Stolbrink, M and Hunter, L and Mathee, S and Meintjes, G and Amosun, S L and Pecoraro, A and Walzl, G and Irusen, E},
doi = {10.7196/AJTCCM.2023.V29I3.676},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Allwood et al. - 2023 - Pulmonary hypertension in adults completing tuberculosis treatment.pdf:pdf},
issn = {2617-0205},
journal = {African Journal of Thoracic and Critical Care Medicine},
keywords = {OA,OA{\_}PMC,Post,Pulmonary hypertension,cor pulmonale,echocardiography,fund{\_}not{\_}ack,original,tuberculosis},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {sep},
number = {3},
pages = {122--126},
pmid = {37970573},
title = {{Pulmonary hypertension in adults completing tuberculosis treatment}},
url = {https://samajournals.co.za/index.php/ajtccm/article/view/676},
volume = {29},
year = {2023}
}

Background. Pulmonary hypertension (PH) after tuberculosis (TB) is typically not included among the chronic lung diseases causing PH (group 3 PH), with few data available to support the inclusion. Objectives. To determine the prevalence of PH in an adult population completing TB treatment. Methods. This single-centre, cross-sectional study only included patients with their first documented episode of TB, and who were in the second half of treatment or had recently completed treatment. PH was assessed using transthoracic echocardiography. Questionnaires were also completed and spirometry and a 6-minute walk test were performed. Results. One hundred patients were enrolled, with a mean age of 37.1 years, of whom 58% were male and 46% HIV positive. The median time since initiation of TB treatment was 22 weeks. The mean (standard deviation) measured right ventricular systolic pressure (RVSP) was 23.6 (6.24) mmHg. One participant had PH (defined as RVSP ≥40 mmHg; 95% confidence interval (CI) 0.0 - 3.0) and a further 3 had possible PH (RVSP ≥35 and \textless40 mmHg), with a combined PH prevalence of 4% (95% CI 0.2 - 7.8). Airflow obstruction on spirometry was found in 13.3% of 98 patients, while 25.5% had a reduced forced vital capacity. There was no association between RVSP or PH/possible PH and sex, age, HIV status, systemic hypertension, spirometry measurements or 6-minute walking distance. Smoking status was associated with RVSP, but not with the presence of PH/possible PH. Conclusion. There was a significant prevalence of PH in this preliminary study of predominantly young patients completing treatment for a first episode of TB. Larger and more detailed studies are warranted.

@article{Gumedze2023,
abstract = {Background. Little is known about the impact of HIV infection on clinical presentation, complications, and morbid pericarditis-relatedoutcomes of tuberculous pericarditis and its predictors.Objective. To assess the impact of HIV infection on presentation and outcomes in the multicountry Investigation of the Management of Pericarditis (IMPI) randomised controlled trial of immunotherapy in tuberculous pericarditis conducted in sub-Saharan Africa.Methods. We compared clinical features and outcomes of 1 370 adult patients treated for tuberculous pericarditis (939 and 431 HIVinfected and uninfected, respectively) enrolled in the IMPI trial. Cox proportional hazards models were used to determine independent predictors of outcomes of HIV-associated tuberculous pericarditis.Results. At presentation, HIV-infected (v. uninfected) patients were younger (median age 34.0 years v. 47.7 years), had lower body mass (mean weight 56 kg v. 60 kg), higher prevalence of tachycardia (58.5{\%} v. 51.9{\%}), hypotension (9.4{\%} v. 3.9{\%}), anaemia (65.9{\%} v. 26.8{\%}), and radiographic pulmonary infiltrates compatible with tuberculosis (35.4{\%} v. 27.4{\%}), but had lower rates of peripheral oedema (37.1{\%} v. 48.3{\%}). HIV-infected (v. uninfected) patients were less likely to develop constrictive pericarditis (4.1{\%} v. 10.0{\%} at 1 year, p{\textless}0.0001 (hazard ratio (HR) 0.41, 95{\%} confidence interval (CI) 0.27 - 0.63, p{\textless}0.0001)). However, there was no difference in case fatality rate at 1 year (14.9{\%} v. 12.2{\%}, respectively, p=0.09; (HR 1.20, 95{\%}CI 0.90 - 1.59, p=0.22)). Among HIV-infected patients, heart failure New York Heart Association (NYHA) class III - IV, low body mass, hypotension, and peripheral oedema were independently associated with death.Conclusion. HIV infection alters the cardiovascular presentation and reduces the incidence of constrictive pericarditis, but does notincrease case fatality. Mortality in HIV-infected patients is independently predicted by markers of pericardial and tuberculosis diseaseseverity.},
author = {Gumedze, F and Pandie, S and Nachenga, J B and Kerbelker, Z and Francis, V and Thabane, L and Smieja, M and Bosch, J and Yusuf, S and Ntsekhe, M and Meintjes, G and Mayosi, B M},
doi = {10.7196/SAMJ.2023.V113I3B.16830},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Gumedze et al. - 2023 - The impact of HIV co-infection on presentation and outcome in adults with tuberculous pericarditis Findings from.pdf:pdf;:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Gumedze et al. - 2023 - The impact of HIV co-infection on presentation and outcome in adults with tuberculous pericarditis Findings f(2).pdf:pdf},
issn = {2078-5135},
journal = {South African Medical Journal},
keywords = {HIV,OA,TB,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {apr},
pages = {1109--1115},
title = {{The impact of HIV co-infection on presentation and outcome in adults with tuberculous pericarditis: findings from the IMPI trial}},
url = {https://samajournals.co.za/index.php/samj/article/view/977},
year = {2023}
}

Background. Little is known about the impact of HIV infection on clinical presentation, complications, and morbid pericarditis-relatedoutcomes of tuberculous pericarditis and its predictors.Objective. To assess the impact of HIV infection on presentation and outcomes in the multicountry Investigation of the Management of Pericarditis (IMPI) randomised controlled trial of immunotherapy in tuberculous pericarditis conducted in sub-Saharan Africa.Methods. We compared clinical features and outcomes of 1 370 adult patients treated for tuberculous pericarditis (939 and 431 HIVinfected and uninfected, respectively) enrolled in the IMPI trial. Cox proportional hazards models were used to determine independent predictors of outcomes of HIV-associated tuberculous pericarditis.Results. At presentation, HIV-infected (v. uninfected) patients were younger (median age 34.0 years v. 47.7 years), had lower body mass (mean weight 56 kg v. 60 kg), higher prevalence of tachycardia (58.5% v. 51.9%), hypotension (9.4% v. 3.9%), anaemia (65.9% v. 26.8%), and radiographic pulmonary infiltrates compatible with tuberculosis (35.4% v. 27.4%), but had lower rates of peripheral oedema (37.1% v. 48.3%). HIV-infected (v. uninfected) patients were less likely to develop constrictive pericarditis (4.1% v. 10.0% at 1 year, p\textless0.0001 (hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.27 - 0.63, p\textless0.0001)). However, there was no difference in case fatality rate at 1 year (14.9% v. 12.2%, respectively, p=0.09; (HR 1.20, 95%CI 0.90 - 1.59, p=0.22)). Among HIV-infected patients, heart failure New York Heart Association (NYHA) class III - IV, low body mass, hypotension, and peripheral oedema were independently associated with death.Conclusion. HIV infection alters the cardiovascular presentation and reduces the incidence of constrictive pericarditis, but does notincrease case fatality. Mortality in HIV-infected patients is independently predicted by markers of pericardial and tuberculosis diseaseseverity.

@article{Hadebe2023,
abstract = {Allergic asthma is a disease driven by T helper 2 (Th2) cells, eosinophilia, airway hyperresponsiveness (AHR) and IgE-secreting B cells. Asthma is largely controlled by corticosteroids and beta 2 adregenic receptor agonists that target and relax airway smooth muscle (ASM). Immunoglobulin M (IgM) isotype secreted by naive B cells is important for class switching but may have other undefined functions. We investigated the role of IgM in a house dust mite (HDM)-induced Th2 allergic asthma model. We sensitised wild-type (WT) and IgM-deficient (IgM-/-) mice with HDM and measured AHR, and Th2 responses. We performed RNA sequencing on the whole lung of WT and IgM-/- mice sensitised to saline or HDM. We validated our AHR data on human ASM by deleting genes using CRISPR and measuring contraction by single-cell force cytometry. We found IgM to be essential in AHR but not Th2 airway inflammation or eosinophilia. RNA sequencing of lung tissue suggested that IgM regulated AHR through modulating brain-specific angiogenesis inhibitor 1-associated protein 2-like protein 1 (Baiap2l1) and other genes. Deletion of BAIAP2L1 led to a differential reduction in human ASM contraction when stimulated with TNF-alpha and acetylcholine, but not IL-13. These findings have implications for future treatment of asthma beyond current therapies.Competing Interest StatementThe authors have declared no competing interest.},
author = {Hadebe, Sabelo and Savulescu, Anca Flavia and Khumalo, Jermaine and Jones, Katelyn and Mangali, Sandisiwe and Mthembu, Nontobeko and Musaigwa, Fungai and Maepa, Welcome and Ndlovu, Hlumani and Ngomti, Amkele and Scibiorek, Martyna and Okendo, Javan and Brombacher, Frank},
doi = {10.1101/2023.08.02.551636},
journal = {bioRxiv},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jan},
pages = {2023.08.02.551636},
title = {{Immunoglobulin M regulates airway hyperresponsiveness independent of T helper 2 allergic inflammation.}},
url = {http://biorxiv.org/content/early/2023/08/05/2023.08.02.551636.abstract},
year = {2023}
}

Allergic asthma is a disease driven by T helper 2 (Th2) cells, eosinophilia, airway hyperresponsiveness (AHR) and IgE-secreting B cells. Asthma is largely controlled by corticosteroids and beta 2 adregenic receptor agonists that target and relax airway smooth muscle (ASM). Immunoglobulin M (IgM) isotype secreted by naive B cells is important for class switching but may have other undefined functions. We investigated the role of IgM in a house dust mite (HDM)-induced Th2 allergic asthma model. We sensitised wild-type (WT) and IgM-deficient (IgM-/-) mice with HDM and measured AHR, and Th2 responses. We performed RNA sequencing on the whole lung of WT and IgM-/- mice sensitised to saline or HDM. We validated our AHR data on human ASM by deleting genes using CRISPR and measuring contraction by single-cell force cytometry. We found IgM to be essential in AHR but not Th2 airway inflammation or eosinophilia. RNA sequencing of lung tissue suggested that IgM regulated AHR through modulating brain-specific angiogenesis inhibitor 1-associated protein 2-like protein 1 (Baiap2l1) and other genes. Deletion of BAIAP2L1 led to a differential reduction in human ASM contraction when stimulated with TNF-alpha and acetylcholine, but not IL-13. These findings have implications for future treatment of asthma beyond current therapies.Competing Interest StatementThe authors have declared no competing interest.

@article{Tamuhla2023,
abstract = {Type 2 diabetes mellitus (T2DM) is managed with combined lifestyle modifications and antidiabetic drugs, but people on treatment often fail to reach glycaemic control. Adherence is important for achieving optimal glycaemic control, and management of diabetes with drugs is a lifelong process, so understanding adherence through analysis of longitudinal medications data is important. Using retrospective routine health data and metformin dispensing records as a proxy for medication use, we describe longitudinal persistence and adherence to oral diabetes medication in a virtual cohort of 10541 people with diabetes (PLWD) in Khayelitsha subdistrict, Cape Town. Adherence was measured in 120-day sliding windows over two years and used to estimate metformin adherence trajectories. Multinomial logistic regression identified factors influencing these trajectories. Analysis of pharmacy dispensing records showed varying medication refill patterns: while some PLWD refilled prescriptions consistently, others had treatment gaps with periods of non-persistence and multiple treatment episodes–from one to five per individual across two years. There was a general trend of decreasing adherence over time across all sliding windows in the two-year period, with only 25{\%} of the study population achieved medication adherence ({\textgreater} = 80{\%} adherence) after two years. Four adherence trajectories; ‘low adherence gradual decline (A), ‘high adherence rapid decline' (B), ‘low adherence gradual increase (C) and ‘adherent' (D) were identified. Only trajectory D represented participants who were adherent at treatment start and remained adherent after two years. Taking HIV antiretroviral treatment before or concurrently with diabetes treatment and taking metformin in combination with sulphonylurea and/or insulin were associated with the long-term adherence (trajectory D). Routine data shows real life medication implementation patterns which might not be seen under controlled study conditions. This study illustrates the utility of these data in describing longitudinal adherence patterns at both an individual and population level.},
author = {Tamuhla, Tsaone and Raubenheimer, Peter and Dave, Joel A and Tiffin, Nicki},
doi = {10.1371/JOURNAL.PGPH.0002730},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Tamuhla et al. - 2023 - Routine health data describe adherence and persistence patterns for oral diabetes medication for a virtual cohor.pdf:pdf},
isbn = {1111111111},
issn = {2767-3375},
journal = {PLOS Global Public Health},
keywords = {Antiretroviral therapy,Diabetes mellitus,Drug adherence,Drug therapy,Gestational diabetes,HIV,HbA1c,Insulin,OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {dec},
number = {12},
pages = {e0002730},
publisher = {Public Library of Science},
title = {{Routine health data describe adherence and persistence patterns for oral diabetes medication for a virtual cohort in the Khayelitsha sub-district of Cape Town, South Africa}},
url = {https://journals.plos.org/globalpublichealth/article?id=10.1371/journal.pgph.0002730},
volume = {3},
year = {2023}
}

Type 2 diabetes mellitus (T2DM) is managed with combined lifestyle modifications and antidiabetic drugs, but people on treatment often fail to reach glycaemic control. Adherence is important for achieving optimal glycaemic control, and management of diabetes with drugs is a lifelong process, so understanding adherence through analysis of longitudinal medications data is important. Using retrospective routine health data and metformin dispensing records as a proxy for medication use, we describe longitudinal persistence and adherence to oral diabetes medication in a virtual cohort of 10541 people with diabetes (PLWD) in Khayelitsha subdistrict, Cape Town. Adherence was measured in 120-day sliding windows over two years and used to estimate metformin adherence trajectories. Multinomial logistic regression identified factors influencing these trajectories. Analysis of pharmacy dispensing records showed varying medication refill patterns: while some PLWD refilled prescriptions consistently, others had treatment gaps with periods of non-persistence and multiple treatment episodes–from one to five per individual across two years. There was a general trend of decreasing adherence over time across all sliding windows in the two-year period, with only 25% of the study population achieved medication adherence (\textgreater = 80% adherence) after two years. Four adherence trajectories; ‘low adherence gradual decline (A), ‘high adherence rapid decline' (B), ‘low adherence gradual increase (C) and ‘adherent' (D) were identified. Only trajectory D represented participants who were adherent at treatment start and remained adherent after two years. Taking HIV antiretroviral treatment before or concurrently with diabetes treatment and taking metformin in combination with sulphonylurea and/or insulin were associated with the long-term adherence (trajectory D). Routine data shows real life medication implementation patterns which might not be seen under controlled study conditions. This study illustrates the utility of these data in describing longitudinal adherence patterns at both an individual and population level.

@article{Jarvis2023,
abstract = {Translating evidence from clinical trials to routine care can take many years, particularly in low-income and middle-income countries, delaying access to life-saving or life-changing treatments. As few as one in five evidence-based health interventions are incorporated into routine use, and the average time lag between evidence availability and practice change is up to 17 years. 1 The results of the AMBITION trial, which provided evidence supporting a simpler, safer treatment for HIV-associated cryptococcal meningitis, were published in full on March 24, 2022. 2 A WHO rapid advice notice was released less than 1 month later, and guidelines were published in July, 2022. 3 The rapid development of WHO guidelines facilitated incorporation of the new regimen into national guidelines in the African countries where the trial was done, and more broadly in other countries in Africa, Asia, Europe, and Latin America, with patients receiving the new treatment as part of routine care within 3 months. In this Comment, we highlight some key lessons to accelerate knowledge translation. 40 years ago, Yusuf and colleagues stated that a good clinical trial should ask an important question and answer it reliably. 4 Cryptococcal meningitis is a leading cause of HIV-associated mortality. 5 Until recently, the standard of care required 7-14 days of daily intravenous infusions of amphotericin B, causing significant toxicities and limiting safe use in most resource-constrained hospitals, with acute mortality rates of 40{\%} or more. 6 Guideline development relies on a comprehensive evidence assessment, appraised by a diverse, representative group of experts, providing an opportunity to identify crucial research gaps. The WHO cryptococcal disease guidelines from 2018 noted that simple treatments for cryptococcal meningitis suitable for low-resource settings were urgently needed. 7 The AMBITION trial evaluated a single high dose of liposomal amphotericin B for treating for HIV-associated cryptococcal meningitis. 2 The trial was sufficiently powered to evaluate safety and efficacy, and was done across five sub-Saharan African countries, enabling assessment of consistency of effects across different settings. The identification of the key questions was further supported by longstanding collaborations, including many African clinical researchers working in diverse health-care settings. Guideline development at WHO follows the Grading of Recommendations, Assessment, Development, and Evaluation process, with explicit consideration of four domains: certainty of the evidence, values and preferences, balance of benefits and harms, and resource implications. Other factors such as equity and human rights, acceptability, and feasibility are also considered. 8 Typically, trials focus only on safety and efficacy. To consider the full range of evidence-to-decision domains, guideline developers are often required to consider indirect evidence, rely on expert judgement, or await the findings of other relevant studies (such as qualitative Source of information Judgement Priority of the problem Published estimate of global disease burden 5 High priority: 152 000 cases of cryptococcal meningitis, resulting in 112 000 cryptococcal-related deaths Balance of benefits and harms Phase 3 clinical endpoint trial (the AMBITION trial) 2 Benefits outweigh harms: non-inferior mortality; fewer adverse events Acceptability to key stakeholders Ethnographic study (the LEOPARD study) 10 embedded within the phase 3 clinical trial; in-depth interviews with trial participants and providers; and direct observations Highly acceptable from the perspective of participants and providers Feasibility of implementation Ethnographic study (the LEOPARD study) 10 embedded within the phase 3 clinical trial; direct observations; and in-depth interviews with trial investigators Feasible: simpler to administer, resulting in fewer side-effects and preferred to the previous standard of care Resource requirements Economic evaluation 9 embedded within the phase 3 clinical trial Cost-effective at a low incremental cost-effectiveness ratio; potentially cost saving in real-world implementation Effect on health equity Equity considerations provided during the guideline meeting Improves equity For a guideline panel to make a recommendation for or against a given intervention, each of these criteria listed in the first column needs to be considered. Gathering information early to inform these recommendations is crucial to accelerating guideline development. Table: Evidence-to-decision table for the treatment of cryptococcal meningitis},
author = {Jarvis, Joseph N and Chou, Roger and Harrison, Thomas S and Lawrence, David S and Muthoga, Charles and Mupeli, Kennedy and Meya, David B and Mwandumba, Henry C and Kanyama, Cecilia and Meintjes, Graeme A and Leeme, Tshepo B and Ndhlovu, Chiratidzo E and Beattie, Pauline and Sued, Omar and {P{\'{e}}rez Casas}, Carmen and Makanga, Michael and Ford, Nathan},
doi = {10.1016/S2214-109X(23)00412-6},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Jarvis et al. - 2023 - Translating evidence into global impact lessons for HIV research and policy development from the AMBITION trial.pdf:pdf},
issn = {2214109X},
journal = {The Lancet Global Health},
keywords = {OA,OA{\_}PMC,commentary,fund{\_}not{\_}ack},
mendeley-tags = {OA,OA{\_}PMC,commentary,fund{\_}not{\_}ack},
month = {nov},
number = {11},
pages = {e1688--e1690},
pmid = {37858577},
publisher = {Elsevier Ltd},
title = {{Translating evidence into global impact: lessons for HIV research and policy development from the AMBITION trial}},
url = {http://www.thelancet.com/article/S2214109X23004126/fulltext http://www.thelancet.com/article/S2214109X23004126/abstract https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(23)00412-6/abstract},
volume = {11},
year = {2023}
}

Translating evidence from clinical trials to routine care can take many years, particularly in low-income and middle-income countries, delaying access to life-saving or life-changing treatments. As few as one in five evidence-based health interventions are incorporated into routine use, and the average time lag between evidence availability and practice change is up to 17 years. 1 The results of the AMBITION trial, which provided evidence supporting a simpler, safer treatment for HIV-associated cryptococcal meningitis, were published in full on March 24, 2022. 2 A WHO rapid advice notice was released less than 1 month later, and guidelines were published in July, 2022. 3 The rapid development of WHO guidelines facilitated incorporation of the new regimen into national guidelines in the African countries where the trial was done, and more broadly in other countries in Africa, Asia, Europe, and Latin America, with patients receiving the new treatment as part of routine care within 3 months. In this Comment, we highlight some key lessons to accelerate knowledge translation. 40 years ago, Yusuf and colleagues stated that a good clinical trial should ask an important question and answer it reliably. 4 Cryptococcal meningitis is a leading cause of HIV-associated mortality. 5 Until recently, the standard of care required 7-14 days of daily intravenous infusions of amphotericin B, causing significant toxicities and limiting safe use in most resource-constrained hospitals, with acute mortality rates of 40% or more. 6 Guideline development relies on a comprehensive evidence assessment, appraised by a diverse, representative group of experts, providing an opportunity to identify crucial research gaps. The WHO cryptococcal disease guidelines from 2018 noted that simple treatments for cryptococcal meningitis suitable for low-resource settings were urgently needed. 7 The AMBITION trial evaluated a single high dose of liposomal amphotericin B for treating for HIV-associated cryptococcal meningitis. 2 The trial was sufficiently powered to evaluate safety and efficacy, and was done across five sub-Saharan African countries, enabling assessment of consistency of effects across different settings. The identification of the key questions was further supported by longstanding collaborations, including many African clinical researchers working in diverse health-care settings. Guideline development at WHO follows the Grading of Recommendations, Assessment, Development, and Evaluation process, with explicit consideration of four domains: certainty of the evidence, values and preferences, balance of benefits and harms, and resource implications. Other factors such as equity and human rights, acceptability, and feasibility are also considered. 8 Typically, trials focus only on safety and efficacy. To consider the full range of evidence-to-decision domains, guideline developers are often required to consider indirect evidence, rely on expert judgement, or await the findings of other relevant studies (such as qualitative Source of information Judgement Priority of the problem Published estimate of global disease burden 5 High priority: 152 000 cases of cryptococcal meningitis, resulting in 112 000 cryptococcal-related deaths Balance of benefits and harms Phase 3 clinical endpoint trial (the AMBITION trial) 2 Benefits outweigh harms: non-inferior mortality; fewer adverse events Acceptability to key stakeholders Ethnographic study (the LEOPARD study) 10 embedded within the phase 3 clinical trial; in-depth interviews with trial participants and providers; and direct observations Highly acceptable from the perspective of participants and providers Feasibility of implementation Ethnographic study (the LEOPARD study) 10 embedded within the phase 3 clinical trial; direct observations; and in-depth interviews with trial investigators Feasible: simpler to administer, resulting in fewer side-effects and preferred to the previous standard of care Resource requirements Economic evaluation 9 embedded within the phase 3 clinical trial Cost-effective at a low incremental cost-effectiveness ratio; potentially cost saving in real-world implementation Effect on health equity Equity considerations provided during the guideline meeting Improves equity For a guideline panel to make a recommendation for or against a given intervention, each of these criteria listed in the first column needs to be considered. Gathering information early to inform these recommendations is crucial to accelerating guideline development. Table: Evidence-to-decision table for the treatment of cryptococcal meningitis

@article{Warner2023,
author = {Warner, Digby F and Wood, Robin},
doi = {10.1002/JIA2.26081},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Warner, Wood - 2023 - New tricks for an old dog opportunities for better tuberculosis control.pdf:pdf},
issn = {17582652},
journal = {Journal of the International AIDS Society},
keywords = {OA,fund{\_}not{\_}ack,perspective},
mendeley-tags = {OA,fund{\_}not{\_}ack,perspective},
month = {mar},
number = {3},
pages = {e26081},
pmid = {36951496},
publisher = {NLM (Medline)},
title = {{New tricks for an old dog: opportunities for better tuberculosis control}},
volume = {26},
year = {2023}
}

@article{Rangaka2023,
abstract = {Approximately 10{\textperiodcentered}6 million people worldwide develop tuberculosis each year, representing a failure in epidemic control that is accentuated by the absence of effective vaccines to prevent infection or disease in adolescents and adults. Without effective vaccines, tuberculosis prevention has relied on testing for Mycobacterium tuberculosis infection and treating with antibiotics to prevent progression to tuberculosis disease, known as tuberculosis preventive treatment (TPT). Novel tuberculosis vaccines are in development and phase 3 efficacy trials are imminent. The development of effective, shorter, and safer TPT regimens has broadened the groups eligible for TPT beyond people with HIV and child contacts of people with tuberculosis; future vaccine trials will be undertaken in an era of increased TPT access. Changes in the prevention standard will have implications for tuberculosis vaccine trials of disease prevention, for which safety and sufficient accrual of cases are crucial. In this paper, we examine the urgent need for trials that allow the evaluation of new vaccines and fulfil the ethical duty of researchers to provide TPT. We observe how HIV vaccine trials have incorporated preventive treatment in the form of pre-exposure prophylaxis, propose trial designs that integrate TPT, and summarise considerations for each design in terms of trial validity, efficiency, participant safety, and ethics. Introduction},
author = {Rangaka, Molebogeng X and Frick, Mike and Churchyard, Gavin and Garc{\'{i}}a-Basteiro, Alberto L and Hatherill, Mark and Hanekom, Willem and Hill, Philip C and Hamada, Yohhei and Quaife, Matthew and Vekemans, Johan and White, Richard G and Cobelens, Frank},
doi = {10.1016/S2213-2600(23)00084-X},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Rangaka et al. - 2023 - Clinical trials of tuberculosis vaccines in the era of increased access to preventive antibiotic treatment.pdf:pdf},
issn = {2213-2600},
journal = {The Lancet Respiratory Medicine},
keywords = {OA,fund{\_}not{\_}ack,perspective},
mendeley-tags = {OA,fund{\_}not{\_}ack,perspective},
month = {mar},
pages = {https://doi.org/10.1016/ S2213--2600(23)00084--X},
pmid = {36966794},
publisher = {Elsevier},
title = {{Clinical trials of tuberculosis vaccines in the era of increased access to preventive antibiotic treatment}},
url = {https://linkinghub.elsevier.com/retrieve/pii/S221326002300084X},
year = {2023}
}

Approximately 10˙6 million people worldwide develop tuberculosis each year, representing a failure in epidemic control that is accentuated by the absence of effective vaccines to prevent infection or disease in adolescents and adults. Without effective vaccines, tuberculosis prevention has relied on testing for Mycobacterium tuberculosis infection and treating with antibiotics to prevent progression to tuberculosis disease, known as tuberculosis preventive treatment (TPT). Novel tuberculosis vaccines are in development and phase 3 efficacy trials are imminent. The development of effective, shorter, and safer TPT regimens has broadened the groups eligible for TPT beyond people with HIV and child contacts of people with tuberculosis; future vaccine trials will be undertaken in an era of increased TPT access. Changes in the prevention standard will have implications for tuberculosis vaccine trials of disease prevention, for which safety and sufficient accrual of cases are crucial. In this paper, we examine the urgent need for trials that allow the evaluation of new vaccines and fulfil the ethical duty of researchers to provide TPT. We observe how HIV vaccine trials have incorporated preventive treatment in the form of pre-exposure prophylaxis, propose trial designs that integrate TPT, and summarise considerations for each design in terms of trial validity, efficiency, participant safety, and ethics. Introduction

@article{Dube2023,
abstract = {Herein, we describe 39 novel quinolone compounds bearing a hydrophilic amine chain and varied substituted benzyloxy units. These compounds demonstrate broad-spectrum activities against acid-fast bacterium, Gram-positive and -negative bacteria, fungi, and leishmania parasite. Compound 30 maintained antitubercular activity against moxifloxacin-, isoniazid-, and rifampicin-resistant Mycobacterium tuberculosis, while 37 exhibited low micromolar activities ({\textless}1 $\mu$g/mL) against World Health Organization (WHO) critical pathogens: Cryptococcus neoformans, Acinetobacter baumannii, and Pseudomonas aeruginosa. Compounds in this study are metabolically robust, demonstrating {\%} remnant of {\textgreater}98{\%} after 30 min in the presence of human, rat, and mouse liver microsomes. Several compounds thus reported here are promising leads for the treatment of diseases caused by infectious agents.},
author = {Dube, Phelelisiwe S and Angula, Klaudia T and Legoabe, Lesetja J and Jordaan, Audrey and Zarella, Jan M Boitz and Warner, Digby F and Doggett, J Stone and Beteck, Richard M},
doi = {10.1021/ACSOMEGA.3C01406},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Dube et al. - 2023 - Quinolone-3-amidoalkanol a new class of potent and broad-spectrum antimicrobial agent.pdf:pdf},
issn = {2470-1343},
journal = {ACS Omega},
keywords = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {may},
pages = {10.1021/acsomega.3c01406},
pmid = {37214682},
publisher = {American Chemical Society},
title = {{Quinolone-3-amidoalkanol: a new class of potent and broad-spectrum antimicrobial agent}},
url = {https://pubs.acs.org/doi/full/10.1021/acsomega.3c01406},
year = {2023}
}

Herein, we describe 39 novel quinolone compounds bearing a hydrophilic amine chain and varied substituted benzyloxy units. These compounds demonstrate broad-spectrum activities against acid-fast bacterium, Gram-positive and -negative bacteria, fungi, and leishmania parasite. Compound 30 maintained antitubercular activity against moxifloxacin-, isoniazid-, and rifampicin-resistant Mycobacterium tuberculosis, while 37 exhibited low micromolar activities (\textless1 $μ$g/mL) against World Health Organization (WHO) critical pathogens: Cryptococcus neoformans, Acinetobacter baumannii, and Pseudomonas aeruginosa. Compounds in this study are metabolically robust, demonstrating % remnant of \textgreater98% after 30 min in the presence of human, rat, and mouse liver microsomes. Several compounds thus reported here are promising leads for the treatment of diseases caused by infectious agents.

@article{Scibiorek2023a,
author = {Scibiorek, Martyna and Mthembu, Nontobeko and Mangali, Sandisiwe and Ngomti, Amkele and Ikwegbue, Paul and Brombacher, Frank and Hadebe, Sabelo},
doi = {10.1038/S41598-023-36670-8},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Scibiorek et al. - 2023 - Author Correction IL-4R$\alpha$ signalling in B cells and T cells play differential roles in acute and chronic atopic.pdf:pdf},
issn = {2045-2322},
journal = {Scientific Reports},
keywords = {OA,fund{\_}ack},
mendeley-tags = {OA,fund{\_}ack},
month = {jun},
number = {1},
pages = {9651},
title = {{Author Correction: IL-4R$\alpha$ signalling in B cells and T cells play differential roles in acute and chronic atopic dermatitis}},
url = {https://www.nature.com/articles/s41598-023-36670-8},
volume = {13},
year = {2023}
}

@article{Alimohamed2023,
author = {Alimohamed, Mohamed Zahir and Mnika, Khuthala and Adadey, Samuel Mawuli and Barbosa-Matos, Rita and Avram, Elena and Nevondwe, Patracia and Akurugu, Wisdom A and Mupfururirwa, Wilson and {de Miranda Cerqueira}, Juliana Xavier and Dore, Rhys and Săbău, Ileana Delia and Kalantari, Silvia and da Silva, Ana Raquel Gouveia Freitas and Anzaku, Abbas Abel and Matimba, Alice and Chauke, Paballo Abel and Johari, Mridul and Nembaware, Victoria and Mroczek, Magdalena},
doi = {10.1038/s41431-023-01487-6},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Alimohamed et al. - 2023 - Advancing intercontinental collaboration in human genetics success story of the African and European Young In.pdf:pdf},
issn = {1476-5438},
journal = {European Journal of Human Genetics},
keywords = {Economics,Ethics,fund{\_}not{\_}ack,perspective},
mendeley-tags = {fund{\_}not{\_}ack,perspective},
month = {oct},
number = {7},
pages = {1--3},
pmid = {37880422},
publisher = {Nature Publishing Group},
title = {{Advancing intercontinental collaboration in human genetics: success story of the African and European Young Investigator Forum}},
url = {https://www.nature.com/articles/s41431-023-01487-6},
volume = {10},
year = {2023}
}

@article{Buthelezi2023,
abstract = {Infectious diseases, particularly Tuberculosis (TB) caused by Mycobacterium tuberculosis, pose a significant global health challenge, with 1.6 million reported deaths in 2021, making it the most fatal disease caused by a single infectious agent. The rise of drug-resistant infectious diseases adds to the urgency of finding effective and safe intervention therapies. Antisense therapy uses antisense oligonucleotides (ASOs) that are short, chemically modified, single-stranded deoxyribonucleotide molecules complementary to their mRNA target. Due to their designed target specificity and inhibition of a disease-causing gene at the mRNA level, antisense therapy has gained interest as a potential therapeutic approach. This type of therapy is currently utilized in numerous diseases, such as cancer and genetic disorders. Currently, there are limited but steadily increasing studies available that report on the use of ASOs as treatment for infectious diseases. This review explores the sustainability of FDA-approved and preclinically tested ASOs as a treatment for infectious diseases and the adaptability of ASOs for chemical modifications resulting in reduced side effects with improved drug delivery; thus, highlighting the potential therapeutic uses of ASOs for treating infectious diseases.},
author = {Buthelezi, Lwanda Abonga and Pillay, Shandre and Ntuli, Noxolo Nokukhanya and Gcanga, Lorna and Guler, Reto},
doi = {10.3390/CELLS12162119},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Buthelezi et al. - 2023 - Antisense therapy for infectious diseases.pdf:pdf},
issn = {2073-4409},
journal = {Cells},
keywords = {OA,OA{\_}PMC,antisense oligonucleotide,antisense therapy,fund{\_}ack,infectious disease,mRNA,review},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,review},
month = {aug},
number = {16},
pages = {2119},
pmid = {37626929},
publisher = {Multidisciplinary Digital Publishing Institute},
title = {{Antisense therapy for infectious diseases}},
url = {https://www.mdpi.com/2073-4409/12/16/2119/htm https://www.mdpi.com/2073-4409/12/16/2119},
volume = {12},
year = {2023}
}

Infectious diseases, particularly Tuberculosis (TB) caused by Mycobacterium tuberculosis, pose a significant global health challenge, with 1.6 million reported deaths in 2021, making it the most fatal disease caused by a single infectious agent. The rise of drug-resistant infectious diseases adds to the urgency of finding effective and safe intervention therapies. Antisense therapy uses antisense oligonucleotides (ASOs) that are short, chemically modified, single-stranded deoxyribonucleotide molecules complementary to their mRNA target. Due to their designed target specificity and inhibition of a disease-causing gene at the mRNA level, antisense therapy has gained interest as a potential therapeutic approach. This type of therapy is currently utilized in numerous diseases, such as cancer and genetic disorders. Currently, there are limited but steadily increasing studies available that report on the use of ASOs as treatment for infectious diseases. This review explores the sustainability of FDA-approved and preclinically tested ASOs as a treatment for infectious diseases and the adaptability of ASOs for chemical modifications resulting in reduced side effects with improved drug delivery; thus, highlighting the potential therapeutic uses of ASOs for treating infectious diseases.

@article{Brown2023,
abstract = {Background. Emerging resistance to bedaquiline (BDQ) threatens to undermine advances in the treatment of drug-resistant tuberculosis (DRTB). Characterizing serial Mycobacterium tuberculosis (Mtb) isolates collected during BDQ-based treatment can provide insights into the etiologies of BDQ resistance in this important group of DRTB patients. Methods. We measured mycobacteria growth indicator tube (MGIT)-based BDQ minimum inhibitory concentrations (MICs) of Mtb isolates collected from 195 individuals with no prior BDQ exposure who were receiving BDQ-based treatment for DRTB. We conducted whole-genome sequencing on serial Mtb isolates from all participants who had any isolate with a BDQ MIC {\textgreater}1 collected before or after starting treatment (95 total Mtb isolates from 24 participants). Results. Sixteen of 24 participants had BDQ-resistant TB (MGIT MIC ≥4 µg/mL) and 8 had BDQ-intermediate infections (MGIT MIC = 2 µg/mL). Participants with pre-existing resistance outnumbered those with resistance acquired during treatment, and 8 of 24 participants had polyclonal infections. BDQ resistance was observed across multiple Mtb strain types and involved a diverse catalog of mmpR5 (Rv0678) mutations, but no mutations in atpE or pepQ. Nine pairs of participants shared genetically similar isolates separated by {\textless}5 single nucleotide polymorphisms, concerning for potential transmitted BDQ resistance. Conclusions. BDQ-resistant TB can arise via multiple, overlapping processes, including transmission of strains with pre-existing resistance. Capturing the within-host diversity of these infections could potentially improve clinical diagnosis, population-level surveillance, and molecular diagnostic test development.},
author = {Brown, Tyler S and Tang, Linrui and Omar, Shaheed Vally and Joseph, Lavania and Meintjes, Graeme A and Maartens, Gary and Wasserman, Sean and Shah, N Sarita and Farhat, Maha R and Gandhi, Neel R and Ismail, Nazir and Brust, James C M and Mathema, Barun},
doi = {10.1093/CID/CIAD596},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Brown et al. - 2023 - Genotype–phenotype characterization of serial iMycobacterium tuberculosisi isolates in bedaquiline-resistant tuber.pdf:pdf},
issn = {1058-4838},
journal = {Clinical Infectious Diseases},
keywords = {OA,bedaquiline,drug resistance,fund{\_}ack,original,tuberculosis,whole-genome sequencing},
mendeley-tags = {OA,fund{\_}ack,original},
month = {oct},
pages = {ciad596},
pmid = {37874928},
title = {{Genotype–phenotype characterization of serial \textit{Mycobacterium tuberculosis} isolates in bedaquiline-resistant tuberculosis}},
url = {https://dx.doi.org/10.1093/cid/ciad596},
year = {2023}
}

Background. Emerging resistance to bedaquiline (BDQ) threatens to undermine advances in the treatment of drug-resistant tuberculosis (DRTB). Characterizing serial Mycobacterium tuberculosis (Mtb) isolates collected during BDQ-based treatment can provide insights into the etiologies of BDQ resistance in this important group of DRTB patients. Methods. We measured mycobacteria growth indicator tube (MGIT)-based BDQ minimum inhibitory concentrations (MICs) of Mtb isolates collected from 195 individuals with no prior BDQ exposure who were receiving BDQ-based treatment for DRTB. We conducted whole-genome sequencing on serial Mtb isolates from all participants who had any isolate with a BDQ MIC \textgreater1 collected before or after starting treatment (95 total Mtb isolates from 24 participants). Results. Sixteen of 24 participants had BDQ-resistant TB (MGIT MIC ≥4 µg/mL) and 8 had BDQ-intermediate infections (MGIT MIC = 2 µg/mL). Participants with pre-existing resistance outnumbered those with resistance acquired during treatment, and 8 of 24 participants had polyclonal infections. BDQ resistance was observed across multiple Mtb strain types and involved a diverse catalog of mmpR5 (Rv0678) mutations, but no mutations in atpE or pepQ. Nine pairs of participants shared genetically similar isolates separated by \textless5 single nucleotide polymorphisms, concerning for potential transmitted BDQ resistance. Conclusions. BDQ-resistant TB can arise via multiple, overlapping processes, including transmission of strains with pre-existing resistance. Capturing the within-host diversity of these infections could potentially improve clinical diagnosis, population-level surveillance, and molecular diagnostic test development.

@article{Middelkoop2023,
abstract = {BACKGROUND Randomised controlled trials (RCT) to determine the influence of vitamin D on bone mineral content (BMC) and fracture risk in children of Black African ancestry are lacking. METHODS We conducted a sub-study nested within a Phase 3 RCT of weekly oral supplementation with 10,000 IU vitamin D3 in HIV-uninfected Cape Town schoolchildren of Black African ancestry aged 6-11 years. Outcomes were BMC at the whole body less head (WBLH) and lumbar spine (LS) and serum concentrations of 25-hydroxyvitamin D3 (25[OH]D3), parathyroid hormone (PTH) and bone turnover markers. Incidence of fractures was an outcome of the main trial. FINDINGS 1682 children were enrolled in the main trial, of whom 450 also participated in the sub-study. Among sub-study participants, end-trial serum 25(OH)D3 concentrations were higher for participants allocated to vitamin D vs. placebo (adjusted mean difference [aMD] 39.9 nmol/L, 95{\%} CI 36.1 to 43.6, P{\textless}0.001) and serum PTH concentrations were lower (aMD -0.55 pmol/L, 95{\%} CI -0.94 to -0.17, P=0.005). However, no interarm differences were seen for WBLH BMC (aMD -8.0 g, 95{\%} CI -30.7 to 14.7) or LS BMC (aMD -0.3 g, 95{\%} CI -1.3 to 0.8), or for serum concentrations of bone turnover markers (P≥0.28). In the main trial, allocation did not influence fracture risk (adjusted odds ratio 0.70, 95{\%} CI 0.27 to 1.85, P=0.48). INTERPRETATION Weekly vitamin D supplementation elevated serum 25(OH)D3 concentrations and suppressed serum PTH concentrations in HIV-uninfected schoolchildren of Black African ancestry but did not influence BMC, bone turnover markers or fracture risk. FUNDING Medical Research Council {\#}{\#}{\#} Competing Interest Statement ARM declares receipt of funding in the last 36 months to support vitamin D research from the following companies who manufacture or sell vitamin D supplements: Pharma Nord Ltd, DSM Nutritional Products Ltd, Thornton {\&} Ross Ltd and Hyphens Pharma Ltd. ARM also declares receipt of vitamin D capsules for clinical trial use from Pharma Nord Ltd, Synergy Biologics Ltd and Cytoplan Ltd; support for attending meetings from Pharma Nord Ltd and Abiogen Pharma Ltd; receipt of consultancy fees from DSM Nutritional Products Ltd and Qiagen Ltd; receipt of a speaker fee from the Linus Pauling Institute; participation on Data and Safety Monitoring Boards for the VITALITY trial (Vitamin D for Adolescents with HIV to reduce musculoskeletal morbidity and immunopathology, Pan African Clinical Trials Registry ref PACTR20200989766029) and the Trial of Vitamin D and Zinc Supplementation for Improving Treatment Outcomes Among COVID-19 Patients in India (ClinicalTrials.gov ref [NCT04641195][1]); and unpaid work as a Programme Committee member for the Vitamin D Workshop. All other authors declare that they have no competing interests. {\#}{\#}{\#} Clinical Trial NCT02880982 {\#}{\#}{\#} Funding Statement This study was funded by the UK Medical Research Council (refs MR/R023050/1 and MR/M026639/1) {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The trial was approved by the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee (Ref: 796/2015) and the London School of Hygiene and Tropical Medicine Observational/Interventions Research Ethics Committee (Ref: 7450-2) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Anonymised data may be requested from the corresponding author to be shared subject to terms of research ethics committee approval. [1]: /lookup/external-ref?link{\_}type=CLINTRIALGOV{\&}access{\_}num=NCT04641195{\&}atom={\%}2Fmedrxiv{\%}2Fearly{\%}2F2023{\%}2F05{\%}2F19{\%}2F2023.05.18.23290153.atom},
author = {Middelkoop, Keren and Micklesfield, Lisa and Walker, Neil and Stewart, Justine and Delport, Carmen and Jolliffe, David and Mendham, Amy and Coussens, Anna K and van Graan, Averalda and Nuttall, James and Tang, Jonathan and Fraser, William and Cooper, Cyrus and Harvey, Nicholas and Hooper, Richard and Wilkinson, Robert J and Bekker, Linda-Gail and Martineau, Adrian},
doi = {10.1101/2023.05.18.23290153},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Middelkoop et al. - 2023 - Influence of vitamin D supplementation on bone mineral content, bone turnover markers and fracture risk in So.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {may},
pages = {2023.05.18.23290153},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Influence of vitamin D supplementation on bone mineral content, bone turnover markers and fracture risk in South African schoolchildren: multicentre double-blind randomised placebo-controlled trial (ViDiKids)}},
url = {https://www.medrxiv.org/content/10.1101/2023.05.18.23290153v1 https://www.medrxiv.org/content/10.1101/2023.05.18.23290153v1.abstract},
year = {2023}
}

BACKGROUND Randomised controlled trials (RCT) to determine the influence of vitamin D on bone mineral content (BMC) and fracture risk in children of Black African ancestry are lacking. METHODS We conducted a sub-study nested within a Phase 3 RCT of weekly oral supplementation with 10,000 IU vitamin D3 in HIV-uninfected Cape Town schoolchildren of Black African ancestry aged 6-11 years. Outcomes were BMC at the whole body less head (WBLH) and lumbar spine (LS) and serum concentrations of 25-hydroxyvitamin D3 (25[OH]D3), parathyroid hormone (PTH) and bone turnover markers. Incidence of fractures was an outcome of the main trial. FINDINGS 1682 children were enrolled in the main trial, of whom 450 also participated in the sub-study. Among sub-study participants, end-trial serum 25(OH)D3 concentrations were higher for participants allocated to vitamin D vs. placebo (adjusted mean difference [aMD] 39.9 nmol/L, 95% CI 36.1 to 43.6, P\textless0.001) and serum PTH concentrations were lower (aMD -0.55 pmol/L, 95% CI -0.94 to -0.17, P=0.005). However, no interarm differences were seen for WBLH BMC (aMD -8.0 g, 95% CI -30.7 to 14.7) or LS BMC (aMD -0.3 g, 95% CI -1.3 to 0.8), or for serum concentrations of bone turnover markers (P≥0.28). In the main trial, allocation did not influence fracture risk (adjusted odds ratio 0.70, 95% CI 0.27 to 1.85, P=0.48). INTERPRETATION Weekly vitamin D supplementation elevated serum 25(OH)D3 concentrations and suppressed serum PTH concentrations in HIV-uninfected schoolchildren of Black African ancestry but did not influence BMC, bone turnover markers or fracture risk. FUNDING Medical Research Council ### Competing Interest Statement ARM declares receipt of funding in the last 36 months to support vitamin D research from the following companies who manufacture or sell vitamin D supplements: Pharma Nord Ltd, DSM Nutritional Products Ltd, Thornton & Ross Ltd and Hyphens Pharma Ltd. ARM also declares receipt of vitamin D capsules for clinical trial use from Pharma Nord Ltd, Synergy Biologics Ltd and Cytoplan Ltd; support for attending meetings from Pharma Nord Ltd and Abiogen Pharma Ltd; receipt of consultancy fees from DSM Nutritional Products Ltd and Qiagen Ltd; receipt of a speaker fee from the Linus Pauling Institute; participation on Data and Safety Monitoring Boards for the VITALITY trial (Vitamin D for Adolescents with HIV to reduce musculoskeletal morbidity and immunopathology, Pan African Clinical Trials Registry ref PACTR20200989766029) and the Trial of Vitamin D and Zinc Supplementation for Improving Treatment Outcomes Among COVID-19 Patients in India (ClinicalTrials.gov ref [NCT04641195][1]); and unpaid work as a Programme Committee member for the Vitamin D Workshop. All other authors declare that they have no competing interests. ### Clinical Trial NCT02880982 ### Funding Statement This study was funded by the UK Medical Research Council (refs MR/R023050/1 and MR/M026639/1) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The trial was approved by the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee (Ref: 796/2015) and the London School of Hygiene and Tropical Medicine Observational/Interventions Research Ethics Committee (Ref: 7450-2) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Anonymised data may be requested from the corresponding author to be shared subject to terms of research ethics committee approval. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04641195&atom=%2Fmedrxiv%2Fearly%2F2023%2F05%2F19%2F2023.05.18.23290153.atom

@article{Lesmes-Rodriguez2023,
abstract = {Background: Globally, the most significant risk factors for adverse COVID-19 outcome are increasing age and cardiometabolic comorbidities. However, underlying coinfections may modulate COVID-19 morbidity and mortality, particularly in regions with high prevalence of infectious diseases. Methods: We retrospectively analyzed serum samples for IgG antibodies against the common circulating coronaviruses HCoV-NL63, HCoV-229E, HCoV-OC43 and HCoV-HKU1 from non-hospitalized and hospitalized confirmed COVID-19 patients recruited during the first (June-August 2020) and second (October 2020-June 2021) COVID-19 wave in Cape Town, South Africa. Patients were grouped according to COVID-19 disease severity: Group 1: previously SARS-CoV-2 infected with positive serology and no symptoms (n=94); Group 2: acutely SARS-CoV-2 infected, hospitalized for COVID-19 and severe symptoms (n=92). Results: The overall anti-HCoV IgG seroprevalence in the entire patient cohort was 60.8{\%} (95{\%} CI: 53.7 – 67.8), with 37.1{\%} HCoV-NL63 (95{\%} CI: 30 – 44), 30.6{\%} HCoV-229E (95{\%} CI: 24 – 37.3), 22.6{\%} HCoV-HKU1 (95{\%} CI: 16.6 – 28.6), and 21.0{\%} HCoV-OC43 (95{\%} CI: 15.1 – 26.8). We observed a significantly higher overall HCoV presence (72.3{\%} versus 48.9{\%}) and coinfection frequency (43.6{\%} versus 19.6{\%}) in group 1 compared to group 2 patients with significantly higher presentation of HCoV-NL63 (67.0{\%} versus 6.6{\%}) and HCoV-HKU1 (31.1{\%} versus 14.1{\%}). However, only antibody titers for HCoV-NL63 were significantly higher in group 1 compared to group 2 patients (p {\textless} 0.0001, 1.90 [95{\%} CI: 0.62 – 2.45] versus 1.32 [95{\%} CI: 0.30 – 2.01]) which was independent of the participants' HIV status. Logistic regression analysis revealed significantly protective effects by previous exposure to HCoV-NL63 [p {\textless} 0.001, adjusted OR = 0.0176 (95{\%} CI: 0.0039 – 0.0786)], while previous HCoV-229E exposure was associated with increased COVID-19 severity [p = 0.0051, adjusted OR = 7.3239 (95{\%} CI: 1.8195–29.4800)]. Conclusion: We conclude that previous exposure to multiple common coronaviruses, and particularly HCoV-NL63, might protect against severe COVID-19, while no previous HCoV exposure or single infection with HCoV-229E might enhance the risk for severe COVID-19. To our knowledge, this is the first report on HCoV seroprevalence in South Africa and its possible association with cross-protection against COVID-19 severity.},
author = {Lesmes-Rodr{\'{i}}guez, Lida C and Lambarey, Humaira and Chetram, Abeen and Riou, Catherine and Wilkinson, Robert J and Joyimbana, Wendy and Jennings, Lauren and Orrell, Catherine and Jaramillo-Hern{\'{a}}ndez, Dumar A and Sch{\"{a}}fer, Georgia},
doi = {10.3389/FVIRO.2023.1125448/BIBTEX},
issn = {2673818X},
journal = {Frontiers in Virology},
keywords = {COVID-19,HCoV-229E,HCoV-HKU1,HCoV-NL63,HCoV-OC43,OA,SARS-CoV-2,Serology,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {feb},
pages = {1125448},
publisher = {Frontiers Media SA},
title = {{Previous exposure to common coronavirus HCoV-NL63 is associated with reduced COVID-19 severity in patients from Cape Town, South Africa}},
volume = {3},
year = {2023}
}

Background: Globally, the most significant risk factors for adverse COVID-19 outcome are increasing age and cardiometabolic comorbidities. However, underlying coinfections may modulate COVID-19 morbidity and mortality, particularly in regions with high prevalence of infectious diseases. Methods: We retrospectively analyzed serum samples for IgG antibodies against the common circulating coronaviruses HCoV-NL63, HCoV-229E, HCoV-OC43 and HCoV-HKU1 from non-hospitalized and hospitalized confirmed COVID-19 patients recruited during the first (June-August 2020) and second (October 2020-June 2021) COVID-19 wave in Cape Town, South Africa. Patients were grouped according to COVID-19 disease severity: Group 1: previously SARS-CoV-2 infected with positive serology and no symptoms (n=94); Group 2: acutely SARS-CoV-2 infected, hospitalized for COVID-19 and severe symptoms (n=92). Results: The overall anti-HCoV IgG seroprevalence in the entire patient cohort was 60.8% (95% CI: 53.7 – 67.8), with 37.1% HCoV-NL63 (95% CI: 30 – 44), 30.6% HCoV-229E (95% CI: 24 – 37.3), 22.6% HCoV-HKU1 (95% CI: 16.6 – 28.6), and 21.0% HCoV-OC43 (95% CI: 15.1 – 26.8). We observed a significantly higher overall HCoV presence (72.3% versus 48.9%) and coinfection frequency (43.6% versus 19.6%) in group 1 compared to group 2 patients with significantly higher presentation of HCoV-NL63 (67.0% versus 6.6%) and HCoV-HKU1 (31.1% versus 14.1%). However, only antibody titers for HCoV-NL63 were significantly higher in group 1 compared to group 2 patients (p \textless 0.0001, 1.90 [95% CI: 0.62 – 2.45] versus 1.32 [95% CI: 0.30 – 2.01]) which was independent of the participants' HIV status. Logistic regression analysis revealed significantly protective effects by previous exposure to HCoV-NL63 [p \textless 0.001, adjusted OR = 0.0176 (95% CI: 0.0039 – 0.0786)], while previous HCoV-229E exposure was associated with increased COVID-19 severity [p = 0.0051, adjusted OR = 7.3239 (95% CI: 1.8195–29.4800)]. Conclusion: We conclude that previous exposure to multiple common coronaviruses, and particularly HCoV-NL63, might protect against severe COVID-19, while no previous HCoV exposure or single infection with HCoV-229E might enhance the risk for severe COVID-19. To our knowledge, this is the first report on HCoV seroprevalence in South Africa and its possible association with cross-protection against COVID-19 severity.

@article{Scheier2023,
abstract = {Multiple additional studies have been reported since the 2022 publication by members of our group of a systematic review and meta-analysis of randomized trials of intensified versus standard prophylactic anticoagulation therapy in patients hospitalized with Coronavirus Disease 2019 (COVID-19) (1). Including all available data in an updated-meta-analysis can be expected to provide more reliable and precise estimates of the effects of treatment on clinical outcomes and thereby strengthen guidance on the use of anticoagulation in the hospitalized COVID-19 patients.},
author = {Scheier, Thomas C and Carlin, Stephanie and Wills, Nicola K and Wasserman, Sean and Mertz, Dominik and Eikelboom, John W and Scheier, Thomas},
doi = {10.1093/OFID/OFAD506},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Scheier et al. - 2023 - Efficacy and safety of intensified versus standard prophylactic anticoagulation therapy in patients hospitalized.pdf:pdf},
issn = {2328-8957},
journal = {Open Forum Infectious Diseases},
keywords = {OA,fund{\_}not{\_}ack,letter},
mendeley-tags = {OA,fund{\_}not{\_}ack,letter},
month = {oct},
pages = {10.1093/ofid/ofad506},
title = {{Efficacy and safety of intensified versus standard prophylactic anticoagulation therapy in patients hospitalized with Coronavirus Disease 2019: updated systematic review and meta-analysis}},
url = {https://dx.doi.org/10.1093/ofid/ofad506},
year = {2023}
}

Multiple additional studies have been reported since the 2022 publication by members of our group of a systematic review and meta-analysis of randomized trials of intensified versus standard prophylactic anticoagulation therapy in patients hospitalized with Coronavirus Disease 2019 (COVID-19) (1). Including all available data in an updated-meta-analysis can be expected to provide more reliable and precise estimates of the effects of treatment on clinical outcomes and thereby strengthen guidance on the use of anticoagulation in the hospitalized COVID-19 patients.

@article{Lanni2023,
abstract = {ABSTRACT Tuberculosis meningitis (TBM) is essentially treated with the first-line regimen used against pulmonary tuberculosis, with a prolonged continuation phase. However, clinical outcomes are poor in comparison, for reasons that are only partially understood, highlighting the need for improved preclinical tools to measure drug distribution and activity at the site of disease. A predictive animal model of TBM would also be of great value to prioritize promising drug regimens to be tested in clinical trials, given the healthy state of the development pipeline for the first time in decades. Here, we report the optimization of a rabbit model of TBM disease induced via inoculation of Mycobacterium tuberculosis into the cisterna magna, recapitulating features typical of clinical TBM: neurological deterioration within months post-infection, acid-fast bacilli in necrotic lesions in the brain and spinal cord, and elevated lactate levels in cerebrospinal fluid (CSF). None of the infected rabbits recovered or controlled the disease. We used young adult rabbits, the size of which allows for spatial drug quantitation in critical compartments of the central nervous system that cannot be collected in clinical studies. To illustrate the translational value of the model, we report the penetration of linezolid from plasma into the CSF, meninges, anatomically distinct brain areas, cervical spine, and lumbar spine. Across animals, we measured the bacterial burden concomitant with neurological deterioration, offering a useful readout for drug efficacy studies. The model thus forms the basis for building a preclinical platform to identify improved regimens and inform clinical trial design. KEYWORDS},
author = {Lanni, Faye and Sainte, Rosleine Antilus and {Hansen Jr.}, Mark and Parigi, Paul and Kaya, Firat and LoMauro, Katherine and Siow, Bernard and Wilkinson, Robert J and Wasserman, Sean and Podell, Brendan K and Gengenbacher, Martin and Dartois, V{\'{e}}ronique},
doi = {10.1128/AAC.00671-23},
editor = {Silverman, Jared A.},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Lanni et al. - 2023 - A preclinical model of TB meningitis to determine drug penetration and activity at the sites of disease.pdf:pdf},
issn = {0066-4804},
journal = {Antimicrobial Agents and Chemotherapy},
keywords = {OA,OA{\_}PMC,disease progression,fund{\_}ack,original,rabbit model,tuberculosis immunopathology,tuberculosis meningitis},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,original},
month = {nov},
number = {12},
pages = {e0067123},
pmid = {37966227},
publisher = {American Society for Microbiology1752 N St., N.W., Washington, DC},
title = {{A preclinical model of TB meningitis to determine drug penetration and activity at the sites of disease}},
url = {https://journals.asm.org/doi/10.1128/aac.00671-23},
volume = {67},
year = {2023}
}

ABSTRACT Tuberculosis meningitis (TBM) is essentially treated with the first-line regimen used against pulmonary tuberculosis, with a prolonged continuation phase. However, clinical outcomes are poor in comparison, for reasons that are only partially understood, highlighting the need for improved preclinical tools to measure drug distribution and activity at the site of disease. A predictive animal model of TBM would also be of great value to prioritize promising drug regimens to be tested in clinical trials, given the healthy state of the development pipeline for the first time in decades. Here, we report the optimization of a rabbit model of TBM disease induced via inoculation of Mycobacterium tuberculosis into the cisterna magna, recapitulating features typical of clinical TBM: neurological deterioration within months post-infection, acid-fast bacilli in necrotic lesions in the brain and spinal cord, and elevated lactate levels in cerebrospinal fluid (CSF). None of the infected rabbits recovered or controlled the disease. We used young adult rabbits, the size of which allows for spatial drug quantitation in critical compartments of the central nervous system that cannot be collected in clinical studies. To illustrate the translational value of the model, we report the penetration of linezolid from plasma into the CSF, meninges, anatomically distinct brain areas, cervical spine, and lumbar spine. Across animals, we measured the bacterial burden concomitant with neurological deterioration, offering a useful readout for drug efficacy studies. The model thus forms the basis for building a preclinical platform to identify improved regimens and inform clinical trial design. KEYWORDS

@article{Burke2023,
abstract = {Summary Over 4 million adults are living with advanced HIV disease with approximately 650 000 fatalities from HIV reported in 2021. People with advanced HIV disease have low immunity and can present to health services in two ways: those who are well but at high risk of developing severe disease, and those who are severely ill. These two groups require specific management approaches that place different demands on the health system. The first group can generally be supported in primary care settings but require differentiated care to meet their needs. The second group are at high risk of death and need focused diagnostics and clinical care, and possibly hospitalisation. Investments in high-quality clinical management of patients with advanced HIV disease who are seriously ill at primary care or hospital level (often only for a brief period of time during their acute illness) improves the likelihood that their condition will stabilise and that they will recover. Providing high-quality and safe clinical care that is accessible to these groups of people living with HIV who are at risk of severe illness and death is a key priority for reaching the global target of zero AIDS deaths.},
author = {Burke, Rachael M and Feasey, Nicholas and Rangaraj, Ajay and Camps, Maria Ruano and Meintjes, Graeme A and El-Sadr, Wafaa M and Ford, Nathan},
doi = {10.1016/S2352-3018(23)00109-1},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Burke et al. - 2023 - Ending AIDS deaths requires improvements in clinical care for people with advanced HIV disease who are seriously i.pdf:pdf},
issn = {2352-3018},
journal = {The Lancet HIV},
keywords = {fund{\_}not{\_}ack,perspective},
mendeley-tags = {fund{\_}not{\_}ack,perspective},
month = {jun},
pages = {10.1016/ S2352--3018(23)00109--1},
pmid = {37301220},
publisher = {Elsevier},
title = {{Ending AIDS deaths requires improvements in clinical care for people with advanced HIV disease who are seriously ill}},
url = {http://www.thelancet.com/article/S2352301823001091/fulltext http://www.thelancet.com/article/S2352301823001091/abstract https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(23)00109-1/abstract},
year = {2023}
}

Summary Over 4 million adults are living with advanced HIV disease with approximately 650 000 fatalities from HIV reported in 2021. People with advanced HIV disease have low immunity and can present to health services in two ways: those who are well but at high risk of developing severe disease, and those who are severely ill. These two groups require specific management approaches that place different demands on the health system. The first group can generally be supported in primary care settings but require differentiated care to meet their needs. The second group are at high risk of death and need focused diagnostics and clinical care, and possibly hospitalisation. Investments in high-quality clinical management of patients with advanced HIV disease who are seriously ill at primary care or hospital level (often only for a brief period of time during their acute illness) improves the likelihood that their condition will stabilise and that they will recover. Providing high-quality and safe clinical care that is accessible to these groups of people living with HIV who are at risk of severe illness and death is a key priority for reaching the global target of zero AIDS deaths.

@article{Kehoe2023,
abstract = {Background: Routinely collected population-wide health data are often used to understand mortality trends including child mortality, as these data are often available more readily or quickly and for lower geographic levels than population-wide mortality data. However, understanding the completeness and accuracy of routine health data sources is essential for their appropriate interpretation and use. This study aims to assess the accuracy of diagnostic coding for public sector in-facility childhood (age {\textless} 5 years) infectious disease deaths (lower respiratory tract infections [LRTI], diarrhoea, meningitis, and tuberculous meningitis [TBM]) in routine hospital information systems (RHIS) through comparison with causes of death identified in a child death audit system (Child Healthcare Problem Identification Programme [Child PIP]) and the vital registration system (Death Notification [DN] Surveillance) in the Western Cape, South Africa and to calculate admission mortality rates (number of deaths in admitted patients per 1000 live births) using the best available data from all sources. Methods: The three data sources: RHIS, Child PIP, and DN Surveillance are integrated and linked by the Western Cape Provincial Health Data Centre using a unique patient identifier. We calculated the deduplicated total number of infectious disease deaths and estimated admission mortality rates using all three data sources. We determined the completeness of Child PIP and DN Surveillance in identifying deaths recorded in RHIS and the level of agreement for causes of death between data sources. Results: Completeness of recorded in-facility infectious disease deaths in Child PIP (23/05/2007–08/02/2021) and DN Surveillance (2010–2013) was 70{\%} and 69{\%} respectively. The greatest agreement in infectious causes of death were for diarrhoea and LRTI: 92{\%} and 84{\%} respectively between RHIS and Child PIP, and 98{\%} and 83{\%} respectively between RHIS and DN Surveillance. In-facility infectious disease admission mortality rates decreased significantly for the province: 1.60 (95{\%} CI: 1.37–1.85) to 0.73 (95{\%} CI: 0.56–0.93) deaths per 1000 live births from 2007 to 2020. Conclusion: RHIS had accurate causes of death amongst children dying from infectious diseases, particularly for diarrhoea and LRTI, with declining in-facility admission mortality rates over time. We recommend integrating data sources to ensure the most accurate assessment of child deaths.},
author = {Kehoe, K and Morden, E and Jacobs, T and Zinyakatira, N and Smith, M and Heekes, A and Murray, J and le Roux, D M and Wessels, T and Richards, M and Eley, B and Jones, H E and Redaniel, M T and Davies, M A},
doi = {10.1186/S12879-023-08012-6/FIGURES/3},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Kehoe et al. - 2023 - Comparison of paediatric infectious disease deaths in public sector health facilities using different data sources.pdf:pdf},
issn = {14712334},
journal = {BMC Infectious Diseases},
keywords = {Data comparison,Data completeness,OA,Paediatric infectious disease deaths,South Africa,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {dec},
number = {104},
pages = {10.1186/s12879--023--08012--6},
pmid = {36814192},
publisher = {BioMed Central Ltd},
title = {{Comparison of paediatric infectious disease deaths in public sector health facilities using different data sources in the Western Cape, South Africa (2007–2021)}},
url = {https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-023-08012-6 http://creativecommons.org/publicdomain/zero/1.0/},
volume = {23},
year = {2023}
}

Background: Routinely collected population-wide health data are often used to understand mortality trends including child mortality, as these data are often available more readily or quickly and for lower geographic levels than population-wide mortality data. However, understanding the completeness and accuracy of routine health data sources is essential for their appropriate interpretation and use. This study aims to assess the accuracy of diagnostic coding for public sector in-facility childhood (age \textless 5 years) infectious disease deaths (lower respiratory tract infections [LRTI], diarrhoea, meningitis, and tuberculous meningitis [TBM]) in routine hospital information systems (RHIS) through comparison with causes of death identified in a child death audit system (Child Healthcare Problem Identification Programme [Child PIP]) and the vital registration system (Death Notification [DN] Surveillance) in the Western Cape, South Africa and to calculate admission mortality rates (number of deaths in admitted patients per 1000 live births) using the best available data from all sources. Methods: The three data sources: RHIS, Child PIP, and DN Surveillance are integrated and linked by the Western Cape Provincial Health Data Centre using a unique patient identifier. We calculated the deduplicated total number of infectious disease deaths and estimated admission mortality rates using all three data sources. We determined the completeness of Child PIP and DN Surveillance in identifying deaths recorded in RHIS and the level of agreement for causes of death between data sources. Results: Completeness of recorded in-facility infectious disease deaths in Child PIP (23/05/2007–08/02/2021) and DN Surveillance (2010–2013) was 70% and 69% respectively. The greatest agreement in infectious causes of death were for diarrhoea and LRTI: 92% and 84% respectively between RHIS and Child PIP, and 98% and 83% respectively between RHIS and DN Surveillance. In-facility infectious disease admission mortality rates decreased significantly for the province: 1.60 (95% CI: 1.37–1.85) to 0.73 (95% CI: 0.56–0.93) deaths per 1000 live births from 2007 to 2020. Conclusion: RHIS had accurate causes of death amongst children dying from infectious diseases, particularly for diarrhoea and LRTI, with declining in-facility admission mortality rates over time. We recommend integrating data sources to ensure the most accurate assessment of child deaths.

@article{Hamada2023a,
abstract = {Background: Non-communicable diseases (NCDs) and NCD risk factors, such as smoking, increase the risk for tuberculosis (TB). Data are scarce on the risk of prevalent TB associated with these factors in the context of population-wide systematic screening and on the association between NCDs and NCD risk factors with different manifestations of TB, where ∼50{\%} being asymptomatic but bacteriologically positive (subclinical). We did an individual participant data (IPD) meta-analysis of national and sub-national TB prevalence surveys to synthesise the evidence on the risk of symptomatic and subclinical TB in people with NCDs or risk factors, which could help countries to plan screening activities. Methods: In this systematic review and IPD meta-analysis, we identified eligible prevalence surveys in low-income and middle-income countries that reported at least one NCD (e.g., diabetes) or NCD risk factor (e.g., smoking, alcohol use) through the archive maintained by the World Health Organization and by searching in Medline and Embase from January 1, 2000 to August 10, 2021. The search was updated on March 23, 2023. We performed a one-stage meta-analysis using multivariable multinomial models. We estimated the proportion of and the odds ratio for subclinical and symptomatic TB compared to people without TB for current smoking, alcohol use, and self-reported diabetes, adjusted for age and gender. Subclinical TB was defined as microbiologically confirmed TB without symptoms of current cough, fever, night sweats, or weight loss and symptomatic TB with at least one of these symptoms. We assessed heterogeneity using forest plots and I2 statistic. Missing variables were imputed through multi-level multiple imputation. This study is registered with PROSPERO (CRD42021272679). Findings: We obtained IPD from 16 national surveys out of 21 national and five sub-national surveys identified (five in Asia and 11 in Africa, N = 740,815). Across surveys, 15.1{\%}–56.7{\%} of TB were subclinical (median: 38.1{\%}). In the multivariable model, current smoking was associated with both subclinical (OR 1.67, 95{\%} CI 1.27–2.40) and symptomatic TB (OR 1.49, 95{\%} CI 1.34–1.66). Self-reported diabetes was associated with symptomatic TB (OR 1.67, 95{\%} CI 1.17–2.40) but not with subclinical TB (OR 0.92, 95{\%} CI 0.55–1.55). For alcohol drinking ≥ twice per week vs no alcohol drinking, the estimates were imprecise (OR 1.59, 95{\%} CI 0.70–3.62) for subclinical TB and OR 1.43, 95{\%} CI 0.59–3.46 for symptomatic TB). For the association between current smoking and symptomatic TB, I2 was high (76.5{\%} (95{\%} CI 62.0–85.4), while the direction of the point estimates was consistent except for three surveys with wide CIs. Interpretation: Our findings suggest that current smokers are more likely to have both symptomatic and subclinical TB. These individuals can, therefore, be prioritised for intensified screening, such as the use of chest X-ray in the context of community-based screening. People with self-reported diabetes are also more likely to have symptomatic TB, but the association is unclear for subclinical TB. Funding: None.},
author = {Hamada, Yohhei and Quartagno, Matteo and Law, Irwin and Malik, Farihah and Bonsu, Frank Adae and Adetifa, Ifedayo M.O. and Adusi-Poku, Yaw and D'Alessandro, Umberto and Bashorun, Adedapo Olufemi and Begum, Vikarunnessa and Lolong, Dina Bisara and Boldoo, Tsolmon and Dlamini, Themba and Donkor, Simon and Dwihardiani, Bintari and Egwaga, Saidi and Farid, Muhammad N. and Anna, Anna Marie and {Mae G Gaviola}, Donna and Husain, Mohammad Mushtuq and Ismail, Farzana and Kaggwa, Mugagga and Kamara, Deus V. and Kasozi, Samuel and Kaswaswa, Kruger and Kirenga, Bruce and Klinkenberg, Eveline and Kondo, Zuweina and Lawanson, Adebola and Macheque, David and Manhi{\c{c}}a, Ivan and Maama-Maime, Llang Bridget and Mfinanga, Sayoki and Moyo, Sizulu and Mpunga, James and Mthiyane, Thuli and Mustikawati, Dyah Erti and Mvusi, Lindiwe and Nguyen, Hoa Binh and Nguyen, Hai Viet and Pangaribuan, Lamria and Patrobas, Philip and Rahman, Mahmudur and Rahman, Mahbubur and Rahman, Mohammed Sayeedur and Raleting, Thato and Riono, Pandu and Ruswa, Nunurai and Rutebemberwa, Elizeus and Rwabinumi, Mugabe Frank and Senkoro, Mbazi and Sharif, Ahmad Raihan and Sikhondze, Welile and Sismanidis, Charalambos and Sovd, Tugsdelger and Stavia, Turyahabwe and Sultana, Sabera and Suriani, Oster and Thomas, Albertina Martha and Tobing, Kristina and {Van der Walt}, Martie and Walusimbi, Simon and Zaman, Mohammad Mostafa and Floyd, Katherine and Copas, Andrew and Abubakar, Ibrahim and Rangaka, Molebogeng X.},
doi = {10.1016/J.ECLINM.2023.102191},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Hamada et al. - 2023 - Association of diabetes, smoking, and alcohol use with subclinical-to-symptomatic spectrum of tuberculosis in 16.pdf:pdf},
issn = {2589-5370},
journal = {eClinicalMedicine},
keywords = {Diabetes,NCD,OA,OA{\_}PMC,Screening,Smoking: tobacco,TB,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {sep},
pages = {102191},
pmid = {37680950},
publisher = {Elsevier},
title = {{Association of diabetes, smoking, and alcohol use with subclinical-to-symptomatic spectrum of tuberculosis in 16 countries: an individual participant data meta-analysis of national tuberculosis prevalence surveys}},
volume = {63},
year = {2023}
}

Background: Non-communicable diseases (NCDs) and NCD risk factors, such as smoking, increase the risk for tuberculosis (TB). Data are scarce on the risk of prevalent TB associated with these factors in the context of population-wide systematic screening and on the association between NCDs and NCD risk factors with different manifestations of TB, where ∼50% being asymptomatic but bacteriologically positive (subclinical). We did an individual participant data (IPD) meta-analysis of national and sub-national TB prevalence surveys to synthesise the evidence on the risk of symptomatic and subclinical TB in people with NCDs or risk factors, which could help countries to plan screening activities. Methods: In this systematic review and IPD meta-analysis, we identified eligible prevalence surveys in low-income and middle-income countries that reported at least one NCD (e.g., diabetes) or NCD risk factor (e.g., smoking, alcohol use) through the archive maintained by the World Health Organization and by searching in Medline and Embase from January 1, 2000 to August 10, 2021. The search was updated on March 23, 2023. We performed a one-stage meta-analysis using multivariable multinomial models. We estimated the proportion of and the odds ratio for subclinical and symptomatic TB compared to people without TB for current smoking, alcohol use, and self-reported diabetes, adjusted for age and gender. Subclinical TB was defined as microbiologically confirmed TB without symptoms of current cough, fever, night sweats, or weight loss and symptomatic TB with at least one of these symptoms. We assessed heterogeneity using forest plots and I2 statistic. Missing variables were imputed through multi-level multiple imputation. This study is registered with PROSPERO (CRD42021272679). Findings: We obtained IPD from 16 national surveys out of 21 national and five sub-national surveys identified (five in Asia and 11 in Africa, N = 740,815). Across surveys, 15.1%–56.7% of TB were subclinical (median: 38.1%). In the multivariable model, current smoking was associated with both subclinical (OR 1.67, 95% CI 1.27–2.40) and symptomatic TB (OR 1.49, 95% CI 1.34–1.66). Self-reported diabetes was associated with symptomatic TB (OR 1.67, 95% CI 1.17–2.40) but not with subclinical TB (OR 0.92, 95% CI 0.55–1.55). For alcohol drinking ≥ twice per week vs no alcohol drinking, the estimates were imprecise (OR 1.59, 95% CI 0.70–3.62) for subclinical TB and OR 1.43, 95% CI 0.59–3.46 for symptomatic TB). For the association between current smoking and symptomatic TB, I2 was high (76.5% (95% CI 62.0–85.4), while the direction of the point estimates was consistent except for three surveys with wide CIs. Interpretation: Our findings suggest that current smokers are more likely to have both symptomatic and subclinical TB. These individuals can, therefore, be prioritised for intensified screening, such as the use of chest X-ray in the context of community-based screening. People with self-reported diabetes are also more likely to have symptomatic TB, but the association is unclear for subclinical TB. Funding: None.

@article{Araujo-Pereira2023,
abstract = {Anemia frequently affects people living with HIV (PLHIV). Nevertheless, the impact of anemia on treatment outcomes of patients with HIV-associated tuberculosis (TB) and the underlying molecular profiles are not fully characterized. The aim of this study was to investigate the interplay between anemia, the systemic inflammatory profile, dissemination of TB and death in HIV-TB patients in an ad hoc analysis of results from a prospective cohort study. 496 hospitalized PLHIV ≥18 years old, with CD4 count {\textless}350 cells/$\mu$L and high clinical suspicion of new TB infection were enrolled in Cape Town between 2014-2016. Patients were classified according to anemia severity in non-anemic, mild, moderate, or severe anemia. Clinical, microbiologic, and immunologic data were collected at baseline. Hierarchical cluster analysis, degree of inflammatory perturbation, survival curves and C-statistics analyses were performed. Through the analysis of several clinical and laboratory parameters, we observed that those with severe anemia exhibited greater systemic inflammation, characterized by high concentrations of IL-8, IL-1RA and IL-6. Furthermore, severe anemia was associated with a higher Mtb dissemination score and a higher risk of death, particularly within 7 days of admission. Most of the patients who died had severe anemia and had a more pronounced systemic inflammatory profile. Therefore, the results presented here reveal that severe anemia is associated with greater TB dissemination and increased risk of death in PLHIV. Early identification of such patients through measurement of Hb levels may drive closer monitoring to reduce mortality. Future investigations are warranted to test whether early interventions impact survival of this vulnerable population.},
author = {Ara{\'{u}}jo-Pereira, Mariana and Schutz, Charlotte and Barreto-Duarte, Beatriz and Barr, David and Villalva-Serra, Klauss and Vinhaes, Caian L. and Ward, Amy and Meintjes, Graeme and Andrade, Bruno B.},
doi = {10.3389/FIMMU.2023.1177432},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Ara{\'{u}}jo-Pereira et al. - 2023 - Interplay between systemic inflammation, anemia, and mycobacterial dissemination and its impact on mortal.pdf:pdf},
issn = {1664-3224},
journal = {Frontiers in Immunology},
keywords = {Anemia,HIV,Mortality,OA,OA{\_}PMC,Tuberculosis,fund{\_}ack,original,systemic inflammation},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,original},
month = {apr},
pages = {1177432},
pmid = {37143662},
publisher = {Frontiers},
title = {{Interplay between systemic inflammation, anemia, and mycobacterial dissemination and its impact on mortality in TB-associated HIV: a prospective cohort study}},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2023.1177432/full},
volume = {14},
year = {2023}
}

Anemia frequently affects people living with HIV (PLHIV). Nevertheless, the impact of anemia on treatment outcomes of patients with HIV-associated tuberculosis (TB) and the underlying molecular profiles are not fully characterized. The aim of this study was to investigate the interplay between anemia, the systemic inflammatory profile, dissemination of TB and death in HIV-TB patients in an ad hoc analysis of results from a prospective cohort study. 496 hospitalized PLHIV ≥18 years old, with CD4 count \textless350 cells/$μ$L and high clinical suspicion of new TB infection were enrolled in Cape Town between 2014-2016. Patients were classified according to anemia severity in non-anemic, mild, moderate, or severe anemia. Clinical, microbiologic, and immunologic data were collected at baseline. Hierarchical cluster analysis, degree of inflammatory perturbation, survival curves and C-statistics analyses were performed. Through the analysis of several clinical and laboratory parameters, we observed that those with severe anemia exhibited greater systemic inflammation, characterized by high concentrations of IL-8, IL-1RA and IL-6. Furthermore, severe anemia was associated with a higher Mtb dissemination score and a higher risk of death, particularly within 7 days of admission. Most of the patients who died had severe anemia and had a more pronounced systemic inflammatory profile. Therefore, the results presented here reveal that severe anemia is associated with greater TB dissemination and increased risk of death in PLHIV. Early identification of such patients through measurement of Hb levels may drive closer monitoring to reduce mortality. Future investigations are warranted to test whether early interventions impact survival of this vulnerable population.

@article{Zhao2023,
abstract = {Background: Dolutegravir concentrations are reduced by efavirenz induction effect necessitating twice daily dolutegravir dosing when co-administered. Efavirenz induction persists for several weeks after stopping, which could potentially select for dolutegravir resistance if switching occurred with unsuppressed HIV-1 RNA levels and standard dolutegravir dosing. We evaluated the need for a lead-in supplementary dolutegravir dose in adults failing first-line tenofovir-emtricitabine-efavirenz (TEE). Methods: We conducted a randomised, double-blind, placebo-controlled, phase 2 trial in Khayelitsha, South Africa. Eligible patients had virologic failure (two consecutive HIV-1 RNA≥1000 copies/mL) on first-line TEE. Participants were randomly assigned (1:1) to switch to 2 tenofovir-lamivudine-dolutegravir (TLD) with a supplementary 50 mg dolutegravir dose or placebo taken 12 hours later for 14 days. Primary outcome was proportion with HIV-1 RNA{\textless}50 copies/mL at week 24. This study was not powered to compare arms. Results: 130 participants were randomised (65 to each arm). Median baseline HIV-1 RNA was 4.0 log 10 copies/mL and 76{\%} had baseline resistance to both tenofovir and lamivudine. One participant died and two were lost to follow-up. At week 24, 55/64 (86{\%}, 95{\%} confidence interval [CI], 75-93{\%}) in the supplementary dolutegravir arm and 53/65 (82{\%}, 95{\%} CI, 70-90{\%}) in the placebo arm had HIV-1 RNA{\textless}50 copies/mL. Grade 3 or 4 adverse events were similar in frequency between arms. None of six participants (3 in each arm) eligible for resistance testing by 24 weeks developed dolutegravir resistance. Conclusions: Our findings do not support the need for initial dolutegravir dose adjustment in patients switching to TLD who failed first-line TEE. Clinical Trials Registration: NCT03991013},
author = {Zhao, Ying and Griesel, Rulan and Omar, Zaayid and Simmons, Bryony and Hill, Andrew and van Zyl, Gert and Keene, Claire and Maartens, Gary and Meintjes, Graeme A},
doi = {10.1093/CID/CIAD023},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Zhao et al. - 2023 - Initial supplementary dose of dolutegravir in second-line antiretroviral therapy a non-comparative, double-blind, r.pdf:pdf},
issn = {1058-4838},
journal = {Clinical Infectious Diseases},
keywords = {Antiretroviral therapy,HIV,OA,dolutegravir,efavirenz,fund{\_}ack,original,second-line},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jan},
number = {10},
pages = {1832--1840},
pmid = {36645792},
title = {{Initial supplementary dose of dolutegravir in second-line antiretroviral therapy: a non-comparative, double-blind, randomised placebo-controlled trial}},
url = {https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciad023/6988111},
volume = {76},
year = {2023}
}

Background: Dolutegravir concentrations are reduced by efavirenz induction effect necessitating twice daily dolutegravir dosing when co-administered. Efavirenz induction persists for several weeks after stopping, which could potentially select for dolutegravir resistance if switching occurred with unsuppressed HIV-1 RNA levels and standard dolutegravir dosing. We evaluated the need for a lead-in supplementary dolutegravir dose in adults failing first-line tenofovir-emtricitabine-efavirenz (TEE). Methods: We conducted a randomised, double-blind, placebo-controlled, phase 2 trial in Khayelitsha, South Africa. Eligible patients had virologic failure (two consecutive HIV-1 RNA≥1000 copies/mL) on first-line TEE. Participants were randomly assigned (1:1) to switch to 2 tenofovir-lamivudine-dolutegravir (TLD) with a supplementary 50 mg dolutegravir dose or placebo taken 12 hours later for 14 days. Primary outcome was proportion with HIV-1 RNA\textless50 copies/mL at week 24. This study was not powered to compare arms. Results: 130 participants were randomised (65 to each arm). Median baseline HIV-1 RNA was 4.0 log 10 copies/mL and 76% had baseline resistance to both tenofovir and lamivudine. One participant died and two were lost to follow-up. At week 24, 55/64 (86%, 95% confidence interval [CI], 75-93%) in the supplementary dolutegravir arm and 53/65 (82%, 95% CI, 70-90%) in the placebo arm had HIV-1 RNA\textless50 copies/mL. Grade 3 or 4 adverse events were similar in frequency between arms. None of six participants (3 in each arm) eligible for resistance testing by 24 weeks developed dolutegravir resistance. Conclusions: Our findings do not support the need for initial dolutegravir dose adjustment in patients switching to TLD who failed first-line TEE. Clinical Trials Registration: NCT03991013

@article{Stadler2023,
abstract = {Shorter (6-9 months), fully oral regimens containing new and repurposed drugs are now the first-choice option for the treatment of drug-resistant tuberculosis (DR-TB). Clofazimine, long used in the treatment of leprosy, is one such repurposed drug that has become a cornerstone of DR-TB treatment and ongoing trials are exploring novel, shorter clofazimine-containing regimens for drug-resistant as well as drug-susceptible tuberculosis. Clofazimine's repurposing was informed by evidence of potent activity against DR-TB strains in vitro and in mice and a treatment-shortening effect in DR-TB patients as part of a multidrug regimen. Clofazimine entered clinical use in the 1950s without the rigorous safety and pharmacokinetic evaluation which is part of modern drug development and current dosing is not evidence-based. Recent studies have begun to characterize clofazimine's exposure-response relationship for safety and efficacy in populations with TB. Despite being better tolerated than some other second-line TB drugs, the extent and impact of adverse effects including skin discolouration and cardiotoxicity are not well understood and together with emergent resistance, may undermine clofazimine use in DR-TB programmes. Furthermore, clofazimine's precise mechanism of action is not well established, as is the genetic basis of clofazimine resistance. In this narrative review, we present an overview of the evidence base underpinning the use and limitations of clofazimine as an antituberculosis drug and discuss advances in the understanding of clofazimine pharmacokinetics, toxicity, and resistance. The unusual pharmacokinetic properties of clofazimine and how these relate to its putative mechanism of action, antituberculosis activity, dosing considerations and adverse effects are highlighted. Finally, we discuss the development of novel riminophenazine analogues as antituberculosis drugs.},
author = {Stadler, Jacob A. M. and Maartens, Gary and Meintjes, Graeme and Wasserman, Sean},
doi = {10.3389/FPHAR.2023.1100488},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Stadler et al. - 2023 - Clofazimine for the treatment of tuberculosis.pdf:pdf},
issn = {1663-9812},
journal = {Frontiers in Pharmacology},
keywords = {B663,Clofazimine,Drug-resistant tuberculosis (DR-TB),Drug-resistant tuberculosis (MDR-TB-),OA,Riminophenazines,Tuberculosis,fund{\_}ack,review},
mendeley-tags = {OA,fund{\_}ack,review},
month = {feb},
pages = {163},
publisher = {Frontiers},
title = {{Clofazimine for the treatment of tuberculosis}},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2023.1100488/full},
volume = {14},
year = {2023}
}

Shorter (6-9 months), fully oral regimens containing new and repurposed drugs are now the first-choice option for the treatment of drug-resistant tuberculosis (DR-TB). Clofazimine, long used in the treatment of leprosy, is one such repurposed drug that has become a cornerstone of DR-TB treatment and ongoing trials are exploring novel, shorter clofazimine-containing regimens for drug-resistant as well as drug-susceptible tuberculosis. Clofazimine's repurposing was informed by evidence of potent activity against DR-TB strains in vitro and in mice and a treatment-shortening effect in DR-TB patients as part of a multidrug regimen. Clofazimine entered clinical use in the 1950s without the rigorous safety and pharmacokinetic evaluation which is part of modern drug development and current dosing is not evidence-based. Recent studies have begun to characterize clofazimine's exposure-response relationship for safety and efficacy in populations with TB. Despite being better tolerated than some other second-line TB drugs, the extent and impact of adverse effects including skin discolouration and cardiotoxicity are not well understood and together with emergent resistance, may undermine clofazimine use in DR-TB programmes. Furthermore, clofazimine's precise mechanism of action is not well established, as is the genetic basis of clofazimine resistance. In this narrative review, we present an overview of the evidence base underpinning the use and limitations of clofazimine as an antituberculosis drug and discuss advances in the understanding of clofazimine pharmacokinetics, toxicity, and resistance. The unusual pharmacokinetic properties of clofazimine and how these relate to its putative mechanism of action, antituberculosis activity, dosing considerations and adverse effects are highlighted. Finally, we discuss the development of novel riminophenazine analogues as antituberculosis drugs.

@article{Davies2023,
abstract = {Objectives: We aimed to compare the clinical severity of Omicron BA.4/BA.5 infection with BA.1 and ear- lier variant infections among laboratory-confirmed SARS-CoV-2 cases in the Western Cape, South Africa, using timing of infection to infer the lineage/variant causing infection. Methods: We included public sector patients aged ≥20 years with laboratory-confirmed COVID-19 be- tween May 01-May 21, 2022 (BA.4/BA.5 wave) and equivalent previous wave periods. We compared the risk between waves of (i) death and (ii) severe hospitalization/death (all within 21 days of diagnosis) using Cox regression adjusted for demographics, comorbidities, admission pressure, vaccination, and pre- vious infection. Results: Among 3793 patients from the BA.4/BA.5 wave and 190,836 patients from previous waves, the risk of severe hospitalization/death was similar in the BA.4/BA.5 and BA.1 waves (adjusted hazard ratio [aHR] 1.12; 95{\%} confidence interval [CI] 0.93; 1.34). Both Omicron waves had a lower risk of severe out- comes than previous waves. Previous infection (aHR 0.29, 95{\%} CI 0.24; 0.36) and vaccination (aHR 0.17; 95{\%} CI 0.07; 0.40 for at least three doses vs no vaccine) were protective. Conclusion: Disease severity was similar among diagnosed COVID-19 cases in the BA .4/BA .5 and BA .1 pe- riods in the context of growing immunity against SARS-CoV-2 due to previous infection and vaccination, both of which were strongly protective},
author = {Davies, Mary-Ann and Morden, Erna and Rousseau, Petro and Arendse, Juanita and Bam, Jamy-Lee and Boloko, Linda and Cloete, Keith and Cohen, Cheryl and Chetty, Nicole and Dane, Pierre and Heekes, Alexa and Hsiao, Nei-Yuan and Hunter, Mehreen and Hussey, Hannah and Jacobs, Theuns and Jassat, Waasila and Kariem, Saadiq and Kassanjee, Reshma and Laenen, Inneke and Roux, Sue Le and Lessells, Richard and Mahomed, Hassan and Maughan, Deborah and Meintjes, Graeme A and Mendelson, Marc and Mnguni, Ayanda and Moodley, Melvin and Murie, Katy and Naude, Jonathan and Ntusi, Ntobeko A B and Paleker, Masudah and Parker, Arifa and Pienaar, David and Preiser, Wolfgang and Prozesky, Hans and Raubenheimer, Peter and Rossouw, Liezel and Schrueder, Neshaad and Smith, Barry and Smith, Mariette and Solomon, Wesley and Symons, Greg and Taljaard, Jantjie and Wasserman, Sean and Wilkinson, Robert J and Wolmarans, Milani and Wolter, Nicole and Boulle, Andrew},
doi = {10.1016/J.IJID.2022.11.024},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Davies et al. - 2023 - Outcomes of laboratory-confirmed SARS-CoV-2 infection during resurgence driven by Omicron lineages BA.4 and BA.5.pdf:pdf},
issn = {1201-9712},
journal = {International Journal of Infectious Diseases},
keywords = {OA,OA{\_}PMC,OA{\_}repository,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,OA{\_}repository,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {feb},
pages = {63--68},
pmid = {36436752},
publisher = {Elsevier},
title = {{Outcomes of laboratory-confirmed SARS-CoV-2 infection during resurgence driven by Omicron lineages BA.4 and BA.5 compared with previous waves in the Western Cape Province, South Africa}},
url = {https://linkinghub.elsevier.com/retrieve/pii/S1201971222006154},
volume = {127},
year = {2023}
}

Objectives: We aimed to compare the clinical severity of Omicron BA.4/BA.5 infection with BA.1 and ear- lier variant infections among laboratory-confirmed SARS-CoV-2 cases in the Western Cape, South Africa, using timing of infection to infer the lineage/variant causing infection. Methods: We included public sector patients aged ≥20 years with laboratory-confirmed COVID-19 be- tween May 01-May 21, 2022 (BA.4/BA.5 wave) and equivalent previous wave periods. We compared the risk between waves of (i) death and (ii) severe hospitalization/death (all within 21 days of diagnosis) using Cox regression adjusted for demographics, comorbidities, admission pressure, vaccination, and pre- vious infection. Results: Among 3793 patients from the BA.4/BA.5 wave and 190,836 patients from previous waves, the risk of severe hospitalization/death was similar in the BA.4/BA.5 and BA.1 waves (adjusted hazard ratio [aHR] 1.12; 95% confidence interval [CI] 0.93; 1.34). Both Omicron waves had a lower risk of severe out- comes than previous waves. Previous infection (aHR 0.29, 95% CI 0.24; 0.36) and vaccination (aHR 0.17; 95% CI 0.07; 0.40 for at least three doses vs no vaccine) were protective. Conclusion: Disease severity was similar among diagnosed COVID-19 cases in the BA .4/BA .5 and BA .1 pe- riods in the context of growing immunity against SARS-CoV-2 due to previous infection and vaccination, both of which were strongly protective

@article{Campanico2023,
abstract = {While N‐acetyl azaaurones have already been disclosed for their potential against tuberculosis (TB), their low metabolic stability remains an unaddressed liability. We now report a study designed to improve the metabolic stability and solubility of the azaaurone scaffold and to identify the structural requirements for antimycobacterial activity. Replacing the N‐acetyl moiety for a N‐carbamoyl group led to analogues with sub‐ and nanomolar potencies against M. tuberculosis H37Rv, as well as equipotent against drug‐susceptible and drug‐resistant M. tuberculosis isolates. The new N‐carbamoyl azaaurones exhibited improved microsomal stability, compared to their N‐acetylated counterparts, with several compounds displaying moderate to high kinetic solubility. The frequency of spontaneous resistance to azaaurones was observed to be in the range of 10‐8, a value that is comparable to current TB drugs in the market. Overall, these results reveal that azaaurones are amenable to structural modifications to improve metabolic and solubility liabilities, and highlight their potential as antimycobacterial agents.},
author = {Campani{\c{c}}o, Andr{\'{e}} and Harjivan, Shrika G and Freitas, Elisabete and Serafini, Marco and Gaspar, Manuela M and Capela, Rita and Gomes, Pedro and Jordaan, Audrey and Madureira, Ana M and Andr{\'{e}}, V{\^{a}}nia and Silva, Andreia B and {Teresa Duarte}, M and Portugal, Isabel and Perdig{\~{a}}o, Jo{\~{a}}o and Moreira, Rui and Warner, Digby F and Lopes, Francisca},
doi = {10.1002/CMDC.202300410},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Campani{\c{c}}o et al. - 2023 - Structural optimization of antimycobacterial azaaurones towards improved solubility and metabolic stability.pdf:pdf},
issn = {1860-7187},
journal = {ChemMedChem},
keywords = {OA,activity relationships,azaaurones * M. tuberculosis * drug discovery * dr,fund{\_}not{\_}ack,original,resistant tuberculosis * Structure},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {oct},
pages = {e202300410},
pmid = {37845182},
publisher = {John Wiley {\&} Sons, Ltd},
title = {{Structural optimization of antimycobacterial azaaurones towards improved solubility and metabolic stability}},
url = {https://onlinelibrary.wiley.com/doi/full/10.1002/cmdc.202300410 https://onlinelibrary.wiley.com/doi/abs/10.1002/cmdc.202300410 https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202300410},
year = {2023}
}

While N‐acetyl azaaurones have already been disclosed for their potential against tuberculosis (TB), their low metabolic stability remains an unaddressed liability. We now report a study designed to improve the metabolic stability and solubility of the azaaurone scaffold and to identify the structural requirements for antimycobacterial activity. Replacing the N‐acetyl moiety for a N‐carbamoyl group led to analogues with sub‐ and nanomolar potencies against M. tuberculosis H37Rv, as well as equipotent against drug‐susceptible and drug‐resistant M. tuberculosis isolates. The new N‐carbamoyl azaaurones exhibited improved microsomal stability, compared to their N‐acetylated counterparts, with several compounds displaying moderate to high kinetic solubility. The frequency of spontaneous resistance to azaaurones was observed to be in the range of 10‐8, a value that is comparable to current TB drugs in the market. Overall, these results reveal that azaaurones are amenable to structural modifications to improve metabolic and solubility liabilities, and highlight their potential as antimycobacterial agents.

@article{Riou2023a,
abstract = {Background. We report the safety and immunogenicity of fractional and full dose Ad26.COV2.S and BNT162b2 in an open label phase 2 trial of participants previously vaccinated with a single dose of Ad26.COV2.S, with 91.4{\%} showing evidence of previous SARS-CoV-2 infection. Methods. A total of 286 adults (with or without HIV) were enrolled {\textgreater}4 months after an Ad26.COV2.S prime and randomized 1:1:1:1 to receive either a full or half-dose booster of Ad26.COV2.S or BNT162b2 vaccine. B cell responses (binding, neutralization and antibody dependent cellular cytotoxicity-ADCC), and spike-specific T-cell responses were evaluated at baseline, 2, 12 and 24 weeks post-boost. Antibody and T-cell immunity targeting the Ad26 vector was also evaluated. Results. No vaccine-associated serious adverse events were recorded. The full- and half-dose BNT162b2 boosted anti-SARS-CoV-2 binding antibody levels (3.9- and 4.5-fold, respectively) and neutralizing antibody levels (4.4- and 10-fold). Binding and neutralizing antibodies following half-dose Ad26.COV2.S were not significantly boosted. Full-dose Ad26.COV2.S did not boost binding antibodies but slightly enhanced neutralizing antibodies (2.1-fold). ADCC was marginally increased only after a full-dose BNT162b2. T-cell responses followed a similar pattern to neutralizing antibodies. Six months post-boost, antibody and T-cell responses had waned to baseline levels. While we detected strong anti-vector immunity, there was no correlation between anti-vector immunity in Ad26.COV2.S recipients and spike-specific neutralizing antibody or T-cell responses post-Ad26.COV2.S boosting. Conclusion. In the context of hybrid immunity, boosting with heterologous full- or half-dose BNT162b2 mRNA vaccine demonstrated superior immunogenicity 2 weeks post-vaccination compared to homologous Ad26.COV2.S, though rapid waning occurred by 12 weeks post-boost. Trial Registration: South African National Clinical Trial Registry (SANCR): DOH-27-012022-7841; Funding: South African Medical Research Council (SAMRC) and South African Department of Health (SA DoH). {\#}{\#}{\#} Competing Interest Statement I have read the journal's policy and the authors of this manuscript have the following competing interests: A.Se. is a consultant for AstraZeneca Pharmaceuticals, Calyptus Pharmaceuticals, Inc, Darwin Health, EmerVax, EUROIMMUN, F. Hoffman-La Roche Ltd, Fortress Biotech, Gilead Sciences, Granite bio., Gritstone Oncology, Guggenheim Securities, Moderna, Pfizer, RiverVest Venture Partners, and Turnstone Biologics. A.G. is a consultant for Pfizer. LJI has filed for patent protection for various aspects of T cell epitope and vaccine design work. All other authors declare no competing interests {\#}{\#}{\#} Clinical Trial The study has been registered to the South African National Clinical Trial Registry (SANCR): DOH-27-012022-7841. {\#}{\#}{\#} Funding Statement yes This study was funded by the South African Medical research Council (SAMRC), the Bill and Melinda Gates Foundation, through the Global Immunology and Immune Sequencing for Epidemic Response (GIISER) program (INV-030570) and the Wellcome Trust (226137/Z/22/Z). P.L.M is supported by the SAMRC (96833) and is an Department of Science and Innovation-National Research Foundation South African Research Chair (98341). A.Si. is supported by the Bill and Melinda Gates foundation (INV-046743) and the SAMRC (D2112300-01). W.A.B. is supported by the EDCTP2 program of the European Union's Horizon 2020 programme (TMA2016SF-1535-CaTCH-22) and the EU-Africa Concerted Action on SARS-CoV-2 Virus Variant and Immunological Surveillance (COVICIS), funded through the EU's Horizon Europe Research and Innovation Programme (101046041). C.R. is supported by the EDCTP2 program (TMA2017SF-1951-TB-SPEC). This project has also been funded in part by the National Institute of Allergy and Infectious Diseases, NIH, Department of Health and Human Services, under Contract No. 75N93021C00016 to A.G. and 75N93019C00065 to A.Se. The Wits RHI site received grant funding from Janssen to conduct the following clinical trials: Ensemble study (3UM1 AI068614-14SI), the Sisonke 1 study (96833), the Sherpa Study (96867) as well as Pfizer for the Pfizer C4591015 study (C4591015), Horizon 1 (VAC31518COV2004) and Horizon 2 (VAC31518COV3006). For the purposes of open access, the authors have applied a CC-BY public copyright license to any author-accepted version. {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study has been approved by the South African Health Products Regulatory Authority (SAHPRA) and all site-specific Human Research Ethics Committees (HREC numbers: Wits 211001B, UKZN: BREC/00003487/2021, UCT 680/2021 SAHPRA: 20210423). All participants provided written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data underlying the findings described in this manuscript may be obtained from the lead authors upon request.},
author = {Riou, Catherine and Bhiman, Jinal N and Ganga, Yashica and Sawry, Shobna and Ayres, Frances and Baguma, Richard and Balla, Sashkia R and Benede, Ntombi and Bernstein, Mallory and Besethi, Asiphe S and Cele, Sandile and Crowther, Carol and Dhar, Mrinmayee and Geyer, Sohair and Gill, Katherine and Grifoni, Alba and Hermanus, Tandile and Kaldine, Haajira and Keeton, Roanne S and Kgagudi, Prudence and Khan, Khadija and Lazarus, Erica and Roux, Jean Le and Lustig, Gila and Madzivhandila, Mashudu and Magugu, Siyabulela FJ and Makhado, Zanele and Manamela, Nelia P and Mkhize, Qiniso and Mosala, Paballo and Motlou, Thopisang P and Mutavhatsindi, Hygon and Mzindle, Nonkululeko B and Nana, Anusha and Nesamari, Rofhiwa and Ngomti, Amkele and Nkayi, Anathi A and Nkosi, Thandeka P and Omondi, Millicent A and Panchia, Ravindre and Patel, Faeezah and Sette, Alessandro and Singh, Upasna and van Graan, Strauss and Venter, Elizabeth M. and Walters, Avril and Moyo-Gwete, Thandeka and Richardson, Simone I. and Garrett, Nigel and Rees, Helen and Bekker, Linda-Gail and Gray, Glenda and Burgers, Wendy A. and Sigal, Alex and Moore, Penny L and Fairlie, Lee},
doi = {10.1101/2023.11.20.23298785},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Riou et al. - 2023 - Safety and immunogenicity of booster vaccination and fractional dosing with Ad26.COV2.S or BNT162b2 in Ad26.COV2.S-.pdf:pdf},
journal = {medRxiv},
keywords = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {nov},
pages = {2023.11.20.23298785},
pmid = {38045321},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Safety and immunogenicity of booster vaccination and fractional dosing with Ad26.COV2.S or BNT162b2 in Ad26.COV2.S-vaccinated participants}},
url = {https://www.medrxiv.org/content/10.1101/2023.11.20.23298785v1 https://www.medrxiv.org/content/10.1101/2023.11.20.23298785v1.abstract},
year = {2023}
}

Background. We report the safety and immunogenicity of fractional and full dose Ad26.COV2.S and BNT162b2 in an open label phase 2 trial of participants previously vaccinated with a single dose of Ad26.COV2.S, with 91.4% showing evidence of previous SARS-CoV-2 infection. Methods. A total of 286 adults (with or without HIV) were enrolled \textgreater4 months after an Ad26.COV2.S prime and randomized 1:1:1:1 to receive either a full or half-dose booster of Ad26.COV2.S or BNT162b2 vaccine. B cell responses (binding, neutralization and antibody dependent cellular cytotoxicity-ADCC), and spike-specific T-cell responses were evaluated at baseline, 2, 12 and 24 weeks post-boost. Antibody and T-cell immunity targeting the Ad26 vector was also evaluated. Results. No vaccine-associated serious adverse events were recorded. The full- and half-dose BNT162b2 boosted anti-SARS-CoV-2 binding antibody levels (3.9- and 4.5-fold, respectively) and neutralizing antibody levels (4.4- and 10-fold). Binding and neutralizing antibodies following half-dose Ad26.COV2.S were not significantly boosted. Full-dose Ad26.COV2.S did not boost binding antibodies but slightly enhanced neutralizing antibodies (2.1-fold). ADCC was marginally increased only after a full-dose BNT162b2. T-cell responses followed a similar pattern to neutralizing antibodies. Six months post-boost, antibody and T-cell responses had waned to baseline levels. While we detected strong anti-vector immunity, there was no correlation between anti-vector immunity in Ad26.COV2.S recipients and spike-specific neutralizing antibody or T-cell responses post-Ad26.COV2.S boosting. Conclusion. In the context of hybrid immunity, boosting with heterologous full- or half-dose BNT162b2 mRNA vaccine demonstrated superior immunogenicity 2 weeks post-vaccination compared to homologous Ad26.COV2.S, though rapid waning occurred by 12 weeks post-boost. Trial Registration: South African National Clinical Trial Registry (SANCR): DOH-27-012022-7841; Funding: South African Medical Research Council (SAMRC) and South African Department of Health (SA DoH). ### Competing Interest Statement I have read the journal's policy and the authors of this manuscript have the following competing interests: A.Se. is a consultant for AstraZeneca Pharmaceuticals, Calyptus Pharmaceuticals, Inc, Darwin Health, EmerVax, EUROIMMUN, F. Hoffman-La Roche Ltd, Fortress Biotech, Gilead Sciences, Granite bio., Gritstone Oncology, Guggenheim Securities, Moderna, Pfizer, RiverVest Venture Partners, and Turnstone Biologics. A.G. is a consultant for Pfizer. LJI has filed for patent protection for various aspects of T cell epitope and vaccine design work. All other authors declare no competing interests ### Clinical Trial The study has been registered to the South African National Clinical Trial Registry (SANCR): DOH-27-012022-7841. ### Funding Statement yes This study was funded by the South African Medical research Council (SAMRC), the Bill and Melinda Gates Foundation, through the Global Immunology and Immune Sequencing for Epidemic Response (GIISER) program (INV-030570) and the Wellcome Trust (226137/Z/22/Z). P.L.M is supported by the SAMRC (96833) and is an Department of Science and Innovation-National Research Foundation South African Research Chair (98341). A.Si. is supported by the Bill and Melinda Gates foundation (INV-046743) and the SAMRC (D2112300-01). W.A.B. is supported by the EDCTP2 program of the European Union's Horizon 2020 programme (TMA2016SF-1535-CaTCH-22) and the EU-Africa Concerted Action on SARS-CoV-2 Virus Variant and Immunological Surveillance (COVICIS), funded through the EU's Horizon Europe Research and Innovation Programme (101046041). C.R. is supported by the EDCTP2 program (TMA2017SF-1951-TB-SPEC). This project has also been funded in part by the National Institute of Allergy and Infectious Diseases, NIH, Department of Health and Human Services, under Contract No. 75N93021C00016 to A.G. and 75N93019C00065 to A.Se. The Wits RHI site received grant funding from Janssen to conduct the following clinical trials: Ensemble study (3UM1 AI068614-14SI), the Sisonke 1 study (96833), the Sherpa Study (96867) as well as Pfizer for the Pfizer C4591015 study (C4591015), Horizon 1 (VAC31518COV2004) and Horizon 2 (VAC31518COV3006). For the purposes of open access, the authors have applied a CC-BY public copyright license to any author-accepted version. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study has been approved by the South African Health Products Regulatory Authority (SAHPRA) and all site-specific Human Research Ethics Committees (HREC numbers: Wits 211001B, UKZN: BREC/00003487/2021, UCT 680/2021 SAHPRA: 20210423). All participants provided written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data underlying the findings described in this manuscript may be obtained from the lead authors upon request.

@incollection{Sawhney2023a,
abstract = {In late December 2019, an outbreak of novel coronavirus disease 2019 (COVID-19) emerged in Wuhan, China, and spread throughout the world very quickly. COVID-19 is a viral disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 patients show flulike symptoms such as sore throat, fatigue, dry cough, high fever, and respiratory problems. On March 11, 2020, the World Health Organization declared the worldwide outbreak of COVID-19 a pandemic. About 760 million people have been infected and more than 6.5 million deaths have been reported globally, and the incidents are not under control in several underserved and underdeveloped regions despite the advances in vaccination modalities. Therefore, treatment options are urgently needed to combat this virus. As it may require a considerable length of time to develop a new drug for COVID-19, it is required to emphasize the repurposing of drugs. No specific vaccines are validated to have significant efficacy against COVID-19. So far, the treatment given is symptomatic and supportive. Broad-spectrum drugs currently under consideration for treatment of COVID-19 include antiviral drugs like remdesivir, favipiravir, interferon, lopinavir and ritonavir (HIV protease inhibitor), ribavirin, anti-malarial/inflammatory drugs chloroquine, hydroxychloroquine, tocilizumab, and corticosteroids. Convalescent plasma of COVID-19 recovered patients was also used for therapeutic purposes as a last resort in worsening conditions. The aim of this section is to discuss the evidence for treatment options available and ongoing efforts towards novel therapies as well as to identify prospective treatment options that could revolutionize the therapeutic approach of COVID-19, especially in chronic conditions. {\textcopyright} 2024 Sabyasachi Dash.},
author = {Sawhney, Gifty and Kumar, Parveen and Parihar, Suraj P and Sharma, Mohit},
booktitle = {RNA Viruses and Neurological Disorders},
doi = {10.1201/9781003285823-11},
isbn = {9781000998399},
keywords = {book{\_}chap},
mendeley-tags = {book{\_}chap},
month = {jan},
pages = {159 -- 178},
publisher = {CRC Press},
title = {{An insight into the symptomatic treatment modalities for COVID-19}},
year = {2023}
}

In late December 2019, an outbreak of novel coronavirus disease 2019 (COVID-19) emerged in Wuhan, China, and spread throughout the world very quickly. COVID-19 is a viral disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 patients show flulike symptoms such as sore throat, fatigue, dry cough, high fever, and respiratory problems. On March 11, 2020, the World Health Organization declared the worldwide outbreak of COVID-19 a pandemic. About 760 million people have been infected and more than 6.5 million deaths have been reported globally, and the incidents are not under control in several underserved and underdeveloped regions despite the advances in vaccination modalities. Therefore, treatment options are urgently needed to combat this virus. As it may require a considerable length of time to develop a new drug for COVID-19, it is required to emphasize the repurposing of drugs. No specific vaccines are validated to have significant efficacy against COVID-19. So far, the treatment given is symptomatic and supportive. Broad-spectrum drugs currently under consideration for treatment of COVID-19 include antiviral drugs like remdesivir, favipiravir, interferon, lopinavir and ritonavir (HIV protease inhibitor), ribavirin, anti-malarial/inflammatory drugs chloroquine, hydroxychloroquine, tocilizumab, and corticosteroids. Convalescent plasma of COVID-19 recovered patients was also used for therapeutic purposes as a last resort in worsening conditions. The aim of this section is to discuss the evidence for treatment options available and ongoing efforts towards novel therapies as well as to identify prospective treatment options that could revolutionize the therapeutic approach of COVID-19, especially in chronic conditions. © 2024 Sabyasachi Dash.

@article{Gessner2023,
abstract = {A DNA damage-inducible mutagenic gene cassette has been implicated in the emergence of drug resistance in Mycobacterium tuberculosis during anti-tuberculosis (TB) chemotherapy. However, the molecular composition and operation of the encoded ‘mycobacterial mutasome' – minimally comprising DnaE2 polymerase and ImuA′ and ImuB accessory proteins – remain elusive. Following exposure of mycobacteria to DNA damaging agents, we observe that DnaE2 and ImuB co-localize with the DNA polymerase III $\beta$ subunit ($\beta$ clamp) in distinct intracellular foci. Notably, genetic inactivation of the mutasome in an imuBAAAAGG mutant containing a disrupted $\beta$ clamp-binding motif abolishes ImuB–$\beta$ clamp focus formation, a phenotype recapitulated pharmacologically by treating bacilli with griselimycin and in biochemical assays in which this $\beta$ clamp-binding antibiotic collapses pre-formed ImuB–$\beta$ clamp complexes. These observations establish the essentiality of the ImuB–$\beta$ clamp interaction for mutagenic DNA repair in mycobacteria, identifying the mutasome as target for adjunctive therapeutics designed to protect anti-TB drugs against emerging resistance.},
author = {Gessner, Sophia and Martin, Zela Alexandria-Mae and Reiche, Michael A and Santos, Joana A and Dinkele, Ryan and Ramudzuli, Atondaho and Dhar, Neeraj and de Wet, Timothy J and Anoosheh, Saber and Lang, Dirk M and Aaron, Jesse and Chew, Teng-Leong and Herrmann, Jennifer and M{\"{u}}ller, Rolf and McKinney, John D and Woodgate, Roger and Mizrahi, Valerie and Venclovas, {\v{C}}eslovas and Lamers, Meindert H and Warner, Digby F},
doi = {10.7554/eLife.75628},
editor = {Stallings, Christina L and Soldati-Favre, Dominique},
issn = {2050-084X},
journal = {eLife},
keywords = {Mycobacterium smegmatis,Mycobacterium tuberculosis,OA,OA{\_}PMC,anti-evolution,antibiotic resistance,fund{\_}not{\_}ack,induced mutagenesis,mutasome,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
pages = {e75628},
pmid = {37530405},
publisher = {eLife Sciences Publications, Ltd},
title = {{Investigating the composition and recruitment of the mycobacterial ImuA′–ImuB–DnaE2 mutasome}},
url = {https://doi.org/10.7554/eLife.75628},
volume = {12},
year = {2023}
}

A DNA damage-inducible mutagenic gene cassette has been implicated in the emergence of drug resistance in Mycobacterium tuberculosis during anti-tuberculosis (TB) chemotherapy. However, the molecular composition and operation of the encoded ‘mycobacterial mutasome' – minimally comprising DnaE2 polymerase and ImuA′ and ImuB accessory proteins – remain elusive. Following exposure of mycobacteria to DNA damaging agents, we observe that DnaE2 and ImuB co-localize with the DNA polymerase III $β$ subunit ($β$ clamp) in distinct intracellular foci. Notably, genetic inactivation of the mutasome in an imuBAAAAGG mutant containing a disrupted $β$ clamp-binding motif abolishes ImuB–$β$ clamp focus formation, a phenotype recapitulated pharmacologically by treating bacilli with griselimycin and in biochemical assays in which this $β$ clamp-binding antibiotic collapses pre-formed ImuB–$β$ clamp complexes. These observations establish the essentiality of the ImuB–$β$ clamp interaction for mutagenic DNA repair in mycobacteria, identifying the mutasome as target for adjunctive therapeutics designed to protect anti-TB drugs against emerging resistance.

@article{Mullins2023,
abstract = {The COVID-19 pandemic continues to affect individuals across the globe, with some individuals experiencing more severe disease than others. The relatively high frequency of re-infections and breakthrough infections observed with SARS-CoV-2 highlights the importance of extending our understanding of immunity to COVID-19. Here, we aim to shed light on the importance of antibody titres and epitope utilization in protection from re-infection. Health care workers are highly exposed to SARS-CoV-2 and are therefore also more likely to become re-infected. We utilized quantitative, multi-antigen, multi-epitope SARS-CoV-2 protein microarrays to measure IgG and IgA titres against various domains of the nucleocapsid and spike proteins. Potential re-infections in a large, diverse health care worker cohort (N = 300) during the second wave of the pandemic were identified by assessing the IgG anti-N titres before and after the second wave. We assessed epitope coverage and antibody titres between the ‘single infection' and ‘re-infection' groups. Clear differences were observed in the breadth of the anti-N response before the second wave, with the epitope coverage for both IgG (p = 0.019) and IgA (p = 0.015) being significantly increased in those who did not become re-infected compared to those who did. Additionally, the IgG anti-N (p = 0.004) and anti-S titres (p = 0.018) were significantly higher in those not re-infected. These results highlight the importance of the breadth of elicited antibody epitope coverage following natural infection in protection from re-infection and disease in the COVID-19 pandemic.},
author = {Mullins, Michelle O and Smith, Muneerah and Maboreke, Hazel and Nel, Andrew J M and Ntusi, Ntobeko A B and Burgers, Wendy A and Blackburn, Jonathan M},
doi = {10.3390/V15020584},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Mullins et al. - 2023 - Epitope coverage of anti-SARS-CoV-2 nucleocapsid IgA and IgG antibodies correlates with protection against re-in.pdf:pdf},
issn = {1999-4915},
journal = {Viruses},
keywords = {COVID-19* / epidemiology,Epitopes,Humans,Immunoglobulin A,Immunoglobulin G,Jonathan M Blackburn,MEDLINE,Michelle O Mullins,Muneerah Smith,NCBI,NIH,NLM,National Center for Biotechnology Information,National Institutes of Health,National Library of Medicine,Nucleocapsid,OA,OA{\_}PMC,PMC9967965,Pandemics,PubMed Abstract,Reinfection,SARS-CoV-2*,doi:10.3390/v15020584,fund{\_}not{\_}ack,original,pmid:36851798},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {feb},
number = {2},
pages = {584},
pmid = {36851798},
publisher = {Viruses},
title = {{Epitope coverage of anti-SARS-CoV-2 nucleocapsid IgA and IgG antibodies correlates with protection against re-infection by new variants in subsequent waves of the COVID-19 pandemic}},
url = {https://pubmed.ncbi.nlm.nih.gov/36851798/},
volume = {15},
year = {2023}
}

The COVID-19 pandemic continues to affect individuals across the globe, with some individuals experiencing more severe disease than others. The relatively high frequency of re-infections and breakthrough infections observed with SARS-CoV-2 highlights the importance of extending our understanding of immunity to COVID-19. Here, we aim to shed light on the importance of antibody titres and epitope utilization in protection from re-infection. Health care workers are highly exposed to SARS-CoV-2 and are therefore also more likely to become re-infected. We utilized quantitative, multi-antigen, multi-epitope SARS-CoV-2 protein microarrays to measure IgG and IgA titres against various domains of the nucleocapsid and spike proteins. Potential re-infections in a large, diverse health care worker cohort (N = 300) during the second wave of the pandemic were identified by assessing the IgG anti-N titres before and after the second wave. We assessed epitope coverage and antibody titres between the ‘single infection' and ‘re-infection' groups. Clear differences were observed in the breadth of the anti-N response before the second wave, with the epitope coverage for both IgG (p = 0.019) and IgA (p = 0.015) being significantly increased in those who did not become re-infected compared to those who did. Additionally, the IgG anti-N (p = 0.004) and anti-S titres (p = 0.018) were significantly higher in those not re-infected. These results highlight the importance of the breadth of elicited antibody epitope coverage following natural infection in protection from re-infection and disease in the COVID-19 pandemic.

@article{Kassanjee2023,
abstract = {Introduction: While a large proportion of people with HIV (PWH) have experienced SARS-CoV-2 infections, there is uncertainty about the role of HIV disease severity on COVID-19 outcomes, especially in lower-income settings. We studied the association of mortality with characteristics of HIV severity and management, and vaccination, among adult PWH. Methods: We analysed observational cohort data on all PWH aged ≥15 years experiencing a diagnosed SARS-CoV-2 infection (until March 2022), who accessed public sector healthcare in the Western Cape province of South Africa. Logistic regression was used to study the association of mortality with evidence of antiretroviral therapy (ART) collection, time since first HIV evidence, CD4 cell count, viral load (among those with evidence of ART collection) and COVID-19 vaccination, adjusting for demographic characteristics, comorbidities, admission pressure, location and time period. Results: Mortality occurred in 5.7{\%} (95{\%} CI: 5.3,6.0) of 17,831 first-diagnosed infections. Higher mortality was associated with lower recent CD4, no evidence of ART collection, high or unknown recent viral load and recent first HIV evidence, differentially by age. Vaccination was protective. The burden of comorbidities was high, and tuberculosis (especially more recent episodes of tuberculosis), chronic kidney disease, diabetes and hypertension were associated with higher mortality, more strongly in younger adults. Conclusions: Mortality was strongly associated with suboptimal HIV control, and the prevalence of these risk factors increased in later COVID-19 waves. It remains a public health priority to ensure PWH are on suppressive ART and vaccinated , and manage any disruptions in care that occurred during the pandemic. The diagnosis and management of comorbidi-ties, including for tuberculosis, should be optimized.},
author = {Kassanjee, Reshma and Davies, Mary-Ann and Ngwenya, Olina and Osei-Yeboah, Richard and Jacobs, Theuns and Morden, Erna and Timmerman, Venessa and Britz, Stefan and Mendelson, Marc and Taljaard, Jantjie and Riou, Julien and Boulle, Andrew and Tiffin, Nicki and Zinyakatira, Nesbert},
doi = {10.1002/JIA2.26104},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Kassanjee et al. - 2023 - COVID-19 among adults living with HIV correlates of mortality among public sector healthcare users in Western.pdf:pdf},
issn = {1758-2652},
journal = {Journal of the International AIDS Society},
keywords = {19,2,CD4 count,COVID,CoV,HIV,OA,OA{\_}PMC,SARS,South Africa,fund{\_}ack,genomics{\_}fund{\_}ack,mortality,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {jun},
number = {6},
pages = {e26104},
pmid = {37339333},
publisher = {John Wiley {\&} Sons, Ltd},
title = {{COVID-19 among adults living with HIV: correlates of mortality among public sector healthcare users in Western Cape, South Africa}},
url = {https://onlinelibrary.wiley.com/doi/full/10.1002/jia2.26104 https://onlinelibrary.wiley.com/doi/abs/10.1002/jia2.26104 https://onlinelibrary.wiley.com/doi/10.1002/jia2.26104},
volume = {26},
year = {2023}
}

Introduction: While a large proportion of people with HIV (PWH) have experienced SARS-CoV-2 infections, there is uncertainty about the role of HIV disease severity on COVID-19 outcomes, especially in lower-income settings. We studied the association of mortality with characteristics of HIV severity and management, and vaccination, among adult PWH. Methods: We analysed observational cohort data on all PWH aged ≥15 years experiencing a diagnosed SARS-CoV-2 infection (until March 2022), who accessed public sector healthcare in the Western Cape province of South Africa. Logistic regression was used to study the association of mortality with evidence of antiretroviral therapy (ART) collection, time since first HIV evidence, CD4 cell count, viral load (among those with evidence of ART collection) and COVID-19 vaccination, adjusting for demographic characteristics, comorbidities, admission pressure, location and time period. Results: Mortality occurred in 5.7% (95% CI: 5.3,6.0) of 17,831 first-diagnosed infections. Higher mortality was associated with lower recent CD4, no evidence of ART collection, high or unknown recent viral load and recent first HIV evidence, differentially by age. Vaccination was protective. The burden of comorbidities was high, and tuberculosis (especially more recent episodes of tuberculosis), chronic kidney disease, diabetes and hypertension were associated with higher mortality, more strongly in younger adults. Conclusions: Mortality was strongly associated with suboptimal HIV control, and the prevalence of these risk factors increased in later COVID-19 waves. It remains a public health priority to ensure PWH are on suppressive ART and vaccinated , and manage any disruptions in care that occurred during the pandemic. The diagnosis and management of comorbidi-ties, including for tuberculosis, should be optimized.

@article{Eikelboom2023,
author = {Eikelboom, John W and Belley-Cote, Emilie and Whitlock, Richard P and Jolly, Sanjit S and Wasserman, Sean and Yusuf, Salim and Committee†, ACT Trials Steering},
doi = {10.1016/S2213-2600(23)00148-0},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Eikelboom et al. - 2023 - ACT trials long-term outcomes.pdf:pdf},
issn = {22132600},
journal = {The Lancet Respiratory Medicine},
keywords = {OA,OA{\_}PMC,fund{\_}not{\_}ack,letter},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,letter},
month = {jun},
number = {6},
pages = {e50},
pmid = {37263712},
publisher = {Elsevier},
title = {{ACT trials: long-term outcomes}},
url = {/pmc/articles/PMC10229098/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10229098/},
volume = {11},
year = {2023}
}

@article{Oderinlo2023,
abstract = {Compounds containing arylpyrrole-, 1,2,4-triazole- and hydrazone structural frameworks have been widely studied and demonstrated to exhibit a wide range of pharmacological properties. Herein, an exploratory series of new 1,2,4-triazole derivatives designed by amalgamation of arylpyrrole and 1,2,4-triazole structural units via a hydrazone linkage is reported. The synthesised compounds were tested in vitro for their potential activity against Mycobacterium tuberculosis (MTB) H37Rv strain. The most promising compound 13 – the derivative without the benzene ring appended to the pyrrole unit displayed acceptable activity (MIC90=3.99 $\mu$M) against MTB H37Rv, while other compounds from the series exhibited modest to weak antimycobacterial activity with MIC90 values in the range between 7.0 and {\textgreater}125 $\mu$M. Furthermore, in silico results, predicated using the SwissADME web tool, show that the prepared compounds display desirable ADME profile with parameters within acceptable range.},
author = {Oderinlo, Ogunyemi O and Jordaan, Audrey and Seldon, Ronnett and Isaacs, Michelle and Hoppe, Heinrich C and Warner, Digby F and Tukulula, Matshawandile and Khanye, Setshaba D},
doi = {10.1002/CMDC.202200572},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Oderinlo et al. - 2023 - Hydrazone-tethered 5-(pyridin-4-yl)-4H-1,2,4-triazole-3-thiol hybrids synthesis, characterisation, in silico AD.pdf:pdf},
issn = {1860-7187},
journal = {ChemMedChem},
keywords = {1,2,4-Triazoles.,Arylpyrroles,Hydrazone,Molecular hybridisation,Mycobacterium tuberculosis,OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
pages = {e202200572},
pmid = {36617507},
publisher = {John Wiley {\&} Sons, Ltd},
title = {{Hydrazone-tethered 5-(pyridin-4-yl)-4H-1,2,4-triazole-3-thiol hybrids: synthesis, characterisation, \textit{in silico} ADME studies, and \textit{in vitro} antimycobacterial evaluation and cytotoxicity}},
url = {https://onlinelibrary.wiley.com/doi/full/10.1002/cmdc.202200572 https://onlinelibrary.wiley.com/doi/abs/10.1002/cmdc.202200572 https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202200572},
year = {2023}
}

Compounds containing arylpyrrole-, 1,2,4-triazole- and hydrazone structural frameworks have been widely studied and demonstrated to exhibit a wide range of pharmacological properties. Herein, an exploratory series of new 1,2,4-triazole derivatives designed by amalgamation of arylpyrrole and 1,2,4-triazole structural units via a hydrazone linkage is reported. The synthesised compounds were tested in vitro for their potential activity against Mycobacterium tuberculosis (MTB) H37Rv strain. The most promising compound 13 – the derivative without the benzene ring appended to the pyrrole unit displayed acceptable activity (MIC90=3.99 $μ$M) against MTB H37Rv, while other compounds from the series exhibited modest to weak antimycobacterial activity with MIC90 values in the range between 7.0 and \textgreater125 $μ$M. Furthermore, in silico results, predicated using the SwissADME web tool, show that the prepared compounds display desirable ADME profile with parameters within acceptable range.

@article{Basit2023,
abstract = {COVID-19 has taken a huge toll on our lives over the last 3 years. Global initiatives put forward by all stakeholders are still in place to combat this pandemic and help us learn lessons for future ones. While the vaccine rollout was not able to curb the spread of the disease for all strains, the research community is still trying to develop effective therapeutics for COVID-19. Although Paxlovid and remdesivir have been approved by the FDA against COVID-19, they are not free of side effects. Therefore, the search for a therapeutic solution with high efficacy continues in the research community. To support this effort, in this latest version (v3) of COVID-19Base, we have summarized the biomedical entities linked to COVID-19 that have been highlighted in the scientific literature after the vaccine rollout. Eight different topic-specific dictionaries, i.e., gene, miRNA, lncRNA, PDB entries, disease, alternative medicines registered under clinical trials, drugs, and the side effects of drugs, were used to build this knowledgebase. We have introduced a BLSTM-based deep-learning model to predict the drug-disease associations that outperforms the existing model for the same purpose proposed in the earlier version of COVID-19Base. For the very first time, we have incorporated disease-gene, disease-miRNA, disease-lncRNA, and drug-PDB associations covering the largest number of biomedical entities related to COVID-19. We have provided examples of and insights into different biomedical entities covered in COVID-19Base to support the research community by incorporating all of these entities under a single platform to provide evidence-based support from the literature. COVID-19Base v3 can be accessed from: https://covidbase-v3.vercel.app/ . The GitHub repository for the source code and data dictionaries is available to the community from: https://github.com/91Abdullah/covidbasev3.0 .},
author = {Basit, Syed Abdullah and Qureshi, Rizwan and Musleh, Saleh and Guler, Reto and Rahman, M. Sohel and Biswas, Kabir H. and Alam, Tanvir},
doi = {10.3389/FPUBH.2023.1125917/BIBTEX},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Basit et al. - 2023 - COVID-19Base v3 Update of the knowledgebase for drugs and biomedical entities linked to COVID-19.pdf:pdf},
issn = {22962565},
journal = {Frontiers in Public Health},
keywords = {CORD-19,COVID - 19,OA,SARS-CoV-2,deep learning,fund{\_}not{\_}ack,machine learning,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {mar},
pages = {579},
publisher = {Frontiers Media SA},
title = {{COVID-19Base v3: Update of the knowledgebase for drugs and biomedical entities linked to COVID-19}},
volume = {11},
year = {2023}
}

COVID-19 has taken a huge toll on our lives over the last 3 years. Global initiatives put forward by all stakeholders are still in place to combat this pandemic and help us learn lessons for future ones. While the vaccine rollout was not able to curb the spread of the disease for all strains, the research community is still trying to develop effective therapeutics for COVID-19. Although Paxlovid and remdesivir have been approved by the FDA against COVID-19, they are not free of side effects. Therefore, the search for a therapeutic solution with high efficacy continues in the research community. To support this effort, in this latest version (v3) of COVID-19Base, we have summarized the biomedical entities linked to COVID-19 that have been highlighted in the scientific literature after the vaccine rollout. Eight different topic-specific dictionaries, i.e., gene, miRNA, lncRNA, PDB entries, disease, alternative medicines registered under clinical trials, drugs, and the side effects of drugs, were used to build this knowledgebase. We have introduced a BLSTM-based deep-learning model to predict the drug-disease associations that outperforms the existing model for the same purpose proposed in the earlier version of COVID-19Base. For the very first time, we have incorporated disease-gene, disease-miRNA, disease-lncRNA, and drug-PDB associations covering the largest number of biomedical entities related to COVID-19. We have provided examples of and insights into different biomedical entities covered in COVID-19Base to support the research community by incorporating all of these entities under a single platform to provide evidence-based support from the literature. COVID-19Base v3 can be accessed from: https://covidbase-v3.vercel.app/ . The GitHub repository for the source code and data dictionaries is available to the community from: https://github.com/91Abdullah/covidbasev3.0 .

@article{AbdelAziz2023,
abstract = {C57BL/6 mice are one of the most widely used inbred strains in biomedical research. Early separation of the breeding colony has led to the development of several sub-strains. Colony separation led to genetic variation development driving numerous phenotypic discrepancies. The reported phenotypic behavior differences between the sub-strains were, however; not consistent in the literature, suggesting the involvement of factors other than host genes. Here, we characterized the cognitive and affective behavior of C57BL/6J and C57BL/6N mice in correlation with the immune cell profile in the brain. Furthermore, faecal microbiota transfer and mice co-housing techniques were used to dissect microbial and environmental factors' contribution, respectively, to cognitive and affective behavior patterns. We first noted a unique profile of locomotor activity, immobility pattern, and spatial and non-spatial learning and memory abilities between the two sub-strains. The phenotypic behavior profile was associated with a distinct difference in the dynamics of type 2 cytokines in the meninges and brain parenchyma. Analysing the contribution of microbiome and environmental factors to the noted behavioral profile, our data indicated that while immobility pattern was genetically driven, locomotor activity and cognitive abilities were highly sensitive to alterations in the gut microbiome and environmental factors. Changes in the phenotypic behavior in response to these factors were associated with changes in immune cell profile. While microglia were highly sensitive to alteration in gut microbiome, immune cells in meninges were more resilient. Collectively, our findings demonstrated a direct impact of environmental conditions on gut microbiota which subsequently impacts the brain immune cell profile that could modulate cognitive and affective behavior. Our data further highlight the importance of characterizing the laboratory available strain/sub-strain to select the most appropriate one that fits best the study purpose.},
author = {{Abdel Aziz}, Nada and Berkiks, Inssaf and Mosala, Paballo and Brombacher, Tiroyaone M and Brombacher, Frank},
doi = {10.3389/FIMMU.2023.1139913/BIBTEX},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Abdel Aziz et al. - 2023 - Environmental and microbial factors influence affective and cognitive behavior in C57BL6 sub-strains.pdf:pdf},
issn = {16643224},
journal = {Frontiers in Immunology},
keywords = {C57BL/6 sub-strains,OA,affective behavior,cognitive function,environmental factor,fund{\_}not{\_}ack,hippocampus,immune cells,meninges,microbiome,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {apr},
pages = {1139913},
pmid = {37180163},
publisher = {Frontiers Media S.A.},
title = {{Environmental and microbial factors influence affective and cognitive behavior in C57BL/6 sub-strains}},
volume = {14},
year = {2023}
}

C57BL/6 mice are one of the most widely used inbred strains in biomedical research. Early separation of the breeding colony has led to the development of several sub-strains. Colony separation led to genetic variation development driving numerous phenotypic discrepancies. The reported phenotypic behavior differences between the sub-strains were, however; not consistent in the literature, suggesting the involvement of factors other than host genes. Here, we characterized the cognitive and affective behavior of C57BL/6J and C57BL/6N mice in correlation with the immune cell profile in the brain. Furthermore, faecal microbiota transfer and mice co-housing techniques were used to dissect microbial and environmental factors' contribution, respectively, to cognitive and affective behavior patterns. We first noted a unique profile of locomotor activity, immobility pattern, and spatial and non-spatial learning and memory abilities between the two sub-strains. The phenotypic behavior profile was associated with a distinct difference in the dynamics of type 2 cytokines in the meninges and brain parenchyma. Analysing the contribution of microbiome and environmental factors to the noted behavioral profile, our data indicated that while immobility pattern was genetically driven, locomotor activity and cognitive abilities were highly sensitive to alterations in the gut microbiome and environmental factors. Changes in the phenotypic behavior in response to these factors were associated with changes in immune cell profile. While microglia were highly sensitive to alteration in gut microbiome, immune cells in meninges were more resilient. Collectively, our findings demonstrated a direct impact of environmental conditions on gut microbiota which subsequently impacts the brain immune cell profile that could modulate cognitive and affective behavior. Our data further highlight the importance of characterizing the laboratory available strain/sub-strain to select the most appropriate one that fits best the study purpose.

@article{Davis2022b,
abstract = {Background: Drug regimens which include intensified antibiotics alongside effective anti-inflammatory therapies may improve outcomes in Tuberculous Meningitis (TBM). Safety data on their use in combination and in the context of HIV is needed to inform clinical trial design. Methods: We conducted a phase 2 open-label parallel-design RCT to assess safety of high-dose rifampicin, linezolid and high-dose aspirin in HIV-associated TBM. Participants were randomised (1.4:1:1) to three treatment arms (arm 1, standard of care (SOC); arm 2 SOC + additional rifampicin (up to 35mg/kg/day)) + linezolid 1200mg/day reducing after 28/7 to 600mg/day; arm 3, as per arm 2 + aspirin 1000mg/day) for 56 days, when the primary outcome of adverse events of special interest (AESI) or death was assessed. Results: 52 participants with HIV-associated TBM were randomised. 59{\%} had mild disease (MRC Grade 1) vs 39{\%} (Grade 2) vs 2{\%} (Grade 3). 33{\%} had microbiologically-confirmed TBM; 41{\%} 'possible', 25{\%} 'probable'. AESI or death occurred in 10/16 (63{\%}) (arm 3) vs 4/14 (29{\%}) (arm 2) vs 6/20 (30{\%}) (arm 1) (p=0.083). The cumulative proportion of AESI or death (Kaplan-Meier) demonstrated worse outcomes in arm 3 vs arm 1 (p=0.04), however only one event in arm 3 was attributable to aspirin and was mild. There was no difference in efficacy (modified Rankin scale) at day 56 between arms. Conclusions: High-dose rifampicin and adjunctive linezolid can safely be added to SOC in HIV-associated TBM. Larger studies are required to evaluate whether potential toxicity associated with these interventions, particularly high-dose aspirin, is outweighed by mortality or morbidity benefit.},
author = {Davis, Angharad G and Wasserman, Sean and Stek, Cari and Maxebengula, Mpumi and Liang, C Jason and Stegmann, Stephani and Koekemoer, Sonya and Jackson, Amanda and Kadernani, Yakub and Bremer, Marise and Daroowala, Remy and Aziz, Saalikha and Goliath, Rene and Sai, Louise Lai and Sihoyiya, Thandi and Denti, Paolo and Lai, Rachel PJ and Crede, Thomas and Naude, Jonathan and Szymanski, Patryk and Vallie, Yakoob and Banderker, Ismail Abbas and Moosa, Muhammed S and Raubenheimer, Peter and Candy, Sally and Offiah, Curtis and Wahl, Gerda and Vorster, Isak and Maartens, Gary and Black, John and Meintjes, Graeme A and Wilkinson, Robert J},
doi = {10.1093/CID/CIAC932},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Davis et al. - 2023 - A phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or wit.pdf:pdf},
issn = {1058-4838},
journal = {Clinical Infectious Diseases},
keywords = {HIV,OA,Tuberculous meningitis,aspirin,fund{\_}ack,linezolid,original,rifampicin},
mendeley-tags = {OA,fund{\_}ack,original},
month = {dec},
number = {8},
pages = {1412--1422},
pmid = {36482216},
title = {{A phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for Human Immunodeficiency Virus-associated tuberculous meningitis: the LASER-TBM trial}},
url = {https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac932/6884164},
volume = {76},
year = {2023}
}

Background: Drug regimens which include intensified antibiotics alongside effective anti-inflammatory therapies may improve outcomes in Tuberculous Meningitis (TBM). Safety data on their use in combination and in the context of HIV is needed to inform clinical trial design. Methods: We conducted a phase 2 open-label parallel-design RCT to assess safety of high-dose rifampicin, linezolid and high-dose aspirin in HIV-associated TBM. Participants were randomised (1.4:1:1) to three treatment arms (arm 1, standard of care (SOC); arm 2 SOC + additional rifampicin (up to 35mg/kg/day)) + linezolid 1200mg/day reducing after 28/7 to 600mg/day; arm 3, as per arm 2 + aspirin 1000mg/day) for 56 days, when the primary outcome of adverse events of special interest (AESI) or death was assessed. Results: 52 participants with HIV-associated TBM were randomised. 59% had mild disease (MRC Grade 1) vs 39% (Grade 2) vs 2% (Grade 3). 33% had microbiologically-confirmed TBM; 41% 'possible', 25% 'probable'. AESI or death occurred in 10/16 (63%) (arm 3) vs 4/14 (29%) (arm 2) vs 6/20 (30%) (arm 1) (p=0.083). The cumulative proportion of AESI or death (Kaplan-Meier) demonstrated worse outcomes in arm 3 vs arm 1 (p=0.04), however only one event in arm 3 was attributable to aspirin and was mild. There was no difference in efficacy (modified Rankin scale) at day 56 between arms. Conclusions: High-dose rifampicin and adjunctive linezolid can safely be added to SOC in HIV-associated TBM. Larger studies are required to evaluate whether potential toxicity associated with these interventions, particularly high-dose aspirin, is outweighed by mortality or morbidity benefit.

@article{Walker2023,
abstract = {Mortality from HIV-associated tuberculosis (HIV-TB) is high, particularly among hospitalised patients. In 433 people living with HIV admitted to hospital with symptoms of TB, we investigated plasma matrix metalloproteinases (MMP) and matrix-derived biomarkers in relation to TB diagnosis, mortality and Mycobacterium tuberculosis ( Mtb) blood stream infection (BSI). Compared to other diagnoses, MMP-8 was elevated in confirmed TB and in Mtb -BSI, positively correlating with extracellular matrix breakdown products. Baseline MMP- 3, -7, -8, -10 and procollagen III N-terminal propeptide (PIIINP) associated with Mtb -BSI and 12-week mortality. These findings implicate MMP dysregulation in pathophysiology of advanced HIV-TB and support MMP inhibition as a host-directed therapeutic strategy for HIV- TB. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Funding Statement NFW was supported by an NIHR Academic Clinical Lectureship and funding from Academy of Medical Sciences UK, MRC UK, British Heart Foundation, Arthritis Research UK, Royal College of Physicians and Diabetes UK (Starter Grant for Clinical Lecturers) and British Infection Association (Project Grant). MS is supported by Wellcome (211360/Z/18/Z) and the National Research Foundation of South Africa (NRF, {\#}UID127558). PTE was supported by MRC MR/P023754/1 and MR/W025728/1. RJW is supported by the Francis Crick Institute which is funded by Wellcome (CC2112), Cancer Research UK (CC2112) and UKRI (CC2112). RJW also receives support from Wellcome (203135), EDCTP (SRIA 2015-1065) and NIH (U01AI115940). CS was funded by the South African Medical Research Council under the National Health Scholars Programme. GM was supported by Wellcome (098316, 214321/Z/18/Z, and 203135/Z/16/Z), and the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (Grant No 64787). The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of this report. The opinions, findings and conclusions expressed in this manuscript reflect those of the authors alone. {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the University of Cape Town Human Research Ethics Committee (HREC ref 057/2013) and London School of Hygiene and Tropical Medicine Research Ethics Committee (ref 11710). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All laboratory data in the present study are available upon reasonable request to the authors},
author = {Walker, N F and Schutz, Charlotte and Ward, A and Barr, David A and Opondo, C and Shey, Muki and Elkington, PT and Wilkinson, Katalin A and Wilkinson, Robert J and Meintjes, Graeme A},
doi = {10.1101/2023.12.12.23299845},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Walker et al. - 2023 - Elevated plasma matrix metalloproteinases associate with Mycobacterium tuberculosis blood stream infection and mo.pdf:pdf},
journal = {medRxiv},
keywords = {HIV,OA,Tuberculosis,fund{\_}ack,matrix metalloproteinase,mortality,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {dec},
pages = {2023.12.12.23299845},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Elevated plasma matrix metalloproteinases associate with \textit{Mycobacterium tuberculosis} blood stream infection and mortality in HIV-associated tuberculosis}},
url = {https://www.medrxiv.org/content/10.1101/2023.12.12.23299845v1 https://www.medrxiv.org/content/10.1101/2023.12.12.23299845v1.abstract},
year = {2023}
}

Mortality from HIV-associated tuberculosis (HIV-TB) is high, particularly among hospitalised patients. In 433 people living with HIV admitted to hospital with symptoms of TB, we investigated plasma matrix metalloproteinases (MMP) and matrix-derived biomarkers in relation to TB diagnosis, mortality and Mycobacterium tuberculosis ( Mtb) blood stream infection (BSI). Compared to other diagnoses, MMP-8 was elevated in confirmed TB and in Mtb -BSI, positively correlating with extracellular matrix breakdown products. Baseline MMP- 3, -7, -8, -10 and procollagen III N-terminal propeptide (PIIINP) associated with Mtb -BSI and 12-week mortality. These findings implicate MMP dysregulation in pathophysiology of advanced HIV-TB and support MMP inhibition as a host-directed therapeutic strategy for HIV- TB. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement NFW was supported by an NIHR Academic Clinical Lectureship and funding from Academy of Medical Sciences UK, MRC UK, British Heart Foundation, Arthritis Research UK, Royal College of Physicians and Diabetes UK (Starter Grant for Clinical Lecturers) and British Infection Association (Project Grant). MS is supported by Wellcome (211360/Z/18/Z) and the National Research Foundation of South Africa (NRF, #UID127558). PTE was supported by MRC MR/P023754/1 and MR/W025728/1. RJW is supported by the Francis Crick Institute which is funded by Wellcome (CC2112), Cancer Research UK (CC2112) and UKRI (CC2112). RJW also receives support from Wellcome (203135), EDCTP (SRIA 2015-1065) and NIH (U01AI115940). CS was funded by the South African Medical Research Council under the National Health Scholars Programme. GM was supported by Wellcome (098316, 214321/Z/18/Z, and 203135/Z/16/Z), and the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (Grant No 64787). The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of this report. The opinions, findings and conclusions expressed in this manuscript reflect those of the authors alone. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the University of Cape Town Human Research Ethics Committee (HREC ref 057/2013) and London School of Hygiene and Tropical Medicine Research Ethics Committee (ref 11710). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All laboratory data in the present study are available upon reasonable request to the authors

@article{Mutavhatsindi2023,
abstract = {2 Objectives. To better understand the pathogenesis of pericardial tuberculosis (PCTB), we sought to characterize the systemic inflammatory profile in people with human immunodeficiency virus (HIV-1) with latent TB infection (LTBI), pulmonary TB (PTB) and PCTB. Methods. Using Luminex, we measured the concentration of 39 analytes in pericardial fluid (PCF) and paired plasma from 18 PCTB participants, and plasma from 16 LTBI and 20 PTB. Follow-up plasma samples were also obtained from PTB and PCTB participants. HLA-DR expression on Mtb-specific CD4 T cells was measured in baseline samples using flow cytometry. Results. Assessment of the overall systemic inflammatory profile by principal component analysis showed that the inflammatory profile of active TB participants was distinct from the LTBI group, while PTB patients could not be distinguished from those with PCTB. When comparing the inflammatory profile between PCF and paired blood, we found that the concentrations of most analytes (24/39) were elevated at site of disease. However, the inflammatory profile in PCF partially mirrored inflammatory events in the blood. After TB treatment completion, the overall plasma inflammatory profile reverted to those observed in the LTBI group. Lastly, HLA-DR expression showed the best performance for TB diagnosis compared to previously described biosignatures built from soluble markers. Conclusion. Our results show that the inflammatory profile in blood was comparable between PTB and PCTB. However, at the site of infection (PCF), inflammation was significantly elevated compared to blood. Additionally, our data emphasize the potential role of HLA-DR expression as a biomarker for TB diagnosis.},
author = {Mutavhatsindi, Hygon and {Du Bruyn}, Elsa and Ruzive, Sheena and Howlett, Patrick and Cerrone, Maddalena and Sher, Alan and Mayer-Barber, Katrin D and Barber, Daniel L and Ntsekhe, Mpiko and Wilkinson, Robert J and Riou, Catherine},
doi = {10.1093/OFID/OFAD128},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Mutavhatsindi et al. - 2023 - Blood and site of disease inflammatory profiles differ in patients with pericardial tuberculosis and Human.pdf:pdf},
issn = {2328-8957},
journal = {Open Forum Infectious Diseases},
keywords = {Inflammatory profile,OA,Pericardial tuberculosis,diagnosis,fund{\_}ack,original,site of disease,treatment response},
mendeley-tags = {OA,fund{\_}ack,original},
month = {mar},
number = {3},
pages = {ofad128},
title = {{Blood and site of disease inflammatory profiles differ in patients with pericardial tuberculosis and Human Immunodeficiency Virus type 1}},
url = {https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofad128/7074136},
volume = {10},
year = {2023}
}

2 Objectives. To better understand the pathogenesis of pericardial tuberculosis (PCTB), we sought to characterize the systemic inflammatory profile in people with human immunodeficiency virus (HIV-1) with latent TB infection (LTBI), pulmonary TB (PTB) and PCTB. Methods. Using Luminex, we measured the concentration of 39 analytes in pericardial fluid (PCF) and paired plasma from 18 PCTB participants, and plasma from 16 LTBI and 20 PTB. Follow-up plasma samples were also obtained from PTB and PCTB participants. HLA-DR expression on Mtb-specific CD4 T cells was measured in baseline samples using flow cytometry. Results. Assessment of the overall systemic inflammatory profile by principal component analysis showed that the inflammatory profile of active TB participants was distinct from the LTBI group, while PTB patients could not be distinguished from those with PCTB. When comparing the inflammatory profile between PCF and paired blood, we found that the concentrations of most analytes (24/39) were elevated at site of disease. However, the inflammatory profile in PCF partially mirrored inflammatory events in the blood. After TB treatment completion, the overall plasma inflammatory profile reverted to those observed in the LTBI group. Lastly, HLA-DR expression showed the best performance for TB diagnosis compared to previously described biosignatures built from soluble markers. Conclusion. Our results show that the inflammatory profile in blood was comparable between PTB and PCTB. However, at the site of infection (PCF), inflammation was significantly elevated compared to blood. Additionally, our data emphasize the potential role of HLA-DR expression as a biomarker for TB diagnosis.

@article{Meya2023,
author = {Meya, David B. and Meintjes, Graeme},
doi = {10.1016/S2352-3018(23)00232-1},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Meya, Meintjes - 2023 - HIV-related CNS infections translating DREAMM into reality.pdf:pdf},
issn = {23523018},
journal = {The Lancet HIV},
keywords = {commentary,fund{\_}not{\_}ack},
mendeley-tags = {commentary,fund{\_}not{\_}ack},
month = {oct},
number = {10},
pages = {e627--e628},
publisher = {Elsevier Ltd},
title = {{HIV-related CNS infections: translating DREAMM into reality}},
url = {http://www.thelancet.com/article/S2352301823002321/fulltext http://www.thelancet.com/article/S2352301823002321/abstract https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(23)00232-1/abstract},
volume = {10},
year = {2023}
}

@article{Pietersen2023,
abstract = {Background Updated World Health Organization (WHO) treatment guidelines prioritize all-oral drug-resistant tuberculosis (DR-TB) regimens. Several poorly tolerated drugs, such as amikacin and para-aminosalicylic acid (PAS), remain treatment options for DR-TB in WHO-recommended longer regimens as Group C drugs. Incomplete treatment with anti-TB drugs increases the risk of treatment failure, relapse, and death. We determined whether missed doses of individual anti-TB drugs, and reasons for their discontinuation, varied in closely monitored hospital settings prior to the 2020 WHO DR-TB treatment guideline updates. Methods We collected retrospective data on adult patients with microbiologically confirmed DR-TB between 2008 and 2015 who were selected for a study of acquired drug resistance in the Western Cape Province of South Africa. Medical records through mid-2017 were reviewed. Patients received directly observed treatment during hospitalization at specialized DR-TB hospitals. Incomplete treatment with individual anti-TB drugs, defined as the failure to take medication as prescribed, regardless of reason, was determined by comparing percent missed doses, stratified by HIV status and DR-TB regimen. We applied a generalized mixed effects model. Results Among 242 patients, 131 (54{\%}) were male, 97 (40{\%}) were living with HIV, 175 (72{\%}) received second-line treatment prior to first hospitalization, and 191 (79{\%}) died during the study period. At initial hospitalization, 134 (55{\%}) patients had Mycobacterium tuberculosis with resistance to rifampicin and isoniazid (multidrug-resistant TB [MDR-TB]) without resistance to ofloxacin or amikacin, and 102 (42{\%}) had resistance to ofloxacin and/or amikacin. Most patients (129 [53{\%}]) had multiple hospitalizations and DST changes occurred in 146 (60{\%}) by the end of their last hospital discharge. Incomplete treatment was significantly higher for amikacin (18{\%}), capreomycin (18{\%}), PAS (17{\%}) and kanamycin (16{\%}) than other DR-TB drugs (P{\textless}0.001), including ethionamide (8{\%}), moxifloxacin (7{\%}), terizidone (7{\%}), ethambutol (7{\%}), and pyrazinamide (6{\%}). Among the most frequently prescribed drugs, second-line injectables had the highest rates of discontinuation for adverse events (range 0.56–1.02 events per year follow-up), while amikacin, PAS and ethionamide had the highest rates of discontinuation for patient refusal (range 0.51–0.68 events per year follow-up). Missed doses did not differ according to HIV status or anti-TB drug combinations. Conclusion We found that incomplete treatment for second-line injectables and PAS during hospitalization was higher than for other anti-TB drugs. To maximize treatment success, interventions to improve person-centered care and mitigate adverse events may be necessary in cases when PAS or amikacin (2020 WHO recommended Group C drugs) are needed.},
author = {Pietersen, Elize and Anderson, Kim and Cox, Helen and Dheda, Keertan and Bian, Aihua and Shepherd, Bryan E and Sterling, Timothy R and Warren, Robin M and {Van Der Heijden}, Yuri F},
doi = {10.1371/JOURNAL.PONE.0281097},
editor = {Ramagopalan, Sreeram V.},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Pietersen et al. - 2023 - Variation in missed doses and reasons for discontinuation of anti-tuberculosis drugs during hospital treatment.pdf:pdf},
isbn = {1111111111},
issn = {1932-6203},
journal = {PLOS ONE},
keywords = {Adverse events,Antibiotic resistance,Charts,Drug therapy,Extensively drug-resistant tuberculosis,HIV,Multi-drug-resistant tuberculosis,OA,OA{\_}PMC,Tuberculosis,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {feb},
number = {2},
pages = {e0281097},
pmid = {36780443},
publisher = {Public Library of Science},
title = {{Variation in missed doses and reasons for discontinuation of anti-tuberculosis drugs during hospital treatment for drug-resistant tuberculosis in South Africa}},
url = {https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0281097},
volume = {18},
year = {2023}
}

Background Updated World Health Organization (WHO) treatment guidelines prioritize all-oral drug-resistant tuberculosis (DR-TB) regimens. Several poorly tolerated drugs, such as amikacin and para-aminosalicylic acid (PAS), remain treatment options for DR-TB in WHO-recommended longer regimens as Group C drugs. Incomplete treatment with anti-TB drugs increases the risk of treatment failure, relapse, and death. We determined whether missed doses of individual anti-TB drugs, and reasons for their discontinuation, varied in closely monitored hospital settings prior to the 2020 WHO DR-TB treatment guideline updates. Methods We collected retrospective data on adult patients with microbiologically confirmed DR-TB between 2008 and 2015 who were selected for a study of acquired drug resistance in the Western Cape Province of South Africa. Medical records through mid-2017 were reviewed. Patients received directly observed treatment during hospitalization at specialized DR-TB hospitals. Incomplete treatment with individual anti-TB drugs, defined as the failure to take medication as prescribed, regardless of reason, was determined by comparing percent missed doses, stratified by HIV status and DR-TB regimen. We applied a generalized mixed effects model. Results Among 242 patients, 131 (54%) were male, 97 (40%) were living with HIV, 175 (72%) received second-line treatment prior to first hospitalization, and 191 (79%) died during the study period. At initial hospitalization, 134 (55%) patients had Mycobacterium tuberculosis with resistance to rifampicin and isoniazid (multidrug-resistant TB [MDR-TB]) without resistance to ofloxacin or amikacin, and 102 (42%) had resistance to ofloxacin and/or amikacin. Most patients (129 [53%]) had multiple hospitalizations and DST changes occurred in 146 (60%) by the end of their last hospital discharge. Incomplete treatment was significantly higher for amikacin (18%), capreomycin (18%), PAS (17%) and kanamycin (16%) than other DR-TB drugs (P\textless0.001), including ethionamide (8%), moxifloxacin (7%), terizidone (7%), ethambutol (7%), and pyrazinamide (6%). Among the most frequently prescribed drugs, second-line injectables had the highest rates of discontinuation for adverse events (range 0.56–1.02 events per year follow-up), while amikacin, PAS and ethionamide had the highest rates of discontinuation for patient refusal (range 0.51–0.68 events per year follow-up). Missed doses did not differ according to HIV status or anti-TB drug combinations. Conclusion We found that incomplete treatment for second-line injectables and PAS during hospitalization was higher than for other anti-TB drugs. To maximize treatment success, interventions to improve person-centered care and mitigate adverse events may be necessary in cases when PAS or amikacin (2020 WHO recommended Group C drugs) are needed.

@article{Motta2023,
abstract = {Abstract Background Tuberculosis is a global health challenge and one of the leading causes of death worldwide. In the last decade, the tuberculosis treatment landscape has dramatically changed. After long years of stagnation, new compounds entered the market (bedaquiline, delamanid and pretomanid) and phase III clinical trials have shown promising results towards shortening duration of treatment for both drug-susceptible (Study 31/A5349, TRUNCATE-TB, SHINE) and drug-resistant tuberculosis (STREAM, NiX-TB, ZeNix, TB-PRACTECAL). Dose optimization of rifamycins and repurposed drugs have also brought hopes of further development of safe and effective regimens. Consequently, international and World Health Organization clinical guidelines have been updated multiple times in the last years to keep pace with these advances. Objectives This narrative review aims to summarize the state-of-the-art on treatment of drug-susceptible and drug-resistant tuberculosis, as well as recent trials results and an overview of ongoing clinical trials. Sources A non-systematic literature review was conducted in PubMed and MEDLINE, focusing on the treatment of tuberculosis. Ongoing clinical trials were listed according to the authors' knowledge, and completed consulting clinicaltrials.gov and other publicly available websites (www.resisttb.org/clinical-trials-progress-report, www.newtbdrugs.org/pipeline/trials). Content This review summarizes the recent, major changes in the landscape for drug-susceptible and drug-resistant treatment, with a specific focus on their potential impact on patient outcomes and programmatic TB management. Moreover, insights in host-directed therapies, and advances in pharmacokinetic and pharmacogenomics are discussed. A thorough outline of ongoing therapeutic clinical trials is presented, highlighting different approaches and goals in current TB clinical research. Implications Future research should be directed to individualize regimens and protect these recent breakthroughs by preventing and identifying the selection of drug resistance and providing widespread, affordable, patient-centered access to new treatment options for all people affected by tuberculosis.},
author = {Motta, Ilaria and Boeree, Martin and Chesov, Dumitru and Dheda, Keertan and G{\"{u}}nther, Gunar and JR, C. Robert Horsburgh and Kherabi, Yousra and Lange, Christoph and Lienhardt, Christian and McIlleron, Helen M and Paton, Nicholas I and Stagg, Helen R and Thwaites, Guy and Udwadia, Zarir and {Van Crevel}, Reinout and Vel{\'{a}}squez, Gustavo E and Wilkinson, Robert J and Guglielmetti, Lorenzo},
doi = {10.1016/J.CMI.2023.07.013},
issn = {1198-743X},
journal = {Clinical Microbiology and Infection},
keywords = {review},
mendeley-tags = {review},
month = {jul},
pmid = {37482332},
publisher = {Elsevier},
title = {{Recent advances in the treatment of tuberculosis}},
url = {http://www.clinicalmicrobiologyandinfection.com/article/S1198743X23003397/fulltext http://www.clinicalmicrobiologyandinfection.com/article/S1198743X23003397/abstract https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(23)00339-7/abstract},
year = {2023}
}

Abstract Background Tuberculosis is a global health challenge and one of the leading causes of death worldwide. In the last decade, the tuberculosis treatment landscape has dramatically changed. After long years of stagnation, new compounds entered the market (bedaquiline, delamanid and pretomanid) and phase III clinical trials have shown promising results towards shortening duration of treatment for both drug-susceptible (Study 31/A5349, TRUNCATE-TB, SHINE) and drug-resistant tuberculosis (STREAM, NiX-TB, ZeNix, TB-PRACTECAL). Dose optimization of rifamycins and repurposed drugs have also brought hopes of further development of safe and effective regimens. Consequently, international and World Health Organization clinical guidelines have been updated multiple times in the last years to keep pace with these advances. Objectives This narrative review aims to summarize the state-of-the-art on treatment of drug-susceptible and drug-resistant tuberculosis, as well as recent trials results and an overview of ongoing clinical trials. Sources A non-systematic literature review was conducted in PubMed and MEDLINE, focusing on the treatment of tuberculosis. Ongoing clinical trials were listed according to the authors' knowledge, and completed consulting clinicaltrials.gov and other publicly available websites (www.resisttb.org/clinical-trials-progress-report, www.newtbdrugs.org/pipeline/trials). Content This review summarizes the recent, major changes in the landscape for drug-susceptible and drug-resistant treatment, with a specific focus on their potential impact on patient outcomes and programmatic TB management. Moreover, insights in host-directed therapies, and advances in pharmacokinetic and pharmacogenomics are discussed. A thorough outline of ongoing therapeutic clinical trials is presented, highlighting different approaches and goals in current TB clinical research. Implications Future research should be directed to individualize regimens and protect these recent breakthroughs by preventing and identifying the selection of drug resistance and providing widespread, affordable, patient-centered access to new treatment options for all people affected by tuberculosis.

@article{Veenstra2023,
abstract = {Background: Treatment-limiting severe cutaneous adverse reactions (SCAR) occur more commonly amongst persons with HIV-associated tuberculosis (TB). The impact of SCAR on long-term HIV/TB outcomes is unknown. Methods: Patients with TB and/or HIV admitted to Groote Schuur Hospital, Cape Town, South Africa with SCAR between 1/10/2018 and 30/09/2021 were eligible. Follow-up data was collected for 6- and 12-month outcomes: mortality, TB and antiretroviral therapy (ART) regimen changes, TB treatment completion, and CD4 count recovery. Results: Forty-eight SCAR admissions included: 34, 11, and 3 HIV-associated TB, HIV-only and TB-only patients with 32, 13 and 3 cases of drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome/toxic epidermal necrolysis and generalised bullous fixed-drug eruption respectively. Nine (19{\%}), all HIV-positive (eight co-infected with TB), were deceased at 12-months, and 12(25{\%}) were lost to follow-up. Amongst TB-SCAR patients, seven (21{\%}) were discharged on all four first-line anti-TB drugs (FLTD), while 12(33{\%}) had regimens with no FLTDs; 24/37(65{\%}) completed TB treatment. Amongst HIV-SCAR patients, 10/31(32{\%}) changed ART regimen. If retained in care (24/36), median (IQR) CD4 counts increased at 12-months post-SCAR (115(62–175) vs. 319(134–439) cells/uL). Conclusion: SCAR admission amongst patients with HIV-associated TB results in substantial mortality, and considerable treatment complexity. However, if retained in care, TB regimens are successfully completed, and immune recovery is good despite SCAR.},
author = {Veenstra, S and Porter, M N and Thwala, B N and Pillay, N and Panieri, M A and van der Westhuizen, J and Phillips, E J and Meintjes, Graeme A and Dlamini, S and Lehloenya, R J and Peter, J},
doi = {10.1016/J.JCTUBE.2023.100374},
issn = {2405-5794},
journal = {Journal of Clinical Tuberculosis and Other Mycobacterial Diseases},
keywords = {CD4 count,DRESS,Drug allergy,Mortality,OA,SJS/TEN,Viral load,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {aug},
pages = {100374},
publisher = {Elsevier},
title = {{Long-term HIV and tuberculosis outcomes in patients hospitalised with severe cutaneous adverse reactions}},
volume = {32},
year = {2023}
}

Background: Treatment-limiting severe cutaneous adverse reactions (SCAR) occur more commonly amongst persons with HIV-associated tuberculosis (TB). The impact of SCAR on long-term HIV/TB outcomes is unknown. Methods: Patients with TB and/or HIV admitted to Groote Schuur Hospital, Cape Town, South Africa with SCAR between 1/10/2018 and 30/09/2021 were eligible. Follow-up data was collected for 6- and 12-month outcomes: mortality, TB and antiretroviral therapy (ART) regimen changes, TB treatment completion, and CD4 count recovery. Results: Forty-eight SCAR admissions included: 34, 11, and 3 HIV-associated TB, HIV-only and TB-only patients with 32, 13 and 3 cases of drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome/toxic epidermal necrolysis and generalised bullous fixed-drug eruption respectively. Nine (19%), all HIV-positive (eight co-infected with TB), were deceased at 12-months, and 12(25%) were lost to follow-up. Amongst TB-SCAR patients, seven (21%) were discharged on all four first-line anti-TB drugs (FLTD), while 12(33%) had regimens with no FLTDs; 24/37(65%) completed TB treatment. Amongst HIV-SCAR patients, 10/31(32%) changed ART regimen. If retained in care (24/36), median (IQR) CD4 counts increased at 12-months post-SCAR (115(62–175) vs. 319(134–439) cells/uL). Conclusion: SCAR admission amongst patients with HIV-associated TB results in substantial mortality, and considerable treatment complexity. However, if retained in care, TB regimens are successfully completed, and immune recovery is good despite SCAR.

@article{Bakali2023,
abstract = {The coenzyme A (CoA) biosynthesis pathway has attracted attention as a potential target for much-needed novel antimicrobial drugs, including for the treatment of tuberculosis (TB), the lethal disease caused by Mycobacterium tuberculosis (Mtb). Seeking to identify inhibitors of Mtb phosphopantetheine adenylyltransferase (MtbPPAT), the enzyme that catalyses the penultimate step in CoA biosynthesis, we performed a fragment screen. In doing so, we discovered three series of fragments that occupy distinct regions of the MtbPPAT active site, presenting a unique opportunity for fragment linking. Here we show how, guided by X-ray crystal structures, we could link weakly-binding fragments to produce an active site binder with a KD {\textless} 20 µM and on-target anti-Mtb activity, as demonstrated using CRISPR interference. This study represents a big step toward validating MtbPPAT as a potential drug target and designing a MtbPPAT-targeting anti-TB drug.},
author = {Bakali, Jamal El and Blaszczyk, Michal and Evans, Joanna C. and Boland, Jennifer A. and McCarthy, William J. and Fathoni, Imam and Dias, Marcio V. B. and Johnson, Eachan O. and Coyne, Anthony G. and Mizrahi, Valerie and Blundell, Tom L. and Abell, Chris and Spry, Christina},
doi = {10.1002/ANIE.202300221},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Bakali et al. - 2023 - Chemical validation of iMycobacterium tuberculosisi phosphopantetheine adenylyltransferase using fragment linking.pdf:pdf},
issn = {1521-3773},
journal = {Angewandte Chemie International Edition},
keywords = {Based,Coenzyme A,Drug Discovery,Enzymes,Fragment,OA,OA{\_}PMC,Tuberculosis,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {apr},
number = {17},
pages = {e202300221},
pmid = {38515507},
publisher = {John Wiley {\&} Sons, Ltd},
title = {{Chemical validation of Mycobacterium tuberculosis phosphopantetheine adenylyltransferase using fragment linking and CRISPR interference**}},
url = {https://onlinelibrary.wiley.com/doi/full/10.1002/anie.202300221 https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.202300221 https://onlinelibrary.wiley.com/doi/10.1002/anie.202300221},
volume = {62},
year = {2023}
}

The coenzyme A (CoA) biosynthesis pathway has attracted attention as a potential target for much-needed novel antimicrobial drugs, including for the treatment of tuberculosis (TB), the lethal disease caused by Mycobacterium tuberculosis (Mtb). Seeking to identify inhibitors of Mtb phosphopantetheine adenylyltransferase (MtbPPAT), the enzyme that catalyses the penultimate step in CoA biosynthesis, we performed a fragment screen. In doing so, we discovered three series of fragments that occupy distinct regions of the MtbPPAT active site, presenting a unique opportunity for fragment linking. Here we show how, guided by X-ray crystal structures, we could link weakly-binding fragments to produce an active site binder with a KD \textless 20 µM and on-target anti-Mtb activity, as demonstrated using CRISPR interference. This study represents a big step toward validating MtbPPAT as a potential drug target and designing a MtbPPAT-targeting anti-TB drug.

@article{Mateza2023,
abstract = {Objective Renal toxicity is more common with tenofovir disoproxil fumarate (TDF) than with tenofovir alafenamide fumarate (TAF). We investigated whether polymorphisms in genes relevant to tenofovir disposition affect renal toxicity among HIV-positive Southern Africans. Methods Genetic sub-study of adults was randomized to initiate TAF or TDF together with dolutegravir and emtricitabine. Outcomes were changes from week 4 to 48 in the estimated glomerular filtration rate (eGFR) and from baseline to week 48 in urine retinol-binding protein and urine $\beta$2-microglobulin adjusted for urinary creatinine (uRBP/Cr and uB2M/Cr). Primary analyses prioritized 14 polymorphisms previously reported to be associated with tenofovir disposition or renal outcomes, and all polymorphisms in 14 selected genes. We also explored genome-wide associations. Results 336 participants were enrolled. Among 14 polymorphisms of primary interest, the lowest P values for change in eGFR, uRBP/Cr, and uB2M/Cr were ABCC4 rs899494 (P = 0.022), ABCC10 rs2125739 (P = 0.07), and ABCC4 rs1059751 (P = 0.0088); and in genes of interest, the lowest P values were ABCC4 rs4148481 (P = 0.0013), rs691857 (P = 0.00039), and PKD2 rs72659631 (P = 0.0011). However, none of these polymorphisms withstood correction for multiple testing. Genome-wide, the lowest P values were COL27A1 rs1687402 (P = 3.4 × 10−9), CDH4 rs66494466 (P = 5.6 × 10−8), and ITGA4 rs3770126 (P = 6.1 × 10−7). Conclusion Two ABCC4 polymorphisms, rs899494 and rs1059751, were nominally associated with change in eGFR and uB2M/Cr, respectively, albeit in the opposite direction of previous reports. COL27A1 polymorphism was genome-wide significantly associated with change in eGFR.},
author = {Mateza, Somila and Bradford, Yuki and Maartens, Gary and Sokhela, Simiso and Chandiwana, Nomathemba C and Venter, Willem D F and Post, Frank A and Ritchie, Marylyn D and Haas, David W and Sinxadi, Phumla},
issn = {1744-6872},
journal = {Pharmacogenetics and Genomics},
keywords = {HIV,OA,fund{\_}ack,original,pharmacogenetics,renal toxicity,tenofovir alafenamide fumarate,tenofovir disoproxil fumarate},
mendeley-tags = {OA,fund{\_}ack,original},
number = {5},
pages = {91--100},
pmid = {37099271},
title = {{Pharmacogenetics of tenofovir renal toxicity in HIV-positive Southern Africans}},
url = {https://journals.lww.com/jpharmacogenetics/Fulltext/9900/Pharmacogenetics{\_}of{\_}tenofovir{\_}renal{\_}toxicity{\_}in.27.aspx},
volume = {33},
year = {2023}
}

Objective Renal toxicity is more common with tenofovir disoproxil fumarate (TDF) than with tenofovir alafenamide fumarate (TAF). We investigated whether polymorphisms in genes relevant to tenofovir disposition affect renal toxicity among HIV-positive Southern Africans. Methods Genetic sub-study of adults was randomized to initiate TAF or TDF together with dolutegravir and emtricitabine. Outcomes were changes from week 4 to 48 in the estimated glomerular filtration rate (eGFR) and from baseline to week 48 in urine retinol-binding protein and urine $β$2-microglobulin adjusted for urinary creatinine (uRBP/Cr and uB2M/Cr). Primary analyses prioritized 14 polymorphisms previously reported to be associated with tenofovir disposition or renal outcomes, and all polymorphisms in 14 selected genes. We also explored genome-wide associations. Results 336 participants were enrolled. Among 14 polymorphisms of primary interest, the lowest P values for change in eGFR, uRBP/Cr, and uB2M/Cr were ABCC4 rs899494 (P = 0.022), ABCC10 rs2125739 (P = 0.07), and ABCC4 rs1059751 (P = 0.0088); and in genes of interest, the lowest P values were ABCC4 rs4148481 (P = 0.0013), rs691857 (P = 0.00039), and PKD2 rs72659631 (P = 0.0011). However, none of these polymorphisms withstood correction for multiple testing. Genome-wide, the lowest P values were COL27A1 rs1687402 (P = 3.4 × 10−9), CDH4 rs66494466 (P = 5.6 × 10−8), and ITGA4 rs3770126 (P = 6.1 × 10−7). Conclusion Two ABCC4 polymorphisms, rs899494 and rs1059751, were nominally associated with change in eGFR and uB2M/Cr, respectively, albeit in the opposite direction of previous reports. COL27A1 polymorphism was genome-wide significantly associated with change in eGFR.

@article{Winkler2023,
abstract = {Molecular Microbiology. 2023;00:1-18. | 1 wileyonlinelibrary.com/journal/mmi 1 | INTRODUC TI ON Two decades ago, publication of the complete genome sequence of Mycobacterium tuberculosis brought into sharp focus a problem that continues to pervade much of (micro)biology, affecting even highly studied model organisms (Kustatscher et al., 2022; Wicke et al., 2023): although the sequences of most M. tuberculosis genes (or, at least, ORFs) could be identified, the functions of {\~{}}60{\%} remained (and still remain) imprecisely predicted or unknown, with experimental validation wanting (Cole et al., 1998). Abstract Advances in sequencing technologies have enabled unprecedented insights into bacterial genome composition and dynamics. However, the disconnect between the rapid acquisition of genomic data and the (much slower) confirmation of inferred genetic function threatens to widen unless techniques for fast, high-throughput functional validation can be applied at scale. This applies equally to Mycobacterium tuberculosis, the leading infectious cause of death globally and a pathogen whose genome, despite being among the first to be sequenced two decades ago, still contains many genes of unknown function. Here, we summarize the evolution of bacterial high-throughput functional genomics, focusing primarily on transposon (Tn)-based mutagenesis and the construction of arrayed mutant libraries in diverse bacterial systems. We also consider the contributions of CRISPR interference as a transformative technique for probing bacterial gene function at scale. Throughout, we situate our analysis within the context of functional genomics of mycobacteria, focusing specifically on the potential to yield insights into M. tuberculosis pathogenicity and vulnerabilities for new drug and regimen development. Finally, we offer suggestions for future approaches that might be usefully applied in elucidating the complex cellular biology of this major human pathogen.},
author = {Winkler, Kristy R and Mizrahi, Valerie and Warner, Digby F and {De Wet}, Timothy J},
doi = {10.1111/MMI.15103},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Winkler et al. - 2023 - High-throughput functional genomics a (myco)bacterial perspective.pdf:pdf},
issn = {1365-2958},
journal = {Molecular Microbiology},
keywords = {CRISPRi,Mycobacterium tuberculosis,OA,Tn,TraSH,fund{\_}not{\_}ack,review,seq,transposon mutagenesis},
mendeley-tags = {OA,fund{\_}not{\_}ack,review},
month = {jun},
pages = {10.1111/mmi.15103},
pmid = {37278255},
publisher = {John Wiley {\&} Sons, Ltd},
title = {{High-throughput functional genomics: a (myco)bacterial perspective}},
url = {https://onlinelibrary.wiley.com/doi/full/10.1111/mmi.15103 https://onlinelibrary.wiley.com/doi/abs/10.1111/mmi.15103 https://onlinelibrary.wiley.com/doi/10.1111/mmi.15103},
year = {2023}
}

Molecular Microbiology. 2023;00:1-18. | 1 wileyonlinelibrary.com/journal/mmi 1 | INTRODUC TI ON Two decades ago, publication of the complete genome sequence of Mycobacterium tuberculosis brought into sharp focus a problem that continues to pervade much of (micro)biology, affecting even highly studied model organisms (Kustatscher et al., 2022; Wicke et al., 2023): although the sequences of most M. tuberculosis genes (or, at least, ORFs) could be identified, the functions of \ 60% remained (and still remain) imprecisely predicted or unknown, with experimental validation wanting (Cole et al., 1998). Abstract Advances in sequencing technologies have enabled unprecedented insights into bacterial genome composition and dynamics. However, the disconnect between the rapid acquisition of genomic data and the (much slower) confirmation of inferred genetic function threatens to widen unless techniques for fast, high-throughput functional validation can be applied at scale. This applies equally to Mycobacterium tuberculosis, the leading infectious cause of death globally and a pathogen whose genome, despite being among the first to be sequenced two decades ago, still contains many genes of unknown function. Here, we summarize the evolution of bacterial high-throughput functional genomics, focusing primarily on transposon (Tn)-based mutagenesis and the construction of arrayed mutant libraries in diverse bacterial systems. We also consider the contributions of CRISPR interference as a transformative technique for probing bacterial gene function at scale. Throughout, we situate our analysis within the context of functional genomics of mycobacteria, focusing specifically on the potential to yield insights into M. tuberculosis pathogenicity and vulnerabilities for new drug and regimen development. Finally, we offer suggestions for future approaches that might be usefully applied in elucidating the complex cellular biology of this major human pathogen.

@article{Moseki2022a,
abstract = {Background Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a frequent complication of cotreatment for TB and human immunodeficiency virus (HIV)-1. We characterized Mycobacterium tuberculosis (Mtb)-specific CD4 T-cell phenotype and transcription factor profile associated with the development of TB-IRIS. Methods We examined the role of CD4 T-cell transcription factors in a murine model of mycobacterial IRIS. In humans, we used a longitudinal study design to compare the magnitude of antiretroviral therapy, activation, transcription factor profile, and cytotoxic potential of Mtb-specific CD4 T cells between TB-IRIS (n = 25) and appropriate non-IRIS control patients (n = 18) using flow cytometry. Results In the murine model, CD4 T-cell expression of Eomesodermin (Eomes), but not Tbet, was associated with experimentally induced IRIS. In patients, TB-IRIS onset was associated with the expansion of Mtb-specific IFN$\gamma$+CD4 T cells (P = .039). Patients with TB-IRIS had higher HLA-DR expression (P = .016), but no differences in the expression of T-bet or Eomes were observed. At TB-IRIS onset, Eomes+Tbet+Mtb-specific IFN$\gamma$+CD4+ T cells showed higher expression of granzyme B in patients with TB-IRIS (P = .026). Conclusions Although the murine model of Mycobacterium avium complex-IRIS suggests that Eomes+CD4 T cells underly IRIS, TB-IRIS was not associated with Eomes expression in patients. Mycobacterium tuberculosis-specific IFN$\gamma$+CD4 T-cell responses in TB-IRIS patients are differentiated, highly activated, and potentially cytotoxic.},
author = {Moseki, Raymond M and Barber, Daniel L and {Du Bruyn}, Elsa and Shey, Muki and {Van der Plas}, Helen and Wilkinson, Robert J and Meintjes, Graeme and Riou, Catherine},
doi = {10.1093/OFID/OFAC546},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Moseki et al. - 2023 - Phenotypic profile of Mycobacterium tuberculosis-specific CD4 T cell responses in people with advanced HIV who de.pdf:pdf},
issn = {2328-8957},
journal = {Open Forum Infectious Diseases},
keywords = {HIV-1/TB coinfection,OA,OA{\_}PMC,Th1 responses,fund{\_}ack,immune activation,original,paradoxical TB-IRIS},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,original},
month = {oct},
number = {1},
pages = {ofac546},
pmid = {36726536},
title = {{Phenotypic profile of \textit{Mycobacterium tuberculosis}-specific CD4 T cell responses in people with advanced HIV who develop Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome}},
url = {https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofac546/6761821},
volume = {10},
year = {2023}
}

Background Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a frequent complication of cotreatment for TB and human immunodeficiency virus (HIV)-1. We characterized Mycobacterium tuberculosis (Mtb)-specific CD4 T-cell phenotype and transcription factor profile associated with the development of TB-IRIS. Methods We examined the role of CD4 T-cell transcription factors in a murine model of mycobacterial IRIS. In humans, we used a longitudinal study design to compare the magnitude of antiretroviral therapy, activation, transcription factor profile, and cytotoxic potential of Mtb-specific CD4 T cells between TB-IRIS (n = 25) and appropriate non-IRIS control patients (n = 18) using flow cytometry. Results In the murine model, CD4 T-cell expression of Eomesodermin (Eomes), but not Tbet, was associated with experimentally induced IRIS. In patients, TB-IRIS onset was associated with the expansion of Mtb-specific IFN$γ$+CD4 T cells (P = .039). Patients with TB-IRIS had higher HLA-DR expression (P = .016), but no differences in the expression of T-bet or Eomes were observed. At TB-IRIS onset, Eomes+Tbet+Mtb-specific IFN$γ$+CD4+ T cells showed higher expression of granzyme B in patients with TB-IRIS (P = .026). Conclusions Although the murine model of Mycobacterium avium complex-IRIS suggests that Eomes+CD4 T cells underly IRIS, TB-IRIS was not associated with Eomes expression in patients. Mycobacterium tuberculosis-specific IFN$γ$+CD4 T-cell responses in TB-IRIS patients are differentiated, highly activated, and potentially cytotoxic.

@incollection{Dinkele2023,
abstract = {Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is the leading infectious killer globally, claiming 1.4 million lives annually. TB control is heavily predicated on treatment of active disease. However, delayed and missed diagnoses, and the six-month duration of standard chemotherapy, contribute to failure of this approach to control the TB epidemic. Enumeration of viable aerosolized Mtb via microbiological culture is complicated by the semi-quantitative nature of "time to positivity" in liquid culture and the slow formation of Colony Forming Units on solid media (four to eight weeks for colonies to become visible). A key motivation informing the development of the RASC platform was the need to capture live, aerosol-derived Mtb for analysis and propagation as part of a larger research program in TB transmission and Mtb aerobiology. Fluorescence microscopy of bioaerosol samples enabled the detection of putative live Mtb in 90{\%} of GeneXpert-confirmed TB patients.},
author = {Dinkele, Ryan and Gessner, Sophia and McKerry, Andrea and Leonard, Bryan and Seldon, Ronnett and Koch, Anastasia S and Morrow, Carl and Gqada, Melitta and Kamariza, Mireille and Bertozzi, Carolyn R and Smith, Brian and McLoud, Courtney and Kamholz, Andrew and Bryden, Wayne and Call, Charles and Kaplan, Gilla and Mizrahi, Valerie and Wood, Robin and Warner, Digby F},
booktitle = {Advances in Medical Imaging, Detection, and Diagnosis},
doi = {10.1201/9781003298038-32},
isbn = {9781003298038},
keywords = {book{\_}chap,original},
mendeley-tags = {book{\_}chap,original},
month = {oct},
pages = {935--954},
publisher = {Jenny Stanford Publishing},
title = {{Capture and visualization of live \textit{Mycobacterium tuberculosis} bacilli from tuberculosis patient bioaerosols}},
url = {https://www.taylorfrancis.com/chapters/edit/10.1201/9781003298038-32/capture-visualization-live-mycobacterium-tuberculosis-bacilli-tuberculosis-patient-bioaerosols-ryan-dinkele-sophia-gessner-andrea-mckerry-bryan-leonard-ronnett-seldon-anastasia-koch-carl},
year = {2023}
}

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is the leading infectious killer globally, claiming 1.4 million lives annually. TB control is heavily predicated on treatment of active disease. However, delayed and missed diagnoses, and the six-month duration of standard chemotherapy, contribute to failure of this approach to control the TB epidemic. Enumeration of viable aerosolized Mtb via microbiological culture is complicated by the semi-quantitative nature of "time to positivity" in liquid culture and the slow formation of Colony Forming Units on solid media (four to eight weeks for colonies to become visible). A key motivation informing the development of the RASC platform was the need to capture live, aerosol-derived Mtb for analysis and propagation as part of a larger research program in TB transmission and Mtb aerobiology. Fluorescence microscopy of bioaerosol samples enabled the detection of putative live Mtb in 90% of GeneXpert-confirmed TB patients.

@article{Harrison2023,
abstract = {The AmBisome Therapy Induction Optimization (AMBITION-cm) trial, conducted in eastern and southern Africa, showed that a single, high dose (10 mg/kg) of liposomal amphotericin B, given with an oral backbone of fluconazole and flucytosine, was noninferior to the World Health Organization (WHO)–recommended regimen of 7 days of amphotericin B deoxycholate plus flucytosine for treatment of human immunodeficiency virus (HIV)–associated cryptococcal meningitis and has been incorporated into WHO treatment guidelines. We believe that the trial also has important implications for the treatment of HIV-associated cryptococcal meningitis in high-income settings. We advance the arguments, supported by evidence where available, that the AMBITION-cm trial regimen is likely to be as fungicidal as the currently recommended 14-day liposomal amphotericin–based treatments, better tolerated with fewer adverse effects, and confer significant economic and practical benefits and, therefore, should be included as a treatment option in guidance for HIV-associated cryptococcal treatment in high-income settings.},
author = {Harrison, Thomas S and Lawrence, David S and Mwandumba, Henry C and Boulware, David R and Hosseinipour, Mina C and Lortholary, Olivier and Meintjes, Graeme A and Mosepele, Mosepele and Jarvis, Joseph N},
doi = {10.1093/cid/ciac792},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Harrison et al. - 2023 - How applicable is the single-dose AMBITION regimen for Human Immunodeficiency Virus–associated cryptococcal men.pdf:pdf},
issn = {1058-4838},
journal = {Clinical Infectious Diseases},
keywords = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {mar},
number = {5},
pages = {944--949},
pmid = {36166405},
title = {{How applicable is the single-dose AMBITION regimen for Human Immunodeficiency Virus–associated cryptococcal meningitis to high-income settings?}},
url = {https://doi.org/10.1093/cid/ciac792},
volume = {76},
year = {2023}
}

The AmBisome Therapy Induction Optimization (AMBITION-cm) trial, conducted in eastern and southern Africa, showed that a single, high dose (10 mg/kg) of liposomal amphotericin B, given with an oral backbone of fluconazole and flucytosine, was noninferior to the World Health Organization (WHO)–recommended regimen of 7 days of amphotericin B deoxycholate plus flucytosine for treatment of human immunodeficiency virus (HIV)–associated cryptococcal meningitis and has been incorporated into WHO treatment guidelines. We believe that the trial also has important implications for the treatment of HIV-associated cryptococcal meningitis in high-income settings. We advance the arguments, supported by evidence where available, that the AMBITION-cm trial regimen is likely to be as fungicidal as the currently recommended 14-day liposomal amphotericin–based treatments, better tolerated with fewer adverse effects, and confer significant economic and practical benefits and, therefore, should be included as a treatment option in guidance for HIV-associated cryptococcal treatment in high-income settings.

@article{Eriksson2023,
abstract = {Purpose: The COVID PROFILE cohort is a longitudinal clinical study based in Victoria Australia, which was established to understand immunity to SARS-CoV-2 in a low transmission population setting and to identify immunological markers of long-term immunity and immune-dysregulation after both infection and vaccination. Additionally, this cohort was established as a biobank resource for researchers to address other health-related immunological questions. Participants: We enrolled 178 adult community members, including household contacts, who had either recovered from a SARS-CoV-2 infection or were SARS-CoV-2 naive. Only participants 18 years of age or older and, in the case of female participants, non-pregnant women at the time of enrollment were included in the study. Detailed COVID-19 clinical data, vaccination status, medical history and demographics was collected. Findings to date: At enrollment, we found that 87.8{\%} of COVID-19 recovered individuals were seropositive with detectable levels of anti-SARS-CoV-2 IgG antibodies. Seronegative COVID-19 recovered individuals included asymptomatic individuals or participants that were enrolled more than 12 months after their COVID-19 diagnosis. Except for one individual who was seropositive at baseline despite a previous SARS-CoV-2 PCR negative diagnosis, all household contacts and other community members enrolled as SARS-CoV-2 PCR negative, were seronegative for all SARS-CoV-2-specific antibodies tested. The infection rate (re-infection or new infection) during 24 months of the study was 42.7{\%}, as determined by either rapid antigen tests, PCRs or serology screens. Of the SARS-CoV-2 recovered participants, 32.6{\%} reported ongoing symptoms at enrollment of which 47{\%} had already experienced ongoing symptoms for more than 12 weeks. Future Plans: COVID PROFILE will be used to comprehensively understand temporal immunity to SARS-CoV-2 and COVID-19 vaccines and to understand the impact of host immunological composition on such immunity and symptom severity. Additionally, studies focusing on understanding immunity following breakthrough infections and immunological risk factors that contribute towards development of long COVID are planned. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Funding Statement This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. This work was supported by WHO Unity funds (2020/1085469-0) and WEHI Philanthropic funds. The funders had no role in study design, data collection and analysis. {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of the Walter and Eliza Hall Institute (WEHI) and Melbourne Health Human Research Committees gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors},
author = {Eriksson, Emily M and Hart, Anne and Forde, Maureen and Foroughi, Siavash and Kiernan-Walker, Nicholas and Mazhari, Ramin and Lucas, Erin C and Margetts, Mai and Farchione, Anthony and Sheerin, Dylan and Ashdown, George and Evans, Rachel and Chen, Catherine and Ruybal-Pesantez, Shazia and Conway, Eamon and Barrios, Marilou H and Cornish, Jasper and Edmonds, Maria and Henneken, Lee M and Ioannidis, Lisa J and Olechnowicz, Sam W Z and Munnings, Ryan B and Groom, Joanna R and Hansen, Diana S and Bowden, Rory and Coussens, Anna K and Tye-Din, Jason A and Bryant, Vanessa L and Mueller, Ivo},
doi = {10.1101/2023.04.27.23289157},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Eriksson et al. - 2023 - Cohort Profile A longitudinal Victorian COVID-19 cohort (COVID PROFILE).pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {apr},
pages = {2023.04.27.23289157},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Cohort Profile: A longitudinal Victorian COVID-19 cohort (COVID PROFILE)}},
url = {https://www.medrxiv.org/content/10.1101/2023.04.27.23289157v1 https://www.medrxiv.org/content/10.1101/2023.04.27.23289157v1.abstract},
year = {2023}
}

Purpose: The COVID PROFILE cohort is a longitudinal clinical study based in Victoria Australia, which was established to understand immunity to SARS-CoV-2 in a low transmission population setting and to identify immunological markers of long-term immunity and immune-dysregulation after both infection and vaccination. Additionally, this cohort was established as a biobank resource for researchers to address other health-related immunological questions. Participants: We enrolled 178 adult community members, including household contacts, who had either recovered from a SARS-CoV-2 infection or were SARS-CoV-2 naive. Only participants 18 years of age or older and, in the case of female participants, non-pregnant women at the time of enrollment were included in the study. Detailed COVID-19 clinical data, vaccination status, medical history and demographics was collected. Findings to date: At enrollment, we found that 87.8% of COVID-19 recovered individuals were seropositive with detectable levels of anti-SARS-CoV-2 IgG antibodies. Seronegative COVID-19 recovered individuals included asymptomatic individuals or participants that were enrolled more than 12 months after their COVID-19 diagnosis. Except for one individual who was seropositive at baseline despite a previous SARS-CoV-2 PCR negative diagnosis, all household contacts and other community members enrolled as SARS-CoV-2 PCR negative, were seronegative for all SARS-CoV-2-specific antibodies tested. The infection rate (re-infection or new infection) during 24 months of the study was 42.7%, as determined by either rapid antigen tests, PCRs or serology screens. Of the SARS-CoV-2 recovered participants, 32.6% reported ongoing symptoms at enrollment of which 47% had already experienced ongoing symptoms for more than 12 weeks. Future Plans: COVID PROFILE will be used to comprehensively understand temporal immunity to SARS-CoV-2 and COVID-19 vaccines and to understand the impact of host immunological composition on such immunity and symptom severity. Additionally, studies focusing on understanding immunity following breakthrough infections and immunological risk factors that contribute towards development of long COVID are planned. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. This work was supported by WHO Unity funds (2020/1085469-0) and WEHI Philanthropic funds. The funders had no role in study design, data collection and analysis. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of the Walter and Eliza Hall Institute (WEHI) and Melbourne Health Human Research Committees gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

@article{Verma2023,
abstract = {Rationale: Standardized dosing of anti-tubercular (TB) drugs leads to variable plasma drug levels, which are associated with adverse drug reactions, delayed treatment response, and relapse. Mutations in genes affecting drug metabolism explain considerable interindividual pharmacokinetic variability; however, pharmacogenomic (PGx) assays that predict metabolism of anti-TB drugs have been lacking. Objectives: To develop a Nanopore sequencing panel and validate its performance in active TB patients to personalize treatment dosing. Measurements and Main Results: We developed a Nanopore sequencing panel targeting 15 single nucleotide polymorphisms (SNP) in 5 genes affecting the metabolism of isoniazid (INH), rifampin (RIF), linezolid and bedaquiline. For validation, we sequenced DNA samples (n=48) from the 1000 genomes project and compared variant calling accuracy with Illumina genome sequencing. We then sequenced DNA samples from patients with active TB (n=100) from South Africa on a MinION Mk1C and evaluated the relationship between genotypes and pharmacokinetic parameters for INH and RIF. Results: The PGx panel achieved 100{\%} concordance with Illumina sequencing in variant identification for the samples from the 1000 Genomes Project. In the clinical cohort, coverage was {\textgreater}100x for 1498/1500 (99.8{\%}) amplicons across the 100 samples. One third (33{\%}) of participants were identified as slow, 47{\%} were intermediate and 20{\%} were rapid isoniazid acetylators. Isoniazid clearance was significantly impacted by acetylator status (p{\textless}0.0001) with median (IQR) clearances of 11.2 L/h (9.3-13.4), 27.2 L/h (22.0-31.7), and 45.1 L/h (34.1-51.1) in slow, intermediate, and rapid acetylators. Rifampin clearance was 17.3{\%} (2.50-29.9) lower in individuals with homozygous AADAC rs1803155 G{\textgreater}A substitutions (p=0.0015). Conclusion: Targeted sequencing can enable detection of polymorphisms influencing TB drug metabolism on a low-cost, portable instrument to personalize dosing for TB treatment or prevention. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Funding Statement This study was supported by the National Institutes of Health (R21 AI172182). RJW receives funding from Wellcome (203135) and from the Francis Crick Institute which is supported by Cancer Research UK (FC2112), UK Research and Innovation-Medical Research Council (CC2112) and Wellcome (CC2112). For the purposes of open access, a CC-BY public copyright has been applied to any author-accepted manuscript arising from this submission. {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Patients with GeneXpert MTB/RIF-confirmed RIF-susceptible pulmonary TB were recruited at the Ubuntu HIV/TB Clinic, Site B, Khayelitsha, South Africa (University of Cape Town Faculty of Health Sciences Human Research Ethics Committee approval 568/2012) as a part of a larger study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data supporting the findings of this manuscript are available in the Supplementary Information files or from the corresponding author upon request.},
author = {Verma, Renu and da Silva, Kesia and Rockwood, Neesha and Wasmann, Roeland E and Yende, Nombuso and Song, Taeksun and Kim, Eugene and Denti, Paolo and Wilkinson, Robert J and Andrews, Jason R},
doi = {10.1101/2023.09.08.23295248},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Verma et al. - 2023 - A Nanopore sequencing-based pharmacogenomic panel to personalize tuberculosis drug dosing.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {sep},
pages = {2023.09.08.23295248},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{A Nanopore sequencing-based pharmacogenomic panel to personalize tuberculosis drug dosing}},
url = {https://www.medrxiv.org/content/10.1101/2023.09.08.23295248v1 https://www.medrxiv.org/content/10.1101/2023.09.08.23295248v1.abstract},
year = {2023}
}

Rationale: Standardized dosing of anti-tubercular (TB) drugs leads to variable plasma drug levels, which are associated with adverse drug reactions, delayed treatment response, and relapse. Mutations in genes affecting drug metabolism explain considerable interindividual pharmacokinetic variability; however, pharmacogenomic (PGx) assays that predict metabolism of anti-TB drugs have been lacking. Objectives: To develop a Nanopore sequencing panel and validate its performance in active TB patients to personalize treatment dosing. Measurements and Main Results: We developed a Nanopore sequencing panel targeting 15 single nucleotide polymorphisms (SNP) in 5 genes affecting the metabolism of isoniazid (INH), rifampin (RIF), linezolid and bedaquiline. For validation, we sequenced DNA samples (n=48) from the 1000 genomes project and compared variant calling accuracy with Illumina genome sequencing. We then sequenced DNA samples from patients with active TB (n=100) from South Africa on a MinION Mk1C and evaluated the relationship between genotypes and pharmacokinetic parameters for INH and RIF. Results: The PGx panel achieved 100% concordance with Illumina sequencing in variant identification for the samples from the 1000 Genomes Project. In the clinical cohort, coverage was \textgreater100x for 1498/1500 (99.8%) amplicons across the 100 samples. One third (33%) of participants were identified as slow, 47% were intermediate and 20% were rapid isoniazid acetylators. Isoniazid clearance was significantly impacted by acetylator status (p\textless0.0001) with median (IQR) clearances of 11.2 L/h (9.3-13.4), 27.2 L/h (22.0-31.7), and 45.1 L/h (34.1-51.1) in slow, intermediate, and rapid acetylators. Rifampin clearance was 17.3% (2.50-29.9) lower in individuals with homozygous AADAC rs1803155 G\textgreaterA substitutions (p=0.0015). Conclusion: Targeted sequencing can enable detection of polymorphisms influencing TB drug metabolism on a low-cost, portable instrument to personalize dosing for TB treatment or prevention. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by the National Institutes of Health (R21 AI172182). RJW receives funding from Wellcome (203135) and from the Francis Crick Institute which is supported by Cancer Research UK (FC2112), UK Research and Innovation-Medical Research Council (CC2112) and Wellcome (CC2112). For the purposes of open access, a CC-BY public copyright has been applied to any author-accepted manuscript arising from this submission. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Patients with GeneXpert MTB/RIF-confirmed RIF-susceptible pulmonary TB were recruited at the Ubuntu HIV/TB Clinic, Site B, Khayelitsha, South Africa (University of Cape Town Faculty of Health Sciences Human Research Ethics Committee approval 568/2012) as a part of a larger study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data supporting the findings of this manuscript are available in the Supplementary Information files or from the corresponding author upon request.

@article{Sossen2023a,
abstract = {Stages of tuberculosis disease can be delineated by radiology, microbiology, and symptoms, but transitions between these stages remain unclear. In a systematic review and meta-analysis of studies of individuals with untreated tuberculosis who underwent follow-up (34 cohorts from 24 studies, with a combined sample of 139 063), we aimed to quantify progression and regression across the tuberculosis disease spectrum by extracting summary estimates to align with disease transitions in a conceptual framework of the natural history of tuberculosis. Progression from microbiologically negative to positive disease (based on smear or culture tests) in participants with baseline radiographic evidence of tuberculosis occurred at an annualised rate of 10{\%} (95{\%} CI 6{\textperiodcentered}2–13{\textperiodcentered}3) in those with chest x-rays suggestive of active tuberculosis, and at a rate of 1{\%} (0{\textperiodcentered}3–1{\textperiodcentered}8) in those with chest x-ray changes suggestive of inactive tuberculosis. Reversion from microbiologically positive to undetectable disease in prospective cohorts occurred at an annualised rate of 12{\%} (6{\textperiodcentered}8–18{\textperiodcentered}0). A better understanding of the natural history of pulmonary tuberculosis, including the risk of progression in relation to radiological findings, could improve estimates of the global disease burden and inform the development of clinical guidelines and policies for treatment and prevention},
author = {Sossen, Bianca and Richards, Alexandra S and Heinsohn, Torben and Frascella, Beatrice and Balzarini, Federica and Oradini-Alacreu, Aurea and Odone, Anna and Rogozinska, Ewelina and H{\"{a}}cker, Brit and Cobelens, Frank and Kranzer, Katharina and Houben, Rein M G J and Esmail, Hanif},
doi = {10.1016/S2213-2600(23)00097-8},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Sossen et al. - 2023 - The natural history of untreated pulmonary tuberculosis in adults a systematic review and meta-analysis.pdf:pdf},
issn = {2213-2600},
journal = {The Lancet Respiratory Medicine},
keywords = {fund{\_}not{\_}ack,review},
mendeley-tags = {fund{\_}not{\_}ack,review},
month = {mar},
pages = {https://doi.org/10.1016/ S2213--2600(23)00097--8},
pmid = {36966795},
publisher = {Elsevier},
title = {{The natural history of untreated pulmonary tuberculosis in adults: a systematic review and meta-analysis}},
url = {https://linkinghub.elsevier.com/retrieve/pii/S2213260023000978},
year = {2023}
}

Stages of tuberculosis disease can be delineated by radiology, microbiology, and symptoms, but transitions between these stages remain unclear. In a systematic review and meta-analysis of studies of individuals with untreated tuberculosis who underwent follow-up (34 cohorts from 24 studies, with a combined sample of 139 063), we aimed to quantify progression and regression across the tuberculosis disease spectrum by extracting summary estimates to align with disease transitions in a conceptual framework of the natural history of tuberculosis. Progression from microbiologically negative to positive disease (based on smear or culture tests) in participants with baseline radiographic evidence of tuberculosis occurred at an annualised rate of 10% (95% CI 6˙2–13˙3) in those with chest x-rays suggestive of active tuberculosis, and at a rate of 1% (0˙3–1˙8) in those with chest x-ray changes suggestive of inactive tuberculosis. Reversion from microbiologically positive to undetectable disease in prospective cohorts occurred at an annualised rate of 12% (6˙8–18˙0). A better understanding of the natural history of pulmonary tuberculosis, including the risk of progression in relation to radiological findings, could improve estimates of the global disease burden and inform the development of clinical guidelines and policies for treatment and prevention

@article{Goig2023,
abstract = {Summary Background Experimental data show that drug-resistance-conferring mutations are often associated with a decrease in the replicative fitness of bacteria in vitro, and that this fitness cost can be mitigated by compensatory mutations; however, the role of compensatory evolution in clinical settings is less clear. We assessed whether compensatory evolution was associated with increased transmission of rifampicin-resistant tuberculosis in Khayelitsha, Cape Town, South Africa. Methods We did a genomic epidemiological study by analysing available M tuberculosis isolates and their associated clinical data from individuals routinely diagnosed with rifampicin-resistant tuberculosis in primary care and hospitals in Khayelitsha, Cape Town, South Africa. Isolates were collected as part of a previous study. All individuals diagnosed with rifampicin-resistant tuberculosis and with linked biobanked specimens were included in this study. We applied whole-genome sequencing, Bayesian reconstruction of transmission trees, and phylogenetic multivariable regression analysis to identify individual and bacterial factors associated with the transmission of rifampicin-resistant M tuberculosis strains. Findings Between Jan 1, 2008, and Dec 31, 2017, 2161 individuals were diagnosed with multidrug-resistant or rifampicin-resistant tuberculosis in Khayelitsha, Cape Town, South Africa. Whole-genome sequences were available for 1168 (54{\%}) unique individual M tuberculosis isolates. Compensatory evolution was associated with smear-positive pulmonary disease (adjusted odds ratio 1{\textperiodcentered}49, 95{\%} CI 1{\textperiodcentered}08–2{\textperiodcentered}06) and a higher number of drug-resistance-conferring mutations (incidence rate ratio 1{\textperiodcentered}38, 95{\%} CI 1{\textperiodcentered}28–1{\textperiodcentered}48). Compensatory evolution was also associated with increased transmission of rifampicin-resistant disease between individuals (adjusted odds ratio 1{\textperiodcentered}55; 95{\%} CI 1{\textperiodcentered}13–2{\textperiodcentered}12), independent of other patient and bacterial factors. Interpretation Our findings suggest that compensatory evolution enhances the in vivo fitness of drug-resistant M tuberculosis genotypes, both within and between patients, and that the in vitro replicative fitness of rifampicin-resistant M tuberculosis measured in the laboratory correlates with the bacterial fitness measured in clinical settings. These results emphasise the importance of enhancing surveillance and monitoring efforts to prevent the emergence of highly transmissible clones capable of rapidly accumulating new drug resistance mutations. This concern becomes especially crucial at present, because treatment regimens incorporating novel drugs are being implemented. Funding Funding for this study was provided by a Swiss and South Africa joint research award (grant numbers 310030{\_}188888, CRSII5{\_}177163, and IZLSZ3{\_}170834), the European Research Council (grant number 883582), and a Wellcome Trust fellowship (to HC; reference number 099818/Z/12/Z). ZS-D was funded through a PhD scholarship from the South African National Research Foundation and RMW was funded through the South African Medical Research Council.},
author = {Goig, Galo A and Menardo, Fabrizio and Salaam-Dreyer, Zubeida and Dippenaar, Anzaan and Streicher, Elizabeth M and Daniels, Johnny and Reuter, Anja and Borrell, Sonia and Reinhard, Miriam and Doetsch, Anna and Beisel, Christian and Warren, Robin M and Cox, Helen and Gagneux, Sebastien},
doi = {10.1016/S2666-5247(23)00110-6},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Goig et al. - 2023 - Effect of compensatory evolution in the emergence and transmission of rifampicin-resistant iMycobacterium tuberculo.pdf:pdf},
issn = {2666-5247},
journal = {The Lancet Microbe},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jun},
pages = {10.1016/S2666--5247(23)00110--6},
pmid = {37295446},
publisher = {Elsevier},
title = {{Effect of compensatory evolution in the emergence and transmission of rifampicin-resistant \textit{Mycobacterium tuberculosis} in Cape Town, South Africa: a genomic epidemiology study}},
url = {http://www.thelancet.com/article/S2666524723001106/fulltext http://www.thelancet.com/article/S2666524723001106/abstract https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(23)00110-6/abstract},
year = {2023}
}

Summary Background Experimental data show that drug-resistance-conferring mutations are often associated with a decrease in the replicative fitness of bacteria in vitro, and that this fitness cost can be mitigated by compensatory mutations; however, the role of compensatory evolution in clinical settings is less clear. We assessed whether compensatory evolution was associated with increased transmission of rifampicin-resistant tuberculosis in Khayelitsha, Cape Town, South Africa. Methods We did a genomic epidemiological study by analysing available M tuberculosis isolates and their associated clinical data from individuals routinely diagnosed with rifampicin-resistant tuberculosis in primary care and hospitals in Khayelitsha, Cape Town, South Africa. Isolates were collected as part of a previous study. All individuals diagnosed with rifampicin-resistant tuberculosis and with linked biobanked specimens were included in this study. We applied whole-genome sequencing, Bayesian reconstruction of transmission trees, and phylogenetic multivariable regression analysis to identify individual and bacterial factors associated with the transmission of rifampicin-resistant M tuberculosis strains. Findings Between Jan 1, 2008, and Dec 31, 2017, 2161 individuals were diagnosed with multidrug-resistant or rifampicin-resistant tuberculosis in Khayelitsha, Cape Town, South Africa. Whole-genome sequences were available for 1168 (54%) unique individual M tuberculosis isolates. Compensatory evolution was associated with smear-positive pulmonary disease (adjusted odds ratio 1˙49, 95% CI 1˙08–2˙06) and a higher number of drug-resistance-conferring mutations (incidence rate ratio 1˙38, 95% CI 1˙28–1˙48). Compensatory evolution was also associated with increased transmission of rifampicin-resistant disease between individuals (adjusted odds ratio 1˙55; 95% CI 1˙13–2˙12), independent of other patient and bacterial factors. Interpretation Our findings suggest that compensatory evolution enhances the in vivo fitness of drug-resistant M tuberculosis genotypes, both within and between patients, and that the in vitro replicative fitness of rifampicin-resistant M tuberculosis measured in the laboratory correlates with the bacterial fitness measured in clinical settings. These results emphasise the importance of enhancing surveillance and monitoring efforts to prevent the emergence of highly transmissible clones capable of rapidly accumulating new drug resistance mutations. This concern becomes especially crucial at present, because treatment regimens incorporating novel drugs are being implemented. Funding Funding for this study was provided by a Swiss and South Africa joint research award (grant numbers 310030_188888, CRSII5_177163, and IZLSZ3_170834), the European Research Council (grant number 883582), and a Wellcome Trust fellowship (to HC; reference number 099818/Z/12/Z). ZS-D was funded through a PhD scholarship from the South African National Research Foundation and RMW was funded through the South African Medical Research Council.

@article{Kroon2023a,
abstract = {Persons living with HIV (PLWH) have an increased risk for tuberculosis (TB). After prolonged and repeated exposure, some PLWH never develop TB and show no evidence of immune sensitization to Mycobacterium tuberculosis (Mtb) as defined by persistently negative tuberculin skin tests (TST) and interferon gamma release assays (IGRA). This group has been identified and defined as HIV+ persistently TB, tuberculin and IGRA negative (HITTIN). To investigate potential innate mechanisms unique to individuals with the HITTIN phenotype we compared their neutrophil Mtb infection response to that of PLWH, with no TB history, but who test persistently IGRA positive, and tuberculin positive (HIT). Neutrophil samples from 17 HITTIN (PMNHITTIN) and 11 HIT (PMNHIT) were isolated and infected with Mtb H37Rv for 1h and 6h. RNA was extracted and used for RNAseq analysis. Since there was no significant differential transcriptional response at 1h between infected PMNHITTIN and PMNHIT, we focused on the 6h timepoint. When compared to uninfected PMN, PMNHITTIN displayed 3106 significantly upregulated and 3548 significantly downregulated differentially expressed genes (DEGs) (absolute cutoff of a log2FC of 0.2, FDR {\textless} 0.05) whereas PMNHIT demonstrated 3816 significantly upregulated and 3794 significantly downregulated DEGs following 6h Mtb infection. Contrasting the log2FC 6h infection response to Mtb from PMNHITTIN against PMNHIT, 2285 genes showed significant differential response between the two groups. Overall PMNHITTIN had a lower fold change response to Mtb infection compared to PMNHIT. According to pathway enrichment, Apoptosis and NETosis were differentially regulated between HITTIN and HIT PMN responses after 6h Mtb infection. To corroborate the blunted NETosis transcriptional response measured among HITTIN, fluorescence microscopy revealed relatively lower neutrophil extracellular trap formation and cell loss in PMNHITTIN compared to PMNHIT, showing that PMNHITTIN have a distinct response to Mtb.},
author = {Kroon, Elouise E and Correa-Macedo, Wilian and Evans, Rachel and Seeger, Allison and Engelbrecht, Lize and Kriel, Jurgen A and Loos, Ben and Okugbeni, Naomi and Orlova, Marianna and Cassart, Pauline and Kinnear, Craig J and Tromp, Gerard C and M{\"{o}}ller, Marlo and Wilkinson, Robert J and Coussens, Anna K and Schurr, Erwin and Hoal, Eileen G},
doi = {10.1371/JOURNAL.PGEN.1010888},
editor = {Stein, Cathy},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Kroon et al. - 2023 - Neutrophil extracellular trap formation and gene programs distinguish TSTIGRA sensitization outcomes among Mycobac.pdf:pdf},
isbn = {1111111111},
issn = {1553-7404},
journal = {PLOS Genetics},
keywords = {Antiretroviral therapy,Flow cytometry,Gene expression,Gene ontologies,Mycobacterium tuberculosis,Neutrophils,OA,OA{\_}PMC,T cells,Tuberculosis,fund{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,original},
month = {aug},
number = {8},
pages = {e1010888},
pmid = {37616312},
publisher = {Public Library of Science},
title = {{Neutrophil extracellular trap formation and gene programs distinguish TST/IGRA sensitization outcomes among \textit{Mycobacterium tuberculosis} exposed persons living with HIV}},
url = {https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1010888},
volume = {19},
year = {2023}
}

Persons living with HIV (PLWH) have an increased risk for tuberculosis (TB). After prolonged and repeated exposure, some PLWH never develop TB and show no evidence of immune sensitization to Mycobacterium tuberculosis (Mtb) as defined by persistently negative tuberculin skin tests (TST) and interferon gamma release assays (IGRA). This group has been identified and defined as HIV+ persistently TB, tuberculin and IGRA negative (HITTIN). To investigate potential innate mechanisms unique to individuals with the HITTIN phenotype we compared their neutrophil Mtb infection response to that of PLWH, with no TB history, but who test persistently IGRA positive, and tuberculin positive (HIT). Neutrophil samples from 17 HITTIN (PMNHITTIN) and 11 HIT (PMNHIT) were isolated and infected with Mtb H37Rv for 1h and 6h. RNA was extracted and used for RNAseq analysis. Since there was no significant differential transcriptional response at 1h between infected PMNHITTIN and PMNHIT, we focused on the 6h timepoint. When compared to uninfected PMN, PMNHITTIN displayed 3106 significantly upregulated and 3548 significantly downregulated differentially expressed genes (DEGs) (absolute cutoff of a log2FC of 0.2, FDR \textless 0.05) whereas PMNHIT demonstrated 3816 significantly upregulated and 3794 significantly downregulated DEGs following 6h Mtb infection. Contrasting the log2FC 6h infection response to Mtb from PMNHITTIN against PMNHIT, 2285 genes showed significant differential response between the two groups. Overall PMNHITTIN had a lower fold change response to Mtb infection compared to PMNHIT. According to pathway enrichment, Apoptosis and NETosis were differentially regulated between HITTIN and HIT PMN responses after 6h Mtb infection. To corroborate the blunted NETosis transcriptional response measured among HITTIN, fluorescence microscopy revealed relatively lower neutrophil extracellular trap formation and cell loss in PMNHITTIN compared to PMNHIT, showing that PMNHITTIN have a distinct response to Mtb.

@article{Scheier2023b,
abstract = {Multiple additional studies have been reported since the 2022 publication by members of our group of a systematic review and meta-analysis of randomized trials of intensified versus standard prophylactic anticoagulation therapy in patients hospitalized with Coronavirus Disease 2019 (COVID-19) (1). Including all available data in an updated-meta-analysis can be expected to provide more reliable and precise estimates of the effects of treatment on clinical outcomes and thereby strengthen guidance on the use of anticoagulation in the hospitalized COVID-19 patients.},
author = {Scheier, Thomas C and Carlin, Stephanie and Wills, Nicola K and Wasserman, Sean and Mertz, Dominik and Eikelboom, John W},
doi = {10.1093/OFID/OFAD506},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Scheier et al. - 2023 - Efficacy and safety of intensified vs standard prophylactic anticoagulation therapy in patients hospitalized wit.pdf:pdf},
journal = {Open Forum Infectious Diseases},
keywords = {OA,fund{\_}not{\_}ack,letter},
mendeley-tags = {OA,fund{\_}not{\_}ack,letter},
month = {nov},
number = {11},
pages = {ofad506},
publisher = {Oxford Academic},
title = {{Efficacy and safety of intensified vs standard prophylactic anticoagulation therapy in patients hospitalized with Coronavirus Disease 2019: updated systematic review and meta-analysis}},
url = {https://dx.doi.org/10.1093/ofid/ofad506},
volume = {10},
year = {2023}
}

Multiple additional studies have been reported since the 2022 publication by members of our group of a systematic review and meta-analysis of randomized trials of intensified versus standard prophylactic anticoagulation therapy in patients hospitalized with Coronavirus Disease 2019 (COVID-19) (1). Including all available data in an updated-meta-analysis can be expected to provide more reliable and precise estimates of the effects of treatment on clinical outcomes and thereby strengthen guidance on the use of anticoagulation in the hospitalized COVID-19 patients.

@article{Wasmann2023,
abstract = {Following infection with Mycobacterium tuberculosis, young children are at high risk of developing severe forms of tuberculosis (TB) disease, including TB meningitis (TBM), which is associated with significant morbidity and mortality. In 2022, the World Health Organization (WHO) conditionally recommended that a 6-month treatment regimen composed of higher doses of isoniazid (H) and rifampicin (R), with pyrazinamide (Z) and ethionamide (Eto) (6HRZEto), be used as an alternative to the standard 12-month regimen (2HRZ-Ethambutol/10HR) in children and adolescents with bacteriologically confirmed or clinically diagnosed TBM. This regimen has been used in South Africa since 1985, in a complex dosing scheme across weight bands using fixed-dose combinations (FDC) available locally at the time. This paper describes the methodology used to develop a new dosing strategy to facilitate implementation of the short TBM regimen based on newer globally available drug formulations. Several dosing options were simulated in a virtual representative population of children using population PK modelling. The exposure target was in line with the TBM regimen implemented in South Africa. The results were presented to a WHO convened expert meeting. Given the difficulty to achieve simple dosing using the globally available RH 75/50 mg FDC, the panel expressed the preference to target a slightly higher rifampicin exposure while keeping isoniazid exposures in line with those used in South Africa. This work informed the WHO operational handbook on the management of TB in children and adolescents, in which dosing strategies for children with TBM using the short TBM treatment regimen are provided.},
author = {Wasmann, Roeland E and Masini, Tiziana and Viney, Kerri and Verkuijl, Sabine and Brands, Annemieke and Hesseling, Anneke C and McIlleron, Helen and Denti, Paolo and Dooley, Kelly E},
doi = {10.3389/FPHAR.2023.1055329},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Wasmann et al. - 2023 - A model-based approach for a practical dosing strategy for the short, intensive treatment regimen for paediatric.pdf:pdf},
issn = {1663-9812},
journal = {Frontiers in Pharmacology},
keywords = {Ethionamide,Isoniazid,NONMEM,OA,Paediatric dosing,Pyrazinamide,Rifampi(ci)n,WHO,fund{\_}not{\_}ack,original,rifampin},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {apr},
pages = {1055329},
publisher = {Frontiers},
title = {{A model-based approach for a practical dosing strategy for the short, intensive treatment regimen for paediatric tuberculous meningitis}},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2023.1055329/full},
volume = {14},
year = {2023}
}

Following infection with Mycobacterium tuberculosis, young children are at high risk of developing severe forms of tuberculosis (TB) disease, including TB meningitis (TBM), which is associated with significant morbidity and mortality. In 2022, the World Health Organization (WHO) conditionally recommended that a 6-month treatment regimen composed of higher doses of isoniazid (H) and rifampicin (R), with pyrazinamide (Z) and ethionamide (Eto) (6HRZEto), be used as an alternative to the standard 12-month regimen (2HRZ-Ethambutol/10HR) in children and adolescents with bacteriologically confirmed or clinically diagnosed TBM. This regimen has been used in South Africa since 1985, in a complex dosing scheme across weight bands using fixed-dose combinations (FDC) available locally at the time. This paper describes the methodology used to develop a new dosing strategy to facilitate implementation of the short TBM regimen based on newer globally available drug formulations. Several dosing options were simulated in a virtual representative population of children using population PK modelling. The exposure target was in line with the TBM regimen implemented in South Africa. The results were presented to a WHO convened expert meeting. Given the difficulty to achieve simple dosing using the globally available RH 75/50 mg FDC, the panel expressed the preference to target a slightly higher rifampicin exposure while keeping isoniazid exposures in line with those used in South Africa. This work informed the WHO operational handbook on the management of TB in children and adolescents, in which dosing strategies for children with TBM using the short TBM treatment regimen are provided.

@article{Richards2023,
abstract = {Summary Background Prevalence surveys show a substantial burden of subclinical (asymptomatic but infectious) tuberculosis, from which individuals can progress, regress, or even persist in a chronic disease state. We aimed to quantify these pathways across the spectrum of tuberculosis disease. Methods We created a deterministic framework of untreated tuberculosis disease with progression and regression between three states of pulmonary tuberculosis disease: minimal (non-infectious), subclinical (asymptomatic but infectious), and clinical (symptomatic and infectious). We obtained data from a previous systematic review of prospective and retrospective studies that followed and recorded the disease state of individuals with tuberculosis in a cohort without treatment. These data were considered in a Bayesian framework, enabling quantitative estimation of tuberculosis disease pathways with rates of transition between states and 95{\%} uncertainty intervals (UIs). Findings We included 22 studies with data from 5942 individuals in our analysis. Our model showed that after 5 years, 40{\%} (95{\%} UI 31{\textperiodcentered}3–48{\textperiodcentered}0) of individuals with prevalent subclinical disease at baseline recover and 18{\%} (13{\textperiodcentered}3–24{\textperiodcentered}0) die from tuberculosis, with 14{\%} (9{\textperiodcentered}9–19{\textperiodcentered}2) still having infectious disease, and the remainder with minimal disease at risk of re-progression. Over 5 years, 50{\%} (40{\textperiodcentered}0–59{\textperiodcentered}1) of individuals with subclinical disease at baseline never develop symptoms. For those with clinical disease at baseline, 46{\%} (38{\textperiodcentered}3–52{\textperiodcentered}2) die and 20{\%} (15{\textperiodcentered}2–25{\textperiodcentered}8) recover from tuberculosis, with the remainder being in or transitioning between the three disease states after 5 years. We estimated the 10-year mortality of people with untreated prevalent infectious tuberculosis to be 37{\%} (30{\textperiodcentered}5–45{\textperiodcentered}4). Interpretation For people with subclinical tuberculosis, classic clinical disease is neither an inevitable nor an irreversible outcome. As such, reliance on symptom-based screening means a large proportion of people with infectious disease might never be detected. Funding TB Modelling and Analysis Consortium and European Research Council.},
author = {Richards, Alexandra S and Sossen, Bianca and Emery, Jon C and Horton, Katherine C and Heinsohn, Torben and Frascella, Beatrice and Balzarini, Federica and Oradini-Alacreu, Aurea and H{\"{a}}cker, Brit and Odone, Anna and McCreesh, Nicky and Grant, Alison D and Kranzer, Katharina and Cobelens, Frank and Esmail, Hanif and Houben, Rein M G J},
doi = {10.1016/S2214-109X(23)00082-7},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Richards et al. - 2023 - Quantifying progression and regression across the spectrum of pulmonary tuberculosis a data synthesis study.pdf:pdf},
issn = {2214-109X},
journal = {The Lancet Global Health},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {mar},
pages = {https://doi.org/10.1016/ S2214--109X(23)00082--7},
pmid = {36966785},
publisher = {Elsevier},
title = {{Quantifying progression and regression across the spectrum of pulmonary tuberculosis: a data synthesis study}},
url = {http://www.thelancet.com/article/S2214109X23000827/fulltext http://www.thelancet.com/article/S2214109X23000827/abstract https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(23)00082-7/abstract},
year = {2023}
}

Summary Background Prevalence surveys show a substantial burden of subclinical (asymptomatic but infectious) tuberculosis, from which individuals can progress, regress, or even persist in a chronic disease state. We aimed to quantify these pathways across the spectrum of tuberculosis disease. Methods We created a deterministic framework of untreated tuberculosis disease with progression and regression between three states of pulmonary tuberculosis disease: minimal (non-infectious), subclinical (asymptomatic but infectious), and clinical (symptomatic and infectious). We obtained data from a previous systematic review of prospective and retrospective studies that followed and recorded the disease state of individuals with tuberculosis in a cohort without treatment. These data were considered in a Bayesian framework, enabling quantitative estimation of tuberculosis disease pathways with rates of transition between states and 95% uncertainty intervals (UIs). Findings We included 22 studies with data from 5942 individuals in our analysis. Our model showed that after 5 years, 40% (95% UI 31˙3–48˙0) of individuals with prevalent subclinical disease at baseline recover and 18% (13˙3–24˙0) die from tuberculosis, with 14% (9˙9–19˙2) still having infectious disease, and the remainder with minimal disease at risk of re-progression. Over 5 years, 50% (40˙0–59˙1) of individuals with subclinical disease at baseline never develop symptoms. For those with clinical disease at baseline, 46% (38˙3–52˙2) die and 20% (15˙2–25˙8) recover from tuberculosis, with the remainder being in or transitioning between the three disease states after 5 years. We estimated the 10-year mortality of people with untreated prevalent infectious tuberculosis to be 37% (30˙5–45˙4). Interpretation For people with subclinical tuberculosis, classic clinical disease is neither an inevitable nor an irreversible outcome. As such, reliance on symptom-based screening means a large proportion of people with infectious disease might never be detected. Funding TB Modelling and Analysis Consortium and European Research Council.

@article{Kimuda2023,
abstract = {Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Inadequate diagnostic testing and treatment regimens adapted from pulmonary tuberculosis without consideration of the unique nature of TBM are among the potential drivers. This review focuses on the progress being made in relation to both diagnosis and treatment of TBM, emphasizing promising future directions. The molecular assay GeneXpert MTB/Rif Ultra has improved sensitivity but has inadequate negative predictive value to “rule-out” TBM. Evaluations of tests focused on the host response and bacterial components are ongoing. Clinical trials are in progress to explore the roles of rifampin, fluoroquinolones, linezolid, and adjunctive aspirin. Though diagnosis has improved, novel modalities are being explored to improve the rapid diagnosis of TBM. Multiple ongoing clinical trials may change current therapies for TBM in the near future.},
author = {Kimuda, Sarah and Kasozi, Derrick and Namombwe, Suzan and Gakuru, Jane and Mugabi, Timothy and Kagimu, Enock and Rutakingirwa, Morris K and Kristoffer, Leon E and Chow, Felicia and Wasserman, Sean and Boulware, David R and Cresswell, Fiona V and Bahr, Nathan C},
doi = {10.1007/S11904-023-00678-6},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Kimuda et al. - 2023 - Advancing diagnosis and treatment in people living with HIV and tuberculosis meningitis.pdf:pdf},
isbn = {0123456789},
issn = {1548-3576},
journal = {Current HIV/AIDS Reports},
keywords = {Medicine/Public Health,OA,OA{\_}PMC,TB,Tuberculosis,Tuberculous meningitis,fund{\_}ack,general,review},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,review},
month = {nov},
number = {6},
pages = {379--393},
pmid = {37947980},
publisher = {Springer},
title = {{Advancing diagnosis and treatment in people living with HIV and tuberculosis meningitis}},
url = {https://link.springer.com/article/10.1007/s11904-023-00678-6},
volume = {20},
year = {2023}
}

Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Inadequate diagnostic testing and treatment regimens adapted from pulmonary tuberculosis without consideration of the unique nature of TBM are among the potential drivers. This review focuses on the progress being made in relation to both diagnosis and treatment of TBM, emphasizing promising future directions. The molecular assay GeneXpert MTB/Rif Ultra has improved sensitivity but has inadequate negative predictive value to “rule-out” TBM. Evaluations of tests focused on the host response and bacterial components are ongoing. Clinical trials are in progress to explore the roles of rifampin, fluoroquinolones, linezolid, and adjunctive aspirin. Though diagnosis has improved, novel modalities are being explored to improve the rapid diagnosis of TBM. Multiple ongoing clinical trials may change current therapies for TBM in the near future.

@article{Chabala9900,
abstract = {Background: Lopinavir/ritonavir plasma concentrations are profoundly reduced when co-administered with rifampicin. Super-boosting of lopinavir/ritonavir is limited by nonavailability of single-entity ritonavir, while double-dosing of co-formulated lopinavir/ritonavir given twice-daily produces suboptimal lopinavir concentrations in young children. We evaluated whether increased daily dosing with modified 8-hourly lopinavir/ritonavir 4:1 would maintain therapeutic plasma concentrations of lopinavir in children living with HIV receiving rifampicin-based antituberculosis treatment. Methods: Children with HIV/tuberculosis coinfection weighing 3.0 to 19.9 kg, on rifampicin-based antituberculosis treatment were commenced or switched to 8-hourly liquid lopinavir/ritonavir 4:1 with increased daily dosing using weight-band dosing approach. A standard twice-daily dosing of lopinavir/ritonavir was resumed 2 weeks after completing antituberculosis treatment. Plasma sampling was conducted during and 4 weeks after completing antituberculosis treatment. Results: Of 20 children enrolled; 15, 1–7 years old, had pharmacokinetics sampling available for analysis. Lopinavir concentrations (median [range]) on 8-hourly lopinavir/ritonavir co-administered with rifampicin (n = 15; area under the curve0–24 55.32 mg/h/L [0.30–398.7 mg/h/L]; Cmax 3.04 mg/L [0.03–18.6 mg/L]; C8hr 0.90 mg/L [0.01–13.7 mg/L]) were lower than on standard dosing without rifampicin (n = 12; area under the curve24 121.63 mg/h/L [2.56–487.3 mg/h/L]; Cmax 9.45 mg/L [0.39–26.4 mg/L]; C12hr 3.03 mg/L [0.01–17.7 mg/L]). During and after rifampicin cotreatment, only 7 of 15 (44.7{\%}) and 8 of 12 (66.7{\%}) children, respectively, achieved targeted pre-dose lopinavir concentrations ≥1mg/L. Conclusions: Modified 8-hourly dosing of lopinavir/ritonavir failed to achieve adequate lopinavir concentrations with concurrent antituberculosis treatment. The subtherapeutic lopinavir exposures on standard dosing after antituberculosis treatment are of concern and requires further evaluation.},
author = {Chabala, Chishala and Turkova, Anna and Kapasa, Monica and LeBeau, Kristen and Tembo, Chimuka H and Zimba, Kevin and Weisner, Lubbe and Zyambo, Khozya and Choo, Louise and Chungu, Chalilwe and Lungu, Joyce and Mulenga, Veronica and Crook, Angela and Gibb, Diana and McIlleron, Helen and trial Team, on behalf of the SHINE},
issn = {0891-3668},
journal = {The Pediatric Infectious Disease Journal},
keywords = {HIV,OA,fund{\_}not{\_}ack,lopinavir/ritonavir,original,pharmacokinetics,rifampicin,tuberculosis},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
number = {10},
pages = {899--904},
pmid = {37506295},
title = {{Inadequate lopinavir concentrations with modified 8-hourly lopinavir/ritonavir 4:1 dosing during rifampicin-based tuberculosis treatment in children living with HIV}},
url = {https://journals.lww.com/pidj/Fulltext/9900/Inadequate{\_}Lopinavir{\_}Concentrations{\_}With{\_}Modified.528.aspx},
volume = {42},
year = {2023}
}

Background: Lopinavir/ritonavir plasma concentrations are profoundly reduced when co-administered with rifampicin. Super-boosting of lopinavir/ritonavir is limited by nonavailability of single-entity ritonavir, while double-dosing of co-formulated lopinavir/ritonavir given twice-daily produces suboptimal lopinavir concentrations in young children. We evaluated whether increased daily dosing with modified 8-hourly lopinavir/ritonavir 4:1 would maintain therapeutic plasma concentrations of lopinavir in children living with HIV receiving rifampicin-based antituberculosis treatment. Methods: Children with HIV/tuberculosis coinfection weighing 3.0 to 19.9 kg, on rifampicin-based antituberculosis treatment were commenced or switched to 8-hourly liquid lopinavir/ritonavir 4:1 with increased daily dosing using weight-band dosing approach. A standard twice-daily dosing of lopinavir/ritonavir was resumed 2 weeks after completing antituberculosis treatment. Plasma sampling was conducted during and 4 weeks after completing antituberculosis treatment. Results: Of 20 children enrolled; 15, 1–7 years old, had pharmacokinetics sampling available for analysis. Lopinavir concentrations (median [range]) on 8-hourly lopinavir/ritonavir co-administered with rifampicin (n = 15; area under the curve0–24 55.32 mg/h/L [0.30–398.7 mg/h/L]; Cmax 3.04 mg/L [0.03–18.6 mg/L]; C8hr 0.90 mg/L [0.01–13.7 mg/L]) were lower than on standard dosing without rifampicin (n = 12; area under the curve24 121.63 mg/h/L [2.56–487.3 mg/h/L]; Cmax 9.45 mg/L [0.39–26.4 mg/L]; C12hr 3.03 mg/L [0.01–17.7 mg/L]). During and after rifampicin cotreatment, only 7 of 15 (44.7%) and 8 of 12 (66.7%) children, respectively, achieved targeted pre-dose lopinavir concentrations ≥1mg/L. Conclusions: Modified 8-hourly dosing of lopinavir/ritonavir failed to achieve adequate lopinavir concentrations with concurrent antituberculosis treatment. The subtherapeutic lopinavir exposures on standard dosing after antituberculosis treatment are of concern and requires further evaluation.

@article{Scibiorek2023,
abstract = {Atopic dermatitis (AD) is a common pruritic inflammatory skin disease with complex environmental and genetic predisposing factors. Primary skin barrier dysfunction and aberrant T helper 2 (TH2) responses to common allergens, together with increased serum IgE antibodies, characterise the disease. B and T cells are essential in the disease manifestation, however, the exact mechanism of how these cells is involved is unclear. Targeting interleukin 4 receptor alpha (IL-4R$\alpha$), an IL-4/IL-13 signalling axis, with dupilumab shows efficacy in AD. We investigated the importance of IL-4R$\alpha$ signalling specifically on B and T cells during acute and chronic models of AD. We used House dust mite (HDM) and Ovalbumin (OVA) in chronic models and a low-calcemic analog of vitamin D (MC903) for acute models of AD. We used mb1creIL-4R$\alpha$−/lox, iLCKcreIL-4R$\alpha$−/lox, LCKcreIL-4R$\alpha$−/lox, CD4creIL-4R$\alpha$−/lox, Foxp3creIL-4R$\alpha$−/lox and IL-4R$\alpha$−/lox littermate controls. IL-4R$\alpha$-responsive B cells were essential in serum IgE levels, but not in epidermal thickening in both chronic and acute models. IL-4R$\alpha$-responsive T cells were essential in epidermal thickening in the pan-T cell, but not CD4 or CD8 T cells suggesting the importance of $\gamma$$\delta$T cells during acute AD. Our results suggest that IL-4R$\alpha$ responsiveness on innate T cells regulates acute atopic dermatitis, while on B cells it regulates IgE.},
author = {Scibiorek, Martyna and Mthembu, Nontobeko and Mangali, Sandisiwe and Ngomti, Amkele and Ikwegbue, Paul and Brombacher, Frank and Hadebe, Sabelo},
doi = {10.1038/s41598-022-26637-6},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Scibiorek et al. - 2023 - IL-4R$\alpha$ signalling in B cells and T cells play differential roles in acute and chronic atopic dermatitis.pdf:pdf},
isbn = {0123456789},
issn = {2045-2322},
journal = {Scientific Reports},
keywords = {CD4,CD8,Gammadelta T cells,Immunology,Interleukins,OA,OA{\_}PMC,T,cell receptor,fund{\_}ack,original,positive T cells},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,original},
month = {jan},
number = {1},
pages = {144},
pmid = {36599893},
publisher = {Nature Publishing Group},
title = {{IL-4R$\alpha$ signalling in B cells and T cells play differential roles in acute and chronic atopic dermatitis}},
url = {https://www.nature.com/articles/s41598-022-26637-6},
volume = {13},
year = {2023}
}

Atopic dermatitis (AD) is a common pruritic inflammatory skin disease with complex environmental and genetic predisposing factors. Primary skin barrier dysfunction and aberrant T helper 2 (TH2) responses to common allergens, together with increased serum IgE antibodies, characterise the disease. B and T cells are essential in the disease manifestation, however, the exact mechanism of how these cells is involved is unclear. Targeting interleukin 4 receptor alpha (IL-4R$α$), an IL-4/IL-13 signalling axis, with dupilumab shows efficacy in AD. We investigated the importance of IL-4R$α$ signalling specifically on B and T cells during acute and chronic models of AD. We used House dust mite (HDM) and Ovalbumin (OVA) in chronic models and a low-calcemic analog of vitamin D (MC903) for acute models of AD. We used mb1creIL-4R$α$−/lox, iLCKcreIL-4R$α$−/lox, LCKcreIL-4R$α$−/lox, CD4creIL-4R$α$−/lox, Foxp3creIL-4R$α$−/lox and IL-4R$α$−/lox littermate controls. IL-4R$α$-responsive B cells were essential in serum IgE levels, but not in epidermal thickening in both chronic and acute models. IL-4R$α$-responsive T cells were essential in epidermal thickening in the pan-T cell, but not CD4 or CD8 T cells suggesting the importance of $γ$$δ$T cells during acute AD. Our results suggest that IL-4R$α$ responsiveness on innate T cells regulates acute atopic dermatitis, while on B cells it regulates IgE.

@article{Hamada2023,
abstract = {Background. A systematic review showed that the accuracy of Mycobacterium tuberculosis antigen-based skin tests (TBSTs) for tuberculosis is similar to that of interferon $\gamma$ release assay, but the safety of TBSTs has not been systematically reviewed. Methods. We searched for studies reporting injection site reactions (ISRs) and systemic adverse events associated with TBSTs. We searched Medline, Embase, e-library, the Chinese Biomedical Literature Database, and the China National Knowledge Infrastructure database for studies through 30 July 2021, and the database search was updated until 22 November 2022. Results. We identified 7 studies for Cy-Tb (Serum Institute of India), 7 (including 2 found through the updated search) for C-TST (Anhui Zhifei Longcom), and 11 for Diaskintest (Generium). The pooled risk of any injection site reactions (ISRs) due to Cy-Tb (n = 2931; 5 studies) did not differ significantly from that for tuberculin skin tests (TSTs; risk ratio, 1.05 [95{\%} confidence interval, .70-1.58]). More than 95{\%} of ISRs were reported as mild or moderate; common ISRs included pain, itching, and rash. In 1 randomized controlled study, 49 of 153 participants (37.6{\%}) given Cy-Tb experience any systemic adverse event (eg, fever and headache), compared with 56 of 149 participants (37.6{\%}) given TST (risk ratio, 0.85 [95{\%} confidence interval, .6-1.2]). In a randomized controlled study in China (n = 14 579), the frequency of systemic adverse events in participants given C-TST was similar to that for TST, and the frequency of ISRs was similar to or lower than that for TST. Reporting of the safety data on Diaskintest was not standardized, precluding meta-analysis. Conclusion. The safety profile of TBSTs appears similar to that of TSTs and is associated with mostly mild ISRs.},
author = {Hamada, Yohhei and Kontsevaya, Irina and Surkova, Elena and Wang, Ting Ting and Wan-Hsin, Liu and Matveev, Aleksandr and Ziganshina, Liliya Eugenevna and Denkinger, Claudia M and Korobitsyn, Alexei and Ismail, Nazir and Abubakar, Ibrahim and Rangaka, Molebogeng X},
doi = {10.1093/OFID/OFAD228},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Hamada et al. - 2023 - A systematic review on the safety of Mycobacterium tuberculosis–specific antigen–based skin tests for tuberculosi.pdf:pdf},
issn = {2328-8957},
journal = {Open Forum Infectious Diseases},
keywords = {IGRA,LTBI,OA,OA{\_}PMC,TST,diagnostics classification description,fund{\_}not{\_}ack,original,skin tests},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {may},
number = {5},
pages = {ofad228},
pmid = {37234516},
publisher = {Oxford Academic},
title = {{A systematic review on the safety of \textit{Mycobacterium tuberculosis}–specific antigen–based skin tests for tuberculosis infection compared with tuberculin skin tests}},
url = {https://academic.oup.com/ofid/article/10/5/ofad228/7147636},
volume = {10},
year = {2023}
}

Background. A systematic review showed that the accuracy of Mycobacterium tuberculosis antigen-based skin tests (TBSTs) for tuberculosis is similar to that of interferon $γ$ release assay, but the safety of TBSTs has not been systematically reviewed. Methods. We searched for studies reporting injection site reactions (ISRs) and systemic adverse events associated with TBSTs. We searched Medline, Embase, e-library, the Chinese Biomedical Literature Database, and the China National Knowledge Infrastructure database for studies through 30 July 2021, and the database search was updated until 22 November 2022. Results. We identified 7 studies for Cy-Tb (Serum Institute of India), 7 (including 2 found through the updated search) for C-TST (Anhui Zhifei Longcom), and 11 for Diaskintest (Generium). The pooled risk of any injection site reactions (ISRs) due to Cy-Tb (n = 2931; 5 studies) did not differ significantly from that for tuberculin skin tests (TSTs; risk ratio, 1.05 [95% confidence interval, .70-1.58]). More than 95% of ISRs were reported as mild or moderate; common ISRs included pain, itching, and rash. In 1 randomized controlled study, 49 of 153 participants (37.6%) given Cy-Tb experience any systemic adverse event (eg, fever and headache), compared with 56 of 149 participants (37.6%) given TST (risk ratio, 0.85 [95% confidence interval, .6-1.2]). In a randomized controlled study in China (n = 14 579), the frequency of systemic adverse events in participants given C-TST was similar to that for TST, and the frequency of ISRs was similar to or lower than that for TST. Reporting of the safety data on Diaskintest was not standardized, precluding meta-analysis. Conclusion. The safety profile of TBSTs appears similar to that of TSTs and is associated with mostly mild ISRs.

@article{Scheepers2022,
abstract = {Global genomic surveillance of SARS-CoV-2 has identified variants associated with increased transmissibility, neutralization resistance and disease severity. Here we report the emergence of the PANGO lineage C.1.2, detected at low prevalence in South Africa and eleven other countries. The initial C.1.2 detection is associated with a high substitution rate, and includes changes within the spike protein that have been associated with increased transmissibility or reduced neutralization sensitivity in SARS-CoV-2 variants of concern or variants of interest. Like Beta and Delta, C.1.2 shows significantly reduced neutralization sensitivity to plasma from vaccinees and individuals infected with the ancestral D614G virus. In contrast, convalescent donors infected with either Beta or Delta show high plasma neutralization against C.1.2. These functional data suggest that vaccine efficacy against C.1.2 will be equivalent to Beta and Delta, and that prior infection with either Beta or Delta will likely offer protection against C.1.2. The SARS-CoV-2 PANGO lineage C.1.2 has been under monitoring by global health authorities as it has spread worldwide. Here, Bhiman and colleagues characterise the emergence of the lineage, and its neutralisation sensitivity using data from vaccinees and previously infected individuals.},
author = {Scheepers, Cathrine and Everatt, Josie and Amoako, Daniel G and Tegally, Houriiyah and Wibmer, Constantinos Kurt and Mnguni, Anele and Ismail, Arshad and Mahlangu, Boitshoko and Lambson, Bronwen E and Martin, Darren P and Wilkinson, Eduan and San, James Emmanuel and Giandhari, Jennifer and Manamela, Nelia and Ntuli, Noxolo and Kgagudi, Prudence and Cele, Sandile and Richardson, Simone I and Pillay, Sureshnee and Mohale, Thabo and Ramphal, Upasana and Naidoo, Yeshnee and Khumalo, Zamantungwa T and Kwatra, Gaurav and Gray, Glenda and Bekker, Linda-Gail and Madhi, Shabir A and Baillie, Vicky and {Van Voorhis}, Wesley C and Treurnicht, Florette K and Venter, Marietjie and Mlisana, Koleka and Wolter, Nicole and Sigal, Alex and Williamson, Carolyn and Hsiao, Nei-yuan and Msomi, Nokukhanya and Maponga, Tongai and Preiser, Wolfgang and Makatini, Zinhle and Lessells, Richard and Moore, Penny L and de Oliveira, Tulio and von Gottberg, Anne and Bhiman, Jinal N},
doi = {10.1038/s41467-022-29579-9},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Scheepers et al. - 2022 - Emergence and phenotypic characterization of the global SARS-CoV-2 C.1.2 lineage.pdf:pdf},
issn = {2041-1723},
journal = {Nature Communications},
keywords = {2,CoV,Epidemiology,OA,SARS,Viral infection,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,genomics{\_}fund{\_}ack,original},
month = {apr},
pages = {1976},
pmid = {35396511},
publisher = {Nature Publishing Group},
title = {{Emergence and phenotypic characterization of the global SARS-CoV-2 C.1.2 lineage}},
url = {https://www.nature.com/articles/s41467-022-29579-9},
volume = {13},
year = {2022}
}

Global genomic surveillance of SARS-CoV-2 has identified variants associated with increased transmissibility, neutralization resistance and disease severity. Here we report the emergence of the PANGO lineage C.1.2, detected at low prevalence in South Africa and eleven other countries. The initial C.1.2 detection is associated with a high substitution rate, and includes changes within the spike protein that have been associated with increased transmissibility or reduced neutralization sensitivity in SARS-CoV-2 variants of concern or variants of interest. Like Beta and Delta, C.1.2 shows significantly reduced neutralization sensitivity to plasma from vaccinees and individuals infected with the ancestral D614G virus. In contrast, convalescent donors infected with either Beta or Delta show high plasma neutralization against C.1.2. These functional data suggest that vaccine efficacy against C.1.2 will be equivalent to Beta and Delta, and that prior infection with either Beta or Delta will likely offer protection against C.1.2. The SARS-CoV-2 PANGO lineage C.1.2 has been under monitoring by global health authorities as it has spread worldwide. Here, Bhiman and colleagues characterise the emergence of the lineage, and its neutralisation sensitivity using data from vaccinees and previously infected individuals.

@article{Tegally2022,
abstract = {Investment in Africa over the past year with regards to SARS-CoV-2 genotyping has led to a massive increase in the number of sequences, exceeding 100,000 genomes generated to track the pandemic on the continent. Our results show an increase in the number of African countries able to sequence within their own borders, coupled with a decrease in sequencing turnaround time. Findings from this genomic surveillance underscores the heterogeneous nature of the pandemic but we observe repeated dissemination of SARS-CoV-2 variants within the continent. Sustained investment for genomic surveillance in Africa is needed as the virus continues to evolve, particularly in the low vaccination landscape. These investments are very crucial for preparedness and response for future pathogen outbreaks.One-Sentence Summary Expanding Africa SARS-CoV-2 sequencing capacity in a fast evolving pandemic.Competing Interest StatementWith the exception of Pardis Sabeti who is a co-founder of and consultant to Sherlock Biosciences and a Board Member of Danaher Corporation and who holds equity in the companies, we the authors have no conflicts of interest to declare.Funding StatementSequencing efforts in the African Union Member States were supported by the Africa Center for Disease Control (Africa CDC) - Africa Pathogen Genomics Initiative (Africa PGI), and the World Health Organization Regional Office for Africa (WHO AFRO) through the transfer of laboratory infrastructure, the provision of reagents and training. The Africa PGI is supported by the African Union, Centers for Disease Control and Prevention (CDC), Bill and Melinda Gates Foundation (BMGF), Illumina Inc, Oxford Nanopore Technologies (ONT) and other partners. In addition, all Institut Pasteur organizations and CERMES in Niger are part of the PEPAIR COVID-19-Afirica project which is funded by the French Ministry for European and Foreign Affairs. KRISP and CERI is furthermore supported in part by grants from the World Health Organization, the Abbott Pandemic Defense Coalition (APDC), the National Institute of Health USA (U01 AI151698) for the United World Antivirus Research Network (UWARN) and the INFORM Africa project through IHVN (U54 TW012041), H3BioNet Africa (Grant {\#} 2020 HTH 062), the South African Department of Science and Innovation (SA DSI) and the South African Medical Research Council (SAMRC) under the BRICS JAF {\#}2020/049. ILRI is also supported by the Ministry for Economic Cooperation and Federal Development of Germany (BMZ). Work conducted at ACEGID is made possible by support provided to ACEGID by a cohort of generous donors through TED{\&}{\#}039;s Audacious Project, including the ELMA Foundation, MacKenzie Scott, the Skoll Foundation, and Open Philanthropy. Work at ACEGID was also partly supported by grants from the National Institute of Allergy and Infectious Diseases (https://www.niaid.nih.gov), NIH-H3Africa (https://h3africa.org) (U01HG007480 and U54HG007480), the World Bank (projects ACE-019 and ACE-IMPACT), the Rockefeller Foundation (Grant {\#}2021 HTH), the Africa CDC through the African Society of Laboratory Medicine [ASLM] (Grant {\#}INV018978), the Wellcome Trust (Project 216619/Z/19/Z) and the Science for Africa Foundation. Sequencing efforts at the National Institute for Communicable Diseases (NICD) was also supported by a conditional grant from the South African National Department of Health as part of the emergency COVID-19 response; a cooperative agreement between the National Institute for Communicable Diseases of the National Health Laboratory Service and the United States Centers for Disease Control and Prevention (FAIN{\#} U01IP001048; NU51IP000930); the South African Medical Research Council (SAMRC, project number 96838); the African Society of Laboratory Medicine (ASLM) and the Bill and Melinda Gates Foundation grant number INV-018978; the UK Foreign, Commonwealth and Development Office and Wellcome (Grant no 221003/Z/20/Z); and the UK Department of Health and Social Care and managed by the Fleming Fund and performed under the auspices of the SEQAFRICA project. Funding for sequencing efforts in Angola was supported through Projecto Bongola (N. 11/MESCTI/PDCT/2020) and OGE INIS (2020/2021). Botswana{\&}{\#}039;s sequencing efforts led by the Botswana Harvard AIDS Institute Partnership was supported by: Foundation for Innovative New Diagnostics(FINDdx); Bill and Melinda Gates Foundation, H3ABioNet [U41HG006941], Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE) and Fogarty International Center (Grant {\#} 5D43TW009610) . H3ABioNet is an initiative of the Human Health and Heredity in Africa Consortium (H3Africa) programme of the African Academy of Science (AAS). HHS/NIH/National Institute of Allergy and Infectious Diseases (NIAID) (5K24AI131928-04; 5K24AI131924-04); SANTHE is a DELTAS Africa Initiative [grant {\#} DEL-15-006]. The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS){\&}{\#}039;s Alliance for Accelerating Excellence in Science in Africa (AESA) and supported by the New Partnership for Africa{\&}{\#}039;s Development Planning and Coordinating Agency (NEPADAgency) with funding from the Wellcome Trust [grant {\#}107752/Z/15/Z] and the United Kingdom (UK) government. From Brazil, Joicymara Santos Xavier was funded by Coordena{\&}{\#}039;ao de Aperfei{\&}{\#}039;oamento de Pessoal de Nivel Superior - Brazil (CAPES) - Finance Code 001. Sequencing efforts from Cote d{\&}{\#}039;Ivoire were funded by the Robert Koch Institute and the German Federal Ministry of Education and Research (BMBF). Sequencing efforts in the Democratic Republic of the Congo were funded by the Bill {\&}amp; Melinda Gates Foundation under grant INV-018030 awarded to CBP and further supported by funding from the Africa CDC through the ASLM (African Society of Laboratory Medicine) for Accelerating SARS-CoV-2 Genomic Surveillance in Africa, the US Centre for Disease Control and Prevention (US CDC), USAMRIID, IRD/Montepellier, UCLA and SACIDS FIND. Efforts from Egypt was funded by the Egyptian Ministry of Health (REF{\#}), the Egyptian Academy for Scientific Research and Technology (ASRT) JESOR project {\#}3046 (Center for Genome and Microbiome Research), the Cairo University anti COVID-19 fund and the Science and Technology Development Fund (STDF), Project ID: 41907. The sequencing effort in Equatorial Guinea was supported by a public-private partnership, the Bioko Island Malaria Elimination Project, composed of the government of Equatorial Guinea Ministries of Mines and Hydrocarbons, and Health and Social Welfare, Marathon EG Production Limited, Noble Energy, Atlantic Methanol Production Company, and EG LNG. Analysis for the Gabon strains was supported by the Science and Technology Research Partnership for Sustainable Development (SATREPS), Japan International Cooperation Agency (JICA), and Japan Agency for Medical Research and Development (AMED) (grant number JP21jm0110013) and a grant from AMED (grant number JP21wm0225003). CIRMF (Gabon) is funded by the Gabonese Government and TOTAL Energy inc. CIRMF is a member of CANTAM supported by EDCTP. The work at WACCBIP (Ghana) was funded by a grant from the Rockefeller Foundation (2021 HTH 006), an Institut de Recherche pour le Developpement (IRD) grant (ARIACOV), African Research Universities Alliance (ARUA) Vaccine Development Hubs grant with funds from Open Society Foundation, National Institute of Health Research (NIHR) (17.63.91) grants using UK aid from the UK Government for a global health research group for Genomic surveillance of malaria in West Africa (Wellcome Sanger Institute, UK) and the World Bank African Centres of Excellence Impact grant (WACCBIP-NCDs: Awandare). In addition to the funding sources from ILRI, KEMRI (Kenyan) contributions to sequencing efforts was supported in part by the National Institute for Health Research (NIHR) (project references 17/63/82 and 16/136/33) using UK aid from the UK Government to support global health research, and The UK Foreign, Commonwealth and Development Office (FCDO) and Wellcome (grant{\#} 220985/Z/20/Z) and the Kenya Medical Research Institute Grant {\#} KEMRI/COV/SPE/012. Contributions from Lesotho was supported by the Africa CDC, African Society for Laboratory Medicine (ALSM) and the South African National Institute for Communicable Diseases (SA NICD). Liberian efforts was funded by the Africa CDC through a subaward from the Bill and Melinda Gates Foundations (REF{\#}), while efforts from Madagascar were funded by the French Ministry for Europe and Foreign Affairs through the REPAIR COVID-19-Africa project coordinated by the Pasteur International Network association. Sequencing from Malawi was supported by Wellcome Trust (REF{\#}). Contributions from Mali was supported by Fogarty International Center and National Institute of Allergy and Infectious Diseases sections of the National Institutes of Health under Leidos-15X051, award numbers U2RTW010673 for the West African Center of Excellence for Global Health Bioinformatics Research Training and U19AI089696 and U19AI129387 for the West Africa International Center of Excellence for Malaria Research. Sequencing efforts from Morocco have been supported by Academie Hassan II of Science and Technology, Morocco. Funding for surveillance, sampling and testing in Madagascar: World Health Organization (WHO), the US Centers for Disease Control and Prevention (US CDC: Grant{\#}U5/IP000812-05), the United States Agency for International Development (USAID: Cooperation Agreement 72068719CA00001), the Office of the Assistant Secretary for Preparedness and Response in the U.S. Department of Health and Human Services (DHHS: grant number IDSEP190051-01-0200). Funding for sequencing: Bill {\&}amp; Melinda Gates Foundation (GCE/ID OPP1211841), Chan Zuckerberg Biohub, and the Innovative Genomics Institute at UC Berkeley. Mozambique acknowledges support from the Mozambican Ministry of Health and the Bill and Melinda Gates Foundation (REF{\#}). Namibian effo},
author = {Tegally, Houriiyah and San, James E and Cotten, Matthew and Tegomoh, Bryan and Mboowa, Gerald and Martin, Darren P and Baxter, Cheryl and Moir, Monika and Lambisia, Arnold and Diallo, Amadou and Amoako, Daniel G and Diagne, Moussa M and Sisay, Abay and Zekri, Abdel-Rahman N and Barakat, Abdelhamid and Gueye, Abdou Salam and Sangare, Abdoul K and Ouedraogo, Abdoul-Salam and Sow, Abdourahmane and Musa, Abdualmoniem O and Sesay, Abdul K and Lagare, Adamou and Kemi, Adedotun-Sulaiman and Abar, Aden Elmi and Johnson, Adeniji A and Fowotade, Adeola and Olubusuyi, Adewumi M and Oluwapelumi, Adeyemi O and Amuri, Adrienne A and Juru, Agnes and Ramadan, Ahmad Mabrouk and Kandeil, Ahmed and Mostafa, Ahmed and Rebai, Ahmed and Sayed, Ahmed and Kazeem, Akano and Balde, Aladje and Christoffels, Alan and Trotter, Alexander J and Campbell, Allan and Keita, Alpha Kabinet and Kone, Amadou and Bouzid, Amal and Souissi, Amal and Agweyu, Ambrose and Gutierrez, Ana V and Page, Andrew J and Yadouleton, Anges and Vinze, Anika and Happi, Anise N and Chouikha, Anissa and Iranzadeh, Arash and Maharaj, Arisha and Batchi-Bouyou, Armel Landry and Ismail, Arshad and Sylverken, Augustina and Goba, Augustine and Femi, Ayoade and Sijuwola, Ayotunde Elijah and Ibrahimi, Azeddine and Marycelin, Baba and Salako, Babatunde Lawal and Oderinde, Bamidele S and Bolajoko, Bankole and Dhaala, Beatrice and Herring, Belinda L and Tsofa, Benjamin and Mvula, Bernard and Njanpop-Lafourcade, Berthe-Marie and Marondera, Blessing T and Khaireh, Bouh Abdi and Kouriba, Bourema and Adu, Bright and Pool, Brigitte and McInnis, Bronwyn and Brook, Cara and Williamson, Carolyn and Anscombe, Catherine and Pratt, Catherine B and Scheepers, Cathrine and Akoua-Koffi, Chantal G and Agoti, Charles N and Loucoubar, Cheikh and Onwuamah, Chika Kingsley and Ihekweazu, Chikwe and Malaka, Christian No{\"{e}}l and Peyrefitte, Christophe and Omoruyi, Chukwuma Ewean and Rafa{\"{i}}, Clotaire Donatien and Morang'a, Collins M and Nokes, D James and Lule, Daniel Bugembe and Bridges, Daniel J and Mukadi-Bamuleka, Daniel and Park, Danny and Baker, David and Doolabh, Deelan and Ssemwanga, Deogratius and Tshiabuila, Derek and Bassirou, Diarra and Amuzu, Dominic S Y and Goedhals, Dominique and Grant, Donald S and Omuoyo, Donwilliams O and Maruapula, Dorcas and Wanjohi, Dorcas Waruguru and Foster-Nyarko, Ebenezer and Lusamaki, Eddy K and Simulundu, Edgar and Ong'era, Edidah M and Ngabana, Edith N and Abworo, Edward O and Otieno, Edward and Shumba, Edwin and Barasa, Edwine and Ahmed, El Bara and Kampira, Elizabeth and Fahime, Elmostafa El and Lokilo, Emmanuel and Mukantwari, Enatha and Cyril, Erameh and Philomena, Eromon and Belarbi, Essia and Simon-Loriere, Etienne and Anoh, Etil{\'{e}} A and Leendertz, Fabian and Taweh, Fahn M and Wasfi, Fares and Abdelmoula, Fatma and Takawira, Faustinos T and Derrar, Fawzi and Ajogbasile, Fehintola V and Treurnicht, Florette and Onikepe, Folarin and Ntoumi, Francine and Muyembe, Francisca M and Ngiambudulu, Francisco and {Zongo Ragomzingba}, Frank Edgard and Dratibi, Fred Athanasius and Iyanu, Fred-Akintunwa and Mbunsu, Gabriel K and Thilliez, Gaetan and Kay, Gemma L and Akpede, George O and George, Uwem E and van Zyl, Gert and Awandare, Gordon A and Schubert, Grit and Maphalala, Gugu P and Ranaivoson, Hafaliana C and Lemriss, Hajar and Omunakwe, Hannah E and Onywera, Harris and Abe, Haruka and Karray, Hela and Nansumba, Hellen and Triki, Henda and {Adje Kadjo}, Herve Alb{\'{e}}ric and Elgahzaly, Hesham and Gumbo, Hlanai and Mathieu, Hota and Kavunga-Membo, Hugo and Smeti, Ibtihel and Olawoye, Idowu B and Adetifa, Ifedayo and Odia, Ikponmwosa and Boubaker, Ilhem Boutiba-Ben and Ssewanyana, Isaac and Wurie, Isatta and Konstantinus, Iyaloo S and {Afiwa Halatoko}, Jacqueline Wemboo and Ayei, James and Sonoo, Janaki and Lekana-Douki, Jean Bernard and Makangara, Jean-Claude C and Tamfum, Jean-Jacques M and Heraud, Jean-Michel and Shaffer, Jeffrey G and Giandhari, Jennifer and Musyoki, Jennifer and Uwanibe, Jessica N and Bhiman, Jinal N and Yasuda, Jiro and Morais, Joana and Mends, Joana Q and Kiconco, Jocelyn and Sandi, John Demby and Huddleston, John and Odoom, John Kofi and Morobe, John M and Gyapong, John O and Kayiwa, John T and Okolie, Johnson C and Xavier, Joicymara Santos and Gyamfi, Jones and {Kofi Bonney}, Joseph Humphrey and Nyandwi, Joseph and Everatt, Josie and Farah, Jouali and Nakaseegu, Joweria and Ngoi, Joyce M and Namulondo, Joyce and Oguzie, Judith U and Andeko, Julia C and Lutwama, Julius J and O'Grady, Justin and Siddle, Katherine J and Victoir, Kathleen and Adeyemi, Kayode T and Tumedi, Kefentse A and Carvalho, Kevin Sanders and Mohammed, Khadija Said and Musonda, Kunda G and Duedu, Kwabena O and Belyamani, Lahcen and Fki-Berrajah, Lamia and Singh, Lavanya and Biscornet, Leon and {de Oliveira Martins}, Leonardo and Chabuka, Lucious and Olubayo, Luicer and Deng, Lul Lojok and Ochola-Oyier, Lynette Isabella and Mine, Madisa and Ramuth, Magalutcheemee and Mastouri, Maha and ElHefnawi, Mahmoud and Mbanne, Maimouna and Matsheka, Maitshwarelo I and Kebabonye, Malebogo and Diop, Mamadou and Momoh, Mambu and {Lima Mendon{\c{c}}a}, Maria da Luz and Venter, Marietjie and Paye, Marietou F and Faye, Martin and Nyaga, Martin M and Mareka, Mathabo and Damaris, Matoke-Muhia and Mburu, Maureen W and Mpina, Maximillian and {Claujens Chastel}, Mfoutou Mapanguy and Owusu, Michael and Wiley, Michael R and Tatfeng, Mirabeau Youtchou and Ayekaba, Mitoha Ondo'o and Abouelhoda, Mohamed and Beloufa, Mohamed Amine and Seadawy, Mohamed G and Khalifa, Mohamed K and Dellagi, Mohammed Koussai and Matobo, Mooko Marethabile and Kane, Mouhamed and Ouadghiri, Mouna and Salou, Mounerou and Mbulawa, Mphaphi B and Saibu, Mudashiru Femi and Mwenda, Mulenga and Kaba, Muluken and Phan, My V T and Abid, Nabil and Touil, Nadia and Rujeni, Nadine and Ismael, Nalia and Top, Ndeye Marieme and Dia, Ndongo and Mabunda, N{\'{e}}dio and Hsiao, Nei-yuan and Silochi, Nelson Boric{\'{o}} and Saasa, Ngonda and Bbosa, Nicholas and Murunga, Nickson and Gumede, Nicksy and Wolter, Nicole and Sitharam, Nikita and Ndodo, Nnaemeka and Ajayi, Nnennaya A and Tordo, No{\"{e}}l and Mbhele, Nokuzola and Razanajatovo, Norosoa H and Iguosadolo, Nosamiefan and Mba, Nwando and Kingsley, Ojide C and Sylvanus, Okogbenin and Peter, Okokhere and Femi, Oladiji and Testimony, Olumade and Ogunsanya, Olusola Akinola and Fakayode, Oluwatosin and Ogah, Onwe E and Faye, Ousmane and Smith-Lawrence, Pamela and Ondoa, Pascale and Combe, Patrice and Nabisubi, Patricia and Semanda, Patrick and Oluniyi, Paul E and Arnaldo, Paulo and Quashie, Peter Kojo and Bejon, Philip and Dussart, Philippe and Bester, Phillip A and Mbala, Placide K and Kaleebu, Pontiano and Abechi, Priscilla and El-Shesheny, Rabeh and Joseph, Rageema and Aziz, Ramy Karam and Essomba, Ren{\'{e}} Ghislain and Ayivor-Djanie, Reuben and Njouom, Richard and Phillips, Richard O and Gorman, Richmond and Kingsley, Robert A and Audu, Rosemary and Carr, Rosina A A and Kabbaj, Sa{\^{a}}d El and Gargouri, Saba and Masmoudi, Saber and Sankhe, Safietou and Mohamed, Sahra Isse and Mhalla, Salma and Hosch, Salome and Kassim, Samar Kamal and Metha, Samar and Trabelsi, Sameh and Lemriss, Sana{\^{a}} and Agwa, Sara Hassan and Mwangi, Sarah Wambui and Doumbia, Seydou and Makiala-Mandanda, Sheila and Aryeetey, Sherihane and Ahmed, Shymaa S and Ahmed, Sidi Mohamed and Elhamoumi, Siham and Moyo, Sikhulile and Lutucuta, Silvia and Gaseitsiwe, Simani and Jalloh, Simbirie and Andriamandimby, Soafy and Oguntope, Sobajo and Grayo, Sol{\`{e}}ne and Lekana-Douki, Sonia and Prosolek, Sophie and Ouangraoua, Soumeya and van Wyk, Stephanie and Schaffner, Stephen F and Kanyerezi, Stephen and Ahuka-Mundeke, Steve and Rudder, Steven and Pillay, Sureshnee and Nabadda, Susan and Behillil, Sylvie and Budiaki, Sylvie L and van der Werf, Sylvie and Mashe, Tapfumanei and Aanniz, Tarik and Mohale, Thabo and Le-Viet, Thanh and Velavan, Thirumalaisamy P and Schindler, Tobias and Maponga, Tongai and Bedford, Trevor and Anyaneji, Ugochukwu J and Chinedu, Ugwu and Ramphal, Upasana and Enouf, Vincent and Nene, Vishvanath and Gorova, Vivianne and Roshdy, Wael H and Karim, Wasim Abdul and Ampofo, William K and Preiser, Wolfgang and Choga, Wonderful T and Ahmed, Yahaya Ali and Ramphal, Yajna and Bediako, Yaw and Naidoo, Yeshnee and Butera, Yvan and de Laurent, Zaydah R and Ouma, Ahmed E O and von Gottberg, Anne and Githinji, George and Moeti, Matshidiso and Tomori, Oyewale and Sabeti, Pardis C and Sall, Amadou A and Oyola, Samuel O and Tebeje, Yenew K and Tessema, Sofonias K and de Oliveira, Tulio and Happi, Christian and Lessells, Richard and Nkengasong, John and Wilkinson, Eduan},
doi = {10.1101/2022.04.17.22273906},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Tegally et al. - 2022 - The evolving SARS-CoV-2 epidemic in Africa insights from rapidly expanding genomic surveillance.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jan},
pages = {2022.04.17.22273906},
title = {{The evolving SARS-CoV-2 epidemic in Africa: insights from rapidly expanding genomic surveillance}},
url = {http://medrxiv.org/content/early/2022/04/20/2022.04.17.22273906.abstract},
year = {2022}
}

Investment in Africa over the past year with regards to SARS-CoV-2 genotyping has led to a massive increase in the number of sequences, exceeding 100,000 genomes generated to track the pandemic on the continent. Our results show an increase in the number of African countries able to sequence within their own borders, coupled with a decrease in sequencing turnaround time. Findings from this genomic surveillance underscores the heterogeneous nature of the pandemic but we observe repeated dissemination of SARS-CoV-2 variants within the continent. Sustained investment for genomic surveillance in Africa is needed as the virus continues to evolve, particularly in the low vaccination landscape. These investments are very crucial for preparedness and response for future pathogen outbreaks.One-Sentence Summary Expanding Africa SARS-CoV-2 sequencing capacity in a fast evolving pandemic.Competing Interest StatementWith the exception of Pardis Sabeti who is a co-founder of and consultant to Sherlock Biosciences and a Board Member of Danaher Corporation and who holds equity in the companies, we the authors have no conflicts of interest to declare.Funding StatementSequencing efforts in the African Union Member States were supported by the Africa Center for Disease Control (Africa CDC) - Africa Pathogen Genomics Initiative (Africa PGI), and the World Health Organization Regional Office for Africa (WHO AFRO) through the transfer of laboratory infrastructure, the provision of reagents and training. The Africa PGI is supported by the African Union, Centers for Disease Control and Prevention (CDC), Bill and Melinda Gates Foundation (BMGF), Illumina Inc, Oxford Nanopore Technologies (ONT) and other partners. In addition, all Institut Pasteur organizations and CERMES in Niger are part of the PEPAIR COVID-19-Afirica project which is funded by the French Ministry for European and Foreign Affairs. KRISP and CERI is furthermore supported in part by grants from the World Health Organization, the Abbott Pandemic Defense Coalition (APDC), the National Institute of Health USA (U01 AI151698) for the United World Antivirus Research Network (UWARN) and the INFORM Africa project through IHVN (U54 TW012041), H3BioNet Africa (Grant # 2020 HTH 062), the South African Department of Science and Innovation (SA DSI) and the South African Medical Research Council (SAMRC) under the BRICS JAF #2020/049. ILRI is also supported by the Ministry for Economic Cooperation and Federal Development of Germany (BMZ). Work conducted at ACEGID is made possible by support provided to ACEGID by a cohort of generous donors through TED's Audacious Project, including the ELMA Foundation, MacKenzie Scott, the Skoll Foundation, and Open Philanthropy. Work at ACEGID was also partly supported by grants from the National Institute of Allergy and Infectious Diseases (https://www.niaid.nih.gov), NIH-H3Africa (https://h3africa.org) (U01HG007480 and U54HG007480), the World Bank (projects ACE-019 and ACE-IMPACT), the Rockefeller Foundation (Grant #2021 HTH), the Africa CDC through the African Society of Laboratory Medicine [ASLM] (Grant #INV018978), the Wellcome Trust (Project 216619/Z/19/Z) and the Science for Africa Foundation. Sequencing efforts at the National Institute for Communicable Diseases (NICD) was also supported by a conditional grant from the South African National Department of Health as part of the emergency COVID-19 response; a cooperative agreement between the National Institute for Communicable Diseases of the National Health Laboratory Service and the United States Centers for Disease Control and Prevention (FAIN# U01IP001048; NU51IP000930); the South African Medical Research Council (SAMRC, project number 96838); the African Society of Laboratory Medicine (ASLM) and the Bill and Melinda Gates Foundation grant number INV-018978; the UK Foreign, Commonwealth and Development Office and Wellcome (Grant no 221003/Z/20/Z); and the UK Department of Health and Social Care and managed by the Fleming Fund and performed under the auspices of the SEQAFRICA project. Funding for sequencing efforts in Angola was supported through Projecto Bongola (N. 11/MESCTI/PDCT/2020) and OGE INIS (2020/2021). Botswana's sequencing efforts led by the Botswana Harvard AIDS Institute Partnership was supported by: Foundation for Innovative New Diagnostics(FINDdx); Bill and Melinda Gates Foundation, H3ABioNet [U41HG006941], Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE) and Fogarty International Center (Grant # 5D43TW009610) . H3ABioNet is an initiative of the Human Health and Heredity in Africa Consortium (H3Africa) programme of the African Academy of Science (AAS). HHS/NIH/National Institute of Allergy and Infectious Diseases (NIAID) (5K24AI131928-04; 5K24AI131924-04); SANTHE is a DELTAS Africa Initiative [grant # DEL-15-006]. The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS)'s Alliance for Accelerating Excellence in Science in Africa (AESA) and supported by the New Partnership for Africa's Development Planning and Coordinating Agency (NEPADAgency) with funding from the Wellcome Trust [grant #107752/Z/15/Z] and the United Kingdom (UK) government. From Brazil, Joicymara Santos Xavier was funded by Coordena'ao de Aperfei'oamento de Pessoal de Nivel Superior - Brazil (CAPES) - Finance Code 001. Sequencing efforts from Cote d'Ivoire were funded by the Robert Koch Institute and the German Federal Ministry of Education and Research (BMBF). Sequencing efforts in the Democratic Republic of the Congo were funded by the Bill & Melinda Gates Foundation under grant INV-018030 awarded to CBP and further supported by funding from the Africa CDC through the ASLM (African Society of Laboratory Medicine) for Accelerating SARS-CoV-2 Genomic Surveillance in Africa, the US Centre for Disease Control and Prevention (US CDC), USAMRIID, IRD/Montepellier, UCLA and SACIDS FIND. Efforts from Egypt was funded by the Egyptian Ministry of Health (REF#), the Egyptian Academy for Scientific Research and Technology (ASRT) JESOR project #3046 (Center for Genome and Microbiome Research), the Cairo University anti COVID-19 fund and the Science and Technology Development Fund (STDF), Project ID: 41907. The sequencing effort in Equatorial Guinea was supported by a public-private partnership, the Bioko Island Malaria Elimination Project, composed of the government of Equatorial Guinea Ministries of Mines and Hydrocarbons, and Health and Social Welfare, Marathon EG Production Limited, Noble Energy, Atlantic Methanol Production Company, and EG LNG. Analysis for the Gabon strains was supported by the Science and Technology Research Partnership for Sustainable Development (SATREPS), Japan International Cooperation Agency (JICA), and Japan Agency for Medical Research and Development (AMED) (grant number JP21jm0110013) and a grant from AMED (grant number JP21wm0225003). CIRMF (Gabon) is funded by the Gabonese Government and TOTAL Energy inc. CIRMF is a member of CANTAM supported by EDCTP. The work at WACCBIP (Ghana) was funded by a grant from the Rockefeller Foundation (2021 HTH 006), an Institut de Recherche pour le Developpement (IRD) grant (ARIACOV), African Research Universities Alliance (ARUA) Vaccine Development Hubs grant with funds from Open Society Foundation, National Institute of Health Research (NIHR) (17.63.91) grants using UK aid from the UK Government for a global health research group for Genomic surveillance of malaria in West Africa (Wellcome Sanger Institute, UK) and the World Bank African Centres of Excellence Impact grant (WACCBIP-NCDs: Awandare). In addition to the funding sources from ILRI, KEMRI (Kenyan) contributions to sequencing efforts was supported in part by the National Institute for Health Research (NIHR) (project references 17/63/82 and 16/136/33) using UK aid from the UK Government to support global health research, and The UK Foreign, Commonwealth and Development Office (FCDO) and Wellcome (grant# 220985/Z/20/Z) and the Kenya Medical Research Institute Grant # KEMRI/COV/SPE/012. Contributions from Lesotho was supported by the Africa CDC, African Society for Laboratory Medicine (ALSM) and the South African National Institute for Communicable Diseases (SA NICD). Liberian efforts was funded by the Africa CDC through a subaward from the Bill and Melinda Gates Foundations (REF#), while efforts from Madagascar were funded by the French Ministry for Europe and Foreign Affairs through the REPAIR COVID-19-Africa project coordinated by the Pasteur International Network association. Sequencing from Malawi was supported by Wellcome Trust (REF#). Contributions from Mali was supported by Fogarty International Center and National Institute of Allergy and Infectious Diseases sections of the National Institutes of Health under Leidos-15X051, award numbers U2RTW010673 for the West African Center of Excellence for Global Health Bioinformatics Research Training and U19AI089696 and U19AI129387 for the West Africa International Center of Excellence for Malaria Research. Sequencing efforts from Morocco have been supported by Academie Hassan II of Science and Technology, Morocco. Funding for surveillance, sampling and testing in Madagascar: World Health Organization (WHO), the US Centers for Disease Control and Prevention (US CDC: Grant#U5/IP000812-05), the United States Agency for International Development (USAID: Cooperation Agreement 72068719CA00001), the Office of the Assistant Secretary for Preparedness and Response in the U.S. Department of Health and Human Services (DHHS: grant number IDSEP190051-01-0200). Funding for sequencing: Bill & Melinda Gates Foundation (GCE/ID OPP1211841), Chan Zuckerberg Biohub, and the Innovative Genomics Institute at UC Berkeley. Mozambique acknowledges support from the Mozambican Ministry of Health and the Bill and Melinda Gates Foundation (REF#). Namibian effo

@article{Koele2022,
abstract = {Interruption of treatment is common in drug-resistant tuberculosis patients. Bedaquiline has a long terminal half-life therefore, restarting after an interruption without a loading dose could incre...},
author = {Koele, Simon E and van Beek, Stijn W and Maartens, Gary and Brust, James C. M. and Svensson, Elin M},
doi = {10.1128/AAC.01749-21},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Koele et al. - 2022 - Optimized loading dose strategies for bedaquiline when restarting interrupted drug-resistant tuberculosis treatmen.pdf:pdf},
issn = {0066-4804},
journal = {Antimicrobial Agents and Chemotherapy},
keywords = {fund{\_}ack,original},
mendeley-tags = {fund{\_}ack,original},
month = {jan},
number = {3},
pages = {e01749--21},
pmid = {35007141},
publisher = {American Society for Microbiology 1752 N St., N.W., Washington, DC},
title = {{Optimized loading dose strategies for bedaquiline when restarting interrupted drug-resistant tuberculosis treatment}},
url = {https://journals.asm.org/doi/abs/10.1128/AAC.01749-21},
volume = {66},
year = {2022}
}

Interruption of treatment is common in drug-resistant tuberculosis patients. Bedaquiline has a long terminal half-life therefore, restarting after an interruption without a loading dose could incre...

@article{Tegally2022c,
abstract = {Investment in SARS-CoV-2 sequencing in Africa over the past year has led to a major increase in the number of sequences generated, now exceeding 100,000 genomes, used to track the pandemic on the c...},
author = {Tegally, Houriiyah and San, James E. and Cotten, Matthew and Moir, Monika and Tegomoh, Bryan and Mboowa, Gerald and Martin, Darren P. and Baxter, Cheryl and Lambisia, Arnold W. and Diallo, Amadou and Amoako, Daniel G. and Diagne, Moussa M. and Sisay, Abay and Zekri, Abdel-Rahman N. and Gueye, Abdou Salam and Sangare, Abdoul K. and Ouedraogo, Abdoul-Salam and Sow, Abdourahmane and Musa, Abdualmoniem O. and Sesay, Abdul K. and Abias, Abe G. and Elzagheid, Adam I. and Lagare, Adamou and Kemi, Adedotun-Sulaiman and Abar, Aden Elmi and Johnson, Adeniji A. and Fowotade, Adeola and Oluwapelumi, Adeyemi O. and Amuri, Adrienne A. and Juru, Agnes and Kandeil, Ahmed and Mostafa, Ahmed and Rebai, Ahmed and Sayed, Ahmed and Kazeem, Akano and Balde, Aladje and Christoffels, Alan and Trotter, Alexander J. and Campbell, Allan and Keita, Alpha K. and Kone, Amadou and Bouzid, Amal and Souissi, Amal and Agweyu, Ambrose and Naguib, Amel and Gutierrez, Ana V. and Nkeshimana, Anatole and Page, Andrew J. and Yadouleton, Anges and Vinze, Anika and Happi, Anise N. and Chouikha, Anissa and Iranzadeh, Arash and Maharaj, Arisha and Batchi-Bouyou, Armel L. and Ismail, Arshad and Sylverken, Augustina A. and Goba, Augustine and Femi, Ayoade and Sijuwola, Ayotunde E. and Marycelin, Baba and Salako, Babatunde L. and Oderinde, Bamidele S. and Bolajoko, Bankole and Diarra, Bassirou and Herring, Belinda L. and Tsofa, Benjamin and Lekana-Douki, Bernard and Mvula, Bernard and Njanpop-Lafourcade, Berthe-Marie and Marondera, Blessing T. and Khaireh, Bouh Abdi and Kouriba, Bourema and Adu, Bright and Pool, Brigitte and McInnis, Bronwyn and Brook, Cara and Williamson, Carolyn and Nduwimana, Cassien and Anscombe, Catherine and Pratt, Catherine B. and Scheepers, Cathrine and Akoua-Koffi, Chantal G. and Agoti, Charles N. and Mapanguy, Chastel M. and Loucoubar, Cheikh and Onwuamah, Chika K. and Ihekweazu, Chikwe and Malaka, Christian N. and Peyrefitte, Christophe and Grace, Chukwa and Omoruyi, Chukwuma E. and Rafa{\"{i}}, Clotaire D. and Morang'a, Collins M. and Erameh, Cyril and Lule, Daniel B. and Bridges, Daniel J. and Mukadi-Bamuleka, Daniel and Park, Danny and Rasmussen, David A. and Baker, David and Nokes, David J. and Ssemwanga, Deogratius and Tshiabuila, Derek and Amuzu, Dominic S. Y. and Goedhals, Dominique and Grant, Donald S. and Omuoyo, Donwilliams O. and Maruapula, Dorcas and Wanjohi, Dorcas W. and Foster-Nyarko, Ebenezer and Lusamaki, Eddy K. and Simulundu, Edgar and Ong'era, Edidah M. and Ngabana, Edith N. and Abworo, Edward O. and Otieno, Edward and Shumba, Edwin and Barasa, Edwine and Ahmed, El Bara and Ahmed, Elhadi A. and Lokilo, Emmanuel and Mukantwari, Enatha and Philomena, Eromon and Belarbi, Essia and Simon-Loriere, Etienne and Anoh, Etil{\'{e}} A. and Manuel, Eusebio and Leendertz, Fabian and Taweh, Fahn M. and Wasfi, Fares and Abdelmoula, Fatma and Takawira, Faustinos T. and Derrar, Fawzi and Ajogbasile, Fehintola V. and Treurnicht, Florette and Onikepe, Folarin and Ntoumi, Francine and Muyembe, Francisca M. and Ragomzingba, Frank E. Z. and Dratibi, Fred A. and Iyanu, Fred-Akintunwa and Mbunsu, Gabriel K. and Thilliez, Gaetan and Kay, Gemma L. and Akpede, George O. and van Zyl, Gert U. and Awandare, Gordon A. and Kpeli, Grace S. and Schubert, Grit and Maphalala, Gugu P. and Ranaivoson, Hafaliana C. and Omunakwe, Hannah E. and Onywera, Harris and Abe, Haruka and Karray, Hela and Nansumba, Hellen and Triki, Henda and Kadjo, Herve Alb{\'{e}}ric Adje and Elgahzaly, Hesham and Gumbo, Hlanai and Mathieu, Hota and Kavunga-Membo, Hugo and Smeti, Ibtihel and Olawoye, Idowu B. and Adetifa, Ifedayo M. O. and Odia, Ikponmwosa and Boubaker, Ilhem Boutiba -Ben and Mohammad, Iluoreh Ahmed and Ssewanyana, Isaac and Wurie, Isatta and Konstantinus, Iyaloo S. and Halatoko, Jacqueline Wemboo Afiwa and Ayei, James and Sonoo, Janaki and Makangara, Jean-Claude C. and Tamfum, Jean-Jacques M. and Heraud, Jean-Michel and Shaffer, Jeffrey G. and Giandhari, Jennifer and Musyoki, Jennifer and Nkurunziza, Jerome and Uwanibe, Jessica N. and Bhiman, Jinal N. and Yasuda, Jiro and Morais, Joana and Kiconco, Jocelyn and Sandi, John D. and Huddleston, John and Odoom, John K. and Morobe, John M. and Gyapong, John O. and Kayiwa, John T. and Okolie, Johnson C. and Xavier, Joicymara S. and Gyamfi, Jones and Wamala, Joseph F. and Bonney, Joseph H. K. and Nyandwi, Joseph and Everatt, Josie and Nakaseegu, Joweria and Ngoi, Joyce M. and Namulondo, Joyce and Oguzie, Judith U. and Andeko, Julia C. and Lutwama, Julius J. and Mogga, Juma J. H. and O'Grady, Justin and Siddle, Katherine J. and Victoir, Kathleen and Adeyemi, Kayode T. and Tumedi, Kefentse A. and Carvalho, Kevin S. and Mohammed, Khadija Said and Dellagi, Koussay and Musonda, Kunda G. and Duedu, Kwabena O. and Fki-Berrajah, Lamia and Singh, Lavanya and Kepler, Lenora M. and Biscornet, Leon and Martins, Leonardo de Oliveira and Chabuka, Lucious and Olubayo, Luicer and Ojok, Lul Deng and Deng, Lul Lojok and Ochola-Oyier, Lynette I. and Tyers, Lynn and Mine, Madisa and Ramuth, Magalutcheemee and Mastouri, Maha and ElHefnawi, Mahmoud and Mbanne, Maimouna and Matsheka, Maitshwarelo I. and Kebabonye, Malebogo and Diop, Mamadou and Momoh, Mambu and Mendon{\c{c}}a, Maria da Luz Lima and Venter, Marietjie and Paye, Marietou F. and Faye, Martin and Nyaga, Martin M. and Mareka, Mathabo and Damaris, Matoke-Muhia and Mburu, Maureen W. and Mpina, Maximillian G. and Owusu, Michael and Wiley, Michael R. and Tatfeng, Mirabeau Y. and Ayekaba, Mitoha Ondo'o and Abouelhoda, Mohamed and Beloufa, Mohamed Amine and Seadawy, Mohamed G. and Khalifa, Mohamed K. and Matobo, Mooko Marethabile and Kane, Mouhamed and Salou, Mounerou and Mbulawa, Mphaphi B. and Mwenda, Mulenga and Allam, Mushal and Phan, My V. T. and Abid, Nabil and Rujeni, Nadine and Abuzaid, Nadir and Ismael, Nalia and Elguindy, Nancy and Top, Ndeye Marieme and Dia, Ndongo and Mabunda, N{\'{e}}dio and Hsiao, Nei-yuan and Silochi, Nelson Boric{\'{o}} and Francisco, Ngiambudulu M. and Saasa, Ngonda and Bbosa, Nicholas and Murunga, Nickson and Gumede, Nicksy and Wolter, Nicole and Sitharam, Nikita and Ndodo, Nnaemeka and Ajayi, Nnennaya A. and Tordo, No{\"{e}}l and Mbhele, Nokuzola and Razanajatovo, Norosoa H. and Iguosadolo, Nosamiefan and Mba, Nwando and Kingsley, Ojide C. and Sylvanus, Okogbenin and Femi, Oladiji and Adewumi, Olubusuyi M. and Testimony, Olumade and Ogunsanya, Olusola A. and Fakayode, Oluwatosin and Ogah, Onwe E. and Oludayo, Ope-Ewe and Faye, Ousmane and Smith-Lawrence, Pamela and Ondoa, Pascale and Combe, Patrice and Nabisubi, Patricia and Semanda, Patrick and Oluniyi, Paul E. and Arnaldo, Paulo and Quashie, Peter Kojo and Okokhere, Peter O. and Bejon, Philip and Dussart, Philippe and Bester, Phillip A. and Mbala, Placide K. and Kaleebu, Pontiano and Abechi, Priscilla and El-Shesheny, Rabeh and Joseph, Rageema and Aziz, Ramy Karam and Essomba, Ren{\'{e}} G. and Ayivor-Djanie, Reuben and Njouom, Richard and Phillips, Richard O. and Gorman, Richmond and Kingsley, Robert A. and Rodrigues, Rosa Maria D. E. S. A. Neto and Audu, Rosemary A. and Carr, Rosina A. A. and Gargouri, Saba and Masmoudi, Saber and Bootsma, Sacha and Sankhe, Safietou and Mohamed, Sahra Isse and Femi, Saibu and Mhalla, Salma and Hosch, Salome and Kassim, Samar Kamal and Metha, Samar and Trabelsi, Sameh and Agwa, Sara Hassan and Mwangi, Sarah Wambui and Doumbia, Seydou and Makiala-Mandanda, Sheila and Aryeetey, Sherihane and Ahmed, Shymaa S. and Ahmed, Side Mohamed and Elhamoumi, Siham and Moyo, Sikhulile and Lutucuta, Silvia and Gaseitsiwe, Simani and Jalloh, Simbirie and Andriamandimby, Soa Fy and Oguntope, Sobajo and Grayo, Sol{\`{e}}ne and Lekana-Douki, Sonia and Prosolek, Sophie and Ouangraoua, Soumeya and van Wyk, Stephanie and Schaffner, Stephen F. and Kanyerezi, Stephen and Ahuka-Mundeke, Steve and Rudder, Steven and Pillay, Sureshnee and Nabadda, Susan and Behillil, Sylvie and Budiaki, Sylvie L. and van der Werf, Sylvie and Mashe, Tapfumanei and Mohale, Thabo and Le-Viet, Thanh and Velavan, Thirumalaisamy P. and Schindler, Tobias and Maponga, Tongai G. and Bedford, Trevor and Anyaneji, Ugochukwu J. and Chinedu, Ugwu and Ramphal, Upasana and George, Uwem E. and Enouf, Vincent and Nene, Vishvanath and Gorova, Vivianne and Roshdy, Wael H. and Karim, Wasim Abdul and Ampofo, William K. and Preiser, Wolfgang and Choga, Wonderful T. and Ahmed, Yahaya Ali and Ramphal, Yajna and Bediako, Yaw and Naidoo, Yeshnee and Butera, Yvan and de Laurent, Zaydah R. and (NGS-Afro), Network for Genomic Surveillance in Africa and Ouma, Ahmed E. O. and von Gottberg, Anne and Githinji, George and Moeti, Matshidiso and Tomori, Oyewale and Sabeti, Pardis C. and Sall, Amadou A. and Oyola, Samuel O. and Tebeje, Yenew K. and Tessema, Sofonias K. and de Oliveira, Tulio and Happi, Christian and Lessells, Richard and Nkengasong, John and Wilkinson, Eduan},
doi = {10.1126/SCIENCE.ABQ5358},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Tegally et al. - 2022 - The evolving SARS-CoV-2 epidemic in Africa Insights from rapidly expanding genomic surveillance(2).pdf:pdf},
issn = {0036-8075},
journal = {Science},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {sep},
number = {6615},
pages = {eabq5358},
publisher = {American Association for the Advancement of Science},
title = {{The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance}},
url = {https://www.science.org/doi/10.1126/science.abq5358},
volume = {378},
year = {2022}
}

Investment in SARS-CoV-2 sequencing in Africa over the past year has led to a major increase in the number of sequences generated, now exceeding 100,000 genomes, used to track the pandemic on the c...

@article{Othman2022,
abstract = {Genomics data are currently being produced at unprecedented rates, resulting in increased knowledge discovery and submission to public data repositories. Despite these advances, genomic information on African-ancestry populations remains significantly low compared with European- and Asian-ancestry populations. This information is typically segmented across several different biomedical data repositories, which often lack sufficient fine-grained structure and annotation to account for the diversity of African populations, leading to many challenges related to the retrieval, representation and findability of such information. To overcome these challenges, we developed the African Genomic Medicine Portal (AGMP), a database that contains metadata on genomic medicine studies conducted on African-ancestry populations. The metadata is curated from two public databases related to genomic medicine, PharmGKB and DisGeNET. The metadata retrieved from these source databases were limited to genomic variants that were associated with disease aetiology or treatment in the context of African-ancestry populations. Over 2000 variants relevant to populations of African ancestry were retrieved. Subsequently, domain experts curated and annotated additional information associated with the studies that reported the variants, including geographical origin, ethnolinguistic group, level of association significance and other relevant study information, such as study design and sample size, where available. The AGMP functions as a dedicated resource through which to access African-specific information on genomics as applied to health research, through querying variants, genes, diseases and drugs. The portal and its corresponding technical documentation, implementation code and content are publicly available.},
author = {Othman, Houcemeddine and Zass, Lyndon and da Rocha, Jorge E.B. and Radouani, Fouzia and Samtal, Chaimae and Benamri, Ichrak and Kumuthini, Judit and Fakim, Yasmina J. and Hamdi, Yosr and Mezzi, Nessrine and Boujemaa, Maroua and Okeke, Chiamaka Jessica and Tendwa, Maureen B. and Sanak, Kholoud and Chaouch, Melek and Panji, Sumir and Kefi, Rym and Sallam, Reem M. and Ghoorah, Anisah W. and Romdhane, Lilia and Kiran, Anmol and Meintjes, Ayton P. and Maturure, Perceval and Jmel, Haifa and Ksouri, Ayoub and Azzouzi, Maryame and Farahat, Mohammed A. and Ahmed, Samah and Sibira, Rania and Turkson, Michael E.E. and Ssekagiri, Alfred and Parker, Ziyaad and Fadlelmola, Faisal M. and Ghedira, Kais and Mulder, Nicola and Kassim, Samar Kamal},
doi = {10.3390/JPM12020265},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Othman et al. - 2022 - African Genomic Medicine Portal a web portal for biomedical applications.pdf:pdf},
issn = {2075-4426},
journal = {Journal of Personalized Medicine},
keywords = {Africa,OA,OA{\_}PMC,clinical genetics,database,fund{\_}not{\_}ack,genomic medicine,original,portal},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {feb},
number = {2},
pages = {265},
pmid = {35207753},
publisher = {Multidisciplinary Digital Publishing Institute},
title = {{African Genomic Medicine Portal: a web portal for biomedical applications}},
url = {https://www.mdpi.com/2075-4426/12/2/265/htm https://www.mdpi.com/2075-4426/12/2/265},
volume = {12},
year = {2022}
}

Genomics data are currently being produced at unprecedented rates, resulting in increased knowledge discovery and submission to public data repositories. Despite these advances, genomic information on African-ancestry populations remains significantly low compared with European- and Asian-ancestry populations. This information is typically segmented across several different biomedical data repositories, which often lack sufficient fine-grained structure and annotation to account for the diversity of African populations, leading to many challenges related to the retrieval, representation and findability of such information. To overcome these challenges, we developed the African Genomic Medicine Portal (AGMP), a database that contains metadata on genomic medicine studies conducted on African-ancestry populations. The metadata is curated from two public databases related to genomic medicine, PharmGKB and DisGeNET. The metadata retrieved from these source databases were limited to genomic variants that were associated with disease aetiology or treatment in the context of African-ancestry populations. Over 2000 variants relevant to populations of African ancestry were retrieved. Subsequently, domain experts curated and annotated additional information associated with the studies that reported the variants, including geographical origin, ethnolinguistic group, level of association significance and other relevant study information, such as study design and sample size, where available. The AGMP functions as a dedicated resource through which to access African-specific information on genomics as applied to health research, through querying variants, genes, diseases and drugs. The portal and its corresponding technical documentation, implementation code and content are publicly available.

@article{Hussey2022c,
abstract = {Abstract Background In low- and middle-income countries where SARS-CoV-2 testing is limited, seroprevalence studies can characterise the scale and determinants of the pandemic, as well as elucidate protection conferred by prior exposure. Methods We conducted repeated cross-sectional serosurveys (July 2020 - November 2021) using residual plasma from routine convenient blood samples from patients with non-COVID-19 conditions from Cape Town, South Africa. SARS-CoV-2 anti-nucleocapsid antibodies and linked clinical information were used to investigate: (1) seroprevalence over time and risk factors associated with seropositivity, (2) ecological comparison of seroprevalence between subdistricts, (3) case ascertainment rates, and (4) the relative protection against COVID-19 associated with seropositivity and vaccination statuses, to estimate variant disease severity. Findings Among the subset sampled, seroprevalence of SARS-CoV-2 in Cape Town increased from 39.2{\%} in July 2020 to 67.8{\%} in November 2021. Poorer communities had both higher seroprevalence and COVID-19 mortality. Only 10{\%} of seropositive individuals had a recorded positive SARS-CoV-2 test. Antibody positivity before the start of the Omicron BA.1 wave (28 November 2021) was strongly protective for severe disease (adjusted odds ratio [aOR] 0.15; 95{\%}CI 0.05-0.46), with additional benefit in those who were also vaccinated (aOR 0.07, 95{\%}CI 0.01-0.35). Interpretation The high population seroprevalence in Cape Town was attained at the cost of substantial COVID-19 mortality. At the individual level, seropositivity was highly protective against subsequent infections and severe COVID-19. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Funding Statement The study is funded by National Health Laboratory service, Western Cape Department of Health, Wellcome Trust, and in part by the Division of Intramural Research, NIAID, NIH. RJW is supported by the Francis Crick Institute which receives funding from Cancer Research UK (FC0010218), Medical Research Council (FC0010218), and Wellcome (FC0010218). He also received funding from Wellcome (203135,222754). {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the University of Cape Town Human Research Ethics Committee (HREC REF 449/2020) and Stellenbosch University Human Research Ethics Committee (N20/08/051). Institutional approval was obtained from the National Health Laboratory Service and the Western Cape Department of Health. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. The Western Cape Department of Health and Wellness evaluates research proposals for all research in the public health sector in the province, subject to standard research ethics, government approval and data governance prescripts. This includes those that draw on routine datasets like the current study.For more information email Health.Research@westerncape.gov.za},
author = {Hussey, Hannah and Vreede, Helena and Davies, Mary-Ann and Heekes, Alexa and Kalk, Emma and Hardie, Diana Ruth and Zyl, Gert Van and Naidoo, Michelle and Morden, Erna and Bam, Jamy-Lee and Zinyakatira, Nesbert and Centner, Chad and Maritz, Jean and Opie, Jessica and Chapanduka, Zivanai and Mahomed, Hassan and Smith, Mariette and Cois, Annibale and Pienaar, David and Redd, Andrew and Preiser, Wolfgang and Wilkinson, Robert J and Chetty, Kamy and Boulle, Andrew and Hsiao, Nei-yuan Marvin},
doi = {10.1101/2022.12.01.22282927},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Hussey et al. - 2022 - Epidemiology and outcomes of SARS-CoV-2 infection associated with anti-nucleocapsid seropositivity in Cape Town,.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {dec},
pages = {2022.12.01.22282927},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Epidemiology and outcomes of SARS-CoV-2 infection associated with anti-nucleocapsid seropositivity in Cape Town, South Africa}},
url = {https://www.medrxiv.org/content/10.1101/2022.12.01.22282927v1 https://www.medrxiv.org/content/10.1101/2022.12.01.22282927v1.abstract},
year = {2022}
}

Abstract Background In low- and middle-income countries where SARS-CoV-2 testing is limited, seroprevalence studies can characterise the scale and determinants of the pandemic, as well as elucidate protection conferred by prior exposure. Methods We conducted repeated cross-sectional serosurveys (July 2020 - November 2021) using residual plasma from routine convenient blood samples from patients with non-COVID-19 conditions from Cape Town, South Africa. SARS-CoV-2 anti-nucleocapsid antibodies and linked clinical information were used to investigate: (1) seroprevalence over time and risk factors associated with seropositivity, (2) ecological comparison of seroprevalence between subdistricts, (3) case ascertainment rates, and (4) the relative protection against COVID-19 associated with seropositivity and vaccination statuses, to estimate variant disease severity. Findings Among the subset sampled, seroprevalence of SARS-CoV-2 in Cape Town increased from 39.2% in July 2020 to 67.8% in November 2021. Poorer communities had both higher seroprevalence and COVID-19 mortality. Only 10% of seropositive individuals had a recorded positive SARS-CoV-2 test. Antibody positivity before the start of the Omicron BA.1 wave (28 November 2021) was strongly protective for severe disease (adjusted odds ratio [aOR] 0.15; 95%CI 0.05-0.46), with additional benefit in those who were also vaccinated (aOR 0.07, 95%CI 0.01-0.35). Interpretation The high population seroprevalence in Cape Town was attained at the cost of substantial COVID-19 mortality. At the individual level, seropositivity was highly protective against subsequent infections and severe COVID-19. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The study is funded by National Health Laboratory service, Western Cape Department of Health, Wellcome Trust, and in part by the Division of Intramural Research, NIAID, NIH. RJW is supported by the Francis Crick Institute which receives funding from Cancer Research UK (FC0010218), Medical Research Council (FC0010218), and Wellcome (FC0010218). He also received funding from Wellcome (203135,222754). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the University of Cape Town Human Research Ethics Committee (HREC REF 449/2020) and Stellenbosch University Human Research Ethics Committee (N20/08/051). Institutional approval was obtained from the National Health Laboratory Service and the Western Cape Department of Health. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. The Western Cape Department of Health and Wellness evaluates research proposals for all research in the public health sector in the province, subject to standard research ethics, government approval and data governance prescripts. This includes those that draw on routine datasets like the current study.For more information email Health.Research@westerncape.gov.za

@article{Davies2022a,
abstract = {Objective: We aimed to compare clinical severity of Omicron BA.4/BA.5 infection with BA.1 and earlier variant infections among laboratory-confirmed SARS-CoV-2 cases in the Western Cape, South Africa, using timing of infection to infer the lineage/variant causing infection. Methods: We included public sector patients aged ≥20 years with laboratory-confirmed COVID-19 between 1-21 May 2022 (BA.4/BA.5 wave) and equivalent prior wave periods. We compared the risk between waves of (i) death and (ii) severe hospitalization/death (all within 21 days of diagnosis) using Cox regression adjusted for demographics, comorbidities, admission pressure, vaccination and prior infection. Results: Among 3,793 patients from the BA.4/BA.5 wave and 190,836 patients from previous waves the risk of severe hospitalization/death was similar in the BA.4/BA.5 and BA.1 waves (adjusted hazard ratio (aHR) 1.01; 95{\%} confidence interval (CI) 0.92; 1.12). Both Omicron waves had lower risk of severe outcomes than previous waves. Prior infection (aHR 0.19, 95{\%} CI 0.16; 0.22) and vaccination (aHR 0.24; 95{\%} CI 0.15; 0.39 for boosted vs. no vaccine) were protective. Conclusion: Disease severity was similar amongst diagnosed COVID-19 cases in the BA.4/BA.5 and BA.1 periods in the context of growing immunity against SARS-CoV-2 due to prior infection and vaccination, both of which were strongly protective. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Funding Statement We acknowledge funding for the Western Cape Provincial Health Data Centre from the Western Cape Department of Health, the US National Institutes for Health (R01 HD080465, U01 AI069924), the Bill and Melinda Gates Foundation (1164272, 1191327), the United States Agency for International Development (72067418CA00023), the European Union (101045989) and the Grand Challenges ICODA pilot initiative delivered by Health Data Research UK and funded by the Bill {\&} Melinda Gates and Minderoo Foundations (INV-017293). Funding was also received from Wellcome (203135/Z/16/Z [RJW, GM, WCPHDC], 222574 [RJW, WCPHDC] 214321/Z/18/Z [GM]) and the Medical Research Council of South Africa (RJW, MAD). RJW additionally receives support from the Francis Crick Institute which is funded by Wellcome (FC0010218), MRC (UK) (FC0010218), and Cancer Research UK (FC0010218). GM is also funded by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (Grant No 64787). The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of this report. The opinions, findings and conclusions expressed in this manuscript reflect those of the authors alone. {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the University of Cape Town and Stellenbosch University Health Research Ethics Committees and Western Cape Government: Health. Individual informed consent requirement was waived for this secondary analysis of de-identified data. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The underlying data are de-identified pseudo-anonymised routine patient records for which patients have not consented to their de-identified data being part of publicly accessible repositories with inherent risks of re-identification. The Western Cape Department of Health and Wellness evaluates research proposals for all research in the public health sector in the Province, including those which draw on similar datasets to the current study, based on routine data, subject to standard research ethics, government approval and data governance prescripts.},
author = {Davies, Mary-Ann and Morden, Erna and Rosseau, Petro and Arendse, Juanita and Bam, Jamy-Lee and Boloko, Linda and Cloete, Keith and Cohen, Cheryl and Chetty, Nicole and Dane, Pierre and Heekes, Alexa and Hsiao, Nei-Yuan and Hunter, Mehreen and Hussey, Hannah and Jacobs, Theuns and Jassat, Waasila and Kariem, Saadiq and Kassanjee, Reshma and Laenen, Inneke and Roux, Sue Le and Lessells, Richard and Mahomed, Hassan and Maughan, Deborah and Meintjes, Graeme A and Mendelson, Marc and Mnguni, Ayanda and Moodley, Melvin and Murie, Katy and Naude, Jonathan and Ntusi, Ntobeko A B and Paleker, Masudah and Parker, Arifa and Pienaar, David and Preiser, Wolfgang and Prozesky, Hans and Raubenheimer, Peter and Rossouw, Liezel and Schreuder, Neshaad and Smith, Barry and Smith, Mariette and Solomon, Wesley and Symons, Greg and Taljaard, Jantjie and Wasserman, Sean and Wilkinson, Robert J and Wolmarans, Milani and Wolter, Nicole and Boulle, Andrew and and Wellness, Western Cape Department of Health and of Health, National Departments and {National Institute for Communicable Diseases in South Africa}},
doi = {10.1101/2022.06.28.22276983},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Davies et al. - 2022 - Outcomes of laboratory-confirmed SARS-CoV-2 infection during resurgence driven by Omicron lineages BA.4 and BA.5.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {jun},
number = {5},
pages = {2022.06.28.22276983},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Outcomes of laboratory-confirmed SARS-CoV-2 infection during resurgence driven by Omicron lineages BA.4 and BA.5 compared with previous waves in the Western Cape Province, South Africa}},
url = {https://www.medrxiv.org/content/10.1101/2022.06.28.22276983v1 https://www.medrxiv.org/content/10.1101/2022.06.28.22276983v1.abstract},
volume = {13},
year = {2022}
}

Objective: We aimed to compare clinical severity of Omicron BA.4/BA.5 infection with BA.1 and earlier variant infections among laboratory-confirmed SARS-CoV-2 cases in the Western Cape, South Africa, using timing of infection to infer the lineage/variant causing infection. Methods: We included public sector patients aged ≥20 years with laboratory-confirmed COVID-19 between 1-21 May 2022 (BA.4/BA.5 wave) and equivalent prior wave periods. We compared the risk between waves of (i) death and (ii) severe hospitalization/death (all within 21 days of diagnosis) using Cox regression adjusted for demographics, comorbidities, admission pressure, vaccination and prior infection. Results: Among 3,793 patients from the BA.4/BA.5 wave and 190,836 patients from previous waves the risk of severe hospitalization/death was similar in the BA.4/BA.5 and BA.1 waves (adjusted hazard ratio (aHR) 1.01; 95% confidence interval (CI) 0.92; 1.12). Both Omicron waves had lower risk of severe outcomes than previous waves. Prior infection (aHR 0.19, 95% CI 0.16; 0.22) and vaccination (aHR 0.24; 95% CI 0.15; 0.39 for boosted vs. no vaccine) were protective. Conclusion: Disease severity was similar amongst diagnosed COVID-19 cases in the BA.4/BA.5 and BA.1 periods in the context of growing immunity against SARS-CoV-2 due to prior infection and vaccination, both of which were strongly protective. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement We acknowledge funding for the Western Cape Provincial Health Data Centre from the Western Cape Department of Health, the US National Institutes for Health (R01 HD080465, U01 AI069924), the Bill and Melinda Gates Foundation (1164272, 1191327), the United States Agency for International Development (72067418CA00023), the European Union (101045989) and the Grand Challenges ICODA pilot initiative delivered by Health Data Research UK and funded by the Bill & Melinda Gates and Minderoo Foundations (INV-017293). Funding was also received from Wellcome (203135/Z/16/Z [RJW, GM, WCPHDC], 222574 [RJW, WCPHDC] 214321/Z/18/Z [GM]) and the Medical Research Council of South Africa (RJW, MAD). RJW additionally receives support from the Francis Crick Institute which is funded by Wellcome (FC0010218), MRC (UK) (FC0010218), and Cancer Research UK (FC0010218). GM is also funded by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (Grant No 64787). The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of this report. The opinions, findings and conclusions expressed in this manuscript reflect those of the authors alone. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the University of Cape Town and Stellenbosch University Health Research Ethics Committees and Western Cape Government: Health. Individual informed consent requirement was waived for this secondary analysis of de-identified data. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The underlying data are de-identified pseudo-anonymised routine patient records for which patients have not consented to their de-identified data being part of publicly accessible repositories with inherent risks of re-identification. The Western Cape Department of Health and Wellness evaluates research proposals for all research in the public health sector in the Province, including those which draw on similar datasets to the current study, based on routine data, subject to standard research ethics, government approval and data governance prescripts.

@article{Wolter2022c,
abstract = {Omicron lineages BA.4 and BA.5 drove a fifth wave of COVID-19 cases in South Africa. We assessed the severity of BA.4/BA.5 infections using the presence/absence of the S-gene target for infections diagnosed using the TaqPath PCR assay between 1 October 2021 and 26 April 2022. We linked national COVID-19 individual-level data including case, laboratory test and hospitalisation data. We assessed severity using multivariable logistic regression comparing the risk of hospitalisation and risk of severe disease, once hospitalised, for Delta, BA.1, BA.2 and BA.4/BA.5 infections. After controlling for factors associated with hospitalisation and severe outcome respectively, BA.4/BA.5-infected individuals had a similar odds of hospitalisation (aOR1.24, 95{\%} CI 0.98–1.55) and severe outcome (aOR 0.71, 95{\%}CI 0.41–1.25) compared to BA.1-infected individuals. Newly emerged Omicron lineages BA.4/BA.5 continue to show reduced clinical severity compared to previous variants, as observed for Omicron BA.1.},
author = {Wolter, Nicole and Jassat, Waasila and Welch, Richard and Moultrie, Harry and Groome, Michelle and Amoako, Daniel and Everatt, Josie and Bhiman, Jinal and Scheepers, Cathrine and Chiwandire, Nicola},
doi = {10.21203/RS.3.RS-1792132/V1},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Wolter et al. - 2022 - Clinical severity of SARS-CoV-2 Omicron BA.4 and BA.5 lineages in South Africa.pdf:pdf},
journal = {Research Square},
keywords = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {jun},
pages = {10.21203/rs.3.rs--1792132/v1},
title = {{Clinical severity of SARS-CoV-2 Omicron BA.4 and BA.5 lineages in South Africa}},
url = {https://www.researchsquare.com https://www.researchsquare.com/article/rs-1792132/v1},
year = {2022}
}

Omicron lineages BA.4 and BA.5 drove a fifth wave of COVID-19 cases in South Africa. We assessed the severity of BA.4/BA.5 infections using the presence/absence of the S-gene target for infections diagnosed using the TaqPath PCR assay between 1 October 2021 and 26 April 2022. We linked national COVID-19 individual-level data including case, laboratory test and hospitalisation data. We assessed severity using multivariable logistic regression comparing the risk of hospitalisation and risk of severe disease, once hospitalised, for Delta, BA.1, BA.2 and BA.4/BA.5 infections. After controlling for factors associated with hospitalisation and severe outcome respectively, BA.4/BA.5-infected individuals had a similar odds of hospitalisation (aOR1.24, 95% CI 0.98–1.55) and severe outcome (aOR 0.71, 95%CI 0.41–1.25) compared to BA.1-infected individuals. Newly emerged Omicron lineages BA.4/BA.5 continue to show reduced clinical severity compared to previous variants, as observed for Omicron BA.1.

@article{Makatsa2022,
abstract = {The development of a highly effective tuberculosis (TB) vaccine is likely dependent on our understanding of what constitutes a protective immune response to TB. Accumulating evidence suggests that CD4+ T cells producing IL-22, a distinct subset termed “Th22” cells, may contribute to protective immunity to TB. Thus, we characterized Mycobacterium tuberculosis–specific Th22 (and Th1 and Th17) cells in 72 people with latent TB infection or TB disease, with and without HIV-1 infection. We investigated the functional properties (IFN-$\gamma$, IL-22, and IL-17 production), memory differentiation (CD45RA, CD27, and CCR7), and activation profile (HLA-DR) of M. tuberculosis–specific CD4+ T cells. In HIV-uninfected individuals with latent TB infection, we detected abundant circulating IFN-$\gamma$–producing CD4+ T cells (median, 0.93{\%}) and IL-22–producing CD4+ T cells (median, 0.46{\%}) in response to M. tuberculosis. The frequency of IL-17–producing CD4+ T cells was much lower, at a median of 0.06{\%}. Consistent with previous studies, IL-22 was produced by a distinct subset of CD4+ T cells and not coexpressed with IL-17. M. tuberculosis–specific IL-22 responses were markedly reduced (median, 0.08{\%}) in individuals with TB disease and HIV coinfection compared with IFN-$\gamma$ responses. M. tuberculosis–specific Th22 cells exhibited a distinct memory and activation phenotype compared with Th1 and Th17 cells. Furthermore, M. tuberculosis–specific IL-22 was produced by conventional CD4+ T cells that required TCR engagement. In conclusion, we confirm that Th22 cells are a component of the human immune response to TB. Depletion of M. tuberculosis–specific Th22 cells during HIV coinfection may contribute to increased risk of TB disease.},
author = {Makatsa, Mohau S and Millicent, F and Omondi, A and Bunjun, Rubina and Wilkinson, Robert J and Riou, Catherine and Burgers, Wendy A},
doi = {10.4049/JIMMUNOL.2200140},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Makatsa et al. - 2022 - Characterization of Mycobacterium tuberculosis–specific Th22 cells and the effect of tuberculosis disease and HI.pdf:pdf},
issn = {0022-1767},
journal = {The Journal of Immunology},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jul},
number = {3},
pages = {446--455},
pmid = {35777848},
publisher = {American Association of Immunologists},
title = {{Characterization of Mycobacterium tuberculosis–specific Th22 cells and the effect of tuberculosis disease and HIV coinfection}},
url = {https://www.jimmunol.org/content/early/2022/06/30/jimmunol.2200140 https://www.jimmunol.org/content/early/2022/06/30/jimmunol.2200140.abstract},
volume = {209},
year = {2022}
}

The development of a highly effective tuberculosis (TB) vaccine is likely dependent on our understanding of what constitutes a protective immune response to TB. Accumulating evidence suggests that CD4+ T cells producing IL-22, a distinct subset termed “Th22” cells, may contribute to protective immunity to TB. Thus, we characterized Mycobacterium tuberculosis–specific Th22 (and Th1 and Th17) cells in 72 people with latent TB infection or TB disease, with and without HIV-1 infection. We investigated the functional properties (IFN-$γ$, IL-22, and IL-17 production), memory differentiation (CD45RA, CD27, and CCR7), and activation profile (HLA-DR) of M. tuberculosis–specific CD4+ T cells. In HIV-uninfected individuals with latent TB infection, we detected abundant circulating IFN-$γ$–producing CD4+ T cells (median, 0.93%) and IL-22–producing CD4+ T cells (median, 0.46%) in response to M. tuberculosis. The frequency of IL-17–producing CD4+ T cells was much lower, at a median of 0.06%. Consistent with previous studies, IL-22 was produced by a distinct subset of CD4+ T cells and not coexpressed with IL-17. M. tuberculosis–specific IL-22 responses were markedly reduced (median, 0.08%) in individuals with TB disease and HIV coinfection compared with IFN-$γ$ responses. M. tuberculosis–specific Th22 cells exhibited a distinct memory and activation phenotype compared with Th1 and Th17 cells. Furthermore, M. tuberculosis–specific IL-22 was produced by conventional CD4+ T cells that required TCR engagement. In conclusion, we confirm that Th22 cells are a component of the human immune response to TB. Depletion of M. tuberculosis–specific Th22 cells during HIV coinfection may contribute to increased risk of TB disease.

@article{VanBeek2022,
abstract = {Background The M2 metabolite of bedaquiline causes QT-interval prolongation, making ECG monitoring of patients receiving bedaquiline for drug-resistant tuberculosis necessary. The objective of this study was to determine the relationship between M2 exposure and Fridericia-corrected QT (QTcF)-interval prolongation and to explore suitable ECG monitoring strategies for six-month bedaquiline treatment. Methods Data from the PROBeX study, a prospective observational cohort study, were used to characterize the relationship between M2 exposure and QTcF. Established non-linear mixed effects models were fitted to pharmacokinetic and ECG data. In a virtual patient population, QTcF values were simulated for scenarios with and without concomitant clofazimine. ECG monitoring strategies to identify patients who need to interrupt treatment (QTcF {\textgreater} 500 ms) were explored. Results 170 patients were included, providing 1131 bedaquiline/M2 plasma concentrations and 1702 QTcF measurements. 2.1{\%} of virtual patients receiving concomitant clofazimine had QTcF {\textgreater} 500 ms at any point during treatment (0.7{\%} without concomitant clofazimine). With monthly monitoring, almost all patients with QTcF {\textgreater} 500 ms were identified by week 12; after week 12, patients were predominantly falsely identified as QTcF {\textgreater} 500 ms due to stochastic measurement error. Following a strategy with monitoring before treatment and at weeks 2, 4, 8 and 12 in simulations with concomitant clofazimine, 93.8{\%} of all patients who should interrupt treatment were identified and 26.4{\%} of all interruptions were unnecessary (92.1{\%} and 32.2{\%}, respectively, without concomitant clofazimine). Conclusion Our simulations enable an informed decision for a suitable ECG monitoring strategy by weighing the risk of missing patients with QTcF {\textgreater} 500 ms and that of interrupting bedaquiline treatment unnecessarily. We propose ECG monitoring before treatment and at weeks 2, 4, 8 and 12 after starting bedaquiline treatment.},
author = {van Beek, Stijn W and Tanneau, L{\'{e}}na{\"{i}}g and Meintjes, Graeme and Wasserman, Sean and Gandhi, Neel R and Campbell, Angie and Viljoen, Charle A and Wiesner, Lubbe and Aarnoutse, Rob E and Maartens, Gary and Brust, James C M and Svensson, Elin M},
doi = {10.1093/OFID/OFAC372},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/van Beek et al. - 2022 - Model-predicted impact of ECG monitoring strategies during bedaquiline treatment.pdf:pdf},
issn = {2328-8957},
journal = {Open Forum Infectious Diseases},
keywords = {OA,OA{\_}PMC,fund{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,original},
month = {jul},
number = {8},
pages = {ofac372},
pmid = {36043179},
title = {{Model-predicted impact of ECG monitoring strategies during bedaquiline treatment}},
url = {https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofac372/6650803},
volume = {9},
year = {2022}
}

Background The M2 metabolite of bedaquiline causes QT-interval prolongation, making ECG monitoring of patients receiving bedaquiline for drug-resistant tuberculosis necessary. The objective of this study was to determine the relationship between M2 exposure and Fridericia-corrected QT (QTcF)-interval prolongation and to explore suitable ECG monitoring strategies for six-month bedaquiline treatment. Methods Data from the PROBeX study, a prospective observational cohort study, were used to characterize the relationship between M2 exposure and QTcF. Established non-linear mixed effects models were fitted to pharmacokinetic and ECG data. In a virtual patient population, QTcF values were simulated for scenarios with and without concomitant clofazimine. ECG monitoring strategies to identify patients who need to interrupt treatment (QTcF \textgreater 500 ms) were explored. Results 170 patients were included, providing 1131 bedaquiline/M2 plasma concentrations and 1702 QTcF measurements. 2.1% of virtual patients receiving concomitant clofazimine had QTcF \textgreater 500 ms at any point during treatment (0.7% without concomitant clofazimine). With monthly monitoring, almost all patients with QTcF \textgreater 500 ms were identified by week 12; after week 12, patients were predominantly falsely identified as QTcF \textgreater 500 ms due to stochastic measurement error. Following a strategy with monitoring before treatment and at weeks 2, 4, 8 and 12 in simulations with concomitant clofazimine, 93.8% of all patients who should interrupt treatment were identified and 26.4% of all interruptions were unnecessary (92.1% and 32.2%, respectively, without concomitant clofazimine). Conclusion Our simulations enable an informed decision for a suitable ECG monitoring strategy by weighing the risk of missing patients with QTcF \textgreater 500 ms and that of interrupting bedaquiline treatment unnecessarily. We propose ECG monitoring before treatment and at weeks 2, 4, 8 and 12 after starting bedaquiline treatment.

@article{Dhana2022,
abstract = {Background Since 2011, WHO has recommended that HIV-positive inpatients be routinely screened for tuberculosis with the WHO four-symptom screen (W4SS) and, if screened positive, receive a molecular WHO-recommended rapid diagnostic test (eg, Xpert MTB/RIF [Xpert] assay). To inform updated WHO tuberculosis screening guidelines, we conducted a systematic review and individual participant data meta-analysis to assess the performance of W4SS and alternative screening tests to guide Xpert testing and compare the diagnostic accuracy of the WHO Xpert algorithm (ie, W4SS followed by Xpert) with Xpert for all HIV-positive inpatients. Methods We searched MEDLINE, Embase, and Cochrane Library from Jan 1, 2011, to March 1, 2020, for studies of adult and adolescent HIV-positive inpatients enrolled regardless of tuberculosis signs and symptoms. The separate reference standards were culture and Xpert. Xpert was selected since it is most likely to be the confirmatory test used in practice. We assessed the proportion of inpatients eligible for Xpert testing using the WHO algorithm; assessed the accuracy of W4SS and alternative screening tests or strategies to guide diagnostic testing; and compared the accuracy of the WHO Xpert algorithm (W4SS followed by Xpert) with Xpert for all. We obtained pooled proportion estimates with a random-effects model, assessed diagnostic accuracy by fitting random-effects bivariate models, and assessed diagnostic yield descriptively. This systematic review has been registered on PROSPERO (CRD42020155895). Findings Of 6162 potentially eligible publications, six were eligible and we obtained data for all of the six publications (n=3660 participants). The pooled proportion of inpatients eligible for an Xpert was 90{\%} (95{\%} CI 89–91; n=3658). Among screening tests to guide diagnostic testing, W4SS and C-reactive protein (≥5 mg/L) had highest sensitivities (≥96{\%}) but low specificities (≤12{\%}); cough (≥2 weeks), haemoglobin concentration ({\textless}8 g/dL), body-mass index ({\textless}18{\textperiodcentered}5 kg/m2 ), and lymphadenopathy had higher specificities (61–90{\%}) but suboptimal sensitivities (12–57{\%}). The WHO Xpert algorithm (W4SS followed by Xpert) had a sensitivity of 76{\%} (95{\%} CI 67–84) and specificity of 93{\%} (88–96; n=637). Xpert for all had similar accuracy to the WHO Xpert algorithm: sensitivity was 78{\%} (95{\%} CI 69–85) and specificity was 93{\%} (87–96; n=639). In two cohorts that had sputum and non-sputum samples collected for culture or Xpert, diagnostic yield of sputum Xpert was 41–70{\%} and 61–64{\%} for urine Xpert. Interpretation The W4SS and other potential screening tests to guide Xpert testing have suboptimal accuracy in HIV- positive inpatients. On the basis of these findings, WHO now strongly recommends molecular rapid diagnostic testing in all medical HIV-positive inpatients in settings where tuberculosis prevalence is higher than 10{\%}.},
author = {Dhana, Ashar and Hamada, Yohhei and Kengne, Andre P and Kerkhoff, Andrew D and Rangaka, Molebogeng X and Kredo, Tamara and Baddeley, Annabel and Miller, Cecily and Gupta-Wright, Ankur and Fielding, Katherine and Wood, Robin and Huerga, Helena and R{\"{u}}cker, Sekai Chenai Mathabire and Heidebrecht, Christine and Wilson, Douglas and Bjerrum, Stephanie and Johansen, Isik S and Thit, Swe Swe and Kyi, Mar Mar and Hanson, Josh and Barr, David A and Meintjes, Graeme and Maartens, Gary},
doi = {10.1016/S2352-3018(22)00002-9},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Dhana et al. - 2022 - Tuberculosis screening among HIV-positive inpatients a systematic review and individual participant data meta-anal.pdf:pdf},
issn = {2352-3018},
journal = {The Lancet HIV},
keywords = {OA,fund{\_}ack,review},
mendeley-tags = {OA,fund{\_}ack,review},
month = {mar},
number = {4},
pages = {E233--E241},
pmid = {35338834},
publisher = {Elsevier},
title = {{Tuberculosis screening among HIV-positive inpatients: a systematic review and individual participant data meta-analysis}},
url = {https://linkinghub.elsevier.com/retrieve/pii/S2352301822000029},
volume = {9},
year = {2022}
}

Background Since 2011, WHO has recommended that HIV-positive inpatients be routinely screened for tuberculosis with the WHO four-symptom screen (W4SS) and, if screened positive, receive a molecular WHO-recommended rapid diagnostic test (eg, Xpert MTB/RIF [Xpert] assay). To inform updated WHO tuberculosis screening guidelines, we conducted a systematic review and individual participant data meta-analysis to assess the performance of W4SS and alternative screening tests to guide Xpert testing and compare the diagnostic accuracy of the WHO Xpert algorithm (ie, W4SS followed by Xpert) with Xpert for all HIV-positive inpatients. Methods We searched MEDLINE, Embase, and Cochrane Library from Jan 1, 2011, to March 1, 2020, for studies of adult and adolescent HIV-positive inpatients enrolled regardless of tuberculosis signs and symptoms. The separate reference standards were culture and Xpert. Xpert was selected since it is most likely to be the confirmatory test used in practice. We assessed the proportion of inpatients eligible for Xpert testing using the WHO algorithm; assessed the accuracy of W4SS and alternative screening tests or strategies to guide diagnostic testing; and compared the accuracy of the WHO Xpert algorithm (W4SS followed by Xpert) with Xpert for all. We obtained pooled proportion estimates with a random-effects model, assessed diagnostic accuracy by fitting random-effects bivariate models, and assessed diagnostic yield descriptively. This systematic review has been registered on PROSPERO (CRD42020155895). Findings Of 6162 potentially eligible publications, six were eligible and we obtained data for all of the six publications (n=3660 participants). The pooled proportion of inpatients eligible for an Xpert was 90% (95% CI 89–91; n=3658). Among screening tests to guide diagnostic testing, W4SS and C-reactive protein (≥5 mg/L) had highest sensitivities (≥96%) but low specificities (≤12%); cough (≥2 weeks), haemoglobin concentration (\textless8 g/dL), body-mass index (\textless18˙5 kg/m2 ), and lymphadenopathy had higher specificities (61–90%) but suboptimal sensitivities (12–57%). The WHO Xpert algorithm (W4SS followed by Xpert) had a sensitivity of 76% (95% CI 67–84) and specificity of 93% (88–96; n=637). Xpert for all had similar accuracy to the WHO Xpert algorithm: sensitivity was 78% (95% CI 69–85) and specificity was 93% (87–96; n=639). In two cohorts that had sputum and non-sputum samples collected for culture or Xpert, diagnostic yield of sputum Xpert was 41–70% and 61–64% for urine Xpert. Interpretation The W4SS and other potential screening tests to guide Xpert testing have suboptimal accuracy in HIV- positive inpatients. On the basis of these findings, WHO now strongly recommends molecular rapid diagnostic testing in all medical HIV-positive inpatients in settings where tuberculosis prevalence is higher than 10%.

@article{Houben2022,
author = {Houben, Rein M G J and Esmail, Hanif and Cobelens, Frank and Williams, Caroline M L and Coussens, Anna K},
doi = {10.1016/S2213-2600(22)00184-9},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Houben et al. - 2022 - Tuberculosis prevalence beyond the tip of the iceberg.pdf:pdf},
isbn = {9789241548168},
issn = {2213-2600},
journal = {The Lancet Respiratory Medicine},
keywords = {OA,commentary,fund{\_}not{\_}ack},
mendeley-tags = {OA,commentary,fund{\_}not{\_}ack},
month = {jun},
number = {6},
pages = {537--539},
pmid = {35659006},
publisher = {Elsevier},
title = {{Tuberculosis prevalence: beyond the tip of the iceberg}},
url = {http://www.thelancet.com/article/S2213260022001849/fulltext http://www.thelancet.com/article/S2213260022001849/abstract https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00184-9/abstract},
volume = {10},
year = {2022}
}

@article{Cele2021,
abstract = {The emergence of Omicron (Pango lineage B.1.1.529), first identified in Botswana and South Africa, may compromise vaccine effectiveness and lead to re-infections1. We investigated whether Omicron escapes antibody neutralization in South Africans vaccinated with Pfizer BNT162b2. We also investigated if Omicron requires the ACE2 receptor to infect cells. We isolated and sequence confirmed live Omicron virus from an infected person in South Africa and compared plasma neutralization of Omicron relative to an ancestral SARS-CoV-2 strain, observing that Omicron still required ACE2 to infect. For neutralization, blood samples were taken soon after vaccination from participants who were vaccinated and previously infected or vaccinated with no evidence of previous infection. Neutralization of ancestral virus was much higher in infected and vaccinated versus vaccinated only participants but both groups showed a 22-fold escape from vaccine elicited neutralization by the Omicron variant. However, in the previously infected and vaccinated group, the level of residual neutralization of Omicron was similar to the level of neutralization of ancestral virus observed in the vaccination only group. These data support the notion that, provided high neutralization capacity is elicited by vaccination/boosting approaches, reasonable effectiveness against Omicron may be maintained.},
author = {Cele, Sandile and Jackson, Laurelle and Khoury, David S and Khan, Khadija and Moyo-Gwete, Thandeka and Tegally, Houriiyah and San, James Emmanuel and Cromer, Deborah and Scheepers, Cathrine and Amoako, Daniel G and Karim, Farina and Bernstein, Mallory and Lustig, Gila and Archary, Derseree and Smith, Muneerah and Ganga, Yashica and Jule, Zesuliwe and Reedoy, Kajal and Hwa, Shi-Hsia and Giandhari, Jennifer and Blackburn, Jonathan M and Gosnell, Bernadett I and {Abdool Karim}, Salim S and Hanekom, Willem and NGS-SA and {COMMIT-KZN Team} and von Gottberg, Anne and Bhiman, Jinal N and Lessells, Richard J and Moosa, Mahomed-Yunus S and Davenport, Miles P and de Oliveira, Tulio and Moore, Penny L and Sigal, Alex},
doi = {10.1038/s41586-021-04387-1},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Cele et al. - 2022 - Omicron extensively but incompletely escapes Pfizer BNT162b2 neutralization.pdf:pdf},
issn = {1476-4687},
journal = {Nature},
keywords = {2,Antimicrobial responses,CoV,OA,SARS,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {dec},
pages = {654--656},
pmid = {35016196},
publisher = {Nature Publishing Group},
title = {{Omicron extensively but incompletely escapes Pfizer BNT162b2 neutralization}},
url = {https://www.nature.com/articles/s41586-021-04387-1},
volume = {602},
year = {2022}
}

The emergence of Omicron (Pango lineage B.1.1.529), first identified in Botswana and South Africa, may compromise vaccine effectiveness and lead to re-infections1. We investigated whether Omicron escapes antibody neutralization in South Africans vaccinated with Pfizer BNT162b2. We also investigated if Omicron requires the ACE2 receptor to infect cells. We isolated and sequence confirmed live Omicron virus from an infected person in South Africa and compared plasma neutralization of Omicron relative to an ancestral SARS-CoV-2 strain, observing that Omicron still required ACE2 to infect. For neutralization, blood samples were taken soon after vaccination from participants who were vaccinated and previously infected or vaccinated with no evidence of previous infection. Neutralization of ancestral virus was much higher in infected and vaccinated versus vaccinated only participants but both groups showed a 22-fold escape from vaccine elicited neutralization by the Omicron variant. However, in the previously infected and vaccinated group, the level of residual neutralization of Omicron was similar to the level of neutralization of ancestral virus observed in the vaccination only group. These data support the notion that, provided high neutralization capacity is elicited by vaccination/boosting approaches, reasonable effectiveness against Omicron may be maintained.

@article{Tikiso2022,
abstract = {Objectives Ethambutol protects against the development of resistance to co-administered drugs in the intensive phase of first-line anti-TB treatment in children. It is especially relevant in settings with a high prevalence of HIV or isoniazid resistance. We describe the population pharmacokinetics of ethambutol in children with TB to guide dosing in this population. Methods We pooled data from 188 intensively sampled children from the DATiC, DNDi and SHINE studies, who received 15–25 mg/kg ethambutol daily according to WHO guidelines. The median (range) age and weight of the cohort were 1.9 (0.3–12.6) years and 9.6 (3.9–34.5) kg, respectively. Children with HIV (HIV+; n = 103) received ART (lopinavir/ritonavir in 92{\%}). Results Ethambutol pharmacokinetics were best described by a two-compartment model with first-order elimination and absorption transit compartments. Clearance was estimated to reach 50{\%} of its mature value by 2 months after birth and 99{\%} by 3 years. Typical steady-state apparent clearance in a 10 kg child was 15.9 L/h. In HIV+ children on lopinavir/ritonavir, bioavailability was reduced by 32{\%} [median (IQR) steady-state Cmax = 0.882 (0.669–1.28) versus 1.66 (1.21–2.15) mg/L). In young children, bioavailability correlated with age. At birth, bioavailability was 73.1{\%} of that in children 3.16 years or older. Conclusions To obtain exposure within the 2–6 mg/L recommended range for Cmax, the current doses must be doubled (or tripled with HIV+ children on lopinavir/ritonavir) for paediatric patients. This raises concerns regarding the potential for ocular toxicity, which would require evaluation.},
author = {Tikiso, Tjokosela and McIlleron, Helen and Abdelwahab, Mahmoud Tareq and Bekker, Adrie and Hesseling, Anneke and Chabala, Chishala and Davies, Geraint and Zar, Heather J. and Rabie, Helena and Andrieux-Meyer, Isabelle and Lee, Janice and Wiesner, Lubbe and Cotton, Mark F. and Denti, Paolo},
doi = {10.1093/JAC/DKAC127},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Tikiso et al. - 2022 - Population pharmacokinetics of ethambutol in African children a pooled analysis.pdf:pdf},
issn = {0305-7453},
journal = {Journal of Antimicrobial Chemotherapy},
keywords = {fund{\_}not{\_}ack,original},
mendeley-tags = {fund{\_}not{\_}ack,original},
month = {apr},
number = {7},
pages = {1949--1959},
pmid = {35466379},
title = {{Population pharmacokinetics of ethambutol in African children: a pooled analysis}},
url = {https://academic.oup.com/jac/advance-article/doi/10.1093/jac/dkac127/6573557},
volume = {77},
year = {2022}
}

Objectives Ethambutol protects against the development of resistance to co-administered drugs in the intensive phase of first-line anti-TB treatment in children. It is especially relevant in settings with a high prevalence of HIV or isoniazid resistance. We describe the population pharmacokinetics of ethambutol in children with TB to guide dosing in this population. Methods We pooled data from 188 intensively sampled children from the DATiC, DNDi and SHINE studies, who received 15–25 mg/kg ethambutol daily according to WHO guidelines. The median (range) age and weight of the cohort were 1.9 (0.3–12.6) years and 9.6 (3.9–34.5) kg, respectively. Children with HIV (HIV+; n = 103) received ART (lopinavir/ritonavir in 92%). Results Ethambutol pharmacokinetics were best described by a two-compartment model with first-order elimination and absorption transit compartments. Clearance was estimated to reach 50% of its mature value by 2 months after birth and 99% by 3 years. Typical steady-state apparent clearance in a 10 kg child was 15.9 L/h. In HIV+ children on lopinavir/ritonavir, bioavailability was reduced by 32% [median (IQR) steady-state Cmax = 0.882 (0.669–1.28) versus 1.66 (1.21–2.15) mg/L). In young children, bioavailability correlated with age. At birth, bioavailability was 73.1% of that in children 3.16 years or older. Conclusions To obtain exposure within the 2–6 mg/L recommended range for Cmax, the current doses must be doubled (or tripled with HIV+ children on lopinavir/ritonavir) for paediatric patients. This raises concerns regarding the potential for ocular toxicity, which would require evaluation.

@article{Musaigwa2022,
abstract = {Schistosomiasis is a potentially lethal parasitic disease that profoundly impacts systemic immune function in chronically infected hosts through mechanisms that remain unknown. Given the immunoregulatory dysregulation experienced in infected individuals, this study examined the impact of chronic schistosomiasis on the sustainability of vaccine-induced immunity in both children living in endemic areas and experimental infections in mice. Data show that chronic Schistosoma mansoni infection impaired the persistence of vaccine specific antibody responses in poliovirus-vaccinated humans and mice. Mechanistically, schistosomiasis primarily fostered plasmablast and plasma cell death in the bone marrow and removal of parasites following praziquantel treatment reversed the observed cell death and partially restored vaccine-induced memory responses associated with increased serum anti-polio antibody responses. Our findings strongly suggest a previously unrecognized mechanism to explain how chronic schistosomiasis interferes with an otherwise effective vaccine regimen and further advocates for therapeutic intervention strategies that reduce schistosomiasis burden in endemic areas prior to vaccination.},
author = {Musaigwa, Fungai and {Donald Kamdem}, Severin and Mpotje, Thabo and Mosala, Paballo and {Abdel Aziz}, Nada and Herbert, Broski R and Brombacher, Frank and {Komguep Nono}, Justin},
doi = {10.1371/JOURNAL.PPAT.1010327},
editor = {Nair, Meera Goh},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Musaigwa et al. - 2022 - Schistosoma mansoni infection induces plasmablast and plasma cell death in the bone marrow and accelerates the.pdf:pdf},
isbn = {1111111111},
issn = {1553-7374},
journal = {PLOS Pathogens},
keywords = {B cells,Bone marrow cells,OA,Parasitic diseases,Plasma cells,Schistosoma mansoni,Schistosomiasis,Spleen,Vaccination and immunization,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {feb},
number = {2},
pages = {e1010327},
pmid = {35157732},
publisher = {Public Library of Science},
title = {{Schistosoma mansoni infection induces plasmablast and plasma cell death in the bone marrow and accelerates the decline of host vaccine responses}},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1010327},
volume = {18},
year = {2022}
}

Schistosomiasis is a potentially lethal parasitic disease that profoundly impacts systemic immune function in chronically infected hosts through mechanisms that remain unknown. Given the immunoregulatory dysregulation experienced in infected individuals, this study examined the impact of chronic schistosomiasis on the sustainability of vaccine-induced immunity in both children living in endemic areas and experimental infections in mice. Data show that chronic Schistosoma mansoni infection impaired the persistence of vaccine specific antibody responses in poliovirus-vaccinated humans and mice. Mechanistically, schistosomiasis primarily fostered plasmablast and plasma cell death in the bone marrow and removal of parasites following praziquantel treatment reversed the observed cell death and partially restored vaccine-induced memory responses associated with increased serum anti-polio antibody responses. Our findings strongly suggest a previously unrecognized mechanism to explain how chronic schistosomiasis interferes with an otherwise effective vaccine regimen and further advocates for therapeutic intervention strategies that reduce schistosomiasis burden in endemic areas prior to vaccination.

@article{Tegally2022d,
abstract = {In many regions of the world, the Alpha, Beta and Gamma SARS-CoV-2 Variants of Concern (VOCs) co-circulated during 2020-21 and fueled waves of infections. During 2021, these variants were almost completely displaced by the Delta variant, causing a third wave of infections worldwide. This phenomenon of global viral lineage displacement was observed again in late 2021, when the Omicron variant disseminated globally. In this study, we use phylogenetic and phylogeographic methods to reconstruct the dispersal patterns of SARS-CoV-2 VOCs worldwide. We find that the source-sink dynamics of SARS-CoV-2 varied substantially by VOC, and identify countries that acted as global hubs of variant dissemination, while other countries became regional contributors to the export of specific variants. We demonstrate a declining role of presumed origin countries of VOCs to their global dispersal: we estimate that India contributed {\textless}15{\%} of all global exports of Delta to other countries and South Africa {\textless}1-2{\%} of all global Omicron exports globally. We further estimate that {\textgreater}80 countries had received introductions of Omicron BA.1 100 days after its inferred date of emergence, compared to just over 25 countries for the Alpha variant. This increased speed of global dissemination was associated with a rebound in air travel volume prior to Omicron emergence in addition to the higher transmissibility of Omicron relative to Alpha. Our study highlights the importance of global and regional hubs in VOC dispersal, and the speed at which highly transmissible variants disseminate through these hubs, even before their detection and characterization through genomic surveillance. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Funding Statement we gratefully acknowledge all sources of funding associated with this work. In particular, KRISP and CERI is supported in part by grants from the Rockefeller Foundation (HTH 017), Abbott Pandemic Defense Coalition (APDC), the African Society for Laboratory Medicine, the National Institute of Health USA (U01 AI151698) for the United World Antivirus Research Network (UWARN) and the INFORM Africa project through IHVN (U54 TW012041), H3BioNet Africa (Grant {\#} 2020 HTH 062), the South African Department of Science and Innovation (SA DSI) and the South African Medical Research Council (SAMRC) under the BRICS JAF {\#}2020/049 and the World Bank (TF0B8412). M.U.G.K. acknowledges support from a Branco Weiss Fellowship, Reuben College Oxford, Google.org, the Foreign, Commonwealth and Development Office and Wellcome (225288/Z/22/Z), The Rockefeller Foundation, and from the European Union Horizon 2020 project MOOD (grant agreement number 874850). O.G.P. and M.U.G.K. acknowledge support from the Oxford Martin School. N.R.F. acknowledges support from Wellcome Trust and Royal Society Sir Henry Dale Fellowship (204311/Z/16/Z), Bill and Melinda Gates Foundation (INV-034540) and Medical Research Council-Sao Paulo Research Foundation (FAPESP) CADDE partnership award (MR/S0195/1 and FAPESP 18/14389-0). The content and findings reported herein are the sole deduction, view and responsibility of the researcher/s and do not reflect the official position and sentiments of the funding agencies. {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The findings of this study are based on sequences and metadata associated with a total of XXX sequences available on GISAID up to November 19, 2022, via gisaid.org/EPI$\backslash${\_}SET$\backslash${\_}XXX. Custom data sources and scripts to reproduce the results of this study are publicly shared on GitHub (https://github.com/CERI-KRISP/SARS$\backslash${\_}CoV$\backslash${\_}2$\backslash${\_}VOC$\backslash${\_}dissemination). The repository contains all of the time scaled ML tree topologies, annotated tree topologies as well as custom data analysis and visualization scripts. Other datasets and pipelines used in this study are openly available and described in the Materials and Methods section.},
author = {Tegally, Houriiyah and Wilkinson, Eduan and Martin, Darren and Moir, Monika and Brito, Anderson and Giovanetti, Marta and Khan, Kamran and Huber, Carmen and Bogoch, Isaac I and San, James Emmanuel and Tsui, Joseph L-H and Poongavanan, Jenicca and Xavier, Joicymara S and {da S Candido}, Darlan and Romero, Filipe and Baxter, Cheryl and Pybus, Oliver G and Lessells, Richard and Faria, Nuno R and Kraemer, Moritz U G and de Oliveira, Tulio},
doi = {10.1101/2022.11.22.22282629},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Tegally et al. - 2022 - Global expansion of SARS-CoV-2 variants of concern dispersal patterns and influence of air travel.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {nov},
pages = {2022.11.22.22282629},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Global expansion of SARS-CoV-2 variants of concern: dispersal patterns and influence of air travel}},
url = {https://www.medrxiv.org/content/10.1101/2022.11.22.22282629v1 https://www.medrxiv.org/content/10.1101/2022.11.22.22282629v1.abstract},
year = {2022}
}

In many regions of the world, the Alpha, Beta and Gamma SARS-CoV-2 Variants of Concern (VOCs) co-circulated during 2020-21 and fueled waves of infections. During 2021, these variants were almost completely displaced by the Delta variant, causing a third wave of infections worldwide. This phenomenon of global viral lineage displacement was observed again in late 2021, when the Omicron variant disseminated globally. In this study, we use phylogenetic and phylogeographic methods to reconstruct the dispersal patterns of SARS-CoV-2 VOCs worldwide. We find that the source-sink dynamics of SARS-CoV-2 varied substantially by VOC, and identify countries that acted as global hubs of variant dissemination, while other countries became regional contributors to the export of specific variants. We demonstrate a declining role of presumed origin countries of VOCs to their global dispersal: we estimate that India contributed \textless15% of all global exports of Delta to other countries and South Africa \textless1-2% of all global Omicron exports globally. We further estimate that \textgreater80 countries had received introductions of Omicron BA.1 100 days after its inferred date of emergence, compared to just over 25 countries for the Alpha variant. This increased speed of global dissemination was associated with a rebound in air travel volume prior to Omicron emergence in addition to the higher transmissibility of Omicron relative to Alpha. Our study highlights the importance of global and regional hubs in VOC dispersal, and the speed at which highly transmissible variants disseminate through these hubs, even before their detection and characterization through genomic surveillance. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement we gratefully acknowledge all sources of funding associated with this work. In particular, KRISP and CERI is supported in part by grants from the Rockefeller Foundation (HTH 017), Abbott Pandemic Defense Coalition (APDC), the African Society for Laboratory Medicine, the National Institute of Health USA (U01 AI151698) for the United World Antivirus Research Network (UWARN) and the INFORM Africa project through IHVN (U54 TW012041), H3BioNet Africa (Grant # 2020 HTH 062), the South African Department of Science and Innovation (SA DSI) and the South African Medical Research Council (SAMRC) under the BRICS JAF #2020/049 and the World Bank (TF0B8412). M.U.G.K. acknowledges support from a Branco Weiss Fellowship, Reuben College Oxford, Google.org, the Foreign, Commonwealth and Development Office and Wellcome (225288/Z/22/Z), The Rockefeller Foundation, and from the European Union Horizon 2020 project MOOD (grant agreement number 874850). O.G.P. and M.U.G.K. acknowledge support from the Oxford Martin School. N.R.F. acknowledges support from Wellcome Trust and Royal Society Sir Henry Dale Fellowship (204311/Z/16/Z), Bill and Melinda Gates Foundation (INV-034540) and Medical Research Council-Sao Paulo Research Foundation (FAPESP) CADDE partnership award (MR/S0195/1 and FAPESP 18/14389-0). The content and findings reported herein are the sole deduction, view and responsibility of the researcher/s and do not reflect the official position and sentiments of the funding agencies. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The findings of this study are based on sequences and metadata associated with a total of XXX sequences available on GISAID up to November 19, 2022, via gisaid.org/EPI$\$_SET$\$_XXX. Custom data sources and scripts to reproduce the results of this study are publicly shared on GitHub (https://github.com/CERI-KRISP/SARS$\$_CoV$\$_2$\$_VOC$\$_dissemination). The repository contains all of the time scaled ML tree topologies, annotated tree topologies as well as custom data analysis and visualization scripts. Other datasets and pipelines used in this study are openly available and described in the Materials and Methods section.

@article{Valley-Omar2022,
abstract = {Routine SARS-CoV-2 surveillance in the Western Cape region of South Africa (January-August 2021) found a reduced RT-PCR amplification efficiency of the RdRp-gene target of the Seegene, Allplex 2019-nCoV diagnostic assay from June 2021 when detecting the Delta variant. We investigated whether the reduced amplification efficiency denoted by an increased RT-PCR cycle threshold value (R$\Delta$E) can be used as an indirect measure of SARS-CoV-2 Delta variant prevalence. We found a significant increase in the median R$\Delta$E for patient samples tested from June 2021, which coincided with the emergence of the SARS-CoV-2 Delta variant within our sample set. Whole genome sequencing on a subset of patient samples identified a highly conserved G15451A, non-synonymous mutation exclusively within the RdRp gene of Delta variants, which may cause reduced RT-PCR amplification efficiency. While whole genome sequencing plays an important in identifying novel SARS-CoV-2 variants, monitoring R$\Delta$E value can serve as a useful surrogate for rapid tracking of Delta variant prevalence.},
author = {Valley-Omar, Ziyaad and Marais, Gert and Iranzadeh, Arash and Naidoo, Michelle and Korsman, Stephen and Maponga, Tongai and Hussey, Hannah and Davies, Mary-Ann and Boulle, Andrew and Doolabh, Deelan and Laubscher, Mariska and Wojno, Justyna and Deetlefs, J.D. and Maritz, Jean and Scott, Lesley and Msomi, Nokukhanya and Naicker, Cherise and Tegally, Houriiyah and de Oliveira, Tulio and Bhiman, Jinal and Williamson, Carolyn and Preiser, Wolfgang and Hardie, Diana and Hsiao, Nei-yuan},
doi = {10.1016/j.jviromet.2022.114471},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Valley-Omar et al. - 2022 - Reduced amplification efficiency of the RNA-dependent-RNA-polymerase target enables tracking of the Delta SA.pdf:pdf},
issn = {01660934},
journal = {Journal of Virological Methods},
keywords = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {apr},
pages = {114471},
pmid = {35051442},
publisher = {Elsevier},
title = {{Reduced amplification efficiency of the RNA-dependent-RNA-polymerase target enables tracking of the Delta SARS-CoV-2 variant using routine diagnostic tests}},
url = {https://linkinghub.elsevier.com/retrieve/pii/S0166093422000180},
volume = {302},
year = {2022}
}

Routine SARS-CoV-2 surveillance in the Western Cape region of South Africa (January-August 2021) found a reduced RT-PCR amplification efficiency of the RdRp-gene target of the Seegene, Allplex 2019-nCoV diagnostic assay from June 2021 when detecting the Delta variant. We investigated whether the reduced amplification efficiency denoted by an increased RT-PCR cycle threshold value (R$Δ$E) can be used as an indirect measure of SARS-CoV-2 Delta variant prevalence. We found a significant increase in the median R$Δ$E for patient samples tested from June 2021, which coincided with the emergence of the SARS-CoV-2 Delta variant within our sample set. Whole genome sequencing on a subset of patient samples identified a highly conserved G15451A, non-synonymous mutation exclusively within the RdRp gene of Delta variants, which may cause reduced RT-PCR amplification efficiency. While whole genome sequencing plays an important in identifying novel SARS-CoV-2 variants, monitoring R$Δ$E value can serve as a useful surrogate for rapid tracking of Delta variant prevalence.

@article{Sheerin2022,
abstract = {Summary Current and previous tuberculosis (TB) increase the risk of COVID-19 mortality and severe disease. To identify mechanisms of immunopathogenic interaction between COVID-19 and TB, we performed a systematic review and patient-level meta-analysis of COVID-19 transcriptomic signatures, spanning disease severity, from whole blood, PBMCs, and BALF. 35 eligible signatures were profiled on 1181 RNA-seq samples from 853 individuals across the spectrum of TB infection. Thirteen COVID-19 gene-signatures had significantly higher "COVID-19 risk scores" in active TB and latent TB progressors compared with non-progressors and uninfected controls (pFCN1- and SPP1-expressing macrophages enriched in severe COVID-19 BALF and active TB blood. Gene ontology and protein-protein interaction networks identified 12-gene disease-exacerbation hot spots between COVID-19 and TB. Finally, we in vitro validated that SARS-CoV-2 infection is increased in human macrophages cultured in the inflammatory milieu of Mtb-infected macrophages, correlating with TMPRSS2, IFNA1, IFNB1, IFNG, TNF, and IL1B induction.},
author = {Sheerin, Dylan and Abhimanyu and Peton, Nashied and Vo, William and Allison, Cody Charles and Wang, Xutao and Johnson, W Evan and Coussens, Anna K},
doi = {10.1016/J.ISCI.2022.104464},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Sheerin et al. - 2022 - Immunopathogenic overlap between COVID-19 and tuberculosis identified from transcriptomic meta-analysis and huma.pdf:pdf},
issn = {2589-0042},
journal = {iScience},
keywords = {Immunology,OA,Pathophysiology,Transcriptomics,Virology,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jun},
number = {6},
pages = {104464},
pmid = {35634577},
publisher = {Elsevier},
title = {{Immunopathogenic overlap between COVID-19 and tuberculosis identified from transcriptomic meta-analysis and human macrophage infection}},
url = {http://www.cell.com/article/S2589004222007350/fulltext http://www.cell.com/article/S2589004222007350/abstract https://www.cell.com/iscience/abstract/S2589-0042(22)00735-0},
volume = {25},
year = {2022}
}

Summary Current and previous tuberculosis (TB) increase the risk of COVID-19 mortality and severe disease. To identify mechanisms of immunopathogenic interaction between COVID-19 and TB, we performed a systematic review and patient-level meta-analysis of COVID-19 transcriptomic signatures, spanning disease severity, from whole blood, PBMCs, and BALF. 35 eligible signatures were profiled on 1181 RNA-seq samples from 853 individuals across the spectrum of TB infection. Thirteen COVID-19 gene-signatures had significantly higher "COVID-19 risk scores" in active TB and latent TB progressors compared with non-progressors and uninfected controls (pFCN1- and SPP1-expressing macrophages enriched in severe COVID-19 BALF and active TB blood. Gene ontology and protein-protein interaction networks identified 12-gene disease-exacerbation hot spots between COVID-19 and TB. Finally, we in vitro validated that SARS-CoV-2 infection is increased in human macrophages cultured in the inflammatory milieu of Mtb-infected macrophages, correlating with TMPRSS2, IFNA1, IFNB1, IFNG, TNF, and IL1B induction.

@article{Roshdy2022,
abstract = {COVID-19 was first diagnosed in Egypt on 14 February 2020. By the end of November 2021, over 333,840 cases and 18,832 deaths had been reported. As part of national genomic surveillance, 1,027 SARS-CoV-2 near whole-genomes had been generated and published by the end of May 2021. Here we describe the genomic epidemiology of SARS-CoV-2 in Egypt over this period using a subset of 976 high-quality Egyptian genomes analysed together with a representative set of global sequences within a phylogenetic framework. We show that a single lineage, C.36, introduced early in the pandemic was responsible for most cases in Egypt. Furthermore, we show that to remain dominant in the face of mounting immunity from previous infection and vaccination, this lineage evolved into various sub-lineages acquiring several mutations known to confer adaptive advantage and pathogenic properties. These results highlight the value of continuous genomic surveillance in regions where VOCs are not predominant and enforcement of public health measures to prevent expansion of existing lineages. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Funding Statement The research reported in this publication/article was supported by an internal grant from the National Research Centre, Ministry of Higher Education and Scientific Research, and Ministry of Health and Population in Egypt. The team from CERI/KRISP was supported by funding from the South African Department of Science and Innovation (DSI) and the South African Medical Research Council (SAMRC) under the BRICS JAF {\#}2020/049. The content and findings reported/illustrated herein are the sole deduction, view and responsibility of the researcher/s and do not reflect the official position and sentiments of the funders. {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval was obtained from the Ethics Committee of the National Research Centre, Giza, Egypt protocol number 14155, on 22 March 2020. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced are available online on GISAID {\textless}http://www.gisaid.org{\textgreater}},
author = {Roshdy, Wael H and Khalifa, Mohamed K and San, James Emmanuel and Tegally, Houriiyah and Wilkinson, Eduan and Showky, Shymaa and Martin, Daren Patrick and Moir, Monika and Naguib, Amel and Elguindy, Nancy and Gomaa, Mokhtar R and Fahim, Manal and Elsood, Hanaa Abu and Mohsen, Amira and Galal, Ramy and Hassany, Mohamed and Lessells, Richard J and Al-Karmalawy, Ahmed A and EL-Shesheny, Rabeh and Kandeil, Ahmed M and Ali, Mohamed A and de Oliveira, Tulio},
doi = {10.1101/2022.01.05.22268646},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Roshdy et al. - 2022 - SARS-CoV-2 genetic diversity and lineage dynamics of in Egypt.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jan},
pages = {2022.01.05.22268646},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{SARS-CoV-2 genetic diversity and lineage dynamics of in Egypt}},
url = {https://www.medrxiv.org/content/10.1101/2022.01.05.22268646v1 https://www.medrxiv.org/content/10.1101/2022.01.05.22268646v1.abstract},
year = {2022}
}

COVID-19 was first diagnosed in Egypt on 14 February 2020. By the end of November 2021, over 333,840 cases and 18,832 deaths had been reported. As part of national genomic surveillance, 1,027 SARS-CoV-2 near whole-genomes had been generated and published by the end of May 2021. Here we describe the genomic epidemiology of SARS-CoV-2 in Egypt over this period using a subset of 976 high-quality Egyptian genomes analysed together with a representative set of global sequences within a phylogenetic framework. We show that a single lineage, C.36, introduced early in the pandemic was responsible for most cases in Egypt. Furthermore, we show that to remain dominant in the face of mounting immunity from previous infection and vaccination, this lineage evolved into various sub-lineages acquiring several mutations known to confer adaptive advantage and pathogenic properties. These results highlight the value of continuous genomic surveillance in regions where VOCs are not predominant and enforcement of public health measures to prevent expansion of existing lineages. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The research reported in this publication/article was supported by an internal grant from the National Research Centre, Ministry of Higher Education and Scientific Research, and Ministry of Health and Population in Egypt. The team from CERI/KRISP was supported by funding from the South African Department of Science and Innovation (DSI) and the South African Medical Research Council (SAMRC) under the BRICS JAF #2020/049. The content and findings reported/illustrated herein are the sole deduction, view and responsibility of the researcher/s and do not reflect the official position and sentiments of the funders. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval was obtained from the Ethics Committee of the National Research Centre, Giza, Egypt protocol number 14155, on 22 March 2020. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced are available online on GISAID \textlesshttp://www.gisaid.org\textgreater

@article{Sawhney2022,
abstract = {Amongst the most significant scientific findings in the last two decades has been the role of inflammatory processes in protecting the host against the causative agents of injury. In this work, we examined the anti-inflammatory activities of Arteannuin-B (1) and its novel spirocyclic-2-isoxazoline derivative (2). Various anti-inflammatory assays were performed in lipopolysaccharide (LPS) induced RAW 264.7 macrophages using enzyme-linked immunosorbent assay, flow cytometric analysis, and western blotting. As a result, treatment with (2) decreased LPS-stimulated inducible nitric oxide synthase protein expression (iNOS), as well as production of nitric oxide (NO), tumor necrosis factor-alpha (TNF-$\alpha$), and interleukin-6 (IL-6) in LPS induced RAW 264.7 cells. Additionally, the effects of (1) and (2) in an acute inflammatory condition were investigated in-vivo by using models like carrageenan-induced paw edema assay, acetic acid-induced writhing and tail immersion model in experimental mice, suggesting that (2) is a more potent anti-inflammatory candidate as compared to (1) with very low cell toxicity. In addition, biocomputational studies and histopathological analysis were also performed to validate the efficiency of (2) as compared to (1).},
author = {Sawhney, Gifty and Ozturk, Mumin and Parihar, Suraj and Brombacher, Frank and Ahmad, Bilal and Bhagat, Asha and Ali, Asif and Ahmed, Zabeer},
doi = {10.21203/RS.3.RS-1881315/V1},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Sawhney et al. - 2022 - Arteannuin-B and its spiro-isoxazoline derivative inhibits LPS induced pro-inflammatory responses in RAW 264.7 m.pdf:pdf},
journal = {Research Square},
keywords = {Innammation,Interleukin-6 (IL-6),Lipopolysaccharide (LPS),Nitric oxide (NO),OA,RAW 2647 cells,Tumor necrosis factor-alpha (TNF-$\alpha$),fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jul},
pages = {https://doi.org/10.21203/rs.3.rs--1881315/v1},
title = {{Arteannuin-B and its spiro-isoxazoline derivative inhibits LPS induced pro-inflammatory responses in RAW 264.7 macrophages and BALB/c mice via down-regulation of NF-$\kappa$$\beta$/P38 MAPK mediated stress signalling}},
url = {https://www.researchsquare.com https://www.researchsquare.com/article/rs-1881315/v1},
year = {2022}
}

Amongst the most significant scientific findings in the last two decades has been the role of inflammatory processes in protecting the host against the causative agents of injury. In this work, we examined the anti-inflammatory activities of Arteannuin-B (1) and its novel spirocyclic-2-isoxazoline derivative (2). Various anti-inflammatory assays were performed in lipopolysaccharide (LPS) induced RAW 264.7 macrophages using enzyme-linked immunosorbent assay, flow cytometric analysis, and western blotting. As a result, treatment with (2) decreased LPS-stimulated inducible nitric oxide synthase protein expression (iNOS), as well as production of nitric oxide (NO), tumor necrosis factor-alpha (TNF-$α$), and interleukin-6 (IL-6) in LPS induced RAW 264.7 cells. Additionally, the effects of (1) and (2) in an acute inflammatory condition were investigated in-vivo by using models like carrageenan-induced paw edema assay, acetic acid-induced writhing and tail immersion model in experimental mice, suggesting that (2) is a more potent anti-inflammatory candidate as compared to (1) with very low cell toxicity. In addition, biocomputational studies and histopathological analysis were also performed to validate the efficiency of (2) as compared to (1).

@article{Riou2021b,
abstract = {Rapid tests to evaluate SARS-CoV-2-specific T cell responses are urgently needed to decipher protective immunity and aid monitoring vaccine-induced immunity. Using a rapid whole blood assay requiring minimal amount of blood, we measured qualitatively and quantitatively SARS-CoV-2-specific CD4T cell responses in 31 healthcare workers, using flow cytometry. 100{\%} of COVID-19 convalescent participants displayed a detectable SARS-CoV-2-specific CD4T cell response. SARS-CoV-2-responding cells were also detected in 40.9{\%} of participants with no COVID-19-associated symptoms or who tested PCR negative. Phenotypic assessment indicated that, in COVID-19 convalescent participants, SARS-CoV-2 CD4 responses displayed an early differentiated memory phenotype with limited capacity to produce IFNɣ. Conversely, in participants with no reported symptoms, SARS-CoV-2 CD4 responses were enriched in late differentiated cells, co-expressing IFNɣ and TNF$\alpha$ and also Granzyme B. This proof-of-concept study presents a scalable alternative to PBMC-based assays to enumerate and phenotype SARS-CoV-2-responding T cells, thus representing a practical tool to monitor adaptive immunity due to natural infection or vaccine trials. In this proof-of-concept study, we show that SARS-CoV-2T cell responses are easily detectable using a rapid whole blood assay requiring minimal blood volume. Such assay represents a suitable tool to monitor adaptive immunity in vaccine trials.},
author = {Riou, Catherine and Sch{\"{a}}fer, Georgia and du Bruyn, Elsa and Goliath, Rene T and Stek, Cari and Mou, Huihui and Hung, Deli and Wilkinson, Katalin A and Wilkinson, Robert J},
doi = {10.1183/13993003.00285-2021},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Riou et al. - 2022 - Rapid, simplified whole blood-based multiparameter assay to quantify and phenotype SARS-CoV-2 specific T cells.pdf:pdf},
issn = {0903-1936},
journal = {European Respiratory Journal},
keywords = {COVID-19,OA,OA{\_}PMC,T cells,Whole blood Assay,fund{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,original},
month = {jun},
number = {1},
pages = {2100285},
pmid = {34140294},
publisher = {European Respiratory Society},
title = {{Rapid, simplified whole blood-based multiparameter assay to quantify and phenotype SARS-CoV-2 specific T cells}},
url = {https://erj.ersjournals.com/content/early/2021/05/28/13993003.00285-2021 https://erj.ersjournals.com/content/early/2021/05/28/13993003.00285-2021.abstract},
volume = {59},
year = {2022}
}

Rapid tests to evaluate SARS-CoV-2-specific T cell responses are urgently needed to decipher protective immunity and aid monitoring vaccine-induced immunity. Using a rapid whole blood assay requiring minimal amount of blood, we measured qualitatively and quantitatively SARS-CoV-2-specific CD4T cell responses in 31 healthcare workers, using flow cytometry. 100% of COVID-19 convalescent participants displayed a detectable SARS-CoV-2-specific CD4T cell response. SARS-CoV-2-responding cells were also detected in 40.9% of participants with no COVID-19-associated symptoms or who tested PCR negative. Phenotypic assessment indicated that, in COVID-19 convalescent participants, SARS-CoV-2 CD4 responses displayed an early differentiated memory phenotype with limited capacity to produce IFNɣ. Conversely, in participants with no reported symptoms, SARS-CoV-2 CD4 responses were enriched in late differentiated cells, co-expressing IFNɣ and TNF$α$ and also Granzyme B. This proof-of-concept study presents a scalable alternative to PBMC-based assays to enumerate and phenotype SARS-CoV-2-responding T cells, thus representing a practical tool to monitor adaptive immunity due to natural infection or vaccine trials. In this proof-of-concept study, we show that SARS-CoV-2T cell responses are easily detectable using a rapid whole blood assay requiring minimal blood volume. Such assay represents a suitable tool to monitor adaptive immunity in vaccine trials.

@article{Alobwede2022b,
abstract = {Vaccination attitudes among healthcare workers (HCWs) predict their level of vaccination uptake and intention to recommend vaccinations to their patients. To our knowledge, no study has been conducted in South Africa to assess hesitancy toward influenza vaccines among HCWs. We adapted a questionnaire developed and validated by Betsch and colleagues and used it to conduct online and face-to-face interviews among HCWs at the start of the COVID-19 vaccine rollout. Multivariate logistic regression was used to assess predictors of influenza vaccine hesitancy. Of 401 participants, 64.5{\%} were women, 49.2{\%} were nurses, and 12.5{\%} were physicians. A total of 54.9{\%} were willing to accept, 20.4{\%} were undecided, and 24.7{\%} intended to refuse influenza vaccination. Participants who were above 25 years of age and physicians were more likely to accept the vaccine. Key predictors of vaccine acceptance were confidence in the effectiveness, consideration of benefits and risks, and willingness to be vaccinated to protect others. Influenza vaccine hesitancy was highest in those who did not trust that influenza vaccines are safe. For future flu seasons, tailored education programs on the safety and effectiveness of flu vaccines targeting younger HCWs, could be vital to improving vaccine uptake.},
author = {Alobwede, Samuel M and Kidzeru, Elvis B and Katoto, Patrick D M C and Lumngwena, Evelyn N and Cooper, Sara and Goliath, Rene and Jackson, Amanda and Wiysonge, Charles S and Shey, Muki S},
doi = {10.3390/VACCINES10081176},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Alobwede et al. - 2022 - Influenza vaccination uptake and hesitancy among healthcare workers in early 2021 at the start of the COVID-19.pdf:pdf},
issn = {2076-393X},
journal = {Vaccines},
keywords = {OA,OA{\_}PMC,South Africa,fund{\_}not{\_}ack,healthcare workers,influenza vaccines,original,vaccine hesitancy},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {jul},
number = {8},
pages = {1176},
pmid = {35893825},
publisher = {Multidisciplinary Digital Publishing Institute},
title = {{Influenza vaccination uptake and hesitancy among healthcare workers in early 2021 at the start of the COVID-19 vaccine rollout in Cape Town, South Africa}},
url = {https://www.mdpi.com/2076-393X/10/8/1176/htm https://www.mdpi.com/2076-393X/10/8/1176},
volume = {10},
year = {2022}
}

Vaccination attitudes among healthcare workers (HCWs) predict their level of vaccination uptake and intention to recommend vaccinations to their patients. To our knowledge, no study has been conducted in South Africa to assess hesitancy toward influenza vaccines among HCWs. We adapted a questionnaire developed and validated by Betsch and colleagues and used it to conduct online and face-to-face interviews among HCWs at the start of the COVID-19 vaccine rollout. Multivariate logistic regression was used to assess predictors of influenza vaccine hesitancy. Of 401 participants, 64.5% were women, 49.2% were nurses, and 12.5% were physicians. A total of 54.9% were willing to accept, 20.4% were undecided, and 24.7% intended to refuse influenza vaccination. Participants who were above 25 years of age and physicians were more likely to accept the vaccine. Key predictors of vaccine acceptance were confidence in the effectiveness, consideration of benefits and risks, and willingness to be vaccinated to protect others. Influenza vaccine hesitancy was highest in those who did not trust that influenza vaccines are safe. For future flu seasons, tailored education programs on the safety and effectiveness of flu vaccines targeting younger HCWs, could be vital to improving vaccine uptake.

@article{Martin2022a,
author = {Martin, Darren P and Lytras, Spyros and Lucaci, Alexander G and Maier, Wolfgang and Gr{\"{u}}ning, Bj{\"{o}}rn and Shank, Stephen D and Weaver, Steven and MacLean, Oscar A and Orton, Richard J and Lemey, Philippe and Boni, Maciej F and Tegally, Houriiyah and Harkins, Gordon W and Scheepers, Cathrine and Bhiman, Jinal N and Everatt, Josie and Amoako, Daniel G and San, James Emmanuel and Giandhari, Jennifer and Sigal, Alex and NGS-SA and Williamson, Carolyn and Hsiao, Nei-yuan and von Gottberg, Anne and {De Klerk}, Arne and Shafer, Robert W and Robertson, David L and Wilkinson, Robert J and Sewell, B Trevor and Lessells, Richard and Nekrutenko, Anton and Greaney, Allison J and Starr, Tyler N and Bloom, Jesse D and Murrell, Ben and Wilkinson, Eduan and Gupta, Ravindra K and de Oliveira, Tulio and {Kosakovsky Pond}, Sergei L},
doi = {10.1093/MOLBEV/MSAC061},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Martin et al. - 2022 - Selection analysis identifies clusters of unusual mutational changes in Omicron lineage BA.1 that likely impact S.pdf:pdf},
isbn = {061/6553617},
issn = {0737-4038},
journal = {Molecular Biology and Evolution},
keywords = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
number = {4},
pages = {msac061},
pmid = {35325204},
title = {{Selection analysis identifies clusters of unusual mutational changes in Omicron lineage BA.1 that likely impact Spike function}},
url = {https://academic.oup.com/mbe/advance-article/doi/10.1093/molbev/msac061/6553617},
volume = {39},
year = {2022}
}

@article{Wolter2022b,
author = {Wolter, Nicole and Jassat, Waasila and von Gottberg, Anne and Cohen, Cheryl and DATCOV-Gen author group},
doi = {10.1016/S0140-6736(22)00981-3},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Wolter et al. - 2022 - Clinical severity of omicron lineage BA.2 infection compared with BA.1 infection in South Africa.pdf:pdf},
isbn = {10.1101/2022},
issn = {0140-6736},
journal = {The Lancet},
keywords = {OA,fund{\_}ack,letter},
mendeley-tags = {OA,fund{\_}ack,letter},
month = {jul},
pages = {10.1016/S0140--6736(22)00981--3},
publisher = {Elsevier},
title = {{Clinical severity of omicron lineage BA.2 infection compared with BA.1 infection in South Africa}},
url = {http://www.thelancet.com/article/S0140673622009813/fulltext http://www.thelancet.com/article/S0140673622009813/abstract https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00981-3/abstract},
year = {2022}
}

@article{Brink2022,
abstract = {Antibiotic stewardship of hospital-acquired infections because of difficult-to-treat resistant (DTR) Gram-negative bacteria is a global challenge. Their increasing prevalence in South Africa has required a shift in prescribing in recent years towards colistin, an antibiotic of last resort. High toxicity levels and developing resistance to colistin are narrowing treatment options further. Recently, two new $\beta$-lactam/$\beta$-lactamase inhibitor combinations, ceftazidime-avibactam and ceftolozane-tazobactam were registered in South Africa, bringing hope of new options for management of these life-threatening infections. However, with increased use in the private sector, increasing levels of resistance to ceftazidime-avibactam are already being witnessed, putting their long-term viability as treatment options of last resort, in jeopardy. This review focuses on how these two vital new antibiotics should be stewarded within a framework that recognises the resistance mechanisms currently predominant in South Africa's multi-drug and DTR Gram-negative bacteria. Moreover, the withholding of their use for resistant infections that can be treated with currently available antibiotics is a critical part of stewardship, if these antibiotics are to be conserved in the long term.},
author = {Brink, Adrian J and Coetzee, Jennifer and Richards, Guy A and Feldman, Charles and Lowman, Warren and Tootla, Hafsah D and Miller, Malcolm G A and Niehaus, Abraham J and Wasserman, Sean and Perovic, Olga and Govind, Chetna N and Schellack, Natalie and Mendelson, Marc},
doi = {10.4102/SAJID.V37I1.453},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Brink et al. - 2022 - Best practices Appropriate use of the new $\beta$-lactam$\beta$-lactamase inhibitor combinations, ceftazidime-avibactam and ce.pdf:pdf},
issn = {2313-1810},
journal = {Southern African Journal of Infectious Diseases},
keywords = {Enterobacterales,Gram,Infectious diseases,OA,Pseudomonas aeruginosa,antimicrobial stewardship,avibactam,bacterial,ceftazidime,ceftolozane,clinical,communicable,diagnosis,epidemiology,fund{\_}not{\_}ack,fungal,guideline,laboratory,lactam/$\beta$,lactamase inhibitor combinations,negatives,parasitic,tazobactam,treatment,viral,$\beta$},
mendeley-tags = {OA,fund{\_}not{\_}ack,guideline},
month = {oct},
number = {1},
pages = {a453},
title = {{Best practices: Appropriate use of the new $\beta$-lactam/$\beta$-lactamase inhibitor combinations, ceftazidime-avibactam and ceftolozane-tazobactam in South Africa}},
url = {https://sajid.co.za/index.php/sajid/article/view/453/1065 https://sajid.co.za/index.php/sajid/article/view/453/1066 https://sajid.co.za/index.php/sajid/article/view/453/1067 https://sajid.co.za/index.php/sajid/article/view/453},
volume = {37},
year = {2022}
}

Antibiotic stewardship of hospital-acquired infections because of difficult-to-treat resistant (DTR) Gram-negative bacteria is a global challenge. Their increasing prevalence in South Africa has required a shift in prescribing in recent years towards colistin, an antibiotic of last resort. High toxicity levels and developing resistance to colistin are narrowing treatment options further. Recently, two new $β$-lactam/$β$-lactamase inhibitor combinations, ceftazidime-avibactam and ceftolozane-tazobactam were registered in South Africa, bringing hope of new options for management of these life-threatening infections. However, with increased use in the private sector, increasing levels of resistance to ceftazidime-avibactam are already being witnessed, putting their long-term viability as treatment options of last resort, in jeopardy. This review focuses on how these two vital new antibiotics should be stewarded within a framework that recognises the resistance mechanisms currently predominant in South Africa's multi-drug and DTR Gram-negative bacteria. Moreover, the withholding of their use for resistant infections that can be treated with currently available antibiotics is a critical part of stewardship, if these antibiotics are to be conserved in the long term.

@article{Tegally2022b,
abstract = {Three lineages (BA.1, BA.2 and BA.3) of the SARS-CoV-2 Omicron variant of concern predominantly drove South Africa's fourth COVID-19 wave. We have now identified two new lineages, BA.4 and BA.5, responsible for a fifth wave of infections. The spike proteins of BA.4 and BA.5 are identical, and comparable to BA.2 except for the addition of 69-70del (present in the Alpha variant and the BA.1 lineage), L452R (present in the Delta variant), F486V and the wild type amino acid at Q493.The two lineages only differ outside of the spike region. The 69-70 deletion in spike allows these lineages to be identified by the proxy marker of S-gene target failure, on the background of variants not possessing this feature . BA.4 and BA.5 have rapidly replaced BA.2, reaching more than 50{\%} of sequenced cases in South Africa by the first week of April 2022. Using a multinomial logistic regression model, we estimate growth advantages for BA.4 and BA.5 of 0.08 (95{\%} CI: 0.08 - 0.09) and 0.10 (95{\%} CI: 0.09 - 0.11) per day respectively over BA.2 in South Africa. The continued discovery of genetically diverse Omicron lineages points to the hypothesis that a discrete reservoir, such as human chronic infections and/or animal hosts, is potentially contributing to further evolution and dispersal of the virus.},
author = {Tegally, Houriiyah and Moir, Monika and Everatt, Josie and Giovanetti, Marta and Scheepers, Cathrine and Wilkinson, Eduan and Subramoney, Kathleen and Makatini, Zinhle and Moyo, Sikhulile and Amoako, Daniel G and Baxter, Cheryl and Althaus, Christian L and Anyaneji, Ugochukwu J and Kekana, Dikeledi and Viana, Raquel and Giandhari, Jennifer and Lessells, Richard J and Maponga, Tongai and Maruapula, Dorcas and Choga, Wonderful and Matshaba, Mogomotsi and Mbulawa, Mpaphi B and Msomi, Nokukhanya and NGS-SA consortium and Naidoo, Yeshnee and Pillay, Sureshnee and Sanko, Tomasz Janusz and San, James E and Scott, Lesley and Singh, Lavanya and Magini, Nonkululeko A and Smith-Lawrence, Pamela and Stevens, Wendy and Dor, Graeme and Tshiabuila, Derek and Wolter, Nicole and Preiser, Wolfgang and Treurnicht, Florette K and Venter, Marietjie and Chiloane, Georginah and McIntyre, Caitlyn and O'Toole, Aine and Ruis, Christopher and Peacock, Thomas P and Roemer, Cornelius and Pond, Sergei L Kosakovsky and Williamson, Carolyn and Pybus, Oliver G and Bhiman, Jinal N and Glass, Allison and Martin, Darren P and Jackson, Ben and Rambaut, Andrew and Laguda-Akingba, Oluwakemi and Gaseitsiwe, Simani and von Gottberg, Anne and de Oliveira, Tulio},
doi = {10.1038/s41591-022-01911-2},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Tegally et al. - 2022 - Emergence of SARS-CoV-2 Omicron lineages BA.4 and BA.5 in South Africa.pdf:pdf},
issn = {1546-170X},
journal = {Nature Medicine},
keywords = {Epidemiology,OA,Phylogeny,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jun},
number = {9},
pages = {1785--1790},
pmid = {35760080},
publisher = {Nature Publishing Group},
title = {{Emergence of SARS-CoV-2 Omicron lineages BA.4 and BA.5 in South Africa}},
url = {https://www.nature.com/articles/s41591-022-01911-2},
volume = {28},
year = {2022}
}

Three lineages (BA.1, BA.2 and BA.3) of the SARS-CoV-2 Omicron variant of concern predominantly drove South Africa's fourth COVID-19 wave. We have now identified two new lineages, BA.4 and BA.5, responsible for a fifth wave of infections. The spike proteins of BA.4 and BA.5 are identical, and comparable to BA.2 except for the addition of 69-70del (present in the Alpha variant and the BA.1 lineage), L452R (present in the Delta variant), F486V and the wild type amino acid at Q493.The two lineages only differ outside of the spike region. The 69-70 deletion in spike allows these lineages to be identified by the proxy marker of S-gene target failure, on the background of variants not possessing this feature . BA.4 and BA.5 have rapidly replaced BA.2, reaching more than 50% of sequenced cases in South Africa by the first week of April 2022. Using a multinomial logistic regression model, we estimate growth advantages for BA.4 and BA.5 of 0.08 (95% CI: 0.08 - 0.09) and 0.10 (95% CI: 0.09 - 0.11) per day respectively over BA.2 in South Africa. The continued discovery of genetically diverse Omicron lineages points to the hypothesis that a discrete reservoir, such as human chronic infections and/or animal hosts, is potentially contributing to further evolution and dispersal of the virus.

@article{Delgado-Diaz2022,
abstract = {Women with a cervicovaginal microbiota dominated by Lactobacillus spp. are at reduced risk of acquiring sexually transmitted infections including HIV, but the biological mechanisms involved remain poorly defined. Here, we performed metaproteomics on vaginal swab samples from young South African women (n = 113) and transcriptomics analysis of cervicovaginal epithelial cell cultures to examine the ability of lactic acid, a metabolite produced by cervicovaginal lactobacilli, to modulate genital epithelial barrier function. Compared to women with Lactobacillus-depleted microbiota, women dominated by vaginal lactobacilli exhibit higher abundance of bacterial lactate dehydrogenase, a key enzyme responsible for lactic acid production, which is independently associated with an increased abundance of epithelial barrier proteins. Physiological concentrations of lactic acid enhance epithelial cell culture barrier integrity and increase intercellular junctional molecule expression. These findings reveal a novel ability of vaginal lactic acid to enhance genital epithelial barrier integrity that may help prevent invasion by sexually transmitted pathogens.},
author = {Delgado-Diaz, David Jose and Jesaveluk, Brianna and Hayward, Joshua A and Tyssen, David and Alisoltani, Arghavan and Potgieter, Matthys and Bell, Liam and Ross, Elizabeth and Iranzadeh, Arash and Allali, Imane and Dabee, Smritee and Barnabas, Shaun and Gamieldien, Hoyam and Blackburn, Jonathan M and Mulder, Nicola and Smith, Steven B and Edwards, Vonetta L and Burgener, Adam D and Bekker, Linda-Gail and Ravel, Jacques and Passmore, Jo-Ann S and Masson, Lindi and Hearps, Anna C and Tachedjian, Gilda},
doi = {10.1186/S40168-022-01337-5},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Delgado-Diaz et al. - 2022 - Lactic acid from vaginal microbiota enhances cervicovaginal epithelial barrier integrity by promoting tight.pdf:pdf},
issn = {20492618},
journal = {Microbiome},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {aug},
number = {1},
pages = {141},
pmid = {36045402},
publisher = {Springer Science and Business Media LLC},
title = {{Lactic acid from vaginal microbiota enhances cervicovaginal epithelial barrier integrity by promoting tight junction protein expression}},
volume = {10},
year = {2022}
}

Women with a cervicovaginal microbiota dominated by Lactobacillus spp. are at reduced risk of acquiring sexually transmitted infections including HIV, but the biological mechanisms involved remain poorly defined. Here, we performed metaproteomics on vaginal swab samples from young South African women (n = 113) and transcriptomics analysis of cervicovaginal epithelial cell cultures to examine the ability of lactic acid, a metabolite produced by cervicovaginal lactobacilli, to modulate genital epithelial barrier function. Compared to women with Lactobacillus-depleted microbiota, women dominated by vaginal lactobacilli exhibit higher abundance of bacterial lactate dehydrogenase, a key enzyme responsible for lactic acid production, which is independently associated with an increased abundance of epithelial barrier proteins. Physiological concentrations of lactic acid enhance epithelial cell culture barrier integrity and increase intercellular junctional molecule expression. These findings reveal a novel ability of vaginal lactic acid to enhance genital epithelial barrier integrity that may help prevent invasion by sexually transmitted pathogens.

@article{Krutikov2021,
abstract = {Summary Background Novel skin-based tests for tuberculosis infection might present suitable alternatives to current tests; however, diagnostic performance of new tests compared with the purified protein derivative-tuberculin skin test (TST) or interferon-$\gamma$ release assays (IGRA) needs systematic assessment. Methods In this systematic review and meta-analysis, we searched English (Medline OVID), Chinese (Chinese Biomedical Literature Database and the China National Knowledge Infrastructure), and Russian (e-library) databases from the inception of each database to May 15, 2019, (with updated search of the Russian and English databases on Oct, 20 2020) using terms "ESAT6" OR "CFP10" AND "skin test" AND "Tuberculosis" OR "C-Tb" OR "Diaskintest". We included studies reporting on the performance of index tests alone or compared with a comparator. Inclusion criteria varied according to review objectives and performance outcome, but reporting of test cut-offs for positivity applied to study population was required from all studies. We used a hierarchy of reference standards for tuberculosis infection consistent with the 2020 WHO framework to evaluate diagnostic performance. Two authors independently reviewed the titles and abstracts for English and Chinese (LF and MK) and Russian studies (MK and VN). Study quality was assessed with QUADAS-2. Pooled random-effects estimates are presented when appropriate for total agreement proportion, sensitivity in microbiologically confirmed tuberculosis and specificity in cohorts with low risk of tuberculosis infection. This study is registered with PROSPERO, CRD42019135572. Findings We identified 1466 original articles, of which 37 (2{\textperiodcentered}5{\%}) studies, including 10 915 individuals (7111 Diaskintest, 2744 C-Tb, 887 EC, 173 DPPD), were included in the qualitative analysis (29 [78{\%}] studies of Diaskintest, five [15{\%}] studies of C-Tb, two [5{\%}] studies of EC-skintest, and one [3{\%}] study of DPPD). 22 (1{\textperiodcentered}5{\%}) studies including 5810 individuals (3143 Diaskintest, 2129 C-Tb, 538 EC-skintest) were included in the quantitative analysis: 15 (68{\%}) of Diaskintest, five (23{\%}) of C-Tb, and two (9{\%}) of EC-skintest. Tested sub-populations included individuals with HIV, children (0–18 years), and individuals exposed to tuberculosis. Studies were heterogeneous with moderate to high risk of bias. Nine head-to-head studies of index test versus TST and IGRA permitted direct comparisons and pooling. In a mixed cohort of people with and without tuberculosis, Diaskintest pooled agreement with IGRA was 87{\textperiodcentered}16{\%} (95{\%} CI 79{\textperiodcentered}47–92{\textperiodcentered}24) and 55{\textperiodcentered}45{\%} (46{\textperiodcentered}08–64{\textperiodcentered}45) with TST-5 mm cut-off (TST5 mm). Diaskintest sensitivity was 91{\textperiodcentered}18{\%} (95{\%} CI 81{\textperiodcentered}72–95{\textperiodcentered}98) compared with 88{\textperiodcentered}24{\%} (78{\textperiodcentered}20–94{\textperiodcentered}01) for TST5 mm, 89{\textperiodcentered}66 (78{\textperiodcentered}83–95{\textperiodcentered}28) for IGRA QuantiFERON, and 90{\textperiodcentered}91{\%} (79{\textperiodcentered}95–96{\textperiodcentered}16) for TSPOT.TB. C-Tb agreement with IGRA in individuals with active tuberculosis was 79{\textperiodcentered}80{\%} (95{\%} CI 76{\textperiodcentered}10–83{\textperiodcentered}07) compared with 78{\textperiodcentered}92{\%} (74{\textperiodcentered}65–82{\textperiodcentered}63) for TST5 mm/15 mm cut-off (TST5 mm/15 mm). TST5/15mm reflects threshold in cohorts that applied stratified cutoffs: 5 mm for HIV-infected, immunocompromised, or BCG-naive individuals, and 15mm for BCG-vaccinated immunocompetent individuals. C-Tb sensitivity was 74{\textperiodcentered}52{\%} (95{\%} CI 70{\textperiodcentered}39–78{\textperiodcentered}25) compared with a sensitivity of 78{\textperiodcentered}18{\%} (67{\textperiodcentered}75–85{\textperiodcentered}94) for TST5 mm/15 mm, and 71{\textperiodcentered}67{\%} (63{\textperiodcentered}44–78{\textperiodcentered}68) for IGRA. Specificity was 97{\textperiodcentered}85{\%} (95{\%} CI 93{\textperiodcentered}96–99{\textperiodcentered}25) for C-Tb versus 93{\textperiodcentered}31{\%} (90{\textperiodcentered}22–95{\textperiodcentered}48) for TST 15 mm cut-off and 99{\textperiodcentered}15{\%} (79{\textperiodcentered}66–99{\textperiodcentered}97) for IGRA. EC-skintest sensitivity was 86{\textperiodcentered}06{\%} (95{\%} CI 82{\textperiodcentered}39–89{\textperiodcentered}07). Interpretation Novel skin-based tests for tuberculosis infection appear to perform similarly to IGRA or TST; however, study quality varied. Evaluation of test performance, patient-important outcomes, and diagnostic use in current clinical algorithms will inform implementation in key populations. Funding StopTB (New Diagnostics Working Group) and FIND. Translations For the Chinese and Russian translations of the abstract see Supplementary Materials section.},
author = {Krutikov, Maria and Faust, Lena and Nikolayevskyy, Vladyslav and Hamada, Yohhei and Gupta, Rishi K and Cirillo, Daniela and Mateelli, Alberto and Korobitsyn, Alexei and Denkinger, Claudia M and Rangaka, Molebogeng X},
doi = {10.1016/S1473-3099(21)00261-9},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Krutikov et al. - 2022 - The diagnostic performance of novel skin-based in-vivo tests for tuberculosis infection compared with purified.pdf:pdf},
issn = {1473-3099},
journal = {The Lancet Infectious Diseases},
keywords = {fund{\_}not{\_}ack,review},
mendeley-tags = {fund{\_}not{\_}ack,review},
month = {oct},
number = {2},
pages = {250--264},
publisher = {Elsevier},
title = {{The diagnostic performance of novel skin-based in-vivo tests for tuberculosis infection compared with purified protein derivative tuberculin skin tests and blood-based in vitro interferon-$\gamma$ release assays: a systematic review and meta-analysis}},
url = {http://www.thelancet.com/article/S1473309921002619/fulltext http://www.thelancet.com/article/S1473309921002619/abstract https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00261-9/abstract},
volume = {22},
year = {2022}
}

Summary Background Novel skin-based tests for tuberculosis infection might present suitable alternatives to current tests; however, diagnostic performance of new tests compared with the purified protein derivative-tuberculin skin test (TST) or interferon-$γ$ release assays (IGRA) needs systematic assessment. Methods In this systematic review and meta-analysis, we searched English (Medline OVID), Chinese (Chinese Biomedical Literature Database and the China National Knowledge Infrastructure), and Russian (e-library) databases from the inception of each database to May 15, 2019, (with updated search of the Russian and English databases on Oct, 20 2020) using terms "ESAT6" OR "CFP10" AND "skin test" AND "Tuberculosis" OR "C-Tb" OR "Diaskintest". We included studies reporting on the performance of index tests alone or compared with a comparator. Inclusion criteria varied according to review objectives and performance outcome, but reporting of test cut-offs for positivity applied to study population was required from all studies. We used a hierarchy of reference standards for tuberculosis infection consistent with the 2020 WHO framework to evaluate diagnostic performance. Two authors independently reviewed the titles and abstracts for English and Chinese (LF and MK) and Russian studies (MK and VN). Study quality was assessed with QUADAS-2. Pooled random-effects estimates are presented when appropriate for total agreement proportion, sensitivity in microbiologically confirmed tuberculosis and specificity in cohorts with low risk of tuberculosis infection. This study is registered with PROSPERO, CRD42019135572. Findings We identified 1466 original articles, of which 37 (2˙5%) studies, including 10 915 individuals (7111 Diaskintest, 2744 C-Tb, 887 EC, 173 DPPD), were included in the qualitative analysis (29 [78%] studies of Diaskintest, five [15%] studies of C-Tb, two [5%] studies of EC-skintest, and one [3%] study of DPPD). 22 (1˙5%) studies including 5810 individuals (3143 Diaskintest, 2129 C-Tb, 538 EC-skintest) were included in the quantitative analysis: 15 (68%) of Diaskintest, five (23%) of C-Tb, and two (9%) of EC-skintest. Tested sub-populations included individuals with HIV, children (0–18 years), and individuals exposed to tuberculosis. Studies were heterogeneous with moderate to high risk of bias. Nine head-to-head studies of index test versus TST and IGRA permitted direct comparisons and pooling. In a mixed cohort of people with and without tuberculosis, Diaskintest pooled agreement with IGRA was 87˙16% (95% CI 79˙47–92˙24) and 55˙45% (46˙08–64˙45) with TST-5 mm cut-off (TST5 mm). Diaskintest sensitivity was 91˙18% (95% CI 81˙72–95˙98) compared with 88˙24% (78˙20–94˙01) for TST5 mm, 89˙66 (78˙83–95˙28) for IGRA QuantiFERON, and 90˙91% (79˙95–96˙16) for TSPOT.TB. C-Tb agreement with IGRA in individuals with active tuberculosis was 79˙80% (95% CI 76˙10–83˙07) compared with 78˙92% (74˙65–82˙63) for TST5 mm/15 mm cut-off (TST5 mm/15 mm). TST5/15mm reflects threshold in cohorts that applied stratified cutoffs: 5 mm for HIV-infected, immunocompromised, or BCG-naive individuals, and 15mm for BCG-vaccinated immunocompetent individuals. C-Tb sensitivity was 74˙52% (95% CI 70˙39–78˙25) compared with a sensitivity of 78˙18% (67˙75–85˙94) for TST5 mm/15 mm, and 71˙67% (63˙44–78˙68) for IGRA. Specificity was 97˙85% (95% CI 93˙96–99˙25) for C-Tb versus 93˙31% (90˙22–95˙48) for TST 15 mm cut-off and 99˙15% (79˙66–99˙97) for IGRA. EC-skintest sensitivity was 86˙06% (95% CI 82˙39–89˙07). Interpretation Novel skin-based tests for tuberculosis infection appear to perform similarly to IGRA or TST; however, study quality varied. Evaluation of test performance, patient-important outcomes, and diagnostic use in current clinical algorithms will inform implementation in key populations. Funding StopTB (New Diagnostics Working Group) and FIND. Translations For the Chinese and Russian translations of the abstract see Supplementary Materials section.

@article{Loots2022,
abstract = {INTRODUCTION: PKC$\delta$ is ubiquitously expressed in mammalian cells and its dysregulation plays a key role in the onset of several incurable diseases and metabolic disorders. However, much remains unknown about the metabolic pathways and disturbances induced by PKC deficiency, as well as the metabolic mechanisms involved. OBJECTIVES: This study aims to use metabolomics to further characterize the function of PKC from a metabolomics standpoint, by comparing the full serum metabolic profiles of PKC deficient mice to those of wild-type mice. METHODS: The serum metabolomes of PKC$\delta$ knock-out mice were compared to that of a wild-type strain using a GCxGC-TOFMS metabolomics research approach and various univariate and multivariate statistical analyses. RESULTS: Thirty-seven serum metabolite markers best describing the difference between PKC$\delta$ knock-out and wild-type mice were identified based on a PCA power value {\textgreater} 0.9, a t-test p-value {\textless} 0.05, or an effect size {\textgreater} 1. XERp prediction was also done to accurately select the metabolite markers within the 2 sample groups. Of the metabolite markers identified, 78.4{\%} (29/37) were elevated and 48.65{\%} of these markers were fatty acids (18/37). It is clear that a total loss of PKC$\delta$ functionality results in an inhibition of glycolysis, the TCA cycle, and steroid synthesis, accompanied by upregulation of the pentose phosphate pathway, fatty acids oxidation, cholesterol transport/storage, single carbon and sulphur-containing amino acid synthesis, branched-chain amino acids (BCAA), ketogenesis, and an increased cell signalling via N-acetylglucosamine. CONCLUSION: The charaterization of the dysregulated serum metabolites in this study, may represent an additional tool for the early detection and screening of PKC$\delta$-deficiencies or abnormalities.},
author = {Loots, Du Toit and Adeniji, Adetomiwa Ayodele and {Van Reenen}, Mari and Ozturk, Mumin and Brombacher, Frank and Parihar, Suraj P},
doi = {10.1007/S11306-022-01949-W/FIGURES/4},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Loots et al. - 2022 - The metabolomics of a protein kinase C delta (PKC$\delta$) knock-out mouse model.pdf:pdf},
issn = {15733890},
journal = {Metabolomics},
keywords = {Auto-immune diseases,Diagnostic biomarker,Metabolic disorder,Metabolomics,Non-communicable disease,OA,OA{\_}PMC,Protein kinase C,Serum samples,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {nov},
number = {11},
pages = {92},
pmid = {36371785},
publisher = {NLM (Medline)},
title = {{The metabolomics of a protein kinase C delta (PKC$\delta$) knock-out mouse model}},
url = {https://link.springer.com/article/10.1007/s11306-022-01949-w},
volume = {18},
year = {2022}
}

INTRODUCTION: PKC$δ$ is ubiquitously expressed in mammalian cells and its dysregulation plays a key role in the onset of several incurable diseases and metabolic disorders. However, much remains unknown about the metabolic pathways and disturbances induced by PKC deficiency, as well as the metabolic mechanisms involved. OBJECTIVES: This study aims to use metabolomics to further characterize the function of PKC from a metabolomics standpoint, by comparing the full serum metabolic profiles of PKC deficient mice to those of wild-type mice. METHODS: The serum metabolomes of PKC$δ$ knock-out mice were compared to that of a wild-type strain using a GCxGC-TOFMS metabolomics research approach and various univariate and multivariate statistical analyses. RESULTS: Thirty-seven serum metabolite markers best describing the difference between PKC$δ$ knock-out and wild-type mice were identified based on a PCA power value \textgreater 0.9, a t-test p-value \textless 0.05, or an effect size \textgreater 1. XERp prediction was also done to accurately select the metabolite markers within the 2 sample groups. Of the metabolite markers identified, 78.4% (29/37) were elevated and 48.65% of these markers were fatty acids (18/37). It is clear that a total loss of PKC$δ$ functionality results in an inhibition of glycolysis, the TCA cycle, and steroid synthesis, accompanied by upregulation of the pentose phosphate pathway, fatty acids oxidation, cholesterol transport/storage, single carbon and sulphur-containing amino acid synthesis, branched-chain amino acids (BCAA), ketogenesis, and an increased cell signalling via N-acetylglucosamine. CONCLUSION: The charaterization of the dysregulated serum metabolites in this study, may represent an additional tool for the early detection and screening of PKC$δ$-deficiencies or abnormalities.

@article{Tamuhla2022,
abstract = {Research involving human participants requires their consent, and it is common practice to capture consent information on paper and store those hard copies, presenting issues such as long-term storage requirements, inefficient retrieval of consent forms for reference or future use, and the potential for transcription errors when transcribing captured informed consent. There have been calls to move to electronic capture of the consent provided by research participants (e-consent) as a way of addressing these issues. A tiered framework for e-consent was designed using the freely available features in the inbuilt REDCap e-consent module. We implemented ‘branching logic', ‘wet signature' and ‘auto-archiver' features to the main informed consent and withdrawal of consent documents. The branching logic feature streamlines the consent process by making follow-up information available depending on participant response, the ‘wet signature' feature enables a timestamped electronic signature to be appended to the e-consent documents and the ‘auto-archiver' allows for PDF copies of the e-consent documents to be stored in the database. When designing the content layout, we provided example participant information text which can be modified as required. Emphasis was placed on the flow of information to optimise participant understanding and this was achieved by merging the consent and participant information into one document where the consent questions were asked immediately after the corresponding participant information. In addition, we have provided example text for a generic human genomic research study, which can be easily edited and modified according to specific requirements. Building informed consent protocols and forms without prior experience can be daunting, so we have provided researchers with a REDCap template that can be directly incorporated into REDCap databases. It prompts researchers about the types of consent they can request for genomics studies and assists them with suggestions for the language they might use for participant information and consent questions. The use of this tiered e-consent module can ensure the accurate and efficient electronic capture and storage of the consents given by participants in a format that can be easily queried and can thus facilitate ethical and effective onward sharing of data and samples whilst upholding individual participant preferences.},
author = {Tamuhla, Tsaone and Tiffin, Nicki and Allie, Taryn},
doi = {10.1186/S12910-022-00860-2/FIGURES/7},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Tamuhla, Tiffin, Allie - 2022 - An e-consent framework for tiered informed consent for human genomic research in the global south, imple.pdf:pdf},
issn = {14726939},
journal = {BMC Medical Ethics},
keywords = {OA,REDCap,Tiered informed consent,fund{\_}ack,original,participant information},
mendeley-tags = {OA,fund{\_}ack,original},
month = {dec},
pages = {119},
publisher = {BioMed Central Ltd},
title = {{An e-consent framework for tiered informed consent for human genomic research in the global south, implemented as a REDCap template}},
url = {https://bmcmedethics.biomedcentral.com/articles/10.1186/s12910-022-00860-2},
volume = {23},
year = {2022}
}

Research involving human participants requires their consent, and it is common practice to capture consent information on paper and store those hard copies, presenting issues such as long-term storage requirements, inefficient retrieval of consent forms for reference or future use, and the potential for transcription errors when transcribing captured informed consent. There have been calls to move to electronic capture of the consent provided by research participants (e-consent) as a way of addressing these issues. A tiered framework for e-consent was designed using the freely available features in the inbuilt REDCap e-consent module. We implemented ‘branching logic', ‘wet signature' and ‘auto-archiver' features to the main informed consent and withdrawal of consent documents. The branching logic feature streamlines the consent process by making follow-up information available depending on participant response, the ‘wet signature' feature enables a timestamped electronic signature to be appended to the e-consent documents and the ‘auto-archiver' allows for PDF copies of the e-consent documents to be stored in the database. When designing the content layout, we provided example participant information text which can be modified as required. Emphasis was placed on the flow of information to optimise participant understanding and this was achieved by merging the consent and participant information into one document where the consent questions were asked immediately after the corresponding participant information. In addition, we have provided example text for a generic human genomic research study, which can be easily edited and modified according to specific requirements. Building informed consent protocols and forms without prior experience can be daunting, so we have provided researchers with a REDCap template that can be directly incorporated into REDCap databases. It prompts researchers about the types of consent they can request for genomics studies and assists them with suggestions for the language they might use for participant information and consent questions. The use of this tiered e-consent module can ensure the accurate and efficient electronic capture and storage of the consents given by participants in a format that can be easily queried and can thus facilitate ethical and effective onward sharing of data and samples whilst upholding individual participant preferences.

@article{Nono2021,
abstract = {Schistosomiasis is a debilitating helminthiasis which commonly establishes as a chronic infection in people from endemic areas. As a potent modulator of the host immune response, the Schistosoma parasite and its associated products can directly interfere with its host's ability to mount adequate immune responses to unrelated antigens. As a result, increased attention is gathering on studies assessing the influence of helminths, particularly the causal agent of schistosomiasis, on host responsiveness to vaccines. However, to date, no consensus has been drawn regarding the influence of schistosomiasis on host vaccine responses. Here, we review available evidence on the influence of transgenerational and direct Schistosoma parasite exposure on host immune responses to unrelated vaccines. In addition, we evaluate the potential of praziquantel (PZQ) treatment in restoring schistosomiasis-impacted vaccine responses.},
author = {Nono, Justin Komguep and Kamdem, Severin Donald and Musaigwa, Fungai and Nnaji, Chukwudi A and Brombacher, Frank},
doi = {10.1016/J.PT.2021.07.009},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Nono et al. - 2022 - Influence of schistosomiasis on host vaccine responses.pdf:pdf},
issn = {1471-4922},
journal = {Trends in Parasitology},
keywords = {fund{\_}ack,human,immunomodulation,praziquantel (PZQ),review,schistosomiasis,vaccine response},
mendeley-tags = {fund{\_}ack,review},
month = {aug},
number = {1},
pages = {67--79},
pmid = {34389214},
publisher = {Elsevier},
title = {{Influence of schistosomiasis on host vaccine responses}},
url = {http://www.cell.com/article/S1471492221001744/fulltext http://www.cell.com/article/S1471492221001744/abstract https://www.cell.com/trends/parasitology/abstract/S1471-4922(21)00174-4},
volume = {38},
year = {2022}
}

Schistosomiasis is a debilitating helminthiasis which commonly establishes as a chronic infection in people from endemic areas. As a potent modulator of the host immune response, the Schistosoma parasite and its associated products can directly interfere with its host's ability to mount adequate immune responses to unrelated antigens. As a result, increased attention is gathering on studies assessing the influence of helminths, particularly the causal agent of schistosomiasis, on host responsiveness to vaccines. However, to date, no consensus has been drawn regarding the influence of schistosomiasis on host vaccine responses. Here, we review available evidence on the influence of transgenerational and direct Schistosoma parasite exposure on host immune responses to unrelated vaccines. In addition, we evaluate the potential of praziquantel (PZQ) treatment in restoring schistosomiasis-impacted vaccine responses.

@article{Papavarnavas2022,
abstract = {Blood cultures are an important diagnostic and antibiotic stewardship tool to aid in treatment, monitoring and prognosis of patients with infection. This guideline is intended to update our 2010 guideline on the optimal use of blood cultures. Since then, there have been significant changes to the definitions of sepsis, guidance on the number of blood cultures recommended per draw, central and peripheral line blood cultures, advances in mitigating culture contamination, updates on the indications for blood cultures, and guidance on performance of follow-up cultures.},
author = {Papavarnavas, N S and Brink, A J and Dlamini, S and Wasserman, Sean and Whitelaw, A and Ntusi, Ntobeko A B and Mendelson, Marc},
doi = {10.7196/SAMJ.2022.v112i6.16537},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Papavarnavas et al. - 2022 - Practice update to optimise the performance and interpretation of blood cultures 2022.pdf:pdf},
journal = {South African Medical Journal},
keywords = {Blood cultures,Central line-associated bloodstream infections,Contamination,Disinfection,Follow-up blood cultures,Infective endocarditis,OA,Sepsis,fund{\_}not{\_}ack,guideline},
mendeley-tags = {OA,fund{\_}not{\_}ack,guideline},
month = {may},
number = {6},
pages = {397--402},
title = {{Practice update to optimise the performance and interpretation of blood cultures: 2022}},
url = {http://www.samj.org.za/index.php/samj/article/view/13587},
volume = {112},
year = {2022}
}

Blood cultures are an important diagnostic and antibiotic stewardship tool to aid in treatment, monitoring and prognosis of patients with infection. This guideline is intended to update our 2010 guideline on the optimal use of blood cultures. Since then, there have been significant changes to the definitions of sepsis, guidance on the number of blood cultures recommended per draw, central and peripheral line blood cultures, advances in mitigating culture contamination, updates on the indications for blood cultures, and guidance on performance of follow-up cultures.

@article{Mazandu2022,
abstract = {The Sickle Cell Disease (SCD) Ontology (SCDO, https://scdontology.h3abionet.org/) provides a comprehensive knowledge base of SCD management, systems and standardized human and machine-readable resources that unambiguously describe terminology and concepts about SCD for researchers, patients and clinicians. The SCDO was launched in 2016 and is continuously updated in quantity, as well as in quality, to effectively support the curation of SCD research, patient databasing and clinical informatics applications. SCD knowledge from the scientific literature is used to update existing SCDO terms and create new terms where necessary. Here, we report major updates to the SCDO, from December 2019 until April 2021, for promoting interoperability and facilitating SCD data harmonization, sharing and integration across different studies and for retrospective multi-site research collaborations. SCDO developers continue to collaborate with the SCD community, clinicians and researchers to improve specific ontology areas and expand standardized descriptions to conditions influencing SCD phenotypic expressions and clinical manifestations of the sickling process, e.g. thalassemias.},
author = {Mazandu, Gaston K and Hotchkiss, Jade and Nembaware, Victoria and Wonkam, Ambroise and Mulder, Nicola and {Sickle Cell Disease Ontology Working Group}},
doi = {10.1093/DATABASE/BAAC014},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Mazandu et al. - 2022 - The Sickle Cell Disease Ontology recent development and expansion of the universal sickle cell knowledge represe.pdf:pdf},
isbn = {014/6562127},
issn = {1758-0463},
journal = {Database},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {apr},
pages = {baac014},
pmid = {35363306},
publisher = {Oxford Academic},
title = {{The Sickle Cell Disease Ontology: recent development and expansion of the universal sickle cell knowledge representation}},
url = {https://academic.oup.com/database/article/doi/10.1093/database/baac014/6562127},
volume = {2022},
year = {2022}
}

The Sickle Cell Disease (SCD) Ontology (SCDO, https://scdontology.h3abionet.org/) provides a comprehensive knowledge base of SCD management, systems and standardized human and machine-readable resources that unambiguously describe terminology and concepts about SCD for researchers, patients and clinicians. The SCDO was launched in 2016 and is continuously updated in quantity, as well as in quality, to effectively support the curation of SCD research, patient databasing and clinical informatics applications. SCD knowledge from the scientific literature is used to update existing SCDO terms and create new terms where necessary. Here, we report major updates to the SCDO, from December 2019 until April 2021, for promoting interoperability and facilitating SCD data harmonization, sharing and integration across different studies and for retrospective multi-site research collaborations. SCDO developers continue to collaborate with the SCD community, clinicians and researchers to improve specific ontology areas and expand standardized descriptions to conditions influencing SCD phenotypic expressions and clinical manifestations of the sickling process, e.g. thalassemias.

@article{Stadler2022,
author = {Stadler, J A M},
doi = {10.7196/AJTCCM.2022.v28i2.224},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Stadler - 2022 - Updated WHO definitions for tuberculosis outcomes simplified, unified and future-proofed.pdf:pdf},
journal = {African Journal of Thoracic and Critical Care Medicine},
keywords = {OA,OA{\_}PMC,editorial,fund{\_}not{\_}ack},
mendeley-tags = {OA,OA{\_}PMC,editorial,fund{\_}not{\_}ack},
month = {jul},
number = {2},
pages = {48},
pmid = {35919922},
title = {{Updated WHO definitions for tuberculosis outcomes: simplified, unified and future-proofed}},
url = {http://ajtccm.org.za/index.php/SARJ/article/view/412/0},
volume = {28},
year = {2022}
}

@article{Margolin2022,
abstract = {Given the complex maturation requirements of viral glycoproteins and the challenge they often pose for expression in plants, the identification of host constraints precluding their efficient production is a priority for the molecular farming of vaccines. Building on previous work to improve viral glycoprotein production in plants, we investigated the production of a soluble SARS-CoV-2 spike comprising the ectopic portion of the glycoprotein. This was successfully transiently expressed in N. benthamiana by co-expressing the human lectin-binding chaperone calreticulin, which substantially increased the accumulation of the glycoprotein. The spike was mostly unprocessed unless the protease furin was co-expressed, despite the inclusion of an enhanced furin cleavage site (RRRRRR). Co-expression of several broad-spectrum protease inhibitors did not improve accumulation of the protein any further. The protein was successfully purified by affinity chromatography and gel filtration, although the purified product was heterogenous and the yields were low. Immunogenicity of the antigen was tested in BALB/c mice, and cellular and antibody responses were elicited after low dose inoculation with the adjuvanted protein. This work constitutes an important proof-of-concept for host plant engineering in the context of rapid vaccine development for SARS-CoV-2 and other emerging viruses.},
author = {Margolin, Emmanuel and Verbeek, Matthew and de Moor, Warren and Chapman, Ros and Meyers, Ann and Sch{\"{a}}fer, Georgia and Williamson, Anna-Lise and Rybicki, Edward},
doi = {10.3389/FPLS.2021.798822},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Margolin et al. - 2022 - Investigating constraints along the plant secretory pathway to improve production of a SARS-CoV-2 spike vaccine.pdf:pdf},
issn = {1664-462X},
journal = {Frontiers in Plant Science},
keywords = {Chaperone,Immunogenicity,Molecular Farming,OA,Protease,Vaccine,degradation,fund{\_}ack,glycoprotein,original,processing,virus},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jan},
pages = {798822},
pmid = {35058959},
publisher = {Frontiers},
title = {{Investigating constraints along the plant secretory pathway to improve production of a SARS-CoV-2 spike vaccine candidate}},
url = {https://www.frontiersin.org/articles/10.3389/fpls.2021.798822/full},
volume = {12},
year = {2022}
}

Given the complex maturation requirements of viral glycoproteins and the challenge they often pose for expression in plants, the identification of host constraints precluding their efficient production is a priority for the molecular farming of vaccines. Building on previous work to improve viral glycoprotein production in plants, we investigated the production of a soluble SARS-CoV-2 spike comprising the ectopic portion of the glycoprotein. This was successfully transiently expressed in N. benthamiana by co-expressing the human lectin-binding chaperone calreticulin, which substantially increased the accumulation of the glycoprotein. The spike was mostly unprocessed unless the protease furin was co-expressed, despite the inclusion of an enhanced furin cleavage site (RRRRRR). Co-expression of several broad-spectrum protease inhibitors did not improve accumulation of the protein any further. The protein was successfully purified by affinity chromatography and gel filtration, although the purified product was heterogenous and the yields were low. Immunogenicity of the antigen was tested in BALB/c mice, and cellular and antibody responses were elicited after low dose inoculation with the adjuvanted protein. This work constitutes an important proof-of-concept for host plant engineering in the context of rapid vaccine development for SARS-CoV-2 and other emerging viruses.

@article{Sheward2022,
abstract = {Despite being the focus of extensive research, we still do not know how to reproducibly elicit cross-neutralizing antibodies against variable pathogens by vaccination. Here, we characterize the ant...},
author = {Sheward, Daniel J and Hermanus, Tandile and Murrell, Ben and Garrett, Nigel and Karim, Salim S Abdool and Morris, Lynn and Moore, Penny L and Williamson, Carolyn},
doi = {10.1128/JVI.00324-22},
editor = {Silvestri, Guido},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Sheward et al. - 2022 - HIV coinfection provides insights for the design of vaccine cocktails to elicit broadly neutralizing antibodies.pdf:pdf},
issn = {0022-538X},
journal = {Journal of Virology},
keywords = {OA,broadly neutralizing antibodies,coinfection,fund{\_}ack,genomics{\_}fund{\_}ack,human immunodeficiency virus,neutralizing antibodies,original,vaccine cocktails,vaccines},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {jun},
number = {14},
pages = {e00324--22},
pmid = {35758668},
publisher = {American Society for Microbiology 1752 N St., N.W., Washington, DC},
title = {{HIV coinfection provides insights for the design of vaccine cocktails to elicit broadly neutralizing antibodies}},
url = {https://journals.asm.org/doi/10.1128/jvi.00324-22},
volume = {96},
year = {2022}
}

Despite being the focus of extensive research, we still do not know how to reproducibly elicit cross-neutralizing antibodies against variable pathogens by vaccination. Here, we characterize the ant...

@article{Alobwede2022c,
abstract = {Background: Healthcare workers are at an increased risk of acquiring vaccine-preventable diseases and are known to be reliable sources of information for the patients and their relatives. Knowledge and attitudes of healthcare workers about vaccines are thus important determinants of their own vaccination uptake and their intention to recommend vaccinations to their patients. However, culturally adapted tools and studies to address vaccine uptake and hesitancy as well as related behaviors among healthcare workers in the Global South are limited. Methods: We propose a mixed methods project to understand the extent and determinants of vaccination hesitancy among healthcare workers and construct a validated scale to measure this complex and context-specific phenomenon in Cape Town. We will summarize responses as counts and percentages for categorical variables and means with standard deviations (or medians with inter quartile ranges) for continuous variables. We will run the Shapiro-Wilks test to assess the normality. Analysis of the variance, chi-square tests, and equivalents will be conducted as appropriate for group comparisons. Logistic regression models will also be performed to assess association between variables. We will focus on the seasonal influenza and COVID-19 vaccines. We will use an existing tool developed and validated in Germany and the United States of America to measure five psychological determinants of vaccination (referred to as the 5C scale), as the basis to develop and validate a scale to measure the scope and determinants of vaccine hesitancy and acceptance among healthcare workers in Cape Town. Discussion and conclusion: Through this study, we hope to expand the scientific evidence base on vaccination acceptance and demand among healthcare workers in South Africa and build resources to enable better understanding of, detection, and response to vaccination hesitancy in Cape Town.},
author = {Alobwede, Samuel Muabe and Katoto, Patrick DMC and Cooper, Sara and Lumngwena, Evelyn N and Kidzeru, Elvis B and Goliath, Rene and Jackson, Amanda and Wiysonge, Charles S and Shey, Muki S},
doi = {10.12688/F1000RESEARCH.123332.1},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Alobwede et al. - 2022 - Cross-cultural adaptation and validation of the 5C scale to identify factors associated with COVID-19 and in(2).pdf:pdf},
issn = {1759796X},
journal = {F1000Research},
keywords = {OA,fund{\_}not{\_}ack,protocol},
mendeley-tags = {OA,fund{\_}not{\_}ack,protocol},
month = {aug},
pages = {975},
publisher = {F1000 Research Ltd},
title = {{Cross-cultural adaptation and validation of the 5C scale to identify factors associated with COVID-19 and influenza vaccine hesitancy among healthcare workers in Cape Town, South Africa – a protocol [version 1; peer review: awaiting peer review]}},
volume = {11},
year = {2022}
}

Background: Healthcare workers are at an increased risk of acquiring vaccine-preventable diseases and are known to be reliable sources of information for the patients and their relatives. Knowledge and attitudes of healthcare workers about vaccines are thus important determinants of their own vaccination uptake and their intention to recommend vaccinations to their patients. However, culturally adapted tools and studies to address vaccine uptake and hesitancy as well as related behaviors among healthcare workers in the Global South are limited. Methods: We propose a mixed methods project to understand the extent and determinants of vaccination hesitancy among healthcare workers and construct a validated scale to measure this complex and context-specific phenomenon in Cape Town. We will summarize responses as counts and percentages for categorical variables and means with standard deviations (or medians with inter quartile ranges) for continuous variables. We will run the Shapiro-Wilks test to assess the normality. Analysis of the variance, chi-square tests, and equivalents will be conducted as appropriate for group comparisons. Logistic regression models will also be performed to assess association between variables. We will focus on the seasonal influenza and COVID-19 vaccines. We will use an existing tool developed and validated in Germany and the United States of America to measure five psychological determinants of vaccination (referred to as the 5C scale), as the basis to develop and validate a scale to measure the scope and determinants of vaccine hesitancy and acceptance among healthcare workers in Cape Town. Discussion and conclusion: Through this study, we hope to expand the scientific evidence base on vaccination acceptance and demand among healthcare workers in South Africa and build resources to enable better understanding of, detection, and response to vaccination hesitancy in Cape Town.

@article{Bruyn2022,
abstract = {Our understanding of the immune response at the site of disease in extra-pulmonary tuberculosis (EPTB) is still limited. In this study, using flow cytometry, we defined the pericardial fluid (PCF) cellular composition and compared the phenotypic and functional profile of Mycobacterium tuberculosis (Mtb)-specific T cells between PCF and whole blood in 16 patients with pericardial TB (PCTB). We found that lymphocytes were the predominant cell type in PCF in PCTB, with a preferential influx of CD4 T cells. The frequencies of TNF-$\alpha$ producing myeloid cells and Mtb-specific T cells were significantly higher in PCF compared to blood. Mtb-specific CD4 T cells in PCF exhibited a distinct phenotype compared to those in blood, with greater GrB expression and lower CD27 and KLRG1 expression. We observed no difference in the production IFN$\gamma$, TNF or IL-2 by Mtb-specific CD4 T cells between the two compartments, but MIP-1$\beta$ production was lower in the PCF T cells. Bacterial loads in the PCF did not relate to the phenotype or function of Mtb-specific CD4 T cells. Upon anti-tubercular treatment completion, HLA-DR, Ki-67 and GrB expression was significantly decreased, and relative IL-2 production was increased in peripheral Mtb-specific CD4 T cells. Overall, using a novel and rapid experimental approach to measure T cell response ex vivo at site of disease, these results provide novel insight into molecular mechanisms and immunopathology at site of TB infection of the pericardium.},
author = {Bruyn, Elsa Du and Ruzive, Sheena and Howlett, Patrick and Jacobs, Ashley J and Arlehamn, Cecilia S Lindestam and Sette, Alessandro and Sher, Alan and Mayer-Barber, Katrin D and Barber, Daniel L and Mayosi, Bongani and Ntsekhe, Mpiko and Wilkinson, Robert J and Riou, Catherine},
doi = {10.1101/2022.05.12.491749},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Bruyn et al. - 2022 - Profile of iMycobacterium tuberculosisi-specific CD4 T cells at the site of disease and blood in pericardial tuber.pdf:pdf},
journal = {bioRxiv},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {may},
pages = {2022.05.12.491749},
publisher = {Cold Spring Harbor Laboratory},
title = {{Profile of \textit{Mycobacterium tuberculosis}-specific CD4 T cells at the site of disease and blood in pericardial tuberculosis}},
url = {https://www.biorxiv.org/content/10.1101/2022.05.12.491749v1 https://www.biorxiv.org/content/10.1101/2022.05.12.491749v1.abstract},
year = {2022}
}

Our understanding of the immune response at the site of disease in extra-pulmonary tuberculosis (EPTB) is still limited. In this study, using flow cytometry, we defined the pericardial fluid (PCF) cellular composition and compared the phenotypic and functional profile of Mycobacterium tuberculosis (Mtb)-specific T cells between PCF and whole blood in 16 patients with pericardial TB (PCTB). We found that lymphocytes were the predominant cell type in PCF in PCTB, with a preferential influx of CD4 T cells. The frequencies of TNF-$α$ producing myeloid cells and Mtb-specific T cells were significantly higher in PCF compared to blood. Mtb-specific CD4 T cells in PCF exhibited a distinct phenotype compared to those in blood, with greater GrB expression and lower CD27 and KLRG1 expression. We observed no difference in the production IFN$γ$, TNF or IL-2 by Mtb-specific CD4 T cells between the two compartments, but MIP-1$β$ production was lower in the PCF T cells. Bacterial loads in the PCF did not relate to the phenotype or function of Mtb-specific CD4 T cells. Upon anti-tubercular treatment completion, HLA-DR, Ki-67 and GrB expression was significantly decreased, and relative IL-2 production was increased in peripheral Mtb-specific CD4 T cells. Overall, using a novel and rapid experimental approach to measure T cell response ex vivo at site of disease, these results provide novel insight into molecular mechanisms and immunopathology at site of TB infection of the pericardium.

@article{Horsnell2022,
abstract = {In recently published work, Hu, Zhang, and colleagues identify SPRR2A as a novel intestinal antimicrobial protein (AMP) that targets Gram-positive bacteria (Hu et al., 2021). Unexpectedly, the authors show that SPRR2A is induced by helminth-elicited type 2 immunity to restrict pathogenic bacteria translocation across the helminth-infection-damaged epithelium.},
author = {Horsnell, William G C and Oudhoff, Menno J},
doi = {10.1016/J.CHOM.2021.12.016},
issn = {1931-3128},
journal = {Cell Host {\&} Microbe},
keywords = {original},
mendeley-tags = {original},
month = {jan},
number = {1},
pages = {1--2},
pmid = {35026130},
publisher = {Elsevier},
title = {{Helminths are positively AMPing up gut de-bugging}},
url = {http://www.cell.com/article/S1931312821005874/fulltext http://www.cell.com/article/S1931312821005874/abstract https://www.cell.com/cell-host-microbe/abstract/S1931-3128(21)00587-4},
volume = {30},
year = {2022}
}

In recently published work, Hu, Zhang, and colleagues identify SPRR2A as a novel intestinal antimicrobial protein (AMP) that targets Gram-positive bacteria (Hu et al., 2021). Unexpectedly, the authors show that SPRR2A is induced by helminth-elicited type 2 immunity to restrict pathogenic bacteria translocation across the helminth-infection-damaged epithelium.

@article{Chengalroyen2022,
abstract = {Natural products provide a rich source of potential antimicrobials for treating infectious diseases for which drug resistance has emerged. Foremost among these diseases is tuberculosis. Assessment of the antimycobacterial activity of nargenicin, a natural product that targets the replicative DNA polymerase of Staphylococcus aureus, revealed that it is a bactericidal genotoxin that induces a DNA damage response in Mycobacterium tuberculosis (Mtb) and inhibits growth by blocking the replicative DNA polymerase, DnaE1. Cryo-electron microscopy revealed that binding of nargenicin to Mtb DnaE1 requires the DNA substrate such that nargenicin is wedged between the terminal base pair and the polymerase and occupies the position of both the incoming nucleotide and templating base. Comparative analysis across three bacterial species suggests that the activity of nargenicin is partly attributable to the DNA binding affinity of the replicative polymerase. This work has laid the foundation for target-led drug discovery efforts focused on Mtb DnaE1.},
author = {Chengalroyen, Melissa D and Mason, Mandy K and Borsellini, Alessandro and Tassoni, Raffaella and Abrahams, Garth L and Lynch, Sasha and Ahn, Yong-Mo and Ambler, Jon and Young, Katherine and Crowley, Brendan M and Olsen, David B and Warner, Digby F and {Barry Iii}, Clifton E and Boshoff, Helena I M and Lamers, Meindert H and Mizrahi, Valerie},
doi = {10.1021/acsinfecdis.1c00643},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Chengalroyen et al. - 2022 - DNA-dependent binding of nargenicin to DnaE1 inhibits replication in Mycobacterium tuberculosis.pdf:pdf},
issn = {2373-8227},
journal = {ACS infectious diseases},
keywords = {DNA damage,DNA polymerase,DnaE1,Mycobacterium tuberculosis,OA,antimicrobial drug discovery,fund{\_}not{\_}ack,nargenicin,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {feb},
number = {3},
pages = {612--625},
pmid = {35143160},
publisher = {American Chemical Society (ACS)},
title = {{DNA-dependent binding of nargenicin to DnaE1 inhibits replication in Mycobacterium tuberculosis}},
url = {https://pubs.acs.org/doi/full/10.1021/acsinfecdis.1c00643 http://www.ncbi.nlm.nih.gov/pubmed/35143160},
volume = {8},
year = {2022}
}

Natural products provide a rich source of potential antimicrobials for treating infectious diseases for which drug resistance has emerged. Foremost among these diseases is tuberculosis. Assessment of the antimycobacterial activity of nargenicin, a natural product that targets the replicative DNA polymerase of Staphylococcus aureus, revealed that it is a bactericidal genotoxin that induces a DNA damage response in Mycobacterium tuberculosis (Mtb) and inhibits growth by blocking the replicative DNA polymerase, DnaE1. Cryo-electron microscopy revealed that binding of nargenicin to Mtb DnaE1 requires the DNA substrate such that nargenicin is wedged between the terminal base pair and the polymerase and occupies the position of both the incoming nucleotide and templating base. Comparative analysis across three bacterial species suggests that the activity of nargenicin is partly attributable to the DNA binding affinity of the replicative polymerase. This work has laid the foundation for target-led drug discovery efforts focused on Mtb DnaE1.

@article{Hussey2022b,
abstract = {Background: The SARS-CoV-2 Delta variant (B.1.617.2) has been associated with more severe disease, particularly when compared to the Alpha variant. Most of this data, however, is from high income countries and less is understood about the variant's disease severity in other settings, particularly in an African context, and when compared to the Beta variant. Methods: A novel proxy marker, RNA-dependent RNA polymerase (RdRp) target delay in the Seegene Allplex TM 2019-nCoV (polymerase chain reaction) PCR assay, was used to identify suspected Delta variant infection in routine laboratory data. All cases diagnosed on this assay in the public sector in the Western Cape, South Africa, from 1 April to 31 July 2021, were included in the dataset provided by the Western Cape Provincial Health Data Centre (PHDC). The PHDC collates information on all COVID-19 related laboratory tests, hospital admissions and deaths for the province. Odds ratios for the association between the proxy marker and death were calculated, adjusted for prior diagnosed infection and vaccination status. Results: A total of 11,355 cases with 700 deaths were included in this study. RdRp target delay (suspected Delta variant) was associated with higher mortality (adjusted odds ratio [aOR] 1.45; 95{\%} confidence interval [CI]: 1.13-1.86), compared to presumptive Beta infection. Prior diagnosed infection during the previous COVID-19 wave, which was driven by the Beta variant, was protective (aOR 0.32; 95{\%}CI: 0.11-0.92) as was vaccination (aOR [95{\%}CI] 0.15 [0.03-0.62] for complete vaccination [≥28 days post a single dose of Ad26.COV2.S or ≥14 days post second BNT162b2 dose]). Conclusion: RdRp target delay, a proxy for infection with the Delta variant, is associated with an increased risk of mortality amongst those who were tested for COVID-19 in our setting.},
author = {Hussey, Hannah and Davies, Mary-Ann and Heekes, Alexa and Williamson, Carolyn and Valley-Omar, Ziyaad and Hardie, Diana and Korsman, Stephen and Doolabh, Deelan and Preiser, Wofgang and Maponga, Tongai and Iranzadeh, Arash and Engelbrecht, Susan and Wasserman, Sean and Schrueder, Neshaad and Boloko, Linda and Symons, Greg and Raubenheimer, Peter and Viljoen, Abraham and Parker, Arifa and Cohen, Cheryl and Jasat, Waasila and Lessells, Richard and Wilkinson, Robert J and Boulle, Andrew and Hsiao, Marvin},
doi = {10.12688/gatesopenres.13654.1},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Hussey et al. - 2022 - Higher mortality associated with the SARS-CoV-2 Delta variant in the Western Cape, South Africa, using RdRp targe.pdf:pdf},
journal = {Gates Open Research},
keywords = {B.1.617.2,Delta,OA,RdRp target delay,SARS-CoV-2,South Africa,clinical severity,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {aug},
pages = {117},
pmid = {37994361},
publisher = {F1000 Research Limited},
title = {{Higher mortality associated with the SARS-CoV-2 Delta variant in the Western Cape, South Africa, using RdRp target delay as a proxy: a cross-sectional study. [version 1; peer review: 2 approved]}},
url = {https://gatesopenresearch.org/articles/6-117},
volume = {6},
year = {2022}
}

Background: The SARS-CoV-2 Delta variant (B.1.617.2) has been associated with more severe disease, particularly when compared to the Alpha variant. Most of this data, however, is from high income countries and less is understood about the variant's disease severity in other settings, particularly in an African context, and when compared to the Beta variant. Methods: A novel proxy marker, RNA-dependent RNA polymerase (RdRp) target delay in the Seegene Allplex TM 2019-nCoV (polymerase chain reaction) PCR assay, was used to identify suspected Delta variant infection in routine laboratory data. All cases diagnosed on this assay in the public sector in the Western Cape, South Africa, from 1 April to 31 July 2021, were included in the dataset provided by the Western Cape Provincial Health Data Centre (PHDC). The PHDC collates information on all COVID-19 related laboratory tests, hospital admissions and deaths for the province. Odds ratios for the association between the proxy marker and death were calculated, adjusted for prior diagnosed infection and vaccination status. Results: A total of 11,355 cases with 700 deaths were included in this study. RdRp target delay (suspected Delta variant) was associated with higher mortality (adjusted odds ratio [aOR] 1.45; 95% confidence interval [CI]: 1.13-1.86), compared to presumptive Beta infection. Prior diagnosed infection during the previous COVID-19 wave, which was driven by the Beta variant, was protective (aOR 0.32; 95%CI: 0.11-0.92) as was vaccination (aOR [95%CI] 0.15 [0.03-0.62] for complete vaccination [≥28 days post a single dose of Ad26.COV2.S or ≥14 days post second BNT162b2 dose]). Conclusion: RdRp target delay, a proxy for infection with the Delta variant, is associated with an increased risk of mortality amongst those who were tested for COVID-19 in our setting.

@article{Kuhlmann2022,
author = {Kuhlmann, Constanze and Mayer, Carla Konstanze and Claassen, Mathilda and Maponga, Tongai and Burgers, Wendy A and Keeton, Roanne and Riou, Catherine and Sutherland, Andrew D and Suliman, Tasnim and Shaw, Megan L and Preiser, Wolfgang},
doi = {10.1016/S0140-6736(22)00090-3},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Kuhlmann et al. - 2022 - Breakthrough infections with SARS-CoV-2 omicron despite mRNA vaccine booster dose.pdf:pdf},
isbn = {10.1101/2021.11.1},
issn = {1474-547X},
journal = {The Lancet},
keywords = {OA,OA{\_}PMC,letter},
mendeley-tags = {OA,OA{\_}PMC,letter},
month = {jan},
number = {10325},
pages = {625--626},
pmid = {35063123},
publisher = {Elsevier},
title = {{Breakthrough infections with SARS-CoV-2 omicron despite mRNA vaccine booster dose.}},
url = {http://www.thelancet.com/article/S0140673622000903/fulltext http://www.thelancet.com/article/S0140673622000903/abstract https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00090-3/abstract http://www.ncbi.nlm.nih.gov/pubmed/35063123 http://},
volume = {399},
year = {2022}
}

@article{Zhao2022,
author = {Zhao, Ying and Maartens, Gary and Meintjes, Graeme A},
doi = {10.4102/SAJHIVMED.V23I1.1428},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Zhao, Maartens, Meintjes - 2022 - Dolutegravir for second-line treatment programmatic implications of new evidence.pdf:pdf},
issn = {2078-6751},
journal = {Southern African Journal of HIV Medicine},
keywords = {OA,editorial,fund{\_}not{\_}ack},
mendeley-tags = {OA,editorial,fund{\_}not{\_}ack},
month = {sep},
number = {1},
pages = {a1428},
title = {{Dolutegravir for second-line treatment: programmatic implications of new evidence}},
url = {https://sajhivmed.org.za/index.php/hivmed/article/view/1428},
volume = {23},
year = {2022}
}

@article{Parker2022,
abstract = {There is still a paucity of evidence on the outcomes of coronavirus disease 2019 (COVID-19) among people living with human immunodeficiency virus (PWH) and those co-infected with tuberculosis (TB), particularly in areas where these conditions are common. We describe the clinical features, laboratory findings and outcome of hospitalised PWH and human immunodeficiency virus (HIV)-uninfected COVID-19 patients as well as those co-infected with tuberculosis (TB). We conducted a multicentre cohort study across three hospitals in Cape Town, South Africa. All adults requiring hospitalisation with confirmed COVID-19 pneumonia from March to July 2020 were analysed. PWH comprised 270 (19{\%}) of 1434 admissions. There were 47 patients with active tuberculosis (3.3{\%}), of whom 29 (62{\%}) were PWH. Three-hundred and seventy-three patients (26{\%}) died. The mortality in PWH (n = 71, 26{\%}) and HIV-uninfected patients (n = 296, 25{\%}) was comparable. In patients with TB, PWH had a higher mortality than HIV-uninfected patients (n = 11, 38{\%} vs n = 3, 20{\%}; p = 0.001). In multivariable survival analysis a higher risk of death was associated with older age (Adjusted Hazard Ratio (AHR) 1.03 95{\%}CI 1.02–1.03, p {\textless} 0.001), male sex (AHR1.38 (95{\%}CI 1.12–1.72, p = 0.003) and being “overweight or obese” (AHR 1.30 95{\%}CI 1.03–1.61 p = 0.024). HIV (AHR 1.28 95{\%}CI 0.95–1.72, p 0.11) and active TB (AHR 1.50 95{\%}CI 0.84–2.67, p = 0.17) were not independently associated with increased risk of COVID-19 death. Risk factors for inpatient mortality in PWH included CD4 cell count {\textless} 200 cells/mm3, higher admission oxygen requirements, absolute white cell counts, neutrophil/lymphocyte ratios, C-reactive protein, and creatinine levels. In a population with high prevalence of HIV and TB, being overweight/obese was associated with increased risk of mortality in COVID-19 hospital admissions, emphasising the need for public health interventions in this patient population.},
author = {Parker, Arifa and Boloko, Linda and Moolla, Muhammad S and Ebrahim, Nabilah and Ayele, Birhanu T and Broadhurst, Alistair G B and Mashigo, Boitumelo and Titus, Gideon and de Wet, Timothy and Boliter, Nicholas and Rosslee, Michael-Jon and Papavarnavas, Nectarios and Abrahams, Riezaah and Mendelson, Marc and Dlamini, Sipho and Taljaard, Jantjie J and Prozesky, Hans W and Mowlana, Abdurasiet and Viljoen, Abraham J and Schrueder, Neshaad and Allwood, Brian W and Lalla, Usha and Dave, Joel A and Calligaro, Greg and Levin, Dion and Maughan, Deborah and Ntusi, Ntobeko A B and Nyasulu, Peter S and Meintjes, Graeme A and Koegelenberg, Coenraad F N and Mnguni, Ayanda T and Wasserman, Sean},
doi = {10.1186/S12879-022-07519-8},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Parker et al. - 2022 - Clinical features and outcomes of COVID-19 admissions in a population with a high prevalence of HIV and tuberculo.pdf:pdf},
issn = {1471-2334},
journal = {BMC Infectious Diseases},
keywords = {Infectious Diseases,Internal Medicine,Medical Microbiology,OA,Parasitology,Tropical Medicine,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jun},
pages = {559},
pmid = {35725387},
publisher = {BioMed Central},
title = {{Clinical features and outcomes of COVID-19 admissions in a population with a high prevalence of HIV and tuberculosis: a multicentre cohort study}},
url = {https://link.springer.com/articles/10.1186/s12879-022-07519-8 https://link.springer.com/article/10.1186/s12879-022-07519-8},
volume = {22},
year = {2022}
}

There is still a paucity of evidence on the outcomes of coronavirus disease 2019 (COVID-19) among people living with human immunodeficiency virus (PWH) and those co-infected with tuberculosis (TB), particularly in areas where these conditions are common. We describe the clinical features, laboratory findings and outcome of hospitalised PWH and human immunodeficiency virus (HIV)-uninfected COVID-19 patients as well as those co-infected with tuberculosis (TB). We conducted a multicentre cohort study across three hospitals in Cape Town, South Africa. All adults requiring hospitalisation with confirmed COVID-19 pneumonia from March to July 2020 were analysed. PWH comprised 270 (19%) of 1434 admissions. There were 47 patients with active tuberculosis (3.3%), of whom 29 (62%) were PWH. Three-hundred and seventy-three patients (26%) died. The mortality in PWH (n = 71, 26%) and HIV-uninfected patients (n = 296, 25%) was comparable. In patients with TB, PWH had a higher mortality than HIV-uninfected patients (n = 11, 38% vs n = 3, 20%; p = 0.001). In multivariable survival analysis a higher risk of death was associated with older age (Adjusted Hazard Ratio (AHR) 1.03 95%CI 1.02–1.03, p \textless 0.001), male sex (AHR1.38 (95%CI 1.12–1.72, p = 0.003) and being “overweight or obese” (AHR 1.30 95%CI 1.03–1.61 p = 0.024). HIV (AHR 1.28 95%CI 0.95–1.72, p 0.11) and active TB (AHR 1.50 95%CI 0.84–2.67, p = 0.17) were not independently associated with increased risk of COVID-19 death. Risk factors for inpatient mortality in PWH included CD4 cell count \textless 200 cells/mm3, higher admission oxygen requirements, absolute white cell counts, neutrophil/lymphocyte ratios, C-reactive protein, and creatinine levels. In a population with high prevalence of HIV and TB, being overweight/obese was associated with increased risk of mortality in COVID-19 hospital admissions, emphasising the need for public health interventions in this patient population.

@article{Rangaka2022,
author = {Rangaka, Molebogeng X and Hamada, Yohhei and Abubakar, Ibrahim},
doi = {10.1016/S2213-2600(22)00123-0},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Rangaka, Hamada, Abubakar - 2022 - Ending the tuberculosis syndemic is COVID-19 the (in)convenient scapegoat for poor progress.pdf:pdf},
isbn = {2022.103939},
issn = {2213-2600},
journal = {The Lancet Respiratory Medicine},
keywords = {commentary,fund{\_}not{\_}ack},
mendeley-tags = {commentary,fund{\_}not{\_}ack},
month = {mar},
number = {6},
pages = {529--531},
pmid = {35338839},
publisher = {Elsevier},
title = {{Ending the tuberculosis syndemic: is COVID-19 the (in)convenient scapegoat for poor progress?}},
url = {http://www.thelancet.com/article/S2213260022001230/fulltext http://www.thelancet.com/article/S2213260022001230/abstract https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00123-0/abstract},
volume = {10},
year = {2022}
}

@article{Mmed2022,
abstract = {Summary Background Mycobacterium tuberculosis bloodstream infection is a leading cause of death in people living with HIV and disseminated bacillary load might be a key driver of disease severity. We aimed to assess Xpert MTB/RIF Ultra (Xpert Ultra) testing of blood as a diagnostic for M tuberculosis bloodstream infection and investigate cycle threshold as a quantitative disease biomarker. Methods In this cohort study, we obtained biobanked blood samples from a large and well characterised cohort of adult patients admitted to hospital in Western Cape, South Africa with suspected HIV-associated tuberculosis and a CD4 count less than 350 cells per $\mu$L. Patients already receiving antituberculosis therapy were excluded. Samples were obtained on recruitment within 72 h of admission to hospital, and patients were followed up for 12 weeks to determine survival. We tested the biobanked blood samples using the Xpert Ultra platform after lysis and wash processing of the blood. We assessed diagnostic yield (proportion of cases detected, with unavailable test results coded as negative) against a microbiological reference, both as a function of markers of critical-illness and compared with other rapid diagnostics (urine lipoarabinomannan and sputum Xpert). Quantitative blood Xpert Ultra results were evaluated as a disease biomarker by assessing association with disease phenotype defined by principal component analysis of 32 host-response markers. Prognostic value compared to other tuberculosis biomarkers was assessed using likelihood ratio testing of nested models predicting 12-week mortality. Findings Between Jan 16, 2014, and Oct 19, 2016, of the 659 participants recruited to the parent study, 582 had an available biobanked blood sample. 447 (77{\%}) of 582 met the microbiological reference standard for tuberculosis diagnosis. Median CD4 count was 62 (IQR 221–33) cells per $\mu$L, and 123 (21{\%}) of participants died by 12-weeks follow-up. Blood Xpert Ultra was positive in 165 (37{\%}) of 447 participants with confirmed tuberculosis by the microbiological reference standard, with a diagnostic yield of 0{\textperiodcentered}37 (95{\%} CI 0{\textperiodcentered}32–0{\textperiodcentered}42). Diagnostic yield increased with lower CD4 count or haemoglobin, and outperformed urine lipoarabinomannan testing in participants with elevated venous lactate. Quantitative blood Xpert Ultra results were more closely associated with mortality than other tuberculosis biomarkers including blood culture, and urine lipoarabinomannan, or urine Xpert (all pr= −0{\textperiodcentered}5; p Interpretation Xpert Ultra testing of pre-processed blood could be used as a rapid diagnostic test in critically ill patients with suspected HIV-associated tuberculosis, while also giving additional prognostic information compared with other available markers. A dose–response relationship between quantitative blood Xpert Ultra results, host-response phenotype, and mortality risk adds to evidence that suggests M tuberculosis bloodstream infection bacillary load is causally related to outcomes. Funding Wellcome Trust, National Institute of Health Fogarty International Center, South African MRC, UK National Institute of Health Research, National Research Foundation of South Africa. Translations For the Xhosa and Afrikaans translations of the abstract see Supplementary Materials section.},
author = {Boloko, Linda and Schutz, Charlotte and Sibiya, Nomfundo and Balfour, Avuyonke and Ward, Amy and Shey, Muki and Nicol, Mark P and Burton, Rosie and Wilkinson, Robert J and Maartens, Gary and Meintjes, Graeme and Barr, David A},
doi = {10.1016/S2666-5247(22)00062-3},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Boloko et al. - 2022 - Xpert Ultra testing of blood in severe HIV-associated tuberculosis to detect and measure iMycobacterium tuberculo.pdf:pdf},
issn = {2666-5247},
journal = {The Lancet Microbe},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {may},
number = {7},
pages = {e521--e532},
pmid = {35644157},
publisher = {Elsevier},
title = {{Xpert Ultra testing of blood in severe HIV-associated tuberculosis to detect and measure \textit{Mycobacterium tuberculosis} blood stream infection: a diagnostic and disease biomarker cohort study}},
url = {http://www.thelancet.com/article/S2666524722000623/fulltext http://www.thelancet.com/article/S2666524722000623/abstract https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(22)00062-3/abstract},
volume = {3},
year = {2022}
}

Summary Background Mycobacterium tuberculosis bloodstream infection is a leading cause of death in people living with HIV and disseminated bacillary load might be a key driver of disease severity. We aimed to assess Xpert MTB/RIF Ultra (Xpert Ultra) testing of blood as a diagnostic for M tuberculosis bloodstream infection and investigate cycle threshold as a quantitative disease biomarker. Methods In this cohort study, we obtained biobanked blood samples from a large and well characterised cohort of adult patients admitted to hospital in Western Cape, South Africa with suspected HIV-associated tuberculosis and a CD4 count less than 350 cells per $μ$L. Patients already receiving antituberculosis therapy were excluded. Samples were obtained on recruitment within 72 h of admission to hospital, and patients were followed up for 12 weeks to determine survival. We tested the biobanked blood samples using the Xpert Ultra platform after lysis and wash processing of the blood. We assessed diagnostic yield (proportion of cases detected, with unavailable test results coded as negative) against a microbiological reference, both as a function of markers of critical-illness and compared with other rapid diagnostics (urine lipoarabinomannan and sputum Xpert). Quantitative blood Xpert Ultra results were evaluated as a disease biomarker by assessing association with disease phenotype defined by principal component analysis of 32 host-response markers. Prognostic value compared to other tuberculosis biomarkers was assessed using likelihood ratio testing of nested models predicting 12-week mortality. Findings Between Jan 16, 2014, and Oct 19, 2016, of the 659 participants recruited to the parent study, 582 had an available biobanked blood sample. 447 (77%) of 582 met the microbiological reference standard for tuberculosis diagnosis. Median CD4 count was 62 (IQR 221–33) cells per $μ$L, and 123 (21%) of participants died by 12-weeks follow-up. Blood Xpert Ultra was positive in 165 (37%) of 447 participants with confirmed tuberculosis by the microbiological reference standard, with a diagnostic yield of 0˙37 (95% CI 0˙32–0˙42). Diagnostic yield increased with lower CD4 count or haemoglobin, and outperformed urine lipoarabinomannan testing in participants with elevated venous lactate. Quantitative blood Xpert Ultra results were more closely associated with mortality than other tuberculosis biomarkers including blood culture, and urine lipoarabinomannan, or urine Xpert (all pr= −0˙5; p Interpretation Xpert Ultra testing of pre-processed blood could be used as a rapid diagnostic test in critically ill patients with suspected HIV-associated tuberculosis, while also giving additional prognostic information compared with other available markers. A dose–response relationship between quantitative blood Xpert Ultra results, host-response phenotype, and mortality risk adds to evidence that suggests M tuberculosis bloodstream infection bacillary load is causally related to outcomes. Funding Wellcome Trust, National Institute of Health Fogarty International Center, South African MRC, UK National Institute of Health Research, National Research Foundation of South Africa. Translations For the Xhosa and Afrikaans translations of the abstract see Supplementary Materials section.

@article{Blumenthal2022,
abstract = {In South Africa, the COVID-19 pandemic occurs against the backdrop of high Human Immunodeficiency Virus (HIV-1), tuberculosis (TB) and non-communicable disease burdens as well as prevalent herpesviruses infections such as Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV). As part of an observational study of adults admitted to Groote Schuur Hospital, Cape Town, South Africa, during the period June – August 2020 and assessed for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, we measured KSHV serology and KSHV and EBV viral load (VL) in peripheral blood in relation to Coronavirus disease 2019 (COVID-19) severity and outcome. A total of 104 patients with PCR-confirmed SARS-CoV-2 infection were included. 61{\%} were men and 39{\%} women with a median age of 53 years (range 21 – 86). 29.8{\%} (95{\%} CI: 21.7 – 39.1{\%}) of the cohort was HIV-1 positive and 41.1{\%} (95{\%} CI: 31.6 – 51.1{\%}) were KSHV seropositive. EBV VL was detectable in 84.4{\%} (95{\%} CI: 76.1 – 84.4{\%}) of the cohort while KSHV DNA was detected in 20.6{\%} (95{\%} CI: 13.6 – 29.2{\%}), with dual EBV/KSHV infection in 17.7{\%} (95{\%} CI: 11.1 – 26.2{\%}). On enrolment, 48 (46.2{\%} (95{\%} CI: 36.8 – 55.7{\%})) COVID-19 patients were classified as severe on the WHO ordinal scale reflecting oxygen therapy and supportive care requirements; 30 of these patients (28.8{\%} (95{\%} CI: 20.8 – 38.0{\%}) died. In COVID-19 patients, detectable KSHV VL was associated with death after adjusting for age, sex, HIV-1 status and detectable EBV VL (p=0.036, adjusted OR=3.17 [95{\%} CI: 1.08 – 9.32]). Furthermore, in HIV-1 negative COVID-19 patients, there was a trend indicating that KSHV VL was related to COVID-19 disease severity (p=0.054, unstandardized co-efficient 0.86 [95{\%} CI: -0.015 – 1.74]) in addition to death (p=0.008, adjusted OR=7.34 [95{\%} CI: 1.69 – 31.49]). While the design of our study cannot distinguish if disease synergy exists between COVID-19 and KSHV nor if either viral infection is fueling the other, these data point to a potential contribution of KSHV infection to COVID-19 outcome, or SARS-CoV-2 infection to KSHV reactivation, particularly in the South African context of high disease burden, that warrants further investigation.},
author = {Blumenthal, Melissa J and Lambarey, Humaira and Chetram, Abeen and Riou, Catherine and Wilkinson, Robert J and Sch{\"{a}}fer, Georgia},
doi = {10.3389/FMICB.2021.795555},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Blumenthal et al. - 2022 - Kaposi's sarcoma-associated herpesvirus, but not Epstein-Barr virus, co-infection associates with coronavirus.pdf:pdf},
issn = {1664-302X},
journal = {Frontiers in Microbiology},
keywords = {COVID-19,KSHV,OA,OA{\_}PMC,SARS-CoV-2,South Africa,fund{\_}ack,genomics{\_}fund{\_}ack,lytic reactivation,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {jan},
pages = {795555},
pmid = {35069495},
publisher = {Frontiers},
title = {{Kaposi's sarcoma-associated herpesvirus, but not Epstein-Barr virus, co-infection associates with coronavirus disease 2019 severity and outcome in South African patients}},
url = {https://www.frontiersin.org/articles/10.3389/fmicb.2021.795555/full},
volume = {12},
year = {2022}
}

In South Africa, the COVID-19 pandemic occurs against the backdrop of high Human Immunodeficiency Virus (HIV-1), tuberculosis (TB) and non-communicable disease burdens as well as prevalent herpesviruses infections such as Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV). As part of an observational study of adults admitted to Groote Schuur Hospital, Cape Town, South Africa, during the period June – August 2020 and assessed for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, we measured KSHV serology and KSHV and EBV viral load (VL) in peripheral blood in relation to Coronavirus disease 2019 (COVID-19) severity and outcome. A total of 104 patients with PCR-confirmed SARS-CoV-2 infection were included. 61% were men and 39% women with a median age of 53 years (range 21 – 86). 29.8% (95% CI: 21.7 – 39.1%) of the cohort was HIV-1 positive and 41.1% (95% CI: 31.6 – 51.1%) were KSHV seropositive. EBV VL was detectable in 84.4% (95% CI: 76.1 – 84.4%) of the cohort while KSHV DNA was detected in 20.6% (95% CI: 13.6 – 29.2%), with dual EBV/KSHV infection in 17.7% (95% CI: 11.1 – 26.2%). On enrolment, 48 (46.2% (95% CI: 36.8 – 55.7%)) COVID-19 patients were classified as severe on the WHO ordinal scale reflecting oxygen therapy and supportive care requirements; 30 of these patients (28.8% (95% CI: 20.8 – 38.0%) died. In COVID-19 patients, detectable KSHV VL was associated with death after adjusting for age, sex, HIV-1 status and detectable EBV VL (p=0.036, adjusted OR=3.17 [95% CI: 1.08 – 9.32]). Furthermore, in HIV-1 negative COVID-19 patients, there was a trend indicating that KSHV VL was related to COVID-19 disease severity (p=0.054, unstandardized co-efficient 0.86 [95% CI: -0.015 – 1.74]) in addition to death (p=0.008, adjusted OR=7.34 [95% CI: 1.69 – 31.49]). While the design of our study cannot distinguish if disease synergy exists between COVID-19 and KSHV nor if either viral infection is fueling the other, these data point to a potential contribution of KSHV infection to COVID-19 outcome, or SARS-CoV-2 infection to KSHV reactivation, particularly in the South African context of high disease burden, that warrants further investigation.

@article{Dhana2022a,
abstract = {Background: WHO recommends urine lateral-flow lipoarabinomannan (LF-LAM) testing with AlereLAM in HIV- positive inpatients only if screening criteria are met. We assessed the performance of WHO screening criteria and alternative screening tests/strategies to guide LF-LAM testing and compared diagnostic accuracy of the WHO AlereLAM algorithm (WHO screening criteria → AlereLAM) with AlereLAM and FujiLAM (a novel LF-LAM test). Methods: We searched MEDLINE, Embase, and Cochrane Library from Jan 1, 2011 to March 1, 2020 for studies among adult/adolescent HIV-positive inpatients regardless of tuberculosis signs and symptoms. The reference standards were 1) AlereLAM or FujiLAM for screening tests/strategies and 2) culture or Xpert for AlereLAM/FujiLAM. We determined proportion of inpatients eligible for AlereLAM using WHO screening criteria; assessed accuracy of WHO criteria and alternative screening tests/strategies to guide LF-LAM testing; compared accuracy of WHO AlereLAM algorithm with AlereLAM/FujiLAM in all; and determined diagnostic yield of AlereLAM, FujiLAM, and Xpert MTB/RIF (Xpert). We estimated pooled proportions with a random-effects model, assessed diagnostic accuracy using random-effects bivariate models, and assessed diagnostic yield descriptively. Findings: We obtained data from all 5 identified studies (n=3,504). The pooled proportion of inpatients eligible for AlereLAM using WHO criteria was 93{\%} (95{\%}CI 91, 95). Among screening tests/strategies to guide LF-LAM testing, WHO criteria, C-reactive protein (≥5 mg/L), and CD4 count ({\textless}200 cells/$\mu$L) had high sensitivities but low specificities; cough (≥2 weeks), haemoglobin ({\textless}8 g/dL), body mass index ({\textless}18.5 kg/m2), lymphadenopathy, and WHO-defined danger signs had higher specificities but suboptimal sensitivities. AlereLAM in all had the same sensitivity (62{\%}) and specificity (88{\%}) as WHO AlereLAM algorithm. Sensitivity of FujiLAM and AlereLAM was 69{\%} and 48{\%}, while specificity was 48{\%} and 96{\%}, respectively. Diagnostic yield of sputum Xpert was 29-41{\%}, AlereLAM was 39-76{\%}, and urine Xpert was 35-62{\%}. In one study, FujiLAM diagnosed 80{\%} of tuberculosis cases (vs 39{\%} for AlereLAM), and sputum Xpert combined with AlereLAM, urine Xpert, or FujiLAM diagnosed 69{\%}, 81{\%}, and 92{\%} of all cases, respectively. Interpretation: WHO criteria and alternative screening tests/strategies have limited utility in guiding LF-LAM testing, suggesting that AlereLAM testing in all HIV-positive medical inpatients be implemented. Routine FujiLAM may improve tuberculosis diagnosis.},
author = {Dhana, Ashar and Hamada, Yohhei and Kengne, Andre P and Kerkhoff, Andrew D and Broger, Tobias and Denkinger, Claudia M and Rangaka, Molebogeng X and Gupta-Wright, Ankur and Fielding, Katherine and Wood, Robin and Huerga, Helena and Rucker, Sekai Chenai Mathabire and Bjerrum, Stephanie and Johansen, Isik S and Thit, Swe Swe and Kyi, Mar Mar and Hanson, Josh and Barr, David A and Meintjes, Graeme and Maartens, Gary},
doi = {10.1016/J.JINF.2022.05.010},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Dhana et al. - 2022 - Diagnostic accuracy of WHO screening criteria to guide lateral-flow lipoarabinomannan testing among HIV-positive i.pdf:pdf},
issn = {0163-4453},
journal = {Journal of Infection},
keywords = {fund{\_}ack,review},
mendeley-tags = {fund{\_}ack,review},
month = {may},
number = {1},
pages = {40--48},
pmid = {35588942},
publisher = {W.B. Saunders},
title = {{Diagnostic accuracy of WHO screening criteria to guide lateral-flow lipoarabinomannan testing among HIV-positive inpatients: a systematic review and individual participant data meta-analysis}},
url = {https://linkinghub.elsevier.com/retrieve/pii/S0163445322002924},
volume = {85},
year = {2022}
}

Background: WHO recommends urine lateral-flow lipoarabinomannan (LF-LAM) testing with AlereLAM in HIV- positive inpatients only if screening criteria are met. We assessed the performance of WHO screening criteria and alternative screening tests/strategies to guide LF-LAM testing and compared diagnostic accuracy of the WHO AlereLAM algorithm (WHO screening criteria → AlereLAM) with AlereLAM and FujiLAM (a novel LF-LAM test). Methods: We searched MEDLINE, Embase, and Cochrane Library from Jan 1, 2011 to March 1, 2020 for studies among adult/adolescent HIV-positive inpatients regardless of tuberculosis signs and symptoms. The reference standards were 1) AlereLAM or FujiLAM for screening tests/strategies and 2) culture or Xpert for AlereLAM/FujiLAM. We determined proportion of inpatients eligible for AlereLAM using WHO screening criteria; assessed accuracy of WHO criteria and alternative screening tests/strategies to guide LF-LAM testing; compared accuracy of WHO AlereLAM algorithm with AlereLAM/FujiLAM in all; and determined diagnostic yield of AlereLAM, FujiLAM, and Xpert MTB/RIF (Xpert). We estimated pooled proportions with a random-effects model, assessed diagnostic accuracy using random-effects bivariate models, and assessed diagnostic yield descriptively. Findings: We obtained data from all 5 identified studies (n=3,504). The pooled proportion of inpatients eligible for AlereLAM using WHO criteria was 93% (95%CI 91, 95). Among screening tests/strategies to guide LF-LAM testing, WHO criteria, C-reactive protein (≥5 mg/L), and CD4 count (\textless200 cells/$μ$L) had high sensitivities but low specificities; cough (≥2 weeks), haemoglobin (\textless8 g/dL), body mass index (\textless18.5 kg/m2), lymphadenopathy, and WHO-defined danger signs had higher specificities but suboptimal sensitivities. AlereLAM in all had the same sensitivity (62%) and specificity (88%) as WHO AlereLAM algorithm. Sensitivity of FujiLAM and AlereLAM was 69% and 48%, while specificity was 48% and 96%, respectively. Diagnostic yield of sputum Xpert was 29-41%, AlereLAM was 39-76%, and urine Xpert was 35-62%. In one study, FujiLAM diagnosed 80% of tuberculosis cases (vs 39% for AlereLAM), and sputum Xpert combined with AlereLAM, urine Xpert, or FujiLAM diagnosed 69%, 81%, and 92% of all cases, respectively. Interpretation: WHO criteria and alternative screening tests/strategies have limited utility in guiding LF-LAM testing, suggesting that AlereLAM testing in all HIV-positive medical inpatients be implemented. Routine FujiLAM may improve tuberculosis diagnosis.

@article{Mutavhatsindi2022,
author = {Mutavhatsindi, Hygon and Riou, Catherine},
doi = {10.1016/J.XPRO.2022.101771},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Mutavhatsindi, Riou - 2022 - Protocol to quantify and phenotype SARS-CoV-2 specific T-cell response using a rapid flow cytometry-based w.pdf:pdf},
issn = {2666-1667},
journal = {STAR Protocols},
keywords = {OA,fund{\_}ack,protocol},
mendeley-tags = {OA,fund{\_}ack,protocol},
month = {sep},
number = {4},
pages = {101771},
publisher = {Elsevier},
title = {{Protocol to quantify and phenotype SARS-CoV-2 specific T-cell response using a rapid flow cytometry-based whole blood assay}},
url = {https://linkinghub.elsevier.com/retrieve/pii/S2666166722006517},
volume = {3},
year = {2022}
}

@article{Richardson2022,
abstract = {Summary Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern (VOCs) exhibit escape from neutralizing antibodies, causing concern about vaccine effectiveness. However, while non-neutralizing cytotoxic functions of antibodies are associated with improved disease outcome and vaccine protection, Fc effector function escape from VOCs is poorly defined. Furthermore, whether VOCs trigger Fc functions with altered specificity, as has been reported for neutralization, is unknown. Here, we demonstrate that the Beta VOC partially evades Fc effector activity in individuals infected with the original (D614G) variant. However, not all functions are equivalently affected, suggesting differential targeting by antibodies mediating distinct Fc functions. Furthermore, Beta and Delta infection trigger responses with significantly improved Fc cross-reactivity against global VOCs compared with D614G-infected or Ad26.COV2.S-vaccinated individuals. This suggests that, as for neutralization, the infecting spike sequence affects Fc effector function. These data have important implications for vaccine strategies that incorporate VOCs, suggesting these may induce broader Fc effector responses.},
author = {Richardson, Simone I and Manamela, Nelia P and Motsoeneng, Boitumelo M and Ntusi, Ntobeko A B and Burgers, Wendy A and Correspondence, Penny L Moore and Kaldine, Haajira and Ayres, Frances and Makhado, Zanele and Mennen, Mathilda and Skelem, Sango and Williams, Noleen and Sullivan, Nancy J and Misasi, John and Gray, Glenda G and Bekker, Linda-Gail and Ueckermann, Veronica and Rossouw, Theresa M and Boswell, Michael T and Moore, Penny L},
doi = {10.1016/J.XCRM.2022.100510},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Richardson et al. - 2022 - SARS-CoV-2 Beta and Delta variants trigger Fc effector function with increased cross-reactivity.pdf:pdf},
issn = {2666-3791},
journal = {Cell Reports Medicine},
keywords = {Ad26.COV2.S,Beta,Delta,Fc effector function,OA,OA{\_}PMC,SARS-CoV-2,fund{\_}ack,original,variant of concern},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,original},
month = {jan},
number = {2},
pages = {100510},
pmid = {35233544},
publisher = {Elsevier},
title = {{SARS-CoV-2 Beta and Delta variants trigger Fc effector function with increased cross-reactivity}},
url = {http://www.cell.com/article/S2666379122000039/fulltext http://www.cell.com/article/S2666379122000039/abstract https://www.cell.com/cell-reports-medicine/abstract/S2666-3791(22)00003-9},
volume = {3},
year = {2022}
}

Summary Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern (VOCs) exhibit escape from neutralizing antibodies, causing concern about vaccine effectiveness. However, while non-neutralizing cytotoxic functions of antibodies are associated with improved disease outcome and vaccine protection, Fc effector function escape from VOCs is poorly defined. Furthermore, whether VOCs trigger Fc functions with altered specificity, as has been reported for neutralization, is unknown. Here, we demonstrate that the Beta VOC partially evades Fc effector activity in individuals infected with the original (D614G) variant. However, not all functions are equivalently affected, suggesting differential targeting by antibodies mediating distinct Fc functions. Furthermore, Beta and Delta infection trigger responses with significantly improved Fc cross-reactivity against global VOCs compared with D614G-infected or Ad26.COV2.S-vaccinated individuals. This suggests that, as for neutralization, the infecting spike sequence affects Fc effector function. These data have important implications for vaccine strategies that incorporate VOCs, suggesting these may induce broader Fc effector responses.

@article{DuBruyn2022,
abstract = {Studies of the immune response at the site of disease in extra-pulmonary tuberculosis (EPTB) disease are scarce. In this study, we compared the cellular profile of Mycobacterium tuberculosis (Mtb)-specific T cells in pericardial fluid and peripheral blood in patients with pericardial TB (PCTB). Whole blood and pericardial fluid (PCF) samples were collected at the time of diagnostic sampling, with repeat blood sampling after completion of anti-tubercular treatment (ATT) in 16 PCTB patients, most of them being HIV-1 infected (n=14). These samples were stimulated ex vivo and the phenotypic and functional cellular profile of PCF and blood was assessed by flow cytometry. We found that lymphocytes were the predominant cell type in PCF in PCTB, with a preferential influx of CD4 T cells. The frequencies of TNF-$\alpha$ producing Mtb-specific granulocytes and Mtb-specific CD4 T cells were significantly higher in PCF compared to blood. Mtb-specific CD4 T cells in PCF exhibited a distinct phenotype compared to those in blood, with greater GrB expression and lower CD27 and KLRG1 expression. We observed no difference in the production IFN$\gamma$, TNF or IL-2 by Mtb-specific CD4 T cells between the two compartments, but MIP-1$\beta$ production was lower in the PCF T cells. Bacterial loads were not associated with alterations in the phenotype or function of Mtb-specific CD4 T cells. Upon ATT completion, HLA-DR, Ki-67 and GrB expression was significantly decreased, and relative IL-2 production was increased in peripheral Mtb-specific CD4 T cells. Overall, using an ex vivo assay to compare the immune response towards Mtb in PCF and in blood, we identified significant difference in the phenotypic profile of Mtb-specific CD4 T response between these two compartments. Moreover, we show that the activation profile of peripheral Mtb-specific CD4 T cells could be used to monitor treatment response in PCTB.},
author = {{Du Bruyn}, Elsa and Ruzive, Sheena and Howlett, Patrick and Cerrone, Maddalena and Jacobs, Ashley J. and Arlehamn, Cecilia S. Lindestam and Sette, Alessandro and Sher, Alan and Mayer-Barber, Katrin D. and Barber, Daniel L. and Mayosi, Bongani and Ntsekhe, Mpiko and Wilkinson, Robert J. and Riou, Catherine},
doi = {10.3389/FIMMU.2022.1009016/BIBTEX},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Du Bruyn et al. - 2022 - Comparison of the frequency and phenotypic profile of Mycobacterium tuberculosis-specific CD4 T cells between t.pdf:pdf},
issn = {16643224},
journal = {Frontiers in Immunology},
keywords = {CD4 response,OA,OA{\_}PMC,Pericardial fluid,Pericardial tuberculosis,fund{\_}ack,original,site of disease,treatment response,whole blood},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,original},
month = {nov},
pages = {1009016},
pmid = {36439130},
publisher = {Frontiers Media SA},
title = {{Comparison of the frequency and phenotypic profile of Mycobacterium tuberculosis-specific CD4 T cells between the site of disease and blood in pericardial tuberculosis}},
volume = {13},
year = {2022}
}

Studies of the immune response at the site of disease in extra-pulmonary tuberculosis (EPTB) disease are scarce. In this study, we compared the cellular profile of Mycobacterium tuberculosis (Mtb)-specific T cells in pericardial fluid and peripheral blood in patients with pericardial TB (PCTB). Whole blood and pericardial fluid (PCF) samples were collected at the time of diagnostic sampling, with repeat blood sampling after completion of anti-tubercular treatment (ATT) in 16 PCTB patients, most of them being HIV-1 infected (n=14). These samples were stimulated ex vivo and the phenotypic and functional cellular profile of PCF and blood was assessed by flow cytometry. We found that lymphocytes were the predominant cell type in PCF in PCTB, with a preferential influx of CD4 T cells. The frequencies of TNF-$α$ producing Mtb-specific granulocytes and Mtb-specific CD4 T cells were significantly higher in PCF compared to blood. Mtb-specific CD4 T cells in PCF exhibited a distinct phenotype compared to those in blood, with greater GrB expression and lower CD27 and KLRG1 expression. We observed no difference in the production IFN$γ$, TNF or IL-2 by Mtb-specific CD4 T cells between the two compartments, but MIP-1$β$ production was lower in the PCF T cells. Bacterial loads were not associated with alterations in the phenotype or function of Mtb-specific CD4 T cells. Upon ATT completion, HLA-DR, Ki-67 and GrB expression was significantly decreased, and relative IL-2 production was increased in peripheral Mtb-specific CD4 T cells. Overall, using an ex vivo assay to compare the immune response towards Mtb in PCF and in blood, we identified significant difference in the phenotypic profile of Mtb-specific CD4 T response between these two compartments. Moreover, we show that the activation profile of peripheral Mtb-specific CD4 T cells could be used to monitor treatment response in PCTB.

@article{Spies2022,
abstract = {Background: Patients with HIV and drug-resistant tuberculosis (TB) are at high risk of death. Objectives: We investigated the association between rifampicin-resistant TB (RR-TB) and mortality in a cohort of patients who were admitted to hospital at the time of TB diagnosis. Method: Adults hospitalised at Khayelitsha Hospital and diagnosed with HIV-associated TB during admission, were enrolled between 2013 and 2016. Clinical, biochemical and microbiological data were prospectively collected and participants were followed up for 12 weeks. Results: Participants with microbiologically confirmed TB ( n = 482) were enrolled a median of two days (interquartile range [IQR]: 1–3 days) following admission. Fifty-three participants (11.0{\%}) had RR-TB. Participants with rifampicin-susceptible TB (RS-TB) received appropriate treatment a median of one day (IQR: 1–2 days) following enrolment compared to three days (IQR: 1–9 days) in participants with RR-TB. Eight participants with RS-TB (1.9{\%}) and six participants with RR-TB (11.3{\%}) died prior to the initiation of appropriate treatment. Mortality at 12 weeks was 87/429 (20.3{\%}) in the RS-TB group and 21/53 (39.6{\%}) in the RR-TB group. RR-TB was a significant predictor of 12-week mortality (hazard ratio: 1.88; 95{\%} confidence interval: 1.07–3.29; P = 0.03). Conclusion: Mortality at 12 weeks in participants with RR-TB was high compared to participants with RS-TB. Delays in the initiation of appropriate treatment and poorer regimen efficacy are proposed as contributors to higher mortality in hospitalised patients with HIV and RR-TB.},
author = {Spies, Ruan and Schutz, Charlotte and Ward, Amy and Balfour, Avuyonke and Shey, Muki and Nicol, Mark and Burton, Rosie and Sossen, Bianca and Wilkinson, Robert and Barr, David and Meintjes, Graeme A},
doi = {10.4102/SAJHIVMED.V23I1.1396},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Spies et al. - 2022 - Rifampicin resistance and mortality in patients hospitalised with HIV-associated tuberculosis.pdf:pdf},
issn = {2078-6751},
journal = {Southern African Journal of HIV Medicine},
keywords = {AIDS,Africa,African,HIV,Khayelitsha Hospital,OA,OA{\_}repository,TB,after,age,analysis,antiretroviral,associated,associated tuberculosis,based,care,data,disease,drug,drug resistant TB,fund{\_}ack,group,guidelines,health,healthcare,individuals,infected,infection,model,months,multi,original,patients,people,population,positive,pregnancy,renal,resistant tuberculosis,rifampicin,risk,services,study,test,testing,therapy,time,treatment,virus,women,workers,years},
mendeley-tags = {OA,OA{\_}repository,fund{\_}ack,original},
month = {sep},
number = {1},
pages = {a1396},
publisher = {AOSIS},
title = {{Rifampicin resistance and mortality in patients hospitalised with HIV-associated tuberculosis}},
url = {https://sajhivmed.org.za/index.php/hivmed/article/view/1396/2859 https://sajhivmed.org.za/index.php/hivmed/article/view/1396/2860 https://sajhivmed.org.za/index.php/hivmed/article/view/1396/2861 https://sajhivmed.org.za/index.php/hivmed/article/view/1396},
volume = {23},
year = {2022}
}

Background: Patients with HIV and drug-resistant tuberculosis (TB) are at high risk of death. Objectives: We investigated the association between rifampicin-resistant TB (RR-TB) and mortality in a cohort of patients who were admitted to hospital at the time of TB diagnosis. Method: Adults hospitalised at Khayelitsha Hospital and diagnosed with HIV-associated TB during admission, were enrolled between 2013 and 2016. Clinical, biochemical and microbiological data were prospectively collected and participants were followed up for 12 weeks. Results: Participants with microbiologically confirmed TB ( n = 482) were enrolled a median of two days (interquartile range [IQR]: 1–3 days) following admission. Fifty-three participants (11.0%) had RR-TB. Participants with rifampicin-susceptible TB (RS-TB) received appropriate treatment a median of one day (IQR: 1–2 days) following enrolment compared to three days (IQR: 1–9 days) in participants with RR-TB. Eight participants with RS-TB (1.9%) and six participants with RR-TB (11.3%) died prior to the initiation of appropriate treatment. Mortality at 12 weeks was 87/429 (20.3%) in the RS-TB group and 21/53 (39.6%) in the RR-TB group. RR-TB was a significant predictor of 12-week mortality (hazard ratio: 1.88; 95% confidence interval: 1.07–3.29; P = 0.03). Conclusion: Mortality at 12 weeks in participants with RR-TB was high compared to participants with RS-TB. Delays in the initiation of appropriate treatment and poorer regimen efficacy are proposed as contributors to higher mortality in hospitalised patients with HIV and RR-TB.

@article{Mohr-Holland2022,
abstract = {BACKGROUND: Data suggest that treatment with newer TB drugs (linezolid [LZD], bedaquiline [BDQ] and delamanid [DLM]), used in Khayelitsha, South Africa, since 2012, reduces mortality due to rifampicin-resistant TB (RR-TB). METHODS: This was a retrospective cohort study to assess 6-month mortality among RR-TB patients diagnosed between 2008 and 2019. RESULTS: By 6 months, 236/2,008 (12{\%}) patients died; 12{\%} (78/651) among those diagnosed in 2008–2011, and respectively 8{\%} (49/619) and 15{\%} (109/738) with and without LZD/BDQ/DLM in 2012–2019. Multivariable analysis showed a small, non-significant mortality reduction with LZD/BDQ/DLM use compared to the 2008–2011 period (aOR 0.79, 95{\%} CI 0.5–1.2). Inpatient treatment initiation (aOR 3.2, 95{\%} CI 2.4–4.4), fluoroquinolone (FQ) resistance (aOR 2.7, 95{\%} CI 1.8–4.2) and female sex (aOR 1.5, 95{\%} CI 1.1–2.0) were also associated with mortality. When restricted to 2012–2019, use of LZD/BDQ/DLM was associated with lower mortality (aOR 0.58, 95{\%} CI 0.39–0.87). CONCLUSIONS: While LZD/BDQ/DLM reduced 6-month mortality between 2012 and 2019, there was no significant effect overall. These findings may be due to initially restricted LZD/BDQ/DLM use for those with high-level resistance or treatment failure. Additional contributors include increased treatment initiation among individuals who would have otherwise died before treatment due to universal drug susceptibility testing from 2012, an effect that also likely contributed to higher mortality among females (survival through to care-seeking).},
author = {Mohr-Holland, E and Daniels, J and Reuter, A and Rodriguez, C A and Mitnick, C and Kock, Y and Cox, V and Furin, J and Cox, Helen},
doi = {10.5588/IJTLD.21.0494},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Mohr-Holland et al. - 2022 - Early mortality during rifampicin-resistant TB treatment.pdf:pdf},
issn = {1027-3719},
journal = {The International Journal of Tuberculosis and Lung Disease},
keywords = {OA,bedaquiline,death,delamanid,drug,fund{\_}not{\_}ack,linezolid,original,resistant tuberculosis},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {feb},
number = {2},
pages = {150--157},
pmid = {35086627},
publisher = {International Union Against Tuberculosis and Lung Disease},
title = {{Early mortality during rifampicin-resistant TB treatment}},
url = {https://www.ingentaconnect.com/content/10.5588/ijtld.21.0494},
volume = {26},
year = {2022}
}

BACKGROUND: Data suggest that treatment with newer TB drugs (linezolid [LZD], bedaquiline [BDQ] and delamanid [DLM]), used in Khayelitsha, South Africa, since 2012, reduces mortality due to rifampicin-resistant TB (RR-TB). METHODS: This was a retrospective cohort study to assess 6-month mortality among RR-TB patients diagnosed between 2008 and 2019. RESULTS: By 6 months, 236/2,008 (12%) patients died; 12% (78/651) among those diagnosed in 2008–2011, and respectively 8% (49/619) and 15% (109/738) with and without LZD/BDQ/DLM in 2012–2019. Multivariable analysis showed a small, non-significant mortality reduction with LZD/BDQ/DLM use compared to the 2008–2011 period (aOR 0.79, 95% CI 0.5–1.2). Inpatient treatment initiation (aOR 3.2, 95% CI 2.4–4.4), fluoroquinolone (FQ) resistance (aOR 2.7, 95% CI 1.8–4.2) and female sex (aOR 1.5, 95% CI 1.1–2.0) were also associated with mortality. When restricted to 2012–2019, use of LZD/BDQ/DLM was associated with lower mortality (aOR 0.58, 95% CI 0.39–0.87). CONCLUSIONS: While LZD/BDQ/DLM reduced 6-month mortality between 2012 and 2019, there was no significant effect overall. These findings may be due to initially restricted LZD/BDQ/DLM use for those with high-level resistance or treatment failure. Additional contributors include increased treatment initiation among individuals who would have otherwise died before treatment due to universal drug susceptibility testing from 2012, an effect that also likely contributed to higher mortality among females (survival through to care-seeking).

@article{Davis2022,
abstract = {Background: Drug regimens which include intensified antibiotics alongside effective anti-inflammatory therapies may improve outcomes in Tuberculous Meningitis (TBM). Safety data on their use in combination and in the context of HIV is needed to inform clinical trial design. Methods: We conducted a phase 2 open-label parallel-design RCT to assess safety of high-dose rifampicin, linezolid and aspirin in HIV-associated TBM. Participants were randomised (1.4:1:1) to three treatment arms (arm 1, standard of care (SOC); arm 2 SOC + additional rifampicin (up to 35mg/kg/day)) + linezolid 1200mg/day reducing after 28/7 to 600mg/day; arm 3, as per arm 2 + aspirin 1000mg/day) for 56 days, when the primary outcome of adverse events of special interest (AESI) or death was assessed. Results: 52 participants were randomised. 59{\%} had mild disease (MRC Grade 1) vs 39{\%} (Grade 2) vs 2{\%} (Grade 3). 33{\%} of participants had microbiologically-confirmed TBM; vs 41{\%} possible or 25{\%} probable. AESI or death occurred in 10/16 (arm 3) vs 4/14 (arm 2) vs 6/20 (arm 1) (p=0.083). The cumulative proportion of AESI or death (Kaplan-Meier method) demonstrated worse outcomes in arm 3 vs arm 1 (p=0.04), however only one event in arm 3 was attributable to aspirin and was mild. There was no difference in efficacy (Modified Rankin Scale) at day 56 between the three arms. Conclusions: High-dose rifampicin and adjunctive linezolid can safely be added to SOC in HIV-associated TBM. Larger studies are required to evaluate whether potential toxicity associated with these interventions, particularly aspirin, is outweighed by mortality or morbidity benefit. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Clinical Trial NCT03927313 {\#}{\#}{\#} Clinical Protocols {\textless}https://wellcomeopenresearch.org/articles/6-136{\textgreater} {\#}{\#}{\#} Funding Statement This study and the investigators listed are supported by Wellcome, EDCTP, Department of Science and Technology (South Africa), Research Councils UK, Cancer Research UK, Meningitis Now and National Institutes of Health. {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Approval for the trial was granted by the University of Cape Town Human Research Ethics Committee (293/2018), Walter Sisulu University Human Research Committee (012/2019) and the South African Health Products Regulatory Authority (20180622). The trial was registered on the South African National Clinical Trials Register (DOH-27-0319-6230), Pan African National Clinical Trials Register (PACTR201902921101705) and clinicaltrials.gov ([NCT03927313][1]). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript [1]: /lookup/external-ref?link{\_}type=CLINTRIALGOV{\&}access{\_}num=NCT03927313{\&}atom={\%}2Fmedrxiv{\%}2Fearly{\%}2F2022{\%}2F07{\%}2F26{\%}2F2022.07.26.22278065.atom},
author = {Davis, Angharad G and Wasserman, Sean and Stek, Cari and Maxebengula, Mpumi and Liang, C. Jason and Stegmann, Stephani and Koekemoer, Sonya and Jackson, Amanda and Kadenani, Yakub and Bremer, Marise and Daroowala, Remy and Aziz, Saalikha and Goliath, Rene T and Sai, Louise Lai and Sihoyiya, Thandi and Denti, Paolo and Lai, Rachel PJ and Crede, Thomas and Naude, Jonathan and Szymanski, Patryk and Vallie, Yakoob and Banderker, Ismail Abbas and Moosa, Muhammed S and Raubenheimer, Peter and Candy, Sally and Offiah, Curtis and Wahl, Gerda and Vorster, Isak and Maartens, Gary and Black, John and Meintjes, Graeme and Wilkinson, Robert J},
doi = {10.1101/2022.07.26.22278065},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Davis et al. - 2022 - A phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or wit.pdf:pdf},
journal = {medRxiv},
keywords = {HIV,OA,Tuberculous meningitis,aspirin,fund{\_}ack,linezolid,original,rifampicin},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jul},
pages = {2022.07.26.22278065},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{A phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for HIV-associated tuberculous meningitis (The LASER-TBM Trial)}},
url = {https://www.medrxiv.org/content/10.1101/2022.07.26.22278065v1 https://www.medrxiv.org/content/10.1101/2022.07.26.22278065v1.abstract},
year = {2022}
}

Background: Drug regimens which include intensified antibiotics alongside effective anti-inflammatory therapies may improve outcomes in Tuberculous Meningitis (TBM). Safety data on their use in combination and in the context of HIV is needed to inform clinical trial design. Methods: We conducted a phase 2 open-label parallel-design RCT to assess safety of high-dose rifampicin, linezolid and aspirin in HIV-associated TBM. Participants were randomised (1.4:1:1) to three treatment arms (arm 1, standard of care (SOC); arm 2 SOC + additional rifampicin (up to 35mg/kg/day)) + linezolid 1200mg/day reducing after 28/7 to 600mg/day; arm 3, as per arm 2 + aspirin 1000mg/day) for 56 days, when the primary outcome of adverse events of special interest (AESI) or death was assessed. Results: 52 participants were randomised. 59% had mild disease (MRC Grade 1) vs 39% (Grade 2) vs 2% (Grade 3). 33% of participants had microbiologically-confirmed TBM; vs 41% possible or 25% probable. AESI or death occurred in 10/16 (arm 3) vs 4/14 (arm 2) vs 6/20 (arm 1) (p=0.083). The cumulative proportion of AESI or death (Kaplan-Meier method) demonstrated worse outcomes in arm 3 vs arm 1 (p=0.04), however only one event in arm 3 was attributable to aspirin and was mild. There was no difference in efficacy (Modified Rankin Scale) at day 56 between the three arms. Conclusions: High-dose rifampicin and adjunctive linezolid can safely be added to SOC in HIV-associated TBM. Larger studies are required to evaluate whether potential toxicity associated with these interventions, particularly aspirin, is outweighed by mortality or morbidity benefit. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT03927313 ### Clinical Protocols \textlesshttps://wellcomeopenresearch.org/articles/6-136\textgreater ### Funding Statement This study and the investigators listed are supported by Wellcome, EDCTP, Department of Science and Technology (South Africa), Research Councils UK, Cancer Research UK, Meningitis Now and National Institutes of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Approval for the trial was granted by the University of Cape Town Human Research Ethics Committee (293/2018), Walter Sisulu University Human Research Committee (012/2019) and the South African Health Products Regulatory Authority (20180622). The trial was registered on the South African National Clinical Trials Register (DOH-27-0319-6230), Pan African National Clinical Trials Register (PACTR201902921101705) and clinicaltrials.gov ([NCT03927313][1]). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03927313&atom=%2Fmedrxiv%2Fearly%2F2022%2F07%2F26%2F2022.07.26.22278065.atom

@article{Kitchin2022,
abstract = {Summary The Janssen (Johnson {\&} Johnson) Ad26.COV2.S non-replicating viral vector vaccine has been widely deployed for COVID-19 vaccination programs in resource-limited settings. Here we confirm that neutralizing and binding antibody responses to Ad26.COV2.S vaccination are stable for 6 months post-vaccination, when tested against multiple SARS-CoV-2 variants. Secondly, using longitudinal samples from individuals who experienced clinically mild breakthrough infections 4 to 5 months after vaccination, we show dramatically boosted binding antibodies, Fc effector function, and neutralization. These high titer responses are of similar magnitude to humoral immune responses measured in convalescent donors who had been hospitalized with severe illness, and are cross-reactive against diverse SARS-CoV-2 variants, including the neutralization-resistant Omicron (B.1.1.529) variant that currently dominates global infections, as well as SARS-CoV-1. These data have implications for population immunity in areas where the Ad26.COV2.S vaccine has been widely deployed, but where ongoing infections continue to occur at high levels.},
author = {Kitchin, Dale and Richardson, Simone I and van der Mescht, Mieke A and Motlou, Thopisang and Mzindle, Nonkululeko and Moyo-Gwete, Thandeka and Makhado, Zanele and Ayres, Frances and Manamela, Nelia P and Spencer, Holly and Lambson, Bronwen and Oosthuysen, Brent and Kaldine, Haajira and du Pisanie, Marizane and Mennen, Mathilda and Skelem, Sango and Williams, Noleen and Ntusi, Ntobeko A B and Burgers, Wendy A and Gray, Glenda G and Bekker, Linda-Gail and Boswell, Michael T and Rossouw, Theresa M and Ueckermann, Veronica and Moore, Penny L},
doi = {10.1016/J.XCRM.2022.100535},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Kitchin et al. - 2022 - Ad26.COV2.S breakthrough infections induce high titers of neutralizing antibodies against Omicron and other SARS.pdf:pdf},
issn = {2666-3791},
journal = {Cell Reports Medicine},
keywords = {Ad26.COV2.S,OA,Omicron,SARS-CoV-2,Variant of concern,antibody-dependent cellular cytotoxicity,breakthrough infection,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {feb},
number = {3},
pages = {100535},
pmid = {35474744},
publisher = {Elsevier},
title = {{Ad26.COV2.S breakthrough infections induce high titers of neutralizing antibodies against Omicron and other SARS-CoV-2 variants of concern}},
url = {http://www.cell.com/article/S2666379122000350/fulltext http://www.cell.com/article/S2666379122000350/abstract https://www.cell.com/cell-reports-medicine/abstract/S2666-3791(22)00035-0},
volume = {3},
year = {2022}
}

Summary The Janssen (Johnson & Johnson) Ad26.COV2.S non-replicating viral vector vaccine has been widely deployed for COVID-19 vaccination programs in resource-limited settings. Here we confirm that neutralizing and binding antibody responses to Ad26.COV2.S vaccination are stable for 6 months post-vaccination, when tested against multiple SARS-CoV-2 variants. Secondly, using longitudinal samples from individuals who experienced clinically mild breakthrough infections 4 to 5 months after vaccination, we show dramatically boosted binding antibodies, Fc effector function, and neutralization. These high titer responses are of similar magnitude to humoral immune responses measured in convalescent donors who had been hospitalized with severe illness, and are cross-reactive against diverse SARS-CoV-2 variants, including the neutralization-resistant Omicron (B.1.1.529) variant that currently dominates global infections, as well as SARS-CoV-1. These data have implications for population immunity in areas where the Ad26.COV2.S vaccine has been widely deployed, but where ongoing infections continue to occur at high levels.

@article{Ariza-Vioque2022,
abstract = {Tuberculous meningitis (TBM) is the most severe and disabling form of tuberculosis (TB), with at least 100,000 cases per year and a mortality rate of up to 50{\%} in individuals co-infected with human immunodeficiency virus type 1 (HIV-1). To evaluate the efficacy and safety of an intensified anti-tubercular regimen and an anti-inflammatory treatment, the INTENSE-TBM project includes a phase III randomised clinical trial (TBM-RCT) in four countries in sub-Saharan Africa (SSA). Within this framework, we designed a comprehensive capacity-building work package ensuring all centres had, or would acquire, the ability to conduct the TBM-RCT and developing a network of skilled researchers, clinical centres and microbiology laboratories. Here, we describe these activities, identify strengths/challenges and share tools adaptable to other projects, particularly in low- and lower-middle income countries with heterogeneous settings and during the coronavirus disease 2019 (COVID-19) pandemic. Despite major challenges, TBM-RCT initiation was achieved in all sites, promoting enhanced local healthcare systems and encouraging further clinical research in SSA. In terms of certified trainings, the achievement levels were 95{\%} (124/131) for good clinical practice, 91{\%} (39/43) for good clinical laboratory practice and 91{\%} (48/53) for infection prevention and control. Platform-based research, developed as part of capacity-building activities for specific projects, may be a valuable tool in fighting future infectious diseases and in developing high-level research in Africa. The INTENSE-TBM project aimed to design a comprehensive work-package on capacity building, ensuring all centres would acquire the ability to conduct a phase III randomised clinical trial on TBM in sub-Saharan Africa, to reduce tuberculous meningitis mortality and morbidity in patients with/without HIV-1 co-infection. Therefore, the INTENSE-TBM project is an example of how an international clinical research consortium can provide opportunities to enhance local capacity building and promote centres without previous experience in clinical research. This article provides practical approaches for implementing effective capacity-building programmes. We highlight how to overcome limitations imposed by the COVID-19 pandemic to successfully complete clinics, laboratory set-ups and personnel training, so as to optimise resources and empower African institutions on a local level. At the same time, our experience shows how capacity-building programmes can deliver long-lasting impact that extends beyond the original aims of the project (e.g. HIV and TB), and support local health systems in fighting other infectious disease (e.g. COVID-19). Research projects in low- and lower-middle income countries with heterogeneous settings could stand to benefit the most.},
author = {Ariza-Vioque, E and Ello, F and Andriamamonjisoa, H and Machault, V and Gonz{\'{a}}lez-Mart{\'{i}}n, J and Calvo-Cort{\'{e}}s, M C and Eholi{\'{e}}, S and Tchabert, G A and Ouassa, T. and Raberahona, M and Rakotoarivelo, R and Razafindrakoto, H. and Rahajamanana, L and Wilkinson, Robert J and Davis, Angharad G and Maxebengula, Mpumi and Abrahams, F and Muzoora, C and Nakigozi, N and Nyehangane, D and Nanjebe, D and Mbega, H and Kaitano, R and Bonnet, M and Debeaudrap, P and Mir{\'{o}}, J M and Anglaret, X and Rakotosamimanana, N and Calmy, A and Bonnet, F and Ambrosioni, J},
doi = {10.1007/S40121-022-00667-Z},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Ariza-Vioque et al. - 2022 - Capacity building in sub-Saharan Africa as part of the INTENSE-TBM project during the COVID-19 pandemic.pdf:pdf},
issn = {2193-6382},
journal = {Infectious Diseases and Therapy},
keywords = {Clinical research,HIV,INTENSE-TBM,Infectious Diseases,Internal Medicine,OA,OA{\_}PMC,Tuberculous meningitis,commentary,fund{\_}not{\_}ack},
mendeley-tags = {OA,OA{\_}PMC,commentary,fund{\_}not{\_}ack},
month = {jun},
pages = {10.1007/s40121--022--00667--z},
pmid = {35767219},
publisher = {Springer},
title = {{Capacity building in sub-Saharan Africa as part of the INTENSE-TBM project during the COVID-19 pandemic}},
url = {https://link.springer.com/article/10.1007/s40121-022-00667-z},
year = {2022}
}

Tuberculous meningitis (TBM) is the most severe and disabling form of tuberculosis (TB), with at least 100,000 cases per year and a mortality rate of up to 50% in individuals co-infected with human immunodeficiency virus type 1 (HIV-1). To evaluate the efficacy and safety of an intensified anti-tubercular regimen and an anti-inflammatory treatment, the INTENSE-TBM project includes a phase III randomised clinical trial (TBM-RCT) in four countries in sub-Saharan Africa (SSA). Within this framework, we designed a comprehensive capacity-building work package ensuring all centres had, or would acquire, the ability to conduct the TBM-RCT and developing a network of skilled researchers, clinical centres and microbiology laboratories. Here, we describe these activities, identify strengths/challenges and share tools adaptable to other projects, particularly in low- and lower-middle income countries with heterogeneous settings and during the coronavirus disease 2019 (COVID-19) pandemic. Despite major challenges, TBM-RCT initiation was achieved in all sites, promoting enhanced local healthcare systems and encouraging further clinical research in SSA. In terms of certified trainings, the achievement levels were 95% (124/131) for good clinical practice, 91% (39/43) for good clinical laboratory practice and 91% (48/53) for infection prevention and control. Platform-based research, developed as part of capacity-building activities for specific projects, may be a valuable tool in fighting future infectious diseases and in developing high-level research in Africa. The INTENSE-TBM project aimed to design a comprehensive work-package on capacity building, ensuring all centres would acquire the ability to conduct a phase III randomised clinical trial on TBM in sub-Saharan Africa, to reduce tuberculous meningitis mortality and morbidity in patients with/without HIV-1 co-infection. Therefore, the INTENSE-TBM project is an example of how an international clinical research consortium can provide opportunities to enhance local capacity building and promote centres without previous experience in clinical research. This article provides practical approaches for implementing effective capacity-building programmes. We highlight how to overcome limitations imposed by the COVID-19 pandemic to successfully complete clinics, laboratory set-ups and personnel training, so as to optimise resources and empower African institutions on a local level. At the same time, our experience shows how capacity-building programmes can deliver long-lasting impact that extends beyond the original aims of the project (e.g. HIV and TB), and support local health systems in fighting other infectious disease (e.g. COVID-19). Research projects in low- and lower-middle income countries with heterogeneous settings could stand to benefit the most.

@article{Harrison2022,
abstract = {The AMBITION-cm phase III randomized controlled trial, conducted in east and southern Africa, showed that a single high dose (10 mg/kg) of liposomal amphotericin B, given with an optimized oral backbone of fluconazole and flucytosine, was non-inferior to the World Health Organization (WHO)-recommended regimen of seven days of amphotericin B deoxycholate plus flucytosine for treatment of HIV-associated cryptococcal meningitis, and has been incorporated into updated WHO treatment guidelines. We believe the trial findings also have important implications for the treatment of HIV-associated cryptococcal meningitis in high-income settings. We advance the arguments, supported by evidence where available, that the AMBITION-cm study regimen is likely to be (i) as fungicidal as the currently recommended 14-day liposomal amphotericin based treatments, (ii) better tolerated with fewer adverse effects, and (iii) confer significant economic and practical benefits, therefore should be included as a treatment option in guidance for HIV-associated cryptococcal treatment in high-income country settings.},
author = {Harrison, Thomas S and Lawrence, David S and Mwandumba, Henry C and Boulware, David R and Hosseinipour, Mina C and Lortholary, Olivier and Meintjes, Graeme and Mosepele, Mosepele and Jarvis, Joseph N},
doi = {10.1093/CID/CIAC792},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Harrison et al. - 2022 - How applicable is the single-dose AMBITION regimen for HIV-associated cryptococcal meningitis to high-income se.pdf:pdf},
issn = {1058-4838},
journal = {Clinical Infectious Diseases},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {sep},
pages = {ciac792},
pmid = {36166405},
title = {{How applicable is the single-dose AMBITION regimen for HIV-associated cryptococcal meningitis to high-income settings?}},
url = {https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac792/6724283},
year = {2022}
}

The AMBITION-cm phase III randomized controlled trial, conducted in east and southern Africa, showed that a single high dose (10 mg/kg) of liposomal amphotericin B, given with an optimized oral backbone of fluconazole and flucytosine, was non-inferior to the World Health Organization (WHO)-recommended regimen of seven days of amphotericin B deoxycholate plus flucytosine for treatment of HIV-associated cryptococcal meningitis, and has been incorporated into updated WHO treatment guidelines. We believe the trial findings also have important implications for the treatment of HIV-associated cryptococcal meningitis in high-income settings. We advance the arguments, supported by evidence where available, that the AMBITION-cm study regimen is likely to be (i) as fungicidal as the currently recommended 14-day liposomal amphotericin based treatments, (ii) better tolerated with fewer adverse effects, and (iii) confer significant economic and practical benefits, therefore should be included as a treatment option in guidance for HIV-associated cryptococcal treatment in high-income country settings.

@article{Jones2022,
abstract = {Lymphoblastic leukemia 1 (Lyl1) is a well-studied transcription factor known to exhibit oncogenic potential in various forms of leukemia with pivotal roles in hematopoietic stem cell biology. While its role in early hematopoiesis is well established, its function in mature innate cells is less explored. Here, we identified Lyl1 as a drastically perturbed gene in the Mycobacterium tuberculosis ( Mtb ) infected mouse macrophage transcriptome. We report that Lyl1 downregulation upon immune stimulation is a host-driven process regulated by NF$\kappa$B and MAP kinase pathways. Interestingly, Lyl1-deficient macrophages have decreased bacterial killing potential with reduced nitric oxide (NO) levels while expressing increased levels of pro-inflammatory interleukin-1 and CXCL1. Lyl1-deficient mice show reduced survival to Mtb HN878 infection with increased bacterial burden and exacerbated inflammatory responses in chronic stages. We observed that increased susceptibility to infection was accompanied by increased neutrophil recruitment and IL-1, CXCL1, and CXCL5 levels in the lung homogenates. Collectively, these results suggest that Lyl1 controls Mtb growth, reduces neutrophilic inflammation and reveals an underappreciated role for Lyl1 in innate immune responses.},
author = {Jones, Shelby-Sara and Ozturk, Mumin and Kieswetter, Nathan Scott and Poswayo, Sibongiseni K L and Hazra, Rudranil and Tamgue, Ousman and Parihar, Suraj P and Suzuki, Harukazu and Brombacher, Frank and Guler, Reto},
doi = {10.3389/FIMMU.2022.948047/BIBTEX},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Jones et al. - 2022 - Lyl1-deficiency promotes inflammatory responses and increases mycobacterial burden in response to Mycobacterium tu.pdf:pdf},
issn = {16643224},
journal = {Frontiers in Immunology},
keywords = {Innate  immunity,Mycobacerium tuberculosis,Neutrophilic inflammation,OA,fund{\_}ack,lymphoblastic leukemia 1,original,transcription factor},
mendeley-tags = {OA,fund{\_}ack,original},
month = {sep},
pages = {948047},
pmid = {36119114},
publisher = {Frontiers Media SA},
title = {{Lyl1-deficiency promotes inflammatory responses and increases mycobacterial burden in response to Mycobacterium tuberculosis infection in mice}},
volume = {13},
year = {2022}
}

Lymphoblastic leukemia 1 (Lyl1) is a well-studied transcription factor known to exhibit oncogenic potential in various forms of leukemia with pivotal roles in hematopoietic stem cell biology. While its role in early hematopoiesis is well established, its function in mature innate cells is less explored. Here, we identified Lyl1 as a drastically perturbed gene in the Mycobacterium tuberculosis ( Mtb ) infected mouse macrophage transcriptome. We report that Lyl1 downregulation upon immune stimulation is a host-driven process regulated by NF$κ$B and MAP kinase pathways. Interestingly, Lyl1-deficient macrophages have decreased bacterial killing potential with reduced nitric oxide (NO) levels while expressing increased levels of pro-inflammatory interleukin-1 and CXCL1. Lyl1-deficient mice show reduced survival to Mtb HN878 infection with increased bacterial burden and exacerbated inflammatory responses in chronic stages. We observed that increased susceptibility to infection was accompanied by increased neutrophil recruitment and IL-1, CXCL1, and CXCL5 levels in the lung homogenates. Collectively, these results suggest that Lyl1 controls Mtb growth, reduces neutrophilic inflammation and reveals an underappreciated role for Lyl1 in innate immune responses.

@article{McIlleron2022,
author = {McIlleron, Helen},
doi = {10.1111/BCP.15220},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/McIlleron - 2022 - Treating children with tuberculosis—using pharmacometrics to do better.pdf:pdf},
issn = {1365-2125},
journal = {British Journal of Clinical Pharmacology},
keywords = {OA,commentary,dose,fund{\_}not{\_}ack,paediatric,pharmacokinetics,tuberculosis treatment},
mendeley-tags = {OA,commentary,fund{\_}not{\_}ack},
month = {jan},
number = {3},
pages = {894--896},
publisher = {John Wiley {\&} Sons, Ltd},
title = {{Treating children with tuberculosis—using pharmacometrics to do better}},
url = {https://onlinelibrary.wiley.com/doi/full/10.1111/bcp.15220 https://onlinelibrary.wiley.com/doi/abs/10.1111/bcp.15220 https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.15220},
volume = {88},
year = {2022}
}

@article{Steigler2022,
abstract = {Background: In the Investigation of the Management of Pericarditis (IMPI) randomized control, 2x2 factorial trial, Mycobacterium indicus pranii (MIP) immunotherapy, adjunctive corticosteroids or MIP combined with corticosteroids was compared to standard tuberculosis (TB) therapy for tuberculous pericarditis (TBP). While MIP and/or the combination of MIP and corticosteroids had no impact on all-cause mortality or pericarditis related outcomes, corticosteroids reduced the incidence of constrictive pericarditis at 12 months. Data suggests that both adjunctive therapies modulate the immune and inflammatory responses to pulmonary TB. Whether they affect systemic antigen-specific T cell responses, key immune mediators of Mycobacterium tuberculosis control, in patients with TBP is unknown. Methods: Participants with definite or probable TBP were randomly assigned to receive five injections of MIP or placebo at 2-week intervals and either 6 weeks of oral prednisolone or placebo. Frequencies of CD4 and CD8 T cells expressing IFN-$\gamma$, IL-2 or TNF in response to MIP or purified protein derivative stimulation were measured by intracellular cytokine staining and flow cytometry up to 24 weeks post treatment. Results: Immunotherapy with MIP did not significantly modulate frequencies of Th1 CD4 and CD8 T cells compared to placebo. Adjunctive prednisolone also did not change mycobacteria-specific CD4 or CD8 T cell responses. By contrast, combinatorial therapy with MIP and prednisolone was associated with a modest increase in frequencies of multifunctional and single cytokine-expressing CD4 T cell responses at 6 and 24 weeks post treatment. Conclusions: Consistent with the lack of a significant clinical effect in the IMPI trial, MIP immunotherapy did not significantly modulate mycobacteria-specific T cell responses. Despite the positive effect of prednisolone on hospitalizations and constrictive pericarditis in the IMPI trial, prednisolone did not significantly reduce pro-inflammatory T cell responses in this sub-study. The modest improvement of mycobacteria-specific T cell upon combinatorial therapy with MIP and prednisolone requires further investigation.},
author = {Steigler, Pia and Chhiba, Mukesh and Francis, Veronica and Keyser, Alana and Abrahams, Deborah and Hanekom, Willem and Ntsekhe, Mpiko and Scriba, Thomas J},
doi = {10.1016/J.JVACX.2022.100177},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Steigler et al. - 2022 - T cell responses to Mycobacterium indicus pranii immunotherapy and adjunctive glucocorticoid therapy in tubercu.pdf:pdf},
issn = {2590-1362},
journal = {Vaccine: X},
keywords = {OA,OA{\_}PMC,fund{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,original},
month = {aug},
pages = {100177},
pmid = {35755143},
publisher = {Elsevier},
title = {{T cell responses to \textit{Mycobacterium indicus pranii} immunotherapy and adjunctive glucocorticoid therapy in tuberculous pericarditis}},
volume = {11},
year = {2022}
}

Background: In the Investigation of the Management of Pericarditis (IMPI) randomized control, 2x2 factorial trial, Mycobacterium indicus pranii (MIP) immunotherapy, adjunctive corticosteroids or MIP combined with corticosteroids was compared to standard tuberculosis (TB) therapy for tuberculous pericarditis (TBP). While MIP and/or the combination of MIP and corticosteroids had no impact on all-cause mortality or pericarditis related outcomes, corticosteroids reduced the incidence of constrictive pericarditis at 12 months. Data suggests that both adjunctive therapies modulate the immune and inflammatory responses to pulmonary TB. Whether they affect systemic antigen-specific T cell responses, key immune mediators of Mycobacterium tuberculosis control, in patients with TBP is unknown. Methods: Participants with definite or probable TBP were randomly assigned to receive five injections of MIP or placebo at 2-week intervals and either 6 weeks of oral prednisolone or placebo. Frequencies of CD4 and CD8 T cells expressing IFN-$γ$, IL-2 or TNF in response to MIP or purified protein derivative stimulation were measured by intracellular cytokine staining and flow cytometry up to 24 weeks post treatment. Results: Immunotherapy with MIP did not significantly modulate frequencies of Th1 CD4 and CD8 T cells compared to placebo. Adjunctive prednisolone also did not change mycobacteria-specific CD4 or CD8 T cell responses. By contrast, combinatorial therapy with MIP and prednisolone was associated with a modest increase in frequencies of multifunctional and single cytokine-expressing CD4 T cell responses at 6 and 24 weeks post treatment. Conclusions: Consistent with the lack of a significant clinical effect in the IMPI trial, MIP immunotherapy did not significantly modulate mycobacteria-specific T cell responses. Despite the positive effect of prednisolone on hospitalizations and constrictive pericarditis in the IMPI trial, prednisolone did not significantly reduce pro-inflammatory T cell responses in this sub-study. The modest improvement of mycobacteria-specific T cell upon combinatorial therapy with MIP and prednisolone requires further investigation.

@article{Nyakato2022,
abstract = {BACKGROUND: Antiretroviral therapy (ART) program mortality maybe underestimated if deceased patients are misclassified as lost. METHODS: We used two-stage inverse probability weighting to account for probability of being: sampled for tracing and found by the tracer. RESULTS: Among 680 children and youth aged {\textless}25 years on ART who were lost and traced in Southern Africa between October 2017-November 2019, estimated mortality was high at 9.1{\%} (62/680). After adjusting for measured covariates and within-site clustering, mortality remained lower for young adults aged 20-24 years compared to infants aged {\textless}2years (adjusted Hazard ratio (aHR): 0.40 (95{\%} confidence interval (CI): 0.31, 0.51)). CONCLUSIONS: Our study confirms high unreported mortality in children and youth who are lost and the need for tracing to assess vital status among those who are lost to accurately report on program mortality.},
author = {Nyakato, Patience and Christ, Benedikt and Anderegg, Nanina and Muhairwe, Josephine and Jefferys, Laura and van Dijk, Janneke and Vinikoor, Michael J and van Lettow, Monique and Chimbetete, Cleophas and Phiri, Sam J and Egger, Matthias and Ballif, Marie and Yiannoutsos, Constantin T and Schomaker, Michael and Kassanjee, Reshma and Davies, Mary-Ann and Cornell, Morna},
doi = {10.1097/QAI.0000000000003090},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Nyakato et al. - 2022 - High unreported mortality in children and youth (25 years) living with HIV who were lost to care from antiretrov.pdf:pdf},
issn = {1525-4135},
journal = {JAIDS},
keywords = {OA{\_}PMC,OA{\_}repository,fund{\_}ack,original},
mendeley-tags = {OA{\_}PMC,OA{\_}repository,fund{\_}ack,original},
month = {dec},
number = {5},
pages = {429--433},
pmid = {36099024},
publisher = {Ovid Technologies (Wolters Kluwer Health)},
title = {{High unreported mortality in children and youth ({\textless}25 years) living with HIV who were lost to care from antiretroviral therapy programs in southern Africa: results from a multicountry tracing study}},
url = {https://journals.lww.com/jaids/Fulltext/2022/12150/High{\_}Unreported{\_}Mortality{\_}in{\_}Children{\_}and{\_}Youth.2.aspx https://boris.unibe.ch/172865/1/High{\_}unreported{\_}mortality{\_}in{\_}children{\_}and{\_}youth.108.pdf https://pubmed.ncbi.nlm.nih.gov/36099024/},
volume = {91},
year = {2022}
}

BACKGROUND: Antiretroviral therapy (ART) program mortality maybe underestimated if deceased patients are misclassified as lost. METHODS: We used two-stage inverse probability weighting to account for probability of being: sampled for tracing and found by the tracer. RESULTS: Among 680 children and youth aged \textless25 years on ART who were lost and traced in Southern Africa between October 2017-November 2019, estimated mortality was high at 9.1% (62/680). After adjusting for measured covariates and within-site clustering, mortality remained lower for young adults aged 20-24 years compared to infants aged \textless2years (adjusted Hazard ratio (aHR): 0.40 (95% confidence interval (CI): 0.31, 0.51)). CONCLUSIONS: Our study confirms high unreported mortality in children and youth who are lost and the need for tracing to assess vital status among those who are lost to accurately report on program mortality.

@article{Gatley2022,
abstract = {Background: Staphylococcus aureus bacteraemia is associated with high hospital mortality. Improvements in outcome have been described with standardised bundles of care. Objectives: To study the adherence of a standardised bundle of care (BOC) recommendations using a consultation pro forma, for all patients admitted with S. aureus bacteraemia to Groote Schuur Hospital over a year. The study further aimed to describe the 90-day mortality in these patients and to assess for an association between adherence to the bundle of care and outcome. Method: A retrospective audit of all unsolicited infectious disease consultations for patients with S. aureus bacteraemia admitted to Groote Schuur Hospital during 2018. Adherence to recommendations of a standard bundle of care was audited. Results: A total of 86 patients were included in the study: 61 (71{\%}) with hospital-associated infection and 25 (29{\%}) with community-associated infection. Over 80{\%} of adherence to treatment recommendations was achieved regarding antibiotic (including vancomycin) usage, source control and use of echocardiography as required. In-hospital mortality was 16{\%}, while the overall 90-day mortality was 18{\%}, with only age as an independent predictor of mortality. No association between adherence to the bundle of care and outcome was found. Conclusion: Adherence to a simple, structured bundle of care was good when using standardised pro forma as communication tools for advice and a structured antibiotic chart for vancomycin administration. Although adherence was not associated with outcome, the overall mortality for S. aureus bacteraemia was improving in the institution under study. Contribution: Our findings support feasibility and ongoing use of bundles of care for S. aureus bacteraemia in similar settings.},
author = {Gatley, Elizabeth M and Boyles, Tom and Dlamini, Sipho and Mendelson, Marc and Namale, Phiona E and Raubenheimer, Peter J and Wasserman, Sean and Gatley, Elizabeth},
doi = {10.4102/SAJID.V37I1.445},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Gatley et al. - 2022 - Adherence to a care bundle for Staphylococcus aureus bacteraemia a retrospective cohort study.pdf:pdf},
issn = {2313-1810},
journal = {Southern African Journal of Infectious Diseases},
keywords = {Infectious diseases,OA,Staphylococcus aureus bacteraemia,adherence,bacterial,bloodstream infections,bundle of care,clinical,communicable,diagnosis,epidemiology,fund{\_}ack,fungal,infectious disease consultation,laboratory,original,parasitic,treatment,viral},
mendeley-tags = {OA,fund{\_}ack,original},
month = {nov},
number = {1},
pages = {9},
title = {{Adherence to a care bundle for Staphylococcus aureus bacteraemia: a retrospective cohort study}},
url = {https://sajid.co.za/index.php/sajid/article/view/445/1103 https://sajid.co.za/index.php/sajid/article/view/445/1104 https://sajid.co.za/index.php/sajid/article/view/445/1105 https://sajid.co.za/index.php/sajid/article/view/445},
volume = {37},
year = {2022}
}

Background: Staphylococcus aureus bacteraemia is associated with high hospital mortality. Improvements in outcome have been described with standardised bundles of care. Objectives: To study the adherence of a standardised bundle of care (BOC) recommendations using a consultation pro forma, for all patients admitted with S. aureus bacteraemia to Groote Schuur Hospital over a year. The study further aimed to describe the 90-day mortality in these patients and to assess for an association between adherence to the bundle of care and outcome. Method: A retrospective audit of all unsolicited infectious disease consultations for patients with S. aureus bacteraemia admitted to Groote Schuur Hospital during 2018. Adherence to recommendations of a standard bundle of care was audited. Results: A total of 86 patients were included in the study: 61 (71%) with hospital-associated infection and 25 (29%) with community-associated infection. Over 80% of adherence to treatment recommendations was achieved regarding antibiotic (including vancomycin) usage, source control and use of echocardiography as required. In-hospital mortality was 16%, while the overall 90-day mortality was 18%, with only age as an independent predictor of mortality. No association between adherence to the bundle of care and outcome was found. Conclusion: Adherence to a simple, structured bundle of care was good when using standardised pro forma as communication tools for advice and a structured antibiotic chart for vancomycin administration. Although adherence was not associated with outcome, the overall mortality for S. aureus bacteraemia was improving in the institution under study. Contribution: Our findings support feasibility and ongoing use of bundles of care for S. aureus bacteraemia in similar settings.

@article{Ford2022,
abstract = {Summary Background The identification and appropriate management of people with advanced HIV disease is a key component in the HIV response. People with HIV who are hospitalised are at a higher risk of death, a risk that might persist after discharge. The aims of this study were to estimate the frequency of negative post-discharge outcomes, and to determine risk factors for such outcomes in people with HIV. Methods Using a broad search strategy combining terms for hospital discharge and HIV infection, we searched MEDLINE via PubMed and Embase from Jan 1, 2003 to Nov 30, 2021 to identify studies reporting outcomes among people with HIV following discharge from hospital. We estimated pooled proportions of readmissions and deaths after hospital discharge using random-effects models. We also did subgroup analyses by setting, region, duration of follow-up, and advanced HIV status at admission, and sensitivity analyses to assess heterogeneity. Findings We obtained data from 29 cohorts, which reported outcomes of people living with HIV after hospital discharge in 92 781 patients. The pooled proportion of patients readmitted to hospital after discharge was 18{\textperiodcentered}8{\%} (95{\%} CI 15{\textperiodcentered}3–22{\textperiodcentered}3) and 14{\textperiodcentered}1{\%} (10{\textperiodcentered}8–17{\textperiodcentered}3) died post-discharge. In sensitivity analyses, no differences were identified in the proportion of patients who were readmitted or died when comparing studies published before 2016 with those published after 2016. Post-discharge mortality was higher in studies from Africa (23{\textperiodcentered}1{\%} [16{\textperiodcentered}5–29{\textperiodcentered}7]) compared with the USA (7{\textperiodcentered}5{\%} [4{\textperiodcentered}4–10{\textperiodcentered}6]). For studies that reported both post-discharge mortality and readmission, the pooled proportion of patients who had this composite adverse outcome was 31{\textperiodcentered}7{\%} (23{\textperiodcentered}9–39{\textperiodcentered}5). Heterogeneity was moderate, and largely explained by patient status and linkage to care. Reported risk factors for readmission included low CD4 cell count at admission, longer length of stay, discharge against medical advice, and not linking to care following discharge; inpatient treatment with antiretroviral therapy (ART) during hospitalisation was protective of post- discharge mortality. Interpretation More than a quarter of patients with HIV had an adverse outcome after hospital discharge with no evidence of improvement in the past 15 years. This systematic review highlights the importance of ensuring post- discharge referral and appropriate management, including ART, to reduce mortality and readmission to hospital among this group of high-risk patients.},
author = {Ford, Nathan and Patten, Gabriela and Rangaraj, Ajay and Davies, Mary-Ann and Meintjes, Graeme A and Ellman, Tom},
doi = {10.1016/S2352-3018(21)00329-5},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Ford et al. - 2022 - Outcomes of people living with HIV after hospital discharge a systematic review and meta-analysis.pdf:pdf},
issn = {2352-3018},
journal = {The Lancet HIV},
keywords = {Gabriela Patten,MEDLINE,NCBI,NIH,NLM,Nathan Ford,National Center for Biotechnology Information,National Institutes of Health,National Library of Medicine,OA,PubMed Abstract,Tom Ellman,doi:10.1016/S2352-3018(21)00329-5,fund{\_}not{\_}ack,pmid:35245507,review},
mendeley-tags = {OA,fund{\_}not{\_}ack,review},
month = {mar},
number = {3},
pages = {e150--e159},
pmid = {35245507},
publisher = {Lancet HIV},
title = {{Outcomes of people living with HIV after hospital discharge: a systematic review and meta-analysis}},
url = {https://pubmed.ncbi.nlm.nih.gov/35245507/},
volume = {9},
year = {2022}
}

Summary Background The identification and appropriate management of people with advanced HIV disease is a key component in the HIV response. People with HIV who are hospitalised are at a higher risk of death, a risk that might persist after discharge. The aims of this study were to estimate the frequency of negative post-discharge outcomes, and to determine risk factors for such outcomes in people with HIV. Methods Using a broad search strategy combining terms for hospital discharge and HIV infection, we searched MEDLINE via PubMed and Embase from Jan 1, 2003 to Nov 30, 2021 to identify studies reporting outcomes among people with HIV following discharge from hospital. We estimated pooled proportions of readmissions and deaths after hospital discharge using random-effects models. We also did subgroup analyses by setting, region, duration of follow-up, and advanced HIV status at admission, and sensitivity analyses to assess heterogeneity. Findings We obtained data from 29 cohorts, which reported outcomes of people living with HIV after hospital discharge in 92 781 patients. The pooled proportion of patients readmitted to hospital after discharge was 18˙8% (95% CI 15˙3–22˙3) and 14˙1% (10˙8–17˙3) died post-discharge. In sensitivity analyses, no differences were identified in the proportion of patients who were readmitted or died when comparing studies published before 2016 with those published after 2016. Post-discharge mortality was higher in studies from Africa (23˙1% [16˙5–29˙7]) compared with the USA (7˙5% [4˙4–10˙6]). For studies that reported both post-discharge mortality and readmission, the pooled proportion of patients who had this composite adverse outcome was 31˙7% (23˙9–39˙5). Heterogeneity was moderate, and largely explained by patient status and linkage to care. Reported risk factors for readmission included low CD4 cell count at admission, longer length of stay, discharge against medical advice, and not linking to care following discharge; inpatient treatment with antiretroviral therapy (ART) during hospitalisation was protective of post- discharge mortality. Interpretation More than a quarter of patients with HIV had an adverse outcome after hospital discharge with no evidence of improvement in the past 15 years. This systematic review highlights the importance of ensuring post- discharge referral and appropriate management, including ART, to reduce mortality and readmission to hospital among this group of high-risk patients.

@article{Sawhney2022a,
abstract = {Host inflammatory responses are key to protection against injury; however, persistent inflammation is detrimental and contributes to morbidity and mortality. Herein, we demonstrated the anti-inflammatory role of Arteannuin-B (1) and its new spirocyclic-2-isoxazoline derivative JR-9 and their side effects in acute inflammatory condition in vivo using LPS-induced cytokines assay, carrageenan-induced paw edema, acetic acid-induced writhing and tail immersion. The results show that the spirocyclic-2-isoxazoline derivative is a potent anti-inflammatory agent with minimal cell toxicity as compared to Arteannuin-B. In addition, the efficacies of these compounds were also validated by flow cytometric, computational, and histopathological analysis. Our results show that the anti-inflammatory response of JR-9 significantly reduces the ability of mouse macrophages to produce NO, TNF-{\&}alpha;, and IL-6 following LPS stimulation. Therefore, JR-9 is a prospective candidate for the development of anti-inflammatory drugs and its molecular mechanism is likely related to the regulation of NF-{\&}kappa;B and MAPK signaling pathway.},
author = {Sawhney, Gifty and Rasool, Javeed Ur and Saroch, Diksha and Ozturk, Mumin and Brombacher, Frank and Ahmad, Bilal and Bhagat, Asha and Ali, Asif and Parihar, Suraj P. and Ahmed, Zabeer},
doi = {10.3390/MOLECULES27228068},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Sawhney et al. - 2022 - Arteannuin-B and (3-chlorophenyl)-2-spiroisoxazoline derivative exhibit anti-inflammatory effects in LPS-activat.pdf:pdf},
issn = {1420-3049},
journal = {Molecules},
keywords = {2,6,Arteannuin,B,BALB/c mice,IL,LPS,NF,OA,RAW 264.7 cells,TNF,cytokines,fund{\_}ack,iNOS,inflammation,isoxazoline derivative,original,spirocyclic,$\alpha$,$\kappa$B},
mendeley-tags = {OA,fund{\_}ack,original},
month = {nov},
pages = {8068},
pmid = {36432169},
publisher = {Multidisciplinary Digital Publishing Institute},
title = {{Arteannuin-B and (3-chlorophenyl)-2-spiroisoxazoline derivative exhibit anti-inflammatory effects in LPS-activated RAW 264.7 macrophages and BALB/c mice-induced proinflammatory responses via downregulation of NF-kappaB/P38 MAPK signaling}},
url = {https://www.mdpi.com/1420-3049/27/22/8068/htm https://www.mdpi.com/1420-3049/27/22/8068},
volume = {27},
year = {2022}
}

Host inflammatory responses are key to protection against injury; however, persistent inflammation is detrimental and contributes to morbidity and mortality. Herein, we demonstrated the anti-inflammatory role of Arteannuin-B (1) and its new spirocyclic-2-isoxazoline derivative JR-9 and their side effects in acute inflammatory condition in vivo using LPS-induced cytokines assay, carrageenan-induced paw edema, acetic acid-induced writhing and tail immersion. The results show that the spirocyclic-2-isoxazoline derivative is a potent anti-inflammatory agent with minimal cell toxicity as compared to Arteannuin-B. In addition, the efficacies of these compounds were also validated by flow cytometric, computational, and histopathological analysis. Our results show that the anti-inflammatory response of JR-9 significantly reduces the ability of mouse macrophages to produce NO, TNF-α, and IL-6 following LPS stimulation. Therefore, JR-9 is a prospective candidate for the development of anti-inflammatory drugs and its molecular mechanism is likely related to the regulation of NF-κB and MAPK signaling pathway.

@article{Zhao9000,
abstract = {Background: Integrase strand transfer inhibitors (InSTIs) decrease HIV plasma viral load faster than other antiretroviral classes. More rapid viral load decline has been associated with higher risk of immune reconstitution inflammatory syndrome (IRIS). There are conflicting reports on the association between InSTI and IRIS. We performed a systematic review and meta-analysis to compare the risk of IRIS among treatment-na{\"{i}}ve HIV-positive patients starting InSTI versus non-InSTI regimens. Methods: We searched PubMed, Scopus, Web of Science, Africa-Wide, and Cochrane databases from earliest available date to 26 November 2021, for randomised controlled trials (RCTs) having intervention arms with InSTI versus control arms without InSTI in patients initiating first-line antiretroviral therapy. The primary outcome was relative risk (RR) of IRIS, while the secondary outcome was RR of paradoxical tuberculosis-associated IRIS (TB-IRIS). Data were combined by random-effects meta-analysis according to the Mantel-Haenszel method. The protocol for this study is registered with PROSPERO, CRD42020213976. Results: We included 14 RCTs comprising 8696 participants from six continents for the primary outcome of IRIS, and a subset of 674 participants (from three RCTs) for the secondary outcome of paradoxical TB-IRIS. Risk of IRIS was similar between InSTI and non-InSTI regimens (RR, 0.93, 95{\%} confidence interval [CI], 0.75 – 1.14). There was a trend towards a lower risk of paradoxical TB-IRIS with InSTI versus efavirenz regimens that was not statistically significant (RR, 0.64, 95{\%} CI, 0.34 – 1.19). Conclusions: In this meta-analysis among treatment-na{\"{i}}ve patients commencing first-line antiretroviral therapy, InSTI regimens were not associated with higher risk of IRIS. Corresponding author Dr Ying Zhao Room N2.09, Werner Beit North, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa Email: zhxyin001@myuct.ac.za Conflicts of Interest and Sources of Funding: This work was supported by the Wellcome Trust through core funding from the Wellcome Centre for Infectious Diseases Research in Africa (203135/Z/16/Z). GrM was supported by the Wellcome Trust (214321/Z/18/Z) and the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (Grant No 64787). M.E.E. was supported by grant (NW17SFRN33630027) from the, American Heart Association. The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of this report. The opinions, findings and conclusions expressed in this manuscript reflect those of the authors alone. The authors have no conflicts of interest to disclose. * Contributed equally to this manuscript Copyright {\textcopyright} 2022 Wolters Kluwer Health, Inc. All rights reserved.},
author = {Zhao, Ying and Hohlfeld, Ameer and Namale, Phiona and Meintjes, Graeme and Maartens, Gary and Engel, Mark E},
doi = {10.1097/QAI.0000000000002937},
issn = {1525-4135},
journal = {Journal of Acquired Immune Deficiency Syndromes},
keywords = {Antiretroviral therapy,HIV,immune reconstitution inflammatory syndrome,integrase inhibitors,review},
mendeley-tags = {review},
title = {{Risk of immune reconstitution inflammatory syndrome with integrase inhibitors versus other classes of antiretrovirals: a systematic review and meta-analysis of randomised trials}},
url = {https://journals.lww.com/jaids/Fulltext/9000/Risk{\_}of{\_}immune{\_}reconstitution{\_}inflammatory.95690.aspx},
year = {2022}
}

Background: Integrase strand transfer inhibitors (InSTIs) decrease HIV plasma viral load faster than other antiretroviral classes. More rapid viral load decline has been associated with higher risk of immune reconstitution inflammatory syndrome (IRIS). There are conflicting reports on the association between InSTI and IRIS. We performed a systematic review and meta-analysis to compare the risk of IRIS among treatment-naïve HIV-positive patients starting InSTI versus non-InSTI regimens. Methods: We searched PubMed, Scopus, Web of Science, Africa-Wide, and Cochrane databases from earliest available date to 26 November 2021, for randomised controlled trials (RCTs) having intervention arms with InSTI versus control arms without InSTI in patients initiating first-line antiretroviral therapy. The primary outcome was relative risk (RR) of IRIS, while the secondary outcome was RR of paradoxical tuberculosis-associated IRIS (TB-IRIS). Data were combined by random-effects meta-analysis according to the Mantel-Haenszel method. The protocol for this study is registered with PROSPERO, CRD42020213976. Results: We included 14 RCTs comprising 8696 participants from six continents for the primary outcome of IRIS, and a subset of 674 participants (from three RCTs) for the secondary outcome of paradoxical TB-IRIS. Risk of IRIS was similar between InSTI and non-InSTI regimens (RR, 0.93, 95% confidence interval [CI], 0.75 – 1.14). There was a trend towards a lower risk of paradoxical TB-IRIS with InSTI versus efavirenz regimens that was not statistically significant (RR, 0.64, 95% CI, 0.34 – 1.19). Conclusions: In this meta-analysis among treatment-naïve patients commencing first-line antiretroviral therapy, InSTI regimens were not associated with higher risk of IRIS. Corresponding author Dr Ying Zhao Room N2.09, Werner Beit North, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa Email: zhxyin001@myuct.ac.za Conflicts of Interest and Sources of Funding: This work was supported by the Wellcome Trust through core funding from the Wellcome Centre for Infectious Diseases Research in Africa (203135/Z/16/Z). GrM was supported by the Wellcome Trust (214321/Z/18/Z) and the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (Grant No 64787). M.E.E. was supported by grant (NW17SFRN33630027) from the, American Heart Association. The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of this report. The opinions, findings and conclusions expressed in this manuscript reflect those of the authors alone. The authors have no conflicts of interest to disclose. * Contributed equally to this manuscript Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

@article{Zwyer2022,
abstract = {In settings with high tuberculosis (TB) endemicity, various genotypes of the Mycobacterium tuberculosis complex (MTBC) often differ in prevalence. However, the factors leading to these differences remain poorly understood. Here we studied the MTBC population in Dar es Salaam, Tanzania over a six-year period, using 1,082 unique patient-derived MTBC whole-genome sequences (WGS) and associated clinical data. We show that the TB epidemic in Dar es Salaam is dominated by multiple genotypes introduced to Tanzania from different parts of the world during the last 300 years. The most common MTBC genotypes deriving from these introductions exhibited differences in transmission rates and in the duration of the infectious period, but little differences in overall fitness, as measured by the effective reproductive number. Moreover, measures of disease severity and bacterial load indicated no differences in virulence between these genotypes during active TB. Instead, the combination of an early introduction and a high transmission rate accounted for the high prevalence of L3.1.1, the most dominant MTBC genotype in our setting. Yet, a longer co-existence with the host population did not always result in a higher transmission rate, suggesting that distinct life-history traits have evolved in the different MTBC genotypes. Taken together, our results point to bacterial factors as important determinants of the TB epidemic in Dar es Salaam. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Funding Statement This work was supported by the Swiss National Science Foundation (https://www.snf.ch; Grant No: CRSII5$\backslash${\_}177163, 310030$\backslash${\_}188888) and the European Research Council (https://erc.europa.eu/; Grant No: 883582). RJW is supported by the Francis Crick Institute which receives funding from Wellcome (FC0010218), Cancer Research UK (FC0010218), and the Medical Research Council (FC0010218). He also receives support from Welcome (203135). {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Nordwest und Zentralschweiz gave ethical approval for this work Ethics committee of Ifakara Health Institute Institutional Review Board board gave ethical approval for this work. Ethics committee of the National Institute for Medical Research in Tanzania Medical Research Coordinating Committee gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors},
author = {Zwyer, Michalela and Rutaihwa, Liliana K and Windels, Etthel and Hella, Jerry and Menardo, Fabrizio and Sasamalo, Mohamed and Borrell, Sonia and Reinhard, Miriam and D{\"{o}}tsch, Anna and Hiza, Hellen and Stritt, Christoph and Sikalengo, George and Fenner, Lukas and Jong, Bouke C De and Kato-Maeda, Midori and Jugheli, Levan and Ernst, Joel D and Niemann, Stephan and Jeljeli, Leila and Ballif, Marie and Egger, Matthias and Rakotosamimanana, Niaina and Yeboah-Manu, Dorothy and Asare, Prince and Malla, Bijaya and Dou, Horng Yunn and Zetola, Nicolas and Wilkinson, Robert J and Cox, Helen and Carter, E Jane and Gnokoro, Joachim and Yotebieng, Marcel and Gotuzzo, Eduardo and Abimiku, Alash'le and Anchalee, Avihingsanon and Xu, Zhi Ming and Fellay, Jacques and Portevin, Damien and Reither, Klaus and Stadler, Tanja and Gagneux, Sebastien and Brites, Daniela},
doi = {10.1101/2022.09.29.22280296},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Zwyer et al. - 2022 - Back-to-Africa introductions of Mycobacterium tuberculosis as the main cause of tuberculosis in Dar es Salaam, Tan.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}ack},
mendeley-tags = {OA,fund{\_}ack},
month = {sep},
pages = {2022.09.29.22280296},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Back-to-Africa introductions of Mycobacterium tuberculosis as the main cause of tuberculosis in Dar es Salaam, Tanzania}},
url = {https://www.medrxiv.org/content/10.1101/2022.09.29.22280296v1 https://www.medrxiv.org/content/10.1101/2022.09.29.22280296v1.abstract},
year = {2022}
}

In settings with high tuberculosis (TB) endemicity, various genotypes of the Mycobacterium tuberculosis complex (MTBC) often differ in prevalence. However, the factors leading to these differences remain poorly understood. Here we studied the MTBC population in Dar es Salaam, Tanzania over a six-year period, using 1,082 unique patient-derived MTBC whole-genome sequences (WGS) and associated clinical data. We show that the TB epidemic in Dar es Salaam is dominated by multiple genotypes introduced to Tanzania from different parts of the world during the last 300 years. The most common MTBC genotypes deriving from these introductions exhibited differences in transmission rates and in the duration of the infectious period, but little differences in overall fitness, as measured by the effective reproductive number. Moreover, measures of disease severity and bacterial load indicated no differences in virulence between these genotypes during active TB. Instead, the combination of an early introduction and a high transmission rate accounted for the high prevalence of L3.1.1, the most dominant MTBC genotype in our setting. Yet, a longer co-existence with the host population did not always result in a higher transmission rate, suggesting that distinct life-history traits have evolved in the different MTBC genotypes. Taken together, our results point to bacterial factors as important determinants of the TB epidemic in Dar es Salaam. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Swiss National Science Foundation (https://www.snf.ch; Grant No: CRSII5$\$_177163, 310030$\$_188888) and the European Research Council (https://erc.europa.eu/; Grant No: 883582). RJW is supported by the Francis Crick Institute which receives funding from Wellcome (FC0010218), Cancer Research UK (FC0010218), and the Medical Research Council (FC0010218). He also receives support from Welcome (203135). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Nordwest und Zentralschweiz gave ethical approval for this work Ethics committee of Ifakara Health Institute Institutional Review Board board gave ethical approval for this work. Ethics committee of the National Institute for Medical Research in Tanzania Medical Research Coordinating Committee gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

@article{Meier2022,
abstract = {Mycobacterium tuberculosis (M.tb) causes tuberculosis (TB) and remains one of the leading causes of mortality due to an infectious pathogen. Host immune responses have been implicated in driving the progression from infection to severe lung disease. We analyzed longitudinal RNA sequencing (RNAseq) data from the whole blood of 74 TB progressors whose samples were grouped into four six-month intervals preceding diagnosis (the GC6-74 study). We additionally analyzed RNAseq data from an independent cohort of 90 TB patients with positron emission tomography-computed tomography (PET-CT) scan results which were used to categorize them into groups with high and low levels of lung damage (the Catalysis TB Biomarker study). These groups were compared to non-TB controls to obtain a complete whole blood transcriptional profile for individuals spanning from early stages of M.tb infection to TB diagnosis. The results revealed a steady increase in the number of genes that were differentially expressed in progressors at time points closer to diagnosis with 278 genes at 13–18 months, 742 at 7–12 months and 5,131 detected 1–6 months before diagnosis and 9,205 detected in TB patients. A total of 2,144 differentially expressed genes were detected when comparing TB patients with high and low levels of lung damage. There was a large overlap in the genes upregulated in progressors 1–6 months before diagnosis (86{\%}) with those in TB patients. A comprehensive pathway analysis revealed a potent activation of neutrophil and platelet mediated defenses including neutrophil and platelet degranulation, and NET formation at both time points. These pathways were also enriched in TB patients with high levels of lung damage compared to those with low. These findings suggest that neutrophils and platelets play a critical role in TB pathogenesis, and provide details of the timing of specific effector mechanisms that may contribute to TB lung pathology.},
author = {Meier, Stuart and Seddon, James A and Maasdorp, Elizna and Kleynhans, L{\'{e}}anie and du Plessis, Nelita and Loxton, Andre G and Malherbe, Stephanus T and Zak, Daniel E and Thompson, Ethan and Duffy, Fergal J and Kaufmann, Stefan H E and Ottenhoff, Tom H M and Scriba, Thomas J and Suliman, Sara and Sutherland, Jayne S and Winter, Jill and Kuivaniemi, Helena and Walzl, Gerhard and Tromp, Gerard and {GC6-74 Consortium} and {Catalysis TB Biomarkers Consortium}},
doi = {10.1371/JOURNAL.PONE.0278295},
editor = {Mummidi, Srinivas},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Meier et al. - 2022 - Neutrophil degranulation, NETosis and platelet degranulation pathway genes are co-induced in whole blood up to six.pdf:pdf},
isbn = {1111111111},
issn = {1932-6203},
journal = {PLOS ONE},
keywords = {Catalysis,Gene expression,Gene ontologies,Mycobacterium tuberculosis,Neutrophils,OA,Platelets,Tuberculosis,Tuberculosis diagnosis and management,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {dec},
number = {12},
pages = {e0278295},
pmid = {36454773},
publisher = {Public Library of Science},
title = {{Neutrophil degranulation, NETosis and platelet degranulation pathway genes are co-induced in whole blood up to six months before tuberculosis diagnosis}},
url = {https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0278295},
volume = {17},
year = {2022}
}

Mycobacterium tuberculosis (M.tb) causes tuberculosis (TB) and remains one of the leading causes of mortality due to an infectious pathogen. Host immune responses have been implicated in driving the progression from infection to severe lung disease. We analyzed longitudinal RNA sequencing (RNAseq) data from the whole blood of 74 TB progressors whose samples were grouped into four six-month intervals preceding diagnosis (the GC6-74 study). We additionally analyzed RNAseq data from an independent cohort of 90 TB patients with positron emission tomography-computed tomography (PET-CT) scan results which were used to categorize them into groups with high and low levels of lung damage (the Catalysis TB Biomarker study). These groups were compared to non-TB controls to obtain a complete whole blood transcriptional profile for individuals spanning from early stages of M.tb infection to TB diagnosis. The results revealed a steady increase in the number of genes that were differentially expressed in progressors at time points closer to diagnosis with 278 genes at 13–18 months, 742 at 7–12 months and 5,131 detected 1–6 months before diagnosis and 9,205 detected in TB patients. A total of 2,144 differentially expressed genes were detected when comparing TB patients with high and low levels of lung damage. There was a large overlap in the genes upregulated in progressors 1–6 months before diagnosis (86%) with those in TB patients. A comprehensive pathway analysis revealed a potent activation of neutrophil and platelet mediated defenses including neutrophil and platelet degranulation, and NET formation at both time points. These pathways were also enriched in TB patients with high levels of lung damage compared to those with low. These findings suggest that neutrophils and platelets play a critical role in TB pathogenesis, and provide details of the timing of specific effector mechanisms that may contribute to TB lung pathology.

@article{Barmania2022,
abstract = {The SARS-CoV-2 virus is responsible for the COVID-19 global public health emergency, and the disease it causes is highly variable in its clinical presentation. Clinical phenotypes are heterogeneous both in terms of presentation of symptoms in the host and response to therapy. Several studies and initiatives have been established to analyse and review host genetic epidemiology associated with COVID-19. Our research group curated these articles into a web-based database using the python application-server framework Django. The database provides a searchable research tool describing current literature surrounding COVID-19 host genetic factors associated with disease outcome. This paper describes the COHG-SA database and provides an overview of the analyses that can be derived from these data.},
author = {Barmania, Fatima and Mellet, Juanita and Ryder, Megan A and Ford, Graeme and Herd, Candice L and Tamuhla, Tsaone and Hendricks, Candice and Giles, Rachel and Kalua, Thumbiko and Joubert, Fourie and Tiffin, Nicki and Pepper, Michael S},
doi = {10.1038/s41431-022-01089-8},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Barmania et al. - 2022 - Coronavirus Host Genetics South Africa (COHG-SA) database—a variant database for gene regions associated with S.pdf:pdf},
issn = {1476-5438},
journal = {European Journal of Human Genetics},
keywords = {Genetic databases,Immunogenetics,Mutation,OA,Viral infection,fund{\_}ack,review},
mendeley-tags = {OA,fund{\_}ack,review},
month = {mar},
pages = {https://doi.org/10.1038/s41431--022--01089--8},
pmid = {35351987},
publisher = {Nature Publishing Group},
title = {{Coronavirus Host Genetics South Africa (COHG-SA) database—a variant database for gene regions associated with SARS-CoV-2 outcomes}},
url = {https://www.nature.com/articles/s41431-022-01089-8},
year = {2022}
}

The SARS-CoV-2 virus is responsible for the COVID-19 global public health emergency, and the disease it causes is highly variable in its clinical presentation. Clinical phenotypes are heterogeneous both in terms of presentation of symptoms in the host and response to therapy. Several studies and initiatives have been established to analyse and review host genetic epidemiology associated with COVID-19. Our research group curated these articles into a web-based database using the python application-server framework Django. The database provides a searchable research tool describing current literature surrounding COVID-19 host genetic factors associated with disease outcome. This paper describes the COHG-SA database and provides an overview of the analyses that can be derived from these data.

@article{Spracklen2022,
abstract = {Introduction: Multisystem inflammatory syndrome in children (MIS-C) is a severe acute inflammatory reaction to SARS-CoV-2 infection in children. There are a lack of data describing differential expression of immune genes in MIS-C compared to healthy children or those with other inflammatory conditions and how expression changes over time. In this study, we investigated expression of immune-related genes in South African MIS-C patients and controls. Methods: The cohort included 30 pre-treatment MIS-C cases and 54 healthy non-inflammatory paediatric controls. Other controls included 34 patients with juvenile systemic lupus erythematosus, Kawasaki disease or other inflammatory conditions. Longitudinal post-treatment MIS-C specimens were available at various timepoints. Expression of 80 immune-related genes was determined by real-time quantitative PCR. Results: A total of 29 differentially expressed genes were identified in pre-treatment MIS-C compared to healthy controls. Up-regulated genes were found to be overrepresented in innate immune pathways including interleukin-1 processing and pyroptosis. Post-treatment follow-up data were available for up to 1,200 hours after first treatment. All down-regulated genes and 17/18 up-regulated genes resolved to normal levels in the timeframe, and all patients clinically recovered. When comparing MIS-C to other febrile conditions, only IL27 expression could differentiate these two groups with high sensitivity and specificity. Conclusions: These data indicate a unique 29-gene signature of MIS-C in South African children. The up-regulation of interleukin-1 and pyroptosis pathway genes highlights the role of the innate immune system in MIS-C. IL-27 is a potent anti-inflammatory and antiviral cytokine that may distinguish MIS-C from other conditions in our setting.},
author = {Spracklen, Timothy F and Mendelsohn, Simon C and Butters, Claire and Facey-Thomas, Heidi and Stander, Raphaella and Abrahams, Debbie and Erasmus, Mzwandile and Baguma, Richard and Day, Jonathan and Scott, Christiaan and Z{\"{u}}hlke, Liesl J and Kassiotis, George and Scriba, Thomas J and Webb, Kate},
doi = {10.3389/FIMMU.2022.992022},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Spracklen et al. - 2022 - IL27 gene expression distinguishes multisystem inflammatory syndrome in children from febrile illness in a Sou.pdf:pdf},
issn = {1664-3224},
journal = {Frontiers in Immunology},
keywords = {COVID - 19,Children,Multisystem inflammatory syndrome,OA,SARS-CoV-2,South Africa,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
pages = {992022},
publisher = {Frontiers},
title = {{IL27 gene expression distinguishes multisystem inflammatory syndrome in children from febrile illness in a South African cohort}},
volume = {13},
year = {2022}
}

Introduction: Multisystem inflammatory syndrome in children (MIS-C) is a severe acute inflammatory reaction to SARS-CoV-2 infection in children. There are a lack of data describing differential expression of immune genes in MIS-C compared to healthy children or those with other inflammatory conditions and how expression changes over time. In this study, we investigated expression of immune-related genes in South African MIS-C patients and controls. Methods: The cohort included 30 pre-treatment MIS-C cases and 54 healthy non-inflammatory paediatric controls. Other controls included 34 patients with juvenile systemic lupus erythematosus, Kawasaki disease or other inflammatory conditions. Longitudinal post-treatment MIS-C specimens were available at various timepoints. Expression of 80 immune-related genes was determined by real-time quantitative PCR. Results: A total of 29 differentially expressed genes were identified in pre-treatment MIS-C compared to healthy controls. Up-regulated genes were found to be overrepresented in innate immune pathways including interleukin-1 processing and pyroptosis. Post-treatment follow-up data were available for up to 1,200 hours after first treatment. All down-regulated genes and 17/18 up-regulated genes resolved to normal levels in the timeframe, and all patients clinically recovered. When comparing MIS-C to other febrile conditions, only IL27 expression could differentiate these two groups with high sensitivity and specificity. Conclusions: These data indicate a unique 29-gene signature of MIS-C in South African children. The up-regulation of interleukin-1 and pyroptosis pathway genes highlights the role of the innate immune system in MIS-C. IL-27 is a potent anti-inflammatory and antiviral cytokine that may distinguish MIS-C from other conditions in our setting.

@article{Tegally2022a,
abstract = {South Africa's fourth COVID-19 wave was driven predominantly by three lineages (BA.1, BA.2 and BA.3) of the SARS-CoV-2 Omicron variant of concern. We have now identified two new lineages, BA.4 and BA.5. The spike proteins of BA.4 and BA.5 are identical, and comparable to BA.2 except for the addition of 69-70del, L452R, F486V and the wild type amino acid at Q493. The 69-70 deletion in spike allows these lineages to be identified by the proxy marker of S-gene target failure with the TaqPath COVID-19 qPCR assay. BA.4 and BA.5 have rapidly replaced BA.2, reaching more than 50{\%} of sequenced cases in South Africa from the first week of April 2022 onwards. Using a multinomial logistic regression model, we estimate growth advantages for BA.4 and BA.5 of 0.08 (95{\%} CI: 0.07 - 0.09) and 0.12 (95{\%} CI: 0.09 - 0.15) per day respectively over BA.2 in South Africa. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Funding Statement This research was supported by the South African Medical Research Council (SAMRC) with funds received from the National Department of Health. Sequencing activities for NICD are supported by a conditional grant from the South African National Department of Health as part of the emergency COVID-19 response; a cooperative agreement between the National Institute for Communicable Diseases of the National Health Laboratory Service and the United States Centers for Disease Control and Prevention (CDC)(grant number 5 U01IP001048-05-00; 1 NU51IP000930-01-00); the African Society of Laboratory Medicine (ASLM) and Africa Centers for Disease Control and Prevention through a sub-award from the Bill and Melinda Gates Foundation grant number INV-018978; the UK Foreign, Commonwealth and Development Office and Wellcome (Grant no 221003/Z/20/Z); and the UK Department of Health and Social Care and managed by the Fleming Fund and performed under the auspices of the SEQAFRICA project. This research was also supported by The Coronavirus Aid, Relief, and Economic Security Act (CARES ACT) through the CDC and the COVID International Task Force (ITF) funds through the CDC under the terms of a subcontract with the African Field Epidemiology Network (AFENET) AF-NICD-001/2021. Sequencing activities at KRISP and CERI are supported in part by grants from the World Health Organization, the Abbott Pandemic Defense Coalition (APDC), the National Institute of Health USA (U01 AI151698) for the United World Antivirus Research Network (UWARN) and the INFORM Africa project through IHVN (U54 TW012041), and the South African Department of Science and Innovation (SA DSI) and the SAMRC under the BRICS JAF {\#}2020/049 {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The project was approved by University of KwaZulu-Natal Biomedical Research Ethics Committee (ref. BREC/00001510/2020), the University of the Witwatersrand Human Research Ethics Committee (HREC) (ref. M180832), Stellenbosch University HREC (ref. N20/04/008 COVID-19) and the University of Cape Town HREC (ref. 383/2020). Individual participant consent was not required for the genomic surveillance. This requirement was waived by the Research Ethics Committees. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced are available online at GISAID database.},
author = {Tegally, Houriiyah and Moir, Monika and Everatt, Josie and Giovanetti, Marta and Scheepers, Cathrine and Wilkinson, Eduan and Subramoney, Kathleen and Moyo, Sikhulile and Amoako, Daniel G and Baxter, Cheryl and Althaus, Christian L and Anyaneji, Ugochukwu J and Kekana, Dikeledi and Viana, Raquel and Giandhari, Jennifer and Lessells, Richard J and Maponga, Tongai and Maruapula, Dorcas and Choga, Wonderful and Matshaba, Mogomotsi and Mayaphi, Simnikiwe and Mbhele, Nokuzola and Mbulawa, Mpaphi B and Msomi, Nokukhanya and Consortium, Ngs-Sa and Naidoo, Yeshnee and Pillay, Sureshnee and Sanko, Tomasz Janusz and San, James E and Scott, Lesley and Singh, Lavanya and Magini, Nonkululeko A and Smith-Lawrence, Pamela and Stevens, Wendy and Dor, Graeme and Tshiabuila, Derek and Wolter, Nicole and Preiser, Wolfgang and Treurnicht, Florette K and Venter, Marietjie and Davids, Michaela and Chiloane, Georginah and Mendes, Adriano and Mcintyre, Caitlyn and O'toole, Aine and Ruis, Christopher and Peacock, Thomas P and Roemer, Cornelius and Williamson, Carolyn and Pybus, Oliver G and Bhiman, Jinal and Glass, Allison and Martin, Darren P and Rambaut, Andrew and Gaseitsiwe, Simani and {Von Gottberg}, Anne and {Tulio De Oliveira}, {\&}},
doi = {10.1101/2022.05.01.22274406},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Tegally et al. - 2022 - Continued emergence and evolution of Omicron in South Africa new BA.4 and BA.5 lineages.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {may},
pages = {2022.05.01.22274406},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Continued emergence and evolution of Omicron in South Africa: new BA.4 and BA.5 lineages}},
url = {https://www.medrxiv.org/content/10.1101/2022.05.01.22274406v1 https://www.medrxiv.org/content/10.1101/2022.05.01.22274406v1.abstract},
year = {2022}
}

South Africa's fourth COVID-19 wave was driven predominantly by three lineages (BA.1, BA.2 and BA.3) of the SARS-CoV-2 Omicron variant of concern. We have now identified two new lineages, BA.4 and BA.5. The spike proteins of BA.4 and BA.5 are identical, and comparable to BA.2 except for the addition of 69-70del, L452R, F486V and the wild type amino acid at Q493. The 69-70 deletion in spike allows these lineages to be identified by the proxy marker of S-gene target failure with the TaqPath COVID-19 qPCR assay. BA.4 and BA.5 have rapidly replaced BA.2, reaching more than 50% of sequenced cases in South Africa from the first week of April 2022 onwards. Using a multinomial logistic regression model, we estimate growth advantages for BA.4 and BA.5 of 0.08 (95% CI: 0.07 - 0.09) and 0.12 (95% CI: 0.09 - 0.15) per day respectively over BA.2 in South Africa. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was supported by the South African Medical Research Council (SAMRC) with funds received from the National Department of Health. Sequencing activities for NICD are supported by a conditional grant from the South African National Department of Health as part of the emergency COVID-19 response; a cooperative agreement between the National Institute for Communicable Diseases of the National Health Laboratory Service and the United States Centers for Disease Control and Prevention (CDC)(grant number 5 U01IP001048-05-00; 1 NU51IP000930-01-00); the African Society of Laboratory Medicine (ASLM) and Africa Centers for Disease Control and Prevention through a sub-award from the Bill and Melinda Gates Foundation grant number INV-018978; the UK Foreign, Commonwealth and Development Office and Wellcome (Grant no 221003/Z/20/Z); and the UK Department of Health and Social Care and managed by the Fleming Fund and performed under the auspices of the SEQAFRICA project. This research was also supported by The Coronavirus Aid, Relief, and Economic Security Act (CARES ACT) through the CDC and the COVID International Task Force (ITF) funds through the CDC under the terms of a subcontract with the African Field Epidemiology Network (AFENET) AF-NICD-001/2021. Sequencing activities at KRISP and CERI are supported in part by grants from the World Health Organization, the Abbott Pandemic Defense Coalition (APDC), the National Institute of Health USA (U01 AI151698) for the United World Antivirus Research Network (UWARN) and the INFORM Africa project through IHVN (U54 TW012041), and the South African Department of Science and Innovation (SA DSI) and the SAMRC under the BRICS JAF #2020/049 ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The project was approved by University of KwaZulu-Natal Biomedical Research Ethics Committee (ref. BREC/00001510/2020), the University of the Witwatersrand Human Research Ethics Committee (HREC) (ref. M180832), Stellenbosch University HREC (ref. N20/04/008 COVID-19) and the University of Cape Town HREC (ref. 383/2020). Individual participant consent was not required for the genomic surveillance. This requirement was waived by the Research Ethics Committees. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced are available online at GISAID database.

@article{Salerno2022,
author = {Salerno, Sara N and Capparelli, Edmund V and McIlleron, Helen and Gerhart, Jacqueline G and Dumond, Julie B and Kashuba, Angela D M and Denti, Paolo and Gonzalez, Daniel},
doi = {10.1002/phar.2703},
issn = {0277-0008},
journal = {Pharmacotherapy},
keywords = {OA,based pharmacokinetic modeling (PBPK),drug,drug interactions (DDI),fund{\_}not{\_}ack,human immunodeficiency virus (HIV),lopinavir (LPV),original,pediatric,physiologically,rifampicin,ritonavir (RTV),tuberculosis (TB)},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {may},
pmid = {35607886},
publisher = {John Wiley {\&} Sons, Ltd},
title = {{Leveraging physiologically‐based pharmacokinetic ( PBPK) modeling to optimize dosing for lopinavir/ritonavir with rifampin in pediatric patients}},
url = {https://onlinelibrary.wiley.com/doi/full/10.1002/phar.2703 https://onlinelibrary.wiley.com/doi/abs/10.1002/phar.2703 https://accpjournals.onlinelibrary.wiley.com/doi/10.1002/phar.2703 https://onlinelibrary.wiley.com/doi/10.1002/phar.2703},
year = {2022}
}

@article{Mashau2022,
abstract = {Summary Background Although flucytosine is a key component of WHO-recommended induction treatment for HIV-associated cryptococcal meningitis, this antifungal agent is not widely available in low-income and middle-income countries due to limited production and cost. In 2018, a national flucytosine access programme was initiated in South Africa. We aimed to determine the effectiveness of flucytosine-containing induction regimens in routine care to motivate for the urgent registration of flucytosine and its inclusion in treatment guidelines. Methods In this cross-sectional study, we compared outcomes of adults aged 18 years and older with incident laboratory-confirmed cryptococcal meningitis treated with or without flucytosine-containing regimens at 19 sentinel hospitals in South Africa. A case of cryptococcosis was defined as illness in an adult with: (1) positive cerebrospinal fluid (CSF) India ink microscopy; (2) a positive CSF cryptococcal antigen test; or (3) culture of Cryptococcus neoformans or Cryptococcus gattii from CSF or any other specimen. We excluded patients without a case report form, those with an unknown or negative HIV serology result, those with a recurrent episode, and those who did not receive antifungal treatment in hospital. We assessed cumulative in-hospital mortality at 14 days and 30 days and calculated the overall crude in-hospital case-fatality ratio. We used random-effects logistic regression to examine the association between treatment group and in-hospital mortality. Findings From July 1, 2018, to March 31, 2020, 10 668 individuals were diagnosed with laboratory-confirmed cryptococcal meningitis, 7787 cases diagnosed at non-enhanced surveillance sites and 567 cases from eight enhanced surveillance sites with no access to flucytosine were excluded. Of 2314 adults with a first episode of cryptococcosis diagnosed at 19 facilities with access to flucytosine, 1996 had a case report form and of these, 1539 received induction antifungal treatment and were confirmed HIV-seropositive first-episode cases. Of 1539 patients who received antifungal therapy, 596 (38{\textperiodcentered}7{\%}) individuals received a flucytosine-containing regimen and 943 (61{\textperiodcentered}3{\%}) received another regimen. The median age was 36 years (IQR 32–43) and 906 (58{\textperiodcentered}9{\%}) participants were male and 633 (41{\textperiodcentered}1{\%}) were female. The crude in-hospital case-fatality ratio was 23{\textperiodcentered}9{\%} (95{\%} CI 20{\textperiodcentered}0–27{\textperiodcentered}0; 143 of 596) in those treated with flucytosine-containing regimens and 37{\textperiodcentered}2{\%} (95{\%} CI 34{\textperiodcentered}0–40{\textperiodcentered}0; 351 of 943) in those treated with other regimens. Patients admitted to non-academic hospitals (adjusted odds ratio [aOR] 1{\textperiodcentered}95 [95{\%} CI 1{\textperiodcentered}53–2{\textperiodcentered}48]; p Interpretation In-hospital mortality among patients treated with a flucytosine-containing regimen was comparable to reduced mortality reported in patients receiving a flucytosine-containing regimen in a recent multicentre African clinical trial. Flucytosine-based treatment can be delivered in routine care in a middle-income country with a substantial survival benefit. Funding National Institute for Communicable Diseases, a Division of the National Health Laboratory Service. Translation For the Zulu translation of the abstract see Supplementary Materials section.},
author = {Mashau, Rudzani C and Meiring, Susan T and Quan, Vanessa C and Nel, Jeremy and Greene, Greg S and Garcia, Andrea and Menezes, Colin and Reddy, Denasha L and Venter, Michelle and Stacey, Sarah and Madua, Matamela and Boretti, Lia and Harrison, Thomas S and Meintjes, Graeme and Shroufi, Amir and Trivino-Duran, Laura and Black, John and Govender, Nelesh P and Abrahams, Shareef and Pearce, Vanessa and Moncho, Masego and Ntlemo, Motlatji Grace and Wadula, Jeanette and Richards, Lauren and Nchabeleng, Maphoshane and Tsitsi, Merika and Moshe, Moamokgethi and Said, Mohammed and Kolojane, Molebogeng and Mothibi, Lesego and Plessis, Nicolette Du and Chomba, Rispah and Thomas, Teena and Avenant, Theunis and Nana, Trusha and Chibabhai, Vindana and Maharj, Adhil and Wilson, Douglas and Naby, Fathima and Dawood, Halima and Han, Khine Swe Swe and Sookan, Lisha and Dlamini, Nomonde and Ramajathan, Praksha and Mahabeer, Prasha and Bhola, Prathna and Naidoo, Romola and Haffejee, Sumayya and Sirkar, Surendra and Ramkillawan, Yeishna and Hamese, Ken and Sibiya, Ngoaka and Mangena, Phetho and Lekalakala, Ruth and Hoyland, Greta and Ntuli, Sindi and Variava, Ebrahim and Khantsi, Ignatius and Mekgoe, Omphile and Brink, Adrian and Prentice, Elizabeth and Reddy, Kessendri and Whitelaw, Andrew and Hoosien, Ebrahim and Zietsman, Inge and Marshall, Terry and Poswa, Xoliswa and Govind, Chetna and Smit, Juanita and Pillay, Keshree and Seetharam, Sharona and Howell, Victoria and Samuel, Catherine and Senekal, Marthinus and Bamford, Colleen and Dreyer, Andries and Marcus, Louis and Lowman, Warren and von Gottberg, Anne and Smith, Anthony and Mathunjwa, Azwifarwi and D'Abreu, Cecilia and Miller, Cecilia and Cohen, Cheryl and Ismail, Farzana and Moultrie, Harry and Ismail, Husna and Weyer, Jacqueline and Kleynhans, Jackie and Rossouw, Jenny and Frean, John and Ebonwu, Joy and Mwansa-Kambafwile, Judith and Thomas, Juno and Bishop, Kate and McCarthy, Kerrigan and Shuping, Liliwe and de Gouveia, Linda and Erasmus, Linda and Puren, Adrian and Blumberg, Lucille and Smith, Marshagne and Makgoba, Martha and Groome, Michelle and du Plessis, Mignon and Ngomane, Mimmy and Manaka, Mokupi and Moremi, Myra and Ismail, Nazir and Legare, Neo and Page, Nicola and Hoho, Nombulelo and Perovic, Olga and Sekwadi, Phuti and Magobo, Rindidzani and Mpembe, Ruth and Walaza, Sibongile and Dlamini, Siyanda and Njikho, Sunnieboy and Lebaka, Tiisetso and Ngubane, Wendy},
doi = {10.1016/S1473-3099(22)00234-1},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Mashau et al. - 2022 - Outcomes of flucytosine-containing combination treatment for cryptococcal meningitis in a South African national.pdf:pdf},
issn = {1473-3099},
journal = {The Lancet Infectious Diseases},
keywords = {fund{\_}not{\_}ack,original},
mendeley-tags = {fund{\_}not{\_}ack,original},
month = {jun},
pages = {S1473--3099(22)00234--1},
pmid = {35750065},
publisher = {Elsevier},
title = {{Outcomes of flucytosine-containing combination treatment for cryptococcal meningitis in a South African national access programme: a cross-sectional observational study}},
url = {http://www.thelancet.com/article/S1473309922002341/fulltext http://www.thelancet.com/article/S1473309922002341/abstract https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(22)00234-1/abstract},
year = {2022}
}

Summary Background Although flucytosine is a key component of WHO-recommended induction treatment for HIV-associated cryptococcal meningitis, this antifungal agent is not widely available in low-income and middle-income countries due to limited production and cost. In 2018, a national flucytosine access programme was initiated in South Africa. We aimed to determine the effectiveness of flucytosine-containing induction regimens in routine care to motivate for the urgent registration of flucytosine and its inclusion in treatment guidelines. Methods In this cross-sectional study, we compared outcomes of adults aged 18 years and older with incident laboratory-confirmed cryptococcal meningitis treated with or without flucytosine-containing regimens at 19 sentinel hospitals in South Africa. A case of cryptococcosis was defined as illness in an adult with: (1) positive cerebrospinal fluid (CSF) India ink microscopy; (2) a positive CSF cryptococcal antigen test; or (3) culture of Cryptococcus neoformans or Cryptococcus gattii from CSF or any other specimen. We excluded patients without a case report form, those with an unknown or negative HIV serology result, those with a recurrent episode, and those who did not receive antifungal treatment in hospital. We assessed cumulative in-hospital mortality at 14 days and 30 days and calculated the overall crude in-hospital case-fatality ratio. We used random-effects logistic regression to examine the association between treatment group and in-hospital mortality. Findings From July 1, 2018, to March 31, 2020, 10 668 individuals were diagnosed with laboratory-confirmed cryptococcal meningitis, 7787 cases diagnosed at non-enhanced surveillance sites and 567 cases from eight enhanced surveillance sites with no access to flucytosine were excluded. Of 2314 adults with a first episode of cryptococcosis diagnosed at 19 facilities with access to flucytosine, 1996 had a case report form and of these, 1539 received induction antifungal treatment and were confirmed HIV-seropositive first-episode cases. Of 1539 patients who received antifungal therapy, 596 (38˙7%) individuals received a flucytosine-containing regimen and 943 (61˙3%) received another regimen. The median age was 36 years (IQR 32–43) and 906 (58˙9%) participants were male and 633 (41˙1%) were female. The crude in-hospital case-fatality ratio was 23˙9% (95% CI 20˙0–27˙0; 143 of 596) in those treated with flucytosine-containing regimens and 37˙2% (95% CI 34˙0–40˙0; 351 of 943) in those treated with other regimens. Patients admitted to non-academic hospitals (adjusted odds ratio [aOR] 1˙95 [95% CI 1˙53–2˙48]; p Interpretation In-hospital mortality among patients treated with a flucytosine-containing regimen was comparable to reduced mortality reported in patients receiving a flucytosine-containing regimen in a recent multicentre African clinical trial. Flucytosine-based treatment can be delivered in routine care in a middle-income country with a substantial survival benefit. Funding National Institute for Communicable Diseases, a Division of the National Health Laboratory Service. Translation For the Zulu translation of the abstract see Supplementary Materials section.

@article{Fendler2021b,
author = {Fendler, Annika and Shepherd, Scott T C and Au, Lewis and Wilkinson, Katalin A and Wu, Mary and Schmitt, Andreas M and Tippu, Zayd and Farag, Sheima and Rogiers, Aljosja and Harvey, Ruth and Carlyle, Eleanor and Edmonds, Kim and {Del Rosario}, Lyra and Lingard, Karla and Mangwende, Mary and Holt, Lucy and Ahmod, Hamid and Korteweg, Justine and Foley, Tara and Barber, Taja and Emslie-Henry, Andrea and Caulfield-Lynch, Niamh and Byrne, Fiona and Shum, Benjamin and Gerard, Camille L and Deng, Daqi and Kjaer, Svend and Song, Ok-Ryul and Queval, Christophe and Kavanagh, Caitlin and Wall, Emma C and Carr, Edward J and Namjou, Sina and Caidan, Simon and Gavrielides, Mike and MacRae, James I and Kelly, Gavin and Peat, Kema and Kelly, Denise and Murra, Aida and Kelly, Kayleigh and O'Flaherty, Molly and Shea, Robyn L and Gardner, Gail and Murray, Darren and Yousaf, Nadia and Jhanji, Shaman and {Van As}, Nicholas and Young, Kate and Furness, Andrew J S and Pickering, Lisa and Beale, Rupert and Swanton, Charles and Gandhi, Sonia and Gamblin, Steve and Bauer, David L V and Kassiotis, George and Howell, Michael and Nicholson, Emma and Walker, Susanna and Wilkinson, Robert J and Larkin, James and Turajlic, Samra},
doi = {10.1016/J.CCELL.2021.12.013},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Fendler et al. - 2022 - Immune responses following third COVID-19 vaccination are reduced in patients with hematological malignancies co.pdf:pdf},
issn = {1535-6108},
journal = {Cancer Cell},
keywords = {OA,OA{\_}PMC,fund{\_}not{\_}ack,letter},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,letter},
month = {dec},
number = {2},
pages = {114--116},
pmid = {34968417},
publisher = {Cell Press},
title = {{Immune responses following third COVID-19 vaccination are reduced in patients with hematological malignancies compared to patients with solid cancer}},
url = {https://linkinghub.elsevier.com/retrieve/pii/S1535610821006668},
volume = {40},
year = {2022}
}

@article{Bekker2022,
abstract = {Summary Background We aimed to assess the effectiveness of a single dose of the Ad26.COV2.S vaccine (Johnson {\&} Johnson) in health-care workers in South Africa during two waves of the South African COVID-19 epidemic. Methods In the single-arm, open-label, phase 3B implementation Sisonke study, health-care workers aged 18 years and older were invited for vaccination at one of 122 vaccination sites nationally. Participants received a single dose of 5 × 1010 viral particles of the Ad26.COV2.S vaccine. Vaccinated participants were linked with their person-level data from one of two national medical insurance schemes (scheme A and scheme B) and matched for COVID-19 risk with an unvaccinated member of the general population. The primary outcome was vaccine effectiveness against severe COVID-19, defined as COVID-19-related admission to hospital, hospitalisation requiring critical or intensive care, or death, in health-care workers compared with the general population, ascertained 28 days or more after vaccination or matching, up to data cutoff. This study is registered with the South African National Clinical Trial Registry, DOH-27-022021-6844, ClinicalTrials.gov, NCT04838795, and the Pan African Clinical Trials Registry, PACTR202102855526180, and is closed to accrual. Findings Between Feb 17 and May 17, 2021, 477 102 health-care workers were enrolled and vaccinated, of whom 357 401 (74{\textperiodcentered}9{\%}) were female and 119 701 (25{\textperiodcentered}1{\%}) were male, with a median age of 42{\textperiodcentered}0 years (33{\textperiodcentered}0–51{\textperiodcentered}0). 215 813 vaccinated individuals were matched with 215 813 unvaccinated individuals. As of data cutoff (July 17, 2021), vaccine effectiveness derived from the total matched cohort was 83{\%} (95{\%} CI 75–89) to prevent COVID-19-related deaths, 75{\%} (69–82) to prevent COVID-19-related hospital admissions requiring critical or intensive care, and 67{\%} (62–71) to prevent COVID-19-related hospitalisations. The vaccine effectiveness for all three outcomes were consistent across scheme A and scheme B. The vaccine effectiveness was maintained in older health-care workers and those with comorbidities including HIV infection. During the course of the study, the beta (B.1.351) and then the delta (B.1.617.2) SARS-CoV-2 variants of concerns were dominant, and vaccine effectiveness remained consistent (for scheme A plus B vaccine effectiveness against COVID-19-related hospital admission during beta wave was 62{\%} [95{\%} CI 42–76] and during delta wave was 67{\%} [62–71], and vaccine effectiveness against COVID-19-related death during beta wave was 86{\%} [57–100] and during delta wave was 82{\%} [74–89]). Interpretation The single-dose Ad26.COV2.S vaccine shows effectiveness against severe COVID-19 disease and COVID-19-related death after vaccination, and against both beta and delta variants, providing real-world evidence for its use globally. Funding National Treasury of South Africa, the National Department of Health, Solidarity Response Fund NPC, The Michael {\&} Susan Dell Foundation, The Elma Vaccines and Immunization Foundation, and the Bill {\&} Melinda Gates Foundation.},
author = {Bekker, Linda-Gail and Garrett, Nigel and Goga, Ameena and Fairall, Lara and Reddy, Tarylee and Yende-Zuma, Nonhlanhla and Kassanjee, Reshma and Collie, Shirley and Sanne, Ian and Boulle, Andrew and Seocharan, Ishen and Engelbrecht, Imke and Davies, Mary-Ann and Champion, Jared and Chen, Tommy and Bennett, Sarah and Mametja, Selaelo and Semenya, Mabatlo and Moultrie, Harry and de Oliveira, Tulio and Lessells, Richard John and Cohen, Cheryl and Jassat, Waasila and Groome, Michelle and Gottberg, Anne Von and Roux, Engelbert Le and Khuto, Kentse and Barouch, Dan and Mahomed, Hassan and Wolmarans, Milani and Rousseau, Petro and Bradshaw, Debbie and Mulder, Michelle and Opie, Jessica and Louw, Vernon and Jacobson, Barry and Rowji, Pradeep and Peter, Jonny G and Takalani, Azwi and Odhiambo, Jackline and Mayat, Fatima and Takuva, Simbarashe and Corey, Lawrence and Gray, Glenda E and Brumskine, William and Naicker, Nivashnee and Makhaza, Disebo and Naicker, Vimla and Naidoo, Logashvari and Spooner, Elizabeth and van Nieuwenhuizen, Elane and Mngadi, Kathryn and Nchabeleng, Maphoshane and Innes, James Craig and Gill, Katherine and Petrick, Friedrich Georg and Barnabas, Shaun and Badal-Faesen, Sharlaa and Kassim, Sheetal and Mahoney, Scott Hayden and Lazarus, Erica and Nana, Anusha and Maboa, Rebone Molobane and Kotze, Philip and Lombaard, Johan and Malan, Daniel Rudolf and Kotze, Sheena and Mohlala, Phuthi and Ward, Amy and Meintjes, Graeme and Urbach, Dorothea and Patel, Faeezah and Diacon, Andreas and Ahmed, Khatija and Grobbelaar, Coert and Mda, Pamela and Dubula, Thozama and Luabeya, Angelique and Mamba, Musawenkosi Bhekithemba and Burgess, Lesley and Dawson, Rodney},
doi = {10.1016/S0140-6736(22)00007-1},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Bekker et al. - 2022 - Effectiveness of the Ad26.COV2.S vaccine in health-care workers in South Africa (the Sisonke study) results from.pdf:pdf},
issn = {0140-6736},
journal = {The Lancet},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {mar},
number = {10330},
pages = {1141--1153},
pmid = {35305740},
publisher = {Elsevier},
title = {{Effectiveness of the Ad26.COV2.S vaccine in health-care workers in South Africa (the Sisonke study): results from a single-arm, open-label, phase 3B, implementation study}},
url = {http://www.thelancet.com/article/S0140673622000071/fulltext http://www.thelancet.com/article/S0140673622000071/abstract https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00007-1/abstract},
volume = {399},
year = {2022}
}

Summary Background We aimed to assess the effectiveness of a single dose of the Ad26.COV2.S vaccine (Johnson & Johnson) in health-care workers in South Africa during two waves of the South African COVID-19 epidemic. Methods In the single-arm, open-label, phase 3B implementation Sisonke study, health-care workers aged 18 years and older were invited for vaccination at one of 122 vaccination sites nationally. Participants received a single dose of 5 × 1010 viral particles of the Ad26.COV2.S vaccine. Vaccinated participants were linked with their person-level data from one of two national medical insurance schemes (scheme A and scheme B) and matched for COVID-19 risk with an unvaccinated member of the general population. The primary outcome was vaccine effectiveness against severe COVID-19, defined as COVID-19-related admission to hospital, hospitalisation requiring critical or intensive care, or death, in health-care workers compared with the general population, ascertained 28 days or more after vaccination or matching, up to data cutoff. This study is registered with the South African National Clinical Trial Registry, DOH-27-022021-6844, ClinicalTrials.gov, NCT04838795, and the Pan African Clinical Trials Registry, PACTR202102855526180, and is closed to accrual. Findings Between Feb 17 and May 17, 2021, 477 102 health-care workers were enrolled and vaccinated, of whom 357 401 (74˙9%) were female and 119 701 (25˙1%) were male, with a median age of 42˙0 years (33˙0–51˙0). 215 813 vaccinated individuals were matched with 215 813 unvaccinated individuals. As of data cutoff (July 17, 2021), vaccine effectiveness derived from the total matched cohort was 83% (95% CI 75–89) to prevent COVID-19-related deaths, 75% (69–82) to prevent COVID-19-related hospital admissions requiring critical or intensive care, and 67% (62–71) to prevent COVID-19-related hospitalisations. The vaccine effectiveness for all three outcomes were consistent across scheme A and scheme B. The vaccine effectiveness was maintained in older health-care workers and those with comorbidities including HIV infection. During the course of the study, the beta (B.1.351) and then the delta (B.1.617.2) SARS-CoV-2 variants of concerns were dominant, and vaccine effectiveness remained consistent (for scheme A plus B vaccine effectiveness against COVID-19-related hospital admission during beta wave was 62% [95% CI 42–76] and during delta wave was 67% [62–71], and vaccine effectiveness against COVID-19-related death during beta wave was 86% [57–100] and during delta wave was 82% [74–89]). Interpretation The single-dose Ad26.COV2.S vaccine shows effectiveness against severe COVID-19 disease and COVID-19-related death after vaccination, and against both beta and delta variants, providing real-world evidence for its use globally. Funding National Treasury of South Africa, the National Department of Health, Solidarity Response Fund NPC, The Michael & Susan Dell Foundation, The Elma Vaccines and Immunization Foundation, and the Bill & Melinda Gates Foundation.

@article{Thungana2022,
abstract = {Objectives Tuberculosis (TB) remains prevalent despite the availability of effective anti-TB medications, and accumulating evidence suggests a high rate of mental disorders in people with TB. This is because TB and psychiatric disorders share several risk factors, such as poverty, homelessness and substance use disorder. Moreover, psychiatric comorbidities in patients with TB are associated with poor treatment outcomes. This study explored the psychiatric comorbidity and clinical correlates in individuals receiving TB treatment. Design A cross-sectional survey over 10 months. Setting Two primary care clinics at King Sabata Dalindyebo district, Mthatha, Eastern Cape, South Africa. Participant Patients receiving TB treatment in the two clinics. Intervention The Mini-International Neuropsychiatric Interview was used to screen for psychiatric disorders. Primary and secondary outcome measures Rates of mental disorders in patients with TB over a 10-month period. Variation in rates by sex, employment status and HIV comorbidity. Results In a sample of 197 participants, most patients were men (62{\%}) and screened positive for a mental disorder (82{\%}) with anxiety (48{\%}), depression (38{\%}) and substance use disorders (43{\%}) being the most common psychiatric conditions. On average, individuals had 4 (SD 2) mental disorders. Females had higher rates of depression (p=0.005) and non-adherence to TB treatment (p=0.003), and alcohol use disorder was more common in males (p{\textless}0.001) and in those non-adherent to TB treatment. Additionally, low education levels and unemployment were associated with depressive and anxiety disorders (p{\textless}0.05). Conclusions Mental disorders are common in patients with TB, and mental health services need to be integrated into the management of patients with TB. Factors linked to mental disorders in this cohort, such as low education, gender and unemployment, may be useful for compiling a risk profile to help identify those with TB who may require more intensive support for their mental health. Data are available upon reasonable request.},
author = {Thungana, Yanga and Wilkinson, Robert J and Zingela, Zukiswa},
doi = {10.1136/BMJOPEN-2021-058013},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Thungana, Wilkinson, Zingela - 2022 - Comorbidity of mental ill-health in tuberculosis patients under treatment in a rural province of S.pdf:pdf},
issn = {2044-6055},
journal = {BMJ Open},
keywords = {Adult psychiatry,OA,PUBLIC HEALTH,Substance misuse,Tuberculosis,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {nov},
pages = {e058013},
pmid = {36410818},
publisher = {British Medical Journal Publishing Group},
title = {{Comorbidity of mental ill-health in tuberculosis patients under treatment in a rural province of South Africa: a cross-sectional survey}},
url = {https://bmjopen.bmj.com/content/12/11/e058013 https://bmjopen.bmj.com/content/12/11/e058013.abstract},
volume = {12},
year = {2022}
}

Objectives Tuberculosis (TB) remains prevalent despite the availability of effective anti-TB medications, and accumulating evidence suggests a high rate of mental disorders in people with TB. This is because TB and psychiatric disorders share several risk factors, such as poverty, homelessness and substance use disorder. Moreover, psychiatric comorbidities in patients with TB are associated with poor treatment outcomes. This study explored the psychiatric comorbidity and clinical correlates in individuals receiving TB treatment. Design A cross-sectional survey over 10 months. Setting Two primary care clinics at King Sabata Dalindyebo district, Mthatha, Eastern Cape, South Africa. Participant Patients receiving TB treatment in the two clinics. Intervention The Mini-International Neuropsychiatric Interview was used to screen for psychiatric disorders. Primary and secondary outcome measures Rates of mental disorders in patients with TB over a 10-month period. Variation in rates by sex, employment status and HIV comorbidity. Results In a sample of 197 participants, most patients were men (62%) and screened positive for a mental disorder (82%) with anxiety (48%), depression (38%) and substance use disorders (43%) being the most common psychiatric conditions. On average, individuals had 4 (SD 2) mental disorders. Females had higher rates of depression (p=0.005) and non-adherence to TB treatment (p=0.003), and alcohol use disorder was more common in males (p\textless0.001) and in those non-adherent to TB treatment. Additionally, low education levels and unemployment were associated with depressive and anxiety disorders (p\textless0.05). Conclusions Mental disorders are common in patients with TB, and mental health services need to be integrated into the management of patients with TB. Factors linked to mental disorders in this cohort, such as low education, gender and unemployment, may be useful for compiling a risk profile to help identify those with TB who may require more intensive support for their mental health. Data are available upon reasonable request.

@phdthesis{Gafar2022a,
author = {Gafar and Fajri},
doi = {10.33612/DISS.252032448},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Gafar, Fajri - 2022 - Optimization of tuberculosis treatment in children and adolescents epidemiological and pharmacological approaches.pdf:pdf},
keywords = {fund{\_}not{\_}ack},
mendeley-tags = {fund{\_}not{\_}ack},
month = {nov},
school = {University of Groningen},
title = {{Optimization of tuberculosis treatment in children and adolescents: epidemiological and pharmacological approaches}},
url = {https://research.rug.nl/en/publications/optimization-of-tuberculosis-treatment-in-children-and-adolescent},
year = {2022}
}

@article{Alobwede2022,
abstract = {Background: Healthcare workers are at an increased risk of acquiring vaccine-preventable diseases and are known to be reliable source of information for the patients and their relatives. Knowledge and attitudes of Healthcare workers about vaccines are thus important determinants of their own vaccination uptake and their intention to recommend vaccinations to their patients. However, culturally adapted tools and studies to address vaccine uptake and hesitancy as well as related behaviours among Healthcare workers in the Global South are limited. Methods: We propose a mixed methods project to understand the extent and determinants of vaccination hesitancy among Healthcare workers and construct a validated scale to measure this complex and context-specific phenomenon in Cape Town. We will summarise responses as counts and percentages for categorical variables and means with standard deviations (or median with inter quartile ranges) for continuous variables. We will run the Shapiro-Wilks test to assess the normality. Analysis of the variance, chi-square tests, and equivalents will be conducted as appropriate for group comparisons. Logistic regression models will also be performed to assess association between variables. We will focus on the seasonal influenza and COVID-19 vaccine. We will use an existing tool developed and validated in Germany and the United States of America to measure five psychological determinants of vaccination (referred to as the 5C scale), as the basis to develop and validate a scale to measure the scope and determinants of vaccine hesitancy and acceptance among Healthcare workers in Cape Town. Discussion and conclusion: Through this study, we hope to expand the scientific evidence based on vaccination acceptance and demand among Healthcare workers in South Africa and build resources to enable better understanding of, detection, and response to vaccination hesitancy in Cape Town. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Funding Statement SMA is supported by Partners in Sexual Health, Cape Town, South Africa. MS is supported by the Wellcome Trust Intermediate Fellowship (Grant{\#}: 211360/18/Z) and the South African National Research Foundation (Grant{\#}: 127558). This manuscript was funded by the South African Medical Research Council (through the Cochrane South Africa baseline funding project code 43500) The funders had and will not have a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. www.wellcome.ac.uk www.samrc.ac.za www.psh.org.za {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: University of Cape Town Human Research Ethics Committee, HREC Reference 858/2020 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Not Applicable I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Not Applicable I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Not Applicable Deidentified research data will be made publicly available when the study is completed and published.},
author = {Alobwede, Samuel Muabe and Katoto, Patrick and Cooper, Sara and Lumngwena, Evelyn and Kidzeru, Elvis and Goliath, Rene and Jackson, Amanda and Wiysonge, Charles and Shey, Muki},
doi = {10.1101/2022.06.06.22276038},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Alobwede et al. - 2022 - Cross-cultural adaptation and validation of the 5C scale to identify factors associated with COVID-19 and influ.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}not{\_}ack,protocol},
mendeley-tags = {OA,fund{\_}not{\_}ack,protocol},
month = {jun},
pages = {2022.06.06.22276038},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Cross-cultural adaptation and validation of the 5C scale to identify factors associated with COVID-19 and influenza vaccine hesitancy among healthcare workers in Cape Town, South Africa – a protocol}},
url = {https://www.medrxiv.org/content/10.1101/2022.06.06.22276038v1 https://www.medrxiv.org/content/10.1101/2022.06.06.22276038v1.abstract},
volume = {17},
year = {2022}
}

Background: Healthcare workers are at an increased risk of acquiring vaccine-preventable diseases and are known to be reliable source of information for the patients and their relatives. Knowledge and attitudes of Healthcare workers about vaccines are thus important determinants of their own vaccination uptake and their intention to recommend vaccinations to their patients. However, culturally adapted tools and studies to address vaccine uptake and hesitancy as well as related behaviours among Healthcare workers in the Global South are limited. Methods: We propose a mixed methods project to understand the extent and determinants of vaccination hesitancy among Healthcare workers and construct a validated scale to measure this complex and context-specific phenomenon in Cape Town. We will summarise responses as counts and percentages for categorical variables and means with standard deviations (or median with inter quartile ranges) for continuous variables. We will run the Shapiro-Wilks test to assess the normality. Analysis of the variance, chi-square tests, and equivalents will be conducted as appropriate for group comparisons. Logistic regression models will also be performed to assess association between variables. We will focus on the seasonal influenza and COVID-19 vaccine. We will use an existing tool developed and validated in Germany and the United States of America to measure five psychological determinants of vaccination (referred to as the 5C scale), as the basis to develop and validate a scale to measure the scope and determinants of vaccine hesitancy and acceptance among Healthcare workers in Cape Town. Discussion and conclusion: Through this study, we hope to expand the scientific evidence based on vaccination acceptance and demand among Healthcare workers in South Africa and build resources to enable better understanding of, detection, and response to vaccination hesitancy in Cape Town. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement SMA is supported by Partners in Sexual Health, Cape Town, South Africa. MS is supported by the Wellcome Trust Intermediate Fellowship (Grant#: 211360/18/Z) and the South African National Research Foundation (Grant#: 127558). This manuscript was funded by the South African Medical Research Council (through the Cochrane South Africa baseline funding project code 43500) The funders had and will not have a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. www.wellcome.ac.uk www.samrc.ac.za www.psh.org.za ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: University of Cape Town Human Research Ethics Committee, HREC Reference 858/2020 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Not Applicable I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Not Applicable I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Not Applicable Deidentified research data will be made publicly available when the study is completed and published.

@article{Daramola2022,
abstract = {Current treatments for asthma help to alleviate clinical symptoms but do not cure the disease. In this study, we explored a novel therapeutic approach for the treatment of house dust mite allergen Der p 1induced asthma by aiming to eliminate specific population of B-cells involved in memory IgE response to Der p 1. To achieve this aim, we developed and evaluated two different proDer p 1-based fusion proteins; an allergen-toxin (proDer p 1-ETA) and an allergen drug conjugate (proDer p 1-SNAP-AURIF) against Der p 1 reactive hybridomas as an in vitro model for Der p 1 reactive human B-cells. The strategy involved the use of proDer p 1 allergen as a cell-specific ligand to selectively deliver the bacterial protein toxin Pseudomonas exotoxin A (ETA) or the synthetic small molecule toxin Auristatin F (AURIF) into the cytosol of Der p 1-reactive cells for highly efficient cell killing. As such, we demonstrated recombinant proDer p 1-fusion proteins were selectively bound by Der p 1-reactive hybridomas as well as primary IgG1 + B cells from HDM sensitized mice. The therapeutic potential of proDer p 1-ETA` and proDer p 1-SNAP-AURIF was confirmed by their selective cytotoxic activities on Der p 1 reactive hybridoma cells. The allergen-toxin demonstrated superior cytotoxic activity, with IC50 values in the single digit nanomolar value, compared to the allergen drug conjugate. Altogether, the proof-of-concept experiments in this study provide a promising approach for the treatment of patients with house dust mite-driven allergic asthma.},
author = {Daramola, A K and Akinrinmade, O A and Fajemisin, E A and Naran, K and Mthembu, N and Hadebe, S and Brombacher, F and Huysamen, A M and Fadeyi, O E and Hunter, R and Barth, S},
doi = {10.1093/IMMADV/LTAC023},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Daramola et al. - 2022 - A recombinant Der p 1-specific allergen-toxin demonstrates superior killing of allergen-reactive IgG hybridomas.pdf:pdf},
issn = {2732-4303},
journal = {Immunotherapy advances},
keywords = {A K Daramola,MEDLINE,NCBI,NIH,NLM,National Center for Biotechnology Information,National Institutes of Health,National Library of Medicine,O A Akinrinmade,OA,OA{\_}PMC,PMC9912260,PubMed Abstract,S Barth,doi:10.1093/immadv/ltac023,fund{\_}not{\_}ack,original,pmid:36789295},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {jan},
number = {1},
pages = {ltac023},
pmid = {36789295},
publisher = {Immunother Adv},
title = {{A recombinant Der p 1-specific allergen-toxin demonstrates superior killing of allergen-reactive IgG+ hybridomas in comparison to its recombinant allergen-drug conjugate}},
url = {https://pubmed.ncbi.nlm.nih.gov/36789295/},
volume = {3},
year = {2022}
}

Current treatments for asthma help to alleviate clinical symptoms but do not cure the disease. In this study, we explored a novel therapeutic approach for the treatment of house dust mite allergen Der p 1induced asthma by aiming to eliminate specific population of B-cells involved in memory IgE response to Der p 1. To achieve this aim, we developed and evaluated two different proDer p 1-based fusion proteins; an allergen-toxin (proDer p 1-ETA) and an allergen drug conjugate (proDer p 1-SNAP-AURIF) against Der p 1 reactive hybridomas as an in vitro model for Der p 1 reactive human B-cells. The strategy involved the use of proDer p 1 allergen as a cell-specific ligand to selectively deliver the bacterial protein toxin Pseudomonas exotoxin A (ETA) or the synthetic small molecule toxin Auristatin F (AURIF) into the cytosol of Der p 1-reactive cells for highly efficient cell killing. As such, we demonstrated recombinant proDer p 1-fusion proteins were selectively bound by Der p 1-reactive hybridomas as well as primary IgG1 + B cells from HDM sensitized mice. The therapeutic potential of proDer p 1-ETA` and proDer p 1-SNAP-AURIF was confirmed by their selective cytotoxic activities on Der p 1 reactive hybridoma cells. The allergen-toxin demonstrated superior cytotoxic activity, with IC50 values in the single digit nanomolar value, compared to the allergen drug conjugate. Altogether, the proof-of-concept experiments in this study provide a promising approach for the treatment of patients with house dust mite-driven allergic asthma.

@article{Chabala2021,
abstract = {Background Dispersible pediatric fixed-dose combination (FDC) tablets delivering higher doses of first-line antituberculosis drugs in World Health Organization–recommended weight bands were introduced in 2015. We report the first pharmacokinetic data for these FDC tablets in Zambian and South African children in the treatment-shortening SHINE trial. Methods Children weighing 4.0–7.9, 8.0–11.9, 12.0–15.9, or 16.0–24.9 kg received 1, 2, 3, or 4 tablets daily, respectively (rifampicin/isoniazid/pyrazinamide [75/50/150 mg], with or without 100 mg ethambutol, or rifampicin/isoniazid [75/50 mg]). Children 25.0–36.9 kg received doses recommended for adults {\textless}37 kg (300, 150, 800, and 550 mg/d, respectively, for rifampicin, isoniazid, pyrazinamide, and ethambutol). Pharmacokinetics were evaluated after at least 2 weeks of treatment. Results In the 77 children evaluated, the median age (interquartile range) was 3.7 (1.4–6.6) years; 40 (52{\%}) were male and 20 (26{\%}) were human immunodeficiency virus positive. The median area under the concentration-time curve from 0 to 24 hours for rifampicin, isoniazid, pyrazinamide, and ethambutol was 32.5 (interquartile range, 20.1–45.1), 16.7 (9.2–25.9), 317 (263–399), and 9.5 (7.5–11.5) mg⋅h/L, respectively, and lower in children than in adults for rifampicin in the 4.0–7.9-, 8–11.9-, and ≥25-kg weight bands, isoniazid in the 4.0–7.9-kg and ≥25-kg weight bands, and ethambutol in all 5 weight bands. Pyrazinamide exposures were similar to those in adults. Conclusions Recommended weight band–based FDC doses result in lower drug exposures in children in lower weight bands and in those ≥25 kg (receiving adult doses). Further adjustments to current doses are needed to match current target exposures in adults. The use of ethambutol at the current World Health Organization–recommended doses requires further evaluation.},
author = {Chabala, Chishala and trial Team, on Behalf of the SHINE and Turkova, Anna and trial Team, on Behalf of the SHINE and Hesseling, Anneke C and trial Team, on Behalf of the SHINE and Zimba, Kevin M and trial Team, on Behalf of the SHINE and van der Zalm, Marieke and trial Team, on Behalf of the SHINE and Kapasa, Monica and trial Team, on Behalf of the SHINE and Palmer, Megan and trial Team, on Behalf of the SHINE and Chirehwa, Maxwell and trial Team, on Behalf of the SHINE and Wiesner, Lubbe and trial Team, on Behalf of the SHINE and Wobudeya, Eric and trial Team, on Behalf of the SHINE and Kinikar, Aarti and trial Team, on Behalf of the SHINE and Mave, Vidya and trial Team, on Behalf of the SHINE and Hissar, Syed and trial Team, on Behalf of the SHINE and Choo, Louise and trial Team, on Behalf of the SHINE and LeBeau, Kristen and trial Team, on Behalf of the SHINE and Mulenga, Veronica and trial Team, on Behalf of the SHINE and Aarnoutse, Robb and trial Team, on Behalf of the SHINE and Gibb, Diana and trial Team, on Behalf of the SHINE and McIlleron, Helen and trial Team, on Behalf of the SHINE},
doi = {10.1093/CID/CIAB725},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Chabala et al. - 2022 - Pharmacokinetics of first-line drugs in children with tuberculosis using WHO-recommended weight band doses and f.pdf:pdf},
journal = {Clinical Infectious Diseases},
keywords = {OA,adult,child,ethambutol,fund{\_}not{\_}ack,original,pyrazinamide,world health organization},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {aug},
number = {10},
pages = {1767--1775},
pmid = {34420049},
title = {{Pharmacokinetics of first-line drugs in children with tuberculosis using WHO-recommended weight band doses and formulations}},
url = {https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab725/6356214},
volume = {74},
year = {2022}
}

Background Dispersible pediatric fixed-dose combination (FDC) tablets delivering higher doses of first-line antituberculosis drugs in World Health Organization–recommended weight bands were introduced in 2015. We report the first pharmacokinetic data for these FDC tablets in Zambian and South African children in the treatment-shortening SHINE trial. Methods Children weighing 4.0–7.9, 8.0–11.9, 12.0–15.9, or 16.0–24.9 kg received 1, 2, 3, or 4 tablets daily, respectively (rifampicin/isoniazid/pyrazinamide [75/50/150 mg], with or without 100 mg ethambutol, or rifampicin/isoniazid [75/50 mg]). Children 25.0–36.9 kg received doses recommended for adults \textless37 kg (300, 150, 800, and 550 mg/d, respectively, for rifampicin, isoniazid, pyrazinamide, and ethambutol). Pharmacokinetics were evaluated after at least 2 weeks of treatment. Results In the 77 children evaluated, the median age (interquartile range) was 3.7 (1.4–6.6) years; 40 (52%) were male and 20 (26%) were human immunodeficiency virus positive. The median area under the concentration-time curve from 0 to 24 hours for rifampicin, isoniazid, pyrazinamide, and ethambutol was 32.5 (interquartile range, 20.1–45.1), 16.7 (9.2–25.9), 317 (263–399), and 9.5 (7.5–11.5) mg⋅h/L, respectively, and lower in children than in adults for rifampicin in the 4.0–7.9-, 8–11.9-, and ≥25-kg weight bands, isoniazid in the 4.0–7.9-kg and ≥25-kg weight bands, and ethambutol in all 5 weight bands. Pyrazinamide exposures were similar to those in adults. Conclusions Recommended weight band–based FDC doses result in lower drug exposures in children in lower weight bands and in those ≥25 kg (receiving adult doses). Further adjustments to current doses are needed to match current target exposures in adults. The use of ethambutol at the current World Health Organization–recommended doses requires further evaluation.

@article{Agamah2022,
abstract = {Advances in omics technologies allow for holistic studies into biological systems. These studies rely on integrative data analysis techniques to obtain a comprehensive view of the dynamics of cellular processes, and molecular mechanisms. Network-based integrative approaches have revolutionized multi-omics analysis by providing the framework to represent interactions between multiple different omics-layers in a graph, which may faithfully reflect the molecular wiring in a cell. Here we review network-based multi-omics/multi-modal integrative analytical approaches. We classify these approaches according to the type of omics data supported, the methods and/or algorithms implemented, their node and/or edge weighting components, and their ability to identify key nodes and subnetworks. We show how these approaches can be used to identify biomarkers, disease subtypes, crosstalk, causality, and molecular drivers of physiological and pathological mechanisms. We provide insight into the most appropriate methods and tools for research questions as showcased around the aetiology and treatment of COVID-19 that can be informed by multi-omics data integration. We conclude with an overview of challenges associated with multi-omics network-based analysis, such as reproducibility, heterogeneity, (biological) interpretability of the results, and we highlight some future directions for network-based integration.},
author = {Agamah, Francis E and Bayjanov, Jumamurat R and Niehues, Anna and Njoku, Kelechi F and Skelton, Michelle and Mazandu, Gaston K and Ederveen, Thomas H A and Mulder, Nicola and Chimusa, Emile R and {'t Hoen}, Peter A C},
doi = {10.3389/FMOLB.2022.967205},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Agamah et al. - 2022 - Computational approaches for network-based integrative multi-omics analysis.pdf:pdf},
issn = {2296-889X},
journal = {Frontiers in Molecular Biosciences},
keywords = {Multi-modal network,OA,OA{\_}PMC,data integration,fund{\_}not{\_}ack,machine learning,multi-omics,network causal inference,network diffusion/propagation,review},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,review},
month = {nov},
pages = {967205},
pmid = {36452456},
publisher = {Frontiers},
title = {{Computational approaches for network-based integrative multi-omics analysis}},
volume = {9},
year = {2022}
}

Advances in omics technologies allow for holistic studies into biological systems. These studies rely on integrative data analysis techniques to obtain a comprehensive view of the dynamics of cellular processes, and molecular mechanisms. Network-based integrative approaches have revolutionized multi-omics analysis by providing the framework to represent interactions between multiple different omics-layers in a graph, which may faithfully reflect the molecular wiring in a cell. Here we review network-based multi-omics/multi-modal integrative analytical approaches. We classify these approaches according to the type of omics data supported, the methods and/or algorithms implemented, their node and/or edge weighting components, and their ability to identify key nodes and subnetworks. We show how these approaches can be used to identify biomarkers, disease subtypes, crosstalk, causality, and molecular drivers of physiological and pathological mechanisms. We provide insight into the most appropriate methods and tools for research questions as showcased around the aetiology and treatment of COVID-19 that can be informed by multi-omics data integration. We conclude with an overview of challenges associated with multi-omics network-based analysis, such as reproducibility, heterogeneity, (biological) interpretability of the results, and we highlight some future directions for network-based integration.

@article{Roshdy2022a,
abstract = {COVID-19 was first diagnosed in Egypt on 14 February 2020. By the end of November 2021, over 333,840 cases and 18,832 deaths had been reported. As part of the national genomic surveillance, 1027 SARS-CoV-2 near whole-genomes were generated and published by the end of July 2021. Here we describe the genomic epidemiology of SARS-CoV-2 in Egypt over this period using a subset of 976 high-quality Egyptian genomes analyzed together with a representative set of global sequences within a phylogenetic framework. A single lineage, C.36, introduced early in the pandemic was responsible for most of the cases in Egypt. Furthermore, to remain dominant in the face of mounting immunity from previous infections and vaccinations, this lineage acquired several mutations known to confer an adaptive advantage. These results highlight the value of continuous genomic surveillance in regions where VOCs are not predominant and the need for enforcement of public health measures to prevent expansion of the existing lineages.},
author = {Roshdy, Wael H and Khalifa, Mohamed K and San, James Emmanuel and Tegally, Houriiyah and Wilkinson, Eduan and Showky, Shymaa and Martin, Darren Patrick and Moir, Monika and Naguib, Amel and Elguindy, Nancy and Gomaa, Mokhtar R and Fahim, Manal and Elsood, Hanaa Abu and Mohsen, Amira and Galal, Ramy and Hassany, Mohamed and Lessells, Richard J and Al-Karmalawy, Ahmed A and El-Shesheny, Rabeh and Kandeil, Ahmed M and Ali, Mohamed A and {De Oliveira}, Tulio},
doi = {10.3390/V14091878},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Roshdy et al. - 2022 - SARS-CoV-2 genetic diversity and lineage dynamics in Egypt during the first 18 months of the pandemic.pdf:pdf},
issn = {1999-4915},
journal = {Viruses},
keywords = {2,CoV,Egypt,OA,OA{\_}PMC,SARS,fund{\_}not{\_}ack,genomic epidemiology,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {aug},
number = {9},
pages = {1878},
pmid = {36146685},
publisher = {Multidisciplinary Digital Publishing Institute},
title = {{SARS-CoV-2 genetic diversity and lineage dynamics in Egypt during the first 18 months of the pandemic}},
url = {https://www.mdpi.com/1999-4915/14/9/1878/htm https://www.mdpi.com/1999-4915/14/9/1878},
volume = {14},
year = {2022}
}

COVID-19 was first diagnosed in Egypt on 14 February 2020. By the end of November 2021, over 333,840 cases and 18,832 deaths had been reported. As part of the national genomic surveillance, 1027 SARS-CoV-2 near whole-genomes were generated and published by the end of July 2021. Here we describe the genomic epidemiology of SARS-CoV-2 in Egypt over this period using a subset of 976 high-quality Egyptian genomes analyzed together with a representative set of global sequences within a phylogenetic framework. A single lineage, C.36, introduced early in the pandemic was responsible for most of the cases in Egypt. Furthermore, to remain dominant in the face of mounting immunity from previous infections and vaccinations, this lineage acquired several mutations known to confer an adaptive advantage. These results highlight the value of continuous genomic surveillance in regions where VOCs are not predominant and the need for enforcement of public health measures to prevent expansion of the existing lineages.

@article{Lawrence2022,
abstract = {Summary Background HIV-associated cryptococcal meningitis is a leading cause of AIDS-related mortality. The AMBITION-cm trial showed that a regimen based on a single high dose of liposomal amphotericin B deoxycholate (AmBisome group) was non-inferior to the WHO-recommended treatment of seven daily doses of amphotericin B deoxycholate (control group) and was associated with fewer adverse events. We present a five-country cost-effectiveness analysis. Methods The AMBITION-cm trial enrolled patients with HIV-associated cryptococcal meningitis from eight hospitals in Botswana, Malawi, South Africa, Uganda, and Zimbabwe. Taking a health service perspective, we collected country-specific unit costs and individual resource-use data per participant over the 10-week trial period, calculating mean cost per participant by group, mean cost-difference between groups, and incremental cost-effectiveness ratio per life-year saved. Non-parametric bootstrapping and scenarios analyses were performed including hypothetical real-world resource use. The trial registration number is ISRCTN72509687, and the trial has been completed. Findings The AMBITION-cm trial enrolled 844 participants, and 814 were included in the intention-to-treat analysis (327 from Uganda, 225 from Malawi, 107 from South Africa, 84 from Botswana, and 71 from Zimbabwe) with 407 in each group, between Jan 31, 2018, and Feb 17, 2021. Using Malawi as a representative example, mean total costs per participant were US{\$}1369 (95{\%} CI 1314–1424) in the AmBisome group and {\$}1237 (1181–1293) in the control group. The incremental cost-effectiveness ratio was {\$}128 (59–257) per life-year saved. Excluding study protocol-driven cost, using a real-world toxicity monitoring schedule, the cost per life-year saved reduced to {\$}80 (15–275). Changes in the duration of the hospital stay and antifungal medication cost showed the greatest effect in sensitivity analyses. Results were similar across countries, with the cost per life-year saved in the real-world scenario ranging from {\$}71 in Botswana to {\$}121 in Uganda. Interpretation The AmBisome regimen was cost-effective at a low incremental cost-effectiveness ratio. The regimen might be even less costly and potentially cost-saving in real-world implementation given the lower drug-related toxicity and the potential for shorter hospital stays. Funding European Developing Countries Clinical Trials Partnership, Swedish International Development Cooperation Agency, Wellcome Trust and Medical Research Council, UKAID Joint Global Health Trials, and the National Institute for Health Research. Translations For the Chichewa, Isixhosa, Luganda, Setswana and Shona translations of the abstract see Supplementary Materials section.},
author = {Lawrence, David S and Muthoga, Charles and Meya, David B and Tugume, Lillian and Williams, Darlisha and Rajasingham, Radha and Boulware, David R and Mwandumba, Henry C and Moyo, Melanie and Dziwani, Eltas N and Maheswaran, Hendramoorthy and Kanyama, Cecilia and Hosseinipour, Mina C and Chawinga, Chimwemwe and Meintjes, Graeme and Schutz, Charlotte and Comins, Kyla and Bango, Funeka and Muzoora, Conrad and Jjunju, Samuel and Nuwagira, Edwin and Mosepele, Mosepele and Leeme, Tshepo and Ndhlovu, Chiratidzo E and Hlupeni, Admire and Shamu, Shepherd and Boyer-Chammard, Timoth{\'{e}}e and Molloy, S{\'{i}}le F and Youssouf, Nabila and Chen, Tao and Shiri, Tinevimbo and Jaffar, Shabbar and Harrison, Thomas S and Jarvis, Joseph N and Niessen, Louis W and Goodall, Jack and Lechiile, Kwana and Mawoko, Norah and Mbangiwa, Tshepiso and Milburn, James and Mmipi, Refilwe and Ponatshego, Ponego and Rulaganyang, Ikanyang and Seatla, Kaelo and Siamisang, Keatlaretse and Tlhako, Nametso and Tsholo, Katlego and April, Samantha and Bekiswa, Abulele and Boloko, Linda and Bookholane, Hloni and Crede, Thomas and Davids, Lee-Ann and Goliath, Rene and Hlungulu, Siphokazi and Hoffman, Regina and Kyepa, Henriette and Masina, Noma and Maughan, Deborah and Mnguni, Trevor and Moosa, Sumaiyya and Morar, Tania and Mpalali, Mkanyiseli and Naude, Jonathan and Oliphant, Ida and Singh, Achita and Sayed, Sumaya and Sebesho, Leago and Shey, Muki and Swanepoel, Loraine and Chasweka, Madalitso and Chimang'anga, Wezi and Chimphambano, Tipatseni and Gondwe, Ebbie and Mzinganjira, Henry and Kadzilimbile, Aubrey and Kateta, Steven and Kossam, Evelyn and Kukacha, Christopher and Lipenga, Bright and Ndaferankhande, John and Ndalama, Maureen and Shah, Reya and Singini, Andreas and Stott, Katherine and Zambasa, Agness and Banda, Towera and Chikaonda, Tarsizio and Chitulo, Gladys and Chiwoko, Lorren and Chome, Nelecy and Gwin, Mary and Kachitosi, Timothy and Kamanga, Beauty and Kazembe, Mussah and Kumwenda, Emily and Kumwenda, Masida and Maya, Chimwemwe and Mhango, Wilberforce and Mphande, Chimwemwe and Msumba, Lusungu and Munthali, Tapiwa and Ngoma, Doris and Nicholas, Simon and Simwinga, Lusayo and Stambuli, Anthony and Tegha, Gerald and Zambezi, Janet and Ahimbisibwe, Cynthia and Akampurira, Andrew and Alice, Anamudde and Cresswell, Fiona and Gakuru, Jane and Kagimu, Enock and Kasibante, John and Kiiza, Daniel and Kisembo, John and Kwizera, Richard and Kugonza, Florence and Laker, Eva and Luggya, Tonny and Lule, Andrew and Musubire, Abdu and Muyise, Rhona and Namujju, Carol Olivie and Ndyetukira, Jane Francis and Nsangi, Laura and Okirworth, Michael and Rhein, Joshua and Rutakingirwa, Morris K and Sadiq, Alisat and Ssebambulidde, Kenneth and Tadeo, Kiiza and Tukundane, Asmus and Atwine, Leo and Buzaare, Peter and Collins, Muganzi and Emily, Ninsima and Inyakuwa, Christine and Kariisa, Samson and Mwesigye, James and Nuwamanya, Simpson and Rodgers, Ankunda and Rukundo, Joan and Rwomushana, Irene and Ssemusu, Mike and Stead, Gavin and Boyd, Kathyrn and Gondo, Secrecy and Kufa, Prosper and Makaha, Edward and Moyo, Colombus and Mtisi, Takudzwa and Mudzinga, Shepherd and Mutata, Constantine and Mwarumba, Taddy and Zinyandu, Tawanda and Alanio, Alexandre and Dromer, Francoise and Lortholary, Olivier and Sturny-Leclere, Aude and Griffin, Philippa and Hafeez, Sophia and Loyse, Angela and van Widenfelt, Erik},
doi = {10.1016/S2214-109X(22)00450-8},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Lawrence et al. - 2022 - Cost-effectiveness of single, high-dose, liposomal amphotericin regimen for HIV-associated cryptococcal meningi.pdf:pdf},
issn = {2214-109X},
journal = {The Lancet Global Health},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {dec},
number = {12},
pages = {e1845--e1854},
pmid = {36400090},
publisher = {Elsevier},
title = {{Cost-effectiveness of single, high-dose, liposomal amphotericin regimen for HIV-associated cryptococcal meningitis in five countries in sub-Saharan Africa: an economic analysis of the AMBITION-cm trial}},
url = {http://www.thelancet.com/article/S2214109X22004508/fulltext http://www.thelancet.com/article/S2214109X22004508/abstract https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(22)00450-8/abstract},
volume = {10},
year = {2022}
}

Summary Background HIV-associated cryptococcal meningitis is a leading cause of AIDS-related mortality. The AMBITION-cm trial showed that a regimen based on a single high dose of liposomal amphotericin B deoxycholate (AmBisome group) was non-inferior to the WHO-recommended treatment of seven daily doses of amphotericin B deoxycholate (control group) and was associated with fewer adverse events. We present a five-country cost-effectiveness analysis. Methods The AMBITION-cm trial enrolled patients with HIV-associated cryptococcal meningitis from eight hospitals in Botswana, Malawi, South Africa, Uganda, and Zimbabwe. Taking a health service perspective, we collected country-specific unit costs and individual resource-use data per participant over the 10-week trial period, calculating mean cost per participant by group, mean cost-difference between groups, and incremental cost-effectiveness ratio per life-year saved. Non-parametric bootstrapping and scenarios analyses were performed including hypothetical real-world resource use. The trial registration number is ISRCTN72509687, and the trial has been completed. Findings The AMBITION-cm trial enrolled 844 participants, and 814 were included in the intention-to-treat analysis (327 from Uganda, 225 from Malawi, 107 from South Africa, 84 from Botswana, and 71 from Zimbabwe) with 407 in each group, between Jan 31, 2018, and Feb 17, 2021. Using Malawi as a representative example, mean total costs per participant were US$}1369 (95{%} CI 1314–1424) in the AmBisome group and {$1237 (1181–1293) in the control group. The incremental cost-effectiveness ratio was $}128 (59–257) per life-year saved. Excluding study protocol-driven cost, using a real-world toxicity monitoring schedule, the cost per life-year saved reduced to {$80 (15–275). Changes in the duration of the hospital stay and antifungal medication cost showed the greatest effect in sensitivity analyses. Results were similar across countries, with the cost per life-year saved in the real-world scenario ranging from $}71 in Botswana to {$121 in Uganda. Interpretation The AmBisome regimen was cost-effective at a low incremental cost-effectiveness ratio. The regimen might be even less costly and potentially cost-saving in real-world implementation given the lower drug-related toxicity and the potential for shorter hospital stays. Funding European Developing Countries Clinical Trials Partnership, Swedish International Development Cooperation Agency, Wellcome Trust and Medical Research Council, UKAID Joint Global Health Trials, and the National Institute for Health Research. Translations For the Chichewa, Isixhosa, Luganda, Setswana and Shona translations of the abstract see Supplementary Materials section.

@article{Moseki2022,
abstract = {Background Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a frequent complication of co-treatment for TB and HIV-1. We characterized Mtb-specific CD4 T cell phenotype and transcription factor profile associated with the development of TB-IRIS. Methods We examined the role of CD4 T-cell transcription factors in a murine model of mycobacterial IRIS. In humans, we compared longitudinally on antiretroviral therapy (ART) the magnitude, activation, transcription factor profile and cytotoxic potential of Mtb-specific CD4 T cells between TB-IRIS (n=25) and appropriate non-IRIS control patients (n=18) using flow cytometry. Results In the murine model, CD4 T cell expression of Eomes, but not Tbet, was associated with experimentally induced IRIS. In patients, TB-IRIS onset was associated with the expansion of Mtb-specific IFN$\gamma$+CD4 T cells (p=0.039). TB-IRIS patients had higher HLA-DR expression (p=0.016), but no differences in the expression of T-bet or Eomes were observed. At TB-IRIS onset, Eomes+Tbet+Mtb-specific IFN$\gamma$+CD4+ T cells showed higher expression of Granzyme B in TB-IRIS patients (p=0.026). Conclusion While the murine model of MAC-IRIS suggests that Eomes+CD4 T cells underly IRIS, TB-IRIS was not associated with Eomes expression in patients. Mtb-specific IFN$\gamma$+CD4 T cell responses in TB-IRIS patients are differentiated, highly activated and potentially cytotoxic.},
author = {Moseki, Raymond M and Barber, Daniel L and Bruyn, Elsa Du and Shey, Muki and der Plas, Helen Van and Wilkinson, Robert J and Meintjes, Graeme and Riou, Catherine},
doi = {10.1101/2022.07.20.500909},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Moseki et al. - 2022 - Phenotypic profile of iMycobacterium tuberculosisi-specific CD4 T cell responses in HIV-positive patients who dev.pdf:pdf},
journal = {bioRxiv},
keywords = {HIV-1/TB coinfection,OA,Th1 responses,fund{\_}ack,immune activation,original,paradoxical TB-IRIS},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jul},
pages = {2022.07.20.500909},
publisher = {Cold Spring Harbor Laboratory},
title = {{Phenotypic profile of \textit{Mycobacterium tuberculosis}-specific CD4 T cell responses in HIV-positive patients who develop Tuberculosis-associated Immune Reconstitution Inflammatory Syndrome}},
url = {https://www.biorxiv.org/content/10.1101/2022.07.20.500909v1 https://www.biorxiv.org/content/10.1101/2022.07.20.500909v1.abstract},
year = {2022}
}

Background Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a frequent complication of co-treatment for TB and HIV-1. We characterized Mtb-specific CD4 T cell phenotype and transcription factor profile associated with the development of TB-IRIS. Methods We examined the role of CD4 T-cell transcription factors in a murine model of mycobacterial IRIS. In humans, we compared longitudinally on antiretroviral therapy (ART) the magnitude, activation, transcription factor profile and cytotoxic potential of Mtb-specific CD4 T cells between TB-IRIS (n=25) and appropriate non-IRIS control patients (n=18) using flow cytometry. Results In the murine model, CD4 T cell expression of Eomes, but not Tbet, was associated with experimentally induced IRIS. In patients, TB-IRIS onset was associated with the expansion of Mtb-specific IFN$γ$+CD4 T cells (p=0.039). TB-IRIS patients had higher HLA-DR expression (p=0.016), but no differences in the expression of T-bet or Eomes were observed. At TB-IRIS onset, Eomes+Tbet+Mtb-specific IFN$γ$+CD4+ T cells showed higher expression of Granzyme B in TB-IRIS patients (p=0.026). Conclusion While the murine model of MAC-IRIS suggests that Eomes+CD4 T cells underly IRIS, TB-IRIS was not associated with Eomes expression in patients. Mtb-specific IFN$γ$+CD4 T cell responses in TB-IRIS patients are differentiated, highly activated and potentially cytotoxic.

@article{Mbandi2022,
abstract = {Immune reconstitution inflammatory syndrome (IRIS) can be a complication of antiretroviral therapy (ART) in patients with advanced HIV, but its pathogenesis is uncertain. In tuberculosis (TB) endemic countries, IRIS is often associated with mycobacterial infections or Bacille-Calmette-Guerin (BCG) vaccination in children. With no predictive or confir-matory tests at present, IRIS remains a diagnosis of exclusion. We tested whether RISK6 and Sweeney3, validated immune-based blood transcriptomic signatures for TB, could predict or diagnose IRIS in HIV+ children and adults. Transcripts were measured by RT-qPCR in BCG-vaccinated children and by microarray in HIV+ adults with TB including TB meningitis (TBM). Signature scores before ART initiation and up to IRIS diagnosis were compared between participants who did or did not develop IRIS. In children, RISK6 and Sweeney3 discriminated IRIS cases from non-IRIS controls before ART, and at diagnosis. In adults with TB, RISK6 discriminated IRIS cases from controls after half-week on ART and at TB-IRIS onset. In adults with TBM, only Sweeney3 discriminated IRIS cases from controls before ART, while both signatures distinguished cases from controls at TB-IRIS onset. Parsimonious whole blood transcriptomic signatures for TB showed potential to predict and diagnose IRIS in HIV+ children and adults. Keywords: Bacille-Calmette-Guerin r host biomarker r immune reconstitution inflammatory syndrome r transcriptomic signature r tuberculosis},
author = {Mbandi, Stanley Kimbung and Painter, Hannah and Penn-Nicholson, Adam and Toefy, Asma and Erasmus, Mzwandile and Hanekom, Willem A and Scriba, Thomas J and Lai, Rachel P J and Marais, Suzaan and Fletcher, Helen A and Meintjes, Graeme and Wilkinson, Robert J and Cotton, Mark F and Pahwa, Savita and Cameron, Mark J and Nemes, Elisa},
doi = {10.1002/EJI.202249815},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Mbandi et al. - 2022 - Host transcriptomic signatures of tuberculosis can predict immune reconstitution inflammatory syndrome in HIV pat.pdf:pdf},
issn = {1521-4141},
journal = {European Journal of Immunology},
keywords = {Bacille,Calmette,Guerin,OA,fund{\_}ack,host biomarker,immune reconstitution inflammatory syndrome,original,transcriptomic signature,tuberculosis},
mendeley-tags = {OA,fund{\_}ack,original},
month = {apr},
pages = {10.1002/eji.202249815},
publisher = {John Wiley {\&} Sons, Ltd},
title = {{Host transcriptomic signatures of tuberculosis can predict immune reconstitution inflammatory syndrome in HIV patients}},
url = {https://onlinelibrary.wiley.com/doi/full/10.1002/eji.202249815 https://onlinelibrary.wiley.com/doi/abs/10.1002/eji.202249815 https://onlinelibrary.wiley.com/doi/10.1002/eji.202249815},
year = {2022}
}

Immune reconstitution inflammatory syndrome (IRIS) can be a complication of antiretroviral therapy (ART) in patients with advanced HIV, but its pathogenesis is uncertain. In tuberculosis (TB) endemic countries, IRIS is often associated with mycobacterial infections or Bacille-Calmette-Guerin (BCG) vaccination in children. With no predictive or confir-matory tests at present, IRIS remains a diagnosis of exclusion. We tested whether RISK6 and Sweeney3, validated immune-based blood transcriptomic signatures for TB, could predict or diagnose IRIS in HIV+ children and adults. Transcripts were measured by RT-qPCR in BCG-vaccinated children and by microarray in HIV+ adults with TB including TB meningitis (TBM). Signature scores before ART initiation and up to IRIS diagnosis were compared between participants who did or did not develop IRIS. In children, RISK6 and Sweeney3 discriminated IRIS cases from non-IRIS controls before ART, and at diagnosis. In adults with TB, RISK6 discriminated IRIS cases from controls after half-week on ART and at TB-IRIS onset. In adults with TBM, only Sweeney3 discriminated IRIS cases from controls before ART, while both signatures distinguished cases from controls at TB-IRIS onset. Parsimonious whole blood transcriptomic signatures for TB showed potential to predict and diagnose IRIS in HIV+ children and adults. Keywords: Bacille-Calmette-Guerin r host biomarker r immune reconstitution inflammatory syndrome r transcriptomic signature r tuberculosis

@article{Esmail2022,
abstract = {Summary We currently have a binomial approach to managing tuberculosis. Those with active disease, ideally confirmed microbiologically, are treated with a standard 6-month, multi-drug regimen and those with latent infection and no evidence of disease with shorter, one or two drug regimens. Clinicians frequently encounter patients that fall between these two management pathways with some but not all features of disease and this will occur more often with the increasing emphasis on chest X-ray-based systematic screening. The view of tuberculosis as a spectrum of disease states is being increasingly recognised and is leading to new diagnostic approaches for early disease. However, the 6-month regimen for treating disease was driven by the duration required to treat the most extensive forms of pulmonary TB and shorter durations appear sufficient for less extensive disease. It is time undertake clinical trials to better define the optimal treatment for tuberculosis across the disease spectrum.},
author = {Esmail, Hanif and Macpherson, Liana and Coussens, Anna K and Houben, Rein M G J},
doi = {10.1016/J.EBIOM.2022.103928},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Esmail et al. - 2022 - Mind the gap – managing tuberculosis across the disease spectrum.pdf:pdf},
issn = {2352-3964},
journal = {eBioMedicine},
keywords = {Diagnosis,Disease spectrum,OA,Subclinical disease,Treatment,Tuberculosis,fund{\_}not{\_}ack,review},
mendeley-tags = {OA,fund{\_}not{\_}ack,review},
pages = {103928},
pmid = {35339424},
publisher = {Elsevier},
title = {{Mind the gap – managing tuberculosis across the disease spectrum}},
url = {http://www.thelancet.com/article/S2352396422001128/fulltext http://www.thelancet.com/article/S2352396422001128/abstract https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(22)00112-8/abstract},
volume = {78},
year = {2022}
}

Summary We currently have a binomial approach to managing tuberculosis. Those with active disease, ideally confirmed microbiologically, are treated with a standard 6-month, multi-drug regimen and those with latent infection and no evidence of disease with shorter, one or two drug regimens. Clinicians frequently encounter patients that fall between these two management pathways with some but not all features of disease and this will occur more often with the increasing emphasis on chest X-ray-based systematic screening. The view of tuberculosis as a spectrum of disease states is being increasingly recognised and is leading to new diagnostic approaches for early disease. However, the 6-month regimen for treating disease was driven by the duration required to treat the most extensive forms of pulmonary TB and shorter durations appear sufficient for less extensive disease. It is time undertake clinical trials to better define the optimal treatment for tuberculosis across the disease spectrum.

@article{Wiysonge2022,
abstract = {Background: We assessed willingness to accept vaccination against coronavirus disease 2019 (COVID- 19) among healthcare workers(HCWs) at the start of South Africa's vaccination roll-out. Research Design and Methods: We conducted a cross-sectional survey among HCWs in Cape Town in March-May 2021 and assessed predictors of vaccination intentions. Results: We recruited 395 participants; 64{\%} women, 49{\%} nurses, and 13{\%} physicians. Of these, 233 (59.0{\%}) would accept and 163 (41.0{\%}) were vaccine hesitant i.e. would either refuse or were unsure whether they would accept COVID-19 vaccination. People who did not trust that COVID-19 vaccines are effective were the most hesitant (p = 0.038). Older participants and physicians were more likely to accept vaccination than younger participants (p {\textless} 0.01) and other HCWs (p = 0.042) respectively. Other predictors of vaccine acceptance were trust that vaccines are compatible with religion (p {\textless} 0.001), consideration of benefits and risks of vaccination (p {\textless} 0.001), willingness to be vaccinated to protect others (p {\textless} 0.001), and viewing vaccination as a collective action for COVID-19 control (p = 0.029). Conclusions: COVID-19 vaccine hesitancy is high among HCWs in Cape Town. Reducing this would require trust-building interventions, including tailored education.},
author = {Wiysonge, Charles S and Alobwede, Samuel M and Katoto, Patrick de Marie C and Kidzeru, Elvis B and Lumngwena, Evelyn N and Cooper, Sara and Goliath, Rene and Jackson, Amanda and Shey, Muki S},
doi = {10.1080/14760584.2022.2023355},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Wiysonge et al. - 2022 - COVID-19 vaccine acceptance and hesitancy among healthcare workers in South Africa.pdf:pdf},
issn = {1476-0584},
journal = {Expert Review of Vaccines},
keywords = {COVID-19 vaccines,OA,South Africa,fund{\_}ack,healthcare workers,original,vaccine attitudes,vaccine confidence,vaccine hesitancy},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jan},
number = {4},
pages = {549--559},
publisher = {Taylor {\&} Francis},
title = {{COVID-19 vaccine acceptance and hesitancy among healthcare workers in South Africa}},
url = {https://www.tandfonline.com/doi/abs/10.1080/14760584.2022.2023355},
volume = {21},
year = {2022}
}

Background: We assessed willingness to accept vaccination against coronavirus disease 2019 (COVID- 19) among healthcare workers(HCWs) at the start of South Africa's vaccination roll-out. Research Design and Methods: We conducted a cross-sectional survey among HCWs in Cape Town in March-May 2021 and assessed predictors of vaccination intentions. Results: We recruited 395 participants; 64% women, 49% nurses, and 13% physicians. Of these, 233 (59.0%) would accept and 163 (41.0%) were vaccine hesitant i.e. would either refuse or were unsure whether they would accept COVID-19 vaccination. People who did not trust that COVID-19 vaccines are effective were the most hesitant (p = 0.038). Older participants and physicians were more likely to accept vaccination than younger participants (p \textless 0.01) and other HCWs (p = 0.042) respectively. Other predictors of vaccine acceptance were trust that vaccines are compatible with religion (p \textless 0.001), consideration of benefits and risks of vaccination (p \textless 0.001), willingness to be vaccinated to protect others (p \textless 0.001), and viewing vaccination as a collective action for COVID-19 control (p = 0.029). Conclusions: COVID-19 vaccine hesitancy is high among HCWs in Cape Town. Reducing this would require trust-building interventions, including tailored education.

@article{Moyo-Gwete2022,
abstract = {As SARS-CoV-2 continues to evolve, several variants of concern (VOCs) have arisen which are defined by multiple mutations in their spike proteins. These VOCs have shown variable escape from antibody responses, and have been shown to trigger qualitatively different antibody responses during infection. By studying plasma from individuals infected with either the original D614G, Beta or Delta variants, we show that the Beta and Delta variants elicit antibody responses that are overall more cross-reactive than those triggered by D614G. Patterns of cross-reactivity varied, and the Beta and Delta variants did not elicit cross-reactive responses to each other. However, Beta-elicited plasma was highly cross-reactive against Delta plus (Delta+) which differs from Delta by a single K417N mutation in the receptor binding domain, suggesting the plasma response targets the N417 residue. To probe this further, we isolated monoclonal antibodies from a Beta-infected individual with plasma responses against Beta, Delta+ and Omicron, which all possess the N417 residue. We isolated a N417-dependent antibody, 084-7D, which showed similar neutralization breadth to the plasma. The 084-7D mAb utilized the IGHV3-23*01 germline gene and had similar somatic hypermutations compared to previously described public antibodies which target the 417 residue. Thus, we have identified a novel antibody which targets a shared epitope found on three distinct VOCs, enabling their cross-neutralization. Understanding antibodies targetting escape mutations such as K417N, which repeatedly emerge through convergent evolution in SARS-CoV-2 variants, may aid in the development of next-generation antibody therapeutics and vaccines.Importance The evolution of SARS-CoV-2 has resulted in variants of concern (VOCs) with distinct spike mutations conferring varying immune escape profiles. These variable mutations also influence the cross-reactivity of the antibody response mounted by individuals infected with each of these variants. This study sought to understand the antibody responses elicited by different SARS-CoV-2 variants, and to define shared epitopes. We show that Beta and Delta infection resulted in antibody responses that were more cross-reactive compared to the original D614G variant, but each with differing patterns of cross-reactivity. We further isolated an antibody from Beta infection, which targeted the N417 site, enabling cross-neutralization of Beta, Delta+ and Omicron, all of which possess this residue. The discovery of antibodies which target escape mutations common to multiple variants highlights conserved epitopes to target in future vaccines and therapeutics.Competing Interest StatementThe authors have declared no competing interest.Funding StatementPLM is supported by the South African Research Chairs Initiative of the Department of Science and Innovation and National Research Foundation of South Africa. This research was supported by the SA Medical Research Council SHIP program and the Bill and Melinda Gates Foundation, through the Global Immunology and Immune Sequencing for Epidemic Response (GIISER) program.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethical clearance was obtained for each cohort from the Human Research Ethics Committees from the University of Pretoria (Approval number: 247/2020) and University of Cape Town (Approval number: R021/2020).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors},
author = {Moyo-Gwete, Thandeka and Madzivhandila, Mashudu and Mkhize, Nonhlanhla N and Kgagudi, Prudence and Ayres, Frances and Lambson, Bronwen E and Manamela, Nelia P and Richardson, Simone I and Makhado, Zanele and van der Mescht, Mieke A and de Beer, Zelda and de Villiers, Talita Roma and Burgers, Wendy A and Ntusi, Ntobeko A B and Rossouw, Theresa and Ueckermann, Veronica and Boswell, Michael T and Moore, Penny L},
doi = {10.1101/2022.04.24.22273395},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Moyo-Gwete et al. - 2022 - Shared N417-dependent epitope on the SARS-CoV-2 Omicron, Beta and Delta-plus variants.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jan},
pages = {2022.04.24.22273395},
title = {{Shared N417-dependent epitope on the SARS-CoV-2 Omicron, Beta and Delta-plus variants}},
url = {http://medrxiv.org/content/early/2022/04/26/2022.04.24.22273395.abstract},
year = {2022}
}

As SARS-CoV-2 continues to evolve, several variants of concern (VOCs) have arisen which are defined by multiple mutations in their spike proteins. These VOCs have shown variable escape from antibody responses, and have been shown to trigger qualitatively different antibody responses during infection. By studying plasma from individuals infected with either the original D614G, Beta or Delta variants, we show that the Beta and Delta variants elicit antibody responses that are overall more cross-reactive than those triggered by D614G. Patterns of cross-reactivity varied, and the Beta and Delta variants did not elicit cross-reactive responses to each other. However, Beta-elicited plasma was highly cross-reactive against Delta plus (Delta+) which differs from Delta by a single K417N mutation in the receptor binding domain, suggesting the plasma response targets the N417 residue. To probe this further, we isolated monoclonal antibodies from a Beta-infected individual with plasma responses against Beta, Delta+ and Omicron, which all possess the N417 residue. We isolated a N417-dependent antibody, 084-7D, which showed similar neutralization breadth to the plasma. The 084-7D mAb utilized the IGHV3-23*01 germline gene and had similar somatic hypermutations compared to previously described public antibodies which target the 417 residue. Thus, we have identified a novel antibody which targets a shared epitope found on three distinct VOCs, enabling their cross-neutralization. Understanding antibodies targetting escape mutations such as K417N, which repeatedly emerge through convergent evolution in SARS-CoV-2 variants, may aid in the development of next-generation antibody therapeutics and vaccines.Importance The evolution of SARS-CoV-2 has resulted in variants of concern (VOCs) with distinct spike mutations conferring varying immune escape profiles. These variable mutations also influence the cross-reactivity of the antibody response mounted by individuals infected with each of these variants. This study sought to understand the antibody responses elicited by different SARS-CoV-2 variants, and to define shared epitopes. We show that Beta and Delta infection resulted in antibody responses that were more cross-reactive compared to the original D614G variant, but each with differing patterns of cross-reactivity. We further isolated an antibody from Beta infection, which targeted the N417 site, enabling cross-neutralization of Beta, Delta+ and Omicron, all of which possess this residue. The discovery of antibodies which target escape mutations common to multiple variants highlights conserved epitopes to target in future vaccines and therapeutics.Competing Interest StatementThe authors have declared no competing interest.Funding StatementPLM is supported by the South African Research Chairs Initiative of the Department of Science and Innovation and National Research Foundation of South Africa. This research was supported by the SA Medical Research Council SHIP program and the Bill and Melinda Gates Foundation, through the Global Immunology and Immune Sequencing for Epidemic Response (GIISER) program.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethical clearance was obtained for each cohort from the Human Research Ethics Committees from the University of Pretoria (Approval number: 247/2020) and University of Cape Town (Approval number: R021/2020).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors

@article{Lambarey2022,
abstract = {In South Africa, high exposure to SARS-CoV-2 occurs primarily in densely populated, low-income communities, which are additionally burdened by highly prevalent Human Immunodeficiency Virus (HIV). With the aim to assess SARS-CoV-2 seroprevalence and its association with HIV-related clinical parameters in non-hospitalized patients likely to be highly exposed to SARS-CoV-2, this observational cross-sectional study was conducted at the Gugulethu Community Health Centre Antiretroviral clinic between October 2020 and June 2021, after the first COVID-19 wave in South Africa and during the second and beginning of the third wave. A total of 150 adult (median age 39 years [range 20–65 years]) HIV-infected patients (69{\%} female; 31{\%} male) were recruited. 95.3{\%} of the cohort was on antiretroviral therapy (ART), had a median CD4 count of 220 cells/µL (range 17–604 cells/µL) and a median HIV viral load (VL) of 49 copies/mL (range 1–1,050,867 copies/mL). Furthermore, 106 patients (70.7{\%}) were SARS-CoV-2 seropositive, and 0{\%} were vaccinated. When stratified for HIV VL, patients with uncontrolled HIV viremia (HIV VL {\textgreater} 1000 copies/mL) had significantly higher odds of SARS-CoV-2 seropositivity than patients with HIV VL {\textless} 1000 copies/mL, after adjusting for age, sex and ART status (p = 0.035, adjusted OR 2.961 [95{\%} CI: 1.078–8.133]). Although the cause–effect relationship could not be determined due to the cross-sectional study design, these results point towards a higher risk of SARS-CoV-2 susceptibility among viremic HIV patients, or impaired HIV viral control due to previous co-infection with SARS-CoV-2.},
author = {Lambarey, Humaira and Blumenthal, Melissa J and Chetram, Abeen and Joyimbana, Wendy and Jennings, Lauren and Tincho, Marius B and Burgers, Wendy A and Orrell, Catherine and Sch{\"{a}}fer, Georgia},
doi = {10.3390/V14061222},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Lambarey et al. - 2022 - SARS-CoV-2 Infection Is Associated with Uncontrolled HIV Viral Load in Non-Hospitalized HIV-Infected Patients f.pdf:pdf},
issn = {1999-4915},
journal = {Viruses},
keywords = {19,2,ART,COVID,CoV,HIV,OA,PLWH,SARS,South Africa,fund{\_}not{\_}ack,original,viral load},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jun},
number = {6},
pages = {1222},
publisher = {Multidisciplinary Digital Publishing Institute},
title = {{SARS-CoV-2 infection is associated with uncontrolled HIV viral load in non-hospitalized HIV-infected patients from Gugulethu, South Africa}},
url = {https://www.mdpi.com/1999-4915/14/6/1222/htm https://www.mdpi.com/1999-4915/14/6/1222},
volume = {14},
year = {2022}
}

In South Africa, high exposure to SARS-CoV-2 occurs primarily in densely populated, low-income communities, which are additionally burdened by highly prevalent Human Immunodeficiency Virus (HIV). With the aim to assess SARS-CoV-2 seroprevalence and its association with HIV-related clinical parameters in non-hospitalized patients likely to be highly exposed to SARS-CoV-2, this observational cross-sectional study was conducted at the Gugulethu Community Health Centre Antiretroviral clinic between October 2020 and June 2021, after the first COVID-19 wave in South Africa and during the second and beginning of the third wave. A total of 150 adult (median age 39 years [range 20–65 years]) HIV-infected patients (69% female; 31% male) were recruited. 95.3% of the cohort was on antiretroviral therapy (ART), had a median CD4 count of 220 cells/µL (range 17–604 cells/µL) and a median HIV viral load (VL) of 49 copies/mL (range 1–1,050,867 copies/mL). Furthermore, 106 patients (70.7%) were SARS-CoV-2 seropositive, and 0% were vaccinated. When stratified for HIV VL, patients with uncontrolled HIV viremia (HIV VL \textgreater 1000 copies/mL) had significantly higher odds of SARS-CoV-2 seropositivity than patients with HIV VL \textless 1000 copies/mL, after adjusting for age, sex and ART status (p = 0.035, adjusted OR 2.961 [95% CI: 1.078–8.133]). Although the cause–effect relationship could not be determined due to the cross-sectional study design, these results point towards a higher risk of SARS-CoV-2 susceptibility among viremic HIV patients, or impaired HIV viral control due to previous co-infection with SARS-CoV-2.

@article{Mullins2022,
author = {Mullins, Michelle O and Smith, Muneerah and Maboreke, Hazel and Nel, Andrew J M and Ntusi, Ntobeko A B and Burgers, Wendy A and Blackburn, Jonathan M},
doi = {10.20944/PREPRINTS202212.0518.V1},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Mullins et al. - 2022 - Epitope coverage of anti-SARS-CoV-2 nucleocapsid IgA and IgG antibodies correlates with protection against re-in.pdf:pdf},
journal = {Preprints},
keywords = {OA,SARS-CoV-2 antibodies,SARS-CoV-2 re-infection,epitope coverage,fund{\_}not{\_}ack,humoral response,immunoassay,original,protein microarray,quantitative antibody binding},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {dec},
pages = {2022120518},
publisher = {Preprints},
title = {{Epitope coverage of anti-SARS-CoV-2 nucleocapsid IgA and IgG antibodies correlates with protection against re-infection by new variants in subsequent waves of the COVID-19 pandemic}},
url = {https://www.preprints.org/manuscript/202212.0518/v1},
year = {2022}
}

@article{Abdelgawad2022a,
abstract = {Background.Early mortality among hospitalized HIV-associated tuberculosis (TB/HIV) patients is high despite treatment. The pharmacokinetics of rifampicin, isoniazid, and pyrazinamide were investigated in hospitalized TB/HIV patients and a cohort of outpatients with TB (with or without HIV) to determine whether drug exposures differed between groups.Methods. Standard first-line TB treatment was given daily as per national guidelines, which consisted of oral 4-drug fixed-dose combination tablets containing 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol. Plasma samples were drawn on the 3rd day of treatment over eight hours post-dose. Rifampicin, isoniazid, and pyrazinamide in plasma were quantified and NONMEM {\textregistered} was used to analyze the data. Results.Data from 60 hospitalized patients (11 of whom died within 12 weeks of starting treatment) and 48 outpatients were available. Median (range) weight and age were 56 (35 - 88) kg, and 37 (19 - 77) years, respectively. Bioavailability and clearance of the three drugs were similar between TB/HIV hospitalized and TB outpatients. However, rifampicin's absorption was slower in hospitalized patients than in outpatients; mean absorption time was 49.9{\%} and 154{\%} more in hospitalized survivors and hospitalized deaths, respectively, than in outpatients. Higher levels of conjugated bilirubin correlated with lower rifampicin clearance. Isoniazid's clearance estimates were 25.5 L/h for fast metabolizers and 9.76 L/h for slow metabolizers. Pyrazinamide's clearance was more variable among hospitalized patients. The variability in clearance among patients was 1.70 and 3.56 times more for hospitalized survivors and hospitalized deaths, respectively, than outpatients. Conclusion.We showed that the pharmacokinetics of first-line TB drugs are not substantially different between hospitalized TB/HIV patients and TB (with or without HIV) outpatients. Hospitalized patients do not seem to be underexposed compared to their outpatient counterparts, as well as hospitalized patients who survived vs who died within 12 weeks of hospitalization.},
author = {Abdelgawad, Noha and Chirehwa, Maxwell and Schutz, Charlotte and Barr, David and Ward, Amy and Janssen, Saskia and Burton, Rosie and Wilkinson, Robert J and Shey, Muki and Wiesner, Lubbe and McIlleron, Helen and Maartens, Gary and Meintjes, Graeme and Denti, Paolo},
doi = {10.12688/WELLCOMEOPENRES.17660.2},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Abdelgawad et al. - 2022 - Pharmacokinetics of antitubercular drugs in patients hospitalized with HIV-associated tuberculosis a populati.pdf:pdf},
issn = {2398502X},
journal = {Wellcome Open Research},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {nov},
pages = {72},
publisher = {F1000 Research Ltd},
title = {{Pharmacokinetics of antitubercular drugs in patients hospitalized with HIV-associated tuberculosis: a population modeling analysis [version 2; peer review: 1 approved, 2 approved with reservations]}},
url = {https://wellcomeopenresearch.org/articles/7-72},
volume = {7},
year = {2022}
}

Background.Early mortality among hospitalized HIV-associated tuberculosis (TB/HIV) patients is high despite treatment. The pharmacokinetics of rifampicin, isoniazid, and pyrazinamide were investigated in hospitalized TB/HIV patients and a cohort of outpatients with TB (with or without HIV) to determine whether drug exposures differed between groups.Methods. Standard first-line TB treatment was given daily as per national guidelines, which consisted of oral 4-drug fixed-dose combination tablets containing 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol. Plasma samples were drawn on the 3rd day of treatment over eight hours post-dose. Rifampicin, isoniazid, and pyrazinamide in plasma were quantified and NONMEM ® was used to analyze the data. Results.Data from 60 hospitalized patients (11 of whom died within 12 weeks of starting treatment) and 48 outpatients were available. Median (range) weight and age were 56 (35 - 88) kg, and 37 (19 - 77) years, respectively. Bioavailability and clearance of the three drugs were similar between TB/HIV hospitalized and TB outpatients. However, rifampicin's absorption was slower in hospitalized patients than in outpatients; mean absorption time was 49.9% and 154% more in hospitalized survivors and hospitalized deaths, respectively, than in outpatients. Higher levels of conjugated bilirubin correlated with lower rifampicin clearance. Isoniazid's clearance estimates were 25.5 L/h for fast metabolizers and 9.76 L/h for slow metabolizers. Pyrazinamide's clearance was more variable among hospitalized patients. The variability in clearance among patients was 1.70 and 3.56 times more for hospitalized survivors and hospitalized deaths, respectively, than outpatients. Conclusion.We showed that the pharmacokinetics of first-line TB drugs are not substantially different between hospitalized TB/HIV patients and TB (with or without HIV) outpatients. Hospitalized patients do not seem to be underexposed compared to their outpatient counterparts, as well as hospitalized patients who survived vs who died within 12 weeks of hospitalization.

@article{Moodie2022,
abstract = {Background The ALVAC/gp120 + MF59 vaccines in the HVTN 702 efficacy trial did not prevent HIV-1 acquisition. Vaccine-matched immunological endpoints that were correlates of HIV-1 acquisition risk in RV144 were measured in HVTN 702 and evaluated as correlates of HIV-1 acquisition. Methods Among 1893 HVTN 702 female vaccinees, 60 HIV-1-seropositive cases and 60 matched seronegative non-cases were sampled. HIV-specific CD4+ T-cell and binding antibody responses were measured 2 weeks post-fourth and fifth immunizations. Cox proportional hazards models assessed pre-specified responses as predictors of HIV-1 acquisition. Results The HVTN 702 Env-specific CD4+ T-cell response rate was significantly higher than in RV144 (63{\%} vs. 40{\%}, P = 0.03) with significantly lower IgG binding antibody response rate and magnitude to 1086.C V1V2 (67{\%} vs. 100{\%}, P{\textless} 0.001; Pmag{\textless} 0.001). Although no significant univariate associations were observed between any T-cell or binding antibody response and HIV-1 acquisition, significant interactions were observed (multiplicity-adjusted P{\textless}=0.03). Among vaccinees with high IgG A244 V1V2 binding antibody responses, vaccine-matched CD4+ T-cell endpoints associated with decreased HIV-1 acquisition (estimated hazard ratios = 0.40-0.49 per 1-SD increase in CD4+ T-cell endpoint). Conclusions HVTN 702 and RV144 had distinct immunogenicity profiles. However, both identified significant correlations (univariate or interaction) for IgG V1V2 and polyfunctional CD4+ T-cells with HIV-1 acquisition.},
author = {Moodie, Zoe and Dintwe, One and Sawant, Sheetal and Grove, Doug and Huang, Yunda and Janes, Holly and Heptinstall, Jack and {Laher Omar}, Faatima and Cohen, Kristen and {De Rosa}, Stephen C and Zhang, Lu and Yates, Nicole L and Sarzotti-Kelsoe, Marcella and Seaton, Kelly E and Laher, Fatima and Bekker, Linda Gail and Malahleha, Mookho and Innes, Craig and Kassim, Sheetal and Naicker, Nivashnee and Govender, Vaneshree and Sebe, Modulakgotla and Singh, Nishanta and Kotze, Philip and Lazarus, Erica and Nchabeleng, Maphoshane and Ward, Amy M and Brumskine, William and Dubula, Thozama and Randhawa, April K and Grunenberg, Nicole and Hural, John and Kee, Jia Jin and Benkeser, David and Jin, Yutong and Carpp, Lindsay N and Allen, Mary and D'Souza, Patricia and Tartaglia, James and DiazGranados, Carlos A and Koutsoukos, Marguerite and Gilbert, Peter B and Kublin, James G and Corey, Lawrence and Andersen-Nissen, Erica and Gray, Glenda E and Tomaras, Georgia D and McElrath, M Juliana},
doi = {10.1093/INFDIS/JIAC260},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Moodie et al. - 2022 - Analysis of the HVTN 702 Phase 2b-3 HIV-1 vaccine trial in South Africa assessing RV144 antibody and T-cell corre.pdf:pdf},
issn = {0022-1899},
journal = {The Journal of Infectious Diseases},
keywords = {fund{\_}not{\_}ack,original},
mendeley-tags = {fund{\_}not{\_}ack,original},
month = {jun},
number = {2},
pages = {246--257},
pmid = {35758878},
title = {{Analysis of the HVTN 702 Phase 2b-3 HIV-1 vaccine trial in South Africa assessing RV144 antibody and T-cell correlates of HIV-1 acquisition risk}},
url = {https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiac260/6618597},
volume = {226},
year = {2022}
}

Background The ALVAC/gp120 + MF59 vaccines in the HVTN 702 efficacy trial did not prevent HIV-1 acquisition. Vaccine-matched immunological endpoints that were correlates of HIV-1 acquisition risk in RV144 were measured in HVTN 702 and evaluated as correlates of HIV-1 acquisition. Methods Among 1893 HVTN 702 female vaccinees, 60 HIV-1-seropositive cases and 60 matched seronegative non-cases were sampled. HIV-specific CD4+ T-cell and binding antibody responses were measured 2 weeks post-fourth and fifth immunizations. Cox proportional hazards models assessed pre-specified responses as predictors of HIV-1 acquisition. Results The HVTN 702 Env-specific CD4+ T-cell response rate was significantly higher than in RV144 (63% vs. 40%, P = 0.03) with significantly lower IgG binding antibody response rate and magnitude to 1086.C V1V2 (67% vs. 100%, P\textless 0.001; Pmag\textless 0.001). Although no significant univariate associations were observed between any T-cell or binding antibody response and HIV-1 acquisition, significant interactions were observed (multiplicity-adjusted P\textless=0.03). Among vaccinees with high IgG A244 V1V2 binding antibody responses, vaccine-matched CD4+ T-cell endpoints associated with decreased HIV-1 acquisition (estimated hazard ratios = 0.40-0.49 per 1-SD increase in CD4+ T-cell endpoint). Conclusions HVTN 702 and RV144 had distinct immunogenicity profiles. However, both identified significant correlations (univariate or interaction) for IgG V1V2 and polyfunctional CD4+ T-cells with HIV-1 acquisition.

@article{Denti2021,
abstract = {Background In 2010, the WHO revised dosing guidelines for treatment of childhood tuberculosis. Our aim was to investigate first-line antituberculosis drug exposures under these guidelines, explore dose optimization using the current dispersible fixed-dose combination (FDC) table of rifampicin/isoniazid/pyrazinamide; 75/50/150 mg , and suggest a new FDC with revised weight-bands. Methods Children with drug-susceptible tuberculosis in Malawi and South Africa underwent pharmacokinetic sampling while receiving first-line tuberculosis drugs as single formulations according the 2010 WHO recommended doses. Nonlinear mixed-effects modelling and simulation was used to design the optimal FDC and weight-band dosing strategy for achieving the pharmacokinetic targets based on literature-derived adult AUC0-24h for rifampicin (38.7-72.9) isoniazid (11.6-26.3) and pyrazinamide (233-429 mg∙h/L). Results 180 children (42{\%} female; 13.9{\%} HIV-infected; median [range] age 1.9 [0.22-12] years; weight 10.7 [3.20-28.8] kg) were administered 1, 2, 3, or 4 FDC tablets (rifampicin/isoniazid/pyrazinamide 75/50/150 mg) daily for 4-8, 8-12, 12-16, and 16-25 kg weight-bands, respectively. Rifampicin exposure (for weight and age) was up to 50{\%} lower than in adults. Increasing the tablet number resulted in adequate rifampicin but relatively high isoniazid and pyrazinamide exposures. Administering 1, 2, 3, or 4 optimized FDC tablets (rifampicin/isoniazid/pyrazinamide 120/35/130 mg) to children {\textless}6, 6-13, 13-20 and 20-25 kg, and 0.5 tablet in {\textless}3-month-olds with immature metabolism, improved exposures to all three drugs. Conclusion Current pediatric FDC doses resulted in low rifampicin exposures. Optimal dosing of all drugs cannot be achieved with the current FDCs. We propose a new FDC formulation and revised weight-bands.},
author = {Denti, Paolo and Wasmann, Roeland E and van Rie, Annelies and Winckler, Jana and Bekker, Adrie and Rabie, Helena and {Hesseling, Anneke}, C and van der Laan, Louvina E and Gonzalez-Martinez, Carmen and Zar, Heather J and Davies, Gerry and Wiesner, Lubbe and Svensson, Elin M and McIlleron, Helen M},
doi = {10.1093/CID/CIAB908},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Denti et al. - 2022 - Optimizing dosing and fixed-dose combinations of rifampicin, isoniazid, and pyrazinamide in pediatric patients wit.pdf:pdf},
journal = {Clinical Infectious Diseases},
keywords = {OA,child,exposure,fund{\_}not{\_}ack,isoniazid,original,pediatrics,pyrazinamide,rifampin,tablet dosage form,tuberculosis},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {oct},
number = {1},
pages = {141--151},
pmid = {34665866},
title = {{Optimizing dosing and fixed-dose combinations of rifampicin, isoniazid, and pyrazinamide in pediatric patients with tuberculosis: a prospective population pharmacokinetic study}},
url = {https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab908/6403131},
volume = {75},
year = {2022}
}

Background In 2010, the WHO revised dosing guidelines for treatment of childhood tuberculosis. Our aim was to investigate first-line antituberculosis drug exposures under these guidelines, explore dose optimization using the current dispersible fixed-dose combination (FDC) table of rifampicin/isoniazid/pyrazinamide; 75/50/150 mg , and suggest a new FDC with revised weight-bands. Methods Children with drug-susceptible tuberculosis in Malawi and South Africa underwent pharmacokinetic sampling while receiving first-line tuberculosis drugs as single formulations according the 2010 WHO recommended doses. Nonlinear mixed-effects modelling and simulation was used to design the optimal FDC and weight-band dosing strategy for achieving the pharmacokinetic targets based on literature-derived adult AUC0-24h for rifampicin (38.7-72.9) isoniazid (11.6-26.3) and pyrazinamide (233-429 mg∙h/L). Results 180 children (42% female; 13.9% HIV-infected; median [range] age 1.9 [0.22-12] years; weight 10.7 [3.20-28.8] kg) were administered 1, 2, 3, or 4 FDC tablets (rifampicin/isoniazid/pyrazinamide 75/50/150 mg) daily for 4-8, 8-12, 12-16, and 16-25 kg weight-bands, respectively. Rifampicin exposure (for weight and age) was up to 50% lower than in adults. Increasing the tablet number resulted in adequate rifampicin but relatively high isoniazid and pyrazinamide exposures. Administering 1, 2, 3, or 4 optimized FDC tablets (rifampicin/isoniazid/pyrazinamide 120/35/130 mg) to children \textless6, 6-13, 13-20 and 20-25 kg, and 0.5 tablet in \textless3-month-olds with immature metabolism, improved exposures to all three drugs. Conclusion Current pediatric FDC doses resulted in low rifampicin exposures. Optimal dosing of all drugs cannot be achieved with the current FDCs. We propose a new FDC formulation and revised weight-bands.

@article{Esmail2022a,
author = {Esmail, Hanif and Narendran, Gopalan and Nunn, Andrew},
doi = {10.4103/ijmr.ijmr_677_22},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Esmail, Narendran, Nunn - 2022 - Drug-resistant tuberculosis promising progress with a note of caution.pdf:pdf},
issn = {0971-5916},
journal = {Indian Journal of Medical Research},
keywords = {OA,editorial,fund{\_}not{\_}ack},
mendeley-tags = {OA,editorial,fund{\_}not{\_}ack},
number = {3 {\&} 4},
pages = {325--328},
pmid = {35647946},
title = {{Drug-resistant tuberculosis: promising progress with a note of caution}},
url = {https://journals.lww.com/ijmr/Fulltext/9000/Drug{\_}resistant{\_}tuberculosis{\_}{\_}Promising{\_}progress.99924.aspx http://www.ijmr.org.in/preprintarticle.asp?id=346422;type=0},
volume = {155},
year = {2022}
}

@article{Osero2022,
abstract = {IL-4 and IL-13 cytokines have been associated with a non-healing phenotype in murine leishmaniasis in L. mexicana -infected BALB/c mice as demonstrated in IL-4−/−, IL-13−/− and IL-4R$\alpha$-/- global knockout miouse studies. However, it is unclear from the studies which cell-type-specific IL-4/IL-13 signaling mediates protection to L. mexicana. Previous studies have ruled out a role for IL-4-mediated protection on CD4+ T cells during L. mexicana infections. A candidate for this role may be non-lymphocyte cells, particularly DCs, as was previously shown in L. major infections, where IL-4 production drives dendritic cell-IL-12 production thereby mediating a type 1 immune response. However, it is unclear if this IL-4-instruction of type 1 immunity also occurs in CL caused by L. Mexicana, since the outcome of cutaneous leishmaniasis often depends on the infecting Leishmania species. Thus, BALB/c mice with cell-specific deletion of the IL-4R$\alpha$ on CD11c+ DCs were infected with L. mexicana promastigotes in the footpad and the clinical phenotype, humoral and cellular immune responses were investigated, compared to the littermate control, IL-4R$\alpha$-/lox mice. Our results show that CL disease progression in BALB/c mice is independent of IL-4R$\alpha$ signaling on DCs as CD11ccreIL-4R$\alpha$-/lox mice had similar footpad lesion progression, parasite loads, humoral responses (IgE, IgG1, IgG 2a/b), and IFN-$\gamma$ cytokine secretion in comparison to littermate controls. Despite this comparable phenotype, IL-4 production in CD11ccreIL-4R$\alpha$-/lox mice was significantly increased with an increasing trend of IL-13 compared to littermate controls. Moreover, the absence of IL-4R$\alpha$ signaling did not significantly alter the frequency of CD4 and CD8 lymphocytes nor their activation, or memory phenotype compared to littermate controls. However, these populations were significantly increased in CD11ccreIL-4R$\alpha$-/lox mice due to greater total cell infiltration into the lymph node. The recruitment of macrophages, DCs, neutrophils, and MoDCs into LN was comparable to littermate IL-4R$\alpha$-/lox mice. Interestingly, the similar levels of IL-12p70 and IL-10 produced by BMDCs between CD11ccreIL-4R$\alpha$-/lox mice and littermate controls highlighted unimpaired IL-4-mediated DC instruction. Nevertheless, maturation/activation and nitrite/urea production were not affected. Together, this study suggests that IL-4 R$\alpha$ signaling on DCs is not key in the regulation of immune-mediated protection in mice against L. mexicana infection.},
author = {Osero, Bernard Ong'ondo and Cele, Zama and Aruleba, Raphael Taiwo and Maine, Rebeng A and Ozturk, Mumin and Lutz, Manfred B and Brombacher, Frank and Hurdayal, Ramona},
doi = {10.3389/FIMMU.2021.759021},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Osero et al. - 2022 - Interleukin-4 responsive dendritic cells are dispensable to host resistance against Leishmania mexicana infection.pdf:pdf},
issn = {1664-3224},
journal = {Frontiers in Immunology},
keywords = {Dendritic Cells,IL-4,IL-4R$\alpha$,Leishmania mexicana,Mice,OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jan},
pages = {759021},
pmid = {35154068},
publisher = {Frontiers},
title = {{Interleukin-4 responsive dendritic cells are dispensable to host resistance against Leishmania mexicana infection}},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2021.759021/full},
volume = {12},
year = {2022}
}

IL-4 and IL-13 cytokines have been associated with a non-healing phenotype in murine leishmaniasis in L. mexicana -infected BALB/c mice as demonstrated in IL-4−/−, IL-13−/− and IL-4R$α$-/- global knockout miouse studies. However, it is unclear from the studies which cell-type-specific IL-4/IL-13 signaling mediates protection to L. mexicana. Previous studies have ruled out a role for IL-4-mediated protection on CD4+ T cells during L. mexicana infections. A candidate for this role may be non-lymphocyte cells, particularly DCs, as was previously shown in L. major infections, where IL-4 production drives dendritic cell-IL-12 production thereby mediating a type 1 immune response. However, it is unclear if this IL-4-instruction of type 1 immunity also occurs in CL caused by L. Mexicana, since the outcome of cutaneous leishmaniasis often depends on the infecting Leishmania species. Thus, BALB/c mice with cell-specific deletion of the IL-4R$α$ on CD11c+ DCs were infected with L. mexicana promastigotes in the footpad and the clinical phenotype, humoral and cellular immune responses were investigated, compared to the littermate control, IL-4R$α$-/lox mice. Our results show that CL disease progression in BALB/c mice is independent of IL-4R$α$ signaling on DCs as CD11ccreIL-4R$α$-/lox mice had similar footpad lesion progression, parasite loads, humoral responses (IgE, IgG1, IgG 2a/b), and IFN-$γ$ cytokine secretion in comparison to littermate controls. Despite this comparable phenotype, IL-4 production in CD11ccreIL-4R$α$-/lox mice was significantly increased with an increasing trend of IL-13 compared to littermate controls. Moreover, the absence of IL-4R$α$ signaling did not significantly alter the frequency of CD4 and CD8 lymphocytes nor their activation, or memory phenotype compared to littermate controls. However, these populations were significantly increased in CD11ccreIL-4R$α$-/lox mice due to greater total cell infiltration into the lymph node. The recruitment of macrophages, DCs, neutrophils, and MoDCs into LN was comparable to littermate IL-4R$α$-/lox mice. Interestingly, the similar levels of IL-12p70 and IL-10 produced by BMDCs between CD11ccreIL-4R$α$-/lox mice and littermate controls highlighted unimpaired IL-4-mediated DC instruction. Nevertheless, maturation/activation and nitrite/urea production were not affected. Together, this study suggests that IL-4 R$α$ signaling on DCs is not key in the regulation of immune-mediated protection in mice against L. mexicana infection.

@article{Margolin2022a,
abstract = {Heterologous glycoprotein production relies on host glycosylation-dependent folding. When the biosynthetic machinery differs from the usual expression host, there is scope to remodel the assembly pathway to enhance glycoprotein production. Here we explore the integration of chaperone coexpression with glyco-engineering to improve the production of a model HIV-1 envelope antigen. Calreticulin was coexpressed to support protein folding together with Leishmania major STT3D oligosaccharyltransferase, to improve glycan occupancy, RNA interference to suppress the formation of truncated glycans, and Nicotiana benthamiana plants lacking $\alpha$1,3-fucosyltransferase and $\beta$1,2-xylosyltransferase was used as an expression host to prevent plant-specific complex N-glycans forming. This approach reduced the formation of undesired aggregates, which predominated in the absence of glyco-engineering. The resulting antigen also exhibited increased glycan occupancy, albeit to a slightly lower level than the equivalent mammalian cell-produced protein. The antigen was decorated almost exclusively with oligomannose glycans, which were less processed compared with Biotechnol Bioeng. 2022;1-19. wileyonlinelibrary.com/journal/bit | 1 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.},
author = {Margolin, Emmanuel and Allen, Joel D and Verbeek, Matthew and Chapman, Ros and Meyers, Ann and {Michiel Van Diepen}, | and Ximba, Phindile and Motlou, Thopisang and Penny, | and Moore, L and Woodward, Jeremy and Strasser, | Richard and Crispin, Max and Williamson, Anna-Lise and Rybicki, Edward P},
doi = {10.1002/BIT.28169},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Margolin et al. - 2022 - Augmenting glycosylation-directed folding pathways enhances the fidelity of HIV Env immunogen production in pla.pdf:pdf},
issn = {1097-0290},
journal = {Biotechnology and Bioengineering},
keywords = {OA,chaperones,engineering,fund{\_}ack,glyco,glycosylation,immunogenicity,neutralization,occupancy,original,vaccine},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jul},
pages = {10.1002/bit.28169},
publisher = {John Wiley {\&} Sons, Ltd},
title = {{Augmenting glycosylation-directed folding pathways enhances the fidelity of HIV Env immunogen production in plants}},
url = {https://onlinelibrary.wiley.com/doi/full/10.1002/bit.28169 https://onlinelibrary.wiley.com/doi/abs/10.1002/bit.28169 https://onlinelibrary.wiley.com/doi/10.1002/bit.28169},
year = {2022}
}

Heterologous glycoprotein production relies on host glycosylation-dependent folding. When the biosynthetic machinery differs from the usual expression host, there is scope to remodel the assembly pathway to enhance glycoprotein production. Here we explore the integration of chaperone coexpression with glyco-engineering to improve the production of a model HIV-1 envelope antigen. Calreticulin was coexpressed to support protein folding together with Leishmania major STT3D oligosaccharyltransferase, to improve glycan occupancy, RNA interference to suppress the formation of truncated glycans, and Nicotiana benthamiana plants lacking $α$1,3-fucosyltransferase and $β$1,2-xylosyltransferase was used as an expression host to prevent plant-specific complex N-glycans forming. This approach reduced the formation of undesired aggregates, which predominated in the absence of glyco-engineering. The resulting antigen also exhibited increased glycan occupancy, albeit to a slightly lower level than the equivalent mammalian cell-produced protein. The antigen was decorated almost exclusively with oligomannose glycans, which were less processed compared with Biotechnol Bioeng. 2022;1-19. wileyonlinelibrary.com/journal/bit | 1 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

@article{HamiltonHealthSciencesHamilton2022,
abstract = {Summary Background The large number of patients worldwide infected with the SARS-CoV-2 virus has overwhelmed health-care systems globally. The Anti-Coronavirus Therapies (ACT) outpatient trial aimed to evaluate anti-inflammatory therapy with colchicine and antithrombotic therapy with aspirin for prevention of disease progression in community patients with COVID-19. Methods The ACT outpatient, open-label, 2 × 2 factorial, randomised, controlled trial, was done at 48 clinical sites in 11 countries. Patients in the community aged 30 years and older with symptomatic, laboratory confirmed COVID-19 who were within 7 days of diagnosis and at high risk of disease progression were randomly assigned (1:1) to receive colchicine 0{\textperiodcentered}6 mg twice daily for 3 days and then 0{\textperiodcentered}6 mg once daily for 25 days versus usual care, and in a second (1:1) randomisation to receive aspirin 100 mg once daily for 28 days versus usual care. Investigators and patients were not masked to treatment allocation. The primary outcome was assessed at 45 days in the intention-to-treat population; for the colchicine randomisation it was hospitalisation or death, and for the aspirin randomisation it was major thrombosis, hospitalisation, or death. The ACT outpatient trial is registered at ClinicalTrials.gov, NCT04324463 and is ongoing. Findings Between Aug 27, 2020, and Feb 10, 2022, 3917 patients were randomly assigned to colchicine or control and to aspirin or control; after excluding 36 patients due to administrative reasons 3881 individuals were included in the analysis (n=1939 colchicine vs n=1942 control; n=1945 aspirin vs 1936 control). Follow-up was more than 99{\%} complete. Overall event rates were 5 (0{\textperiodcentered}1{\%}) of 3881 for major thrombosis, 123 (3{\textperiodcentered}2{\%}) of 3881 for hospitalisation, and 23 (0{\textperiodcentered}6{\%}) of 3881 for death; 66 (3{\textperiodcentered}4{\%}) of 1939 patients allocated to colchicine and 65 (3{\textperiodcentered}3{\%}) of 1942 patients allocated to control experienced hospitalisation or death (hazard ratio [HR] 1{\textperiodcentered}02, 95{\%} CI 0{\textperiodcentered}72–1{\textperiodcentered}43, p=0{\textperiodcentered}93); and 59 (3{\textperiodcentered}0{\%}) of 1945 of patients allocated to aspirin and 73 (3{\textperiodcentered}8{\%}) of 1936 patients allocated to control experienced major thrombosis, hospitalisation, or death (HR 0{\textperiodcentered}80, 95{\%} CI 0{\textperiodcentered}57–1{\textperiodcentered}13, p=0{\textperiodcentered}21). Results for the primary outcome were consistent in all prespecified subgroups, including according to baseline vaccination status, timing of randomisation in relation to onset of symptoms (post-hoc analysis), and timing of enrolment according to the phase of the pandemic (post-hoc analysis). There were more serious adverse events with colchicine than with control (34 patients [1{\textperiodcentered}8{\%}] of 1939 vs 27 [1{\textperiodcentered}4{\%}] of 1942) but none in either group that led to discontinuation of study interventions. There was no increase in serious adverse events with aspirin versus control (31 [1{\textperiodcentered}6{\%}] vs 31 [1{\textperiodcentered}6{\%}]) and none that led to discontinuation of study interventions. Interpretation The results provide no support for the use of colchicine or aspirin to prevent disease progression or death in outpatients with COVID-19. Funding Canadian Institutes for Health Research, Bayer, Population Health Research Institute, Hamilton Health Sciences Research Institute, and Thistledown Foundation. Translations For the Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.},
author = {Eikelboom, John W and Jolly, Sanjit S and Belley-Cote, Emilie P and Whitlock, Richard P and Rangarajan, Sumathy and Xu, Lizhen and Heenan, Laura and Bangdiwala, Shrikant I and Tarhuni, Wadea M and Hassany, Mohamed and Kontsevaya, Anna and Harper, William and {Kumar Sharma}, Sanjib and Lopez-Jaramillo, Patricio and Dans, Antonio L and Palileo-Villanueva, Lia M and Avezum, Alvaro and Pais, Prem and Xavier, Denis and Felix, Camilo and Yusufali, Afzalhussein and Lopes, Renato D and Berwanger, Otavio and Ali, Zeeshan and Wasserman, Sean and Anand, Sonia S and Bosch, Jackie and Choudhri, Shurjeel and Farkouh, Michael E and Loeb, Mark and Yusuf, Salim},
doi = {10.1016/S2213-2600(22)00299-5},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Eikelboom et al. - 2022 - Colchicine and aspirin in community patients with COVID-19 (ACT) an open-label, factorial, randomised, control.pdf:pdf},
issn = {2213-2600},
journal = {The Lancet Respiratory Medicine},
keywords = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {oct},
number = {12},
pages = {1160--1168},
pmid = {36228639},
publisher = {Elsevier},
title = {{Colchicine and aspirin in community patients with COVID-19 (ACT): an open-label, factorial, randomised, controlled trial}},
url = {http://www.thelancet.com/article/S2213260022002995/fulltext http://www.thelancet.com/article/S2213260022002995/abstract https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(22)00299-5/abstract},
volume = {10},
year = {2022}
}

Summary Background The large number of patients worldwide infected with the SARS-CoV-2 virus has overwhelmed health-care systems globally. The Anti-Coronavirus Therapies (ACT) outpatient trial aimed to evaluate anti-inflammatory therapy with colchicine and antithrombotic therapy with aspirin for prevention of disease progression in community patients with COVID-19. Methods The ACT outpatient, open-label, 2 × 2 factorial, randomised, controlled trial, was done at 48 clinical sites in 11 countries. Patients in the community aged 30 years and older with symptomatic, laboratory confirmed COVID-19 who were within 7 days of diagnosis and at high risk of disease progression were randomly assigned (1:1) to receive colchicine 0˙6 mg twice daily for 3 days and then 0˙6 mg once daily for 25 days versus usual care, and in a second (1:1) randomisation to receive aspirin 100 mg once daily for 28 days versus usual care. Investigators and patients were not masked to treatment allocation. The primary outcome was assessed at 45 days in the intention-to-treat population; for the colchicine randomisation it was hospitalisation or death, and for the aspirin randomisation it was major thrombosis, hospitalisation, or death. The ACT outpatient trial is registered at ClinicalTrials.gov, NCT04324463 and is ongoing. Findings Between Aug 27, 2020, and Feb 10, 2022, 3917 patients were randomly assigned to colchicine or control and to aspirin or control; after excluding 36 patients due to administrative reasons 3881 individuals were included in the analysis (n=1939 colchicine vs n=1942 control; n=1945 aspirin vs 1936 control). Follow-up was more than 99% complete. Overall event rates were 5 (0˙1%) of 3881 for major thrombosis, 123 (3˙2%) of 3881 for hospitalisation, and 23 (0˙6%) of 3881 for death; 66 (3˙4%) of 1939 patients allocated to colchicine and 65 (3˙3%) of 1942 patients allocated to control experienced hospitalisation or death (hazard ratio [HR] 1˙02, 95% CI 0˙72–1˙43, p=0˙93); and 59 (3˙0%) of 1945 of patients allocated to aspirin and 73 (3˙8%) of 1936 patients allocated to control experienced major thrombosis, hospitalisation, or death (HR 0˙80, 95% CI 0˙57–1˙13, p=0˙21). Results for the primary outcome were consistent in all prespecified subgroups, including according to baseline vaccination status, timing of randomisation in relation to onset of symptoms (post-hoc analysis), and timing of enrolment according to the phase of the pandemic (post-hoc analysis). There were more serious adverse events with colchicine than with control (34 patients [1˙8%] of 1939 vs 27 [1˙4%] of 1942) but none in either group that led to discontinuation of study interventions. There was no increase in serious adverse events with aspirin versus control (31 [1˙6%] vs 31 [1˙6%]) and none that led to discontinuation of study interventions. Interpretation The results provide no support for the use of colchicine or aspirin to prevent disease progression or death in outpatients with COVID-19. Funding Canadian Institutes for Health Research, Bayer, Population Health Research Institute, Hamilton Health Sciences Research Institute, and Thistledown Foundation. Translations For the Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.

@article{Mondleki2022,
abstract = {Background: Dolutegravir, a component of the preferred first-line antiretroviral therapy regimen, has been associated with increased weight gain. South Africa has a high prevalence of obesity, especially among women. Understanding dolutegravir exposure in patients with obesity is important for dose optimisation. Objectives: We compared the pharmacokinetic parameters of dolutegravir in Southern African adults living with HIV with and without obesity. Method: Blood samples were collected at various time points over a 24 h-period for dolutegravir assays. Non-compartmental analysis was conducted and geometric mean ratios (GMRs), with 90{\%} confidence intervals (CIs), were generated to compare dolutegravir pharmacokinetic parameters between the groups. Regression analyses to assess predictors of dolutegravir exposure were done. Results: Forty participants were enrolled, 26 were women and 10 had obesity. Dolutegravir area under the concentration-time curve to 24-h and the maximum concentrations were not statistically significantly lower in participants with obesity: GMR 0.91 (90{\%} CI: 0.71–1.16) and GMR 0.86 (90{\%} CI: 0.68–1.07), respectively. In a multivariate linear regression analysis adjusting for age, gender, body mass index, creatinine clearance and randomisation arm (tenofovir alafenamide or tenofovir disoproxil fumarate), a unit increase in body mass index was associated with 1.2{\%} lower dolutegravir area under the concentration-time curve to 24-h ( P = 0.035). Conclusion: Dolutegravir exposure was marginally lower in participants with obesity, but this is not clinically significant. Our findings suggest that there is no need to dose adjust dolutegravir in people with obesity.},
author = {Mondleki, Enkosi and Banda, Clifford G and Chandiwana, Nomathemba C and Sokhela, Simiso and Wiesner, Lubbe and Venter, Francois and Maartens, Gary and Sinxadi, Phumla Z},
doi = {10.4102/SAJHIVMED.V23I1.1452},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Mondleki et al. - 2022 - Effect of obesity on dolutegravir exposure in Black Southern African adults living with HIV.pdf:pdf},
issn = {2078-6751},
journal = {Southern African Journal of HIV Medicine},
keywords = {AIDS,Africa,African,HIV,OA,South Africa,after,age,analysis,antiretroviral,antiretroviral treatment optimisation,associated,based,care,data,disease,dolutegravir,drug,fund{\_}ack,group,guidelines,health,healthcare,individuals,infected,infection,model,months,obesity,original,patients,people,pharmacokinetics,population,positive,pregnancy,renal,risk,services,study,test,testing,therapy,time,treatment,virus,women,workers,years},
mendeley-tags = {OA,fund{\_}ack,original},
month = {dec},
number = {1},
pages = {a1452},
title = {{Effect of obesity on dolutegravir exposure in Black Southern African adults living with HIV}},
url = {https://sajhivmed.org.za/index.php/hivmed/article/view/1452/2983 https://sajhivmed.org.za/index.php/hivmed/article/view/1452/2984 https://sajhivmed.org.za/index.php/hivmed/article/view/1452/2985 https://sajhivmed.org.za/index.php/hivmed/article/view/1452},
volume = {23},
year = {2022}
}

Background: Dolutegravir, a component of the preferred first-line antiretroviral therapy regimen, has been associated with increased weight gain. South Africa has a high prevalence of obesity, especially among women. Understanding dolutegravir exposure in patients with obesity is important for dose optimisation. Objectives: We compared the pharmacokinetic parameters of dolutegravir in Southern African adults living with HIV with and without obesity. Method: Blood samples were collected at various time points over a 24 h-period for dolutegravir assays. Non-compartmental analysis was conducted and geometric mean ratios (GMRs), with 90% confidence intervals (CIs), were generated to compare dolutegravir pharmacokinetic parameters between the groups. Regression analyses to assess predictors of dolutegravir exposure were done. Results: Forty participants were enrolled, 26 were women and 10 had obesity. Dolutegravir area under the concentration-time curve to 24-h and the maximum concentrations were not statistically significantly lower in participants with obesity: GMR 0.91 (90% CI: 0.71–1.16) and GMR 0.86 (90% CI: 0.68–1.07), respectively. In a multivariate linear regression analysis adjusting for age, gender, body mass index, creatinine clearance and randomisation arm (tenofovir alafenamide or tenofovir disoproxil fumarate), a unit increase in body mass index was associated with 1.2% lower dolutegravir area under the concentration-time curve to 24-h ( P = 0.035). Conclusion: Dolutegravir exposure was marginally lower in participants with obesity, but this is not clinically significant. Our findings suggest that there is no need to dose adjust dolutegravir in people with obesity.

@article{Haas2022,
author = {Haas, David W and Abdelwahab, Mahmoud Tareq and van Beek, Stijn W and Baker, Paxton and Maartens, Gary and Bradford, Yuki and Ritchie, Marylyn D and Wasserman, Sean and Meintjes, Graeme and Beeri, Karen and Gandhi, Neel R and Svensson, Elin M and Denti, Paolo and Brust, James C M},
doi = {10.1093/INFDIS/JIAC024},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Haas et al. - 2022 - Pharmacogenetics of between-individual variability in plasma clearance of bedaquiline and clofazimine in South Afri.pdf:pdf},
issn = {0022-1899},
journal = {The Journal of Infectious Diseases},
keywords = {bedaquiline,clofazimine,cyp3a5 gene,drug clearance,fund{\_}ack,genome,original,pharmacogenetics,plasma,polymorphism},
mendeley-tags = {fund{\_}ack,original},
month = {jan},
pages = {jiac024},
pmid = {35091749},
publisher = {Oxford University Press (OUP)},
title = {{Pharmacogenetics of between-individual variability in plasma clearance of bedaquiline and clofazimine in South Africa}},
url = {https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiac024/6517045},
year = {2022}
}

@article{Cindi2022,
abstract = {Background Dolutegravir is a component of preferred antiretroviral therapy (ART) regimens. We characterised the pharmacogenetics of dolutegravir exposure following ART initiation in the ADVANCE trial in South Africa. Methods Genome-wide genotyping followed by imputation was performed. We developed a population pharmacokinetic model for dolutegravir using non-linear mixed-effects modelling. Linear regression models examined associations with unexplained variability in dolutegravir area under the concentration-time curve (AUCVAR). Results Genetic associations were evaluable in 284 individuals. Of nine polymorphisms previously associated with dolutegravir pharmacokinetics, the lowest P-value with AUCVAR was UGT1A1 rs887829 (P = 1.8 × 10−4), which was also associated with log10 bilirubin (P = 8.6 × 10−13). After adjusting for rs887829, AUCVAR was independently associated with rs28899168 in the UGT1A locus (P = 0.02), as were bilirubin concentrations (P = 7.7 × 10−8). In the population pharmacokinetic model, rs887829 T/T and C/T were associated with 25.9{\%} and 10.8{\%} decreases in dolutegravir clearance, respectively, compared to C/C. The lowest P-value for AUCVAR genome-wide was CAMKMT rs343942 (P = 2.4 × 10−7). Conclusions In South Africa, rs887829 and rs28899168 in the UGT1A locus were independently associated with dolutegravir AUCVAR. The novel rs28899168 association warrants replication. This study enhances understanding of dolutegravir pharmacogenetics in Africa.},
author = {Cindi, Zinhle and Kawuma, Aida N and Maartens, Gary and Bradford, Yuki and Venter, Francois and Sokhela, Simiso and Chandiwana, Nomathemba and Wasmann, Roeland E and Denti, Paolo and Wiesner, Lubbe and Ritchie, Marylyn D and Haas, David W and Sinxadi, Phumla},
doi = {10.1093/INFDIS/JIAC174},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Cindi et al. - 2022 - Pharmacogenetics of dolutegravir plasma exposure among southernern Africans with HIV.pdf:pdf},
issn = {0022-1899},
journal = {The Journal of Infectious Diseases},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {may},
number = {9},
pages = {1616--1625},
title = {{Pharmacogenetics of dolutegravir plasma exposure among southernern Africans with HIV}},
url = {https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiac174/6580078},
volume = {226},
year = {2022}
}

Background Dolutegravir is a component of preferred antiretroviral therapy (ART) regimens. We characterised the pharmacogenetics of dolutegravir exposure following ART initiation in the ADVANCE trial in South Africa. Methods Genome-wide genotyping followed by imputation was performed. We developed a population pharmacokinetic model for dolutegravir using non-linear mixed-effects modelling. Linear regression models examined associations with unexplained variability in dolutegravir area under the concentration-time curve (AUCVAR). Results Genetic associations were evaluable in 284 individuals. Of nine polymorphisms previously associated with dolutegravir pharmacokinetics, the lowest P-value with AUCVAR was UGT1A1 rs887829 (P = 1.8 × 10−4), which was also associated with log10 bilirubin (P = 8.6 × 10−13). After adjusting for rs887829, AUCVAR was independently associated with rs28899168 in the UGT1A locus (P = 0.02), as were bilirubin concentrations (P = 7.7 × 10−8). In the population pharmacokinetic model, rs887829 T/T and C/T were associated with 25.9% and 10.8% decreases in dolutegravir clearance, respectively, compared to C/C. The lowest P-value for AUCVAR genome-wide was CAMKMT rs343942 (P = 2.4 × 10−7). Conclusions In South Africa, rs887829 and rs28899168 in the UGT1A locus were independently associated with dolutegravir AUCVAR. The novel rs28899168 association warrants replication. This study enhances understanding of dolutegravir pharmacogenetics in Africa.

@article{Riou2021c,
abstract = {SARS-CoV-2 variants have emerged that escape neutralization and potentially impact vaccine efficacy. T cell responses play a role in protection from reinfection and severe disease, but the potential for spike mutations to affect T cell immunity is incompletely understood. We assessed neutralizing antibody and T cell responses in 44 South African COVID-19 patients infected either with the Beta variant (dominant from November 2020 to May 2021) or infected prior to its emergence (first wave, Wuhan strain), to provide an overall measure of immune evasion. We show that robust spike-specific CD4 and CD8 T cell responses were detectable in Beta-infected patients, similar to first wave patients. Using peptides spanning the Beta- mutated regions, we identified CD4 T cell responses targeting the wild type peptides in 12/22 first wave patients, all of whom failed to recognize corresponding Beta-mutated peptides. However, responses to mutated regions formed only a small proportion (15.7{\%}) of the overall CD4 response, and few patients (3/44) mounted CD8 responses that targeted the mutated regions. Among the spike epitopes tested, we identified three epitopes containing the D215, L18, or D80 residues that were specifically recognized by CD4 T cells, and their mutated versions were associated with a loss of response. This study shows that in spite of loss of recognition of immunogenic CD4 epitopes, CD4 and CD8 T cell responses to Beta are preserved overall. These observations may explain why several vaccines have retained the ability to protect against severe COVID-19 even with substantial loss of neutralizing antibody activity against Beta.},
author = {Riou, Catherine and Keeton, Roanne and Moyo-Gwete, Thandeka and Hermanus, Tandile and Kgagudi, Prudence and Baguma, Richard and Valley-Omar, Ziyaad and Smith, Mikhail and Tegally, Houriiyah and Doolabh, Deelan and Iranzadeh, Arash and Tyers, Lynn and Mutavhatsindi, Hygon and Tincho, Marius B and Benede, Ntombi and Marais, Gert and Chinhoyi, Lionel R and Mennen, Mathilda and Skelem, Sango and du Bruyn, Elsa and Stek, Cari and SA-CIN and de Oliveira, Tulio and Williamson, Carolyn and Moore, Penny L and Wilkinson, Robert J and Ntusi, Ntobeko A B and Burgers, Wendy A},
doi = {https://doi.org/10.1126/scitranslmed.abj6824},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Riou et al. - 2022 - Escape from recognition of SARS-CoV-2 Beta variant spike epitopes but overall preservation of T cell immunity.pdf:pdf},
issn = {1946-6242},
journal = {Science Translational Medicine},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {dec},
number = {631},
pages = {eabj6824},
pmid = {34931886},
title = {{Escape from recognition of SARS-CoV-2 Beta variant spike epitopes but overall preservation of T cell immunity.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/34931886},
volume = {14},
year = {2022}
}

SARS-CoV-2 variants have emerged that escape neutralization and potentially impact vaccine efficacy. T cell responses play a role in protection from reinfection and severe disease, but the potential for spike mutations to affect T cell immunity is incompletely understood. We assessed neutralizing antibody and T cell responses in 44 South African COVID-19 patients infected either with the Beta variant (dominant from November 2020 to May 2021) or infected prior to its emergence (first wave, Wuhan strain), to provide an overall measure of immune evasion. We show that robust spike-specific CD4 and CD8 T cell responses were detectable in Beta-infected patients, similar to first wave patients. Using peptides spanning the Beta- mutated regions, we identified CD4 T cell responses targeting the wild type peptides in 12/22 first wave patients, all of whom failed to recognize corresponding Beta-mutated peptides. However, responses to mutated regions formed only a small proportion (15.7%) of the overall CD4 response, and few patients (3/44) mounted CD8 responses that targeted the mutated regions. Among the spike epitopes tested, we identified three epitopes containing the D215, L18, or D80 residues that were specifically recognized by CD4 T cells, and their mutated versions were associated with a loss of response. This study shows that in spite of loss of recognition of immunogenic CD4 epitopes, CD4 and CD8 T cell responses to Beta are preserved overall. These observations may explain why several vaccines have retained the ability to protect against severe COVID-19 even with substantial loss of neutralizing antibody activity against Beta.

@article{Wolter2022d,
abstract = {Omicron lineages BA.4 and BA.5 drove a fifth wave of COVID-19 cases in South Africa. Here, we use the presence/absence of the S-gene target as a proxy for SARS-CoV-2 variant/lineage for infections diagnosed using the TaqPath PCR assay between 1 October 2021 and 26 April 2022. We link national COVID-19 individual-level data including case, laboratory test and hospitalisation data. We assess severity using multivariable logistic regression comparing the risk of hospitalisation and risk of severe disease, once hospitalised, for Delta, BA.1, BA.2 and BA.4/BA.5 infections. After controlling for factors associated with hospitalisation and severe outcome respectively, BA.4/BA.5-infected individuals had a similar odds of hospitalisation (aOR 1.24, 95{\%} CI 0.98–1.55) and severe outcome (aOR 0.72, 95{\%} CI 0.41–1.26) compared to BA.1-infected individuals. Newly emerged Omicron lineages BA.4/BA.5 showed similar severity to the BA.1 lineage and continued to show reduced clinical severity compared to the Delta variant. South Africa experienced a resurgence in COVID-19 in 2022 driven by Omicron subvariants BA.4 and BA.5. Here, the authors investigate the severity of infections caused by these subvariants, and find no difference in the risk of severe outcomes when compared to Omicron BA.1, whilst all Omicron subvariants were less severe than Delta.},
author = {Wolter, Nicole and Jassat, Waasila and Walaza, Sibongile and Welch, Richard and Moultrie, Harry and Groome, Michelle J. and Amoako, Daniel Gyamfi and Everatt, Josie and Bhiman, Jinal N. and Scheepers, Cathrine and Tebeila, Naume and Chiwandire, Nicola and du Plessis, Mignon and Govender, Nevashan and Ismail, Arshad and Glass, Allison and Mlisana, Koleka and Stevens, Wendy and Treurnicht, Florette K. and Subramoney, Kathleen and Makatini, Zinhle and Hsiao, Nei-yuan and Parboosing, Raveen and Wadula, Jeannette and Hussey, Hannah and Davies, Mary-Ann and Boulle, Andrew and von Gottberg, Anne and Cohen, Cheryl},
doi = {10.1038/s41467-022-33614-0},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Wolter et al. - 2022 - Clinical severity of SARS-CoV-2 Omicron BA.4 and BA.5 lineages compared to BA.1 and Delta in South Africa.pdf:pdf},
issn = {2041-1723},
journal = {Nature Communications},
keywords = {2,CoV,Epidemiology,OA,Risk factors,SARS,Viral infection,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {oct},
pages = {5860},
pmid = {36195617},
publisher = {Nature Publishing Group},
title = {{Clinical severity of SARS-CoV-2 Omicron BA.4 and BA.5 lineages compared to BA.1 and Delta in South Africa}},
url = {https://www.nature.com/articles/s41467-022-33614-0},
volume = {13},
year = {2022}
}

Omicron lineages BA.4 and BA.5 drove a fifth wave of COVID-19 cases in South Africa. Here, we use the presence/absence of the S-gene target as a proxy for SARS-CoV-2 variant/lineage for infections diagnosed using the TaqPath PCR assay between 1 October 2021 and 26 April 2022. We link national COVID-19 individual-level data including case, laboratory test and hospitalisation data. We assess severity using multivariable logistic regression comparing the risk of hospitalisation and risk of severe disease, once hospitalised, for Delta, BA.1, BA.2 and BA.4/BA.5 infections. After controlling for factors associated with hospitalisation and severe outcome respectively, BA.4/BA.5-infected individuals had a similar odds of hospitalisation (aOR 1.24, 95% CI 0.98–1.55) and severe outcome (aOR 0.72, 95% CI 0.41–1.26) compared to BA.1-infected individuals. Newly emerged Omicron lineages BA.4/BA.5 showed similar severity to the BA.1 lineage and continued to show reduced clinical severity compared to the Delta variant. South Africa experienced a resurgence in COVID-19 in 2022 driven by Omicron subvariants BA.4 and BA.5. Here, the authors investigate the severity of infections caused by these subvariants, and find no difference in the risk of severe outcomes when compared to Omicron BA.1, whilst all Omicron subvariants were less severe than Delta.

@article{Maitre2022,
abstract = {Tuberculous meningitis (TBM) is the most lethal and disabling form of tuberculosis (TB), particularly in sub-Saharan Africa. Current anti-TB treatment is poorly effective since TBM mortality reaches 40{\%} in HIV-negative patients and up to 70{\%} in HIV-co-infected patients. To reduce TBM-induced morbidity and mortality, the INTENSE-TBM trial evaluates two interventions in both HIV-infected and uninfected patients: an anti-TB treatment intensification using oral high-dose rifampicin (35 mg/kg daily) and linezolid (1200 mg daily and then 600 mg daily) during the first 8 weeks of the anti-TB treatment and the use of adjunctive aspirin (200 mg daily). This is a randomized controlled, phase III, multicenter, 2 × 2 factorial plan superiority trial. The trial has four arms, combining the two experimental treatments (intensified TBM regimen and aspirin) with the two reference treatments (WHO standard TB treatment and placebo), and is open-label for anti-TB treatment and double-blind placebo-controlled for aspirin treatment. This trial is conducted in adults or adolescents of age ≥15 years with TBM defined as “definite,” “probable,” or “possible” using Tuberculosis Meningitis International Research Consortium criteria, in four African countries: Ivory Coast, Madagascar, Uganda, and South Africa. The primary outcome is all-cause death between inclusion and week 40. The INTENSE-TBM trial represents a key opportunity to enhance TBM treatment with widely available existing drugs notably in high-incidence settings of both TB and HIV. The trial design is pragmatic and the results will permit early and effective applications in TBM patient care, in both HIV and TB high-incidence countries. ClinicalTrials.gov NCT04145258. Registered on October 30, 2019.},
author = {Maitre, Thomas and Bonnet, Maryline and Calmy, Alexandra and Raberahona, Mihaja and Rakotoarivelo, Rivonirina Andry and Rakotosamimanana, Niaina and Ambrosioni, Juan and Mir{\'{o}}, Jos{\'{e}} M and Debeaudrap, Pierre and Muzoora, Conrad and Davis, Angharad and Meintjes, Graeme A and Wasserman, Sean and Wilkinson, Robert J and Eholi{\'{e}}, Serge and Nogbou, Fr{\'{e}}d{\'{e}}ric Ello and Calvo-Cortes, Maria-Camilla and Chazallon, Corine and Machault, Vanessa and Anglaret, Xavier and Bonnet, Fabrice},
doi = {10.1186/S13063-022-06772-1},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Maitre et al. - 2022 - Intensified tuberculosis treatment to reduce the mortality of HIV-infected and uninfected patients with tuberculo.pdf:pdf},
issn = {1745-6215},
journal = {Trials},
keywords = {Biomedicine,Health Sciences,Medicine,Medicine/Public Health,OA,Spasticity,Statistics for Life Sciences,fund{\_}ack,general,protocol},
mendeley-tags = {OA,fund{\_}ack,protocol},
month = {nov},
pages = {928},
pmid = {36348453},
publisher = {BioMed Central},
title = {{Intensified tuberculosis treatment to reduce the mortality of HIV-infected and uninfected patients with tuberculosis meningitis (INTENSE-TBM): study protocol for a phase III randomized controlled trial}},
url = {https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-022-06772-1},
volume = {23},
year = {2022}
}

Tuberculous meningitis (TBM) is the most lethal and disabling form of tuberculosis (TB), particularly in sub-Saharan Africa. Current anti-TB treatment is poorly effective since TBM mortality reaches 40% in HIV-negative patients and up to 70% in HIV-co-infected patients. To reduce TBM-induced morbidity and mortality, the INTENSE-TBM trial evaluates two interventions in both HIV-infected and uninfected patients: an anti-TB treatment intensification using oral high-dose rifampicin (35 mg/kg daily) and linezolid (1200 mg daily and then 600 mg daily) during the first 8 weeks of the anti-TB treatment and the use of adjunctive aspirin (200 mg daily). This is a randomized controlled, phase III, multicenter, 2 × 2 factorial plan superiority trial. The trial has four arms, combining the two experimental treatments (intensified TBM regimen and aspirin) with the two reference treatments (WHO standard TB treatment and placebo), and is open-label for anti-TB treatment and double-blind placebo-controlled for aspirin treatment. This trial is conducted in adults or adolescents of age ≥15 years with TBM defined as “definite,” “probable,” or “possible” using Tuberculosis Meningitis International Research Consortium criteria, in four African countries: Ivory Coast, Madagascar, Uganda, and South Africa. The primary outcome is all-cause death between inclusion and week 40. The INTENSE-TBM trial represents a key opportunity to enhance TBM treatment with widely available existing drugs notably in high-incidence settings of both TB and HIV. The trial design is pragmatic and the results will permit early and effective applications in TBM patient care, in both HIV and TB high-incidence countries. ClinicalTrials.gov NCT04145258. Registered on October 30, 2019.

@article{Sossen2022,
abstract = {BACKGROUND Key stages in TB disease can be delineated by radiology, microbiology and symptoms, but transition between relevant stages remains unclear. We sought to quantify progression and regression across the spectrum of TB disease by systematically reviewing studies of individuals with untreated TB undergoing follow up. METHODS We searched PubMED, EMBASE and Web of Science until December 31st 1960, the Index Medicus between 1895 and 1945, and extensive investigator collections without date restriction - in English and German. Eligible studies were observational cohorts and clinical trials, presenting adults/adolescents with TB or recent TB exposure, undergoing follow-up for at least 12 months without therapeutic intervention. Two authors independently reviewed titles/abstracts and full texts for inclusion. Quality was assessed with a modified Newcastle-Ottawa Score, excluding highly biased studies. Summary estimates were extracted to align with TB disease transitions in a conceptual model, and we used meta-analysis of proportions with random-effects to synthesise the extracted data. This study is registered with PROSPERO (CRD42019152585). FINDINGS 10477 titles were screened and 1648 full texts reviewed. 223 met inclusion criteria. 109 were excluded for high risk of bias and 90 did not have extractable data. 24 studies (34 cohorts) were included. Progression from microbiologically negative to positive disease in those with radiographic TB evidence occurred at an annualized rate of 9.71{\%} (95{\%} CI:6.17-13.34) with active TB imaging, and 1.06{\%} (95{\%} CI:0.31-1.82) with inactive TB imaging. Reversion from microbiologically-positive to -undetectable in prospective cohorts occurred at an annualized rate of 12.40{\%} (95{\%} CI: 6.81-17.99). Studies reported symptoms poorly not allowing for direct estimation of transitions for subclinical (asymptomatic, culture positive) disease. INTERPRETATION We present the risk of progression in those with radiographic evidence of disease and the rate of self-cure for microbiologically positive disease to inform global disease burden estimates, clinical guidelines and policy decisions. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Clinical Protocols {\textless}https://www.crd.york.ac.uk/prospero/display{\_}record.php?RecordID=152585{\textgreater} {\#}{\#}{\#} Funding Statement This study was funded by Bill and Melinda Gates Foundation via a grant to the TB Modelling and Analysis Consortium {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript},
author = {Sossen, Bianca and Richards, Alexandra and Heinsohn, Torben and Frascella, Beatrice and Balzarini, Federica and Oradini--Alacreu, Aurea and Odone, Anna and Rogozinska, Ewelina and Hacker, Brit and Cobelens, Frank and Kranzer, Katharina and Houben, Rein M G J and Esmail, Hanif},
doi = {10.1101/2022.08.30.22279374},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Sossen et al. - 2022 - The natural history of untreated pulmonary tuberculosis in adults a systematic review and meta-analysis.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {aug},
pages = {2022.08.30.22279374},
pmid = {36966795},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{The natural history of untreated pulmonary tuberculosis in adults: a systematic review and meta-analysis}},
url = {https://www.medrxiv.org/content/10.1101/2022.08.30.22279374v1 https://www.medrxiv.org/content/10.1101/2022.08.30.22279374v1.abstract},
year = {2022}
}

BACKGROUND Key stages in TB disease can be delineated by radiology, microbiology and symptoms, but transition between relevant stages remains unclear. We sought to quantify progression and regression across the spectrum of TB disease by systematically reviewing studies of individuals with untreated TB undergoing follow up. METHODS We searched PubMED, EMBASE and Web of Science until December 31st 1960, the Index Medicus between 1895 and 1945, and extensive investigator collections without date restriction - in English and German. Eligible studies were observational cohorts and clinical trials, presenting adults/adolescents with TB or recent TB exposure, undergoing follow-up for at least 12 months without therapeutic intervention. Two authors independently reviewed titles/abstracts and full texts for inclusion. Quality was assessed with a modified Newcastle-Ottawa Score, excluding highly biased studies. Summary estimates were extracted to align with TB disease transitions in a conceptual model, and we used meta-analysis of proportions with random-effects to synthesise the extracted data. This study is registered with PROSPERO (CRD42019152585). FINDINGS 10477 titles were screened and 1648 full texts reviewed. 223 met inclusion criteria. 109 were excluded for high risk of bias and 90 did not have extractable data. 24 studies (34 cohorts) were included. Progression from microbiologically negative to positive disease in those with radiographic TB evidence occurred at an annualized rate of 9.71% (95% CI:6.17-13.34) with active TB imaging, and 1.06% (95% CI:0.31-1.82) with inactive TB imaging. Reversion from microbiologically-positive to -undetectable in prospective cohorts occurred at an annualized rate of 12.40% (95% CI: 6.81-17.99). Studies reported symptoms poorly not allowing for direct estimation of transitions for subclinical (asymptomatic, culture positive) disease. INTERPRETATION We present the risk of progression in those with radiographic evidence of disease and the rate of self-cure for microbiologically positive disease to inform global disease burden estimates, clinical guidelines and policy decisions. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Protocols \textlesshttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=152585\textgreater ### Funding Statement This study was funded by Bill and Melinda Gates Foundation via a grant to the TB Modelling and Analysis Consortium ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript

@article{Rajpoot2022,
abstract = {Advanced computational tools focusing on protein–protein interaction (PPI) based drug development is a powerful platform to accelerate the therapeutic development of small lead molecules and repurp...},
author = {Rajpoot, S. and Srivastava, G. and Siddiqi, M.I. and Saqib, U. and Parihar, S.P. and Hirani, N. and Baig, M.S.},
doi = {10.1080/1062936X.2022.2035817},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Rajpoot et al. - 2022 - Identification of novel inhibitors targeting TIRAP interactions with BTK and PKC$\delta$ in inflammation through an in.pdf:pdf},
issn = {1062-936X},
journal = {SAR and QSAR in Environmental Research},
keywords = {BTK,PKC$\delta$,PPIs,TIRAP,fund{\_}not{\_}ack,homology modelling,inflammatory responses,macrophages,original,repurposed drugs,structural analysis},
mendeley-tags = {fund{\_}not{\_}ack,original},
month = {feb},
number = {3},
pages = {141--166},
publisher = {Taylor {\&} Francis},
title = {{Identification of novel inhibitors targeting TIRAP interactions with BTK and PKC$\delta$ in inflammation through an in silico approach}},
url = {https://www.tandfonline.com/doi/abs/10.1080/1062936X.2022.2035817},
volume = {33},
year = {2022}
}

Advanced computational tools focusing on protein–protein interaction (PPI) based drug development is a powerful platform to accelerate the therapeutic development of small lead molecules and repurp...

@article{10.3389/fimmu.2022.873985,
abstract = {BackgroundTuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a clinical aggravation of TB symptoms observed among a fraction of HIV coinfected patients shortly after the start of antiretroviral therapy (ART). Of note, TB-IRIS is characterized by exacerbated inflammation and tissue damage that occurs in response to the elevated production of CD4+ T cell-derived IFN-$\gamma$. Nevertheless, the possible participation of CD8+ T cells in TB-IRIS development remains unclear.MethodsWe performed a comprehensive assessment of the composition of CD8+ T cell memory subsets and their association with circulating inflammation-related molecules in TB-HIV coinfected patients initiating ART.ResultsWe found that TB-IRIS individuals display higher frequencies of Antigen-experienced CD8+ T cells during the onset of IRIS and that the levels of these cells positively correlate with baseline mycobacterial smear grade. TB-IRIS individuals exhibited higher frequencies of effector memory and lower percentages of na{\"{i}}ve CD8+ T cells than their Non-IRIS counterparts. In both TB-IRIS and Non-IRIS patients, ART commencement was associated with fewer significant correlations among memory CD8+ T cells and cells from other immune compartments. Networks analysis revealed distinct patterns of correlation between each memory subset with inflammatory cytokines suggesting different dynamics of CD8+ T cell memory subsets reconstitution. TB-IRIS patients displayed lower levels of memory cells positive for CXCR3 (a chemokine receptor that plays a role in trafficking activated CD8+ T cells to the tissues) than Non-IRIS individuals before and after ART. Furthermore, we found that CXCR3+ na{\"{i}}ve CD8+ T cells were inversely associated with the risk of TB-IRIS development. On the other hand, we noticed that the frequencies of CXCR3+ effector CD8+ T cells were positively associated with the probability of TB-IRIS development.ConclusionOur data suggest that TB-IRIS individuals display a distinct profile of memory CD8+ T cell subsets reconstitution after ART initiation. Moreover, our data point to a differential association between the frequencies of CXCR3+ CD8+ T cells and the risk of TB-IRIS development. Collectively, our findings lend insights into the potential role of memory CD8+ T cells in TB-IRIS pathophysiology.},
author = {Tib{\'{u}}rcio, Rafael and Narendran, Gopalan and Barreto-Duarte, Beatriz and Queiroz, Artur T L and Ara{\'{u}}jo-Pereira, Mariana and Anbalagan, Selvaraj and Nayak, Kaustuv and Ravichandran, Narayanan and Subramani, Rajasekaran and Antonelli, Lis R V and Satagopan, Kumar and Anbalagan, Komathi and Porter, Brian O and Sher, Alan and Swaminathan, Soumya and Sereti, Irini and Andrade, Bruno B},
doi = {10.3389/fimmu.2022.873985},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Tib{\'{u}}rcio et al. - 2022 - Frequency of CXCR3 CD8 T-lymphocyte subsets in peripheral blood is associated with the risk of paradoxical tube.pdf:pdf},
issn = {1664-3224},
journal = {Frontiers in Immunology},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
pages = {873985},
pmid = {35432354},
title = {{Frequency of CXCR3+ CD8+ T-lymphocyte subsets in peripheral blood is associated with the risk of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome development in advanced HIV disease}},
url = {https://www.frontiersin.org/article/10.3389/fimmu.2022.873985},
volume = {13},
year = {2022}
}

BackgroundTuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a clinical aggravation of TB symptoms observed among a fraction of HIV coinfected patients shortly after the start of antiretroviral therapy (ART). Of note, TB-IRIS is characterized by exacerbated inflammation and tissue damage that occurs in response to the elevated production of CD4+ T cell-derived IFN-$γ$. Nevertheless, the possible participation of CD8+ T cells in TB-IRIS development remains unclear.MethodsWe performed a comprehensive assessment of the composition of CD8+ T cell memory subsets and their association with circulating inflammation-related molecules in TB-HIV coinfected patients initiating ART.ResultsWe found that TB-IRIS individuals display higher frequencies of Antigen-experienced CD8+ T cells during the onset of IRIS and that the levels of these cells positively correlate with baseline mycobacterial smear grade. TB-IRIS individuals exhibited higher frequencies of effector memory and lower percentages of naïve CD8+ T cells than their Non-IRIS counterparts. In both TB-IRIS and Non-IRIS patients, ART commencement was associated with fewer significant correlations among memory CD8+ T cells and cells from other immune compartments. Networks analysis revealed distinct patterns of correlation between each memory subset with inflammatory cytokines suggesting different dynamics of CD8+ T cell memory subsets reconstitution. TB-IRIS patients displayed lower levels of memory cells positive for CXCR3 (a chemokine receptor that plays a role in trafficking activated CD8+ T cells to the tissues) than Non-IRIS individuals before and after ART. Furthermore, we found that CXCR3+ naïve CD8+ T cells were inversely associated with the risk of TB-IRIS development. On the other hand, we noticed that the frequencies of CXCR3+ effector CD8+ T cells were positively associated with the probability of TB-IRIS development.ConclusionOur data suggest that TB-IRIS individuals display a distinct profile of memory CD8+ T cell subsets reconstitution after ART initiation. Moreover, our data point to a differential association between the frequencies of CXCR3+ CD8+ T cells and the risk of TB-IRIS development. Collectively, our findings lend insights into the potential role of memory CD8+ T cells in TB-IRIS pathophysiology.

@article{Gupte2022,
abstract = {Background Biomarkers of unfavourable tuberculosis (TB) treatment outcomes are needed to accelerate new drug and regimen development. Whether plasma cytokine levels can predict unfavourable TB treatment outcomes is unclear. Methods We identified and internally validated the association between 20 a priori selected plasma inflammatory markers and unfavourable treatment outcomes of failure, recurrence and all-cause mortality among adults with drug-sensitive pulmonary TB in India. We externally validated these findings in two independent cohorts of predominantly diabetic and HIV co-infected TB patients in India and South Africa, respectively. Results Pre-treatment interferon-$\gamma$, interleukin (IL)-13 and IL-6 were associated with treatment failure in the discovery analysis. Internal validation confirmed higher pre-treatment IL-6 concentrations among failure cases compared with controls. External validation among predominantly diabetic TB patients found an association between pre-treatment IL-6 concentrations and subsequent recurrence and death. Similarly, external validation among predominantly HIV co-infected TB patients found an association between pre-treatment IL-6 concentrations and subsequent treatment failure and death. In a pooled analysis of 363 TB cases from the Indian and South African validation cohorts, high pre-treatment IL-6 concentrations were associated with higher risk of failure (adjusted OR (aOR) 2.16, 95{\%} CI 1.08–4.33; p=0.02), recurrence (aOR 5.36, 95{\%} CI 2.48–11.57; p{\textless}0.001) and death (aOR 4.62, 95{\%} CI 1.95–10.95; p{\textless}0.001). Adding baseline IL-6 to a risk prediction model comprised of low body mass index, high smear grade and cavitation improved model performance by 15{\%} (C-statistic 0.66 versus 0.76; p=0.02). Conclusions Pre-treatment IL-6 is a biomarker for unfavourable TB treatment outcomes. Future studies should identify optimal IL-6 concentrations for point-of-care risk prediction. Pre-treatment IL-6 is a biomarker for unfavourable tuberculosis treatment outcomes independent of disease severity and improves the performance of risk prediction models comprised of established clinical predictors {\textless}https://bit.ly/38394xE{\textgreater}},
author = {Gupte, Akshay N and Kumar, Pavan and Ara{\'{u}}jo-Pereira, Mariana and Kulkarni, Vandana and Paradkar, Mandar and Pradhan, Neeta and Menon, Pradeep and Chandrasekaran, Padmapriya Darasini and Hanna, Luke-Elizabeth and {Yogendra Shivakumar}, Shri Vijay Bala and Rockwood, Neesha and {Du Bruyn}, Elsa and Karyakarte, Rajesh and Gaikwad, Sanjay and Bollinger, Robert and Golub, Jonathan and Gupte, Nikhil and Viswanathan, Vijay and Wilkinson, Robert J and Mave, Vidya and Babu, Subash and Kornfeld, Hardy and Andrade, Bruno B and Gupta, Amita},
doi = {10.1183/13993003.00905-2021},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Gupte et al. - 2022 - Baseline IL-6 is a biomarker for unfavourable tuberculosis treatment outcomes a multisite discovery and validation.pdf:pdf},
issn = {0903-1936},
journal = {European Respiratory Journal},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {apr},
number = {4},
pages = {2100905},
pmid = {34711538},
publisher = {European Respiratory Society},
title = {{Baseline IL-6 is a biomarker for unfavourable tuberculosis treatment outcomes: a multisite discovery and validation study}},
url = {https://erj.ersjournals.com/content/59/4/2100905 https://erj.ersjournals.com/content/59/4/2100905.abstract},
volume = {59},
year = {2022}
}

Background Biomarkers of unfavourable tuberculosis (TB) treatment outcomes are needed to accelerate new drug and regimen development. Whether plasma cytokine levels can predict unfavourable TB treatment outcomes is unclear. Methods We identified and internally validated the association between 20 a priori selected plasma inflammatory markers and unfavourable treatment outcomes of failure, recurrence and all-cause mortality among adults with drug-sensitive pulmonary TB in India. We externally validated these findings in two independent cohorts of predominantly diabetic and HIV co-infected TB patients in India and South Africa, respectively. Results Pre-treatment interferon-$γ$, interleukin (IL)-13 and IL-6 were associated with treatment failure in the discovery analysis. Internal validation confirmed higher pre-treatment IL-6 concentrations among failure cases compared with controls. External validation among predominantly diabetic TB patients found an association between pre-treatment IL-6 concentrations and subsequent recurrence and death. Similarly, external validation among predominantly HIV co-infected TB patients found an association between pre-treatment IL-6 concentrations and subsequent treatment failure and death. In a pooled analysis of 363 TB cases from the Indian and South African validation cohorts, high pre-treatment IL-6 concentrations were associated with higher risk of failure (adjusted OR (aOR) 2.16, 95% CI 1.08–4.33; p=0.02), recurrence (aOR 5.36, 95% CI 2.48–11.57; p\textless0.001) and death (aOR 4.62, 95% CI 1.95–10.95; p\textless0.001). Adding baseline IL-6 to a risk prediction model comprised of low body mass index, high smear grade and cavitation improved model performance by 15% (C-statistic 0.66 versus 0.76; p=0.02). Conclusions Pre-treatment IL-6 is a biomarker for unfavourable TB treatment outcomes. Future studies should identify optimal IL-6 concentrations for point-of-care risk prediction. Pre-treatment IL-6 is a biomarker for unfavourable tuberculosis treatment outcomes independent of disease severity and improves the performance of risk prediction models comprised of established clinical predictors \textlesshttps://bit.ly/38394xE\textgreater

@article{Angula2022,
abstract = {A recent study identified quinolone-based thiosemicarbazone with an MIC90 value of 2 µM against Mycobacterium tuberculosis (Mtb). Herein, we report further optimization of the previous hit, which led to the discovery of quinolone-tethered aminoguanidine molecules with generally good antitubercular activity. Compounds 7f and 8e emerged as the hits of the series with submicromolar antitubercular activity, exhibiting MIC90 values of 0.49/0.90 and 0.49/0.60 µM, respectively, in the 7H9 CAS GLU Tx medium. This shows a fivefold increase in antitubercular activity compared to the previous study. Target compounds were also screened against ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens. However, the series generally exhibited poor antibacterial activities, with only compounds 8d and 8e demonstrating {\textgreater}50{\%} growth inhibition of Staphylococcus aureus and Pseudomonas aeruginosa at 32 µg/ml. The compounds displayed selective antitubercular activity as they showed no cytotoxicity effects against two noncancerous human cell lines. In silico studies predict 7f to have good solubility, no inhibitory effect on cytochrome P450 isoenzymes, and to be a non-pan-assay interfering compound.},
author = {Angula, Klaudia T and Legoabe, Lesetja J and Jordaan, Audrey and Warner, Digby F and Beteck, Richard M},
doi = {10.1002/ARDP.202200172},
issn = {1521-4184},
journal = {Archiv der Pharmazie},
keywords = {ESKAPE pathogens,aminoguanidine,fund{\_}not{\_}ack,original,quinolones,thiosemicarzone,tuberculosis},
mendeley-tags = {fund{\_}not{\_}ack,original},
month = {jun},
pages = {e2200172},
publisher = {John Wiley {\&} Sons, Ltd},
title = {{Investigation of quinolone-tethered aminoguanidine as novel antibacterial agents}},
url = {https://onlinelibrary.wiley.com/doi/full/10.1002/ardp.202200172 https://onlinelibrary.wiley.com/doi/abs/10.1002/ardp.202200172 https://onlinelibrary.wiley.com/doi/10.1002/ardp.202200172},
year = {2022}
}

A recent study identified quinolone-based thiosemicarbazone with an MIC90 value of 2 µM against Mycobacterium tuberculosis (Mtb). Herein, we report further optimization of the previous hit, which led to the discovery of quinolone-tethered aminoguanidine molecules with generally good antitubercular activity. Compounds 7f and 8e emerged as the hits of the series with submicromolar antitubercular activity, exhibiting MIC90 values of 0.49/0.90 and 0.49/0.60 µM, respectively, in the 7H9 CAS GLU Tx medium. This shows a fivefold increase in antitubercular activity compared to the previous study. Target compounds were also screened against ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens. However, the series generally exhibited poor antibacterial activities, with only compounds 8d and 8e demonstrating \textgreater50% growth inhibition of Staphylococcus aureus and Pseudomonas aeruginosa at 32 µg/ml. The compounds displayed selective antitubercular activity as they showed no cytotoxicity effects against two noncancerous human cell lines. In silico studies predict 7f to have good solubility, no inhibitory effect on cytochrome P450 isoenzymes, and to be a non-pan-assay interfering compound.

@article{Wouters2022,
abstract = {Background: Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an important complication in patients with HIV-associated tuberculosis (TB) starting antiretroviral treatment (ART) in sub-Saharan Africa. The PredART-trial recently showed that prophylactic prednisone reduces the incidence of paradoxical TB-IRIS by 30{\%} in a population at high risk. This paper reports the impact of the intervention on health-related quality of life (HRQoL), a secondary endpoint of the trial, measured by an amended version of the PROQOL-HIV instrument—the instrument's validity and reliability is also assessed. Methods: A total of 240 adult participants (antiretroviral treatment (ART)-na{\"{i}}ve, TB-HIV co-infected with CD4 count ≤100 cells/$\mu$L) were recruited and randomized (1:1) to (1) a prednisone arm or (2) a placebo arm. In this sub-study of the PredART-trial we evaluated (1) the performance of an HIV-specific HR-QoL instrument amended for TB-IRIS, i.e., the PROQOL-HIV/TB in patients with HIV-associated TB starting ART (reliability, internal and external construct validity and invariance across time) and (2) the impact of prednisone on self-reported HR-QoL in this population through mixed models. Results: The PROQOL-HIV/TB scale displayed acceptable internal reliability and good internal and external validity. This instrument, including the factor structure with the eight sub-dimensions, can thus be applied for measuring HR-QoL among HIV-TB patients at high risk for TB-IRIS. Prophylactic prednisone was statistically significantly associated only with the ‘Physical Health and Symptoms'-subscale: a four-week course of prednisone resulted in an earlier improvement in the physical dimension of HR-QoL compared to placebo. Conclusion: We demonstrated that the PROQOL-HIV/TB scale adequately measures different aspects of self-reported HR-QoL in HIV-TB patients. Although more research is needed to understand how other domains related to HR-QoL can be improved, targeting patients at high risk for developing TB-IRIS with a four-week course of prednisone has a beneficial effect on the physical aspects of patient-reported quality of life.},
author = {Wouters, Edwin and Stek, Cari and Swartz, Alison and Buyze, Jozefien and Schutz, Charlotte and Thienemann, Friedrich and Wilkinson, Robert J and Meintjes, Graeme A and Lynen, Lutgarde and N{\"{o}}stlinger, Christiana},
doi = {10.3389/FPSYG.2022.983028},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Wouters et al. - 2022 - Prednisone for the prevention of tuberculosis-associated IRIS (randomized controlled trial) Impact on the health.pdf:pdf},
issn = {16641078},
journal = {Frontiers in Psychology},
keywords = {OA,South Africa,TB-IRIS,fund{\_}ack,original,prednisone,quality of life,tuberculosis},
mendeley-tags = {OA,fund{\_}ack,original},
month = {oct},
pages = {983028},
pmid = {36275235},
publisher = {Frontiers Media S.A.},
title = {{Prednisone for the prevention of tuberculosis-associated IRIS (randomized controlled trial): Impact on the health-related quality of life}},
url = {https://www.frontiersin.org/articles/10.3389/fpsyg.2022.983028/full},
volume = {13},
year = {2022}
}

Background: Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an important complication in patients with HIV-associated tuberculosis (TB) starting antiretroviral treatment (ART) in sub-Saharan Africa. The PredART-trial recently showed that prophylactic prednisone reduces the incidence of paradoxical TB-IRIS by 30% in a population at high risk. This paper reports the impact of the intervention on health-related quality of life (HRQoL), a secondary endpoint of the trial, measured by an amended version of the PROQOL-HIV instrument—the instrument's validity and reliability is also assessed. Methods: A total of 240 adult participants (antiretroviral treatment (ART)-naïve, TB-HIV co-infected with CD4 count ≤100 cells/$μ$L) were recruited and randomized (1:1) to (1) a prednisone arm or (2) a placebo arm. In this sub-study of the PredART-trial we evaluated (1) the performance of an HIV-specific HR-QoL instrument amended for TB-IRIS, i.e., the PROQOL-HIV/TB in patients with HIV-associated TB starting ART (reliability, internal and external construct validity and invariance across time) and (2) the impact of prednisone on self-reported HR-QoL in this population through mixed models. Results: The PROQOL-HIV/TB scale displayed acceptable internal reliability and good internal and external validity. This instrument, including the factor structure with the eight sub-dimensions, can thus be applied for measuring HR-QoL among HIV-TB patients at high risk for TB-IRIS. Prophylactic prednisone was statistically significantly associated only with the ‘Physical Health and Symptoms'-subscale: a four-week course of prednisone resulted in an earlier improvement in the physical dimension of HR-QoL compared to placebo. Conclusion: We demonstrated that the PROQOL-HIV/TB scale adequately measures different aspects of self-reported HR-QoL in HIV-TB patients. Although more research is needed to understand how other domains related to HR-QoL can be improved, targeting patients at high risk for developing TB-IRIS with a four-week course of prednisone has a beneficial effect on the physical aspects of patient-reported quality of life.

@article{Barr2022,
abstract = {Background Despite being highly prevalent in hospitalised patients with severe HIV-associated tuberculosis (TB) and sepsis, little is known about the mycobacteriology of Mycobacterium tuberculosis bloodstream infection (MTBBSI). We developed methods to serially measure bacillary load in blood and used these to characterise MTBBSI response to anti-TB therapy (ATT) and relationship with mortality. Methods We established a microscopy method for direct visualisation ofM. tuberculosis bacilli in blood using a novel lysis-concentration protocol and the fluorescent probe, 4-N,N-dimethylaminonaphthalimide-trehalose (DMN-Tre). We tested blood using GeneXpert{\`{O}} MTB/RIF-Ultra (Xpert-ultra) and Myco/F lytic culture after processing blood through lysis-wash steps to remove PCR inhibitors and anti-microbial drug carry-over. HIV-positive patients pre- dicted to have MTBBSI gave blood samples 0, 4, 24, 48 and 72 h after ATT initiation. Bacillary loads were quantified using microscopy, Xpert-ultra cycle threshold, and culture time-to-positivity. Pharmacodynamics were modelled using these measures combined on an ordinal scale, including association with 12-week mortality. Findings M. tuberculosis was detected in 27 of28 recruited participants; 25 (89{\%}) by blood Xpert-ultra, 22 (79{\%}) by DMN-Tre microscopy, and 21 (75{\%}) by Myco/F lytic blood culture. Eight (29{\%}) participants died by 12-week follow- up. In a combined pharmacodynamic model, predicted probabilities ofnegative DMN-Tre microscopy, blood Xpert- ultra, or blood culture after 72 h treatment were 0¢64, 0¢27, and 0¢94, respectively, in those who survived, compared with 0¢23, 0¢06, and 0¢71 in those who died (posterior probability ofslower clearance ofMTBBSI in those that died {\textgreater}0¢99). DMN-Tre microscopy of blood demonstrated heterogenous bacillary morphologies, including microcolo- nies and clumps. Bacillary cell-length varied significantly with ATT exposure (mean cell-length increase 0¢13 log- µm/day; 95{\%}CrI 0¢10?0¢16). Interpretation Pharmacodynamics ofMTBBSI treatment can be captured using DMN-Tre microscopy, blood Xpert- ultra and culture. This could facilitate interventional trials in severe HIV-associated TB.},
author = {Barr, David A. and Schutz, Charlotte and Balfour, Avuyonke and Shey, Muki and Kamariza, Mireille and Bertozzi, Carolyn R and de Wet, Timothy J and Dinkele, Ryan and Ward, Amy and Haigh, Kathryn A and Kanyik, Jean-Paul and Mizrahi, Valerie and Nicol, Mark P and Wilkinson, Robert J and Lalloo, David G and Warner, Digby F and Meintjes, Graeme A and Davies, Gerry},
doi = {10.1016/J.EBIOM.2022.103949},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Barr et al. - 2022 - Serial measurement of M. tuberculosis in blood from critically-ill patients with HIV-associated tuberculosis.pdf:pdf},
issn = {2352-3964},
journal = {eBioMedicine},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {apr},
pages = {103949},
pmid = {35325781},
publisher = {Elsevier},
title = {{Serial measurement of \textit{M. tuberculosis} in blood from critically-ill patients with HIV-associated tuberculosis}},
url = {https://linkinghub.elsevier.com/retrieve/pii/S2352396422001335},
volume = {78},
year = {2022}
}

Background Despite being highly prevalent in hospitalised patients with severe HIV-associated tuberculosis (TB) and sepsis, little is known about the mycobacteriology of Mycobacterium tuberculosis bloodstream infection (MTBBSI). We developed methods to serially measure bacillary load in blood and used these to characterise MTBBSI response to anti-TB therapy (ATT) and relationship with mortality. Methods We established a microscopy method for direct visualisation ofM. tuberculosis bacilli in blood using a novel lysis-concentration protocol and the fluorescent probe, 4-N,N-dimethylaminonaphthalimide-trehalose (DMN-Tre). We tested blood using GeneXpertÒ MTB/RIF-Ultra (Xpert-ultra) and Myco/F lytic culture after processing blood through lysis-wash steps to remove PCR inhibitors and anti-microbial drug carry-over. HIV-positive patients pre- dicted to have MTBBSI gave blood samples 0, 4, 24, 48 and 72 h after ATT initiation. Bacillary loads were quantified using microscopy, Xpert-ultra cycle threshold, and culture time-to-positivity. Pharmacodynamics were modelled using these measures combined on an ordinal scale, including association with 12-week mortality. Findings M. tuberculosis was detected in 27 of28 recruited participants; 25 (89%) by blood Xpert-ultra, 22 (79%) by DMN-Tre microscopy, and 21 (75%) by Myco/F lytic blood culture. Eight (29%) participants died by 12-week follow- up. In a combined pharmacodynamic model, predicted probabilities ofnegative DMN-Tre microscopy, blood Xpert- ultra, or blood culture after 72 h treatment were 0¢64, 0¢27, and 0¢94, respectively, in those who survived, compared with 0¢23, 0¢06, and 0¢71 in those who died (posterior probability ofslower clearance ofMTBBSI in those that died \textgreater0¢99). DMN-Tre microscopy of blood demonstrated heterogenous bacillary morphologies, including microcolo- nies and clumps. Bacillary cell-length varied significantly with ATT exposure (mean cell-length increase 0¢13 log- µm/day; 95%CrI 0¢10?0¢16). Interpretation Pharmacodynamics ofMTBBSI treatment can be captured using DMN-Tre microscopy, blood Xpert- ultra and culture. This could facilitate interventional trials in severe HIV-associated TB.

@article{Dinkele2022,
abstract = {Rationale: Interrupting tuberculosis (TB) transmission requires an improved understanding of how and when the causative organism, Mycobacterium tuberculosis (Mtb), is aerosolized. Although cough is...},
author = {Dinkele, Ryan and Gessner, Sophia and McKerry, Andrea and Leonard, Bryan and Leukes, Juane and Seldon, Ronnett and Warner, Digby F and Wood, Robin},
doi = {10.1164/RCCM.202110-2378OC},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Dinkele et al. - 2022 - Aerosolization of iMycobacterium tuberculosisi by tidal breathing.pdf:pdf},
isbn = {2021102378},
issn = {1073-449X},
journal = {American Journal of Respiratory and Critical Care Medicine},
keywords = {OA,TB transmission,bioaerosol,cough,forced vital capacity,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jul},
number = {2},
pages = {206--216},
pmid = {35584342},
publisher = {American Thoracic Society},
title = {{Aerosolization of \textit{Mycobacterium tuberculosis} by tidal breathing}},
url = {www.atsjournals.org.},
volume = {206},
year = {2022}
}

Rationale: Interrupting tuberculosis (TB) transmission requires an improved understanding of how and when the causative organism, Mycobacterium tuberculosis (Mtb), is aerosolized. Although cough is...

@article{Jongeneel2022,
abstract = {Genomics policy development involves assessing a wide range of issues extending from specimen collection and data sharing to whether and how to utilize advanced technologies in clinical practice and public health initiatives. A survey was conducted among African scientists and stakeholders with an interest in genomic medicine, seeking to evaluate: 1) Their knowledge and understanding of the field. 2) The institutional environment and infrastructure available to them. 3) The state and awareness of the field in their country. 4) Their perception of potential barriers to implementation of precision medicine. We discuss how the information gathered in the survey could instruct the policies of African institutions seeking to implement precision, and more specifically, genomic medicine approaches in their health care systems in the following areas: 1) Prioritization of infrastructures. 2) Need for translational research. 3) Information dissemination to potential users. 4) Training programs for specialized personnel. 5) Engaging political stakeholders and the public. A checklist with key requirements to assess readiness for implementation of genomic medicine programs is provided to guide the process from scientific discovery to clinical application.},
author = {Jongeneel, C Victor and Kotze, Maritha J and Bhaw-Luximon, Archana and Fadlelmola, Faisal M and Fakim, Yasmina J and Hamdi, Yosr and Kassim, Samar Kamal and Kumuthini, Judit and Nembaware, Victoria and Radouani, Fouzia and Tiffin, Nicki and Mulder, Nicola},
doi = {10.3389/fgene.2022.769919},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Jongeneel et al. - 2022 - A view on genomic medicine activities in Africa implications for policy.pdf:pdf},
issn = {1664-8021},
journal = {Frontiers in Genetics},
keywords = {Africa,OA,Personalized genomic medicine,Readiness level,Translational research,capacity development,fund{\_}ack,infrastructure,original,precision medicine stakeholders},
mendeley-tags = {OA,fund{\_}ack,original},
month = {apr},
pages = {769919},
pmid = {35571023},
publisher = {Frontiers},
title = {{A view on genomic medicine activities in Africa: implications for policy}},
url = {https://www.frontiersin.org/articles/10.3389/fgene.2022.769919/full},
volume = {13},
year = {2022}
}

Genomics policy development involves assessing a wide range of issues extending from specimen collection and data sharing to whether and how to utilize advanced technologies in clinical practice and public health initiatives. A survey was conducted among African scientists and stakeholders with an interest in genomic medicine, seeking to evaluate: 1) Their knowledge and understanding of the field. 2) The institutional environment and infrastructure available to them. 3) The state and awareness of the field in their country. 4) Their perception of potential barriers to implementation of precision medicine. We discuss how the information gathered in the survey could instruct the policies of African institutions seeking to implement precision, and more specifically, genomic medicine approaches in their health care systems in the following areas: 1) Prioritization of infrastructures. 2) Need for translational research. 3) Information dissemination to potential users. 4) Training programs for specialized personnel. 5) Engaging political stakeholders and the public. A checklist with key requirements to assess readiness for implementation of genomic medicine programs is provided to guide the process from scientific discovery to clinical application.

@article{Aziz2022,
abstract = {Schistosomiasis is the second most debilitating neglected tropical disease globally after malaria, with no available therapy to control disease-driven immunopathology. Although schistosomiasis induces a markedly heterogenous immune response, type 2 immunity is the dominating immune response following oviposition. While type 2 immunity has a crucial role in granuloma formation and host survival during the acute stage of disease, its chronic activation can result in tissue scarring, fibrosis, and organ impairment. Here, we discuss recent advances in schistosomiasis, demonstrating how different immune and non-immune cells and signaling pathways are involved in the induction, maintenance, and regulation of type 2 immunity. A better understanding of these immune responses during schistosomiasis is essential to inform the potential development of candidate therapeutic strategies that fine-tune type 2 immunity to ideally modulate schistosomiasis immunopathology.},
author = {Aziz, Nada Abdel and Musaigwa, Fungai and Mosala, Paballo and Berkiks, Inssaf and Brombacher, Frank},
doi = {10.1016/J.IT.2022.06.005},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Aziz et al. - 2022 - Type 2 immunity a two-edged sword in schistosomiasis immunopathology.pdf:pdf},
issn = {1471-4906},
journal = {Trends in Immunology},
keywords = {IL4R$\alpha$,fibro-granulomatous inflammation,fund{\_}not{\_}ack,review,schistosomiasis,type 2 immunity},
mendeley-tags = {fund{\_}not{\_}ack,review},
month = {jul},
pages = {10.1016/j.it.2022.06.005},
pmid = {35835714},
publisher = {Elsevier},
title = {{Type 2 immunity: a two-edged sword in schistosomiasis immunopathology}},
url = {http://www.cell.com/article/S1471490622001211/fulltext http://www.cell.com/article/S1471490622001211/abstract https://www.cell.com/trends/immunology/abstract/S1471-4906(22)00121-1},
year = {2022}
}

Schistosomiasis is the second most debilitating neglected tropical disease globally after malaria, with no available therapy to control disease-driven immunopathology. Although schistosomiasis induces a markedly heterogenous immune response, type 2 immunity is the dominating immune response following oviposition. While type 2 immunity has a crucial role in granuloma formation and host survival during the acute stage of disease, its chronic activation can result in tissue scarring, fibrosis, and organ impairment. Here, we discuss recent advances in schistosomiasis, demonstrating how different immune and non-immune cells and signaling pathways are involved in the induction, maintenance, and regulation of type 2 immunity. A better understanding of these immune responses during schistosomiasis is essential to inform the potential development of candidate therapeutic strategies that fine-tune type 2 immunity to ideally modulate schistosomiasis immunopathology.

@article{Besson2022,
abstract = {A series of 25 new benzothiazole-urea-quinoline hybrid compounds were synthesized successfully via a three-step synthetic sequence involving an amidation coupling reaction as a critical step. The structures of the synthesized compounds were confirmed by routine spectroscopic tools (1H and 13C NMR and IR) and by mass spectrometry (HRMS). In vitro evaluation of these hybrid compounds for their antitubercular inhibitory activity against the Mycobacterium tuberculosis H37Rv pMSp12::GPF bioreporter strain was undertaken. Of the 25 tested compounds, 17 exhibited promising anti-TB activities of less than 62.5 {\&}micro;M (MIC90). Specifically, 13 compounds (6b, 6g, 6i{\&}ndash;j, 6l, 6o{\&}ndash;p, 6r{\&}ndash;t, and 6x{\&}ndash;y) showed promising activity with MIC90 values in the range of 1{\&}ndash;10 {\&}micro;M, while compound 6u, being the most active, exhibited sub-micromolar activity (0.968 {\&}micro;M) in the CAS assay. In addition, minimal cytotoxicity against the HepG2 cell line (cell viability above 75{\%}) in 11 of the 17 compounds, at their respective MIC90 concentrations, was observed, with 6u exhibiting 100{\%} cell viability. The hybridization of the quinoline, urea, and benzothiazole scaffolds demonstrated a synergistic relationship because the activities of resultant hybrids were vastly improved compared to the individual entities. In silico ADME predictions showed that the majority of these compounds have drug-like properties and are less likely to potentially cause cardiotoxicity (QPlogHERG {\textgreater} {\&}minus;5). The results obtained in this study indicate that the majority of the synthesized compounds could serve as valuable starting points for future optimizations as new antimycobacterial agents.},
author = {Besson, Thierry and Marchand, Pascal and Moodley, Rashmika and Mashaba, Chakes and Rakodi, Goitsemodimo H and Ncube, Nomagugu B and Maphoru, Mabuatsela V and Balogun, Mohammed O and Jordan, Audrey and Warner, Digby F and Khan, Rene and Tukulula, Matshawandile},
doi = {10.3390/PH15050576},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Besson et al. - 2022 - New quinoline-urea-benzothiazole hybrids as promising antitubercular agents synthesis, in vitro antitubercular ac.pdf:pdf},
issn = {1424-8247},
journal = {Pharmaceuticals},
keywords = {HepG2 cell line,OA,antitubercular activity,benzothiazole hybrids,cytotoxicity,fund{\_}not{\_}ack,in silico ADME properties,minimum inhibitory concentration,original,quinoline,urea},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {may},
number = {5},
pages = {576},
pmid = {35631402},
publisher = {Multidisciplinary Digital Publishing Institute},
title = {{New quinoline-urea-benzothiazole hybrids as promising antitubercular agents: synthesis, \textit{in vitro} antitubercular activity, cytotoxicity studies, and \textit{in silico} ADME profiling}},
url = {https://www.mdpi.com/1424-8247/15/5/576/htm https://www.mdpi.com/1424-8247/15/5/576},
volume = {15},
year = {2022}
}

A series of 25 new benzothiazole-urea-quinoline hybrid compounds were synthesized successfully via a three-step synthetic sequence involving an amidation coupling reaction as a critical step. The structures of the synthesized compounds were confirmed by routine spectroscopic tools (1H and 13C NMR and IR) and by mass spectrometry (HRMS). In vitro evaluation of these hybrid compounds for their antitubercular inhibitory activity against the Mycobacterium tuberculosis H37Rv pMSp12::GPF bioreporter strain was undertaken. Of the 25 tested compounds, 17 exhibited promising anti-TB activities of less than 62.5 µM (MIC90). Specifically, 13 compounds (6b, 6g, 6i–j, 6l, 6o–p, 6r–t, and 6x–y) showed promising activity with MIC90 values in the range of 1–10 µM, while compound 6u, being the most active, exhibited sub-micromolar activity (0.968 µM) in the CAS assay. In addition, minimal cytotoxicity against the HepG2 cell line (cell viability above 75%) in 11 of the 17 compounds, at their respective MIC90 concentrations, was observed, with 6u exhibiting 100% cell viability. The hybridization of the quinoline, urea, and benzothiazole scaffolds demonstrated a synergistic relationship because the activities of resultant hybrids were vastly improved compared to the individual entities. In silico ADME predictions showed that the majority of these compounds have drug-like properties and are less likely to potentially cause cardiotoxicity (QPlogHERG \textgreater −5). The results obtained in this study indicate that the majority of the synthesized compounds could serve as valuable starting points for future optimizations as new antimycobacterial agents.

@article{Viana2022,
abstract = {The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic in southern Africa has been characterised by three distinct waves. The first was associated with a mix of SARS-CoV-2 lineages, whilst the second and third waves were driven by the Beta and Delta variants, respectively. In November 2021, genomic surveillance teams in South Africa and Botswana detected a new SARS-CoV-2 variant associated with a rapid resurgence of infections in Gauteng Province, South Africa. Within three days of the first genome being uploaded, it was designated a variant of concern (Omicron) by the World Health Organization and, within three weeks, had been identified in 87 countries. The Omicron variant is exceptional for carrying over 30 mutations in the spike glycoprotein, predicted to influence antibody neutralization and spike function. Here, we describe the genomic profile and early transmission dynamics of Omicron, highlighting the rapid spread in regions with high levels of population immunity.},
author = {Viana, Raquel and Moyo, Sikhulile and Amoako, Daniel G and Tegally, Houriiyah and Scheepers, Cathrine and Althaus, Christian L and Anyaneji, Ugochukwu J and Bester, Phillip A and Boni, Maciej F. and Chand, Mohammed and Choga, Wonderful T. and Colquhoun, Rachel and Davids, Michaela and Deforche, Koen and Doolabh, Deelan and du Plessis, Louis and Engelbrecht, Susan and Everatt, Josie and Giandhari, Jennifer and Giovanetti, Marta and Hardie, Diana and Hill, Verity and Hsiao, Nei-Yuan and Iranzadeh, Arash and Ismail, Arshad and Joseph, Charity and Joseph, Rageema and Koopile, Legodile and {Kosakovsky Pond}, Sergei L. and Kraemer, Moritz U. G. and Kuate-Lere, Lesego and Laguda-Akingba, Oluwakemi and Lesetedi-Mafoko, Onalethatha and Lessells, Richard J. and Lockman, Shahin and Lucaci, Alexander G. and Maharaj, Arisha and Mahlangu, Boitshoko and Maponga, Tongai and Mahlakwane, Kamela and Makatini, Zinhle and Marais, Gert and Maruapula, Dorcas and Masupu, Kereng and Matshaba, Mogomotsi and Mayaphi, Simnikiwe and Mbhele, Nokuzola and Mbulawa, Mpaphi B. and Mendes, Adriano and Mlisana, Koleka and Mnguni, Anele and Mohale, Thabo and Moir, Monika and Moruisi, Kgomotso and Mosepele, Mosepele and Motsatsi, Gerald and Motswaledi, Modisa S. and Mphoyakgosi, Thongbotho and Msomi, Nokukhanya and Mwangi, Peter N. and Naidoo, Yeshnee and Ntuli, Noxolo and Nyaga, Martin and Olubayo, Lucier and Pillay, Sureshnee and Radibe, Botshelo and Ramphal, Yajna and Ramphal, Upasana and San, James E. and Scott, Lesley and Shapiro, Roger and Singh, Lavanya and Smith-Lawrence, Pamela and Stevens, Wendy and Strydom, Amy and Subramoney, Kathleen and Tebeila, Naume and Tshiabuila, Derek and Tsui, Joseph and van Wyk, Stephanie and Weaver, Steven and Wibmer, Constantinos K. and Wilkinson, Eduan and Wolter, Nicole and Zarebski, Alexander E. and Zuze, Boitumelo and Goedhals, Dominique and Preiser, Wolfgang and Treurnicht, Florette and Venter, Marietje and Williamson, Carolyn and Pybus, Oliver G. and Bhiman, Jinal and Glass, Allison and Martin, Darren P. and Rambaut, Andrew and Gaseitsiwe, Simani and von Gottberg, Anne and de Oliveira, Tulio},
doi = {10.1038/D41586-021-03832-5},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Viana et al. - 2022 - Rapid epidemic expansion of the SARS-CoV-2 Omicron variant in southern Africa.pdf:pdf},
issn = {0028-0836},
journal = {Nature},
keywords = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {jan},
pages = {679--686},
pmid = {35042229},
title = {{Rapid epidemic expansion of the SARS-CoV-2 Omicron variant in southern Africa}},
url = {https://www.nature.com/articles/d41586-021-03832-5},
volume = {603},
year = {2022}
}

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic in southern Africa has been characterised by three distinct waves. The first was associated with a mix of SARS-CoV-2 lineages, whilst the second and third waves were driven by the Beta and Delta variants, respectively. In November 2021, genomic surveillance teams in South Africa and Botswana detected a new SARS-CoV-2 variant associated with a rapid resurgence of infections in Gauteng Province, South Africa. Within three days of the first genome being uploaded, it was designated a variant of concern (Omicron) by the World Health Organization and, within three weeks, had been identified in 87 countries. The Omicron variant is exceptional for carrying over 30 mutations in the spike glycoprotein, predicted to influence antibody neutralization and spike function. Here, we describe the genomic profile and early transmission dynamics of Omicron, highlighting the rapid spread in regions with high levels of population immunity.

@article{AntimycobacterialSusceptibilityTestingGroup2022,
abstract = {Approximately 85 000 deaths globally in 2019 were due to drug-resistant tuberculosis (TB), which corresponds to 7{\%} of global deaths attributable to bacterial antimicrobial resistance [1]. Yet concerns have been mounting that drug-resistant TB was being underestimated because the approaches to define susceptibility and resistance to anti-TB agents had not kept up with those used for other major bacterial pathogens [2–9]. Here, we outline the recent, evidence-based initiatives spearheaded by the World Health Organization (WHO) and others to update breakpoints (traditionally referred to as critical concentrations (CCs)) that are used for phenotypic antimicrobial susceptibility testing (AST), also called drug susceptibility testing in the TB literature. Inappropriately high breakpoints have resulted in systematic false-susceptible AST results to anti-TB drugs. MIC, PK/PD and clinical outcome data should be combined when setting breakpoints to minimise the emergence and spread of antimicrobial resistance. {\textless}https://bit.ly/3i43wb6{\textgreater} We thank Andrew Vernon and others who are acknowledged in the respective WHO reports covered in this viewpoint for sharing relevant data.},
author = {Georghiou, Sophia B. and Rodwell, Timothy C. and Korobitsyn, Alexei and Abbadi, Said H. and Ajbani, Kanchan and Alffenaar, Jan-Willem and Alland, David and Alvarez, Nataly and Andres, S{\"{o}}nke and Ardizzoni, Elisa and Aubry, Alexandra and Baldan, Rossella and Ballif, Marie and Barilar, Ivan and B{\"{o}}ttger, Erik C. and Chakravorty, Soumitesh and Claxton, Pauline M. and Cirillo, Daniela M. and Comas, I{\~{n}}aki and Coulter, Chris and Denkinger, Claudia M. and Derendinger, Brigitta and Desmond, Edward P. and de Steenwinkel, Jurriaan E.M. and Dheda, Keertan and Diacon, Andreas H. and Dolinger, David L. and Dooley, Kelly E. and Egger, Matthias and Ehsani, Soudeh and Farhat, Maha R. and Fattorini, Lanfranco and Finci, Iris and {Le Ray}, Laure Fournier and Furi{\'{o}}, Victoria and Groenheit, Ramona and Gumbo, Tawanda and Heysell, Scott K. and Hillemann, Doris and Hoffmann, Harald and Hsueh, Po-Ren and Hu, Yi and Huang, Hairong and Hussain, Alamdar and Ismail, Farzana and Izumi, Kiyohiko and Jagielski, Tomasz and Johnson, John L. and Kambli, Priti and Kaniga, Kon{\'{e}} and {Eranga Karunaratne}, G.H.R. and Sharma, Meenu Kaushal and Keller, Peter M. and Kelly, Ellis C. and Kholina, Margarita and Kohli, Mikashmi and Kranzer, Katharina and Laurenson, Ian F. and Limberis, Jason and {Grace Lin}, S-Y. and Liu, Yongge and L{\'{o}}pez-Gav{\'{i}}n, Alexandre and Lyander, Anna and Machado, Diana and Martinez, Elena and Masood, Faisal and Mitarai, Satoshi and Mvelase, Nomonde R. and Niemann, Stefan and Nikolayevskyy, Vladyslav and Maurer, Florian P. and Merker, Matthias and Miotto, Paolo and Omar, Shaheed V. and Otto-Knapp, Ralf and Palaci, Mois{\'{e}}s and {Palacios Guti{\'{e}}rrez}, Juan Jos{\'{e}} and Peacock, Sharon J. and Peloquin, Charles A. and Perera, Jennifer and Pierre-Audigier, Catherine and Pholwat, Suporn and Posey, James E. and Prammananan, Therdsak and Rigouts, Leen and Robledo, Jaime and Rockwood, Neesha and Rodrigues, Camilla and Salfinger, Max and Schechter, Marcos C. and Seifert, Marva and Sengstake, Sarah and Shinnick, Thomas and Shubladze, Natalia and Sintchenko, Vitali and Sirgel, Frederick and Somasundaram, Sulochana and Sterling, Timothy R. and Spitaleri, Andrea and Streicher, Elizabeth and Supply, Philip and Svensson, Erik and Tagliani, Elisa and Tahseen, Sabira and Takaki, Akiko and Theron, Grant and Torrea, Gabriela and {Van Deun}, Armand and van Ingen, Jakko and {Van Rie}, Annelies and van Soolingen, Dick and {Vargas Jr}, Roger and Venter, Amour and Veziris, Nicolas and Villellas, Cristina and Viveiros, Miguel and Warren, Robin and Wen, Shu'an and Werngren, Jim and Wilkinson, Robert J. and Yang, Caie and Yılmaz, F. Ferda and Zhang, Tingting and Zimenkov, Danila and Ismail, Nazir and K{\"{o}}ser, Claudio U. and Sch{\"{o}}n, Thomas},
doi = {10.1183/13993003.00166-2022},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Antimycobacterial Susceptibility Testing Group - 2022 - Updating the approaches to define susceptibility and resistance to anti-tubercul.pdf:pdf;:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Group et al. - 2022 - Updating the approaches to define susceptibility and resistance to anti-tuberculosis agents implications for diagn.pdf:pdf},
issn = {0903-1936},
journal = {European Respiratory Journal},
keywords = {OA,editorial,fund{\_}ack},
mendeley-tags = {OA,editorial,fund{\_}ack},
month = {apr},
number = {4},
pages = {2200166},
pmid = {35422426},
publisher = {European Respiratory Society},
title = {{Updating the approaches to define susceptibility and resistance to anti-tuberculosis agents: implications for diagnosis and treatment}},
url = {https://erj.ersjournals.com/content/59/4/2200166 https://erj.ersjournals.com/content/59/4/2200166.abstract http://erj.ersjournals.com/lookup/doi/10.1183/13993003.00166-2022},
volume = {59},
year = {2022}
}

Approximately 85 000 deaths globally in 2019 were due to drug-resistant tuberculosis (TB), which corresponds to 7% of global deaths attributable to bacterial antimicrobial resistance [1]. Yet concerns have been mounting that drug-resistant TB was being underestimated because the approaches to define susceptibility and resistance to anti-TB agents had not kept up with those used for other major bacterial pathogens [2–9]. Here, we outline the recent, evidence-based initiatives spearheaded by the World Health Organization (WHO) and others to update breakpoints (traditionally referred to as critical concentrations (CCs)) that are used for phenotypic antimicrobial susceptibility testing (AST), also called drug susceptibility testing in the TB literature. Inappropriately high breakpoints have resulted in systematic false-susceptible AST results to anti-TB drugs. MIC, PK/PD and clinical outcome data should be combined when setting breakpoints to minimise the emergence and spread of antimicrobial resistance. \textlesshttps://bit.ly/3i43wb6\textgreater We thank Andrew Vernon and others who are acknowledged in the respective WHO reports covered in this viewpoint for sharing relevant data.

@article{Martin2022,
abstract = {Among the 30 non-synonymous nucleotide substitutions in the Omicron S-gene are 13 that have only rarely been seen in other SARS-CoV-2 sequences. These mutations cluster within three functionally important regions of the S-gene at sites that will likely impact (i) interactions between subunits of the Spike trimer and the predisposition of subunits to shift from down to up configurations, (ii) interactions of Spike with ACE2 receptors, and (iii) the priming of Spike for membrane fusion. We show here that, based on both the rarity of these 13 mutations in intrapatient sequencing reads and patterns of selection at the codon sites where the mutations occur in SARS-CoV-2 and related sarbecoviruses, prior to the emergence of Omicron the mutations would have been predicted to decrease the fitness of any genomes within which they occurred. We further propose that the mutations in each of the three clusters therefore cooperatively interact to both mitigate their individual fitness costs, and adaptively alter the function of Spike. Given the evident epidemic growth advantages of Omicron over all previously known SARS-CoV-2 lineages, it is crucial to determine both how such complex and highly adaptive mutation constellations were assembled within the Omicron S-gene, and why, despite unprecedented global genomic surveillance efforts, the early stages of this assembly process went completely undetected. {\#}{\#}{\#} Competing Interest Statement JDB consults for Moderna, Flagship Labs 77, and Oncorus. JDB, AJG, and TNS are inventors on Fred Hutch licensed patents related to deep mutational scanning of viral proteins.},
author = {Martin, Darren P and Lytras, Spyros and Lucaci, Alexander G and Maier, Wolfgang and Gr{\"{u}}ning, Bj{\"{o}}rn and Shank, Stephen D and Weaver, Steven and MacLean, Oscar A and Orton, Richard J and Lemey, Philippe and Boni, Maciej F and Tegally, Houriiyah and Harkins, Gordon and Scheepers, Cathrine and Bhiman, Jinal N and Everatt, Josie and Amoako, Daniel G and San, James Emmanuel and Giandhari, Jennifer and Sigal, Alex and NGS-SA and Williamson, Carolyn and Hsiao, Nei-yuan and von Gottberg, Anne and Klerk, Arne De and Shafer, Robert W and Robertson, David L and Wilkinson, Robert J and Sewell, B Trevor and Lessells, Richard and Nekrutenko, Anton and Greaney, Allison J. and Starr, Tyler N. and Bloom, Jesse D. and Murrell, Ben and Wilkinson, Eduan and Gupta, Ravindra K and de Oliveira, Tulio and Pond, Sergei L Kosakovsky},
doi = {10.1101/2022.01.14.476382},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Martin et al. - 2022 - Selection analysis identifies unusual clustered mutational changes in Omicron lineage BA.1 that likely impact Spi.pdf:pdf},
journal = {bioRxiv},
keywords = {OA,OA{\_}PMC,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {jan},
pages = {2022.01.14.476382},
pmid = {35075456},
publisher = {Cold Spring Harbor Laboratory},
title = {{Selection analysis identifies unusual clustered mutational changes in Omicron lineage BA.1 that likely impact Spike function}},
url = {https://www.biorxiv.org/content/10.1101/2022.01.14.476382v1 https://www.biorxiv.org/content/10.1101/2022.01.14.476382v1.abstract},
year = {2022}
}

Among the 30 non-synonymous nucleotide substitutions in the Omicron S-gene are 13 that have only rarely been seen in other SARS-CoV-2 sequences. These mutations cluster within three functionally important regions of the S-gene at sites that will likely impact (i) interactions between subunits of the Spike trimer and the predisposition of subunits to shift from down to up configurations, (ii) interactions of Spike with ACE2 receptors, and (iii) the priming of Spike for membrane fusion. We show here that, based on both the rarity of these 13 mutations in intrapatient sequencing reads and patterns of selection at the codon sites where the mutations occur in SARS-CoV-2 and related sarbecoviruses, prior to the emergence of Omicron the mutations would have been predicted to decrease the fitness of any genomes within which they occurred. We further propose that the mutations in each of the three clusters therefore cooperatively interact to both mitigate their individual fitness costs, and adaptively alter the function of Spike. Given the evident epidemic growth advantages of Omicron over all previously known SARS-CoV-2 lineages, it is crucial to determine both how such complex and highly adaptive mutation constellations were assembled within the Omicron S-gene, and why, despite unprecedented global genomic surveillance efforts, the early stages of this assembly process went completely undetected. ### Competing Interest Statement JDB consults for Moderna, Flagship Labs 77, and Oncorus. JDB, AJG, and TNS are inventors on Fred Hutch licensed patents related to deep mutational scanning of viral proteins.

@article{Meintjes2022,
author = {Meintjes, Graeme A},
doi = {10.4102/SAJID.V37I2.405},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Meintjes - 2022 - Hope and challenges working at the frontiers of medical knowledge.pdf:pdf},
issn = {2313-1810},
journal = {Southern African Journal of Infectious Diseases},
keywords = {OA,commentary,fund{\_}not{\_}ack},
mendeley-tags = {OA,commentary,fund{\_}not{\_}ack},
month = {feb},
number = {2},
pages = {a405},
pmid = {35284568},
title = {{Hope and challenges working at the frontiers of medical knowledge}},
url = {https://sajid.co.za/index.php/sajid/article/view/405},
volume = {37},
year = {2022}
}

@article{Krause2022,
abstract = {Neutralizing antibodies strongly correlate with protection for COVID-19 vaccines, but the corresponding memory B cells that form to protect against future infection are relatively understudied. Here we examine the effect of prior SARS-CoV-2 infection on the magnitude and phenotype of the B cell response to single dose Johnson and Johnson (Ad26.COV2.S) vaccination in South African health care workers. SARS-CoV- 2 speci?c memory responses expand in response to Ad26.COV2.S and are maintained for the study duration (84 days) in all individuals. However, prior infection is associated with a greater frequency of these cells, a more prominent germinal center (GC) response, and increased class switched memory (CSM). These B cell features correlated with both neutralization and antibody-dependent cytotoxicity (ADCC) activity, and with the frequency of SARS-CoV-2 speci?c circulating T follicular helper cells (cTfh). In addition, the SARS-CoV-2 speci?c CD8+ T cell response correlated with increased memory B cell lung- homing, which was sustained in the infected group. Finally, although vaccination achieved equivalent B cell activation regardless of infection history, it was negatively impacted by age. These data show that phenotyping the B cell response to vaccination can provide mechanistic insight into the impact of prior infection on GC homing, CSM, cTfh, and neutralization activity. These data can provide early signals and mechanistic understanding to inform studies of vaccine boosting, durability, and co-morbidities.},
author = {Krause, Rob and Richardson, Simone and Makhado, Zanele and Manamela, Nelia and Hermanus, Tandile and Mkhize, Nono and Keeton, Roanne and Benede, Ntombi and Mennen, Mathilda and Riou, Catherine},
doi = {10.21203/RS.3.RS-1170883/V1},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Krause et al. - 2022 - SARS-CoV-2 specific B cell memory drives improved class switching and tissue homing responses to single dose Ad26.pdf:pdf},
journal = {Research Square},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jan},
pages = {10.21203/rs.3.rs--1170883/v1},
title = {{SARS-CoV-2 specific B cell memory drives improved class switching and tissue homing responses to single dose Ad26.COV2.S vaccination in previously infected recipients}},
url = {https://www.researchsquare.com https://www.researchsquare.com/article/rs-1170883/v1},
year = {2022}
}

Neutralizing antibodies strongly correlate with protection for COVID-19 vaccines, but the corresponding memory B cells that form to protect against future infection are relatively understudied. Here we examine the effect of prior SARS-CoV-2 infection on the magnitude and phenotype of the B cell response to single dose Johnson and Johnson (Ad26.COV2.S) vaccination in South African health care workers. SARS-CoV- 2 speci?c memory responses expand in response to Ad26.COV2.S and are maintained for the study duration (84 days) in all individuals. However, prior infection is associated with a greater frequency of these cells, a more prominent germinal center (GC) response, and increased class switched memory (CSM). These B cell features correlated with both neutralization and antibody-dependent cytotoxicity (ADCC) activity, and with the frequency of SARS-CoV-2 speci?c circulating T follicular helper cells (cTfh). In addition, the SARS-CoV-2 speci?c CD8+ T cell response correlated with increased memory B cell lung- homing, which was sustained in the infected group. Finally, although vaccination achieved equivalent B cell activation regardless of infection history, it was negatively impacted by age. These data show that phenotyping the B cell response to vaccination can provide mechanistic insight into the impact of prior infection on GC homing, CSM, cTfh, and neutralization activity. These data can provide early signals and mechanistic understanding to inform studies of vaccine boosting, durability, and co-morbidities.

@article{Preez2022,
author = {du Preez, Charn{\'{e}} and Legoabe, Lesetja J and Jordaan, Audrey and Jesumoroti, Omobolanle J and Warner, Digby F and Beteck, Richard M},
doi = {10.1111/CBDD.14174},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/du Preez et al. - 2022 - Arylnitro monocarbonyl curcumin analogues synthesis and iin vitroi antitubercular evaluation.pdf:pdf},
issn = {1747-0285},
journal = {Chemical Biology {\&} Drug Design},
keywords = {OA,analogues,aryl nitro,curcumin,fund{\_}not{\_}ack,original,synthesis,tuberculosis},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {nov},
pages = {10.1111/cbdd.14174},
pmid = {36350112},
publisher = {John Wiley {\&} Sons, Ltd},
title = {{Arylnitro monocarbonyl curcumin analogues: synthesis and \textit{in vitro} antitubercular evaluation}},
url = {https://onlinelibrary.wiley.com/doi/full/10.1111/cbdd.14174 https://onlinelibrary.wiley.com/doi/abs/10.1111/cbdd.14174 https://onlinelibrary.wiley.com/doi/10.1111/cbdd.14174},
year = {2022}
}

@article{Griesel2022,
abstract = {Background Dolutegravir has been associated with neuropsychiatric adverse events (NPAEs), but relationships between dolutegravir concentrations and NPAEs are unclear. Objectives To determine in an African population whether a concentration–response relationship exists between dolutegravir and treatment-emergent NPAEs, and whether selected loss-of-function polymorphisms in genes encoding UDP-glucuronosyltransferase-1A1 (the major metabolizing enzyme for dolutegravir) and organic cation transporter-2 (involved in neurotransmitter transport and inhibited by dolutegravir) are associated with NPAEs. Methods Antiretroviral therapy-naive participants randomized to dolutegravir-based therapy in the ADVANCE study were enrolled into a pharmacokinetic sub-study. Primary outcome was change in mental health screening [modified mini screen (MMS)] and sleep quality from baseline to weeks 4, 12 and 24. Dolutegravir exposure was estimated using a population pharmacokinetic model. Polymorphisms analysed were UGT1A1 rs887829 and SLC22A2 rs316019. Results Data from 464 participants were available for pharmacokinetic analyses and 301 for genetic analyses. By multivariable linear regression, higher dolutegravir exposure was associated with worsening sleep quality only at week 12 [coefficient = −0.854 (95{\%} CI −1.703 to −0.005), P = 0.049], but with improved MMS score at weeks 12 and 24 [coefficient = −1.255 (95{\%} CI −2.250 to −0.261), P = 0.013 and coefficient = −1.199 (95{\%} CI −2.030 to −0.368), P = 0.005, respectively]. The UGT1A1 and SLC22A2 polymorphisms were not associated with change in MMS score or sleep quality. Conclusions Only at week 12 did we find evidence of a relationship between dolutegravir exposure and worsening sleep quality. However, higher dolutegravir exposure was associated with improved MMS scores, suggesting a possible beneficial effect.},
author = {Griesel, Rulan and Sinxadi, Phumla and Kawuma, Aida and Joska, John and Sokhela, Simiso and Akpomiemie, Godspower and Venter, Francois and Denti, Paolo and Haas, David W and Maartens, Gary},
doi = {10.1093/JAC/DKAC290},
issn = {0305-7453},
journal = {Journal of Antimicrobial Chemotherapy},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {aug},
number = {11},
pages = {3110--3117},
pmid = {36031789},
title = {{Pharmacokinetic and pharmacogenetic associations with dolutegravir neuropsychiatric adverse events in an African population}},
url = {https://academic.oup.com/jac/advance-article/doi/10.1093/jac/dkac290/6678151},
volume = {77},
year = {2022}
}

Background Dolutegravir has been associated with neuropsychiatric adverse events (NPAEs), but relationships between dolutegravir concentrations and NPAEs are unclear. Objectives To determine in an African population whether a concentration–response relationship exists between dolutegravir and treatment-emergent NPAEs, and whether selected loss-of-function polymorphisms in genes encoding UDP-glucuronosyltransferase-1A1 (the major metabolizing enzyme for dolutegravir) and organic cation transporter-2 (involved in neurotransmitter transport and inhibited by dolutegravir) are associated with NPAEs. Methods Antiretroviral therapy-naive participants randomized to dolutegravir-based therapy in the ADVANCE study were enrolled into a pharmacokinetic sub-study. Primary outcome was change in mental health screening [modified mini screen (MMS)] and sleep quality from baseline to weeks 4, 12 and 24. Dolutegravir exposure was estimated using a population pharmacokinetic model. Polymorphisms analysed were UGT1A1 rs887829 and SLC22A2 rs316019. Results Data from 464 participants were available for pharmacokinetic analyses and 301 for genetic analyses. By multivariable linear regression, higher dolutegravir exposure was associated with worsening sleep quality only at week 12 [coefficient = −0.854 (95% CI −1.703 to −0.005), P = 0.049], but with improved MMS score at weeks 12 and 24 [coefficient = −1.255 (95% CI −2.250 to −0.261), P = 0.013 and coefficient = −1.199 (95% CI −2.030 to −0.368), P = 0.005, respectively]. The UGT1A1 and SLC22A2 polymorphisms were not associated with change in MMS score or sleep quality. Conclusions Only at week 12 did we find evidence of a relationship between dolutegravir exposure and worsening sleep quality. However, higher dolutegravir exposure was associated with improved MMS scores, suggesting a possible beneficial effect.

@article{Wolter2022a,
abstract = {Early data indicated that infection with Omicron BA.1 sub-lineage was associated with a lower risk of hospitalisation and severe illness, compared to Delta infection. Recently, the BA.2 sub-lineage has increased in many areas globally. We aimed to assess the severity of BA.2 infections compared to BA.1 in South Africa. We performed data linkages for (i) national COVID-19 case data, (ii) SARS-CoV-2 laboratory test data, and (iii) COVID-19 hospitalisations data, nationally. For cases identified using TaqPath COVID-19 PCR, infections were designated as S-gene target failure (SGTF, proxy for BA.1) or S-gene positive (proxy for BA.2). Disease severity was assessed using multivariable logistic regression models comparing individuals with S-gene positive infection to SGTF-infected individuals diagnosed between 1 December 2021 to 20 January 2022. From week 49 (starting 5 December 2021) through week 4 (ending 29 January 2022), the proportion of S-gene positive infections increased from 3{\%} (931/31,271) to 80{\%} (2,425/3,031). The odds of being admitted to hospital did not differ between individuals with S-gene positive (BA.2 proxy) infection compared to SGTF (BA.1 proxy) infection (adjusted odds ratio (aOR) 0.96, 95{\%} confidence interval (CI) 0.85-1.09). Among hospitalised individuals, after controlling for factors associated with severe disease, the odds of severe disease did not differ for individuals with S-gene positive infection compared to SGTF infection (aOR 0.91, 95{\%}CI 0.68-1.22). These data suggest that while BA.2 may have a competitive advantage over BA.1 in some settings, the clinical profile of illness remains similar. {\#}{\#}{\#} Competing Interest Statement CC has received grant support from South African Medical Research Council, UK Foreign, Commonwealth and Development Office and Wellcome Trust, US Centers for Disease Control and Prevention and Sanofi Pasteur. NW has received grant support from Sanofi Pasteur and the Bill and Melinda Gates Foundation. AvG has received grant support from US Centers for Disease Control and Prevention, Africa Centres for Disease Control and Prevention, African Society for Laboratory Medicine (ASLM), South African Medical Research Council, WHO AFRO, The Fleming Fund and Wellcome Trust. RW declares personal shareholding in the following companies: Adcock Ingram Holdings Ltd, Dischem Pharmacies Ltd, Discovery Ltd, Netcare Ltd, Aspen Pharmacare Holdings Ltd. All other authors declare no conflict of interest. {\#}{\#}{\#} Funding Statement This study was funded by the South African Medical Research Council with funds received from the National Department of Health. Sequencing activities for NICD are supported by a conditional grant from the South African National Department of Health as part of the emergency COVID-19 response; a cooperative agreement between the National Institute for Communicable Diseases of the National Health Laboratory Service and the United States Centers for Disease Control and Prevention (grant number 5 U01IP001048-05-00); the African Society of Laboratory Medicine (ASLM) and Africa Centers for Disease Control and Prevention through a sub-award from the Bill and Melinda Gates Foundation grant number INV-018978; the UK Foreign, Commonwealth and Development Office and Wellcome (Grant no 221003/Z/20/Z); and the UK Department of Health and Social Care and managed by the Fleming Fund and performed under the auspices of the SEQAFRICA project. This research was also supported by The Coronavirus Aid, Relief, and Economic Security Act (CARES ACT) through the Centers for Disease Control and Prevention (CDC) and the COVID International Task Force (ITF) funds through the CDC under the terms of a subcontract with the African Field Epidemiology Network (AFENET) AF-NICD-001/2021. Screening for SGTF at UCT was supported by the Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), which is supported by core funding from the Wellcome Trust (203135/Z/16/Z and 222754). {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval was obtained from the Human Research Ethics Committee (Medical) of University of the Witwatersrand for the collection of COVID-19 case and test data as part of essential communicable disease surveillance (M210752), and for the DATCOV surveillance programme (M2010108). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data used in this manuscript are available upon reasonable request. Proposals should be directed to cherylc{\{}at{\}}nicd.ac.za.},
author = {Wolter, Nicole and Jassat, Waasila and author Group, DATCOV-Gen and von Gottberg, Anne and Cohen, Cheryl},
doi = {10.1101/2022.02.17.22271030},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Wolter et al. - 2022 - Clinical severity of Omicron sub-lineage BA.2 compared to BA.1 in South Africa.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {feb},
pages = {2022.02.17.22271030},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Clinical severity of Omicron sub-lineage BA.2 compared to BA.1 in South Africa}},
url = {https://www.medrxiv.org/content/10.1101/2022.02.17.22271030v1 https://www.medrxiv.org/content/10.1101/2022.02.17.22271030v1.abstract},
year = {2022}
}

Early data indicated that infection with Omicron BA.1 sub-lineage was associated with a lower risk of hospitalisation and severe illness, compared to Delta infection. Recently, the BA.2 sub-lineage has increased in many areas globally. We aimed to assess the severity of BA.2 infections compared to BA.1 in South Africa. We performed data linkages for (i) national COVID-19 case data, (ii) SARS-CoV-2 laboratory test data, and (iii) COVID-19 hospitalisations data, nationally. For cases identified using TaqPath COVID-19 PCR, infections were designated as S-gene target failure (SGTF, proxy for BA.1) or S-gene positive (proxy for BA.2). Disease severity was assessed using multivariable logistic regression models comparing individuals with S-gene positive infection to SGTF-infected individuals diagnosed between 1 December 2021 to 20 January 2022. From week 49 (starting 5 December 2021) through week 4 (ending 29 January 2022), the proportion of S-gene positive infections increased from 3% (931/31,271) to 80% (2,425/3,031). The odds of being admitted to hospital did not differ between individuals with S-gene positive (BA.2 proxy) infection compared to SGTF (BA.1 proxy) infection (adjusted odds ratio (aOR) 0.96, 95% confidence interval (CI) 0.85-1.09). Among hospitalised individuals, after controlling for factors associated with severe disease, the odds of severe disease did not differ for individuals with S-gene positive infection compared to SGTF infection (aOR 0.91, 95%CI 0.68-1.22). These data suggest that while BA.2 may have a competitive advantage over BA.1 in some settings, the clinical profile of illness remains similar. ### Competing Interest Statement CC has received grant support from South African Medical Research Council, UK Foreign, Commonwealth and Development Office and Wellcome Trust, US Centers for Disease Control and Prevention and Sanofi Pasteur. NW has received grant support from Sanofi Pasteur and the Bill and Melinda Gates Foundation. AvG has received grant support from US Centers for Disease Control and Prevention, Africa Centres for Disease Control and Prevention, African Society for Laboratory Medicine (ASLM), South African Medical Research Council, WHO AFRO, The Fleming Fund and Wellcome Trust. RW declares personal shareholding in the following companies: Adcock Ingram Holdings Ltd, Dischem Pharmacies Ltd, Discovery Ltd, Netcare Ltd, Aspen Pharmacare Holdings Ltd. All other authors declare no conflict of interest. ### Funding Statement This study was funded by the South African Medical Research Council with funds received from the National Department of Health. Sequencing activities for NICD are supported by a conditional grant from the South African National Department of Health as part of the emergency COVID-19 response; a cooperative agreement between the National Institute for Communicable Diseases of the National Health Laboratory Service and the United States Centers for Disease Control and Prevention (grant number 5 U01IP001048-05-00); the African Society of Laboratory Medicine (ASLM) and Africa Centers for Disease Control and Prevention through a sub-award from the Bill and Melinda Gates Foundation grant number INV-018978; the UK Foreign, Commonwealth and Development Office and Wellcome (Grant no 221003/Z/20/Z); and the UK Department of Health and Social Care and managed by the Fleming Fund and performed under the auspices of the SEQAFRICA project. This research was also supported by The Coronavirus Aid, Relief, and Economic Security Act (CARES ACT) through the Centers for Disease Control and Prevention (CDC) and the COVID International Task Force (ITF) funds through the CDC under the terms of a subcontract with the African Field Epidemiology Network (AFENET) AF-NICD-001/2021. Screening for SGTF at UCT was supported by the Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), which is supported by core funding from the Wellcome Trust (203135/Z/16/Z and 222754). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval was obtained from the Human Research Ethics Committee (Medical) of University of the Witwatersrand for the collection of COVID-19 case and test data as part of essential communicable disease surveillance (M210752), and for the DATCOV surveillance programme (M2010108). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data used in this manuscript are available upon reasonable request. Proposals should be directed to cherylc\at\nicd.ac.za.

@article{Satti2022,
abstract = {Tuberculosis vaccine development is hindered by the lack of validated immune correlates of protection. Exploring immune correlates of risk of disease and/or infection in prospective samples can inform this field. We investigate whether previously identified immune correlates of risk of TB disease also associate with increased risk of M.tb infection in BCG-vaccinated South African infants, who became infected with M.tb during 2-3 years of follow-up. M.tb infection is defined by conversion to positive reactivity in the QuantiFERON test. We demonstrate that inflammation and immune activation are associated with risk of M.tb infection. Ag85A-specific IgG is elevated in infants that were subsequently infected with M.tb, and this is coupled with upregulated gene expression of immunoglobulin-associated genes and type-I interferon. Plasma levels of IFN- {\$}{\$}$\backslash$alpha{\$}{\$} 2, TNF- {\$}{\$}$\backslash$alpha{\$}{\$} , CXCL10 (IP-10) and complement C2 are also higher in infants that were subsequently infected with M.tb. The identification of immune correlates of protection in humans would inform on the design and development of tuberculosis vaccine candidates. In this work, authors examine samples collected from South African infants, to determine whether the correlates of risk of tuberculosis disease, previously identified in this population, are also correlates of risk of M. tuberculosis infection.},
author = {Satti, Iman and Wittenberg, Rachel E and Li, Shuailin and Harris, Stephanie A and Tanner, Rachel and Cizmeci, Deniz and Jacobs, Ashley and Williams, Nicola and Mulenga, Humphrey and Fletcher, Helen A and Scriba, Thomas J and Tameris, Michele and Hatherill, Mark and McShane, Helen},
doi = {10.1038/s41467-022-34061-7},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Satti et al. - 2022 - Inflammation and immune activation are associated with risk of iMycobacterium tuberculosisi infection in BCG-vacci.pdf:pdf},
issn = {2041-1723},
journal = {Nature Communications},
keywords = {Bacterial infection,Infectious,OA,OA{\_}PMC,Tuberculosis,disease epidemiology,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {nov},
pages = {6594},
pmid = {36329009},
publisher = {Nature Publishing Group},
title = {{Inflammation and immune activation are associated with risk of \textit{Mycobacterium tuberculosis} infection in BCG-vaccinated infants}},
url = {https://www.nature.com/articles/s41467-022-34061-7},
volume = {13},
year = {2022}
}

Tuberculosis vaccine development is hindered by the lack of validated immune correlates of protection. Exploring immune correlates of risk of disease and/or infection in prospective samples can inform this field. We investigate whether previously identified immune correlates of risk of TB disease also associate with increased risk of M.tb infection in BCG-vaccinated South African infants, who became infected with M.tb during 2-3 years of follow-up. M.tb infection is defined by conversion to positive reactivity in the QuantiFERON test. We demonstrate that inflammation and immune activation are associated with risk of M.tb infection. Ag85A-specific IgG is elevated in infants that were subsequently infected with M.tb, and this is coupled with upregulated gene expression of immunoglobulin-associated genes and type-I interferon. Plasma levels of IFN- $}{$$\$alpha$}{$ 2, TNF- $}{$$\$alpha$}{$ , CXCL10 (IP-10) and complement C2 are also higher in infants that were subsequently infected with M.tb. The identification of immune correlates of protection in humans would inform on the design and development of tuberculosis vaccine candidates. In this work, authors examine samples collected from South African infants, to determine whether the correlates of risk of tuberculosis disease, previously identified in this population, are also correlates of risk of M. tuberculosis infection.

@article{Denti2021a,
author = {Denti, Paolo and Wasmann, Roeland E and Francis, Jose and McIlleron, Helen and Sugandhi, Nandita and Cressey, Tim R and Mirochnick, Mark and Capparelli, Edmund V and Penazzato, Martina},
doi = {10.1016/S2352-4642(21)00302-3},
issn = {2352-4642},
journal = {The Lancet Child {\&} Adolescent Health},
keywords = {commentary},
mendeley-tags = {commentary},
month = {oct},
number = {1},
pages = {9--10},
pmid = {34678142},
publisher = {Elsevier},
title = {{One dose does not fit all: revising the WHO paediatric dosing tool to include the non-linear effect of body size and maturation}},
url = {http://www.thelancet.com/article/S2352464221003023/fulltext http://www.thelancet.com/article/S2352464221003023/abstract https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00302-3/abstract},
volume = {6},
year = {2022}
}

@article{Wasserman2022,
abstract = {Background: Linezolid is recommended for treating drug-resistant TB. Adverse events are a concern to prescri-bers but have not been systematically studied at the standard dose, and the relationship between linezolid exposure and clinical toxicity is not completely elucidated. Patients and methods: We conducted an observational cohort study to describe the incidence and determinants of linezolid toxicity, and to determine a drug exposure threshold for toxicity, among patients with rifam-picin-resistant TB in South Africa. Linezolid exposures were estimated from a population pharmacokinetic model. Mixed-effects modelling was used to analyse toxicity outcomes. Results: One hundred and fifty-one participants, 63{\%} HIV positive, were enrolled and followed for a median of 86 weeks. Linezolid was permanently discontinued for toxicity in 32 (21{\%}) participants. Grade 3 or 4 linezolid-associated adverse events occurred in 21 (14{\%}) participants. Mean haemoglobin concentrations increased with time on treatment (0.03 g/dL per week; 95{\%} CI 0.02-0.03). Linezolid trough concentration, male sex and age (but not HIV positivity) were independently associated with a decrease in haemoglobin .2 g/dL. Trough line-zolid concentration of 2.5 mg/L or higher resulted in optimal model performance to describe changing haemo-globin and treatment-emergent anaemia (adjusted OR 2.9; 95{\%} CI 1.3-6.8). SNPs 2706A. G and 3010G. A in mitochondrial DNA were not associated with linezolid toxicity. Conclusions: Permanent discontinuation of linezolid was common, but linezolid-containing therapy was associated with average improvement in toxicity measures. HIV co-infection was not independently associated with linezolid toxicity. Linezolid trough concentration of 2.5 mg/L should be evaluated as a target for therapeutic drug monitoring.},
author = {Wasserman, Sean and Brust, James C M and Abdelwahab, Mahmoud T and Little, Francesca and Denti, Paolo and Wiesner, Lubbe and Gandhi, Neel R and Meintjes, Graeme and Maartens, Gary},
doi = {10.1093/JAC/DKAC019},
issn = {0305-7453},
journal = {Journal of Antimicrobial Chemotherapy},
keywords = {OA,anemia,hemoglobin,linezolid,original,toxic effect,trough concentration},
mendeley-tags = {OA,original},
number = {4},
pages = {1146--1154},
pmid = {35134182},
publisher = {Oxford University Press (OUP)},
title = {{Linezolid toxicity in patients with drug-resistant tuberculosis: a prospective cohort study}},
url = {https://academic.oup.com/jac/advance-article/doi/10.1093/jac/dkac019/6520540},
volume = {77},
year = {2022}
}

Background: Linezolid is recommended for treating drug-resistant TB. Adverse events are a concern to prescri-bers but have not been systematically studied at the standard dose, and the relationship between linezolid exposure and clinical toxicity is not completely elucidated. Patients and methods: We conducted an observational cohort study to describe the incidence and determinants of linezolid toxicity, and to determine a drug exposure threshold for toxicity, among patients with rifam-picin-resistant TB in South Africa. Linezolid exposures were estimated from a population pharmacokinetic model. Mixed-effects modelling was used to analyse toxicity outcomes. Results: One hundred and fifty-one participants, 63% HIV positive, were enrolled and followed for a median of 86 weeks. Linezolid was permanently discontinued for toxicity in 32 (21%) participants. Grade 3 or 4 linezolid-associated adverse events occurred in 21 (14%) participants. Mean haemoglobin concentrations increased with time on treatment (0.03 g/dL per week; 95% CI 0.02-0.03). Linezolid trough concentration, male sex and age (but not HIV positivity) were independently associated with a decrease in haemoglobin .2 g/dL. Trough line-zolid concentration of 2.5 mg/L or higher resulted in optimal model performance to describe changing haemo-globin and treatment-emergent anaemia (adjusted OR 2.9; 95% CI 1.3-6.8). SNPs 2706A. G and 3010G. A in mitochondrial DNA were not associated with linezolid toxicity. Conclusions: Permanent discontinuation of linezolid was common, but linezolid-containing therapy was associated with average improvement in toxicity measures. HIV co-infection was not independently associated with linezolid toxicity. Linezolid trough concentration of 2.5 mg/L should be evaluated as a target for therapeutic drug monitoring.

@article{Alobwede2022a,
abstract = {Vaccination attitudes among healthcare workers (HCWs) is a vital factor for measuring their level of vaccination uptake and intention to recommend vaccinations to their patients. To our knowledge, no study has been conducted in South Africa to assess hesitancy to influenza vaccines among HCWs. We used questionnaire adapted from Betsch and colleagues to conduct an online and face-to-face cross-sectional study among HCWs at the start of COVID-19 vaccine roll-out prior to the flu season. Main outcome was influenza vaccine hesitancy. We used multivariate logistic regression to assess predictors of influenza vaccine hesitancy. Of 401 participants, 64.5{\%} were women, 49.2{\%} nurses, and 12.5{\%} physicians. A total of 54.9{\%} were willing to accept vaccination, 20.4{\%} were undecided, and 24.7{\%} intended to refuse. Older participants above 17-25 years and physicians were likely to receive the vaccine. Key predictors of vaccine acceptance were confidence in the effectiveness, consideration of benefits and risks, and willingness to be vaccinated to protect others. Influenza vaccine hesitancy was highest in those who did not trust that influenza vaccines are safe. For future flu seasons, tailored education programs targeting younger HCWs and more information about the composition of flu vaccines would be vital to improve vaccine uptake.},
author = {Alobwede, Samuel Muabe and Kidzeru, Elvis and Katoto, Patrick DeMarie and Lumngwena, Evelyn Ngwa and Cooper, Sara and Goliathl, Rene and Jackson, Amanda and Wiysonge, Charles S and Shey, Muki S},
doi = {10.20944/PREPRINTS202206.0123.V1},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Alobwede et al. - 2022 - Influenza vaccination hesitancy and acceptance among healthcare workers in Cape Town, South Africa.pdf:pdf},
journal = {Preprints},
keywords = {Healthcare workers (HCWs),Influenza vaccines,OA,South Africa,Vaccine hesitancy,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jun},
pages = {2022060123},
publisher = {Preprints},
title = {{Influenza vaccination hesitancy and acceptance among healthcare workers in Cape Town, South Africa}},
url = {https://www.preprints.org/manuscript/202206.0123/v1},
year = {2022}
}

Vaccination attitudes among healthcare workers (HCWs) is a vital factor for measuring their level of vaccination uptake and intention to recommend vaccinations to their patients. To our knowledge, no study has been conducted in South Africa to assess hesitancy to influenza vaccines among HCWs. We used questionnaire adapted from Betsch and colleagues to conduct an online and face-to-face cross-sectional study among HCWs at the start of COVID-19 vaccine roll-out prior to the flu season. Main outcome was influenza vaccine hesitancy. We used multivariate logistic regression to assess predictors of influenza vaccine hesitancy. Of 401 participants, 64.5% were women, 49.2% nurses, and 12.5% physicians. A total of 54.9% were willing to accept vaccination, 20.4% were undecided, and 24.7% intended to refuse. Older participants above 17-25 years and physicians were likely to receive the vaccine. Key predictors of vaccine acceptance were confidence in the effectiveness, consideration of benefits and risks, and willingness to be vaccinated to protect others. Influenza vaccine hesitancy was highest in those who did not trust that influenza vaccines are safe. For future flu seasons, tailored education programs targeting younger HCWs and more information about the composition of flu vaccines would be vital to improve vaccine uptake.

@article{Butters2022,
abstract = {Multisystem inflammatory syndrome is a severe manifestation of SARS-CoV-2 in children. The incidence of MIS-C after infection is poorly understood. There are very few cohorts describing MIS-C in Africa despite MIS-C being more common in Black children worldwide. A cohort of children with MIS-C and healthy children was recruited from May 2020 until May 2021 from the two main paediatric hospitals in Cape Town, South Africa. Clinical and demographic data were collected, and serum was tested for SARS-CoV-2 antibodies. The incidence of MIS-C was calculated using an estimation of population exposure from seroprevalence in the healthy group. Summary data, non-parametric comparisons and logistic regression analyses were performed. Sixty eight children with MIS-C were recruited with a median age of 7 years (3.6, 9.9). Ninety seven healthy children were recruited with a 30{\%} seroprevalence. The estimated incidence of MIS-C was 22/100 000 exposures in the city in this time. Black children were over-represented in the MIS-C group (62{\%} vs 37{\%}, p = 0.002). The most common clinical features in MIS-C were fever (100{\%}), tachycardia (98.5{\%}), rash (85.3{\%}), conjunctivitis (77.9{\%}), abdominal pain (60.3{\%}) and hypotension (60.3{\%}). The median haemoglobin, sodium, neutrophil count, white cell count, CRP, ferritin, cardiac (pro-BNP, trop-T) and coagulation markers (D-dimer and fibrinogen) were markedly deranged in MIS-C. Cardiac, pulmonary, central nervous and renal organ systems were involved in 71{\%}, 29.4{\%}, 27.9{\%} and 27.9{\%} respectively. Ninety four percent received intravenous immune globulin, 64.7{\%} received methylprednisolone and 61.7{\%} received both. Forty percent required ICU admission, 38.2{\%} required inotropic support, 38.2{\%} required oxygen therapy, 11.8{\%} required invasive ventilation and 6{\%} required peritoneal dialysis. Older age was an independent predictor for the requirement for ionotropic support (OR = 1.523, CI 1.074, 2.16, p = 0.018). The median hospital stay duration was 7 days with no deaths. The lack of reports from Southern Africa does not reflect a lack of cases of MIS-C. MIS-C poses a significant burden to children in the region as long as the pandemic continues. MIS-C disproportionately affects black children. The clinical manifestations and outcomes of MIS-C in this region highlight the need for improved surveillance, reporting and data to inform diagnosis and treatment.},
author = {Butters, Claire and Abraham, Deepthi Raju and Stander, Raphaella and Facey-Thomas, Heidi and Abrahams, Debbie and Faleye, Ayodele and Allie, Nazneen and Soni, Khushbu and Rabie, Helena and Scott, Christiaan and Z{\"{u}}hlke, Liesl and Webb, Kate},
doi = {10.1186/S12887-022-03308-Z},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Butters et al. - 2022 - The clinical features and estimated incidence of MIS-C in Cape Town, South Africa.pdf:pdf},
issn = {1471-2431},
journal = {BMC Pediatrics},
keywords = {Internal Medicine,OA,Pediatrics,Southern Ethiopia,fund{\_}ack,original,prospective study},
mendeley-tags = {OA,fund{\_}ack,original},
month = {may},
pages = {241},
pmid = {35501710},
publisher = {BioMed Central},
title = {{The clinical features and estimated incidence of MIS-C in Cape Town, South Africa}},
url = {https://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-022-03308-z},
volume = {22},
year = {2022}
}

Multisystem inflammatory syndrome is a severe manifestation of SARS-CoV-2 in children. The incidence of MIS-C after infection is poorly understood. There are very few cohorts describing MIS-C in Africa despite MIS-C being more common in Black children worldwide. A cohort of children with MIS-C and healthy children was recruited from May 2020 until May 2021 from the two main paediatric hospitals in Cape Town, South Africa. Clinical and demographic data were collected, and serum was tested for SARS-CoV-2 antibodies. The incidence of MIS-C was calculated using an estimation of population exposure from seroprevalence in the healthy group. Summary data, non-parametric comparisons and logistic regression analyses were performed. Sixty eight children with MIS-C were recruited with a median age of 7 years (3.6, 9.9). Ninety seven healthy children were recruited with a 30% seroprevalence. The estimated incidence of MIS-C was 22/100 000 exposures in the city in this time. Black children were over-represented in the MIS-C group (62% vs 37%, p = 0.002). The most common clinical features in MIS-C were fever (100%), tachycardia (98.5%), rash (85.3%), conjunctivitis (77.9%), abdominal pain (60.3%) and hypotension (60.3%). The median haemoglobin, sodium, neutrophil count, white cell count, CRP, ferritin, cardiac (pro-BNP, trop-T) and coagulation markers (D-dimer and fibrinogen) were markedly deranged in MIS-C. Cardiac, pulmonary, central nervous and renal organ systems were involved in 71%, 29.4%, 27.9% and 27.9% respectively. Ninety four percent received intravenous immune globulin, 64.7% received methylprednisolone and 61.7% received both. Forty percent required ICU admission, 38.2% required inotropic support, 38.2% required oxygen therapy, 11.8% required invasive ventilation and 6% required peritoneal dialysis. Older age was an independent predictor for the requirement for ionotropic support (OR = 1.523, CI 1.074, 2.16, p = 0.018). The median hospital stay duration was 7 days with no deaths. The lack of reports from Southern Africa does not reflect a lack of cases of MIS-C. MIS-C poses a significant burden to children in the region as long as the pandemic continues. MIS-C disproportionately affects black children. The clinical manifestations and outcomes of MIS-C in this region highlight the need for improved surveillance, reporting and data to inform diagnosis and treatment.

@article{Nicola2022,
author = {Nicola, Andr{\'{e}} Moraes and Desai, Jigar V and Swidergall, Marc and Shey, Muki and Dambuza, Ivy M},
doi = {10.3389/fimmu.2022.880037},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Nicola et al. - 2022 - Editorial Immunological memory to fungal infections and vaccine development.pdf:pdf},
issn = {1664-3224},
journal = {Frontiers in Immunology},
keywords = {Aspergillosis,Fungi,Histoplasmosis,Immunological memory,Mycoses,OA,Paracoccidioidomycosis,Vaccine,editorial,fund{\_}not{\_}ack},
mendeley-tags = {OA,editorial,fund{\_}not{\_}ack},
month = {apr},
pages = {880037},
pmid = {35572566},
publisher = {Frontiers},
title = {{Editorial: Immunological memory to fungal infections and vaccine development}},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2022.880037/full},
volume = {13},
year = {2022}
}

@article{Roux2022,
abstract = {Objective Champions are recognised as important to driving organisational change in healthcare quality improvement initiatives in high-income settings. In low-income and middle-income countries with a high disease burden and constrained human resources, their role is highly relevant yet understudied. Within a broader study on policy implementation for decentralised drug-resistant tuberculosis care in South Africa, we characterised the role, strategies and organisational context of emergent policy champions. Design Interviews with 34 healthcare workers in three South African provinces identified the presence of individuals who had a strong influence on driving policy implementation forward. Additional interviews were conducted with 13 participants who were either identified as champions in phase II or were healthcare workers in facilities in which the champions operated. Thematic analyses using a socio-ecological framework further explored their strategies and the factors enabling or obstructing their agency. Results All champions occupied senior managerial posts and were accorded legitimacy and authority by their communities. ‘Disease-centred' champions had a high level of clinical expertise and placed emphasis on clinical governance and clinical outcomes, while ‘patient-centred' champions promoted pathways of care that would optimise patients' recovery while minimising disruption in other spheres of their lives. Both types of champions displayed high levels of resourcefulness and flexibility to adapt strategies to the resource-constrained organisational context. Conclusion Policymakers can learn from champions' experiences regarding barriers and enablers to implementation to adapt policy. Research is needed to understand what factors can promote the sustainability of champion-led policy implementation, and to explore best management practices to support their initiatives. Data are available on reasonable request.},
author = {Roux, Sacha Roxanne Le and Jassat, Waasila and Dickson, Lindy and Mitrani, Leila and Cox, Helen and Mlisana, Koleka and Black, John and Loveday, Marian and Grant, Alison D and Moshabela, Mosa and Kielmann, Karina and Nicol, Mark P},
doi = {10.1136/BMJGH-2022-008907},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Roux et al. - 2022 - The role of emergent champions in policy implementation for decentralised drug-resistant tuberculosis care in South.pdf:pdf},
issn = {2059-7908},
journal = {BMJ Global Health},
keywords = {OA,OA{\_}repository,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,OA{\_}repository,fund{\_}not{\_}ack,original},
month = {dec},
number = {12},
pages = {e008907},
publisher = {BMJ Specialist Journals},
title = {{The role of emergent champions in policy implementation for decentralised drug-resistant tuberculosis care in South Africa}},
url = {https://gh.bmj.com/content/7/12/e008907 https://gh.bmj.com/content/7/12/e008907.abstract},
volume = {7},
year = {2022}
}

Objective Champions are recognised as important to driving organisational change in healthcare quality improvement initiatives in high-income settings. In low-income and middle-income countries with a high disease burden and constrained human resources, their role is highly relevant yet understudied. Within a broader study on policy implementation for decentralised drug-resistant tuberculosis care in South Africa, we characterised the role, strategies and organisational context of emergent policy champions. Design Interviews with 34 healthcare workers in three South African provinces identified the presence of individuals who had a strong influence on driving policy implementation forward. Additional interviews were conducted with 13 participants who were either identified as champions in phase II or were healthcare workers in facilities in which the champions operated. Thematic analyses using a socio-ecological framework further explored their strategies and the factors enabling or obstructing their agency. Results All champions occupied senior managerial posts and were accorded legitimacy and authority by their communities. ‘Disease-centred' champions had a high level of clinical expertise and placed emphasis on clinical governance and clinical outcomes, while ‘patient-centred' champions promoted pathways of care that would optimise patients' recovery while minimising disruption in other spheres of their lives. Both types of champions displayed high levels of resourcefulness and flexibility to adapt strategies to the resource-constrained organisational context. Conclusion Policymakers can learn from champions' experiences regarding barriers and enablers to implementation to adapt policy. Research is needed to understand what factors can promote the sustainability of champion-led policy implementation, and to explore best management practices to support their initiatives. Data are available on reasonable request.

@article{Bedeker2022,
abstract = {There is an increasing recognition of the importance of including benefit sharing in research programmes in order to ensure equitable and just distribution of the benefits arising from research. Whilst there are global efforts to promote benefit sharing when using non-human biological resources, benefit sharing plans and implementation do not yet feature prominently in research programmes, funding applications or requirements by ethics review boards. Whilst many research stakeholders may agree with the concept of benefit sharing, it can be difficult to operationalise benefit sharing within research programmes. We present a framework designed to assist with identifying benefit sharing opportunities in research programmes. The framework has two dimensions: the first represents microlevel, mesolevel and macrolevel stakeholders as defined using a socioecological model; and the second identifies nine different types of benefit sharing that might be achieved during a research programme. We provide an example matrix identifying different types of benefit sharing that might be undertaken during genomics research, and present a case study evaluating benefit sharing in Africa during the SARS-CoV-2 pandemic. This framework, with examples, is intended as a practical tool to assist research stakeholders with identifying opportunities for benefit sharing, and inculcating intentional benefit sharing in their research programmes from inception.},
author = {Bedeker, Anja and Nichols, Michelle and Allie, Taryn and Tamuhla, Tsaone and van Heusden, Peter and Olorunsogbon, Olorunyomi and Tiffin, Nicki and {PHA4GE Ethics and Data-Sharing Working Group}},
doi = {10.1136/bmjgh-2021-008096},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Bedeker et al. - 2022 - A framework for the promotion of ethical benefit sharing in health research.pdf:pdf},
isbn = {2021008096},
issn = {2059-7908},
journal = {BMJ global health},
keywords = {OA,OA{\_}PMC,fund{\_}ack,original,public health},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,original},
month = {feb},
number = {2},
pages = {e008096},
pmid = {35144922},
publisher = {BMJ Specialist Journals},
title = {{A framework for the promotion of ethical benefit sharing in health research.}},
url = {https://gh.bmj.com/content/7/2/e008096 https://gh.bmj.com/content/7/2/e008096.abstract http://www.ncbi.nlm.nih.gov/pubmed/35144922},
volume = {7},
year = {2022}
}

There is an increasing recognition of the importance of including benefit sharing in research programmes in order to ensure equitable and just distribution of the benefits arising from research. Whilst there are global efforts to promote benefit sharing when using non-human biological resources, benefit sharing plans and implementation do not yet feature prominently in research programmes, funding applications or requirements by ethics review boards. Whilst many research stakeholders may agree with the concept of benefit sharing, it can be difficult to operationalise benefit sharing within research programmes. We present a framework designed to assist with identifying benefit sharing opportunities in research programmes. The framework has two dimensions: the first represents microlevel, mesolevel and macrolevel stakeholders as defined using a socioecological model; and the second identifies nine different types of benefit sharing that might be achieved during a research programme. We provide an example matrix identifying different types of benefit sharing that might be undertaken during genomics research, and present a case study evaluating benefit sharing in Africa during the SARS-CoV-2 pandemic. This framework, with examples, is intended as a practical tool to assist research stakeholders with identifying opportunities for benefit sharing, and inculcating intentional benefit sharing in their research programmes from inception.

@article{Keeton2022,
abstract = {The SARS-CoV-2 Omicron variant has multiple Spike (S) protein mutations1,2 that contribute to escape from antibody neutralization3–6 and reduce vaccine protection from infection7,8. The extent to which other components of the adaptive response such as T cells may still target Omicron and contribute to protection from severe outcomes is unknown. We assessed the ability of T cells to react with Omicron spike in participants who were vaccinated with Ad26.CoV2.S, BNT162b2, or unvaccinated convalescent COVID-19 patients (n=70). We found that 70-80{\%} of the CD4+ and CD8+ T cell response to spike was maintained across study groups. Moreover, the magnitude of Omicron cross-reactive T cells was similar to Beta and Delta variants, despite Omicron harboring considerably more mutations. In Omicron-infected hospitalized patients (n=19), there were comparable T cell responses to ancestral spike, nucleocapsid and membrane proteins to those patients hospitalized in previous waves dominated by the ancestral, Beta or Delta variants (n=49). Thus, despite Omicron's extensive mutations and reduced susceptibility to neutralizing antibodies, the majority of T cell responses, induced by vaccination or infection, cross-recognize the variant. It remains to be determined whether well-preserved T cell immunity to Omicron contributes to protection from severe COVID-19, and is linked to early clinical observations from South Africa and elsewhere9–12.},
author = {Keeton, Roanne and Tincho, Marius B and Ngomti, Amkele and Baguma, Richard and Benede, Ntombi and Suzuki, Akiko and Khan, Khadija and Cele, Sandile and Bernstein, Mallory and Karim, Farina and Madzorera, Sharon V and Moyo-Gwete, Thandeka and Mennen, Mathilda and Skelem, Sango and Adriaanse, Marguerite and Mutithu, Daniel and Aremu, Olukayode and Stek, Cari and du Bruyn, Elsa and {Van Der Mescht}, Mieke A and de Beer, Zelda and de Villiers, Talita R and Bodenstein, Annie and van den Berg, Gretha and Mendes, Adriano and Strydom, Amy and Venter, Marietjie and Giandhari, Jennifer and Naidoo, Yeshnee and Pillay, Sureshnee and Tegally, Houriiyah and Grifoni, Alba and Weiskopf, Daniela and Sette, Alessandro and Wilkinson, Robert J and de Oliveira, Tulio and Bekker, Linda-Gail and Gray, Glenda and Ueckermann, Veronica and Rossouw, Theresa and Boswell, Michael T and Bihman, Jinal and Moore, Penny L and Sigal, Alex and Ntusi, Ntobeko A B and Burgers, Wendy A and Riou, Catherine},
doi = {10.1038/s41586-022-04460-3},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Keeton et al. - 2022 - T cell responses to SARS-CoV-2 spike cross-recognize Omicron.pdf:pdf},
issn = {1476-4687},
journal = {Nature},
keywords = {2,CoV,Lymphocyte activation,OA,SARS,Viral infection,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {jan},
pages = {488--492},
pmid = {35102311},
publisher = {Nature Publishing Group},
title = {{T cell responses to SARS-CoV-2 spike cross-recognize Omicron}},
url = {https://www.nature.com/articles/s41586-022-04460-3},
volume = {603},
year = {2022}
}

The SARS-CoV-2 Omicron variant has multiple Spike (S) protein mutations1,2 that contribute to escape from antibody neutralization3–6 and reduce vaccine protection from infection7,8. The extent to which other components of the adaptive response such as T cells may still target Omicron and contribute to protection from severe outcomes is unknown. We assessed the ability of T cells to react with Omicron spike in participants who were vaccinated with Ad26.CoV2.S, BNT162b2, or unvaccinated convalescent COVID-19 patients (n=70). We found that 70-80% of the CD4+ and CD8+ T cell response to spike was maintained across study groups. Moreover, the magnitude of Omicron cross-reactive T cells was similar to Beta and Delta variants, despite Omicron harboring considerably more mutations. In Omicron-infected hospitalized patients (n=19), there were comparable T cell responses to ancestral spike, nucleocapsid and membrane proteins to those patients hospitalized in previous waves dominated by the ancestral, Beta or Delta variants (n=49). Thus, despite Omicron's extensive mutations and reduced susceptibility to neutralizing antibodies, the majority of T cell responses, induced by vaccination or infection, cross-recognize the variant. It remains to be determined whether well-preserved T cell immunity to Omicron contributes to protection from severe COVID-19, and is linked to early clinical observations from South Africa and elsewhere9–12.

@article{Gausi2022,
abstract = {Background: The WHO-endorsed shorter-course regimen for MDR-TB includes high-dose isoniazid. The pharma-cokinetics of high-dose isoniazid within MDR-TB regimens has not been well described. Objectives: To characterize isoniazid pharmacokinetics at 5-15 mg/kg as monotherapy or as part of the MDR-TB treatment regimen. Methods: We used non-linear mixed-effects modelling to evaluate the combined data from INHindsight, a 7 day early bactericidal activity study with isoniazid monotherapy, and PODRtb, an observational study of patients on MDR-TB treatment including terizidone, pyrazinamide, moxifloxacin, kanamycin, ethionamide and/or isoniazid. Results: A total of 58 and 103 participants from the INHindsight and PODRtb studies, respectively, were included in the analysis. A two-compartment model with hepatic elimination best described the data. N-acetyltransfer-ase 2 (NAT2) genotype caused multi-modal clearance, and saturable first-pass was observed beyond 10 mg/kg dosing. Saturable isoniazid kinetics predicted an increased exposure of approximately 50{\%} beyond linearity at 20 mg/kg dosing. Participants treated with the MDR-TB regimen had a 65.6{\%} lower AUC compared with participants on monotherapy. Ethionamide co-administration was associated with a 29{\%} increase in isoniazid AUC. Conclusions: Markedly lower isoniazid exposures were observed in participants on combination MDR-TB treatment compared with monotherapy. Isoniazid displays saturable kinetics at doses .10 mg/kg. The safety implications of these phenomena remain unclear.},
author = {Gausi, Kamunkhwala and Chirehwa, Maxwell and Ignatius, Elisa H and Court, Richard and Sun, Xin and Moran, Laura and Hafner, Richard and Wiesner, Lubbe and Rosenkranz, Susan L and de Jager, Veronique and de Vries, Nihal and Harding, Joseph and Gumbo, Tawanda and Swindells, Susan and Diacon, Andreas and Dooley, Kelly E and McIlleron, Helen and Denti, Paolo},
doi = {10.1093/JAC/DKAC188},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Gausi et al. - 2022 - Pharmacokinetics of standard versus high-dose isoniazid for treatment of multidrug-resistant tuberculosis.pdf:pdf},
issn = {0305-7453},
journal = {Journal of Antimicrobial Chemotherapy},
keywords = {fund{\_}not{\_}ack,original},
mendeley-tags = {fund{\_}not{\_}ack,original},
month = {aug},
number = {9},
pages = {2489--2499},
pmid = {35678468},
publisher = {Oxford Academic},
title = {{Pharmacokinetics of standard versus high-dose isoniazid for treatment of multidrug-resistant tuberculosis}},
url = {https://academic.oup.com/jac/article/77/9/2489/6604654},
volume = {77},
year = {2022}
}

Background: The WHO-endorsed shorter-course regimen for MDR-TB includes high-dose isoniazid. The pharma-cokinetics of high-dose isoniazid within MDR-TB regimens has not been well described. Objectives: To characterize isoniazid pharmacokinetics at 5-15 mg/kg as monotherapy or as part of the MDR-TB treatment regimen. Methods: We used non-linear mixed-effects modelling to evaluate the combined data from INHindsight, a 7 day early bactericidal activity study with isoniazid monotherapy, and PODRtb, an observational study of patients on MDR-TB treatment including terizidone, pyrazinamide, moxifloxacin, kanamycin, ethionamide and/or isoniazid. Results: A total of 58 and 103 participants from the INHindsight and PODRtb studies, respectively, were included in the analysis. A two-compartment model with hepatic elimination best described the data. N-acetyltransfer-ase 2 (NAT2) genotype caused multi-modal clearance, and saturable first-pass was observed beyond 10 mg/kg dosing. Saturable isoniazid kinetics predicted an increased exposure of approximately 50% beyond linearity at 20 mg/kg dosing. Participants treated with the MDR-TB regimen had a 65.6% lower AUC compared with participants on monotherapy. Ethionamide co-administration was associated with a 29% increase in isoniazid AUC. Conclusions: Markedly lower isoniazid exposures were observed in participants on combination MDR-TB treatment compared with monotherapy. Isoniazid displays saturable kinetics at doses .10 mg/kg. The safety implications of these phenomena remain unclear.

@article{Dangarembizi2022,
abstract = {The emergence of deadly fungal infections in Africa is primarily driven by a disproportionately high burden of human immunodeficiency virus (HIV) infections, lack of access to quality health care and the unavailability of effective antifungal drugs. Immunocompromised people in Africa are therefore at high risk of infection from opportunistic fungal pathogens such as Cryptococcus neoformans and Pneumocystis jirovecii, which are associated with high morbidity, mortality, and related socioeconomic impacts. Other emerging fungal threats include Emergomyces spp., Histoplasma spp., Blastomyces spp., and healthcare-associated multi-drug resistant Candida auris. Socioeconomic development and the Covid-19 pandemic may influence shifts in epidemiology of invasive fungal diseases on the continent. This review discusses the epidemiology, clinical manifestations, and current management strategies available for these emerging fungal diseases in Africa. We also discuss gaps in knowledge, policy, and research to inform future efforts at managing these fungal threats},
author = {Dangarembizi, Rachael and Wasserman, Sean and Hoving, Jennifer Claire},
doi = {10.1111/PIM.12953},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Dangarembizi, Wasserman, Hoving - 2022 - Emerging and re-emerging fungal threats in Africa.pdf:pdf},
issn = {1365-3024},
journal = {Parasite Immunology},
keywords = {dimorphic fungal pathogens,emerging fungi,fund{\_}ack,fungal pathogens,opportunistic fungal infections,review},
mendeley-tags = {fund{\_}ack,review},
month = {sep},
pages = {e12953},
pmid = {36175380},
publisher = {John Wiley {\&} Sons, Ltd},
title = {{Emerging and re-emerging fungal threats in Africa}},
url = {https://onlinelibrary.wiley.com/doi/full/10.1111/pim.12953 https://onlinelibrary.wiley.com/doi/abs/10.1111/pim.12953 https://onlinelibrary.wiley.com/doi/10.1111/pim.12953},
year = {2022}
}

The emergence of deadly fungal infections in Africa is primarily driven by a disproportionately high burden of human immunodeficiency virus (HIV) infections, lack of access to quality health care and the unavailability of effective antifungal drugs. Immunocompromised people in Africa are therefore at high risk of infection from opportunistic fungal pathogens such as Cryptococcus neoformans and Pneumocystis jirovecii, which are associated with high morbidity, mortality, and related socioeconomic impacts. Other emerging fungal threats include Emergomyces spp., Histoplasma spp., Blastomyces spp., and healthcare-associated multi-drug resistant Candida auris. Socioeconomic development and the Covid-19 pandemic may influence shifts in epidemiology of invasive fungal diseases on the continent. This review discusses the epidemiology, clinical manifestations, and current management strategies available for these emerging fungal diseases in Africa. We also discuss gaps in knowledge, policy, and research to inform future efforts at managing these fungal threats

@article{Omondi2022,
abstract = {Helminth infection-driven changes to immunity in the female reproductive tract (FRT) is an immune axis that is currently understudied but can have major implications for the control of FRT infections. Here we address how human hookworm infection associates with vaginal immune profile and risk of Human papillomavirus (HPV) infection. Stool, blood, cervical swabs and vaginal flushes were collected from women from the Central region of Togo to screen for hookworms (Ancylostoma duodenale) and high carcinogenic risk HPV types, via Kato Katz and PCR, respectively. Cytokine, chemokine and immunoglobulin levels were analysed in cervicovaginal lavages and plasma samples. A pronounced mixed Type 1/Type 2 immune response was detected in the vaginal fluids of women with hookworm infection and this immune signature was a notable feature in hookworm-HPV co-infected women. Moreover, hookworm infection is positively associated with increased risk and load of HPV infection. These findings highlight helminth infection as a significant risk factor for acquiring a sexually transmitted viral infection and potentially raising the risk of subsequent pathology.},
author = {Omondi, Millicent A and Kamassa, Eya H and Katawa, Gnatoulma and Tchopba, Christ{\`{e}}le N and Vogelbusch, Celina and Parcina, Marijo and Tchadi{\'{e}}, Edlom P and Amessoudji, Oukoe M and Arndts, Kathrin and Karou, Simplice D and Ameyapoh, Yaovi and Kolou, Malew{\'{e}} and Hoerauf, Achim and Layland, Laura E and Horsnell, William G C and Ritter, Manuel},
doi = {10.3389/FIMMU.2022.1009968},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Omondi et al. - 2022 - Hookworm infection associates with a vaginal Type 1Type 2 immune signature and increased HPV load.pdf:pdf},
issn = {1664-3224},
journal = {Frontiers in Immunology},
keywords = {HPV - human papillomavirus,Helminths,Immune Modulation,OA,Sexually-transmitted diseases,fund{\_}ack,hookworm,original,type 1 and type 2 immunity},
mendeley-tags = {OA,fund{\_}ack,original},
month = {oct},
pages = {1009968},
publisher = {Frontiers},
title = {{Hookworm infection associates with a vaginal Type 1/Type 2 immune signature and increased HPV load}},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2022.1009968/full},
volume = {13},
year = {2022}
}

Helminth infection-driven changes to immunity in the female reproductive tract (FRT) is an immune axis that is currently understudied but can have major implications for the control of FRT infections. Here we address how human hookworm infection associates with vaginal immune profile and risk of Human papillomavirus (HPV) infection. Stool, blood, cervical swabs and vaginal flushes were collected from women from the Central region of Togo to screen for hookworms (Ancylostoma duodenale) and high carcinogenic risk HPV types, via Kato Katz and PCR, respectively. Cytokine, chemokine and immunoglobulin levels were analysed in cervicovaginal lavages and plasma samples. A pronounced mixed Type 1/Type 2 immune response was detected in the vaginal fluids of women with hookworm infection and this immune signature was a notable feature in hookworm-HPV co-infected women. Moreover, hookworm infection is positively associated with increased risk and load of HPV infection. These findings highlight helminth infection as a significant risk factor for acquiring a sexually transmitted viral infection and potentially raising the risk of subsequent pathology.

@article{Kieswetter2022,
abstract = {Background: Previously, we evaluated the intracellular mycobactericidal activity of the minor groove binder, S-MGB-364 against the clinical Mycobacterium tuberculosis (Mtb) strain HN878 in macrophages. Objectives: To assess the mycobactericidal activity of S-MGB-364 in Mtb-infected mice. Further, we investigated a plausible DNA binding mechanism of action of S-MGB-364. Methods: The anti-TB and host immune effects of intranasal S-MGB-364 or S-MGB-364 encapsulated in non-ionic surfactant vesicles (NIV) were assessed in Mtb-infected mice by cfu enumeration, ELISA, histology, and flow cytometry. DNA binding was examined using native mass spectrometry and UV-vis thermal melt determination. S-MGB interference with DNA-centric biological events was assessed using a representative panel of Mtb and human topoisomerase I, and gyrase assays. Results: S-MGB-364 bound strongly to DNA as a dimer, significantly increasing the stability of the DNA:S-MGB complex compared with DNA alone. Moreover, S-MGB-364 inhibited the relaxation of Mtb topoisomerase I but not the human form. In macrophages, S-MGB-364 or S-MGB-364-NIV did not cause DNA damage as shown by the low $\gamma$-H2AX expression. Importantly, in the lungs, the intranasal administration of S-MGB-364 or S-MGB-364-NIV formulation in Mtb-infected mice was non-toxic and resulted in a 1 log cfu reduction in mycobacter-ial burden, reduced the expression of proinflammatory cytokines/chemokines, altered immune cell recruitment, and importantly reduced recruitment of neutrophils. Conclusions: Together, these data provide proof of concept for S-MGBs as novel anti-TB therapeutics in vivo.},
author = {Kieswetter, Nathan S and Ozturk, Mumin and Hlaka, Lerato and Chia, Julius Ebua and Nichol, Ryan J O and Cross, Jasmine M and McGee, Leah M C and Tyson-Hirst, Izaak and Beveridge, Rebecca and Brombacher, Frank and Carter, Katharine C and Suckling, Colin J and Scott, Fraser J and Guler, Reto},
doi = {10.1093/JAC/DKAC001},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Kieswetter et al. - 2022 - Intranasally administered S-MGB-364 displays antitubercular activity and modulates the host immune response t.pdf:pdf},
issn = {0305-7453},
journal = {Journal of Antimicrobial Chemotherapy},
keywords = {OA,antitubercular agents,chemical surfactants,chemokines,cytokine,dimers,dna,dna topoisomerases,enzyme-linked immunosorbent assay,flow cytometry,fund{\_}ack,histology,immune response,infections,intranasal administration,lung,macrophages,mass spectrometry,mice,mycobacterium tuberculosis,neutrophils,noninvasive ventilation,original,pharmacokinetics,proof of concept studies,pulmonary surfactants,tuberculosis,type i,vaccine information sheets,vesicle},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jan},
number = {4},
pages = {1061--1071},
pmid = {35084027},
publisher = {Oxford University Press (OUP)},
title = {{Intranasally administered S-MGB-364 displays antitubercular activity and modulates the host immune response to \textit{Mycobacterium tuberculosis} infection}},
url = {https://academic.oup.com/jac/advance-article/doi/10.1093/jac/dkac001/6515318},
volume = {77},
year = {2022}
}

Background: Previously, we evaluated the intracellular mycobactericidal activity of the minor groove binder, S-MGB-364 against the clinical Mycobacterium tuberculosis (Mtb) strain HN878 in macrophages. Objectives: To assess the mycobactericidal activity of S-MGB-364 in Mtb-infected mice. Further, we investigated a plausible DNA binding mechanism of action of S-MGB-364. Methods: The anti-TB and host immune effects of intranasal S-MGB-364 or S-MGB-364 encapsulated in non-ionic surfactant vesicles (NIV) were assessed in Mtb-infected mice by cfu enumeration, ELISA, histology, and flow cytometry. DNA binding was examined using native mass spectrometry and UV-vis thermal melt determination. S-MGB interference with DNA-centric biological events was assessed using a representative panel of Mtb and human topoisomerase I, and gyrase assays. Results: S-MGB-364 bound strongly to DNA as a dimer, significantly increasing the stability of the DNA:S-MGB complex compared with DNA alone. Moreover, S-MGB-364 inhibited the relaxation of Mtb topoisomerase I but not the human form. In macrophages, S-MGB-364 or S-MGB-364-NIV did not cause DNA damage as shown by the low $γ$-H2AX expression. Importantly, in the lungs, the intranasal administration of S-MGB-364 or S-MGB-364-NIV formulation in Mtb-infected mice was non-toxic and resulted in a 1 log cfu reduction in mycobacter-ial burden, reduced the expression of proinflammatory cytokines/chemokines, altered immune cell recruitment, and importantly reduced recruitment of neutrophils. Conclusions: Together, these data provide proof of concept for S-MGBs as novel anti-TB therapeutics in vivo.

@article{Wills2022a,
abstract = {Background Randomised controlled trials (RCTs) have reported inconsistent effects from intensified anticoagulation on clinical outcomes in Covid-19. We performed an aggregate data meta-analysis from available trials to quantify effect on non-fatal and fatal outcomes and identify subgroups who may benefit. Methods We searched multiple databases for RCTs comparing intensified (intermediate or therapeutic dose) versus standard prophylactic dose anticoagulation in adults with laboratory-confirmed Covid-19 through 19 January 2022. The primary efficacy outcome was all-cause mortality at end of follow-up or discharge. We used random effects meta-analysis to estimate pooled risk ratios for mortality, thrombotic, and bleeding events, and performed subgroup analysis for clinical setting and dose of intensified anticoagulation. Results Eleven RCTs were included (n = 5873). Intensified anticoagulation was not associated with a reduction in mortality for up to 45 days compared with prophylactic anticoagulation: 17.5{\%} (501/2861) died in the intensified anticoagulation group and 18.8{\%} (513/2734) died in the prophylactic anticoagulation group, relative risk (RR) 0.93; 95{\%}CI, 0.79 - 1.10. On subgroup analysis, there was a possible signal of mortality reduction for inpatients admitted to general wards, although with low precision and high heterogeneity (5 studies; RR 0.84; 95{\%} CI, 0.49 - 1.44; I 2 = 75{\%}) and not significantly different to studies performed in the ICU (interaction P = 0.51). Risk of venous thromboembolism was reduced with intensified anticoagulation compared with prophylaxis (8 studies; RR 0.53, 95{\%}CI 0.41 - 0.69; I 2 = 0{\%}). This effect was driven by therapeutic rather than intermediate dosing on subgroup analysis (interaction P =0.04). Major bleeding was increased with use of intensified anticoagulation (RR 1.73, 95{\%} CI 1.17 - 2.56) with no interaction for dosing and clinical setting. Conclusion Intensified anticoagulation has no effect on short term mortality among hospitalised adults with Covid-19 and is associated with increased risk of bleeding. The observed reduction in venous thromboembolism risk and trend towards reduced mortality in non-ICU hospitalised patients requires exploration in additional RCTs. Summary In this aggregate data meta-analysis, use of intensified anticoagulation had no effect on short term mortality among hospitalised adults with Covid-19 and was associated with increased risk of bleeding.},
author = {Wills, Nicola K and Nair, Nikhil and Patel, Kashyap and Sikder, Omaike and Adriaanse, Marguerite and Eikelboom, John and Wasserman, Sean},
doi = {10.1093/OFID/OFAC285},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Wills et al. - 2022 - Efficacy and safety of intensified versus standard prophylactic anticoagulation therapy in patients with coronavir.pdf:pdf},
journal = {Open Forum Infectious Diseases},
keywords = {COVID-19,OA,bleeding,fund{\_}ack,intensified anticoagulation,mortality,review,thrombosis},
mendeley-tags = {OA,fund{\_}ack,review},
month = {jul},
number = {7},
pages = {ofac285},
pmid = {35291298},
publisher = {Oxford Academic},
title = {{Efficacy and safety of intensified versus standard prophylactic anticoagulation therapy in patients with coronavirus disease 2019: a systematic review and meta-analysis}},
url = {https://academic.oup.com/ofid/article/9/7/ofac285/6603481},
volume = {9},
year = {2022}
}

Background Randomised controlled trials (RCTs) have reported inconsistent effects from intensified anticoagulation on clinical outcomes in Covid-19. We performed an aggregate data meta-analysis from available trials to quantify effect on non-fatal and fatal outcomes and identify subgroups who may benefit. Methods We searched multiple databases for RCTs comparing intensified (intermediate or therapeutic dose) versus standard prophylactic dose anticoagulation in adults with laboratory-confirmed Covid-19 through 19 January 2022. The primary efficacy outcome was all-cause mortality at end of follow-up or discharge. We used random effects meta-analysis to estimate pooled risk ratios for mortality, thrombotic, and bleeding events, and performed subgroup analysis for clinical setting and dose of intensified anticoagulation. Results Eleven RCTs were included (n = 5873). Intensified anticoagulation was not associated with a reduction in mortality for up to 45 days compared with prophylactic anticoagulation: 17.5% (501/2861) died in the intensified anticoagulation group and 18.8% (513/2734) died in the prophylactic anticoagulation group, relative risk (RR) 0.93; 95%CI, 0.79 - 1.10. On subgroup analysis, there was a possible signal of mortality reduction for inpatients admitted to general wards, although with low precision and high heterogeneity (5 studies; RR 0.84; 95% CI, 0.49 - 1.44; I 2 = 75%) and not significantly different to studies performed in the ICU (interaction P = 0.51). Risk of venous thromboembolism was reduced with intensified anticoagulation compared with prophylaxis (8 studies; RR 0.53, 95%CI 0.41 - 0.69; I 2 = 0%). This effect was driven by therapeutic rather than intermediate dosing on subgroup analysis (interaction P =0.04). Major bleeding was increased with use of intensified anticoagulation (RR 1.73, 95% CI 1.17 - 2.56) with no interaction for dosing and clinical setting. Conclusion Intensified anticoagulation has no effect on short term mortality among hospitalised adults with Covid-19 and is associated with increased risk of bleeding. The observed reduction in venous thromboembolism risk and trend towards reduced mortality in non-ICU hospitalised patients requires exploration in additional RCTs. Summary In this aggregate data meta-analysis, use of intensified anticoagulation had no effect on short term mortality among hospitalised adults with Covid-19 and was associated with increased risk of bleeding.

@article{Mutavhatsindi2022a,
abstract = {Objectives: To better understand the pathogenesis of pericardial tuberculosis (PCTB), we sought to characterize the systemic inflammatory profile in HIV-1-infected participants with latent TB infection (LTBI), pulmonary TB (PTB) and PCTB. Methods: Using Luminex, we measured 39 analytes in pericardial fluid (PCF) and paired plasma from 18 PCTB participants, and plasma from 16 LTBI and 20 PTB. Follow-up plasma samples were also obtained from PTB and PCTB participants. HLA-DR expression on Mtb-specific CD4 T cells was measured in baseline samples using flow cytometry. Results: Assessment of the overall systemic inflammatory profile by principal component analysis showed that the inflammatory profile of active TB participants was distinct from the LTBI group, while PTB patients could not be distinguished from those with PCTB. In the LTBI group, 12 analytes showed a positive association with plasma HIV-1 viral load, and most of these associations were lost in the diseased groups. When comparing the inflammatory profile between PCF and paired blood, we found that the concentrations of most analytes (24/39) were elevated at site of disease. However, the inflammatory profile in PCF partially mirrored inflammatory events in the blood. After TB treatment completion, the overall plasma inflammatory profile reverted to those observed in the LTBI group. Lastly, HLA-DR expression showed the best performance for TB diagnosis compared to previously described biosignatures built from soluble markers. Conclusion: Our results describe the inflammatory profile associated with PTB and PCTB and emphasize the potential role of HLA-DR as a promising biomarker for TB diagnosis. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest.},
author = {Mutavhatsindi, Hygon and Bruyn, Elsa Du and Ruzive, Sheena and Howlett, Patrick and Sher, Alan and Mayer-Barber, Katrin D and Barber, Daniel L and Ntsekhe, Mpiko and Wilkinson, Robert J and Riou, Catherine},
doi = {10.1101/2022.10.21.513232},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Mutavhatsindi et al. - 2022 - Blood and site of disease inflammatory profiles differ in HIV-1-infected pericardial tuberculosis patients.pdf:pdf},
journal = {bioRxiv},
keywords = {51,Inflammatory profile,OA,Pericardial tuberculosis,diagnosis,fund{\_}ack,original,site of disease},
mendeley-tags = {OA,fund{\_}ack,original},
month = {oct},
pages = {2022.10.21.513232},
publisher = {Cold Spring Harbor Laboratory},
title = {{Blood and site of disease inflammatory profiles differ in HIV-1-infected pericardial tuberculosis patients}},
url = {https://www.biorxiv.org/content/10.1101/2022.10.21.513232v1 https://www.biorxiv.org/content/10.1101/2022.10.21.513232v1.abstract},
year = {2022}
}

Objectives: To better understand the pathogenesis of pericardial tuberculosis (PCTB), we sought to characterize the systemic inflammatory profile in HIV-1-infected participants with latent TB infection (LTBI), pulmonary TB (PTB) and PCTB. Methods: Using Luminex, we measured 39 analytes in pericardial fluid (PCF) and paired plasma from 18 PCTB participants, and plasma from 16 LTBI and 20 PTB. Follow-up plasma samples were also obtained from PTB and PCTB participants. HLA-DR expression on Mtb-specific CD4 T cells was measured in baseline samples using flow cytometry. Results: Assessment of the overall systemic inflammatory profile by principal component analysis showed that the inflammatory profile of active TB participants was distinct from the LTBI group, while PTB patients could not be distinguished from those with PCTB. In the LTBI group, 12 analytes showed a positive association with plasma HIV-1 viral load, and most of these associations were lost in the diseased groups. When comparing the inflammatory profile between PCF and paired blood, we found that the concentrations of most analytes (24/39) were elevated at site of disease. However, the inflammatory profile in PCF partially mirrored inflammatory events in the blood. After TB treatment completion, the overall plasma inflammatory profile reverted to those observed in the LTBI group. Lastly, HLA-DR expression showed the best performance for TB diagnosis compared to previously described biosignatures built from soluble markers. Conclusion: Our results describe the inflammatory profile associated with PTB and PCTB and emphasize the potential role of HLA-DR as a promising biomarker for TB diagnosis. ### Competing Interest Statement The authors have declared no competing interest.

@article{Griesel2021a,
abstract = {AIM Dolutegravir is associated with more weight gain than efavirenz in people starting antiretroviral therapy (ART). We investigated the concentration-response relationships of efavirenz and dolutegravir with weight gain. METHODS We determined concentration-response relationships of dolutegravir and efavirenz (both combined with tenofovir disoproxil fumarate and emtricitabine) with changes in weight and fat distribution, derived from dual-energy x-ray absorptiometry scans, in a nested study of ART-na{\"{i}}ve participants from a randomised controlled trial. Pharmacokinetic parameters used in analyses were efavirenz mid-dosing interval (MDI) concentrations and estimated dolutegravir area under the concentration-time curve (AUC0-24) using a population pharmacokinetic model developed in the study population. Study outcomes were percentage changes from baseline to week 48 in weight, and visceral and subcutaneous adipose tissue (VAT and SAT) mass. RESULTS Pharmacokinetic data were available for 158 and 233 participants in the efavirenz arm and dolutegravir arms respectively; 57.0{\%} were women. On multivariable linear regression there were independent negative associations between efavirenz concentrations and changes in both weight (P {\textless}0.001) and SAT mass (P = 0.002).; estimated dolutegravir AUC0-24 was not associated with change in weight (P = 0.109) but was negatively associated with change in VAT mass (P = 0.025). CONCLUSION We found an independent negative concentration-response relationship between efavirenz concentrations and weight change in ART-na{\"{i}}ve participants. Dolutegravir concentrations were not independently associated with weight change. These findings suggest that weight gain differences between efavirenz and dolutegravir are driven by efavirenz toxicity impairing weight gain rather than by off-target effects of dolutegravir causing weight gain.},
author = {Griesel, Rulan and Kawuma, Aida N and Wasmann, Roeland and Sokhela, Simiso and Akpomiemie, Godspower and Venter, W D Francois and Wiesner, Lubbe and Denti, Paolo and Sinxadi, Phumla and Maartens, Gary},
doi = {10.1111/BCP.15177},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Griesel et al. - 2022 - Concentration-response relationships of dolutegravir and efavirenz with weight change after starting antiretrovi.pdf:pdf},
issn = {1365-2125},
journal = {British Journal of Clinical Pharmacology},
keywords = {concentration,dolutegravir,efavirenz,fund{\_}ack,original,response relationship,subcutaneous adipose tissue,visceral adipose tissue,weight gain},
mendeley-tags = {fund{\_}ack,original},
month = {dec},
number = {3},
pages = {883--893},
pmid = {34954840},
publisher = {John Wiley {\&} Sons, Ltd},
title = {{Concentration-response relationships of dolutegravir and efavirenz with weight change after starting antiretroviral therapy}},
url = {https://onlinelibrary.wiley.com/doi/full/10.1111/bcp.15177 https://onlinelibrary.wiley.com/doi/abs/10.1111/bcp.15177 https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.15177},
volume = {88},
year = {2022}
}

AIM Dolutegravir is associated with more weight gain than efavirenz in people starting antiretroviral therapy (ART). We investigated the concentration-response relationships of efavirenz and dolutegravir with weight gain. METHODS We determined concentration-response relationships of dolutegravir and efavirenz (both combined with tenofovir disoproxil fumarate and emtricitabine) with changes in weight and fat distribution, derived from dual-energy x-ray absorptiometry scans, in a nested study of ART-naïve participants from a randomised controlled trial. Pharmacokinetic parameters used in analyses were efavirenz mid-dosing interval (MDI) concentrations and estimated dolutegravir area under the concentration-time curve (AUC0-24) using a population pharmacokinetic model developed in the study population. Study outcomes were percentage changes from baseline to week 48 in weight, and visceral and subcutaneous adipose tissue (VAT and SAT) mass. RESULTS Pharmacokinetic data were available for 158 and 233 participants in the efavirenz arm and dolutegravir arms respectively; 57.0% were women. On multivariable linear regression there were independent negative associations between efavirenz concentrations and changes in both weight (P \textless0.001) and SAT mass (P = 0.002).; estimated dolutegravir AUC0-24 was not associated with change in weight (P = 0.109) but was negatively associated with change in VAT mass (P = 0.025). CONCLUSION We found an independent negative concentration-response relationship between efavirenz concentrations and weight change in ART-naïve participants. Dolutegravir concentrations were not independently associated with weight change. These findings suggest that weight gain differences between efavirenz and dolutegravir are driven by efavirenz toxicity impairing weight gain rather than by off-target effects of dolutegravir causing weight gain.

@article{Eikelboom2022a,
abstract = {BACKGROUND COVID-19 disease is accompanied by a dysregulated immune response and hypercoagulability. The Anti-Coronavirus Therapies (ACT) inpatient trial aimed to evaluate anti-inflammatory therapy with colchicine and antithrombotic therapy with the combination of rivaroxaban and aspirin for prevention of disease progression in patients hospitalised with COVID-19. METHODS The ACT inpatient, open-label, 2 × 2 factorial, randomised, controlled trial was done at 62 clinical centres in 11 countries. Patients aged at least 18 years with symptomatic, laboratory confirmed COVID-19 who were within 72 h of hospitalisation or worsening clinically if already hospitalised were randomly assigned (1:1) to receive colchicine 1{\textperiodcentered}2 mg followed by 0{\textperiodcentered}6 mg 2 h later and then 0{\textperiodcentered}6 mg twice daily for 28 days versus usual care; and in a second (1:1) randomisation, to the combination of rivaroxaban 2{\textperiodcentered}5 mg twice daily plus aspirin 100 mg once daily for 28 days versus usual care. Investigators and patients were not masked to treatment allocation. The primary outcome, assessed at 45 days in the intention-to-treat population, for the colchicine randomisation was the composite of the need for high-flow oxygen, mechanical ventilation, or death; and for the rivaroxaban plus aspirin randomisation was the composite of major thrombosis (myocardial infarction, stroke, acute limb ischaemia, or pulmonary embolism), the need for high-flow oxygen, mechanical ventilation, or death. The trial is registered at www. CLINICALTRIALS gov, NCT04324463 and is ongoing. FINDINGS Between Oct 2, 2020, and Feb 10, 2022, at 62 sites in 11 countries, 2749 patients were randomly assigned to colchicine or control and the combination of rivaroxaban and aspirin or to the control. 2611 patients were included in the analysis of colchicine (n=1304) versus control (n=1307); 2119 patients were included in the analysis of rivaroxaban and aspirin (n=1063) versus control (n=1056). Follow-up was more than 98{\%} complete. Overall, 368 (28{\textperiodcentered}2{\%}) of 1304 patients allocated to colchicine and 356 (27{\textperiodcentered}2{\%}) of 1307 allocated to control had a primary outcome (hazard ratio [HR] 1{\textperiodcentered}04, 95{\%} CI 0{\textperiodcentered}90-1{\textperiodcentered}21, p=0{\textperiodcentered}58); and 281 (26{\textperiodcentered}4{\%}) of 1063 patients allocated to the combination of rivaroxaban and aspirin and 300 (28{\textperiodcentered}4{\%}) of 1056 allocated to control had a primary outcome (HR 0{\textperiodcentered}92, 95{\%} CI 0{\textperiodcentered}78-1{\textperiodcentered}09, p=0{\textperiodcentered}32). Results were consistent in subgroups defined by vaccination status, disease severity at baseline, and timing of randomisation in relation to onset of symptoms. There was no increase in the number of patients who had at least one serious adverse event for colchicine versus control groups (87 [6{\textperiodcentered}7{\%}] of 1304 vs 90 [6{\textperiodcentered}9{\%}] of 1307) or with rivaroxaban and aspirin versus control groups (85 [8{\textperiodcentered}0{\%}] vs 91 [8{\textperiodcentered}6{\%}]). Among patients assigned to colchicine, 8 (0{\textperiodcentered}61{\%}) had adverse events that led to discontinuation of study drug, mostly gastrointestinal in nature. 17 (1{\textperiodcentered}6{\%}) patients assigned to the combination of rivaroxaban and aspirin had bleeding compared with seven (0{\textperiodcentered}66{\%}) of those allocated to control (p=0{\textperiodcentered}042); the number of serious bleeding events was two (0{\textperiodcentered}19{\%}) versus six (0{\textperiodcentered}57{\%}), respectively (p=0{\textperiodcentered}18). No patients assigned to rivaroxaban and aspirin had serious adverse events that led to discontinuation of study drug. INTERPRETATION Among patients hospitalised with COVID-19, neither colchicine nor the combination of rivaroxaban and aspirin prevent disease progression or death. FUNDING Canadian Institutes for Health Research, Bayer, Population Health Research Institute, Hamilton Health Sciences Research Institute, Thistledown Foundation. TRANSLATIONS For the Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.},
author = {Eikelboom, John W and Jolly, Sanjit S and Belley-Cote, Emilie P and Whitlock, Richard P and Rangarajan, Sumathy and Xu, Lizhen and Heenan, Laura and Bangdiwala, Shrikant I and {Luz Diaz}, Maria and Diaz, Rafael and Yusufali, Afzalhussein and {Kumar Sharma}, Sanjib and Tarhuni, Wadea M and Hassany, Mohamed and Avezum, Alvaro and Harper, William and Wasserman, Sean and Almas, Aysha and Drapkina, Oxana and Felix, Camilo and Lopes, Renato D and Berwanger, Otavio and Lopez-Jaramillo, Patricio and Anand, Sonia S and Bosch, Jackie and Choudhri, Shurjeel and Farkouh, Michael E and Loeb, Mark and Yusuf, Salim},
doi = {10.1016/S2213-2600(22)00298-3/ATTACHMENT/0E625616-834E-4F9C-B8FB-1BE0075BA10B/MMC4.PDF},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Eikelboom et al. - 2022 - Colchicine and the combination of rivaroxaban and aspirin in patients hospitalised with COVID-19 (ACT) an open.pdf:pdf},
issn = {2213-2619},
journal = {The Lancet Respiratory Medicine},
keywords = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {oct},
number = {12},
pages = {1169--1177},
pmid = {36228641},
publisher = {Elsevier},
title = {{Colchicine and the combination of rivaroxaban and aspirin in patients hospitalised with COVID-19 (ACT): an open-label, factorial, randomised, controlled trial.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/36228641},
volume = {10},
year = {2022}
}

BACKGROUND COVID-19 disease is accompanied by a dysregulated immune response and hypercoagulability. The Anti-Coronavirus Therapies (ACT) inpatient trial aimed to evaluate anti-inflammatory therapy with colchicine and antithrombotic therapy with the combination of rivaroxaban and aspirin for prevention of disease progression in patients hospitalised with COVID-19. METHODS The ACT inpatient, open-label, 2 × 2 factorial, randomised, controlled trial was done at 62 clinical centres in 11 countries. Patients aged at least 18 years with symptomatic, laboratory confirmed COVID-19 who were within 72 h of hospitalisation or worsening clinically if already hospitalised were randomly assigned (1:1) to receive colchicine 1˙2 mg followed by 0˙6 mg 2 h later and then 0˙6 mg twice daily for 28 days versus usual care; and in a second (1:1) randomisation, to the combination of rivaroxaban 2˙5 mg twice daily plus aspirin 100 mg once daily for 28 days versus usual care. Investigators and patients were not masked to treatment allocation. The primary outcome, assessed at 45 days in the intention-to-treat population, for the colchicine randomisation was the composite of the need for high-flow oxygen, mechanical ventilation, or death; and for the rivaroxaban plus aspirin randomisation was the composite of major thrombosis (myocardial infarction, stroke, acute limb ischaemia, or pulmonary embolism), the need for high-flow oxygen, mechanical ventilation, or death. The trial is registered at www. CLINICALTRIALS gov, NCT04324463 and is ongoing. FINDINGS Between Oct 2, 2020, and Feb 10, 2022, at 62 sites in 11 countries, 2749 patients were randomly assigned to colchicine or control and the combination of rivaroxaban and aspirin or to the control. 2611 patients were included in the analysis of colchicine (n=1304) versus control (n=1307); 2119 patients were included in the analysis of rivaroxaban and aspirin (n=1063) versus control (n=1056). Follow-up was more than 98% complete. Overall, 368 (28˙2%) of 1304 patients allocated to colchicine and 356 (27˙2%) of 1307 allocated to control had a primary outcome (hazard ratio [HR] 1˙04, 95% CI 0˙90-1˙21, p=0˙58); and 281 (26˙4%) of 1063 patients allocated to the combination of rivaroxaban and aspirin and 300 (28˙4%) of 1056 allocated to control had a primary outcome (HR 0˙92, 95% CI 0˙78-1˙09, p=0˙32). Results were consistent in subgroups defined by vaccination status, disease severity at baseline, and timing of randomisation in relation to onset of symptoms. There was no increase in the number of patients who had at least one serious adverse event for colchicine versus control groups (87 [6˙7%] of 1304 vs 90 [6˙9%] of 1307) or with rivaroxaban and aspirin versus control groups (85 [8˙0%] vs 91 [8˙6%]). Among patients assigned to colchicine, 8 (0˙61%) had adverse events that led to discontinuation of study drug, mostly gastrointestinal in nature. 17 (1˙6%) patients assigned to the combination of rivaroxaban and aspirin had bleeding compared with seven (0˙66%) of those allocated to control (p=0˙042); the number of serious bleeding events was two (0˙19%) versus six (0˙57%), respectively (p=0˙18). No patients assigned to rivaroxaban and aspirin had serious adverse events that led to discontinuation of study drug. INTERPRETATION Among patients hospitalised with COVID-19, neither colchicine nor the combination of rivaroxaban and aspirin prevent disease progression or death. FUNDING Canadian Institutes for Health Research, Bayer, Population Health Research Institute, Hamilton Health Sciences Research Institute, Thistledown Foundation. TRANSLATIONS For the Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.

@article{Bonnet2022,
abstract = {Background: Tuberculous meningitis (TBM) is the most lethal and disabling form of tuberculosis (TB) particularly in sub-Saharan Africa. Current anti-TB treatment is poorly effective since TBM mortality reaches 40{\%} in HIV negative patients and up to 70{\%} in HIV co-infected patients. To reduce TBM induced morbidity and mortality, the INTENSE-TBM trial evaluates two},
author = {Bonnet, Fabrice},
doi = {10.21203/RS.3.RS-1941581/V1},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Bonnet - 2022 - Intensified tuberculosis treatment to reduce the mortality of HIV-infected and uninfected patients with tuberculosis men.pdf:pdf},
journal = {Research Square},
keywords = {Aspirin,HIV,High-dose rifampicin,Linezolid,OA,Randomized Controlled Trial,Tuberculous meningitis,fund{\_}ack,protocol},
mendeley-tags = {OA,fund{\_}ack,protocol},
month = {sep},
pages = {doi.org/10.21203/rs.3.rs--1941581/v1},
title = {{Intensified tuberculosis treatment to reduce the mortality of HIV-infected and uninfected patients with tuberculosis meningitis (INTENSE-TBM): Study protocol for a Phase III Randomized Controlled Trial}},
url = {https://www.researchsquare.com https://www.researchsquare.com/article/rs-1941581/v1},
year = {2022}
}

Background: Tuberculous meningitis (TBM) is the most lethal and disabling form of tuberculosis (TB) particularly in sub-Saharan Africa. Current anti-TB treatment is poorly effective since TBM mortality reaches 40% in HIV negative patients and up to 70% in HIV co-infected patients. To reduce TBM induced morbidity and mortality, the INTENSE-TBM trial evaluates two

@article{Porter2022,
abstract = {Severe cutaneous adverse reactions related to first-line antituberculosis drugs are associated with high mortality and long-term morbidity. Oral sequential drug challenge, as a form of drug provocation testing, helps to salvage therapy by identifying culprit drugs but is associated with risk and is costly. IFN-$\gamma$ enzyme-linked immune absorbent spot (ELISpot), an adjunctive in vitro diagnostic tool, may help to guide risk-stratification approaches. To determine the diagnostic accuracy of IFN-$\gamma$ ELISpot against full-dose sequential drug challenge, we analyzed samples collected prospectively at multiple time points in 32 patients with first-line antituberculosis drug‒associated severe cutaneous adverse reaction (81{\%} HIV infected, 25 with drug reaction with eosinophilia and systemic symptoms, and 7 with Stevens‒Johnson syndrome/toxic epidermal necrolysis). Sensitivity of IFN-$\gamma$ ELISpot was 33{\%} (4 of 12), 13{\%} (1 of 8), 11{\%} (1 of 9), and 0{\%} (0 of 4) for rifampicin, isoniazid, pyrazinamide, and ethambutol, respectively (positivity threshold ≥50 spot forming units/million cells). Specificity was 100{\%} for all the four drugs. Rifampicin IFN-$\gamma$ ELISpot sensitivity increased to 58{\%} (7 of 12) if a threshold of 20 spot forming units was used and to 75{\%} (3 of 4) when restricted to samples {\textless}12 weeks after acute severe cutaneous adverse reaction event; specificity remained 100{\%} for both. IFN-$\gamma$ ELISpot offers adequate risk stratification of rifampicin severe cutaneous adverse reaction using acute samples and lowered threshold for positivity. Given the low sensitivity of IFN-$\gamma$ ELISpot for other first-line antituberculosis drugs, additional optimization is needed to improve risk-stratification potential.},
author = {Porter, Mireille and Choshi, Phuti and Pedretti, Sarah and Chimbetete, Tafadzwa and Smith, Rhodine and Meintjes, Graeme A and Phillips, Elizabeth and Lehloenya, Rannakoe and Peter, Jonny},
doi = {10.1016/j.jid.2022.05.1059},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Porter et al. - 2022 - IFN-$\gamma$ ELISpot in severe cutaneous adverse reactions to first-line anti-tuberculosis drugs in an HIV endemic setti.pdf:pdf},
issn = {0022202X},
journal = {Journal of Investigative Dermatology},
keywords = {ART,DRESS,ELISpot,FLTB,RegiSCAR,Registry of Severe Cutaneous Adverse Reactions,SCAR,SDC,SFU,SJS/TEN,Stevens‒Johnson syndrome/toxic epidermal necrolysi,TB,antiretroviral therapy,drug reaction with eosinophilia and systemic sympt,enzyme-linked immune absorbent spot,first-line antituberculosis,fund{\_}ack,original,sequential drug challenge,severe cutaneous adverse reaction,spot-forming unit,tuberculosis},
mendeley-tags = {fund{\_}ack,original},
month = {jun},
pages = {10.1016/j.jid.2022.05.1059},
pmid = {35659939},
publisher = {Elsevier BV},
title = {{IFN-$\gamma$ ELISpot in severe cutaneous adverse reactions to first-line anti-tuberculosis drugs in an HIV endemic setting}},
url = {http://www.jidonline.org/article/S0022202X22015007/fulltext http://www.jidonline.org/article/S0022202X22015007/abstract https://www.jidonline.org/article/S0022-202X(22)01500-7/abstract},
year = {2022}
}

Severe cutaneous adverse reactions related to first-line antituberculosis drugs are associated with high mortality and long-term morbidity. Oral sequential drug challenge, as a form of drug provocation testing, helps to salvage therapy by identifying culprit drugs but is associated with risk and is costly. IFN-$γ$ enzyme-linked immune absorbent spot (ELISpot), an adjunctive in vitro diagnostic tool, may help to guide risk-stratification approaches. To determine the diagnostic accuracy of IFN-$γ$ ELISpot against full-dose sequential drug challenge, we analyzed samples collected prospectively at multiple time points in 32 patients with first-line antituberculosis drug‒associated severe cutaneous adverse reaction (81% HIV infected, 25 with drug reaction with eosinophilia and systemic symptoms, and 7 with Stevens‒Johnson syndrome/toxic epidermal necrolysis). Sensitivity of IFN-$γ$ ELISpot was 33% (4 of 12), 13% (1 of 8), 11% (1 of 9), and 0% (0 of 4) for rifampicin, isoniazid, pyrazinamide, and ethambutol, respectively (positivity threshold ≥50 spot forming units/million cells). Specificity was 100% for all the four drugs. Rifampicin IFN-$γ$ ELISpot sensitivity increased to 58% (7 of 12) if a threshold of 20 spot forming units was used and to 75% (3 of 4) when restricted to samples \textless12 weeks after acute severe cutaneous adverse reaction event; specificity remained 100% for both. IFN-$γ$ ELISpot offers adequate risk stratification of rifampicin severe cutaneous adverse reaction using acute samples and lowered threshold for positivity. Given the low sensitivity of IFN-$γ$ ELISpot for other first-line antituberculosis drugs, additional optimization is needed to improve risk-stratification potential.

@article{Brankin2022,
abstract = {The Comprehensive Resistance Prediction for Tuberculosis: an International Consortium (CRyPTIC) presents here a compendium of 15,211 Mycobacterium tuberculosis global clinical isolates, all of which have undergone whole genome sequencing (WGS) and have had their minimum inhibitory concentrations to 13 antitubercular drugs measured in a single assay. It is the largest matched phenotypic and genotypic dataset for M. tuberculosis to date. Here, we provide a summary detailing the breadth of data collected, along with a description of how the isolates were collected and uniformly processed in CRyPTIC partner laboratories across 23 countries. The compendium contains 6,814 isolates resistant to at least one drug, including 2,129 samples that fully satisfy the clinical definitions of rifampicin resistant (RR), multi-drug resistant (MDR), pre-extensively drug resistant (pre-XDR) or extensively drug resistant (XDR). Accurate prediction of resistance status (sensitive/resistant) to eight antitubercular drugs by using a genetic mutation catalogue is presented along with the presence of suspected resistance-conferring mutations for isolates resistant to the newly introduced drugs bedaquiline, clofazimine, delamanid and linezolid. Finally, a case study of rifampicin mono-resistance demonstrates how this compendium could be used to advance our genetic understanding of rare resistance phenotypes. The compendium is fully open-source and it is hoped that the dataset will facilitate and inspire future research for years to come. {\#}{\#}{\#} Competing Interest Statement E.R. is employed by Public Health England and holds an honorary contract with Imperial College London. I.F.L. is Director of the Scottish Mycobacteria Reference Laboratory. S.N. receives funding from German Center for Infection Research, Excellenz Cluster Precision Medicine in Chronic Inflammation, Leibniz Science Campus Evolutionary Medicine of the LUNG (EvoLUNG)tion EXC 2167. P.S. is a consultant at Genoscreen. T.R. is funded by NIH and DoD and receives salary support from the non-profit organization FIND. T.R. is a co-founder, board member and shareholder of Verus Diagnostics Inc, a company that was founded with the intent of developing diagnostic assays. Verus Diagnostics was not involved in any way with data collection, analysis or publication of the results. T.R. has not received any financial support from Verus Diagnostics. UCSD Conflict of Interest office has reviewed and approved T.R.s role in Verus Diagnostics Inc. T.R. is a co-inventor of a provisional patent for a TB diagnostic assay (provisional patent {\#}: 63/048.989). T.R. is a co-inventor on a patent associated with the processing of TB sequencing data (European Patent Application No. 14840432.0 {\&} USSN 14/912,918). T.R. has agreed to donate all present and future interest in and rights to royalties from this patent to UCSD to ensure that he does not receive any financial benefits from this patent. S.S. is working and holding ESOPs at HaystackAnalytics Pvt. Ltd. (Product: Using whole genome sequencing for drug susceptibility testing for Mycobacterium tuberculosis). G.F.G. is listed as an inventor on patent applications for RBD-dimer-based CoV vaccines. The patents for RBD-dimers as protein subunit vaccines for SARS-CoV-2 have been licensed to Anhui Zhifei Longcom Biopharmaceutical Co. Ltd, China.},
author = {Brankin, Alice and Malone, Kerri M and Consortium, The CRyPTIC},
doi = {10.1101/2021.09.14.460274},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Brankin, Malone, Consortium - 2022 - A data compendium of iMycobacterium tuberculosisi antibiotic resistance.pdf:pdf},
journal = {bioRxiv},
keywords = {OA,dataset,fund{\_}ack,original},
mendeley-tags = {OA,dataset,fund{\_}ack,original},
month = {mar},
pages = {2021.09.14.460274},
publisher = {Cold Spring Harbor Laboratory},
title = {{A data compendium of \textit{Mycobacterium tuberculosis} antibiotic resistance}},
url = {https://www.biorxiv.org/content/10.1101/2021.09.14.460274v3 https://www.biorxiv.org/content/10.1101/2021.09.14.460274v3.abstract},
year = {2022}
}

The Comprehensive Resistance Prediction for Tuberculosis: an International Consortium (CRyPTIC) presents here a compendium of 15,211 Mycobacterium tuberculosis global clinical isolates, all of which have undergone whole genome sequencing (WGS) and have had their minimum inhibitory concentrations to 13 antitubercular drugs measured in a single assay. It is the largest matched phenotypic and genotypic dataset for M. tuberculosis to date. Here, we provide a summary detailing the breadth of data collected, along with a description of how the isolates were collected and uniformly processed in CRyPTIC partner laboratories across 23 countries. The compendium contains 6,814 isolates resistant to at least one drug, including 2,129 samples that fully satisfy the clinical definitions of rifampicin resistant (RR), multi-drug resistant (MDR), pre-extensively drug resistant (pre-XDR) or extensively drug resistant (XDR). Accurate prediction of resistance status (sensitive/resistant) to eight antitubercular drugs by using a genetic mutation catalogue is presented along with the presence of suspected resistance-conferring mutations for isolates resistant to the newly introduced drugs bedaquiline, clofazimine, delamanid and linezolid. Finally, a case study of rifampicin mono-resistance demonstrates how this compendium could be used to advance our genetic understanding of rare resistance phenotypes. The compendium is fully open-source and it is hoped that the dataset will facilitate and inspire future research for years to come. ### Competing Interest Statement E.R. is employed by Public Health England and holds an honorary contract with Imperial College London. I.F.L. is Director of the Scottish Mycobacteria Reference Laboratory. S.N. receives funding from German Center for Infection Research, Excellenz Cluster Precision Medicine in Chronic Inflammation, Leibniz Science Campus Evolutionary Medicine of the LUNG (EvoLUNG)tion EXC 2167. P.S. is a consultant at Genoscreen. T.R. is funded by NIH and DoD and receives salary support from the non-profit organization FIND. T.R. is a co-founder, board member and shareholder of Verus Diagnostics Inc, a company that was founded with the intent of developing diagnostic assays. Verus Diagnostics was not involved in any way with data collection, analysis or publication of the results. T.R. has not received any financial support from Verus Diagnostics. UCSD Conflict of Interest office has reviewed and approved T.R.s role in Verus Diagnostics Inc. T.R. is a co-inventor of a provisional patent for a TB diagnostic assay (provisional patent #: 63/048.989). T.R. is a co-inventor on a patent associated with the processing of TB sequencing data (European Patent Application No. 14840432.0 & USSN 14/912,918). T.R. has agreed to donate all present and future interest in and rights to royalties from this patent to UCSD to ensure that he does not receive any financial benefits from this patent. S.S. is working and holding ESOPs at HaystackAnalytics Pvt. Ltd. (Product: Using whole genome sequencing for drug susceptibility testing for Mycobacterium tuberculosis). G.F.G. is listed as an inventor on patent applications for RBD-dimer-based CoV vaccines. The patents for RBD-dimers as protein subunit vaccines for SARS-CoV-2 have been licensed to Anhui Zhifei Longcom Biopharmaceutical Co. Ltd, China.

@article{Szekely2022,
abstract = {Rationale There is an urgent need for rapid, non-sputum point-of-care diagnostics to detect tuberculosis. Objectives This prospective trial in seven high tuberculosis burden countries set out to evaluate the diagnostic accuracy of the point-of-care urine-based lipoarabinomannan assay FUJIFILM SILVAMP TB LAM (FujiLAM) among inpatient and outpatient people living with HIV. Methods Diagnostic performance of FujiLAM at point of care was assessed among adult people with HIV against a mycobacterial reference standard (sputum culture, blood culture, and Xpert Ultra from urine and sputum at enrollment, and additional sputum culture ≤7 days from enrollment), an extended mycobacterial reference standard including available non-study test results, and a composite reference standard including clinical evaluation. Measurements and Main Results: Of 1624 participants enrolled, 294 (18.0{\%}) were classified as TB positive by extended mycobacterial reference standard. Median age was 40 years, median CD4 cell count was 372 cells/ul, 52{\%} were female and 78{\%} were taking antiretroviral therapy at enrollment. Overall FujiLAM sensitivity was 54.8{\%} (95{\%} CI: 49.1-60.4), and overall specificity was 85.1{\%} (83.1-86.9), against the extended mycobacterial reference standard. Sensitivity and specificity estimates varied between sites, ranging from 26.5{\%} (95{\%} CI: 17.4{\%}-38.0{\%}) to 83.3{\%} (43.6{\%}-97.0{\%}), and 75.0 (65.0{\%}-82.9{\%}) to 96.5 (92.1{\%}-98.5{\%}), respectively. Post-hoc exploratory analysis identified significant variability in the performance of the six FujiLAM lots used in this study. Conclusions Lot variability limited interpretation of FujiLAM test performance. Although the results with the current version of FujiLAM are too variable for clinical decision-making, the lipoarabinomannan biomarker still holds promise for tuberculosis diagnostics. {\#}{\#}{\#} Competing Interest Statement RS, AM, CMD and MR are or were employed by FIND, the global alliance for diagnostics at the time of the study. FIND is a not-for-profit foundation that supports the evaluation of publicly prioritized tuberculosis assays and the implementation of WHO-approved (guidance and prequalification) assays using donor grants. FIND has product evaluation agreements with several private sector companies that design diagnostics for tuberculosis and other diseases. These agreements strictly define FIND's independence and neutrality with regard to these private sector companies. TB reports patents in the field of TB detection and is a shareholder of Avelo Inc. {\#}{\#}{\#} Clinical Trial NCT04089423 {\#}{\#}{\#} Funding Statement This work was funded by the Global Health Innovative Technology Fund (GHIT Grant Number G2017-207), the KfW (Grant Number 2020 60 457), Commonwealth of Australia represented by the Department of Foreign Affairs and Trade (DFAT Grant Number 70957) and the Netherlands Enterprise Agency (Grant Number PDP15CH14). Graeme Meintjes was supported by the Wellcome Trust (098316, 214321/Z/18/Z, and 203135/Z/16/Z), and the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (Grant No 64787). Peter MacPherson was funded by Wellcome (206575/Z/17/Z). This research was funded in part by the Wellcome Trust. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ethics committees of UCT Human Research Ethics Committee, Western Cape Government Health Impact Assessment (South Africa); College of Medicine Research Support Centre (Malawi); Biomedical Research Ethics Committee, National Health Research Authority (Zambia); Infectious Disease Institute Scientific review Committee, Mulago Hospital REC, Uganda National Council for Science and Technology (Uganda); Ifakara Health Institute Scientific Committee, Tanzania Medicines and medical Devices Authority, National Institute for Medical Research (Tanzania); National Lung Hospital Ethics Committee, Ministry of Health (Viet Nam); IRB of Faculty of Medicine, Chulalongkorn University, Bangkok Metropolitan Administration Human Research Ethics Committee, Bamrasnaradura Infectious Diseases Institute (Thailand) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Individual, de-identified participant data will be shared, including data dictionaries. Other documents that have been made available include the study protocol and statistical analysis plan. Templates of the informed consent forms may be shared upon request. The data will be available immediately following publication with no end date. The data will be shared with anyone who wishes to access the data. The data will be available for any purpose of analyses. For data, please contact the corresponding author.},
author = {Sz{\'{e}}kely, Rita and Sossen, Bianca and Mukoka, Madalo and Muyoyeta, Monde and Nakabugo, Elizabeth and Hella, Jerry and Nguyen, Hung Van and Ubolyam, Sasiwimol and Chikamatsu, Kinuyo and Mac{\'{e}}, Aur{\'{e}}lien and Vermeulen, Marcia and Centner, Chad M and Nyangu, Sarah and Sanjase, Nsala and Sasamalo, Mohamed and Dinh, Huong Thi and Ngo, Anh and Manosuthi, Weerawat and Jirajariyavej, Supunnee and Mitarai, Satoshi and Nguyen, Viet Nhung and Avihingsanon, Anchalee and Reither, Klaus and Nakiyingi, Lydia and Kerkhoff, Andrew D and Macpherson, Peter and Meintjes, Graeme A and Denkinger, Claudia M and Ruhwald, Morten},
doi = {10.1101/2022.09.07.22278961},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Sz{\'{e}}kely et al. - 2022 - Multicentre accuracy trial of FUJIFILM SILVAMP TB LAM test in people with HIV reveals lot variability.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {sep},
pages = {2022.09.07.22278961},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Multicentre accuracy trial of FUJIFILM SILVAMP TB LAM test in people with HIV reveals lot variability}},
url = {https://www.medrxiv.org/content/10.1101/2022.09.07.22278961v1 https://www.medrxiv.org/content/10.1101/2022.09.07.22278961v1.abstract},
year = {2022}
}

Rationale There is an urgent need for rapid, non-sputum point-of-care diagnostics to detect tuberculosis. Objectives This prospective trial in seven high tuberculosis burden countries set out to evaluate the diagnostic accuracy of the point-of-care urine-based lipoarabinomannan assay FUJIFILM SILVAMP TB LAM (FujiLAM) among inpatient and outpatient people living with HIV. Methods Diagnostic performance of FujiLAM at point of care was assessed among adult people with HIV against a mycobacterial reference standard (sputum culture, blood culture, and Xpert Ultra from urine and sputum at enrollment, and additional sputum culture ≤7 days from enrollment), an extended mycobacterial reference standard including available non-study test results, and a composite reference standard including clinical evaluation. Measurements and Main Results: Of 1624 participants enrolled, 294 (18.0%) were classified as TB positive by extended mycobacterial reference standard. Median age was 40 years, median CD4 cell count was 372 cells/ul, 52% were female and 78% were taking antiretroviral therapy at enrollment. Overall FujiLAM sensitivity was 54.8% (95% CI: 49.1-60.4), and overall specificity was 85.1% (83.1-86.9), against the extended mycobacterial reference standard. Sensitivity and specificity estimates varied between sites, ranging from 26.5% (95% CI: 17.4%-38.0%) to 83.3% (43.6%-97.0%), and 75.0 (65.0%-82.9%) to 96.5 (92.1%-98.5%), respectively. Post-hoc exploratory analysis identified significant variability in the performance of the six FujiLAM lots used in this study. Conclusions Lot variability limited interpretation of FujiLAM test performance. Although the results with the current version of FujiLAM are too variable for clinical decision-making, the lipoarabinomannan biomarker still holds promise for tuberculosis diagnostics. ### Competing Interest Statement RS, AM, CMD and MR are or were employed by FIND, the global alliance for diagnostics at the time of the study. FIND is a not-for-profit foundation that supports the evaluation of publicly prioritized tuberculosis assays and the implementation of WHO-approved (guidance and prequalification) assays using donor grants. FIND has product evaluation agreements with several private sector companies that design diagnostics for tuberculosis and other diseases. These agreements strictly define FIND's independence and neutrality with regard to these private sector companies. TB reports patents in the field of TB detection and is a shareholder of Avelo Inc. ### Clinical Trial NCT04089423 ### Funding Statement This work was funded by the Global Health Innovative Technology Fund (GHIT Grant Number G2017-207), the KfW (Grant Number 2020 60 457), Commonwealth of Australia represented by the Department of Foreign Affairs and Trade (DFAT Grant Number 70957) and the Netherlands Enterprise Agency (Grant Number PDP15CH14). Graeme Meintjes was supported by the Wellcome Trust (098316, 214321/Z/18/Z, and 203135/Z/16/Z), and the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (Grant No 64787). Peter MacPherson was funded by Wellcome (206575/Z/17/Z). This research was funded in part by the Wellcome Trust. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ethics committees of UCT Human Research Ethics Committee, Western Cape Government Health Impact Assessment (South Africa); College of Medicine Research Support Centre (Malawi); Biomedical Research Ethics Committee, National Health Research Authority (Zambia); Infectious Disease Institute Scientific review Committee, Mulago Hospital REC, Uganda National Council for Science and Technology (Uganda); Ifakara Health Institute Scientific Committee, Tanzania Medicines and medical Devices Authority, National Institute for Medical Research (Tanzania); National Lung Hospital Ethics Committee, Ministry of Health (Viet Nam); IRB of Faculty of Medicine, Chulalongkorn University, Bangkok Metropolitan Administration Human Research Ethics Committee, Bamrasnaradura Infectious Diseases Institute (Thailand) gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Individual, de-identified participant data will be shared, including data dictionaries. Other documents that have been made available include the study protocol and statistical analysis plan. Templates of the informed consent forms may be shared upon request. The data will be available immediately following publication with no end date. The data will be shared with anyone who wishes to access the data. The data will be available for any purpose of analyses. For data, please contact the corresponding author.

@article{Hall2022,
abstract = {BACKGROUND Mycobacterium tuberculosis whole-genome sequencing (WGS) has been widely used for genotypic drug susceptibility testing (DST) and outbreak investigation. For both applications, Illumina technology is used by most public health laboratories; however, Nanopore technology developed by Oxford Nanopore Technologies has not been thoroughly evaluated. The aim of this study was to determine whether Nanopore sequencing data can provide equivalent information to Illumina for transmission clustering and genotypic DST for M tuberculosis. METHODS In this genomic analysis, we analysed 151 M tuberculosis isolates from Madagascar, South Africa, and England, which were collected between 2011 and 2018, using phenotypic DST and matched Illumina and Nanopore data. Illumina sequencing was done with the MiSeq, HiSeq 2500, or NextSeq500 platforms and Nanopore sequencing was done on the MinION or GridION platforms. Using highly reliable PacBio sequencing assemblies and pairwise distance correlation between Nanopore and Illumina data, we optimise Nanopore variant filters for detecting single-nucleotide polymorphisms (SNPs; using BCFtools software). We then used those SNPs to compare transmission clusters identified by Nanopore with the currently used UK Health Security Agency Illumina pipeline (COMPASS). We compared Illumina and Nanopore WGS-based DST predictions using the Mykrobe software and mutation catalogue. FINDINGS The Nanopore BCFtools pipeline identified SNPs with a median precision of 99{\textperiodcentered}3{\%} (IQR 99{\textperiodcentered}1-99{\textperiodcentered}6) and recall of 90{\textperiodcentered}2{\%} (88{\textperiodcentered}1-94{\textperiodcentered}2) compared with a precision of 99{\textperiodcentered}6{\%} (99{\textperiodcentered}4-99{\textperiodcentered}7) and recall of 91{\textperiodcentered}9{\%} (87{\textperiodcentered}6-98{\textperiodcentered}6) using the Illumina COMPASS pipeline. Using a threshold of 12 SNPs for putative transmission clusters, Illumina identified 98 isolates as unrelated and 53 as belonging to 19 distinct clusters (size range 2-7). Nanopore reproduced 15 out of 19 clusters perfectly; two clusters were merged into one cluster, one cluster had a single sample missing, and one cluster had an additional sample adjoined. Illumina-based clusters were also closely replicated using a five SNP threshold and clustering accuracy was maintained using mixed Illumina and Nanopore datasets. Genotyping resistance variants with Nanopore was highly concordant with Illumina, having zero discordant SNPs across more than 3000 SNPs and four insertions or deletions (indels), across 60 000 indels. INTERPRETATION Illumina and Nanopore technologies can be used independently or together by public health laboratories performing M tuberculosis genotypic DST and outbreak investigations. As a result, clinical and public health institutions making decisions on which sequencing technology to adopt for tuberculosis can base the choice on cost (which varies by country), batching, and turnaround time. FUNDING Academy for Medical Sciences, Oxford Wellcome Institutional Strategic Support Fund, and the Swiss South Africa Joint Research Award (Swiss National Science Foundation and South African National Research Foundation).},
author = {Hall, Michael B and Rabodoarivelo, Marie Sylvianne and Koch, Anastasia S and Dippenaar, Anzaan and George, Sophie and Grobbelaar, Melanie and Warren, Robin and Walker, Timothy M and Cox, Helen and Gagneux, Sebastien and Crook, Derrick and Peto, Tim and Rakotosamimanana, Niaina and {Grandjean Lapierre}, Simon and Iqbal, Zamin},
doi = {10.1016/s2666-5247(22)00301-9},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Hall et al. - 2022 - Evaluation of Nanopore sequencing for iMycobacterium tuberculosisi drug susceptibility testing and outbreak investi.pdf:pdf},
issn = {26665247},
journal = {The Lancet Microbe},
keywords = {OA,fund{\_}not{\_}ack,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {feb},
number = {2},
pages = {e84--e92},
pmid = {36549315},
publisher = {Elsevier BV},
title = {{Evaluation of Nanopore sequencing for \textit{Mycobacterium tuberculosis} drug susceptibility testing and outbreak investigation: a genomic analysis}},
url = {http://www.thelancet.com/article/S2666524722003019/fulltext http://www.thelancet.com/article/S2666524722003019/abstract https://www.thelancet.com/journals/lanmic/article/PIIS2666-5247(22)00301-9/abstract},
volume = {4},
year = {2022}
}

BACKGROUND Mycobacterium tuberculosis whole-genome sequencing (WGS) has been widely used for genotypic drug susceptibility testing (DST) and outbreak investigation. For both applications, Illumina technology is used by most public health laboratories; however, Nanopore technology developed by Oxford Nanopore Technologies has not been thoroughly evaluated. The aim of this study was to determine whether Nanopore sequencing data can provide equivalent information to Illumina for transmission clustering and genotypic DST for M tuberculosis. METHODS In this genomic analysis, we analysed 151 M tuberculosis isolates from Madagascar, South Africa, and England, which were collected between 2011 and 2018, using phenotypic DST and matched Illumina and Nanopore data. Illumina sequencing was done with the MiSeq, HiSeq 2500, or NextSeq500 platforms and Nanopore sequencing was done on the MinION or GridION platforms. Using highly reliable PacBio sequencing assemblies and pairwise distance correlation between Nanopore and Illumina data, we optimise Nanopore variant filters for detecting single-nucleotide polymorphisms (SNPs; using BCFtools software). We then used those SNPs to compare transmission clusters identified by Nanopore with the currently used UK Health Security Agency Illumina pipeline (COMPASS). We compared Illumina and Nanopore WGS-based DST predictions using the Mykrobe software and mutation catalogue. FINDINGS The Nanopore BCFtools pipeline identified SNPs with a median precision of 99˙3% (IQR 99˙1-99˙6) and recall of 90˙2% (88˙1-94˙2) compared with a precision of 99˙6% (99˙4-99˙7) and recall of 91˙9% (87˙6-98˙6) using the Illumina COMPASS pipeline. Using a threshold of 12 SNPs for putative transmission clusters, Illumina identified 98 isolates as unrelated and 53 as belonging to 19 distinct clusters (size range 2-7). Nanopore reproduced 15 out of 19 clusters perfectly; two clusters were merged into one cluster, one cluster had a single sample missing, and one cluster had an additional sample adjoined. Illumina-based clusters were also closely replicated using a five SNP threshold and clustering accuracy was maintained using mixed Illumina and Nanopore datasets. Genotyping resistance variants with Nanopore was highly concordant with Illumina, having zero discordant SNPs across more than 3000 SNPs and four insertions or deletions (indels), across 60 000 indels. INTERPRETATION Illumina and Nanopore technologies can be used independently or together by public health laboratories performing M tuberculosis genotypic DST and outbreak investigations. As a result, clinical and public health institutions making decisions on which sequencing technology to adopt for tuberculosis can base the choice on cost (which varies by country), batching, and turnaround time. FUNDING Academy for Medical Sciences, Oxford Wellcome Institutional Strategic Support Fund, and the Swiss South Africa Joint Research Award (Swiss National Science Foundation and South African National Research Foundation).

@article{Al-Zubaidi2022,
abstract = {Multidrug-resistant (MDR) tuberculosis (TB) is defined by the resistance of Mycobacterium tuberculosis, the causative organism, to the first-line antibiotics rifampicin and isoniazid. Mitigating or...},
annote = {OA in biorxiv: RNase HI depletion strongly potentiates cell killing by rifampicin in mycobacteria (biorxiv.org)},
author = {Al-Zubaidi, Abeer and Cheung, Chen-Yi and Cook, Gregory M and Taiaroa, George and Mizrahi, Valerie and Lott, J Shaun and Dawes, Stephanie S},
doi = {10.1128/AAC.02091-21},
issn = {0066-4804},
journal = {Antimicrobial Agents and Chemotherapy},
keywords = {OA,R-loop,RNase HI,antibiotic development,antibiotic resistance,antibiotic synergy,fund{\_}not{\_}ack,original,rifampicin},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {sep},
number = {10},
pages = {10.1128/aac.02091--21},
pmid = {36154174},
publisher = {American Society for Microbiology 1752 N St., N.W., Washington, DC},
title = {{RNase HI depletion strongly potentiates cell killing by rifampicin in Mycobacteria}},
url = {https://journals.asm.org/doi/10.1128/aac.02091-21},
volume = {66},
year = {2022}
}

Multidrug-resistant (MDR) tuberculosis (TB) is defined by the resistance of Mycobacterium tuberculosis, the causative organism, to the first-line antibiotics rifampicin and isoniazid. Mitigating or...

@article{Eikelboom2022,
abstract = {Background Effective treatments for COVID-19 are urgently needed but conducting randomized trials during the pandemic has been challenging. Methods The Anti-Coronavirus Therapy (ACT) trials are parallel factorial international trials that aimed to enroll 3,500 outpatients and 2,500 inpatients with symptomatic COVID-19. The outpatient trial is evaluating colchicine versus usual care, and aspirin versus usual care. The primary outcome for the colchicine randomization is hospitalization or death, and for the aspirin randomization is major thrombosis, hospitalization, or death. The inpatient trial is evaluating colchicine versus usual care, and the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily versus usual care. The primary outcome for the colchicine randomization is need for high flow oxygen, mechanical ventilation, or death, and for the rivaroxaban plus aspirin randomization is major thrombotic events, need for high flow oxygen, mechanical ventilation, or death. Results At the completion of enrolment on February 10, 2022, the outpatient trial had enrolled 3,917 patients and the inpatient trial 2,754 patients. Challenges encountered included lack of preliminary data about the interventions under evaluation, uncertainties related to the expected event rates, delays in regulatory and ethics approvals and in obtaining study interventions, as well as the changing pattern of the COVID-19 pandemic. Conclusions The ACT trials will determine the efficacy of anti-inflammatory therapy with colchicine and antithrombotic therapy with aspirin given alone or in combination with rivaroxaban across the spectrum of mild, moderate, and severe COVID-19. Lessons learned from the conduct of these trials will inform planning of future trials.},
author = {Eikelboom, John and Rangarajan, Sumathy and Jolly, Sanjit S and Belley-Cote, Emilie P and Whitlock, Richard and Beresh, Heather and Lewis, Gayle and Xu, Lizhen and Chan, Noel and Bangdiwala, Shrikant and Diaz, Rafael and Orlandini, Andres and Hassany, Mohamed and Tarhuni, Wadea M and Yusufali, A M and Sharma, Sanjib Kumar and Kontsevaya, Anna and Lopez-Jaramillo, Patricio and Avezum, Alvaro and Dans, Antonio L and Wasserman, Sean and Felix, Camilo and Kazmi, Khawar and Pais, Prem and Xavier, Denis and Lopes, Renato D and Berwanger, Otavio and Nkeshimana, Menelas and Harper, William and Loeb, Mark and Choudhri, Shurjeel and Farkouh, Michael E and Bosch, Jackie and Anand, Sonia S and Yusuf, Salim},
doi = {10.1016/j.cjco.2022.02.010},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Eikelboom et al. - 2022 - The Anti-Coronavirus Therapies (ACT) Trials design, baseline characteristics, and challenges.pdf:pdf},
issn = {2589790X},
journal = {CJC Open},
keywords = {OA,fund{\_}not{\_}ack,protocol},
mendeley-tags = {OA,fund{\_}not{\_}ack,protocol},
month = {mar},
pages = {10.1016/j.cjco.2022.02.010},
pmid = {35252829},
publisher = {Elsevier BV},
title = {{The Anti-Coronavirus Therapies (ACT) Trials: design, baseline characteristics, and challenges}},
url = {http://www.cjcopen.ca/article/S2589790X22000488/fulltext http://www.cjcopen.ca/article/S2589790X22000488/abstract https://www.cjcopen.ca/article/S2589-790X(22)00048-8/abstract https://linkinghub.elsevier.com/retrieve/pii/S2589790X22000488},
year = {2022}
}

Background Effective treatments for COVID-19 are urgently needed but conducting randomized trials during the pandemic has been challenging. Methods The Anti-Coronavirus Therapy (ACT) trials are parallel factorial international trials that aimed to enroll 3,500 outpatients and 2,500 inpatients with symptomatic COVID-19. The outpatient trial is evaluating colchicine versus usual care, and aspirin versus usual care. The primary outcome for the colchicine randomization is hospitalization or death, and for the aspirin randomization is major thrombosis, hospitalization, or death. The inpatient trial is evaluating colchicine versus usual care, and the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily versus usual care. The primary outcome for the colchicine randomization is need for high flow oxygen, mechanical ventilation, or death, and for the rivaroxaban plus aspirin randomization is major thrombotic events, need for high flow oxygen, mechanical ventilation, or death. Results At the completion of enrolment on February 10, 2022, the outpatient trial had enrolled 3,917 patients and the inpatient trial 2,754 patients. Challenges encountered included lack of preliminary data about the interventions under evaluation, uncertainties related to the expected event rates, delays in regulatory and ethics approvals and in obtaining study interventions, as well as the changing pattern of the COVID-19 pandemic. Conclusions The ACT trials will determine the efficacy of anti-inflammatory therapy with colchicine and antithrombotic therapy with aspirin given alone or in combination with rivaroxaban across the spectrum of mild, moderate, and severe COVID-19. Lessons learned from the conduct of these trials will inform planning of future trials.

@article{Abdelgawad2022,
abstract = {Background. Early mortality among hospitalized HIV-associated tuberculosis (TB/HIV) patients is high despite treatment. The pharmacokinetics of rifampicin, isoniazid, and pyrazinamide were investigated in hospitalized TB/HIV patients and a cohort of outpatients with TB (with or without HIV) to determine whether drug exposures differed between groups. Methods. Standard first-line TB treatment was given daily as per national guidelines, which consisted of oral 4-drug fixed-dose combination tablets containing 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol. Plasma samples were drawn on the 3rd day of treatment over eight hours post-dose. Rifampicin, isoniazid, and pyrazinamide in plasma were quantified and NONMEM {\&}reg; was used to analyze the data. Results. Data from 60 hospitalized patients (11 of whom died within 12 weeks of starting treatment) and 48 outpatients were available. Median (range) weight and age were 56 (35 - 88) kg, and 37 (19 - 77) years, respectively. Bioavailability and clearance of the three drugs were similar between TB/HIV hospitalized and TB outpatients. However, rifampicin's absorption was slower in hospitalized patients than in outpatients; mean absorption time was 49.9{\%} and 154{\%} more in hospitalized survivors and hospitalized deaths, respectively, than in outpatients. Higher levels of conjugated bilirubin correlated with lower rifampicin clearance. Isoniazid's clearance estimates were 25.5 L/h for fast metabolizers and 9.76 L/h for slow metabolizers. Pyrazinamide's clearance was more variable among hospitalized patients. The variability in clearance among patients  was 1.70 and 3.56 times more for hospitalized survivors and hospitalized deaths, respectively, than outpatients.   Conclusion. We showed that the pharmacokinetics of first-line TB drugs are not substantially different between hospitalized TB/HIV patients and TB (with or without HIV) outpatients. Hospitalized patients do not seem to be underexposed compared to their outpatient counterparts.},
author = {Abdelgawad, Noha and Chirehwa, Maxwell and Schutz, Charlotte and Barr, David and Ward, Amy and Janssen, Saskia and Burton, Rosie and Wilkinson, Robert J. and Shey, Muki and Wiesner, Lubbe and McIlleron, Helen and Maartens, Gary and Meintjes, Graeme and Denti, Paolo},
doi = {10.12688/wellcomeopenres.17660.1},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Abdelgawad et al. - 2022 - A comparison of the population pharmacokinetics of rifampicin, isoniazid and pyrazinamide between hospitalize.pdf:pdf},
isbn = {10.35802/211360},
issn = {2398-502X},
journal = {Wellcome Open Research},
keywords = {Data Curation,Hospitalization,Janssen S: Data Curation,Maartens G: Conceptualization,McIlleron H: Conceptualization,Meintjes G: Conceptualization,Modelling {\&} Simulation,OA,Population pharmacokinetics,Resources,Schutz C: Investigation,Shey M: Methodology,TB/HIV,Tuberculosis,Ward A: Investigation,Wiesner L: Methodology,Wilkinson RJ: Conceptualization,Writing-Review {\&} Editing,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {feb},
pages = {72},
publisher = {F1000 Research Limited},
title = {{A comparison of the population pharmacokinetics of rifampicin, isoniazid and pyrazinamide between hospitalized and non-hospitalized tuberculosis patients with or without HIV [version 1; peer review: awaiting peer review]}},
url = {https://wellcomeopenresearch.org/articles/7-72},
volume = {7},
year = {2022}
}

Background. Early mortality among hospitalized HIV-associated tuberculosis (TB/HIV) patients is high despite treatment. The pharmacokinetics of rifampicin, isoniazid, and pyrazinamide were investigated in hospitalized TB/HIV patients and a cohort of outpatients with TB (with or without HIV) to determine whether drug exposures differed between groups. Methods. Standard first-line TB treatment was given daily as per national guidelines, which consisted of oral 4-drug fixed-dose combination tablets containing 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol. Plasma samples were drawn on the 3rd day of treatment over eight hours post-dose. Rifampicin, isoniazid, and pyrazinamide in plasma were quantified and NONMEM ® was used to analyze the data. Results. Data from 60 hospitalized patients (11 of whom died within 12 weeks of starting treatment) and 48 outpatients were available. Median (range) weight and age were 56 (35 - 88) kg, and 37 (19 - 77) years, respectively. Bioavailability and clearance of the three drugs were similar between TB/HIV hospitalized and TB outpatients. However, rifampicin's absorption was slower in hospitalized patients than in outpatients; mean absorption time was 49.9% and 154% more in hospitalized survivors and hospitalized deaths, respectively, than in outpatients. Higher levels of conjugated bilirubin correlated with lower rifampicin clearance. Isoniazid's clearance estimates were 25.5 L/h for fast metabolizers and 9.76 L/h for slow metabolizers. Pyrazinamide's clearance was more variable among hospitalized patients. The variability in clearance among patients was 1.70 and 3.56 times more for hospitalized survivors and hospitalized deaths, respectively, than outpatients. Conclusion. We showed that the pharmacokinetics of first-line TB drugs are not substantially different between hospitalized TB/HIV patients and TB (with or without HIV) outpatients. Hospitalized patients do not seem to be underexposed compared to their outpatient counterparts.

@article{Moyo-Gwete2022a,
abstract = {The evolution of SARS-CoV-2 has resulted in variants of concern (VOCs) with distinct spike mutations conferring various immune escape profiles. These variable mutations also influence the cross-rea...},
author = {Moyo-Gwete, Thandeka and Madzivhandila, Mashudu and Mkhize, Nonhlanhla N and Kgagudi, Prudence and Ayres, Frances and Lambson, Bronwen E and Manamela, Nelia P and Richardson, Simone I and Makhado, Zanele and van der Mescht, Mieke A and de Beer, Zelda and de Villiers, Talita Roma and Burgers, Wendy A and Ntusi, Ntobeko A B and Rossouw, Theresa and Ueckermann, Veronica and Boswell, Michael T and Moore, Penny L},
doi = {10.1128/JVI.00558-22},
editor = {Gallagher, Tom},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Moyo-Gwete et al. - 2022 - Shared N417-dependent epitope on the SARS-CoV-2 Omicron, Beta, and Delta Plus variants.pdf:pdf},
issn = {0022-538X},
journal = {Journal of Virology},
keywords = {OA,OA{\_}PMC,SARS-CoV-2,antibody cross-reactivity,antibody isolation,fund{\_}not{\_}ack,original,variants},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}not{\_}ack,original},
month = {jul},
number = {15},
pages = {e00558--22},
pmid = {35867572},
publisher = {American Society for Microbiology 1752 N St., N.W., Washington, DC},
title = {{Shared N417-dependent epitope on the SARS-CoV-2 Omicron, Beta, and Delta Plus variants}},
url = {https://journals.asm.org/doi/10.1128/jvi.00558-22},
volume = {96},
year = {2022}
}

The evolution of SARS-CoV-2 has resulted in variants of concern (VOCs) with distinct spike mutations conferring various immune escape profiles. These variable mutations also influence the cross-rea...

@article{VandenBerg2022,
abstract = {There is a need for effective therapy for COVID-19 pneumonia. Convalescent plasma has antiviral activity and early observational studies suggested benefit in reducing COVID-19 severity. We investigated the safety and efficacy of convalescent plasma in hospitalized patients with COVID-19 in a population with a high HIV prevalence and where few therapeutic options were available. We performed a double-blinded, multicenter, randomized controlled trial in one private and three public sector hospitals in South Africa. Adult participants with COVID-19 pneumonia requiring non-invasive oxygen were randomized 1:1 to receive a single transfusion of 200 mL of either convalescent plasma or 0.9{\%} saline solution. The primary outcome measure was hospital discharge and/or improvement of ≥ 2 points on the World Health Organisation Blueprint Ordinal Scale for Clinical Improvement by day 28 of enrolment. The trial was stopped early for futility by the Data and Safety Monitoring Board. 103 participants, including 21 HIV positive individuals, were randomized at the time of premature trial termination: 52 in the convalescent plasma and 51 in the placebo group. The primary outcome occurred in 31 participants in the convalescent plasma group and and 32 participants in the placebo group (relative risk 1.03 (95{\%} CI 0.77 to 1.38). Two grade 1 transfusion-related adverse events occurred. Participants who improved clinically received convalescent plasma with a higher median anti-SARS-CoV-2 neutralizing antibody titre compared with those who did not (298 versus 205 AU/mL). Our study contributes additional evidence for recommendations against the use of convalescent plasma for COVID-19 pneumonia. Safety and feasibility in this population supports future investigation for other indications.},
author = {van den Berg, Karin and Glatt, Tanya Nadia and Vermeulen, Marion and Little, Francesca and Swanevelder, Ronel and Barrett, Claire and Court, Richard and Bremer, Marise and Nyoni, Cynthia and Swarts, Avril and Mmenu, Cordelia and Crede, Thomas and Kritzinger, Gerdien and Naude, Jonathan and Szymanski, Patryk and Cowley, James and Moyo-Gwete, Thandeka and Moore, Penny L and Black, John and Singh, Jaimendra and Bhiman, Jinal N and Baijnath, Prinita and Mody, Priyesh and Malherbe, Jacques and Potgieter, Samantha and van Vuuren, Cloete and Maasdorp, Shaun and Wilkinson, Robert J and Louw, Vernon J and Wasserman, Sean},
doi = {10.1038/s41598-022-06221-8},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/van den Berg et al. - 2022 - Convalescent plasma in the treatment of moderate to severe COVID-19 pneumonia a randomized controlled trial.pdf:pdf},
isbn = {0123456789},
issn = {2045-2322},
journal = {Scientific Reports},
keywords = {Clinical trial design,Clinical trials,OA,OA{\_}PMC,Randomized controlled trials,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {dec},
number = {1},
pages = {2552},
pmid = {35169169},
publisher = {Nature Publishing Group},
title = {{Convalescent plasma in the treatment of moderate to severe COVID-19 pneumonia: a randomized controlled trial (PROTECT-Patient Trial)}},
url = {https://www.nature.com/articles/s41598-022-06221-8},
volume = {12},
year = {2022}
}

There is a need for effective therapy for COVID-19 pneumonia. Convalescent plasma has antiviral activity and early observational studies suggested benefit in reducing COVID-19 severity. We investigated the safety and efficacy of convalescent plasma in hospitalized patients with COVID-19 in a population with a high HIV prevalence and where few therapeutic options were available. We performed a double-blinded, multicenter, randomized controlled trial in one private and three public sector hospitals in South Africa. Adult participants with COVID-19 pneumonia requiring non-invasive oxygen were randomized 1:1 to receive a single transfusion of 200 mL of either convalescent plasma or 0.9% saline solution. The primary outcome measure was hospital discharge and/or improvement of ≥ 2 points on the World Health Organisation Blueprint Ordinal Scale for Clinical Improvement by day 28 of enrolment. The trial was stopped early for futility by the Data and Safety Monitoring Board. 103 participants, including 21 HIV positive individuals, were randomized at the time of premature trial termination: 52 in the convalescent plasma and 51 in the placebo group. The primary outcome occurred in 31 participants in the convalescent plasma group and and 32 participants in the placebo group (relative risk 1.03 (95% CI 0.77 to 1.38). Two grade 1 transfusion-related adverse events occurred. Participants who improved clinically received convalescent plasma with a higher median anti-SARS-CoV-2 neutralizing antibody titre compared with those who did not (298 versus 205 AU/mL). Our study contributes additional evidence for recommendations against the use of convalescent plasma for COVID-19 pneumonia. Safety and feasibility in this population supports future investigation for other indications.

@article{Jesumoroti2022,
abstract = {Tuberculosis (TB) is one of the leading causes of death worldwide. Developing new anti-TB compounds using cost-effective processes is critical to reduce TB incidence and accomplish the End TB Strategy milestone. Herein, we describe the synthesis and structure–activity relationships of a library of thirty 7H-Pyrrolo[2,3-d]pyrimidine derivatives providing insights into the contributions of different aromatic, aryl and alkyl substitution at the C-4 position of the 7-deazapurine ring. The minimum inhibitory concentration (MIC) of the compounds against the green fluorescent protein (GFP) reporter strain of Mycobacterium tuberculosis was assayed using the standard broth microdilution method, and cell toxicity was determined using the MTT assay. Sixteen compounds displayed in vitro activity against the GFP reporter strain of Mycobacterium tuberculosis with MIC90 values of 0.488–62.5 µM. This study highlights the most potent derivative, N-(4-phenoxy phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine with a MIC90 value of 0.488 µM and was non-cytotoxic to the Vero cell line. Moreover, all the potent compounds from this series have a ClogP value less than 4 and molecular weight {\textless} 400; thus, likely to maintain drug-likeness during lead optimisation.},
author = {Jesumoroti, Omobolanle Janet and Beteck, Richard M and Jordaan, Audrey and Warner, Digby F and Legoabe, Lesetja J},
doi = {10.1007/S11030-022-10453-1},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Jesumoroti et al. - 2022 - Exploration of 4-aminopyrrolo2,3-dpyrimidine as antitubercular agents.pdf:pdf},
isbn = {0123456789},
issn = {1573-501X},
journal = {Molecular Diversity},
keywords = {Biochemistry,OA,Organic Chemistry,Pharmacy,Polymer Sciences,Tuberculosis,fund{\_}not{\_}ack,general,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {may},
pmid = {35598185},
publisher = {Springer},
title = {{Exploration of 4-aminopyrrolo[2,3-d]pyrimidine as antitubercular agents}},
url = {https://link.springer.com/article/10.1007/s11030-022-10453-1},
year = {2022}
}

Tuberculosis (TB) is one of the leading causes of death worldwide. Developing new anti-TB compounds using cost-effective processes is critical to reduce TB incidence and accomplish the End TB Strategy milestone. Herein, we describe the synthesis and structure–activity relationships of a library of thirty 7H-Pyrrolo[2,3-d]pyrimidine derivatives providing insights into the contributions of different aromatic, aryl and alkyl substitution at the C-4 position of the 7-deazapurine ring. The minimum inhibitory concentration (MIC) of the compounds against the green fluorescent protein (GFP) reporter strain of Mycobacterium tuberculosis was assayed using the standard broth microdilution method, and cell toxicity was determined using the MTT assay. Sixteen compounds displayed in vitro activity against the GFP reporter strain of Mycobacterium tuberculosis with MIC90 values of 0.488–62.5 µM. This study highlights the most potent derivative, N-(4-phenoxy phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine with a MIC90 value of 0.488 µM and was non-cytotoxic to the Vero cell line. Moreover, all the potent compounds from this series have a ClogP value less than 4 and molecular weight \textless 400; thus, likely to maintain drug-likeness during lead optimisation.

@article{Hussey2022,
abstract = {Background Emerging data suggest that SARS-CoV-2 Omicron variant of concern (VOC)is associated with reduced risk of severe disease. The extent to which this reflects a difference in the inherent virulence of Omicron, or just higher levels of population immunity, is currently not clear. Methods RdRp target delay (RTD: a difference in cycle threshold value of RdRp - E {\textgreater} 3.5) in the Seegene AllplexTM 2019-nCoV PCR assay is a proxy marker for the Delta VOC. The absence of this proxy marker in the transition period was used to identify suspected Omicron VOC infections. Cox regression was performed for the outcome of hospital admission in those who tested positive for SARS-CoV-2 on the Seegene AllplexTM assay from 1 November to 14 December 2021 in the Western Cape Province, South Africa, public sector. Vaccination status at time of diagnosis, as well as prior diagnosed infection and comorbidities, were adjusted for. Results 150 cases with RTD (proxy for Delta) and 1486 cases without RTD (proxy for Omicron) were included. Cases without RTD had a lower hazard of admission (adjusted Hazard Ratio [aHR] of 0.56, 95{\%} confidence interval [CI] 0.34-0.91). Complete vaccination was protective of admission with an aHR of 0.45 (95{\%}CI 0.26-0.77). Conclusion Omicron has resulted in a lower risk of hospital admission, compared to contemporaneous Delta infection in the Western Cape Province, when using the proxy marker of RTD. Under-ascertainment of reinfections with an immune escape variant like Omicron remains a challenge to accurately assessing variant virulence. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Funding Statement This study was funded by the Grand Challenges ICODA pilot initiative delivered by Health Data Research UK and funded by the Bill {\&} Melinda Gates and the Minderoo Foundations (INV-017293), and by a research Flagship grant from the South African Medical Research Council. Additional support was provided by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC0010218), the UK Medical Research Council (FC0010218), and the Wellcome Trust (FC0010218) as well as Wellcome (203135, 222574). {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the University of Cape Town Research Ethics Committee (HREC 460/2020). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.},
author = {Hussey, Hannah and Davies, Mary-Ann and Heekes, Alexa and Williamson, Carolyn and Valley-Omar, Ziyaad and Hardie, Diana Ruth and Korsman, Stephen and Doolabh, Deelan and Preiser, Wolfgang and Maponga, Tongai and Iranzadeh, Arash and Wasserman, Sean and Schreuder, Neshaad and Boloko, Linda and Symons, Greg and Raubenheimer, Peter and Viljoen, Braam and Solomon, Wesley and Rousseau, Petro and Parker, Arifa and Wolter, Nicole and Cohen, Cheryl and JASSAT, WAASILA and Lessels, Richard and Wilkinson, Robert J and Boulle, Andrew and Hsiao, Nei-yuan},
doi = {10.1101/2022.01.13.22269211},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Hussey et al. - 2022 - Assessing the clinical severity of the Omicron variant in the Western Cape Province, South Africa, using the diag.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {jan},
pages = {2022.01.13.22269211},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Assessing the clinical severity of the Omicron variant in the Western Cape Province, South Africa, using the diagnostic PCR proxy marker of RdRp target delay to distinguish between Omicron and Delta infections: a survival analysis}},
url = {https://www.medrxiv.org/content/10.1101/2022.01.13.22269211v1 https://www.medrxiv.org/content/10.1101/2022.01.13.22269211v1.abstract},
year = {2022}
}

Background Emerging data suggest that SARS-CoV-2 Omicron variant of concern (VOC)is associated with reduced risk of severe disease. The extent to which this reflects a difference in the inherent virulence of Omicron, or just higher levels of population immunity, is currently not clear. Methods RdRp target delay (RTD: a difference in cycle threshold value of RdRp - E \textgreater 3.5) in the Seegene AllplexTM 2019-nCoV PCR assay is a proxy marker for the Delta VOC. The absence of this proxy marker in the transition period was used to identify suspected Omicron VOC infections. Cox regression was performed for the outcome of hospital admission in those who tested positive for SARS-CoV-2 on the Seegene AllplexTM assay from 1 November to 14 December 2021 in the Western Cape Province, South Africa, public sector. Vaccination status at time of diagnosis, as well as prior diagnosed infection and comorbidities, were adjusted for. Results 150 cases with RTD (proxy for Delta) and 1486 cases without RTD (proxy for Omicron) were included. Cases without RTD had a lower hazard of admission (adjusted Hazard Ratio [aHR] of 0.56, 95% confidence interval [CI] 0.34-0.91). Complete vaccination was protective of admission with an aHR of 0.45 (95%CI 0.26-0.77). Conclusion Omicron has resulted in a lower risk of hospital admission, compared to contemporaneous Delta infection in the Western Cape Province, when using the proxy marker of RTD. Under-ascertainment of reinfections with an immune escape variant like Omicron remains a challenge to accurately assessing variant virulence. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the Grand Challenges ICODA pilot initiative delivered by Health Data Research UK and funded by the Bill & Melinda Gates and the Minderoo Foundations (INV-017293), and by a research Flagship grant from the South African Medical Research Council. Additional support was provided by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC0010218), the UK Medical Research Council (FC0010218), and the Wellcome Trust (FC0010218) as well as Wellcome (203135, 222574). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the University of Cape Town Research Ethics Committee (HREC 460/2020). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.

@article{Marincowitz2022,
abstract = {Background Uneven vaccination and less resilient health care systems mean hospitals in LMICs are at risk of being overwhelmed during periods of increased COVID-19 infection. Risk-scores proposed for rapid triage of need for admission from the emergency department (ED) have been developed in higher-income settings during initial waves of the pandemic. Methods Routinely collected data for public hospitals in the Western Cape, South Africa from the 27th August 2020 to 11th March 2022 were used to derive a cohort of 446,084 ED patients with suspected COVID-19. The primary outcome was death or ICU admission at 30 days. The cohort was divided into derivation and Omicron variant validation sets. We developed the LMIC-PRIEST score based on the coefficients from multivariable analysis in the derivation cohort and existing triage practices. We externally validated accuracy in the Omicron period and a UK cohort. Results We analysed 305,564 derivation, 140,520 Omicron and 12,610 UK validation cases. Over 100 events per predictor parameter were modelled. Multivariable analyses identified eight predictor variables retained across models. We used these findings and clinical judgement to develop a score based on South African Triage Early Warning Scores which also included age, sex, oxygen saturation, inspired oxygen, diabetes and heart disease. The LMIC-PRIEST score achieved C-statistics: 0.82 (95{\%} CI: 0.82 to 0.83) development cohort; 0.79 (95{\%} CI: 0.78 to 0.80) Omicron cohort; and 0.79 (95{\%} CI: 0.79 to 0.80) UK cohort. Differences in prevalence of outcomes led to imperfect calibration in external validation. However, use of the score at thresholds of three or less would allow identification of very low-risk patients (NPV ≥0.99) who could be rapidly discharged using information collected at initial assessment. Conclusion The LMIC-PRIEST score shows good discrimination and high sensitivity at lower thresholds and can be used to rapidly identify low-risk patients in LMIC ED settings.Competing Interest StatementThe authors have declared no competing interest.Funding StatementCM is a National Institute for Health Research (NIHR) Clinical Lecturer in Emergency Medicine (Grant Number Not Applicable/NA). This work is part of the Grand Challenges ICODA pilot initiative, delivered by Health Data Research UK and funded by the Bill {\&}amp; Melinda Gates Foundation and the Minderoo Foundation. The Provincial Health Data Centre (PHDC), Health Intelligence Directorate, Western Cape Government Health and Wellness acknowledges funding from the United States National Institutes of Health (R01HD080465, U01AI069911), Bill and Melinda Gates Foundation (1164272; 1191327; INV-004657, INV-017293), the Wellcome Trust (203135/Z/16/Z), the United States Agency for International Development (72067418CA00023)Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The study was approved by the University of Cape Town Human Research Ethics Committee (HREC 594/2021), and the Western Cape Health Research Committee (WC{\_}202111{\_}034). All data were de-identified at source before being provided to the research team.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe data used for this study are subject to a data sharing agreement with the Western Cape Government Department of Health and Wellness, which prohibits further sharing of patient- level data. Access to these and related data should be requested directly from this organisation and is subject to the necessary ethical and organisational approval processes.},
author = {Marincowitz, Carl and Hodkinson, Pater and McAlpine, David and Fuller, Gordon and Goodacre, Steve and Bath, Peter and Sbaffi, Laura and Hasan, Madina and Omer, Yasein and Wallis, Lee},
doi = {10.1101/2022.11.06.22281986},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Marincowitz et al. - 2022 - LMIC-PRIEST Derivation and validation of a clinical severity score for acutely ill adults with suspected COV.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jan},
pages = {2022.11.06.22281986},
title = {{LMIC-PRIEST: Derivation and validation of a clinical severity score for acutely ill adults with suspected COVID-19 in a middle-income setting}},
url = {http://medrxiv.org/content/early/2022/11/07/2022.11.06.22281986.abstract},
year = {2022}
}

Background Uneven vaccination and less resilient health care systems mean hospitals in LMICs are at risk of being overwhelmed during periods of increased COVID-19 infection. Risk-scores proposed for rapid triage of need for admission from the emergency department (ED) have been developed in higher-income settings during initial waves of the pandemic. Methods Routinely collected data for public hospitals in the Western Cape, South Africa from the 27th August 2020 to 11th March 2022 were used to derive a cohort of 446,084 ED patients with suspected COVID-19. The primary outcome was death or ICU admission at 30 days. The cohort was divided into derivation and Omicron variant validation sets. We developed the LMIC-PRIEST score based on the coefficients from multivariable analysis in the derivation cohort and existing triage practices. We externally validated accuracy in the Omicron period and a UK cohort. Results We analysed 305,564 derivation, 140,520 Omicron and 12,610 UK validation cases. Over 100 events per predictor parameter were modelled. Multivariable analyses identified eight predictor variables retained across models. We used these findings and clinical judgement to develop a score based on South African Triage Early Warning Scores which also included age, sex, oxygen saturation, inspired oxygen, diabetes and heart disease. The LMIC-PRIEST score achieved C-statistics: 0.82 (95% CI: 0.82 to 0.83) development cohort; 0.79 (95% CI: 0.78 to 0.80) Omicron cohort; and 0.79 (95% CI: 0.79 to 0.80) UK cohort. Differences in prevalence of outcomes led to imperfect calibration in external validation. However, use of the score at thresholds of three or less would allow identification of very low-risk patients (NPV ≥0.99) who could be rapidly discharged using information collected at initial assessment. Conclusion The LMIC-PRIEST score shows good discrimination and high sensitivity at lower thresholds and can be used to rapidly identify low-risk patients in LMIC ED settings.Competing Interest StatementThe authors have declared no competing interest.Funding StatementCM is a National Institute for Health Research (NIHR) Clinical Lecturer in Emergency Medicine (Grant Number Not Applicable/NA). This work is part of the Grand Challenges ICODA pilot initiative, delivered by Health Data Research UK and funded by the Bill & Melinda Gates Foundation and the Minderoo Foundation. The Provincial Health Data Centre (PHDC), Health Intelligence Directorate, Western Cape Government Health and Wellness acknowledges funding from the United States National Institutes of Health (R01HD080465, U01AI069911), Bill and Melinda Gates Foundation (1164272; 1191327; INV-004657, INV-017293), the Wellcome Trust (203135/Z/16/Z), the United States Agency for International Development (72067418CA00023)Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The study was approved by the University of Cape Town Human Research Ethics Committee (HREC 594/2021), and the Western Cape Health Research Committee (WC_202111_034). All data were de-identified at source before being provided to the research team.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThe data used for this study are subject to a data sharing agreement with the Western Cape Government Department of Health and Wellness, which prohibits further sharing of patient- level data. Access to these and related data should be requested directly from this organisation and is subject to the necessary ethical and organisational approval processes.

@article{Amaral2022,
abstract = {Cellular necrosis during Mycobacterium tuberculosis (Mtb) infection promotes both immunopathology and bacterial dissemination. Glutathione peroxidase-4 (Gpx4) is an enzyme that plays a critical role in preventing iron-dependent lipid peroxidation–mediated cell death (ferroptosis), a process previously implicated in the necrotic pathology seen in Mtb-infected mice. Here, we document altered GPX4 expression, glutathione levels, and lipid peroxidation in patients with active tuberculosis and assess the role of this pathway in mice genetically deficient in or overexpressing Gpx4. We found that Gpx4-deficient mice infected with Mtb display substantially increased lung necrosis and bacterial burdens, while transgenic mice overexpressing the enzyme show decreased bacterial loads and necrosis. Moreover, Gpx4-deficient macrophages exhibited enhanced necrosis upon Mtb infection in vitro, an outcome suppressed by the lipid peroxidation inhibitor, ferrostatin-1. These findings provide support for the role of ferroptosis in Mtb-induced necrosis and implicate the Gpx4/GSH axis as a target for host-directed therapy of tuberculosis.},
author = {Amaral, Eduardo P and Foreman, Taylor W and Namasivayam, Sivaranjani and Hilligan, Kerry L and Kauffman, Keith D and {Barbosa Bomfim}, Caio Cesar and Costa, Diego L and Barreto-Duarte, Beatriz and Gurgel-Rocha, Clarissa and Santana, Monique Freire and Cordeiro-Santos, Marcelo and {Du Bruyn}, Elsa and Riou, Catherine and Aberman, Kate and Wilkinson, Robert John and Barber, Daniel L and Mayer-Barber, Katrin D and Andrade, Bruno B and Sher, Alan},
doi = {10.1084/jem.20220504},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Amaral et al. - 2022 - GPX4 regulates cellular necrosis and host resistance in Mycobacterium tuberculosis infection.pdf:pdf},
issn = {0022-1007},
journal = {Journal of Experimental Medicine},
keywords = {OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {sep},
number = {11},
pages = {e20220504},
pmid = {36069923},
title = {{GPX4 regulates cellular necrosis and host resistance in Mycobacterium tuberculosis infection}},
url = {https://doi.org/10.1084/jem.20220504},
volume = {219},
year = {2022}
}

Cellular necrosis during Mycobacterium tuberculosis (Mtb) infection promotes both immunopathology and bacterial dissemination. Glutathione peroxidase-4 (Gpx4) is an enzyme that plays a critical role in preventing iron-dependent lipid peroxidation–mediated cell death (ferroptosis), a process previously implicated in the necrotic pathology seen in Mtb-infected mice. Here, we document altered GPX4 expression, glutathione levels, and lipid peroxidation in patients with active tuberculosis and assess the role of this pathway in mice genetically deficient in or overexpressing Gpx4. We found that Gpx4-deficient mice infected with Mtb display substantially increased lung necrosis and bacterial burdens, while transgenic mice overexpressing the enzyme show decreased bacterial loads and necrosis. Moreover, Gpx4-deficient macrophages exhibited enhanced necrosis upon Mtb infection in vitro, an outcome suppressed by the lipid peroxidation inhibitor, ferrostatin-1. These findings provide support for the role of ferroptosis in Mtb-induced necrosis and implicate the Gpx4/GSH axis as a target for host-directed therapy of tuberculosis.

@article{Acquah2022,
abstract = {Tuberculosis (TB) remains a public health crisis, requiring the urgent identification of new anti-mycobacterial drugs. We screened several organic and aqueous marine invertebrate extracts for their in vitro inhibitory activity against the causative organism, Mycobacterium tuberculosis. Here, we report the results obtained for 54 marine invertebrate extracts. The chemical components of two of the extracts were dereplicated, using 1H NMR and HR-LCMS with GNPS molecular networking, and these extracts were further subjected to an activity-guided isolation process to purify the bioactive components. Hyrtios reticulatus yielded heteronemin 1 and Jaspis splendens was found to produce the bengamide class of compounds, of which bengamides P 2 and Q 3 were isolated, while a new derivative, bengamide S 5, was putatively identified and its structure predicted, based on the similarity of its MS/MS fragmentation pattern to those of other bengamides. The isolated bioactive metabolites and semi-pure fractions exhibited M. tuberculosis growth inhibitory activity, in the range {\textless}0.24 to 62.50 µg/mL. This study establishes the bengamides as potent antitubercular compounds, with the first report of whole-cell antitubercular activity of bengamides P 2 and Q 3.},
author = {Acquah, Kojo Sekyi and Beukes, Denzil R and Seldon, Ronnett and Jordaan, Audrey and Sunassee, Suthananda N and Warner, Digby F and Gammon, David W},
doi = {10.3390/medicines9020009},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Acquah et al. - 2022 - Identification of antimycobacterial natural products from a library of marine invertebrate extracts.pdf:pdf},
issn = {2305-6320},
journal = {Medicines},
keywords = {OA,antitubercular,bengamides,drug discovery,fund{\_}not{\_}ack,heteronemin,marine natural product,molecular networking,original},
mendeley-tags = {OA,fund{\_}not{\_}ack,original},
month = {jan},
number = {2},
pages = {9},
pmid = {35200753},
publisher = {Multidisciplinary Digital Publishing Institute},
title = {{Identification of antimycobacterial natural products from a library of marine invertebrate extracts}},
url = {https://www.mdpi.com/2305-6320/9/2/9/htm https://www.mdpi.com/2305-6320/9/2/9},
volume = {9},
year = {2022}
}

Tuberculosis (TB) remains a public health crisis, requiring the urgent identification of new anti-mycobacterial drugs. We screened several organic and aqueous marine invertebrate extracts for their in vitro inhibitory activity against the causative organism, Mycobacterium tuberculosis. Here, we report the results obtained for 54 marine invertebrate extracts. The chemical components of two of the extracts were dereplicated, using 1H NMR and HR-LCMS with GNPS molecular networking, and these extracts were further subjected to an activity-guided isolation process to purify the bioactive components. Hyrtios reticulatus yielded heteronemin 1 and Jaspis splendens was found to produce the bengamide class of compounds, of which bengamides P 2 and Q 3 were isolated, while a new derivative, bengamide S 5, was putatively identified and its structure predicted, based on the similarity of its MS/MS fragmentation pattern to those of other bengamides. The isolated bioactive metabolites and semi-pure fractions exhibited M. tuberculosis growth inhibitory activity, in the range \textless0.24 to 62.50 µg/mL. This study establishes the bengamides as potent antitubercular compounds, with the first report of whole-cell antitubercular activity of bengamides P 2 and Q 3.

@article{Davies2022,
abstract = {Objectives: We aimed to compare COVID-19 outcomes in the Omicron-driven fourth wave with prior waves in the Western Cape, the contribution of undiagnosed prior infection to differences in outcomes in a context of high seroprevalence due to prior infection, and whether protection against severe disease conferred by prior infection and/or vaccination was maintained. Methods: In this cohort study, we included public sector patients aged ≥20 years with a laboratory confirmed COVID-19 diagnosis between 14 November-11 December 2021 (wave four) and equivalent prior wave periods. We compared the risk between waves of the following outcomes using Cox regression: death, severe hospitalization or death and any hospitalization or death (all ≤14 days after diagnosis) adjusted for age, sex, comorbidities, geography, vaccination and prior infection. Results: We included 5,144 patients from wave four and 11,609 from prior waves. Risk of all outcomes was lower in wave four compared to the Delta-driven wave three (adjusted Hazard Ratio (aHR) [95{\%} confidence interval (CI)] for death 0.27 [0.19; 0.38]. Risk reduction was lower when adjusting for vaccination and prior diagnosed infection (aHR:0.41, 95{\%} CI: 0.29; 0.59) and reduced further when accounting for unascertained prior infections (aHR: 0.72). Vaccine protection was maintained in wave four (aHR for outcome of death: 0.24; 95{\%} CI: 0.10; 0.58). Conclusions: In the Omicron-driven wave, severe COVID-19 outcomes were reduced mostly due to protection conferred by prior infection and/or vaccination, but intrinsically reduced virulence may account for an approximately 25{\%} reduced risk of severe hospitalization or death compared to Delta. {\#}{\#}{\#} Competing Interest Statement The authors have declared no competing interest. {\#}{\#}{\#} Funding Statement We acknowledge funding for the Western Cape Provincial Health Data Centre from the Western Cape Department of Health, the US National Institutes for Health (R01 HD080465, U01 AI069924), the Bill and Melinda Gates Foundation (1164272, 119327), the United States Agency for International Development (72067418CA00023), the European Union (101045989), the Wellcome Trust (203135/Z/16/Z, 222574) and the Medical Research Council of South Africa. RJW receives support from the Francis Crick Institute which is funded by Wellcome (FC0010218), MRC (UK) (FC0010218) and Cancer Research UK (FC0010218). He also receives support from Wellcome (203135, 222574) and the Medical Research Council of South Africa. {\#}{\#}{\#} Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Human Research Ethics Committee, University of Cape Town Faculty of Health Sciences, South Africa I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.},
author = {Davies, Mary-Ann and Kassanjee, Reshma and Rousseau, Petro and Morden, Erna and Johnson, Leigh and Solomon, Wesley and Hsiao, Nei-Yuan and Hussey, Hannah and Meintjes, Graeme A and Paleker, Masudah and Jacobs, Theuns and Raubenheimer, Peter and Heekes, Alexa and Dane, Pierre and Bam, Jamy-Lee and Smith, Mariette and Preiser, Wolfgang and Pienaar, David and Mendelson, Marc and Naude, Jonathan and Schreuder, Neshaad and Mnguni, Ayanda and Roux, Susan Le and Murie, Katie and Prozesky, Hans and Mahomed, Hassan and Rossouw, Liezel and Wasserman, Sean and Maughan, Deborah and Boloko, Linda and Smith, Barry and Taljaard, Jantjie and Symons, Greg and Ntusi, Ntobeko A B and Parker, Arifa and Wolter, Nicole and Jassat, Waasila and Cohen, Cheryl and Lessells, Richard and Wilkinson, Robert J and Arendse, Juanita and Kariem, Saadiq and Moodley, Melvin and Vallabhjee, Krish and Wolmarans, Milani and Boulle, Andrew},
doi = {10.1101/2022.01.12.22269148},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Davies et al. - 2022 - Outcomes of laboratory-confirmed SARS-CoV-2 infection in the Omicron-driven fourth wave compared with previous wa.pdf:pdf},
journal = {medRxiv},
keywords = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {jan},
pages = {2022.01.12.22269148},
pmid = {35043121},
publisher = {Cold Spring Harbor Laboratory Press},
title = {{Outcomes of laboratory-confirmed SARS-CoV-2 infection in the Omicron-driven fourth wave compared with previous waves in the Western Cape Province, South Africa}},
url = {https://www.medrxiv.org/content/10.1101/2022.01.12.22269148v1 https://www.medrxiv.org/content/10.1101/2022.01.12.22269148v1.abstract},
volume = {13},
year = {2022}
}

Objectives: We aimed to compare COVID-19 outcomes in the Omicron-driven fourth wave with prior waves in the Western Cape, the contribution of undiagnosed prior infection to differences in outcomes in a context of high seroprevalence due to prior infection, and whether protection against severe disease conferred by prior infection and/or vaccination was maintained. Methods: In this cohort study, we included public sector patients aged ≥20 years with a laboratory confirmed COVID-19 diagnosis between 14 November-11 December 2021 (wave four) and equivalent prior wave periods. We compared the risk between waves of the following outcomes using Cox regression: death, severe hospitalization or death and any hospitalization or death (all ≤14 days after diagnosis) adjusted for age, sex, comorbidities, geography, vaccination and prior infection. Results: We included 5,144 patients from wave four and 11,609 from prior waves. Risk of all outcomes was lower in wave four compared to the Delta-driven wave three (adjusted Hazard Ratio (aHR) [95% confidence interval (CI)] for death 0.27 [0.19; 0.38]. Risk reduction was lower when adjusting for vaccination and prior diagnosed infection (aHR:0.41, 95% CI: 0.29; 0.59) and reduced further when accounting for unascertained prior infections (aHR: 0.72). Vaccine protection was maintained in wave four (aHR for outcome of death: 0.24; 95% CI: 0.10; 0.58). Conclusions: In the Omicron-driven wave, severe COVID-19 outcomes were reduced mostly due to protection conferred by prior infection and/or vaccination, but intrinsically reduced virulence may account for an approximately 25% reduced risk of severe hospitalization or death compared to Delta. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement We acknowledge funding for the Western Cape Provincial Health Data Centre from the Western Cape Department of Health, the US National Institutes for Health (R01 HD080465, U01 AI069924), the Bill and Melinda Gates Foundation (1164272, 119327), the United States Agency for International Development (72067418CA00023), the European Union (101045989), the Wellcome Trust (203135/Z/16/Z, 222574) and the Medical Research Council of South Africa. RJW receives support from the Francis Crick Institute which is funded by Wellcome (FC0010218), MRC (UK) (FC0010218) and Cancer Research UK (FC0010218). He also receives support from Wellcome (203135, 222574) and the Medical Research Council of South Africa. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Human Research Ethics Committee, University of Cape Town Faculty of Health Sciences, South Africa I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.