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AbstractIntroductionAntiretroviral therapy (ART) has reduced morbidity and mortality in sub‐Saharan Africa, but the burden of coexistent cardiopulmonary disease in perinatally HIV‐positive adolescents on antiretroviral therapy (ART) has not been well described. The aim of this study was to investigate the prevalence and associations of cardiopulmonary dysfunction in adolescents with perinatally acquired HIV on ART.MethodsFor this cross‐sectional analysis, 515 perinatally HIV‐positive adolescents ages 9 to 14 years on ART for at least six months, and a comparator group of 110 age‐matched HIV‐uninfected adolescents were tested between August 2013 and April 2015 using echocardiography, six‐minute walk test (6MWT) and spirometry. Those with either abnormal spirometry or abnormal 6MWT and any right or left systolic or diastolic dysfunction or abnormal mean pulmonary arterial pressure were considered as having impaired cardiopulmonary function. Logistic regression was used to investigate determinants of impaired cardiopulmonary function.ResultsOverall, 474 adolescents with perinatally acquired HIV (mean [SD] age, 12 [1.6] years; median [IQR] ART duration, 7 [4.6 to 9.3] years; median [IQR] CD4 count, 712 [571 to 959] cell/mm3) and 109 HIV‐uninfected adolescents mean (SD) age 11.8 (1.8) years, had successful cardiac and lung function testing. Impaired cardiopulmonary function was detected in 13% of adolescents with perinatally acquired HIV and 8% of HIV‐uninfected adolescents, p = 0.136. Among adolescents with perinatally acquired HIV, those with low tricuspid annular plane systolic excursion (TAPSE) had significantly lower mean FEV1, 1.5 L versus 1.6 L, p = 0.011. Height (OR 0.7, 95%CI 0.5 to 0.9), body mass index (OR 0.7, 95%CI 0.5 to 0.9) and past pulmonary tuberculosis (OR 2.3, 95%CI 1.2 to 4.4) were significantly associated with a low cardiopulmonary function.ConclusionsDespite being on ART, cardiopulmonary dysfunction occurs in an appreciable proportion of perinatally HIV‐infected adolescents but no significant difference to uninfected controls. This finding requires further exploration. Factors associated with dysfunction may be amenable to public health interventions to reduce cardiopulmonary disease in this population.

Background The role of the human microbiome in health and disease is an emerging and important area of research; however, there is a concern that African populations are under-represented in human microbiome studies. We, therefore, conducted a systematic survey of African human microbiome studies to provide an overview and identify research gaps. Our secondary objectives were: (i) to determine the number of peer-reviewed publications; (ii) to identify the extent to which the researches focused on diseases identified by the World Health Organization [WHO] State of Health in the African Region Report as being the leading causes of morbidity and mortality in 2018; (iii) to describe the extent and pattern of collaborations between researchers in Africa and the rest of the world; and (iv) to identify leadership and funders of the studies. Methodology We systematically searched Medline via PubMed, Scopus, CINAHL, Academic Search Premier, Africa-Wide Information through EBSCOhost, and Web of Science from inception through to 1st April 2020. We included studies that characterized samples from African populations using next-generation sequencing approaches. Two reviewers independently conducted the literature search, title and abstract, and full-text screening, as well as data extraction. Results We included 168 studies out of 5515 records retrieved. Most studies were published in PLoS One (13%; 22/168), and samples were collected from 33 of the 54 African countries. The country where most studies were conducted was South Africa (27/168), followed by Kenya (23/168) and Uganda (18/168). 26.8% (45/168) focused on diseases of significant public health concern in Africa. Collaboration between scientists from the United States of America and Africa was most common (96/168). The first and/or last authors of 79.8% of studies were not affiliated with institutions in Africa. Major funders were the United States of America National Institutes of Health (45.2%; 76/168), Bill and Melinda Gates Foundation (17.8%; 30/168), and the European Union (11.9%; 20/168). Conclusions There are significant gaps in microbiome research in Africa, especially those focusing on diseases of public health importance. There is a need for local leadership, capacity building, intra-continental collaboration, and national government investment in microbiome research within Africa. Video Abstract

AbstractIntroductionThere are limited data on Tuberculosis (TB) in adolescents with perinatally acquired HIV (APHIV). We examined the incidence and determinants of TB infection and disease in the Cape Town Adolescent Antiretroviral Cohort (CTAAC).MethodsYouth between nine and fourteen years on antiretroviral therapy (ART) for more than six months in public sector care, and age‐matched HIV‐negative adolescents, were enrolled between July 2013 through March 2015 and followed six‐monthly. Data were censored on 31 October 2018. Symptom screening, chest radiograph, viral load, CD4 count, QuantiFERON (QFT) and sputum for Xpert MTB/RIF, microscopy, culture and sensitivity were performed annually. TB infection was defined by a QFT of >0.35 IU/mL. TB diagnosis was defined as confirmed (culture or Xpert MTB/RIF positive) or unconfirmed (clinical diagnosis and started on TB treatment). Analyses examined the incidence and determinants of TB infection and disease.ResultsOverall 496 HIV+ and 103 HIV‐negative participants (median age at enrolment 12 years (interquartile range, IQR 10.6 to 13.3) were followed for a median of 3.1 years (IQR 3.0 to 3.4); 50% (298/599) were male. APHIV initiated ART at median age 4.4 years (IQR 2.1 to 7.6). At enrolment, 376/496 (76%) had HIV viral load <40 copies/mL, median CD4 count was 713 cells/mm3 and 179/559 (32%) were QFT+, with no difference by HIV status (APHIV 154/468, 33%; HIV negative 25/91, 27%; p = 0.31). The cumulative QFT+ prevalence was similar (APHIV 225/492, 46%; 95%CI 41% to 50%; HIV negative 44/98, 45%; 95% CI 35% to 55%; p = 0.88). APHIV had a higher incidence of all TB disease than HIV‐negative adolescents (2.2/100PY, 95% CI 1.6 to 3.1 vs. 0.3/100PY, 95% CI 0.04 to 2.2; IRR 7.36, 95% CI 1.01 to 53.55). The rate of bacteriologically confirmed TB in APHIV was 1.3/100 PY compared to 0.3/100PY for HIV‐negative adolescents, suggesting a fourfold increased risk of developing TB disease in APHIV despite access to ART. In addition, a positive QFT at enrolment was not predictive of TB in this population.ConclusionsHigh incidence rates of TB disease occur in APHIV despite similar QFT conversion rates to HIV‐negative adolescents. Strategies to prevent TB in this vulnerable group must be strengthened.

AbstractIntroductionThere is a growing population of children who are HIV‐exposed and uninfected (HEU) with the successful expansion of antiretroviral therapy (ART) use in pregnancy. Children who are HEU are at risk of delayed neurodevelopment; however, there is limited research on early brain growth and maturation. We aimed to investigate the effects of in utero exposure to HIV/ART on brain structure of infants who are HEU compared to HIV‐unexposed (HU).MethodsMagnetic resonance imaging using a T2‐weighted sequence was undertaken in a subgroup of infants aged 2–6 weeks enrolled in the Drakenstein Child Health Study birth cohort, South Africa, between 2012 and 2015. Mother–child pairs received antenatal and postnatal HIV testing and ART per local guidelines. We compared subcortical and total grey matter volumes between HEU and HU groups using multivariable linear regression adjusting for infant age, sex, intracranial volume and socio‐economic variables. We further assessed associations between brain volumes with maternal CD4 cell count and ART exposure.ResultsOne hundred forty‐six infants (40 HEU; 106 HU) with high‐resolution images were included in this analysis (mean age 3 weeks; 50.7% male). All infants who were HEU were exposed to ART (88% maternal triple ART). Infants who were HEU had smaller caudate volumes bilaterally (5.4% reduction, p < 0.05) compared to HU infants. There were no group differences in other subcortical volumes (all p > 0.2). Total grey matter volume was also reduced in infants who were HEU (2.1% reduction, p < 0.05). Exploratory analyses showed that low maternal CD4 cell count (<350 cells/mm3) was associated with decreased infant grey matter volumes. There was no relationship between timing of ART exposure and grey matter volumes.ConclusionsLower caudate and total grey matter volumes were found in infants who were HEU compared to HU in the first weeks of life, and maternal immunosuppression was associated with reduced volumes. These findings suggest that antenatal HIV exposure may impact early structural brain development and improved antenatal HIV management may have the potential to optimize neurodevelopmental outcomes of children who are HEU.

AbstractIntroductionAdolescents with perinatally acquired HIV (PHIV) are at risk of chronic disease due to long‐standing immune suppression, HIV disease and antiretroviral therapy (ART) exposure. However, there are few data on multisystem disease in this population. We investigated the overlapping burden of neurocognitive, cardiovascular, respiratory and/or renal impairment among PHIV positive (PHIV+) adolescents.MethodsIn this cross‐sectional analysis, participants aged 9 to 14 years on ART for >6 months were recruited from seven sites across Cape Town from July 2013 through March 2015, together with age‐matched HIV‐negative (HIV‐) adolescents. Impairment at enrolment was assessed across neurocognitive functioning (using the youth‐International HIV Dementia Scale); cardiac function (echocardiogram abnormality); respiratory function (abnormal spirometry) and renal function (abnormal glomerular filtration rate).Results and DiscussionOverall, 384 PHIV+ and 95 HIV‐ adolescents were included (mean age, 11.9 years; 49% female). Median age of ART initiation was 4.2 years (IQR: 1.7 to 7.6) and median CD4 count was 709 (IQR: 556 to 944) with 302 (79%) of PHIV+ adolescents virologically suppressed. Abacavir and Zidovudine were the most commonly used nucleoside reverse transcriptase inhibitors (NRTIs) with 60% of adolescents on non‐nucleoside reverse transcriptase inhibitors (NNRTI) and 38% on a protease inhibitor (PI). Among PHIV+ adolescents, 167 (43.5%) had single system impairment only, 110 (28.6%) had two systems involved, and 39 (10.2%) had three or four systems involved. PHIV+ participants had more 2‐system and 3‐system impairment than HIV‐, 110 (28.6%) versus 17 (17.9%), p = 0.03 and 39 (10.2%) versus 3 (4.3%), p = 0.03. PHIV+ participants who had failed a year of school (73.8% vs. 46.4%, p = 0.00) and with a viral load >1000 copies/mL at enrolment (16.8% vs. 8.1%, p = 0.03) were more likely to have dual or multisystem impairment. Of those with cardiac impairment, 86.7% had an additional system impaired. Similarly, in those with neurocognitive impairment, almost 60% had additional systems impaired and of those with respiratory impairment, 74% had additional systems impaired.ConclusionsDespite relatively early ART initiation, there is a substantial burden of multisystem chronic impairment among PHIV+ adolescents. This phenomenon needs to be further explored as this population ages and begins to engage in adult lifestyle factors that may compound these impairments.

Childhood asthma is a huge global health burden. The spectrum of disease, diagnosis, and management vary depending on where children live in the world and how their community can care for them. Global improvement in diagnosis and management has been unsatisfactory, despite ever more evidence‐based guidelines. Guidelines alone are insufficient and need supplementing by government support, changes in policy, access to diagnosis and effective therapy for all children, with research to improve implementation. We propose a worldwide charter for all children with asthma, a roadmap to better education and training which can be adapted for local use. It includes access to effective basic asthma medications. It is not about new expensive medications and biologics as much can be achieved without these. If implemented carefully, the overall cost of care is likely to fall and the global future health and life chance of children with asthma will greatly improve. The key to success will be community involvement together with the local and national development of asthma champions. We call on governments, institutions, and healthcare services to support its implementation.

Childhood asthma is a huge global health burden. The spectrum of disease, diagnosis, and management vary depending on where children live in the world and how their community can care for them. Global improvement in diagnosis and management has been unsatisfactory, despite ever more evidence-based guidelines. Guidelines alone are insufficient and need supplementing by government support, changes in policy, access to diagnosis and effective therapy for all children, with research to improve implementation. We propose a worldwide charter for all children with asthma, a roadmap to better education and training which can be adapted for local use. It includes access to effective basic asthma medications. It is not about new expensive medications and biologics as much can be achieved without these. If implemented carefully, the overall cost of care is likely to fall and the global future health and life chance of children with asthma will greatly improve. The key to success will be community involvement together with the local and national development of asthma champions. We call on governments, institutions, and healthcare services to support its implementation.

Background Lung health is a critical area for research in sub-Saharan Africa. The International Multidisciplinary Programme to Address Lung Health and TB in Africa (IMPALA) is a collaborative programme that seeks to fill evidence gaps to address high-burden lung health issues in Africa. In order to generate demand for and facilitate use of IMPALA research by policy-makers and other decision-makers at the regional level, an analysis of regional lung health policies and stakeholders will be undertaken to inform a programmatic strategy for policy engagement. Methods and analysis This analysis will be conducted in three phases. The first phase will be a rapid desk review of regional lung health policies and stakeholders that seeks to understand the regional lung health policy landscape, which issues are prioritised in existing regional policy, key regional actors, and opportunities for engagement with key stakeholders. The second phase will be a rapid desk review of the scientific literature, expanding on the work in the first phase by looking at the external factors that influence regional lung health policy, the ways in which regional bodies influence policy at the national level, investments in lung health, structures for discussion and advocacy, and the role of evidence at the regional level. The third phase will involve a survey of IMPALA partners and researchers as well as interviews with key regional stakeholders to further shed light on regional policies, including policy priorities and gaps, policy implementation status and challenges, stakeholders, and platforms for engagement and promoting uptake of evidence. Discussion Health policy analysis provides insights into power dynamics and the political nature of the prioritisation of health issues, which are often overlooked. In order to ensure the uptake of new knowledge and evidence generated by IMPALA, it is important to consider these complex factors.

BACKGROUND: Over the last 30 years, South Africa has experienced four 'colliding epidemics' of HIV and tuberculosis, chronic illness and mental health, injury and violence, and maternal, neonatal, and child mortality, which have had substantial effects on health and well-being. Using data from the 2019 Global Burden of Diseases, Injuries and Risk Factors Study (GBD 2019), we evaluated national and provincial health trends and progress towards important Sustainable Development Goal targets from 1990 to 2019. METHODS: We analysed GBD 2019 estimates of mortality, non-fatal health loss, summary health measures and risk factor burden, comparing trends over 1990-2007 and 2007-2019. Additionally, we decomposed changes in life expectancy by cause of death and assessed healthcare system performance. RESULTS: Across the nine provinces, inequalities in mortality and life expectancy increased over 1990-2007, largely due to differences in HIV/AIDS, then decreased over 2007-2019. Demographic change and increases in non-communicable diseases nearly doubled the number of years lived with disability between 1990 and 2019. From 1990 to 2019, risk factor burdens generally shifted from communicable and nutritional disease risks to non-communicable disease and injury risks; unsafe sex remained the top risk factor. Despite widespread improvements in healthcare system performance, the greatest gains were generally in economically advantaged provinces. CONCLUSIONS: Reductions in HIV/AIDS and related conditions have led to improved health since 2007, though most provinces still lag in key areas. To achieve health targets, provincial governments should enhance health investments and exchange of knowledge, resources and best practices alongside populations that have been left behind, especially following the COVID-19 pandemic.

BACKGROUND: Over the last 30 years, South Africa has experienced four 'colliding epidemics' of HIV and tuberculosis, chronic illness and mental health, injury and violence, and maternal, neonatal, and child mortality, which have had substantial effects on health and well-being. Using data from the 2019 Global Burden of Diseases, Injuries and Risk Factors Study (GBD 2019), we evaluated national and provincial health trends and progress towards important Sustainable Development Goal targets from 1990 to 2019. METHODS: We analysed GBD 2019 estimates of mortality, non-fatal health loss, summary health measures and risk factor burden, comparing trends over 1990–2007 and 2007–2019. Additionally, we decomposed changes in life expectancy by cause of death and assessed healthcare system performance. RESULTS: Across the nine provinces, inequalities in mortality and life expectancy increased over 1990–2007, largely due to differences in HIV/AIDS, then decreased over 2007–2019. Demographic change and increases in non-communicable diseases nearly doubled the number of years lived with disability between 1990 and 2019. From 1990 to 2019, risk factor burdens generally shifted from communicable and nutritional disease risks to non-communicable disease and injury risks; unsafe sex remained the top risk factor. Despite widespread improvements in healthcare system performance, the greatest gains were generally in economically advantaged provinces. CONCLUSIONS: Reductions in HIV/AIDS and related conditions have led to improved health since 2007, though most provinces still lag in key areas. To achieve health targets, provincial governments should enhance health investments and exchange of knowledge, resources and best practices alongside populations that have been left behind, especially following the COVID-19 pandemic.

Background: Influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus are the most common viruses associated with acute lower respiratory infections in young children (<5 years) and older people (≥65 years). A global report of the monthly activity of these viruses is needed to inform public health strategies and programmes for their control. Methods: In this systematic analysis, we compiled data from a systematic literature review of studies published between Jan 1, 2000, and Dec 31, 2017; online datasets; and unpublished research data. Studies were eligible for inclusion if they reported laboratory-confirmed incidence data of human infection of influenza virus, respiratory syncytial virus, parainfluenza virus, or metapneumovirus, or a combination of these, for at least 12 consecutive months (or 52 weeks equivalent); stable testing practice throughout all years reported; virus results among residents in well-defined geographical locations; and aggregated virus results at least on a monthly basis. Data were extracted through a three-stage process, from which we calculated monthly annual average percentage (AAP) as the relative strength of virus activity. We defined duration of epidemics as the minimum number of months to account for 75% of annual positive samples, with each component month defined as an epidemic month. Furthermore, we modelled monthly AAP of influenza virus and respiratory syncytial virus using site-specific temperature and relative humidity for the prediction of local average epidemic months. We also predicted global epidemic months of influenza virus and respiratory syncytial virus on a 5° by 5° grid. The systematic review in this study is registered with PROSPERO, number CRD42018091628. Findings: We initally identified 37 335 eligible studies. Of 21 065 studies remaining after exclusion of duplicates, 1081 full-text articles were assessed for eligibility, of which 185 were identified as eligible. We included 246 sites for influenza virus, 183 sites for respiratory syncytial virus, 83 sites for parainfluenza virus, and 65 sites for metapneumovirus. Influenza virus had clear seasonal epidemics in winter months in most temperate sites but timing of epidemics was more variable and less seasonal with decreasing distance from the equator. Unlike influenza virus, respiratory syncytial virus had clear seasonal epidemics in both temperate and tropical regions, starting in late summer months in the tropics of each hemisphere, reaching most temperate sites in winter months. In most temperate sites, influenza virus epidemics occurred later than respiratory syncytial virus (by 0·3 months [95% CI −0·3 to 0·9]) while no clear temporal order was observed in the tropics. Parainfluenza virus epidemics were found mostly in spring and early summer months in each hemisphere. Metapneumovirus epidemics occurred in late winter and spring in most temperate sites but the timing of epidemics was more diverse in the tropics. Influenza virus epidemics had shorter duration (3·8 months [3·6 to 4·0]) in temperate sites and longer duration (5·2 months [4·9 to 5·5]) in the tropics. Duration of epidemics was similar across all sites for respiratory syncytial virus (4·6 months [4·3 to 4·8]), as it was for metapneumovirus (4·8 months [4·4 to 5·1]). By comparison, parainfluenza virus had longer duration of epidemics (6·3 months [6·0 to 6·7]). Our model had good predictability in the average epidemic months of influenza virus in temperate regions and respiratory syncytial virus in both temperate and tropical regions. Through leave-one-out cross validation, the overall prediction error in the onset of epidemics was within 1 month (influenza virus −0·2 months [−0·6 to 0·1]; respiratory syncytial virus 0·1 months [−0·2 to 0·4]). Interpretation: This study is the first to provide global representations of month-by-month activity of influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus. Our model is helpful in predicting the local onset month of influenza virus and respiratory syncytial virus epidemics. The seasonality information has important implications for health services planning, the timing of respiratory syncytial virus passive prophylaxis, and the strategy of influenza virus and future respiratory syncytial virus vaccination. Funding: European Union Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU).