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Summary Background A large, double-blind, randomised, placebo-controlled trial of repeat BCG found 49% efficacy against leprosy but no protection against tuberculosis after 6–9 years’ follow-up in 1995. We report here additional follow-up, which resulted in greatly increased tuberculosis case numbers, and allowed subgroup analysis. Methods Nearly 47 000 individuals of all ages living in northern Malawi with a BCG vaccine scar were randomly assigned (1:1) between 1986 and 1989 to receive a second BCG or placebo. The investigators and project staff remained masked to all interventions. Enhanced passive surveillance ensured ascertainment of tuberculosis and leprosy to the end of 2018. Tuberculosis case definitions included rigorous microbiological or histological confirmation. Prespecified subgroup analyses were by tuberculosis type, age at vaccination, time since vaccination, previous tuberculin reactivity, HIV status and Mycobacterium tuberculosis lineage. The original trial is registered with ISRCTN registry, ISRCTN11311670. Findings In follow-up until Dec 31, 2018, 824 participants had developed tuberculosis, including 786 with pulmonary disease, of whom 383 (63%) of 607 with known HIV status were HIV positive. There was no effect of a second BCG overall (odds ratio [OR] 0·92; 95% CI 0·80–1·05), or for pulmonary (0·93; 0·81–1·07), or lymph node tuberculosis (0·60; 0·31–1·17). The OR was lower for those with known HIV-negative tuberculosis (0·77; 0·59–1·00), for those vaccinated as children (aged

The burden of kidney disease in many African countries is unknown. Equations used to estimate kidney function from serum creatinine have limited regional validation. We sought to determine the most accurate way to measure kidney function and thus estimate the prevalence of impaired kidney function in African populations.We measured serum creatinine, cystatin C, and glomerular filtration rate (GFR) using the slope-intercept method for iohexol plasma clearance (mGFR) in population cohorts from Malawi, Uganda, and South Africa. We compared performance of creatinine and cystatin C-based estimating equations to mGFR, modelled and validated a new creatinine-based equation, and developed a multiple imputation model trained on the mGFR sample using age, sex, and creatinine as the variables to predict the population prevalence of impaired kidney function in west, east, and southern Africa.Of 3025 people who underwent measured GFR testing (Malawi n=1020, South Africa n=986, and Uganda n=1019), we analysed data for 2578 participants who had complete data and adequate quality measurements. Among 2578 included participants, creatinine-based equations overestimated kidney function compared with mGFR, worsened by use of ethnicity coefficients. The greatest bias occurred at low kidney function, such that the proportion with GFR of less than 60 mL/min per 1·73 mEstimating GFR using serum creatinine substantially underestimates the individual and population-level burden of impaired kidney function in Africa with implications for understanding disease progression and complications, clinical care, and service provision. Scalable and affordable ways to accurately identify impaired kidney function in Africa are urgently needed.The GSK Africa Non-Communicable Disease Open Lab.For the Luganda, Chichewa and Xitsonga translations of the abstract see Supplementary Materials section.

Introduction Low high-density lipoprotein (HDL) is widely used as a marker of cardiovascular disease risk, although this relationship is not causal and is likely mediated through associations with other risk factors. Low HDL is extremely common in sub-Saharan African populations, and this has often been interpreted to indicate that these populations will have increased cardiovascular risk. We aimed to determine whether the association between HDL and other cardiovascular risk factors differed between populations in sub-Saharan Africa and the UK.Methods We compared data from adults living in Uganda and Malawi (n=26 216) and in the UK (n=8747). We examined unadjusted and adjusted levels of HDL and applied the WHO recommended cut-offs for prevalence estimates. We used spline and linear regression to assess the relationship between HDL and other cardiovascular risk factors.Results HDL was substantially lower in the African than in the European studies (geometric mean 0.9textendash1.2 mmol/L vs 1.3textendash1.8 mmol/L), with African prevalence of low HDL as high as 77geometric mean 3.3textendash3.9 mmol/L vs 4.6textendash5.4 mmol/L). In comparison with European studies the relationship between HDL and adiposity (body mass index, waist to hip ratio) was greatly attenuated in African studies and the relationship with non-HDL cholesterol reversed: in African studies low HDL was associated with lower non-HDL cholesterol. The association between sex and HDL was also different; using the WHO sex-specific definitions, low HDL was substantially more common among women (69textendash77 than men (41textendash59 in Uganda/Malawi.Conclusion The relationship between HDL and sex, adiposity and non-HDL cholesterol in sub-Saharan Africa is different from European populations. In sub-Saharan Africans low HDL is a marker of low overall cholesterol and sex differences are markedly attenuated. Therefore low HDL in isolation is unlikely to indicate raised cardiovascular risk and the WHO sex-based cut-offs are inappropriate.Data from the EXTEND study are available through application to the Peninsula Research Bank (https://exetercrfnihr.org/about/exeter-10000-prb/). For enquiries about access to the Exeter Family Study please contact BS (B.Shields@exeter.ac.uk). The MEIRU data are available through the LSHTM Research Data Compass (https://datacompass.lshtm.ac.uk/961/).

Background The prevalence of excess adiposity, as measured by elevated body mass index (BMI) and waist-hip ratio (WHR), is increasing in sub-Saharan African (SSA) populations. This could add a considerable burden of cardiovascular and metabolic diseases for which these populations are currently ill-prepared. Evidence from white, European origin populations shows that higher adiposity leads to an adverse lipid profile; whether these associations are similar in all SSA populations requires further exploration. This study compared the association of BMI and WHR with lipid profile in urban Malawi with a contemporary cohort with contrasting socioeconomic, demographic, and ethnic characteristics in the United Kingdom (UK). Methods We used data from 1248 adolescents (mean 18.7 years) and 2277 Malawian adults (mean 49.8 years), all urban-dwelling, and from 3201 adolescents (mean 17.8 years) and 6323 adults (mean 49.7 years) resident in the UK. Adiposity measures and fasting lipids were assessed in both settings, and the associations of BMI and WHR with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) were assessed by sex and age groups in both studies. Results Malawian female adults were more adipose and had more adverse lipid profiles than their UK counterparts. In contrast, Malawian adolescent and adult males were leaner and had more favourable lipid profiles than in the UK. Higher BMI and WHR were associated with increased TC, LDL-C and TG and reduced HDL-C in both settings. The magnitude of the associations of BMI and WHR with lipids was mostly similar or slightly weaker in the Malawian compared with the UK cohort in both adolescents and adults. One exception was the stronger association between increasing adiposity and elevated TC and LDL-C in Malawian compared to UK men. Conclusions Malawian adult women have greater adiposity and more adverse lipid profiles compared with their UK counterparts. Similar associations of adiposity with adverse lipid profiles were observed for Malawian and UK adults in most age and sex groups studied. Sustained efforts are urgently needed to address the excess adiposity and adverse lipid profiles in Malawi to mitigate a future epidemic of cardio-metabolic disease among the poorest populations.

Understanding host and pathogen factors that influence tuberculosis (TB) transmission can inform strategies to eliminate the spread of Mycobacterium tuberculosis (Mtb). Determining transmission links between cases of TB is complicated by a long and variable latency period and undiagnosed cases, although methods are improving through the application of probabilistic modelling and whole-genome sequence analysis. Using a large dataset of 1857 whole-genome sequences and comprehensive metadata from Karonga District, Malawi, over 19 years, we reconstructed Mtb transmission networks using a two-step Bayesian approach that identified likely infector and recipient cases, whilst robustly allowing for incomplete case sampling. We investigated demographic and pathogen genomic variation associated with transmission and clustering in our networks. We found that whilst there was a significant decrease in the proportion of infectors over time, we found higher transmissibility and large transmission clusters for lineage 2 (Beijing) strains. By performing evolutionary convergence testing (phyC) and genome-wide association analysis (GWAS) on transmitting versus non-transmitting cases, we identified six loci, PPE54, accD2, PE_PGRS62, rplI, Rv3751 and Rv2077c, that were associated with transmission. This study provides a framework for reconstructing large-scale Mtb transmission networks. We have highlighted potential host and pathogen characteristics that were linked to increased transmission in a high-burden setting and identified genomic variants that, with validation, could inform further studies into transmissibility and TB eradication.

Understanding host and pathogen factors that influence tuberculosis (TB) transmission can inform strategies to eliminate the spread of Mycobacterium tuberculosis (Mtb). Determining transmission links between cases of TB is complicated by a long and variable latency period and undiagnosed cases, although methods are improving through the application of probabilistic modelling and whole-genome sequence analysis. Using a large dataset of 1857 whole-genome sequences and comprehensive metadata from Karonga District, Malawi, over 19 years, we reconstructed Mtb transmission networks using a two-step Bayesian approach that identified likely infector and recipient cases, whilst robustly allowing for incomplete case sampling. We investigated demographic and pathogen genomic variation associated with transmission and clustering in our networks. We found that whilst there was a significant decrease in the proportion of infectors over time, we found higher transmissibility and large transmission clusters for lineage 2 (Beijing) strains. By performing evolutionary convergence testing (phyC) and genome-wide association analysis (GWAS) on transmitting versus non-transmitting cases, we identified six loci, PPE54, accD2, PE_PGRS62, rplI, Rv3751 and Rv2077c, that were associated with transmission. This study provides a framework for reconstructing large-scale Mtb transmission networks. We have highlighted potential host and pathogen characteristics that were linked to increased transmission in a high-burden setting and identified genomic variants that, with validation, could inform further studies into transmissibility and TB eradication.

Background: Low high-density lipoprotein (HDL) is widely used as a marker of cardiovascular disease risk, despite lack of evidence of a casual role. It is extremely common in sub-Saharan African populations, where reported cardiovascular risk is low. We aimed to determine whether the association between HDL and other cardiovascular risk factors differed between populations in sub-Saharan Africa and the UK. Methods: We compared data from adults living in Uganda and Malawi (n=26,216) and the UK (n=8,747). We examined unadjusted and adjusted levels of HDL, and applied WHO recommended cut-offs for prevalence estimates. We used spline and linear regression to assess the relationship between HDL and other cardiovascular risk factors. Findings: Geometric-mean HDL was substantially lower in the African than European studies (0.9-1.2mmol/l vs 1.3-1.8mmol/l), with African prevalence of low-HDL as high as 77%. In comparison to European studies the relationship between HDL and adiposity (BMI, waist-hip ratio) was greatly attenuated in African studies, and the relationship with non-HDL cholesterol reversed: low HDL was associated with lower non-HDL. The association between sex and HDL was also markedly different; using WHO sex-specific definitions low-HDL was substantially more common among women (69-77%) than men (41-59%) in Uganda/Malawi. Interpretation: The relationship between HDL and sex, adiposity and Non-HDL cholesterol in sub-Saharan Africa is markedly different from European populations. Low HDL is a marker of low overall cholesterol, and sex differences are markedly attenuated. Therefore low HDL may not be a reliable marker of cardiovascular risk in Sub-Saharan Africa, and WHO sex based cut-offs are inappropriate. Funding Statement: This work is funded by the National Institute of Health and Social Care (UK), NIHR Global Health Group 17/63/131. Declaration of Interests: All authors report no conflicts of interest in relation to this work. Ethics Approval Statement: The Ugandan cohort was approved by the Uganda Virus Research Institute Science and Ethics Committee and the Uganda National Council of Science and Technology. The Malawian study was approved by the National Health Sciences Research Committee of Malawi nd London School of Hygiene and Tropical Medicine Ethics Committee, UK.The Exeter 10,000 study was approved by the UK NHS Health Research Authority South West Ethics Committee. The Exeter Family Study was approved by the University of Exeter Research Ethics Committee, UK.

Background: Sub-Saharan Africa faces region-specific risk factors for chronic kidney disease (CKD), such as nephrotoxic herbal medicines, antiretroviral therapy and infections, in addition to hypertension and diabetes. However, large epidemiological studies from this area are scarce. Methods: In a cross-sectional survey of non-communicable diseases, we conducted a prevalence sub-study of CKD in two Malawian populations. Study participants (N=5264) of 18 years of age and above were recruited and data on demographics and CKD risk factors were collected. Glomerular filtration rate was estimated (eGFR) using the CKD-EPI equation. Results: The prevalence of eGFR2 was 1.4% (95% CI 1.1 – 1.7%) and eGFR2 was 20.6% (95% CI 19.5 – 21.7%). The rural area had higher age-standardized prevalence of both eGFR2, at 1.8% (95% CI 1.4 – 2.3) and eGFR 2 of 0.69 (95% CI 0.49–0.96; p=0.03). Of participants with eGFR2, 14 (19.4%) had no history of hypertension, diabetes or HIV, while 36 (50%) had a single risk factor of being hypertensive. Conclusions: Impaired renal function is prevalent, but lower than expected, in rural and urban Malawi. Further research is needed to increase understanding of CKD incidence, survival and validation of eGFR calculations in this population.

BackgroundEvidence from high-income countries shows that higher adiposity results in an adverse lipid profile, but it is unclear whether this association is similar in Sub-Saharan African (SSA) populations. This study aimed to assess the association between total and central adiposity measures and lipid profile in Malawi, exploring differences by sex and area of residence (rural/urban).MethodsData from 12,847 rural and 12,096 urban Malawian residents were used. The associations of body mass index (BMI) and waist-hip ratio (WHR) with fasting lipids (total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprote in-cholesterol (HDL-C) and triglycerides (TG)) were assessed by area and sex.ResultsA great proportion of adults have high BMI and WHR, and this was associated with adverse lipid profiles; higher BMI and WHR were linearly associated with increased TC, LDL-C and TG and reduced HDL-C. BMI was more strongly related to fasting lipids than was WHR. The associations of adiposity with adverse lipid profile were stronger in urban compared with rural residents.ConclusionsThe consistent associations observed of higher adiposity with adverse lipid profiles in females and males living in rural and urban areas of Malawi highlight the emerging adverse cardio-metabolic epidemic in this poor population. Our findings underline the potential utility of BMI in estimating cardiovascular risk and highlight the need for greater investment to understand the long-term health outcomes of obesity and adverse lipid profiles and the extent to which lifestyle changes and treatments effectively prevent and modify adverse cardio-metabolic outcomes.Key messagesHigher body mass index (BMI) and waist to hip ratio (WHR) are associated with increased total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) and triglycerides (TG) and reduced high density lipoprotein-cholesterol (HDL-C) in a large sub-Saharan African population.Total adiposity is more strongly associated with adverse lipid profile than central adiposity.Despite the higher BMI and the less favourable lipid profile in urban residents, stronger associations between BMI and TC, LDL-C and TG are observed in rural than urban residents.

Background Mixed, polyclonal Mycobacterium tuberculosis infection occurs in natural populations. Developing an effective method for detecting such cases is important in measuring the success of treatment and reconstruction of transmission between patients. Using whole genome sequence (WGS) data, we assess two methods for detecting mixed infection: (i) a combination of the number of heterozygous sites and the proportion of heterozygous sites to total SNPs, and (ii) Bayesian model-based clustering of allele frequencies from sequencing reads at heterozygous sites. Results In silico and in vitro artificially mixed and known pure M. tuberculosis samples were analysed to determine the specificity and sensitivity of each method. We found that both approaches were effective in distinguishing between pure strains and mixed infection where there was relatively high (> 10%) proportion of a minor strain in the mixture. A large dataset of clinical isolates (n = 1963) from the Karonga Prevention Study in Northern Malawi was tested to examine correlations with patient characteristics and outcomes with mixed infection. The frequency of mixed infection in the population was found to be around 10%, with an association with year of diagnosis, but no association with age, sex, HIV status or previous tuberculosis. Conclusions Mixed Mycobacterium tuberculosis infection was identified in silico using whole genome sequence data. The methods presented here can be applied to population-wide analyses of tuberculosis to estimate the frequency of mixed infection, and to identify individual cases of mixed infections. These cases are important when considering the evolution and transmission of the disease, and in patient treatment. Electronic supplementary material The online version of this article (10.1186/s12864-018-4988-z) contains supplementary material, which is available to authorized users.

Background: \ud High dietary sodium intake is a major risk factor for hypertension. Data on population sodium intake are scanty in sub-Saharan Africa, despite a high hypertension prevalence in most countries.\ud \ud Objective: \ud We aimed to determine daily sodium intake in urban and rural communities in Malawi.\ud \ud Design: \ud In an observational cross-sectional survey, data were collected on estimated household-level per capita sodium intake, based on how long participants reported that a defined quantity of plain salt lasts in a household. In a subset of 2078 participants, 24-h urinary sodium was estimated from a morning spot urine sample.\ud \ud Results: \ud Of 29,074 participants, 52.8% of rural and 50.1% of urban individuals lived in households with an estimated per capita plain salt consumption >5 g/d. Of participants with urinary sodium data, 90.8% of rural and 95.9% of urban participants had estimated 24-h urinary sodium >2 g/d; there was no correlation between household per capita salt intake and estimated 24-h urinary sodium excretion. Younger adults were more likely to have high urinary sodium and to eat food prepared outside the home than were those over the age of 60 y. Households with a member with previously diagnosed hypertension had reduced odds (OR: 0.59; 95% CI: 0.51, 0.68) of per capita household plain salt intake >5 g/d, compared with those where hypertension was undiagnosed.\ud \ud Conclusions: \ud Sodium consumption exceeds the recommended amounts for most of the population in rural and urban Malawi. Population-level interventions for sodium intake reduction with a wide focus are needed, targeting both sources outside the home as well as home cooking. This trial was registered at clinicaltrials.gov as NCT03422185.

To improve understanding of the factors influencing tuberculosis transmission and the role of pathogen variation, we sequenced all available specimens from patients diagnosed over 15 years in a whole district in Malawi. Mycobacterium tuberculosis lineages were assigned and transmission networks constructed, allowing ≤10 single nucleotide polymorphisms (SNPs) difference. We defined disease as due to recent infection if the network-determined source was within 5 years, and assessed transmissibility from forward transmissions resulting in disease. High-quality sequences were available for 1687 disease episodes (72% of all culture-positive episodes): 66% of patients linked to at least one other patient. The between-patient mutation rate was 0.26 SNPs/year (95% CI 0.21–0.31). We showed striking differences by lineage in the proportion of disease due to recent transmission and in transmissibility (highest for lineage-2 and lowest for lineage-1) that were not confounded by immigration, HIV status or drug resistance. Transmissions resulting in disease decreased markedly over time. DOI: http://dx.doi.org/10.7554/eLife.05166.001, eLife digest Tuberculosis is an important public health threat around the globe and is particularly common in developing countries. It is difficult to control the spread of the disease because the bacteria that cause it can spread when an infected individual coughs or sneezes. It may take years for an infected individual to develop symptoms of tuberculosis so it can be hard to trace the source of an outbreak, and people infected with HIV are particularly susceptible to the disease. The bacterium that causes the majority of cases of tuberculosis is called Mycobacterium tuberculosis. There are several different varieties or ‘lineages’ of M. tuberculosis, and it is thought that they may vary in their ability to spread and cause disease. However, the results of previous studies have been inconsistent and there also seems to be a lot of variation between strains within the same lineage. In this study, Guerra-Assunção et al. used an approach called whole genome sequencing alongside more traditional methods to study the spread of tuberculosis in Malawi. They sequenced the genomes of every available sample of M. tuberculosis collected from patients in the Karonga district of Malawi over a 15-year period. This produced high-quality DNA sequence data about the bacteria responsible for almost 1700 cases of disease. Using this massive amount of data, Guerra-Assunção et al. constructed networks that showed how the bacteria had spread in the community. This revealed that there were differences between the ability of the various M. tuberculosis lineages to cause disease and to spread in communities. For example, lineage 1 was less likely than the other lineages to cause disease soon after infecting an individual and was less able to spread. The data also show that the proportion of cases of disease due to recent infection declined substantially during the 15-year period. This indicates that the tuberculosis and HIV control programmes in the area have been successful. Guerra-Assunção et al.'s findings show that it is possible to understand how tuberculosis is transmitted on a large scale. The next challenge is to understand why the lineages differ in their ability to cause disease and spread between individuals. DOI: http://dx.doi.org/10.7554/eLife.05166.002

Background. Recurrent tuberculosis is a major health burden and may be due to relapse with the original strain or reinfection with a new strain. Methods. In a population-based study in northern Malawi, patients with tuberculosis diagnosed from 1996 to 2010 were actively followed after the end of treatment. Whole-genome sequencing with approximately 100-fold coverage was performed on all available cultures. Results of IS6110 restriction fragment-length polymorphism analyses were available for cultures performed up to 2008. Results. Based on our data, a difference of ≤10 single-nucleotide polymorphisms (SNPs) was used to define relapse, and a difference of >100 SNPs was used to define reinfection. There was no evidence of mixed infections among those classified as reinfections. Of 1471 patients, 139 had laboratory-confirmed recurrences: 55 had relapse, and 20 had reinfection; for 64 type of recurrence was unclassified. Almost all relapses occurred in the first 2 years. Human immunodeficiency virus infection was associated with reinfection but not relapse. Relapses were associated with isoniazid resistance, treatment before 2007, and lineage-3 strains. We identified several gene variants associated with relapse. Lineage-2 (Beijing) was overrepresented and lineage-1 underrepresented among the reinfecting strains (P = .004). Conclusions. While some of the factors determining recurrence depend on the patient and their treatment, differences in the Mycobacterium tuberculosis genome appear to have a role in both relapse and reinfection.

Background In Africa, albendazole and ivermectin are currently used in combination for annual mass drug administration (MDA) for lymphatic filariasis (LF) elimination. Rapid and sustained clearance is desirable for public health impact and elimination of LF. Increasing the dose and/or frequency of albendazole and ivermectin treatment may be more effective in clearing microfilariae than standard MDA. Methods We conducted a randomised controlled open label trial in northern Malawi comparing three modified treatment groups to standard dosage of ivermectin and albendazole in adults with confirmed circulating LF antigen and microfilaria. Participants were followed-up every 6 months for 2 years for repeat microfilarial counts and safety assessments. Results A total of 1851 adults were screened and 70 with microfilarial counts >80 microfilariae/ml were randomised. All treatment groups achieved a significant reduction of microfilariae levels by 12- and 24-months of follow-up. Doubling the standard dose and administering it twice yearly showed a non-significant tendency towards faster and more complete clearance. There were no serious adverse reactions. Conclusions In this small study, all regimens effectively cleared microfilaria. Standard treatment may be adequate in settings like Malawi but not in all endemic settings and larger studies are required to demonstrate benefit of higher dosages. [ClinicalTrials.gov identifier: NCT01213576].