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Strain-specific genomic diversity in the Mycobacterium tuberculosis complex (MTBC) is an important factor in pathogenesis that may affect virulence, transmissibility, host response and emergence of drug resistance. Several systems have been proposed to classify MTBC strains into distinct lineages and families. Here, we investigate single-nucleotide polymorphisms (SNPs) as robust (stable) markers of genetic variation for phylogenetic analysis. We identify ~92k SNP across a global collection of 1,601 genomes. The SNP-based phylogeny is consistent with the gold-standard regions of difference (RD) classification system. Of the ~7k strain-specific SNPs identified, 62 markers are proposed to discriminate known circulating strains. This SNP-based barcode is the first to cover all main lineages, and classifies a greater number of sublineages than current alternatives. It may be used to classify clinical isolates to evaluate tools to control the disease, including therapeutics and vaccines whose effectiveness may vary by strain type. Genetic variation in Mycobacterium tuberculosis complex (MTBC) bacteria is responsible for differences in factors such as virulence and transmissibility. Here, the authors analyse the genomes of 1,601 MTBC isolates from diverse geographic locations and identify 62 SNPs that may be used to resolve lineages and sublineages of these strains.

Molecular data are now widely used in epidemiological studies to investigate the transmission, distribution, biology, and diversity of pathogens. Our objective was to establish recommendations to support good scientific reporting of molecular epidemiological studies to encourage authors to consider specific threats to valid inference. The statement Strengthening the Reporting of Molecular Epidemiology for Infectious Diseases (STROME-ID) builds upon the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) initiative. The STROME-ID statement was developed by a working group of epidemiologists, statisticians, bioinformaticians, virologists, and microbiologists with expertise in control of infection and communicable diseases. The statement focuses on issues relating to the reporting of epidemiological studies of infectious diseases using molecular data that were not addressed by STROBE. STROME-ID addresses terminology, measures of genetic diversity within pathogen populations, laboratory methods, sample collection, use of molecular markers, molecular clocks, timeframe, multiple-strain infections, non-independence of infectious-disease data, missing data, ascertainment bias, consistency between molecular and epidemiological data, and ethical considerations with respect to infectious-disease research. In total, 20 items were added to the 22 item STROBE checklist. When used, the STROME-ID recommendations should advance the quality and transparency of scientific reporting, with clear benefits for evidence reviews and health-policy decision making.

We aimed to assess whether interferon-γ release assays (IGRAs) can predict the development of active tuberculosis and whether the predictive ability of these tests is better than that of the tuberculin skin test (TST). Longitudinal studies of the predictive value for active tuberculosis of in-house or commercial IGRAs were identified through searches of PubMed, Embase, Biosis, and Web of Science and complementary manual searches up to June 30, 2011. Eligible studies included adults or children, with or without HIV, who were free of active tuberculosis at study baseline. We summarised incidence rates in forest plots and pooled data with random-effects models when appropriate. We calculated incidence rate ratios (IRR) for rates of disease progression in IGRA-positive versus IGRA-negative individuals. 15 studies had a combined sample size of 26 680 participants. Incidence of tuberculosis during a median follow-up of 4 years (IQR 2–6), even in IGRA-positive individuals, was 4–48 cases per 1000 person-years. Seven studies with no possibility of incorporation bias and reporting baseline stratification on the basis of IGRA results showed a moderate association between positive results and subsequent tuberculosis (pooled unadjusted IRR 2·10, 95% CI 1·42–3·08). Compared with test-negative results, IGRA-positive and TST-positive results were much the same with regard to the risk of tuberculosis (pooled IRR in the five studies that used both was 2·11 [95% CI 1·29–3·46] for IGRA vs 1·60 [0·94–2·72] for TST at the 10 mm cutoff). However, the proportion of IGRA-positive individuals in seven of 11 studies that assessed both IGRAs and TST was generally lower than TST-positive individuals. Neither IGRAs nor the TST have high accuracy for the prediction of active tuberculosis, although use of IGRAs in some populations might reduce the number of people considered for preventive treatment. Until more predictive biomarkers are identified, existing tests for latent tuberculosis infection should be chosen on the basis of relative specificity in different populations, logistics, cost, and patients' preferences rather than on predictive ability alone. Special Programme for Research and Training in Tropical Diseases (WHO), Wellcome Trust, Canadian Institutes of Health Research, UK Medical Research Council, and the European and Developing Countries Clinical Trials Partnership.

Antiretroviral therapy reduces the risk of tuberculosis, but tuberculosis is more common in people with HIV than in people without HIV. We aimed to assess the effect of isoniazid preventive therapy on the risk of tuberculosis in people infected with HIV-1 concurrently receiving antiretroviral therapy. For this pragmatic randomised double-blind, placebo-controlled trial in Khayelitsha, South Africa, we randomly assigned (1:1) patients to receive either isoniazid preventive therapy or a placebo for 12 months (could be completed during 15 months). Randomisation was done with random number generator software. Participants, physicians, and pharmacy staff were masked to group assignment. The primary endpoint was time to development of incident tuberculosis (definite, probable, or possible). We excluded tuberculosis at screening by sputum culture. We did a modified intention-to-treat analysis and excluded all patients randomly assigned to groups who withdrew before receiving study drug or whose baseline sputum culture results suggested prevalent tuberculosis. This study is registered with ClinicalTrials.gov, number NCT00463086. 1329 participants were randomly assigned to receive isoniazid preventive therapy (n=662) or placebo (n=667) between Jan 31, 2008, and Sept 31, 2011, and contributed 3227 person-years of follow-up to the analysis. We recorded 95 incident cases of tuberculosis; 37 were in the isoniazid preventive therapy group (2·3 per 100 person-years, 95% CI 1·6–3·1), and 58 in the placebo group (3·6 per 100 person-years, 2·8–4·7; hazard ratio [HR] 0·63, 95% CI 0·41–0·94). Study drug was discontinued because of grade 3 or 4 raised alanine transaminase concentrations in 19 of 662 individuals in the isoniazid preventive therapy group and ten of the 667 individuals in the placebo group (risk ratio 1·9, 95% CI 0·90–4·09). We noted no evidence that the effect of isoniazid preventive therapy was restricted to patients who were positive on tuberculin skin test or interferon gamma release assay (adjusted HR for patients with negative tests 0·43 [0·21–0·86] and 0·43 [0·20–0·96]; for positive tests 0·86 [0·37–2·00] and 0·55 [0·26–1·24], respectively). Without a more predictive test or a multivariate algorithm that predicts benefit, isoniazid preventive therapy should be recommended to all patients receiving antiretroviral therapy in moderate or high incidence areas irrespective of tuberculin skin test or interferon gamma release assay status. Department of Health of South Africa, the Wellcome Trust, Médecins Sans Frontières, European and Developing Countries Clinical Trials Partnership, Foundation for Innovation and New Diagnostics, the European Union, and Hasso Plattner (Institute of Infectious Diseases and Molecular Medicine, University of Cape Town).

The proportion of tuberculosis attributable to transmission from close contacts is not well known. Comparison of the genome of strains from index patients and prior contacts allows transmission to be confirmed or excluded. In Karonga District, Malawi, all tuberculosis patients are asked about prior contact with others with tuberculosis. All available strains from culture-positive patients were sequenced. Up to 10 single nucleotide polymorphisms between index patients and their prior contacts were allowed for confirmation, and ≥ 100 for exclusion. The population attributable fraction was estimated from the proportion of confirmed transmissions and the proportion of patients with contacts. From 1997-2010 there were 1907 new culture-confirmed tuberculosis patients, of whom 32% reported at least one family contact and an additional 11% had at least one other contact; 60% of contacts had smear-positive disease. Among case-contact pairs with sequences available, transmission was confirmed from 38% (62/163) smear-positive prior contacts and 0/17 smear-negative prior contacts. Confirmed transmission was more common in those related to the prior contact (42.4%, 56/132) than in non-relatives (19.4%, 6/31, p = 0.02), and in those with more intense contact, to younger index cases, and in more recent years. The proportion of tuberculosis attributable to known contacts was estimated to be 9.4% overall. In this population known contacts only explained a small proportion of tuberculosis cases. Even those with a prior family contact with smear positive tuberculosis were more likely to have acquired their infection elsewhere.

To assess the magnitude of loss to follow-up in smear- or culture-positive tuberculosis patients before treatment initiation and outcomes among patients who were traced. Ovid Medline and Global Health databases were searched for studies published between 1994 and January 2013 that described pre-treatment loss to follow-up in patients with smear- or culture-positive tuberculosis in routine national tuberculosis programmes (NTPs) in low- and lower-middle-income countries and in countries with a high burden of tuberculosis. Data on the proportion of patients who did not initiate treatment after their tuberculosis diagnosis were extracted from studies meeting inclusion criteria. Where available, data on causes and outcomes, including initiation of tuberculosis treatment at another facility, were investigated. Heterogeneity and publication bias were assessed and random-effects meta-analyses by subgroup (region) were performed. Twenty-three eligible studies were identified, with a total of 34 706 smear- or culture-positive tuberculosis patients from 14 countries (8 in Africa, 5 in Asia and 1 in the western Pacific). Most studies were retrospective and linked laboratory and treatment registers to identify pre-treatment loss to follow-up. Pre-treatment loss to follow-up varied from 4 to 38% and was common in studies from Africa (random-effects weighted proportion, WP: 18%; 95% confidence interval, CI: 13-22) and Asia (WP: 13%; 95% CI: 10-15). Pre-treatment loss to follow-up, common in most settings, can hinder tuberculosis control efforts. By not counting individuals who are lost to follow-up before treatment when reporting standard programme indicators, NTPs underestimate case detection rates and mortality and overestimate cure rates.

School dropout has been linked to early pregnancy and marriage but less is known about the effect of school performance. We aimed to assess whether school performance influenced age at sexual debut, pregnancy and marriage, and from what age school drop-out and performance were associated with these later life events. Data from 2007-2016 from a demographic surveillance site in northern Malawi with annual updating of schooling status and grades, and linked sexual behaviour surveys, were analysed to assess the associations of age-specific school performance (measured as age-for-grade) and status (in or out of school) on subsequent age at sexual debut, pregnancy and marriage. Landmark analysis with Cox regression was used to estimate hazard ratios of sexual debut, pregnancy and marriage by schooling at selected (landmark) ages, controlling for socio-economic factors. Information on at least one outcome was available for >16,000 children seen at ages 10-18. Sexual debut was available on a subset aged ≥15 by 2011. For girls, being out of school was strongly associated with earlier sexual debut, pregnancy and marriage. For example, using schooling status at age 14, compared to girls in primary, those who had dropped out had adjusted hazard ratios of subsequent sexual debut, pregnancy and marriage of 5.39 (95% CI 3.27-8.86), 2.39 (1.82-3.12), and 2.76 (2.08-3.67) respectively. For boys, the equivalent association with sexual debut was weak, 1.92 (0.81-4.55), but that with marriage was strong, 3.74 (2.28-6.11), although boys married later. Being overage-for-grade was not associated with sexual debut for girls or boys. For girls, being overage-for-grade from age 10 was associated with earlier pregnancy and marriage (e.g. adjusted hazard ratio 2.84 (1.32-6.17) for pregnancy and 3.19 (1.47-6.94) for marriage, for those ≥3 years overage compared to those on track at age 10). For boys, overage-for-grade was associated with earlier marriage from age 12, with stronger associations at older ages (e.g. adjusted hazard ratio 2.41 (1.56-3.70) for those ≥3 years overage compared to those on track at age 14). For girls ≥3 years overage at age 14, 39% were pregnant before they were 18, compared to 18% of those who were on track. The main limitation was the use of reported ages of sexual debut, pregnancy and marriage. School progression at ages as young as 10 can predict teenage pregnancy and marriage, even after adjusting for socio-economic factors. Early education interventions may reduce teenage pregnancy and marriage as well as improving learning.

Background HIV risk remains unacceptably high among adolescent girls and young women (AGYW) in southern and eastern Africa, reflecting structural and social inequities that drive new infections. In 2015, PEPFAR (the United States President’s Emergency Plan for AIDS Relief) with private-sector partners launched the DREAMS Partnership, an ambitious package of interventions in 10 sub-Saharan African countries. DREAMS aims to reduce HIV incidence by 40% among AGYW over two years by addressing multiple causes of AGYW vulnerability. This protocol outlines an impact evaluation of DREAMS in four settings. Methods To achieve an impact evaluation that is credible and timely, we describe a mix of methods that build on longitudinal data available in existing surveillance sites prior to DREAMS roll-out. In three long-running surveillance sites (in rural and urban Kenya and rural South Africa), the evaluation will measure: (1) population-level changes over time in HIV incidence and socio-economic, behavioural and health outcomes among AGYW and young men (before, during, after DREAMS); and (2) causal pathways linking uptake of DREAMS interventions to ‘mediators’ of change such as empowerment, through to behavioural and health outcomes, using nested cohort studies with samples of ~ 1000–1500 AGYW selected randomly from the general population and followed for two years. In Zimbabwe, where DREAMS includes an offer of pre-exposure HIV prophylaxis (PrEP), cohorts of young women who sell sex will be followed for two years to measure the impact of ‘DREAMS+PrEP’ on HIV incidence among young women at highest risk of HIV. In all four settings, process evaluation and qualitative studies will monitor the delivery and context of DREAMS implementation. The primary evaluation outcome is HIV incidence, and secondary outcomes include indicators of sexual behavior change, and social and biological protection. Discussion DREAMS is, to date, the most ambitious effort to scale-up combinations or ‘packages’ of multi-sectoral interventions for HIV prevention. Evidence of its effectiveness in reducing HIV incidence among AGYW, and demonstrating which aspects of the lives of AGYW were changed, will offer valuable lessons for replication.

Asymptomatic ebolavirus infection could greatly influence transmission dynamics, but there is little consensus on how frequently it occurs or even if it exists. This paper summarises the available evidence on seroprevalence of Ebola, Sudan and Bundibugyo virus IgG in people without known ebolavirus disease. Through systematic review, we identified 51 studies with seroprevalence results in sera collected from 1961 to 2016. We tabulated findings by study population, contact, assay, antigen and positivity threshold used, and present seroprevalence point estimates and 95% confidence intervals. We classified sampled populations in three groups: those with household or known case-contact; those living in outbreak or epidemic areas but without reported case-contact; and those living in areas with no recorded cases of ebolavirus disease. We performed meta-analysis only in the known case-contact group since this is the only group with comparable exposures between studies. Eight contact studies fitted our inclusion criteria, giving an overall estimate of seroprevalence in contacts with no reported symptoms of 3.3% (95% CI 2.4–4.4, P <0.001), but with substantial heterogeneity.