The observation that Tcf3 (MGI name: Tcf7l1) bound the same genes as core stem cell transcription factors, Oct4 (MGI name:Pou5f1), Sox2 and Nanog, revealed a potentially important aspect of the poorly understood mechanism whereby Wnts stimulate self renewal of pluripotent mouse embryonic stem (ES) cells. Although the conventional view of Tcf proteins as the β-catenin-binding effectors of Wnt signaling suggested Tcf3-β-catenin mediated activation of target genes would stimulate ES cell self renewal, here we show that an antagonistic relationship between Wnt3a and Tcf3 on gene expression is important for regulating ES cell self renewal. Genetic ablation of Tcf3 replaced the requirement for exogenous Wnt3a or GSK3-inhibition for self renewal of ES cells, demonstrating that inhibition of Tcf3-repressor is the necessary downstream effect of Wnt signaling. Interestingly, the molecular mechanism underlying Wnt’s effects required both Tcf3-β-catenin and Tcf1-β-catenin interactions, as they each contributed to Wnt stimulation of self renewal and gene expression. Finally, the combination of Tcf3 and Tcf1 was necessary to recruit Wnt-stabilized β-catenin to Oct4 binding sites in ES cell chromatin. These results elucidate the molecular link between the effects of Wnt and the regulation of the Oct4/Sox2/Nanog network.

SummaryBackgroundTuberculosis in children is increasingly recognised as an important component of the global tuberculosis burden, with an estimated 1 million cases in 2015. Although younger children are vulnerable to severe forms of tuberculosis disease, no age-disaggregated estimates of paediatric tuberculosis mortality exist, and tuberculosis has never been included in official estimates of under-5 child mortality. We aimed to produce a global mortality burden estimate in children using a complementary approach not dependent on vital registration data.MethodsIn this mathematical modelling study, we estimated deaths in children younger than 5 years and those aged 5–14 years for 217 countries and territories using a case-fatality-based approach. We used paediatric tuberculosis notification data and HIV and antiretroviral treatment estimates to disaggregate the WHO paediatric tuberculosis incidence estimates by age, HIV, and treatment status. We then applied systematic review evidence on corresponding case-fatality ratios.FindingsWe estimated that 239 000 (95% uncertainty interval [UI] 194 000–298 000) children younger than 15 years died from tuberculosis worldwide in 2015; 80% (191 000, 95% UI 132 000–257 000) of these deaths were in children younger than 5 years. More than 70% (182 000, 140 000–239 000) of deaths occurred in the WHO southeast Asia and Africa regions. We estimated that 39 000 (17%, 23 000–73 000) paediatric tuberculosis deaths worldwide were in children with HIV infections, with 31 000 (36%, 19 000–59 000) in the WHO Africa region. More than 96% (230 000, 185 000–289 000) of all tuberculosis deaths occurred in children not receiving tuberculosis treatment.InterpretationTuberculosis is a top ten cause of death in children worldwide and a key omission from previous analyses of under-5 mortality. Almost all these deaths occur in children not on tuberculosis treatment, implying substantial scope to reduce this burden.FundingUNITAID, National Institutes of Health, and National Institute for Health Research.

Background Multidrug-resistant tuberculosis (MDR-TB) threatens to reverse recent reductions in global tuberculosis (TB) incidence. Although children under 15 years of age constitute >25% of the worldwide population, the global incidence of MDR-TB disease in children has never been quantified. Methods Our approach for estimating regional and global annual incidence of MDR-TB in children required development of two models: one to estimate the setting-specific risk of MDR-TB among child TB cases, and a second to estimate the setting-specific incidence of TB disease in children. The model for MDR-TB risk among children with TB required a systematic literature review. We multiplied the setting-specific estimates of MDR-TB risk and TB incidence to estimate regional and global incidence of MDR-TB disease in children in 2010. Findings We identified 3,403 papers, of which 97 studies met inclusion criteria for the systematic review of MDR-TB risk. Thirty-one studies reported the risk of MDR-TB among both children and treatment-naïve adults with TB and were used for evaluating the linear association between MDR-TB risk in these two patient groups. We found that the setting-specific risk of MDR-TB was nearly identical in children and treatment-naïve adults with TB, consistent with the assertion that MDR-TB in both groups reflects the local risk of transmitted MDR-TB. Applying these calculated risks, we estimated that around 1,000,000 (95% Confidence Interval: 938,000 – 1,055,000) children developed TB disease in 2010, among whom 32,000 (95% Confidence Interval: 26,000 – 39,000) had MDR-TB. Interpretation Our estimates highlight a massive detection gap for children with TB and MDR-TB disease. Future estimates can be refined as more and better TB data and new diagnostic tools become available.

Background Case fatality ratios among children with tuberculosis disease are poorly understood, particularly among HIV-infected cases and those not receiving tuberculosis treatment. Methods We carried out a systematic review of the published literature to identify studies of population-representative samples of pediatric (<15 years old) tuberculosis cases. We used random effects meta-analysis to produce pooled estimates of case fatality ratios. We stratified our analyses by whether or not children received tuberculosis treatment, age (0–4 years, 5–14 years), and HIV status. Findings We identified 31 papers comprising 35 datasets representing 82,436 children with tuberculosis disease, of whom 9,273 died. Among children with tuberculosis from the pretreatment era, the pooled case fatality ratio was 21.9% (95% confidence interval [CI]: 18.1%, 26.4%). The pooled case fatality ratio was significantly higher among children aged 0–4 years (43.6%; 95% CI: 36.8%, 50.6%) than among children aged 5–14 years (14.9%; 95% CI: 11.5%, 19.1%). In recent studies where the majority of children had tuberculosis treatment, the pooled case fatality ratio was 0.9% (95% CI: 0.5%, 1.6%). USA surveillance data suggest a substantially higher case fatality ratio among HIV-infected children receiving TB treatment, compared with HIV-uninfected children, especially without antiretroviral treatment. Interpretation Without adequate treatment, children with tuberculosis disease, especially those under five years of age, are at high risk of death. HIV-infected children have an increased mortality risk, even when receiving tuberculosis treatment. Funding US National Institutes of Health, Janssen Global Public Health

To halt the global tuberculosis epidemic, transmission must be stopped to prevent new infections and new cases. Identification of individuals with tuberculosis and prompt initiation of effective treatment to rapidly render them non-infectious is crucial to this task. However, in settings of high tuberculosis burden, active case-finding is often not implemented, resulting in long delays in diagnosis and treatment. A range of strategies to find cases and ensure prompt and correct treatment have been shown to be effective in high tuberculosis-burden settings. The population-level effect of targeted active case-finding on reducing tuberculosis incidence has been shown by studies and projected by mathematical modelling. The inclusion of targeted active case-finding in a comprehensive epidemic-control strategy for tuberculosis should contribute substantially to a decrease in tuberculosis incidence.

Contact investigations among individuals living with drug-susceptible tuberculosis patients (source cases) have shown a high yield of tuberculosis disease and latent tuberculosis, but the yield of such investigations in households of drug-resistant tuberculosis source cases is unknown. In this systematic review and meta-analysis, we found 25 studies that evaluated a median of 111 (interquartile range, 21-302) household contacts of drug-resistant tuberculosis source cases. The pooled yield was 7.8% (95% CI, 5.6%-10.0%) for active tuberculosis and 47.2% (95% CI, 30.0%-61.4%) for latent tuberculosis, although there was significant statistical heterogeneity (P < .0001). More than 50% of secondary cases with drug susceptibility test results were concordant with those of the source case. Among studies that followed household members, the majority of secondary cases were detected within 1 year of the source case's diagnosis. Household contact investigation around drug-resistant tuberculosis patients is a high-yield intervention for detection of drug-resistant tuberculosis and prevention of ongoing transmission.

Tuberculosis is an infectious disease that may result from recent transmission or from an infection acquired many years in the past; there is no diagnostic test to distinguish the two causes. Cases resulting from recent transmission are particularly concerning from a public health standpoint. To describe recent tuberculosis transmission in the United States, we used a field-validated plausible source-case method to estimate cases likely resulting from recent transmission during January 2011–September 2014. We classified cases as resulting from either limited or extensive recent transmission based on transmission cluster size. We used logistic regression to analyze patient characteristics associated with recent transmission. Of 26,586 genotyped cases, 14% were attributable to recent transmission, 39% of which were attributable to extensive recent transmission. The burden of cases attributed to recent transmission was geographically heterogeneous and poorly predicted by tuberculosis incidence. Extensive recent transmission was positively associated with American Indian/Alaska Native (adjusted prevalence ratio [aPR] = 3.6 (95% confidence interval [CI] 2.9–4.4), Native Hawaiian/Pacific Islander (aPR = 3.2, 95% CI 2.3–4.5), and black (aPR = 3.0, 95% CI 2.6–3.5) race, and homelessness (aPR = 2.3, 95% CI 2.0–2.5). Extensive recent transmission was negatively associated with foreign birth (aPR = 0.2, 95% CI 0.2–0.2). Tuberculosis control efforts should prioritize reducing transmission among higher-risk populations.

SummaryBackgroundTuberculosis is recognised as a major cause of morbidity and mortality in children, with most cases in children going undiagnosed and resulting in poor outcomes. Household contact management, which aims to identify children with active tuberculosis and to provide preventive therapy for those with HIV or those younger than 5 years, has long been recommended but has very poor coverage globally. New guidelines include widespread provision of preventive therapy to children with a positive tuberculin skin test (TST) who are older than 5 years.MethodsIn this mathematical modelling study, we provide the first global and national estimates of the impact of moving from zero to full coverage of household contact management (with and without preventive therapy for TST-positive children older than 5 years). We assembled data on tuberculosis notifications, household structure, household contact co-prevalence of tuberculosis disease and infection, the efficacy of preventive therapy, and the natural history of childhood tuberculosis. We used a model to estimate households visited, children screened, and treatment courses given for active and latent tuberculosis. We calculated the numbers of tuberculosis cases, deaths, and life-years lost because of tuberculosis for each intervention scenario and country.FindingsWe estimated that full implementation of household contact management would prevent 159 500 (75% uncertainty interval [UI] 147 000–170 900) cases of tuberculosis and 108 400 (75% UI 98 800–116 700) deaths in children younger than 15 years (representing the loss of 7 305 000 [75% UI 6 663 000–7 874 000] life-years). We estimated that preventing one child death from tuberculosis would require visiting 48 households, screening 77 children, giving 48 preventive therapy courses, and giving two tuberculosis treatments versus no household contact management.InterpretationHousehold contact management could substantially reduce childhood disease and death caused by tuberculosis globally. Funding and research to optimise its implementation should be prioritised.FundingUK Medical Research Council, US National Institutes of Health, Fulbright Commission, Janssen Global Public Health.