We conducted a case-control study among children in Lima, Peru to identify factors associated with tuberculosis disease. Known close contact with someone with tuberculosis disease, prior hospitalization, and history of anemia were associated with a higher tuberculosis disease rate. Consumption of fruits/vegetables ≥5 days/week was associated with a lower rate. Isoniazid uptake was low among children with a known contact.
Global control of tuberculosis has become increasingly complicated with the emergence of multidrug-resistant strains of Mycobacterium tuberculosis First-line treatments are anchored by two antibiotics, rifampin and isoniazid. Most rifampin resistance occurs through the acquisition of missense mutations in the rifampin resistance-determining region, an 81-base pair region encoding the rifampin binding site on the β subunit of RNA polymerase (rpoB). Although these mutations confer a survival advantage in the presence of rifampin, they may alter the normal process of transcription, thereby imposing significant fitness costs. Because the downstream biochemical consequences of the rpoB mutations are unknown, we used an organism-wide screen to identify the number and types of lipids changed after rpoB mutation. A new mass spectrometry-based profiling platform systematically compared ∼10,000 cell wall lipids in a panel of rifampin-resistant mutants within two genetically distinct strains, CDC1551and W-Beijing. This unbiased lipidomic survey detected quantitative alterations (>2-fold, p < 0.05) in more than 100 lipids in each mutant. By focusing on molecular events that change among most mutants and in both genetic backgrounds, we found that rifampin resistance mutations lead to altered concentrations of mycobactin siderophores and acylated sulfoglycolipids. These findings validate a new organism-wide lipidomic analysis platform for drug-resistant mycobacteria and provide direct evidence for characteristic remodeling of cell wall lipids in rifampin-resistant strains of M. tuberculosis The specific links between rifampin resistance and named lipid factors provide diagnostic and therapeutic targets that may be exploited to address the problem of drug resistance.
Background. A significant proportion of tuberculosis (TB) patients globally make their initial visit for medical care to either an informal provider or a private practitioner, and many are not formally notified. Involvement of private practitioners (PPs) in a public–private mix for TB (TB-PPM) provides an opportunity for improving TB control. However, context-specific interventions beyond public–private agreements and mandatory notification are needed. In this study we will evaluate whether a tailored intervention package can increase TB notifications from PPs in Indonesia.Methods. This is a cluster-randomized trial of a multi-component public health intervention. 36 community health centre (CHC) areas will be selected as study locations and randomly allocated to intervention and control arms (1:1). PPs in the intervention areas will be identified using a mapping exercise and recruited into the study if they are eligible and consent. They will receive a tailored intervention package including in-person education about TB management along with bimonthly electronic refreshers, context-specific selection of referral pathways, and access to a TB-reporting app developed in collaboration with the National TB programme. The primary hypothesis is that the intervention package will increase the TB notification rate. The primary outcome will be measured by collecting notification data from the CHCs in intervention and control arms at the end of a 1-year observation period and comparing with the 1-year pre-intervention. The primary analysis will be intention-to-treat at the cluster level, using a generalised mixed model with repeated measures of TB notifications for 1 year pre- and 1 year post-intervention.Discussion. The results from this study will provide evidence on whether a tailored intervention package is effective in increasing the number of TB notifications, and whether the PPs refer presumptive TB cases correctly. The study results will guide policy in the development of TB-PPM in Indonesia and similar settings.
High-throughput TCR sequencing allows interrogation of the human TCR repertoire, potentially connecting TCR sequences to antigenic targets. Unlike the highly polymorphic MHC proteins, monomorphic Ag-presenting molecules such as MR1, CD1d, and CD1b present Ags to T cells with species-wide TCR motifs. CD1b tetramer studies and a survey of the 27 published CD1b-restricted TCRs demonstrated a TCR motif in humans defined by the TCR β-chain variable gene 4-1 (TRBV4-1) region. Unexpectedly, TRBV4-1 was involved in recognition of CD1b regardless of the chemical class of the carried lipid. Crystal structures of two CD1b-specific TRBV4-1+ TCRs show that germline-encoded residues in CDR1 and CDR3 regions of TRBV4-1-encoded sequences interact with each other and consolidate the surface of the TCR. Mutational studies identified a key positively charged residue in TRBV4-1 and a key negatively charged residue in CD1b that is shared with CD1c, which is also recognized by TRBV4-1 TCRs. These data show that one TCR V region can mediate a mechanism of recognition of two related monomorphic Ag-presenting molecules that does not rely on a defined lipid Ag.
The molecular basis for isoniazid resistance in Mycobacterium tuberculosis is complex. Putative isoniazid resistance mutations have been identified in katG, ahpC, inhA, kasA, and ndh. However, small sample sizes and related potential biases in sample selection have precluded the development of statistically valid and significant population genetic analyses of clinical isoniazid resistance. We present the first large-scale analysis of 240 alleles previously associated with isoniazid resistance in a diverse set of 608 isoniazid-susceptible and 403 isoniazid-resistant clinical M. tuberculosis isolates. We detected 12 mutant alleles in isoniazid-susceptible isolates, suggesting that these alleles are not involved in isoniazid resistance. However, mutations in katG, ahpC, and inhA were strongly associated with isoniazid resistance, while kasA mutations were associated with isoniazid susceptibility. Remarkably, the distribution of isoniazid resistance-associated mutations was different in isoniazid-monoresistant isolates from that in multidrug-resistant isolates, with significantly fewer isoniazid resistance mutations in the isoniazid-monoresistant group. Mutations in katG315 were significantly more common in the multidrug-resistant isolates. Conversely, mutations in the inhA promoter were significantly more common in isoniazid-monoresistant isolates. We tested for interactions among mutations and resistance to different drugs. Mutations in katG, ahpC, and inhA were associated with rifampin resistance, but only katG315 mutations were associated with ethambutol resistance. There was also a significant inverse association between katG315 mutations and mutations in ahpC or inhA and between mutations in kasA and mutations in ahpC. Our results suggest that isoniazid resistance and the evolution of multidrug-resistant strains are complex dynamic processes that may be influenced by interactions between genes and drug-resistant phenotypes.
TB control is limited in part by the length of antibiotic treatment needed to prevent recurrent disease. To probe mechanisms underlying survival under antibiotic pressure, we performed a genetic screen for M. tuberculosis mutants with altered susceptibility to treatment using the mouse model of TB. We identified multiple genes involved in a range of functions which alter sensitivity to antibiotics. In particular, we found glycerol catabolism mutants were less susceptible to treatment and that common variation in a homopolymeric region in the glpK gene was associated with drug resistance in clinical isolates. These studies indicate that reversible high-frequency variation in carbon metabolic pathways can produce phenotypically drug-tolerant clones and have a role in the development of resistance.
Tuberculosis (TB) remains disproportionately concentrated among the poor, yet known determinants of TB reactivation may fail to explain observed disparities in disease rates according to wealth. Reviewing data on TB disparities in India and the wealth distribution of known TB risk factors, we describe how social mixing patterns could be contributing to TB disparities. Wealth-assortative mixing, whereby individuals are more likely to be in contact with others from similar socio-economic backgrounds, amplifies smaller differences in risk of TB, resulting in large population-level disparities. As disparities and assortativeness increase, TB becomes more difficult to control, an effect that is obscured by looking at population averages of epidemiological parameters, such as case detection rates. We illustrate how TB control efforts may benefit from preferential targeting toward the poor. In India, an equivalent-scale intervention could have a substantially greater impact if targeted at those living below the poverty line than with a population-wide strategy. In addition to potential efficiencies in targeting higher-risk populations, TB control efforts would lead to a greater reduction in secondary TB cases per primary case diagnosed if they were preferentially targeted at the poor. We highlight the need to collect programmatic data on TB disparities and explicitly incorporate equity considerations into TB control plans.
BackgroundBetween April and June, 2012, a reactive cholera vaccination campaign was done in Haiti with an oral inactivated bivalent whole-cell vaccine. We aimed to assess the effectiveness of the vaccine in a case-control study and to assess the likelihood of bias in that study in a bias-indicator study.MethodsResidents of Bocozel or Grand Saline who were eligible for the vaccination campaign (ie, age ≥12 months, not pregnant, and living in the region at the time of the vaccine campaign) were included. In the primary case-control study, cases had acute watery diarrhoea, sought treatment at one of three participating cholera treatment units, and had a stool sample positive for cholera by culture. For each case, four control individuals who did not seek treatment for acute watery diarrhoea were matched by location of residence, enrolment time (within 2 weeks of the case), and age (1–4 years, 5–15 years, and >15 years). Cases in the bias-indicator study were individuals with acute watery diarrhoea with a negative stool sample for cholera. Controls were selected in the same manner as in the primary case-control study. Trained staff used standard laboratory procedures to do rapid tests and stool cultures from study cases. Participants were interviewed to collect data on sociodemographic characteristics, risk factors for cholera, and self-reported vaccination. Data were analysed by conditional logistic regression, adjusting for matching factors.FindingsFrom Oct 24, 2012, to March 9, 2014, 114 eligible individuals presented with acute watery diarrhoea and were enrolled, 25 of whom were subsequently excluded. 47 participants were analysed as cases in the vaccine effectiveness case-control study and 42 as cases in the bias-indicator study. 33 (70%) of 47 cholera cases self-reported vaccination versus 167 (89%) of 188 controls (vaccine effectiveness 63%, 95% CI 8–85). 27 (57%) of 47 cases had certified vaccination versus 147 (78%) of 188 controls (vaccine effectiveness 58%, 13–80). Neither self-reported nor verified vaccination was significantly associated with non-cholera diarrhoea (vaccine effectiveness 18%, 95% CI −208 to 78 by self-report and −21%, −238 to 57 by verified vaccination).InterpretationBivalent whole-cell oral cholera vaccine effectively protected against cholera in Haiti from 4 months to 24 months after vaccination. Vaccination is an important component of efforts to control cholera epidemics.FundingNational Institutes of Health, Delivering Oral Vaccines Effectively project, and Department of Global Health and Social Medicine at Harvard Medical School.
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