The global epidemic of drug-resistant tuberculosis is a catastrophic example of how antimicrobial resistance is undermining the public health gains made possible by combination drug therapy. Recent evidence points to unappreciated bacterial factors that accelerate the emergence of drug resistance. In a genome-wide association study of Mycobacterium tuberculosis isolates from China, we find mutations in the gene encoding the transcription factor prpR enriched in drug-resistant strains. prpR mutations confer conditional drug tolerance to three of the most effective classes of antibiotics by altering propionyl-CoA metabolism. prpR-mediated drug tolerance is carbon-source dependent, and while readily detectable during infection of human macrophages, is not captured by standard susceptibility testing. These data define a previously unrecognized and clinically prevalent class of M. tuberculosis variants that undermine antibiotic efficacy and drive drug resistance.

We estimated long-term tuberculosis (TB) trends in the US population and assessed prospects for TB elimination. We used a detailed simulation model allowing for changes in TB transmission, immigration, and other TB risk determinants. Five hypothetical scenarios were evaluated from 2017 to 2100: 1) maintain current TB prevention and treatment activities (base case); 2) provision of latent TB infection testing and treatment for new legal immigrants; 3) increased uptake of latent TB infection screening and treatment among high-risk populations, including a 3-month isoniazid-rifapentine regimen; 4) improved TB case detection; and 5) improved TB treatment quality. Under the base case, we estimate that by 2050, TB incidence will decline to 14 cases per million, a 52% (95% posterior interval (PI): 35, 67) reduction from 2016, and 82% (95% posterior interval: 78, 86) of incident TB will be among persons born outside of the United States. Intensified TB control could reduce incidence by 77% (95% posterior interval: 66, 85) by 2050. We predict TB may be eliminated in US-born but not non-US-born persons by 2100. Results were sensitive to numbers of people entering the United States with latent or active TB, and were robust to alternative interpretations of epidemiologic evidence. TB elimination in the United States remains a distant goal; however, strengthening TB prevention and treatment could produce important health benefits.

Family Health Strategy, the primary health care program in Brazil, has been scaled up throughout the country, but its expansion has been heterogeneous across municipalities. We investigate if there are unique municipal characteristics that can explain the timing of uptake and the pattern of expansion of the Family Health Strategy from years 1998 to 2012. We categorized municipalities in six groups based on the relative speed of the Family Health Strategy uptake and the pattern of Family Health Strategy coverage expansion. We assembled data for 11 indicators for years 2000 and 2010, for 5,507 municipalities, and assessed differences in indicators across the six groups, which we mapped to examine spatial heterogeneities. Important factors differentiating early and late adopters of the Family Health Strategy were supply of doctors and population density. Sustained coverage expansion was related mainly to population size, marginal benefits of the program and doctors’ supply. The uptake was widespread nationwide with no distinct patterns among regions, but highly heterogeneous at the state and municipal level. The Brazilian experience of expanding primary health care offers three lessons in relation to factors influencing diffusion of primary health care. First, the funding mechanism is critical for program implementation, and must be accompanied by ways to support the supply of primary care physicians in low density areas. Second, in more developed and bigger areas the main challenge is lack of incentives to pursue universal coverage, especially due to the availability of private insurance. Third, population size is a crucial element to guarantee coverage sustainability over time.

Mosaic interspecifically acquired alleles of the multiple transferable resistance () efflux pump operon correlate with increased resistance to azithromycin in in epidemiological studies. However, whether and how these alleles cause resistance is unclear. Here, we use population genomics, transformations, and transcriptional analyses to dissect the relationship between variant alleles and azithromycin resistance. We find that the locus encompassing the transcriptional repressor and the pump is a hot spot of interspecific recombination introducing alleles from and into , with multiple rare haplotypes in linkage disequilibrium at and the promoter region. Transformations demonstrate that resistance to azithromycin, as well as to other antimicrobial compounds such as polymyxin B and crystal violet, is mediated through epistasis between these two loci and that the full-length mosaic allele is required. Gene expression profiling reveals the mechanism of resistance in mosaics couples novel alleles with promoter mutations that increase expression of the pump. Overall, our results demonstrate that epistatic interactions at gained from multiple neisserial species has contributed to increased gonococcal resistance to diverse antimicrobial agents. is the sexually transmitted bacterial pathogen responsible for more than 100 million cases of gonorrhea worldwide each year. The incidence of resistance to the macrolide azithromycin has increased in the past decade; however, a large proportion of the genetic basis of resistance remains unexplained. This study is the first to conclusively demonstrate the acquisition of macrolide resistance through alleles from other species, demonstrating that commensal bacteria are a reservoir for antibiotic resistance to macrolides, extending the role of interspecies mosaicism in resistance beyond what has been previously described for cephalosporins. Ultimately, our results emphasize that future fine-mapping of genome-wide interspecies mosaicism may be valuable in understanding the pathways to antimicrobial resistance. Our results also have implications for diagnostics and public health surveillance and control, as they can be used to inform the development of sequence-based tools to monitor and control the spread of antibiotic-resistant gonorrhea.

Mathematical modelling is commonly used to evaluate infectious disease control policy and is influential in shaping policy and budgets. Mathematical models necessarily make assumptions about disease natural history and, if these assumptions are not valid, the results of these studies can be biased. We did a systematic review of published tuberculosis transmission models to assess the validity of assumptions about progression to active disease after initial infection (PROSPERO ID CRD42016030009). We searched PubMed, Web of Science, Embase, Biosis, and Cochrane Library, and included studies from the earliest available date (Jan 1, 1962) to Aug 31, 2017. We identified 312 studies that met inclusion criteria. Predicted tuberculosis incidence varied widely across studies for each risk factor investigated. For population groups with no individual risk factors, annual incidence varied by several orders of magnitude, and 20-year cumulative incidence ranged from close to 0% to 100%. A substantial proportion of modelled results were inconsistent with empirical evidence: for 10-year cumulative incidence, 40% of modelled results were more than double or less than half the empirical estimates. These results demonstrate substantial disagreement between modelling studies on a central feature of tuberculosis natural history. Greater attention to reproducing known features of epidemiology would strengthen future tuberculosis modelling studies, and readers of modelling studies are recommended to assess how well those studies demonstrate their validity.

Influenza vaccination aims to prevent infection by influenza virus and reduce associated morbidity and mortality; however, vaccine effectiveness (VE) can be modest, especially for subtype A(H3N2). Low VE has been attributed to mismatches between the vaccine and circulating influenza strains and to the vaccine’s elicitation of protective immunity in only a subset of the population. The low H3N2 VE in the 2012-2013 season was attributed to egg-adaptive mutations that created antigenic mismatch between the actual vaccine strain (IVR-165) and both the intended vaccine strain (A/Victoria/361/2011) and the predominant circulating strains (clades 3C.2 and 3C.3).

The Unified Health System (Sistema Único de Saúde (SUS)) has enabled substantial progress towards Universal Health Coverage (UHC) in Brazil. However, structural weakness, economic and political crises and austerity policies that have capped public expenditure growth are threatening its sustainability and outcomes. This paper analyses the Brazilian health system progress since 2000 and the current and potential effects of the coalescing economic and political crises and the subsequent austerity policies. We use literature review, policy analysis and secondary data from governmental sources in 2000-2017 to examine changes in political and economic context, health financing, health resources and healthcare service coverage in SUS. We find that, despite a favourable context, which enabled expansion of UHC from 2003 to 2014, structural problems persist in SUS, including gaps in organisation and governance, low public funding and suboptimal resource allocation. Consequently, large regional disparities exist in access to healthcare services and health outcomes, with poorer regions and lower socioeconomic population groups disadvantaged the most. These structural problems and disparities will likely worsen with the austerity measures introduced by the current government, and risk reversing the achievements of SUS in improving population health outcomes. The speed at which adverse effects of the current and political crises are manifested in the Brazilian health system underscores the importance of enhancing health system resilience to counteract external shocks (such as economic and political crises) and internal shocks (such as sector-specific austerity policies and rapid ageing leading to rise in disease burden) to protect hard-achieved progress towards UHC.