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Background: The importance of remote infection with M.tuberculosis as a cause of tuberculosis disease (TB) is unclear, with limited evidence of impact on TB rates beyond 10 years. Our objective was to assess rates of tuberculosis over 30 years by M.tuberculosis infection status at baseline in Karonga District, Northern Malawi. Materials and methods: Population-based surveys of tuberculin skin testing (TST) from the 1980s were linked with follow-up and TB surveillance in Karonga district. We compared rates of microbiologically-confirmed TB by baseline TST induration <5mm (no evidence of M.tuberculosis infection) and those with baseline TST >17mm (evidence of M.tuberculosis infection), using hazard ratios by time since baseline and attributable risk percent. The attributable risk percent was calculated to estimate the proportion of TB in those infected that can be attributed to that prior infection. We analysed whole genome sequences of M.tuberculosis strains to identify recent transmission. Results: Over 412,959 person-years, 208 incident TB episodes were recorded. Compared to the small induration group, rates of TB were much higher in the first two years in the large induration group, and remained higher to 20 years: age, sex and area-adjusted hazard ratios (HR) 2–9 years post-TST 4.27 (95%CI 2.56–7.11); 10–19 years after TST 2.15 (1.10–4.21); ≥20 years post-TST 1.88 (0.76–4.65). The attributable risk percent of remote infection was 76.6% (60.9–85.9) 2–9 years post-TST, and 53.5% (9.1–76.2) 10–19 years post-TST. Individuals with large TST indurations had higher rates of unique-strain TB (HR adjusted for age, sex and area = HR 6.56 (95% CI 1.96–22.99)), suggesting disease following remote infection, but not of linked-strain TB (recent transmission). Conclusions: M.tuberculosis infection can increase the risk of TB far beyond 10 years, accounting for a substantial proportion of TB occurring among those remotely infected. [ABSTRACT FROM AUTHOR]

Leprosy is a chronic infection of the skin and peripheral nerves caused by Mycobacterium leprae. Despite recent improvements in disease control, leprosy remains an important cause of infectious disability globally. Large-scale genetic association studies in Chinese, Vietnamese and Indian populations have identified over 30 susceptibility loci for leprosy. There is a significant burden of leprosy in Africa, however it is uncertain whether the findings of published genetic association studies are generalizable to African populations. To address this, we conducted a genome-wide association study (GWAS) of leprosy in Malawian (327 cases, 436 controls) and Malian (247 cases, 368 controls) individuals. In that analysis, we replicated four risk loci previously reported in China, Vietnam and India; MHC Class I and II, LACC1 and SLC29A3. We further identified a novel leprosy susceptibility locus at 10q24 (rs2015583; combined p = 8.81 × 10−9; OR = 0.51 [95% CI 0.40 − 0.64]). Using publicly-available data we characterise regulatory activity at this locus, identifying ACTR1A as a candidate mediator of leprosy risk. This locus shows evidence of recent positive selection and demonstrates pleiotropy with established risk loci for inflammatory bowel disease and childhood-onset asthma. A shared genetic architecture for leprosy and inflammatory bowel disease has been previously described. We expand on this, strengthening the hypothesis that selection pressure driven by leprosy has shaped the evolution of autoimmune and atopic disease in modern populations. More broadly, our data highlights the importance of defining the genetic architecture of disease across genetically diverse populations, and that disease insights derived from GWAS in one population may not translate to all affected populations. Author summary: Leprosy remains a leading cause of infectious disability globally. Human genetic variation is a major determinant of susceptibility to infection, including leprosy. Large-scale genetic association studies have been pivotal in advancing our understanding of leprosy biology. These studies have been performed in Chinese, Vietnamese and Indian populations, and it remains unclear whether these insights are informative of leprosy susceptibility in African populations. To address this, we performed a genome-wide association study of leprosy susceptibility in Malawi and Mali. In doing so we replicate known leprosy susceptibility loci at MHC class I and II, LACC1 and SLC29A3. Furthermore, we identify a novel leprosy susceptibility locus, which has been under recent selection pressure, which demonstrates pleiotropy with inflammatory bowel disease and atopic disease. We identify expression of ACTR1A in CD4+ T cells as candidate effector of leprosy risk at this locus. These data deepen our understanding of leprosy biology and further implicate this ancient pathogen in the evolution of immune-mediated diseases in modern populations. [ABSTRACT FROM AUTHOR]

Background: The aim of this study is to explore whether transmission of M. leprae has ceased in Spain, based upon the patterns and trends of notified cases. Methodology: Data on new cases reported to the National Leprosy Registry between the years 2003–2018 were extracted. In absence of detailed travel history, cases were considered "autochthonous" or "imported" based on whether they were born within or outside of Spain. These data were analyzed by age, sex, clinical type, country of origin, and location of residence at time of notification. Principal findings: Data were available on 61 autochthonous and 199 imported cases since 2003. There were clear declines in incidence in both groups, and more imported than autochthonous cases every year since 2006. Autochthonous cases were more frequently multibacillary and had older age at diagnosis compared to imported cases. All the autochthonous cases had been born before 1985 and were more than 25 years old at diagnosis. Male-to-female ratio increased with time for autochthonous cases (except for the last time period). The imported cases originated from 25 countries, half of them from Brasil and Paraguay. Autochthonous cases were mainly distributed in the traditionally endemic regions, especially Andalucía and the eastern Mediterranean coast. Conclusions: Autochthonous and imported cases have different epidemiologic patterns in Spain. There was a clear decline in incidence rates of autochthonous disease, and patterns consistent with those reported from other regions where transmission has ceased. Autochthonous transmission of M. leprae is likely to have now effectively stopped in Spain. Author summary: There is increasing interest in the potential for cessation of transmission of M Leprae. In several European countries, as social and economic conditions have improved, leprosy rates have declined and transmission appears to have stopped. The epidemiology of leprosy is still not fully understood: the study of leprosy in countries with low incidence rates can give valuable information on its epidemiology that could inform eradication campaigns in other countries. Leprosy has been endemic in Spain for centuries and, despite very low incidence in the last decades, new autochthonous cases are diagnosed every year. In this study, we analyse the epidemiologic trends of autochthonous leprosy in Spain in recent years. Our data provide insights into the dramatic decline of leprosy in Spain since 1950, and, for the cases diagnosed after 2003, show a shift from a predominace of disease attributable to locally acquired infection to overwhelming predominance of disease attributable to infections acquired elsewhere. The comparison of patterns of disease between the autochthonous and imported cases shows important differences, suggesting that the most recent autochthonous cases were those with long incubation periods after infections which were acquired many years ago. The epidemiologic trends are similar to those found in other countries with declining incidence and suggest that transmission effectively stopped in Spain more than two decades ago. [ABSTRACT FROM AUTHOR]

Background: Changes in children’s contact patterns between termtime and school holidays affect the transmission of several respiratory-spread infections. Transmission of varicella zoster virus (VZV), the causative agent of chickenpox, has also been linked to the school calendar in several settings, but temporal changes in the proportion of young children attending childcare centres may have influenced this relationship. Methods: We used two modelling methods (a simple difference equations model and a Time series Susceptible Infectious Recovered (TSIR) model) to estimate fortnightly values of a contact parameter (the per capita rate of effective contact between two specific individuals), using GP consultation data for chickenpox in England and Wales from 1967–2008. Results: The estimated contact parameters were 22–31% lower during the summer holiday than during termtime. The relationship between the contact parameter and the school calendar did not change markedly over the years analysed. Conclusions: In England and Wales, reductions in contact between children during the school summer holiday lead to a reduction in the transmission of VZV. These estimates are relevant for predicting how closing schools and nurseries may affect an outbreak of an emerging respiratory-spread pathogen. [ABSTRACT FROM AUTHOR]

The formation of spatial genetic structure (SGS) may originate from different patterns of seed deposition in the landscape, and is mostly determined by seed dispersal limitation. After dispersal, mechanisms such as filtering by environmental factors or attack by herbivores/pathogens throughout plant development stages, and potentially either disrupt or intensify SGS patterns. We investigated how the genotype of Protium subserratum (Burseraceae), a common tree species in the Ducke Reserve, Brazil, is distributed across the landscape. We used seven microsatellite markers to assess the SGS among plants at different life stages and in different environments. By quantifying the patterns of relatedness among plants of different sizes, we inferred the ontogenetic stage in which SGS changes occurred, and compared these effects across soil types. Relatedness among seedlings decreased when distance between seedlings increased, especially for the youngest seedlings. However, this trend was not continued by older plants, as relatedness values were higher among neighboring individuals of the juvenile and adult size class. Contrasting relatedness patterns between seedlings and larger individuals suggests a trade-off between the negative effects of being near closely-related adults (e.g. due to herbivore and pathogen attack) and the advantage of being in a site favorable to establishment. We also found that soil texture strongly influenced density-dependence patterns, as young seedlings in clay soils were more related to each other than were seedlings in bottomland sandy soils, suggesting that the mechanisms that create and maintain patterns of SGS within a population may interact with environmental heterogeneity. [ABSTRACT FROM AUTHOR]

Background: The rise in tuberculosis (TB) incidence following generalized HIV epidemics can overwhelm TB control programmes in resource-limited settings, sometimes accompanied by rising rates of drug resistance. This has led to claims that DOTS-based TB control has failed in such settings. However, few studies have described the effect of a sustained and well-supported DOTS programme on TB incidence and drug resistance over a long period. We present long-term trends in incidence and drug resistance in rural Malawi. Methods: Karonga District in northern Malawi has an adult HIV prevalence of ∼10%. A research group, the Karonga Prevention Study, collaborates with the National Tuberculosis Programme to support core TB control activities. Bacteriological, demographic and clinical (including HIV status) information from all patients starting TB treatment in the District have been recorded since 1988. During that period isolates from each culture-positive TB patient were exported for drug sensitivity testing. Antiretroviral therapy (ART) has been widely available since 2005. Results: Incidence of new smear-positive adult TB peaked at 124/100,000/year in the mid-90s, but has since fallen to 87/100,000/year. Drug sensitivity information was available for 95% (3132/3307) of all culture-positive cases. Initial resistance to isoniazid was around 6% with no evidence of an increase. Fewer than 1% of episodes involved a multi-drug resistant strain. Discussion: In this setting with a generalised HIV epidemic and medium TB burden, a well-supported DOTS programme enhanced by routine culture and drug sensitivity testing may well have reduced TB incidence and maintained drug resistance at low levels. [ABSTRACT FROM AUTHOR]

Among trapping mechanisms in carnivorous plants, those termed 'active' have especially fascinated scientists since Charles Darwin's early works because trap movements are involved. Fast snap-trapping and suction of prey are two of the most spectacular examples for how these plants actively catch animals, mainly arthropods, for a substantial nutrient supply. We show that Drosera glanduligera, a sundew from southern Australia, features a sophisticated catapult mechanism: Prey animals walking near the edge of the sundew trigger a touch-sensitive snap-tentacle, which swiftly catapults them onto adjacent sticky glue-tentacles; the insects are then slowly drawn within the concave trap leaf by sticky tentacles. This is the first detailed documentation and analysis of such catapult-flypaper traps in action and highlights a unique and surprisingly complex mechanical adaptation to carnivory. [ABSTRACT FROM AUTHOR]

Broad-scale geographic gradients in species richness have now been extensively documented, but their historical underpinning is still not well understood. While the importance of productivity, temperature, and a scale dependence of the determinants of diversity is broadly acknowledged, we argue here that limitation to a single analysis scale and data pseudo-replication have impeded an integrated evolutionary and ecological understanding of diversity gradients. We develop and apply a hierarchical analysis framework for global diversity gradients that incorporates an explicit accounting of past environmental variation and provides an appropriate measurement of richness. Due to environmental niche conservatism, organisms generally reside in climatically defined bioregions, or ‘‘evolutionary arenas,’’ characterized by in situ speciation and extinction. These bioregions differ in age and their total productivity and have varied over time in area and energy available for diversification. We show that, consistently across the four major terrestrial vertebrate groups, current-day species richness of the world’s main 32 bioregions is best explained by a model that integrates area and productivity over geological time together with temperature. Adding finer scale variation in energy availability as an ecological predictor of within-bioregional patterns of richness explains much of the remaining global variation in richness at the 110 km grain. These results highlight the separate evolutionary and ecological effects of energy availability and provide a first conceptual and empirical integration of the key drivers of broad-scale richness gradients. Avoiding the pseudo-replication that hampers the evolutionary interpretation of non-hierarchical macroecological analyses, our findings integrate evolutionary and ecological mechanisms at their most relevant scales and offer a new synthesis regarding global diversity gradients. [ABSTRACT FROM AUTHOR]

Background: BCG vaccination is administered in infancy in most countries with the aim of providing protection against tuberculosis. There is increasing interest in the role of vitamin D in immunity to tuberculosis. This study objective was to determine if there was an association between circulating 25(OH)D concentrations and BCG vaccination status and cytokine responses following BCG vaccination in infants. Methods: Blood samples were collected from UK infants who were vaccinated with BCG at 3 (n = 47) and 12 (n = 37) months post BCG vaccination. These two time-points are denoted as time-point 1 and time-point 2. Two blood samples were also collected from age-matched unvaccinated infants (n = 32 and 28 respectively), as a control group. Plasma vitamin D concentrations (25(OH)D) were measured by radio-immunoassay. The cytokine IFNc was measured in supernatants from diluted whole blood stimulated with M.tuberculosis (M.tb) PPD for 6 days. Results: 58% of infants had some level of hypovitaminosis (25(OH)D ,30ng/ml) at time-point 1, and this increased to 97% 9 months later. BCG vaccinated infants were almost 6 times (CI: 1.8-18.6) more likely to have sufficient vitamin D concentrations than unvaccinated infants at time-point 1, and the association remained strong after controlling for season of blood collection, ethnic group and sex. Among vaccinees, there was also a strong inverse association between IFNc response to M.tb PPD and vitamin D concentration, with infants with higher vitamin D concentrations having lower IFNc responses. Conclusions: Vitamin D may play an immuno-regulatory role following BCG vaccination. The increased vitamin D concentrations in BCG vaccinated infants could have important implications: vitamin D may play a role in immunity induced by BCG vaccination and may contribute to non-specific effects observed following BCG vaccination. [ABSTRACT FROM AUTHOR]

Background: Despite increasing interest in possible differences in virulence and transmissibility between different genotypes of M. tuberculosis, very little is known about how genotypes within a population change over decades, or about relationships to HIV infection. Methods and Principal Findings: In a population-based study in rural Malawi we have examined smears and cultures from tuberculosis patients over a 20-year period using spoligotyping. Isolates were grouped into spoligotype families and lineages following previously published criteria. Time trends, HIV status, drug resistance and outcome were examined by spoligotype family and lineage. In addition, transmissibility was examined among pairs of cases with known epidemiological contact by assessing the proportion of transmissions confirmed for each lineage, on the basis of IS6110 RFLP similarity of the M tuberculosis strains. 760 spoligotypes were obtained from smears from 518 patients from 1986-2002, and 377 spoligotypes from cultures from 347 patients from 2005-2008. There was good consistency in patients with multiple specimens. Among 781 patients with first episode tuberculosis, the majority (76%) had Lineage 4 (''European/American'') strains; 9% had Lineage 3 (''East-African/Indian''); 8% Lineage 1 (''Indo-Oceanic''); and 2% Lineage 2 (''East-Asian''); others unclassifiable. Over time the proportion of Lineage 4 decreased from >90% to 60%, with an increase in the other 3 lineages (p<0.001). Lineage 1 strains were more common in those with HIV infection, even after adjusting for age, sex and year. There were no associations with drug resistance or outcome, and no differences by lineage in the proportion of pairs in which transmission was confirmed. Conclusions: This is the first study to describe long term trends in the four M. tuberculosis lineages in a population. Lineage 4 has probably been longstanding in this population, with relatively recent introductions and spread of Lineages1-3, perhaps influenced by the HIV epidemic. [ABSTRACT FROM AUTHOR]

Background: As HIV-related deaths increase in a population the usual association between low socioeconomic status and child mortality may change, particularly as death rates from other causes decline. Methods/Principal Findings: As part of a demographic surveillance system in northern Malawi in 2002-6, covering a population of 32,000, information was collected on socio-economic status of the households. Deaths were classified as HIV/ AIDS-related or not by verbal autopsy. Poisson regression models were used to assess the association of socio-economic indicators with all-cause mortality, AIDS-mortality and non-AIDS mortality among children. There were 195 deaths in infants, 109 in children aged 1-4 years, and 38 in children aged 5-15. All-cause child mortality in infants and 1-4 year olds was similar in households with higher and lower socio-economic status. In infants 13% of deaths were attributed to AIDS, and there were no clear trends with socio-economic status for AIDS or non-AIDS causes. For 1-4 year olds 27% of deaths were attributed to AIDS. AIDS mortality was higher among those with better built houses, and lowest in those with income from farming and fishing, whereas non-AIDS mortality was higher in those with worse built houses, lowest in those with income from employment, and decreased with increasing household assets. Conclusions/Significance: In this population, since HIV infection among adults was initially more common among the less poor, childhood mortality patterns have changed. The usual gap in survival between the poor and the less poor has been lost, but because the less poor have been disproportionately affected by HIV, rather than because of relative improvement in the survival of the poorest. [ABSTRACT FROM AUTHOR]

Background: Eight outbreaks of paralytic polio attributable to circulating vaccine-derived poliovirus (cVDPV) have highlighted the risks associated with oral poliovirus vaccine (OPV) use in areas of low vaccination coverage and poor hygiene. As the Polio Eradication Initiative enters its final stages, it is important to consider the extent to which these viruses spread under different conditions, so that appropriate strategies can be devised to prevent or respond to future cVDPV outbreaks. Methods and Findings: This paper examines epidemiological (temporal, geographic, age, vaccine history, social group, ascertainment), and virological (type, genetic diversity, virulence) parameters in order to infer the numbers of individuals likely to have been infected in each of these cVDPV outbreaks, and in association with single acute flaccid paralysis (AFP) cases attributable to VDPVs. Although only 114 virologically-confirmed paralytic cases were identified in the eight cVDPV outbreaks, it is likely that a minimum of hundreds of thousands, and more likely several million individuals were infected during these events, and that many thousands more have been infected by VDPV lineages within outbreaks which have escaped detection. Conclusions: Our estimates of the extent of cVDPV circulation suggest widespread transmission in some countries, as might be expected from endemic wild poliovirus transmission in these same settings. These methods for inferring extent of infection will be useful in the context of identifying future surveillance needs, planning for OPV cessation and preparing outbreak response plans. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization (WHO) released new Child Growth Standards in 2006 to replace the current National Center for Health Statistics (NCHS) growth reference. We assessed how switching from the NCHS to the newly released WHO Growth Standards affects the estimated prevalence of wasting, underweight and stunting, and the pattern of risk factors identified. Methodology/Principal Findings: Data were drawn from a village-informant driven Demographic Surveillance System in Northern Malawi. Children (n = 1328) were visited twice at 0-4 months and 11-15 months. Data were collected on the demographic and socio-economic environment of the child, health history, maternal and child anthropometry and child feeding practices. Weight-for-length, weight-for-age and length-for-age were derived in z-scores using the two growth references. In early infancy, prevalence estimates were 2.9, 6.1, and 8.5 fold higher for stunting, underweight, and wasting respectively using the WHO standards compared to NCHS reference (p<0.001 for all). At one year, prevalence estimates for wasting and stunting did not differ significantly according to reference used, but the prevalence of underweight was half that with the NCHS reference (p<0.001). Patterns of risk factors were similar with the two growth references for all outcomes at one year although the strength of association was higher with WHO standards. Conclusions/Significance: Differences in prevalence estimates differed in magnitude but not direction from previous studies. The scale of these differences depends on the population's nutritional status thus it should not be assumed a priori. The increase in estimated prevalence of wasting in early infancy has implications for feeding programs targeting lactating mothers and ante-natal multiple micronutrients supplementation to tackle small birth size. Risk factors identified using WHO standards remain comparable with findings based on the NCHS reference in similar settings. Further research should aim to identify whether the young infants additionally diagnosed as malnourished by this new standard are more appropriate targets for interventions than those identified with the NCHS reference. [ABSTRACT FROM AUTHOR]

Background. Tuberculosis causes significant morbidity and mortality worldwide, especially in sub-Saharan Africa. DC-SIGN, encoded byCD209, is a receptor capable of binding and internalizing Mycobacterium tuberculosis. Previous studies have reported that the CD209 promoter single nucleotide polymorphism (SNP)-336A/G exerts an effect on CD209 expression and is associated with human susceptibility to dengue, HIV-1 and tuberculosis in humans. The present study investigates the role of the CD209 - 336A/G variant in susceptibility to tuberculosis in a large sample of individuals from sub-Saharan Africa. Methods and Findings. A total of 2,176 individuals enrolled in tuberculosis case-control studies from four sub-Saharan Africa countries were genotyped for the CD209 -336A/G SNP (rs4804803). Significant overall protection against pulmonary tuberculosis was observed with the -336G allele when the study groups were combined (n= 914 controls vs. 1262 cases, Mantel-Haenszel 2x2 χ²=7.47, P = 0.006, odds ratio = 0.86, 95%CI 0.77-0.96). In addition, the patients with -336GG were associated with a decreased risk of cavitory tuberculosis, a severe form of tuberculosis disease (n = 557, Pearson's 2×2 χ²=17.34, P = 0.00003, odds ratio = 0.42, 95%CI 0.27-0.65). This direction of association is opposite to a previously observed result in a smaller study of susceptibility to tuberculosis in a South African Coloured population, but entirely in keeping with the previously observed protective effect of the -336G allele. Conclusion. This study finds that the CD209 -336G variant allele is associated with significant protection against tuberculosis in individuals from sub-Saharan Africa and, furthermore, cases with -336GG were significantly less likely to develop tuberculosisinduced lung cavitation. Previous in vitro work demonstrated that the promoter variant -336G allele causes down-regulation of CD209 mRNA expression. Our present work suggests that decreased levels of the DC-SIGN receptor may therefore be protective against both clinical tuberculosis in general and cavitory tuberculosis disease in particular. This is consistent with evidence that Mycobacteria can utilize DC-SIGN binding to suppress the protective pro-inflammatory immune response. [ABSTRACT FROM AUTHOR]

Leprosy is an infectious disease caused by the obligate intracellular pathogen Mycobacterium leprae and remains endemic in many parts of the world. Despite several major studies on susceptibility to leprosy, few genomic loci have been replicated independently. We have conducted an association analysis of more than 1,500 individuals from different case-control and family studies, and observed consistent associations between genetic variants in both TLR1 and the HLA-DRB1/DQA1 regions with susceptibility to leprosy (TLR1 I602S, case-control P = 5.7 x 10(-8), OR = 0.31, 95% CI = 0.20-0.48, and HLA-DQA1 rs1071630, case-control P = 4.9 x 10(-14), OR = 0.43, 95% CI = 0.35-0.54). The effect sizes of these associations suggest that TLR1 and HLA-DRB1/DQA1 are major susceptibility genes in susceptibility to leprosy. Further population differentiation analysis shows that the TLR1 locus is extremely differentiated. The protective dysfunctional 602S allele is rare in Africa but expands to become the dominant allele among individuals of European descent. This supports the hypothesis that this locus may be under selection from mycobacteria or other pathogens that are recognized by TLR1 and its co-receptors. These observations provide insight into the long standing host-pathogen relationship between human and mycobacteria and highlight the key role of the TLR pathway in infectious diseases.