To identify susceptibility loci for visceral leishmaniasis we undertook genome-wide association studies in two populations; 989 cases and 1089 controls from India, and 357 cases in 308 Brazilian families (1970 individuals). The HLA-DRB1-HLA-DQA1 locus was the only region to show strong evidence of association in both populations. Replication at this region was undertaken in a second Indian population comprising 941 cases and 990 controls, resulting in Pcombined=2.76×10−17 and OR(95%CI)=1.41(1.30-1.52) across the three cohorts at rs9271858. A conditional analysis provided evidence for multiple associations within the HLA-DRB1-HLA-DQA1 region, and a model in which risk differed between three groups of haplotypes better explained the signal and was significant in the Indian discovery and replication cohorts. In conclusion the HLA-DRB1-HLA-DQA1 HLA class II region contributes to visceral leishmaniasis susceptibility in India and Brazil, suggesting shared genetic risk factors for visceral leishmaniasis that cross the epidemiological divides of geography and parasite species.

SUMMARY Ninety percent of the 500,000 annual new cases of visceral leishmaniasis occur in India/Bangladesh/Nepal, Sudan and Brazil. Importantly, 80-90% of human infections are sub-clinical or asymptomatic, usually associated with strong cell-mediated immunity. Understanding the environmental and genetic risk factors that determine why two people with the same exposure to infection differ in susceptibility could provide important leads for improved therapies. Recent research using candidate gene association analysis and genome-wide linkage studies (GWLS) in collections of families from Sudan, Brazil and India have identified a number of genes/regions related both to environmental risk factors (e.g. iron), as well as genes that determine type 1 versus type 2 cellular immune responses. However, until now all of the allelic association studies carried out have been underpowered to find genes of small effect sizes (odds ratios or OR<2), and GWLS using multicase pedigrees have only been powered to find single major genes, or at best oligogenic control. The accumulation of large DNA banks from India and Brazil now makes it possible to undertake genome-wide asscociation studies (GWAS), which are ongoing as part of phase two of the Wellcome Trust Case Control Consortium. Data from this analysis should seed research into novel genes and mechanisms that influence susceptibility to visceral leishmaniasis.

In this phase III trial for diagnostics for visceral leishmaniasis (VL) in India, we compared parasitological diagnosis with several serological tests: direct agglutination test (freeze dried; DAT-FD), rK-39 strip test, rK-26 strip test and a latex agglutination test for antigen detection in urine (KAtex) in 452 subjects from the endemic regions of Bihar, India. The subjects were segregated into four categories: 230 confirmed patients, 52 probable cases, 70 non-cases and 100 healthy endemic controls. The first two groups were used for estimating sensitivity, the latter two for specificity. Sensitivity of DAT-FD was 98.9%, rK-39: 98.9%, KAtex: 67.0% and rK-26: 21.3%. Sensitivity of DAT-FD on blood taken on filter paper (DAT-FDF) was 99.3%, which was comparable with that using serum. Specificity of serological tests was comparable and high (DAT-FD and DAT-FDF: 94%, rK-39 strip test: 97%, KAtex: 99% and rK-26 strip test: 100%). The classical 'gold standard' parasitological demonstration in splenic smear performed poorly as it missed 18.4% of cases that benefited from VL treatment. Reproducibility of the serological tests between field and central laboratories was excellent (kappa = 1.0, 0.99, 0.96 and 0.94 respectively for microscopy, DAT-FD, rK-39 strip test and rK-26 strip test). A high degree of agreement was observed between DAT-FD and rK-39 strip test (kappa = 0.986). Although DAT-FD and rK-39 strip test were highly sensitive with excellent specificity, the ease of use of the latter makes it most suitable for the diagnosis of VL in the field conditions.

An important risk factor for nosocomial infection in an intensive care unit (ICU) is prior colonization. This study was undertaken to determine the spectrum of bacterial colonization and predisposing risk factors in patients being admitted to an ICU in India, with special emphasis on extended-spectrum b-lactamase (ESBL)-and metallo-b-lactamase (MBL)-producing Gramnegative bacteria. Nasal, oral and rectal swab samples were collected and processed for isolation of ESBL-producing Gram-negative bacteria and MBL-producing Pseudomonas aeruginosa and Acinetobacter species. Bacterial colonization (of one or more sites) on admission was detected in 51 out of 96 patients included in the study. Non-fermenters, i.e. P. aeruginosa and Acinetobacter baumannii, were the most common colonizers, present in 37 patients, with simultaneous colonization in 12 patients. A total of 16 patients were colonized with MBL-producing members of the family Enterobacteriaceae, out of which 11 isolates (from 5 patients) were also carrying ESBL-encoding genes. As for MBLs, most of our patients have shown colonization with ESBL-producing bacteria. On admission, 47 of 51 patients (92 %) have been colonized by ESBL-producing members of the family Enterobacteriaceae, at one or more of the three anatomical sites. The most common MBL subtype was bla IMP (51.56 %), whereas bla CTX was the most common gene (84.9 %) identified among ESBL producers. Risk factors for colonization on admission to the ICU were hospitalization for more than 48 h, use of ¢3 groups of antibiotics, co-morbidities and mechanical ventilation for more than 48 h prior to ICU admission. There is an increasing incidence of MBLs and ESBLs in the Indian population. The identified risk factors can be used as a guide for empiric antibiotic therapy targeted to these resistant bacteria.

The organ-on-a-chip (OoC) paves a way for biomedical applications ranging from preclinical to clinical translational precision. The current trends in the in vitro modeling is to reduce the complexity of human organ anatomy to the fundamental cellular microanatomy as an alternative of recreating the entire cell milieu that allows systematic analysis of medicinal absorption of compounds, metabolism, and mechanistic investigation. The OoC devices accurately represent human physiology in vitro; however, it is vital to choose the correct chip materials. The potential chip materials include inorganic, elastomeric, thermoplastic, natural, and hybrid materials. Despite the fact that polydimethylsiloxane is the most commonly utilized polymer for OoC and microphysiological systems, substitute materials have been continuously developed for its advanced applications. The evaluation of human physiological status can help to demonstrate using noninvasive OoC materials in real-time procedures. Therefore, this Review examines the materials used for fabricating OoC devices, the application-oriented pros and cons, possessions for device fabrication and biocompatibility, as well as their potential for downstream biochemical surface alteration and commercialization. The convergence of emerging approaches, such as advanced materials, artificial intelligence, machine learning, three-dimensional (3D) bioprinting, and genomics, have the potential to perform OoC technology at next generation. Thus, OoC technologies provide easy and precise methodologies in cost-effective clinical monitoring and treatment using standardized protocols, at even personalized levels. Because of the inherent utilization of the integrated materials, employing the OoC with biomedical approaches will be a promising methodology in the healthcare industry.

Our understanding of the genetics of skin pigmentation has been largely skewed towards populations of European ancestry, imparting less attention to South Asian populations, who behold huge pigmentation diversity. Here, we investigate skin pigmentation variation in a cohort of 1,167 individuals in the Middle Gangetic Plain of the Indian subcontinent. Our data confirm the association of rs1426654 with skin pigmentation among South Asians, consistent with previous studies, and also show association for rs2470102 single nucleotide polymorphism. Our haplotype analyses further help us delineate the haplotype distribution across social categories and skin color. Taken together, our findings suggest that the social structure defined by the caste system in India has a profound influence on the skin pigmentation patterns of the subcontinent. In particular, social category and associated single nucleotide polymorphisms explain about 32% and 6.4%, respectively, of the total phenotypic variance. Phylogeography of the associated single nucleotide polymorphisms studied across 52 diverse populations of the Indian subcontinent shows wide presence of the derived alleles, although their frequencies vary across populations. Our results show that both polymorphisms (rs1426654 and rs2470102) play an important role in the skin pigmentation diversity of South Asians.

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BackgroundGenome wide linkage studies (GWLS) have provided evidence for loci controlling visceral leishmaniasis on Chromosomes 1p22, 6q27, 22q12 in Sudan and 6q27, 9p21, 17q11-q21 in Brazil. Genome wide studies from the major focus of disease in India have not previously been reported.Methods and FindingsWe undertook a GWLS in India in which a primary ∼10 cM (515 microsatellites) scan was carried out in 58 multicase pedigrees (74 nuclear families; 176 affected, 353 total individuals) and replication sought in 79 pedigrees (102 nuclear families; 218 affected, 473 total individuals). The primary scan provided evidence (≥2 adjacent markers allele-sharing LOD≥0.59; nominal P≤0.05) for linkage on Chromosomes 2, 5, 6, 7, 8, 10, 11, 20 and X, with peaks at 6p25.3-p24.3 and 8p23.1-p21.3 contributed to largely by 31 Hindu families and at Xq21.1-q26.1 by 27 Muslim families. Refined mapping confirmed linkage across all primary scan families at 2q12.2-q14.1 and 11q13.2-q23.3, but only 11q13.2-q23.3 replicated (combined LOD = 1.59; P = 0.0034). Linkage at 6p25.3-p24.3 and 8p23.1-p21.3, and at Xq21.1-q26.1, was confirmed by refined mapping for primary Hindu and Muslim families, respectively, but only Xq21.1-q26.1 replicated across all Muslim families (combined LOD 1.49; P = 0.0045). STRUCTURE and SMARTPCA did not identify population genetic substructure related to religious group. Classification and regression tree, and spatial interpolation, analyses confirm geographical heterogeneity for linkages at 6p25.3-p24.3, 8p23.1-p21.3 and Xq21.1-q26.1, with specific clusters of families contributing LOD scores of 2.13 (P = 0.0009), 1.75 (P = 0.002) and 1.84 (P = 0.001), respectively.ConclusionsGWLS has identified novel loci that show geographical heterogeneity in their influence on susceptibility to VL in India.