The neonatal gut microbiome and global health.

The role of gut microbiome in health, a century-old concept, has been on the center stage of medical research recently. While different body sites, disease conditions, and populations have been targeted, neonatal and early infancy appear to be the most suitable period for such interventions. It is intriguing to note that, unlike traditional use in diarrhea and maintenance of gastrointestinal health, microbiome-mediating therapies have now addressed the most serious medical conditions in young infants such as necrotizing enterocolitis and neonatal sepsis. Unfortunately, almost all new endeavors in this space have been carried out in the Western world leaving behind millions of neonates that can benefit from such manipulations while serving as a large resource for further learning. In this review, an attempt has been made to quantify the global burden of neonatal morbidity and mortality, examples presented on interventions that have failed as a result of drawing from studies conducted in the West, and a case made for manipulating the neonatal gut microbiome to address the biggest killers in early life. A brief comparative analysis has been made to demonstrate the differences in the gut microbiota of North and South and a large clinical trial of synbiotics conducted by our group in a South Asian setting has been presented. Although challenging, the value of conducting such global health research is introduced with an intent to invite medical scientists to engage in well-planned, scientifically robust research endeavors. This can bring about innovation while saving and serving the most vulnerable citizens now and protecting them from the negative health consequences in the later part of their lives, ultimately shaping a resilient and equitable world as pledged by 193 United Nations member countries in 2015.

Risk factors for community-acquired bacterial infection among young infants in South Asia: a longitudinal cohort study with nested case-control analysis.

OBJECTIVE: Risk factors predisposing infants to community-acquired bacterial infections during the first 2 months of life are poorly understood in South Asia. Identifying risk factors for infection could lead to improved preventive measures and antibiotic stewardship. METHODS: Five sites in Bangladesh, India and Pakistan enrolled mother-child pairs via population-based pregnancy surveillance by community health workers. Medical, sociodemographic and epidemiological risk factor data were collected. Young infants aged 0-59 days with signs of possible serious bacterial infection (pSBI) and age-matched controls provided blood and respiratory specimens that were analysed by blood culture and real-time PCR. These tests were used to build a Bayesian partial latent class model (PLCM) capable of attributing the probable cause of each infant's infection in the ANISA study. The collected risk factors from all mother-child pairs were classified and analysed against the PLCM using bivariate and stepwise logistic multivariable regression modelling to determine risk factors of probable bacterial infection. RESULTS: Among 63 114 infants born, 14 655 were assessed and 6022 had signs of pSBI; of these, 81% (4859) provided blood samples for culture, 71% (4216) provided blood samples for quantitative PCR (qPCR) and 86% (5209) provided respiratory qPCR samples. Risk factors associated with bacterial-attributed infections included: low (relative risk (RR) 1.73, 95% credible interval (CrI) 1.42 to 2.11) and very low birth weight (RR 5.77, 95% CrI 3.73 to 8.94), male sex (RR 1.27, 95% CrI 1.07 to 1.52), breathing problems at birth (RR 2.50, 95% CrI 1.96 to 3.18), premature rupture of membranes (PROMs) (RR 1.27, 95% CrI 1.03 to 1.58) and being in the lowest three socioeconomic status quintiles (first RR 1.52, 95% CrI 1.07 to 2.16; second RR 1.41, 95% CrI 1.00 to 1.97; third RR 1.42, 95% CrI 1.01 to 1.99). CONCLUSION: Distinct risk factors: birth weight, male sex, breathing problems at birth and PROM were significantly associated with the development of bacterial sepsis across South Asian community settings, supporting refined clinical discernment and targeted use of antimicrobials.

Infectious aetiologies of neonatal illness in south Asia classified using WHO definitions: a primary analysis of the ANISA study.

BACKGROUND: Globally, neonatal mortality accounts for almost half of all deaths in children younger than 5 years. Aetiological agents of neonatal infection are difficult to identify because the clinical signs are non-specific. Using data from the Aetiology of Neonatal Infections in south Asia (ANISA) cohort, we aimed to describe the spectrum of infectious aetiologies of acute neonatal illness categorised post-hoc using the 2015 WHO case definitions of critical illness, clinical severe infection, and fast breathing only. METHODS: Eligible infants were aged 0-59 days with possible serious bacterial infection and healthy infants enrolled in the ANISA study in Bangladesh, India, and Pakistan. We applied a partial latent class Bayesian model to estimate the prevalence of 27 pathogens detectable on PCR, pathogens detected by blood culture only, and illness not attributed to any infectious aetiology. Infants with at least one clinical specimen available were included in the analysis. We assessed the prevalence of these aetiologies according to WHO's case definitions of critically ill, clinical severe infection, and infants with late onset, isolated fast breathing. For the clinical severe definition, we compared the prevalence of signs by bacterial versus viral aetiology. FINDINGS: There were 934 infants (992 episodes) in the critically ill category, 3769 (4000 episodes) in the clinical severe infection category, and 738 (771 episodes) in the late-onset isolated fast breathing category. We estimated the proportion of illness attributable to bacterial infection was 32·7% in infants in the critically ill group, 15·6% in the clinical severe infection group, and 8·8% among infants with late-onset isolated fast breathing group. An infectious aetiology was not identified in 58-82% of infants in these categories. Among 4000 episodes of clinical severe infection, those with bacterial versus viral attribution had higher proportions of hypothermia, movement only when stimulated, convulsions, and poor feeding. INTERPRETATION: Our modelled results generally support the revised WHO case definitions, although a revision of the most severe case definition could be considered. Clinical criteria do not clearly differentiate between young infants with and without infectious aetiologies. Our results highlight the need for improved point-of-care diagnostics, and further study into neonatal deaths and episodes with no identified aetiology, to ensure antibiotic stewardship and targeted interventions. FUNDING: The Bill and Melinda Gates Foundation.

Community-based asthma assessment in young children: adaptations for a multicentre longitudinal study in South Asia.

Background: Systematic assessment of childhood asthma is challenging in low- and middle-income country (LMIC) settings due to the lack of standardised and validated methodologies. We describe the contextual challenges and adaptation strategies in the implementation of a community-based asthma assessment in four resource-constrained settings in Bangladesh, India, and Pakistan. Method: We followed a group of children of age 6-8 years for 12 months to record their respiratory health outcomes. The study participants were enrolled at four study sites of the 'Aetiology of Neonatal Infection in South Asia (ANISA)' study. We standardised the research methods for the sites, trained field staff for uniform data collection and provided a 'Child Card' to the caregiver to record the illness history of the participants. We visited the children on three different occasions to collect data on respiratory-related illnesses. The lung function of the children was assessed in the outreach clinics using portable spirometers before and after 6-minute exercise, and capillary blood was examined under light microscopes to determine eosinophil levels. Results: We enrolled 1512 children, 95.5% (1476/1512) of them completed the follow-up, and 81.5% (1232/1512) participants attended the lung function assessment tests. Pre- and post-exercise spirometry was performed successfully in 88.6% (1091/1232) and 85.7% (1056/1232) of children who attempted these tests. Limited access to health care services, shortage of skilled human resources, and cultural diversity were the main challenges in adopting uniform procedures across all sites. Designing the study implementation plan based on the local contexts and providing extensive training of the healthcare workers helped us to overcome these challenges. Conclusion: This study can be seen as a large-scale feasibility assessment of applying spirometry and exercise challenge tests in community settings of LMICs and provides confidence to build capacity to evaluate children's respiratory outcomes in future translational research studies.

Lactiplantibacillus plantarum-Nomad and Ideal Probiotic.

Probiotics are increasingly recognized as capable of positively modulating several aspects of human health. There are numerous attributes that make an ideal probiotic. Lactiplantibacillus plantarum (Lp) exhibits an ecological and metabolic flexibility that allows it to thrive in a variety of environments. The present review will highlight the genetic and functional characteristics of Lp that make it an ideal probiotic and summarizes the current knowledge about its potential application as a prophylactic or therapeutic intervention.

Bacterial and Fungal Gut Community Dynamics Over the First 5 Years of Life in Predominantly Rural Communities in Ghana.

BACKGROUND: Bacterial and fungal microbiotas are increasingly recognized as important in health and disease starting early in life. However, microbiota composition has not yet been investigated in most rural, low-resource settings, and in such settings, bacterial and fungal microbiotas have not been compared. Thus, we applied 16S and ITS2 amplicon sequencing, respectively, to investigate bacterial and fungal fecal microbiotas in rural Ghanaian children cross-sectionally from birth to 5 years of age. Corresponding maternal fecal and breast milk microbiotas were additionally investigated. RESULTS: While bacterial communities differed systematically across the age spectrum in composition and diversity, the same was not observed for the fungal microbiota. We also identified a novel and dramatic change in the maternal postpartum microbiota. This change included much higher abundance of Escherichia coli and much lower abundance of Prevotella in the first vs. fourth week postpartum. While infants shared more bacterial taxa with their mother's stool and breast milk than with those of unrelated mothers, there were far fewer shared fungal taxa. CONCLUSION: Given the known ability of commensal fungi to influence host health, the distinct pattern of their acquisition likely has important health consequences. Similarly, the dynamics of mothers' bacterial microbiotas around the time of birth may have important consequences for their children's health. Both topics require further study.

Immunoglobulin Receptors Expression in Indian Colon Cancer Patients and Healthy Subjects Using a Noninvasive Approach and Flowcytometry.

BACKGROUND: Isolation of viable colonocytes from human stool is a noninvasive and convenient approach that can be used for diagnostic, screening, management, and research on various gastrointestinal (GI) diseases including colon cancer. Limited studies are available globally and for the first time in this article, we have reported the immunoglobulin (Ig) (IgA and IgG) receptors concentration on viable colonocytes for Indian colon cancer patients using this noninvasive approach. MATERIALS AND METHODS: Viable colonocytes from stool were isolated by the Somatic Cell Sampling and Recovery method (Noninvasive Technology, USA) and processed for the assessment of Igs (IgA and IgG) receptors expression using standard immunophenotyping and flow cytometry. RESULTS: IgA and IgG receptor expression was measured and reported on these viable colonocytes. There was a significant difference in the expression of IgA and IgG receptors on viable colonocytes between colon cancer patients and healthy individuals. CONCLUSION: This noninvasive technique is a promising approach for the detection of molecular and immunological markers that will help clinicians in the diagnosis, screening, monitoring, and management of different GI diseases including colon cancer.

Genome Sequence of Lactiplantibacillus plantarum ATCC 202195, a Probiotic Strain That Reduces Sepsis and Other Infections during Early Infancy.

The draft genome of probiotic Lactiplantibacillus plantarum ATCC 202195, with the trademark PPLP-217, is comprised of 3,368,305 bp with a G+C content of 44.3% and no plasmids. The strain is able to grow on lactose, raffinose, and fructooligosaccharides.

Influence of rs1042713 and rs1042714 polymorphisms of ß2-adrenergic receptor gene with erythrocyte cAMP in sickle cell disease patients from Odisha State, India.

The vaso-occlusive crisis (VOCs) in sickle cell disease (SCD) is often associated with stress. Epinephrine released during stress acts via beta 2-adrenergic receptors (ß2-AR or ADRB2) to stimulate the synthesis of cyclic adenosine monophosphate (cAMP) in the red blood cells (RBCs). Higher cAMP levels promote adhesion of sickled RBCs to vascular endothelium, a major contributor for VOCs. Several single-nucleotide polymorphisms (SNPs) of the ß2-AR gene have been reported; two of them at codon 16 (rs1042713) and codon 27 (rs1042714) have been extensively studied for their clinical relevance. Therefore, we assessed the influence of polymorphism at these two sites of the ß2-AR gene on the RBC cAMP concentrations with and without epinephrine stimulation in SCD subjects. We determined the frequency distribution of different genotypes of codon 16 and codon 27 of the ß2-AR gene using the Sanger sequencing method in the SCD subjects. We measured the RBC-cAMP levels at baseline and after stimulation with epinephrine, to ascertain the influence of different genotypes in determining cAMP levels. There was no difference in the socio-demographic and hematological indicators in different genotypes of both codon 16 and 27. In the sham-treated erythrocytes, the cAMP levels were significantly different with three genotypes of codon 16 (F = 3.39, P = 0.036; one way ANOVA) but not with different genotypes of codon 27. A significant increase in cAMP levels was noticed with epinephrine treatment in all genotypes of codons 16 and 27 (P = 0.001; Wilcoxon signed-rank test). However, the extent of increase in the epinephrine-treated cAMP values from the sham-treated (baseline) cAMP values was significantly different between the three genotypes of codon 16 (H = 8.74; P = 0.012; Kruskal-Wallis test) but not in codon 27 genotypes. Polymorphism in codon 16 (rs1042713) of the ß2-AR gene influences cAMP concentrations in the RBC both before and after epinephrine treatment. Higher cAMP levels may lead to increased adhesion of sickle cell RBCs to vascular endothelium and may increase the frequency of VOCs.

Frequency and determinants of health care utilization for symptomatic reproductive tract infections in rural Indian women: A cross-sectional study.

INTRODUCTION: The public health burden of reproductive tract infections (RTIs) among women in rural areas of low-income countries is poorly addressed because health care seeking for treatment of RTIs is inadequate. There are gaps in knowledge about whether low care seeking behavior stems from challenges in accessing health care versus women's recognition of and response to RTI-specific disease symptoms. We aim to identify determinants of care seeking behavior and analyze the difference in utilization of health care resources in response to symptoms of an RTI versus non-RTI disease symptoms in rural India. This will aid in the design of interventions that promote RTI care seeking behavior. METHODS: Our analysis uses data from a cross-sectional, population-based surveillance survey among rural, non-pregnant women in Odisha, India, from 2013-2014 (n = 3,600). We utilized bivariate logistic regression to determine the degree that certain determinants are associated with a woman's likelihood to seek RTI treatment, and chi-Squared tests to assess for differences in health care resources used for non-RTI versus RTI symptoms. RESULTS: Married women were significantly more likely to seek health care for RTI symptoms (Odds Ratio (OR) = 1.9, 95% Confidence Interval (CI): 1.2-3.0) while unmarried adolescents were less likely to seek treatment (OR = 0.4, CI: 0.2-0.6). There was no association between RTI health care seeking with education level, belief about whether symptoms can be treated, or poverty. The majority (73.8%) of women who did not seek treatment for RTI symptoms reported not seeking treatment because they did not know treatment was needed. Women utilized formal health care providers at a higher rate in response to RTI symptoms than in response to their most recent symptoms of any kind (p = 0.003). CONCLUSIONS: Community-based reproductive health education interventions are needed to increase health care seeking behavior for RTIs in rural Indian women. Interventions should target unmarried women and focus on both sexual health education and access to care.

Understanding and Enhancing Sepsis Survivorship. Priorities for Research and Practice.

An estimated 14.1 million patients survive sepsis each year. Many survivors experience poor long-term outcomes, including new or worsened neuropsychological impairment; physical disability; and vulnerability to further health deterioration, including recurrent infection, cardiovascular events, and acute renal failure. However, clinical trials and guidelines have focused on shorter-term survival, so there are few data on promoting longer-term recovery. To address this unmet need, the International Sepsis Forum convened a colloquium in February 2018 titled "Understanding and Enhancing Sepsis Survivorship." The goals were to identify gaps and limitations of current research and shorter- and longer-term priorities for understanding and enhancing sepsis survivorship. Twenty-six experts from eight countries participated. The top short-term priorities identified by nominal group technique culminating in formal voting were to better leverage existing databases for research, develop and disseminate educational resources on postsepsis morbidity, and partner with sepsis survivors to define and achieve research priorities. The top longer-term priorities were to study mechanisms of long-term morbidity through large cohort studies with deep phenotyping, build a harmonized global sepsis registry to facilitate enrollment in cohorts and trials, and complete detailed longitudinal follow-up to characterize the diversity of recovery experiences. This perspective reviews colloquium discussions, the identified priorities, and current initiatives to address them.

Probiotic Studies in Neonatal Mice Using Gavage.

Adult mouse models have been widely used to understand the mechanism behind disease progression in humans. The applicability of studies done in adult mouse models to neonatal diseases is limited. To better understand disease progression, host responses and long-term impact of interventions in neonates, a neonatal mouse model likely is a better fit. The sparse use of neonatal mouse models can in part be attributed to the technical difficulties of working with these small animals. A neonatal mouse model was developed to determine the effects of probiotic administration in early life and to specifically assess the ability to establish colonization in the newborn mouse intestinal tract. Specifically, to assess probiotic colonization in the neonatal mouse, Lactobacillus plantarum (LP) was delivered directly into the neonatal mouse gastrointestinal tract. To this end, LP was administered to mice by feeding through intra-esophageal (IE) gavage. A highly reproducible method was developed to standardize the process of IE gavage that allows an accurate administration of probiotic dosages while minimizing trauma, an aspect particularly important given the fragility of newborn mice. Limitations of this process include possibilities of esophageal irritation or damage and aspiration if gavaged incorrectly. This approach represents an improvement on current practices because IE gavage into the distal esophagus reduces the chances of aspiration. Following gavage, the colonization profile of the probiotic was traced using quantitative polymerase chain reaction (qPCR) of the extracted intestinal DNA with LP specific primers. Different litter settings and cage management techniques were used to assess the potential for colonization-spread. The protocol details the intricacies of IE neonatal mouse gavage and subsequent colonization quantification with LP.

Independent urban effect on hypertension of older Indians: identification of a knowledge gap from a Study on Global AGEing and Health.

Among older Indians, more cardiovascular diseases and risk factors are observed in the city dwellers than in the rural population. Clustering of socioeconomic privileges and consequent obesity in the Indian cities are known to underlie this phenomenon. But, it is unclear whether an independent urban effect exists on age-related ailments, unexplained by concentration of privileges and excess weight in the Indian cities. Hence, we aimed to estimate the independent urban effect on hypertension among older Indians after controlling for these factors. Nationally representative data of Indians aged 50 years and older (n = 7273) were collected by Study on global AGEing and health. Hypertension was defined as systolic and/or diastolic blood pressure >139 and > 89 mm Hg, respectively, and/or someone receiving antihypertensive medications. Permanent place of residence (urban/rural) during interview was recorded. Socioeconomic determinants included caste, occupation, assets, and education. Body mass index, abdominal circumference, smoking, alcohol, and physical activity were also controlled. The age- and sex-adjusted odds ratio of hypertension for urban residents was 1.64 (146-1.83), which partially attenuated to 1.22 (1.07-1.38) after controlling for all the covariates. This study highlights 22% excess odds of hypertension among the older Indian city dwellers, unexplained by the greater urban concentration of socioeconomic privileges and obesity. Future research should explore the constituents of this urban effect.

Association between unhygienic menstrual management practices and prevalence of lower reproductive tract infections: a hospital-based cross-sectional study in Odisha, India.

BACKGROUND: The extent to which reproductive tract infections (RTIs) are associated with poor menstrual hygiene management (MHM) practices has not been extensively studied. We aimed to determine whether poor menstrual hygiene practices were associated with three common infections of the lower reproductive tract; Bacterial vaginosis (BV), Candida, and Trichomonas vaginalis (TV). METHODS: Non-pregnant women of reproductive age (18-45 years) and attending one of two hospitals in Odisha, India, between April 2015 and February 2016 were recruited for the study. A standardized questionnaire was used to collect information on: MHM practices, clinical symptoms for the three infections, and socio-economic and demographic information. Specimens from posterior vaginal fornix were collected using swabs for diagnosis of BV, Candida and TV infection. RESULTS: A total of 558 women were recruited for the study of whom 62.4% were diagnosed with at least one of the three tested infections and 52% presented with one or more RTI symptoms. BV was the most prevalent infection (41%), followed by Candida infection (34%) and TV infection (5.6%). After adjustment for potentially confounding factors, women diagnosed with Candida infection were more likely to use reusable absorbent material (aPRR = 1.54, 95%CI 1.2-2.0) and practice lower frequency of personal washing (aPRR = 1.34, 95%CI 1.07-1.7). Women with BV were more likely to practice personal washing less frequently (aPRR = 1.25, 95%CI 1.0-1.5), change absorbent material outside a toilet facility (aPRR = 1.21, 95%CI 1.0-1.48) whilst a higher frequency of absorbent material changing was protective (aPRR = 0.56, 95%CI 0.4-0.75). No studied factors were found to be associated with TV infection. In addition, among women reusing absorbent material, Candida but not BV or TV - infection was more frequent who dried their pads inside their houses and who stored the cloth hidden in the toilet compartment. CONCLUSION: The results of our study add to growing number of studies which demonstrate a strong and consistent association between poor menstrual hygiene practices and higher prevalence of lower RTIs.

Causes and incidence of community-acquired serious infections among young children in south Asia (ANISA): an observational cohort study.

BACKGROUND: More than 500 000 neonatal deaths per year result from possible serious bacterial infections (pSBIs), but the causes are largely unknown. We investigated the incidence of community-acquired infections caused by specific organisms among neonates in south Asia. METHODS: From 2011 to 2014, we identified babies through population-based pregnancy surveillance at five sites in Bangladesh, India, and Pakistan. Babies were visited at home by community health workers up to ten times from age 0 to 59 days. Illness meeting the WHO definition of pSBI and randomly selected healthy babies were referred to study physicians. The primary objective was to estimate proportions of specific infectious causes by blood culture and Custom TaqMan Array Cards molecular assay (Thermo Fisher, Bartlesville, OK, USA) of blood and respiratory samples. FINDINGS: 6022 pSBI episodes were identified among 63 114 babies (95·4 per 1000 livebirths). Causes were attributed in 28% of episodes (16% bacterial and 12% viral). Mean incidence of bacterial infections was 13·2 (95% credible interval [CrI] 11·2-15·6) per 1000 livebirths and of viral infections was 10·1 (9·4-11·6) per 1000 livebirths. The leading pathogen was respiratory syncytial virus (5·4, 95% CrI 4·8-6·3 episodes per 1000 livebirths), followed by Ureaplasma spp (2·4, 1·6-3·2 episodes per 1000 livebirths). Among babies who died, causes were attributed to 46% of pSBI episodes, among which 92% were bacterial. 85 (83%) of 102 blood culture isolates were susceptible to penicillin, ampicillin, gentamicin, or a combination of these drugs. INTERPRETATION: Non-attribution of a cause in a high proportion of patients suggests that a substantial proportion of pSBI episodes might not have been due to infection. The predominance of bacterial causes among babies who died, however, indicates that appropriate prevention measures and management could substantially affect neonatal mortality. Susceptibility of bacterial isolates to first-line antibiotics emphasises the need for prudent and limited use of newer-generation antibiotics. Furthermore, the predominance of atypical bacteria we found and high incidence of respiratory syncytial virus indicated that changes in management strategies for treatment and prevention are needed. Given the burden of disease, prevention of respiratory syncytial virus would have a notable effect on the overall health system and achievement of Sustainable Development Goal. FUNDING: Bill & Melinda Gates Foundation.

Higher vaginal pH in Trichomonas vaginalis infection with intermediate Nugent score in reproductive-age women-a hospital-based cross-sectional study in Odisha, India.

A close association between Trichomonas vaginalis (TV) infection and bacterial vaginosis (BV) has been reported. Some other studies have found association is stronger with intermediate Nugent score than BV. Most studies have used wet mount microscopy, a relatively insensitive method, to detect TV infection. We wanted to study the association of TV infection with BV and with intermediate Nugent score. We undertook a cross-sectional hospital-based study of 1110 non-pregnant women from Odisha state, India, aged between 18 and 45 years, collecting vaginal swabs for diagnosis of BV by Nugent score (NS) criteria and TV by PCR analysis. TV infection was found in 13.3% of women with intermediate Nugent score (NS 4-6) and 13.6% with BV (NS 7-10). Before adjustment, TV infection was associated with BV, intermediate Nugent, vaginal pH ≥ 4.5, and age group between 26 and 35 years. Multivariate analysis confirmed that TV infection was more likely to have raised vaginal pH, either BV or intermediate Nugent. Proportion of TV cases increased sequentially with the increase in Nugent score up to NS 6, after which a decline was observed. Vaginal pH was higher in the TV-infected group than the uninfected group in women with intermediate Nugent, but no difference was noticed in women with BV. TV infection was equally prevalent in women with intermediate Nugent as well as BV. In the intermediate Nugent group women, TV infection was found only when vaginal pH was raised, indicating a crucial role of vaginal pH in determining TV infection.

Impact of involvement of non-formal health providers on TB case notification among migrant slum-dwelling populations in Odisha, India.

BACKGROUND: Migrant labourers living in the slums of urban and industrial patches across India make up a key sub-population so far controlling Tuberculosis (TB) in the country is concerned. This is because many TB patients from these communities- remain under reached by the Revised National Tuberculosis Control Programme (RNTCP) of India. This marginalized community usually seeks early-stage healthcare from "friendly neighbourhood" non-formal health providers (NFHPs). Because, RNTCP has limited capacity to involve the NFHPs, an implementation research project was conceived, whereby an external partner would engage with the NFHPs to enable them to identify early TB symptomatics from this key sub-population who would be then tested using Xpert MTB/RIF technology. Diagnosed TB cases among them would be referred promptly to RNTCP for treatment. This paper aimed to describe the project and its impact. METHODS: Adopting a quasi-experimental before-after design, four RNTCP units from two major urban-industrial areas of Odisha were selected for intervention, which spanned five quarters and covered 151,400 people, of which 30% were slum-dwelling migrants. Two similar units comprised the control population. The hypothesis was, reaching the under reached in the intervention area through NFHPs would increase TB notification from these traditionally under-notifying units. RNTCP notification data during intervention was compared with pre-intervention era, adjusted for contemporaneous changes in control population. RESULTS: The project detected 488 Xpert+ TB cases, of whom 466 were administered RNTCP treatment. This translated into notification of additional 198 new bacteriologically positive cases to RNTCP, a 30% notification surge, after adjustment for 2% decline in control. This meant an average quarterly increase in notification of 41.20(20.08, 62.31; p<0.001) cases. The increase was immediate, evident from the rise in level in the time series analysis by 50.42(10.28, 90.55; p = 0.02) cases. CONCLUSION: Engagement with NFHPs contributed to an increase in TB notification to RNTCP from key under reached, slum-dwelling migrant populations.

Corrigendum: A randomized synbiotic trial to prevent sepsis among infants in rural India.

This corrects the article DOI: 10.1038/nature23480.

From menarche to menopause: A population-based assessment of water, sanitation, and hygiene risk factors for reproductive tract infection symptoms over life stages in rural girls and women in India.

Women face greater challenges than men in accessing water, sanitation, and hygiene (WASH) resources to address their daily needs, and may respond to these challenges by adopting unsafe practices that increase the risk of reproductive tract infections (RTIs). WASH practices may change as women transition through socially-defined life stage experiences, like marriage and pregnancy. Thus, the relationship between WASH practices and RTIs might vary across female reproductive life stages. This cross-sectional study assessed the relationship between WASH exposures and self-reported RTI symptoms in 3,952 girls and women from two rural districts in India, and tested whether social exposures represented by reproductive life stage was an effect modifier of associations. In fully adjusted models, RTI symptoms were less common in women using a latrine without water for defecation versus open defecation (Odds Ratio (OR) = 0.69; Confidence Interval (CI) = 0.48, 0.98) and those walking shorter distances to a bathing location (OR = 0.79, CI = 0.63, 0.99), but there was no association between using a latrine with a water source and RTIs versus open defecation (OR = 1.09; CI = 0.69, 1.72). Unexpectedly, RTI symptoms were more common for women bathing daily with soap (OR = 6.55, CI = 3.60, 11.94) and for women washing their hands after defecation with soap (OR = 10.27; CI = 5.53, 19.08) or ash/soil/mud (OR = 6.02; CI = 3.07, 11.77) versus water only or no hand washing. WASH practices of girls and women varied across reproductive life stages, but the associations between WASH practices and RTI symptoms were not moderated by or confounded by life stage status. This study provides new evidence that WASH access and practices are associated with self-reported reproductive tract infection symptoms in rural Indian girls and women from different reproductive life stages. However, the counterintuitive directions of effect for soap use highlights that causality and mechanisms of effect cannot be inferred from this study design. Future research is needed to understand whether improvements in water and sanitation access could improve the practice of safe hygiene behaviors and reduce the global burden of RTIs in women.

A randomized synbiotic trial to prevent sepsis among infants in rural India.

Sepsis in early infancy results in one million annual deaths worldwide, most of them in developing countries. No efficient means of prevention is currently available. Here we report on a randomized, double-blind, placebo-controlled trial of an oral synbiotic preparation (Lactobacillus plantarum plus fructooligosaccharide) in rural Indian newborns. We enrolled 4,556 infants that were at least 2,000 g at birth, at least 35 weeks of gestation, and with no signs of sepsis or other morbidity, and monitored them for 60 days. We show a significant reduction in the primary outcome (combination of sepsis and death) in the treatment arm (risk ratio 0.60, 95% confidence interval 0.48-0.74), with few deaths (4 placebo, 6 synbiotic). Significant reductions were also observed for culture-positive and culture-negative sepsis and lower respiratory tract infections. These findings suggest that a large proportion of neonatal sepsis in developing countries could be effectively prevented using a synbiotic containing L. plantarum ATCC-202195.