A missense variant in FTCD is associated with arsenic metabolism and toxicity phenotypes in Bangladesh.

Inorganic arsenic (iAs) is a carcinogen, and exposure to iAs via food and water is a global public health problem. iAs-contaminated drinking water alone affects >100 million people worldwide, including ~50 million in Bangladesh. Once absorbed into the blood stream, most iAs is converted to mono-methylated (MMA) and then di-methylated (DMA) forms, facilitating excretion in urine. Arsenic metabolism efficiency varies among individuals, in part due to genetic variation near AS3MT (arsenite methyltransferase; 10q24.32). To identify additional arsenic metabolism loci, we measured protein-coding variants across the human exome for 1,660 Bangladeshi individuals participating in the Health Effects of Arsenic Longitudinal Study (HEALS). Among the 19,992 coding variants analyzed exome-wide, the minor allele (A) of rs61735836 (p.Val101Met) in exon 3 of FTCD (formiminotransferase cyclodeaminase) was associated with increased urinary iAs% (P = 8x10-13), increased MMA% (P = 2x10-16) and decreased DMA% (P = 6x10-23). Among 2,401 individuals with arsenic-induced skin lesions (an indicator of arsenic toxicity and cancer risk) and 2,472 controls, carrying the low-efficiency A allele (frequency = 7%) was associated with increased skin lesion risk (odds ratio = 1.35; P = 1x10-5). rs61735836 is in weak linkage disequilibrium with all nearby variants. The high-efficiency/major allele (G/Valine) is human-specific and eliminates a start codon at the first 5´-proximal Kozak sequence in FTCD, suggesting selection against an alternative translation start site. FTCD is critical for catabolism of histidine, a process that generates one-carbon units that can enter the one-carbon/folate cycle, which provides methyl groups for arsenic metabolism. In our study population, FTCD and AS3MT SNPs together explain ~10% of the variation in DMA% and support a causal effect of arsenic metabolism efficiency on arsenic toxicity (i.e., skin lesions). In summary, this work identifies a coding variant in FTCD associated with arsenic metabolism efficiency, providing new evidence supporting the established link between one-carbon/folate metabolism and arsenic toxicity.

Correction: A missense variant in FTCD is associated with arsenic metabolism and toxicity phenotypes in Bangladesh.

[This corrects the article DOI: 10.1371/journal.pgen.1007984.].

Personal exposure to household air pollution and lung function in rural Bangladesh: A population-based cross-sectional study.

We assessed whether personal exposure to household air pollution [PM2.5 and black carbon (BC)] is associated with lung functions (FEV1, FVC, and their ratio) in non-smoking adults in rural Bangladesh. We measured personal exposure to PM2.5 using gravimetric analysis of PM2.5 mass and BC by reflectance measurement between April 2016 and June 2019. The average 24-hour PM2.5 and BC concentration was 141.0µgm-3 and 13.8µgm-3 for females, and 91.7 µgm-3 and 10.1 µgm-3 for males, respectively. A 1 µgm-3 increase in PM2.5 resulted in a 0.02 ml reduction in FEV1, 0.43 ml reduction in FVC, and 0.004% reduction in FEV1/FVC. We also found a similar inverse relationship between BC and lung functions (9.6 ml decrease in FEV1 and 18.5 ml decrease in FVC per 1µgm-3 increase in BC). A higher proportion of non-smoking biomass fuel users (50.1% of the females and 46.7% of the males) had restrictive patterns of lung function abnormalities, which need further exploration.

Rotavirus Vaccine Trials in International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) and Future Use of the Vaccine in Bangladesh.

Safe and effective rotavirus vaccines (RVs) are needed to reduce the enormous public health burden of rotavirus illness in developing countries. Vaccination is critical for effective control of rotavirus infection since it cannot be prevented with improvements in water and sanitation. The International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) has completed several groundbreaking RV trials (Phase I-Phase IV). The safety, immunogenicity, efficacy, and effectiveness of different RVs were evaluated among both urban and rural populations. In this study, we present the results, policy implications, and lessons learned for successful implementation of these trials as well as future directions for rotavirus vaccination in Bangladesh.

Impact of Rotavirus Vaccine Introduction in Children Less Than 2 Years of Age Presenting for Medical Care With Diarrhea in Rural Matlab, Bangladesh.

BACKGROUND: Following the conclusion of a human rotavirus vaccine (HRV) cluster-randomized, controlled trial (CRT) in Matlab, Bangladesh, HRV was included in Matlab's routine immunization program. We describe the population-level impact of programmatic rotavirus vaccination in Bangladesh in children <2 years of age. METHODS: Interrupted time series were used to estimate the impact of HRV introduction. We used diarrheal surveillance collected between 2000 and 2014 within the 2 service delivery areas (International Centre for Diarrhoeal Disease Research, Bangladesh [icddr,b] service area [ISA] and government service area [GSA]) of the Matlab Health and Demographic Surveillance System, administered by icddr,b. Age group-specific incidence rates were calculated for both rotavirus-positive (RV+) and rotavirus-negative (RV-) diarrhea diagnoses of any severity presenting to the hospital. We used 2 models to assess the impact within each service area: Model 1 used the pre-vaccine time period in all villages (HRV- and control-only) and Model 2 combined the pre-vaccine time period and the CRT time period, using outcomes from control-only villages. RESULTS: Both models demonstrated a downward trend in RV+ diarrheal incidences in the ISA villages during 3.5 years of routine HRV use, though only Model 2 was statistically significant. Significant impacts of HRV on RV+ diarrhea incidences in GSA villages were not observed in either model. Differences in population-level impacts between the 2 delivery areas may be due to the varied rotavirus vaccine coverage and presentation rates to the hospital. CONCLUSIONS: This study provides initial evidence of the population-level impact of rotavirus vaccines in children <2 years of age in Matlab, Bangladesh. Further studies are needed of the rotavirus vaccine impact after the nationwide introduction in Bangladesh.

The effect of age on DNA methylation in whole blood among Bangladeshi men and women.

BACKGROUND: It is well-known that methylation changes occur as humans age, however, understanding how age-related changes in DNA methylation vary by sex is lacking. In this study, we characterize the effect of age on DNA methylation in a sex-specific manner and determine if these effects vary by genomic context. We used the Illumina HumanMethylation 450 K array and DNA derived from whole blood for 400 adult participants (189 males and 211 females) from Bangladesh to identify age-associated CpG sites and regions and characterize the location of these age-associated sites with respect to CpG islands (vs. shore, shelf, or open sea) and gene regions (vs. intergenic). We conducted a genome-wide search for age-associated CpG sites (among 423,604 sites) using a reference-free approach to adjust for cell type composition (the R package RefFreeEWAS) and performed an independent replication analysis of age-associated CpGs. RESULTS: The number of age-associated CpGs (p < 5 x 10- 8) were 986 among men and 3479 among women of which 2027(63.8%) and 572 (64.1%) replicated (using Bonferroni adjusted p < 1.2 × 10- 5). For both sexes, age-associated CpG sites were more likely to be hyper-methylated with increasing age (compared to hypo-methylated) and were enriched in CpG islands and promoter regions compared with other locations and all CpGs on the array. Although we observed strong correlation between chronological age and previously-developed epigenetic age models (r ≈ 0.8), among our top (based on lowest p-value) age-associated CpG sites only 12 for males and 44 for females are included in these prediction models, and the median chronological age compared to predicted age was 44 vs. 51.7 in males and 45 vs. 52.1 in females. CONCLUSIONS: Our results describe genome-wide features of age-related changes in DNA methylation. The observed associations between age and methylation were generally consistent for both sexes, although the associations tended to be stronger among women. Our population may have unique age-related methylation changes that are not captured in the established methylation-based age prediction model we used, which was developed to be non-tissue-specific.

Food as medicine: Selenium enriched lentils offer relief against chronic arsenic poisoning in Bangladesh.

Chronic arsenic (As) exposure is a major environmental threat to human health affecting >100 million people worldwide. Low blood selenium (Se) increases the risk of As-induced health problems. Our aim was to reduce As toxicity through a naturally Se-rich lentil diet. In a randomized, double-blind, placebo-control trial in Bangladesh, 405 participants chronically exposed to As were enrolled. The intervention arm (Se-group) consumed Se-rich lentils (55 µg Se/day); the control arm received lentils of similar nutrient profile except with low Se (1.5 µg Se/day). Anthropometric measurements, blood, urine and stool samples, were taken at baseline, 3 and 6 months; hair at baseline and 6 months after intervention. Morbidity data were collected fortnightly. Measurements included total As in all biological samples, As metabolites in urine, and total Se in blood and urine. Intervention with Se-rich lentils resulted in higher urinary As excretion (p = 0.001); increased body mass index (p ≤ 0.01), and lower incidence of asthma (p = 0.05) and allergy (p = 0.02) compared to the control group. The Se-group demonstrated increased excretion of urinary As metabolite, dimethylarsinic acid (DMA) at 6 months compared to control group (p = 0.008). Consuming Se-rich lentils can increase As excretion and improve the health indicators in the presence of continued As exposure.

A Ten Year Immunopersistence Study of Hepatitis E Antibodies in Rural Bangladesh.

Hepatitis E virus (HEV) is a major cause of acute, viral hepatitis in Southeast Asia. Several studies have suggested that antibody persistence after HEV infection may be transient, possibly increasing the risk of re-infection and contributing to the frequency of outbreaks in HEV endemic regions. The specific conditions under which antibodies to HEV are lost, or "sero-reversion" occurs, are poorly understood. Here, one hundred participants from population-based studies in rural Bangladesh were revisited in 2015, ten years after a documented HEV infection to examine long-term antibody persistence. Twenty percent (95% confidence interval: 12.0, 28.0) no longer had detectable antibodies at follow-up, suggesting that antibodies generally persist for at least a decade after infection in rural Bangladesh. Those who were seronegative at follow-up were generally younger at infection than those who remained positive (14.4 years versus 33.6 years, P > 0.0001). This age-dependent antibody loss could partially explain cross-sectional sero-prevalence data from South East Asia where children have reportedly low antibody prevalence. The results of this study provide new insight into the immunological persistence of HEV infection in a micronutrient deficient rural population of South Asia, highlighting the importance of age at infection in the ability to produce long-lasting antibodies against HEV.

Screening for gene-environment (G×E) interaction using omics data from exposed individuals: an application to gene-arsenic interaction.

Identifying gene-environment interactions is a central challenge in the quest to understand susceptibility to complex, multi-factorial diseases. Developing an understanding of how inter-individual variability in inherited genetic variation alters the effects of environmental exposures will enhance our knowledge of disease mechanisms and improve our ability to predict disease and target interventions to high-risk sub-populations. Limited progress has been made identifying gene-environment interactions in the epidemiological setting using existing statistical approaches for genome-wide searches for interaction. In this paper, we describe a novel two-step approach using omics data to conduct genome-wide searches for gene-environment interactions. Using existing genome-wide SNP data from a large Bangladeshi cohort study specifically designed to assess the effect of arsenic exposure on health, we evaluated gene-arsenic interactions by first conducting genome-wide searches for SNPs that modify the effect of arsenic on molecular phenotypes (gene expression and DNA methylation features). Using this set of SNPs showing evidence of interaction with arsenic in relation to molecular phenotypes, we then tested SNP-arsenic interactions in relation to skin lesions, a hallmark characteristic of arsenic toxicity. With the emergence of additional omics data in the epidemiologic setting, our approach may have the potential to boost power for genome-wide interaction research, enabling the identification of interactions that will enhance our understanding of disease etiology and our ability to develop interventions targeted at susceptible sub-populations.

Scrub typhus masquerading as HELLP syndrome and puerperal sepsis in an asymptomatic malaria patient.

Scrub typhus and malaria can involve multiple organ systems and are notoriously known for varied presentations. However, clinical malaria or scrub typhus is unusual without fever. On the other hand, altered sensorium with or without fever, dehydration, hemorrhage and hemolysis may lead to low blood pressure. Presence of toxic granules and elevated band forms in such patients can even mimic sepsis. When such a patient is in the peripartum period, it creates a strong clinical dilemma for the physician especially in unbooked obstetric cases. We present such a case where a 26-year-old unbooked female presented on second postpartum day with severe anemia, altered sensorium, difficulty in breathing along with jaundice and gum bleeding without history of fever. Rapid diagnostic test for malaria was negative and no eschar was seen. These parameters suggested a diagnosis of HELLP (Hemolysis, Elevated Liver enzymes, Low Platelet) syndrome with or without puerperal sepsis. Subsequently she was diagnosed as having asymptomatic malaria and scrub typhus and responded to the treatment of it. The biochemical changes suggestive of HELLP syndrome also subsided. We present this case to emphasize the fact that mere absence of fever and eschar does not rule out scrub typhus. It should also be considered as a differential diagnosis in patients with symptoms and signs suggesting HELLP syndrome. Asymptomatic malaria can complicate case scenario towards puerperal sepsis by giving false toxic granules and band form in such situations.

Genome-wide association study identifies chromosome 10q24.32 variants associated with arsenic metabolism and toxicity phenotypes in Bangladesh.

Arsenic contamination of drinking water is a major public health issue in many countries, increasing risk for a wide array of diseases, including cancer. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity; however, the basis of this variation is not well understood. Here, we have performed the first genome-wide association study (GWAS) of arsenic-related metabolism and toxicity phenotypes to improve our understanding of the mechanisms by which arsenic affects health. Using data on urinary arsenic metabolite concentrations and approximately 300,000 genome-wide single nucleotide polymorphisms (SNPs) for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P<5×10(-8)) for percentages of both monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) near the AS3MT gene (arsenite methyltransferase; 10q24.32), with five genetic variants showing independent associations. In a follow-up analysis of 1,085 individuals with arsenic-induced premalignant skin lesions (the classical sign of arsenic toxicity) and 1,794 controls, we show that one of these five variants (rs9527) is also associated with skin lesion risk (P = 0.0005). Using a subset of individuals with prospectively measured arsenic (n = 769), we show that rs9527 interacts with arsenic to influence incident skin lesion risk (P = 0.01). Expression quantitative trait locus (eQTL) analyses of genome-wide expression data from 950 individual's lymphocyte RNA suggest that several of our lead SNPs represent cis-eQTLs for AS3MT (P = 10(-12)) and neighboring gene C10orf32 (P = 10(-44)), which are involved in C10orf32-AS3MT read-through transcription. This is the largest and most comprehensive genomic investigation of arsenic metabolism and toxicity to date, the only GWAS of any arsenic-related trait, and the first study to implicate 10q24.32 variants in both arsenic metabolism and arsenical skin lesion risk. The observed patterns of associations suggest that MMA% and DMA% have distinct genetic determinants and support the hypothesis that DMA is the less toxic of these two methylated arsenic species. These results have potential translational implications for the prevention and treatment of arsenic-associated toxicities worldwide.

Evidence-based management of isolated dentoalveolar fractures: a systematic review.

Dentoalveolar (DA) trauma, which can involve tooth, alveolar bone, and surrounding soft tissues, is a significant dentofacial emergency. In emergency settings, physicians might lack comprehensive knowledge of timely procedures, causing delays for specialist referral. This systematic review assesses the literature on isolated DA fractures, emphasizing intervention timing and splinting techniques and duration in both children and adults. This systematic review adhered to PRISMA guidelines and involved a thorough search across PubMed, Google Scholar, Semantic Scholar, and the Cochrane Library from January 1980 to December 2022. Inclusion and exclusion criteria guided study selection, with data extraction and analysis centered on demographics, etiology, injury site, diagnostics, treatment timelines, and outcomes in pediatric (2-12 years) and adult (>12 years) populations. This review analyzed 26 studies, categorized by age into pediatrics (2-12 years) and adults (>12 years). Falls were a common etiology, primarily affecting the anterior maxilla. Immediate management involved replantation, repositioning, and splinting within 24 hours (pediatric) or 48 hours (adult). Composite resin-bonded splints were common. Endodontic treatment was done within a timeframe of 3 days to 12 weeks for children and 2-12 weeks for adults. Tailored management based on patient age, tooth development stage, time elapsed, and resource availability is essential.

Immunization of rabbits with nematode Ascaris lumbricoides antigens induces antibodies cross-reactive to house dust mite Dermatophagoides farinae antigens.

There are controversial reports on the relationship between helminthic infection and allergic diseases. Although IgE cross-reactivity between nematode Ascaris antigens and house dust-mite allergens in allergic patients have been reported, whether Ascaris or the mite is the primary sensitizer remains unknown. Here we found that immunization of naïve animals with Ascaris lumbricoides (Al) antigens induced production of antibodies cross-reactive to mite antigens from Dermatophagoides farinae (Df). Sera from Bangladeshi children showed IgE reactivity to Ascaris and mite extracts. IgG from rabbits immunized with Al extract exhibited reactivity to Df antigens. Treatment of the anti-Al antibody with Df antigen-coupled beads eliminated the reactivity to Df antigens. In immunoblot analysis, an approximately 100-kDa Df band was the most reactive to anti-Al IgG. The present study is the first step towards the establishment of animal models to study the relationship between Ascaris infection and mite-induced allergic diseases.

Effects of exclusive breastfeeding intervention on child growth and body composition: the MINIMat trial, Bangladesh.

AIM: Exclusive breastfeeding (EBF) for 6 months is recommended for optimal infant health, but the evidence for longer-term impacts is weak. We examined whether randomization to receive EBF counselling (BFC) in rural Bangladeshi women had an impact on childhood growth trajectories and body composition. METHODS: In the Maternal and Infant Nutrition Interventions in Matlab trial, 4436 pregnant women were randomized to six equally sized, food and micronutrient groups. Of these, 3214 were randomized during the last trimester of pregnancy to receive either BFC or the usual/standard health message (UHM). Their infants were extensively followed up, with anthropometric measurements between 0 and 54 months and assessment of body composition at 54 months. RESULTS: The mean duration of EBF in the BFC group was 111 days compared to 76 days in the UHM group (mean difference: 35.0 days, 95% CI 30.6-39.5, p < 0.001). There was no difference in growth trajectories between the BFC and UHM groups and no difference in body composition at 54 months. Children exposed to prenatal multiple micronutrients (vs 60 mg iron and folate) combined with BFC (vs UHM), however, had slower linear growth (mean difference -0.17 SD score, p < 0.01). CONCLUSION: Exclusive breastfeeding counselling resulted in neither differential growth trajectories in infancy and childhood, nor body composition differences at 54 months. The combination of prenatal multiple micronutrient supplementation (MMS) and BFC was unfavourable for linear growth during 0-54 months, which raises questions about possible negative effects of MMS.

Nonendoscopic intraoral approach for condylar fracture management-a systematic review.

OBJECTIVE: The recent trend favors the open reduction and internal fixation of condylar fractures to prevent long-term consequences. Nonendoscopic intraoral approach is an option for management without a visible scar. The purpose of this systematic review was to explore the evidence, armamentarium, methods of reduction and fixation, challenges, and complications. STUDY DESIGN: We have systematically reviewed published articles on the intraoral approach for condylar fracture management following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search was conducted in PubMed, Google Scholar, Semantic Scholar, and Cochrane library database, to find relevant articles from January 1980 to March 2022. Descriptive statistics were applied to obtain the results. RESULTS: Finally, 23 studies were included. The incision described for the intraoral approach was similar to sagittal split osteotomy in all studies. A wide array of specialized instruments, methods, and challenges has been outlined for visualization, reduction, and fixation. The incidence of complications in the entire review was 23% (72/306). CONCLUSION: The challenges encountered in the nonendoscopic intraoral approach for condylar fracture management can be negated with the use of specialized instruments and with experience. However, further research is warranted for a specialized set of miniature instruments to ease the procedure, make it time-efficient and optimize hardware selection.

Deep tubewell use is associated with increased household microbial contamination in rural Bangladesh: Results from a prospective cohort study among households in rural Bangladesh.

Deep tubewells are important sources of arsenic mitigation in rural Bangladesh. Compared to commonly available shallow tubewells, deep tubewells tap into deeper low-arsenic aquifers and greatly reduce exposure to arsenic in drinking-water. However, benefits from these more distant and expensive sources may be compromised by higher levels of microbial contamination at point-of-use (POU). This paper examines differences in microbial contamination levels at source and POU among households using deep tubewells and shallow tubewells, and investigates factors associated with POU microbial contamination among deep tubewell users. We assessed a prospective longitudinal cohort of 500 rural households in Matlab, Bangladesh, across 135 villages. Concentration of Escherichia coli (E. coli) in water samples at source and POU using Compartment Bag Tests (CBTs) was measured across rainy and dry seasons. We employed linear mixed-effect regression models to measure the effect of different factors on log E. coli concentrations among deep tubewell users. CBT results show that log E. coli concentrations are similar at source and at POU during the first dry and rainy season, but are significantly higher at POU among deep tubewell users during the second dry season. Log E. coli at POU among deep tubewell users is positively associated with both presence (exponentiated beta exp(b) = 2.52, 95% Confidence Interval (CI) = 1.70, 3.73) and concentration of E. coli (exp(b) = 1.36, 95% CI = 1.19, 1.54) at source, and walking time to the tubewell source (exp(b) = 1.39, 95% CI = 1.15, 1.69). Drinking-water during the second dry season is associated with reduced log E. coli (exp(b) = 0.33, 95% CI = 0.23, 0.57) compared to the rainy season. These results suggest that while households that use deep tubewells have lower arsenic exposure, they may be at higher risk of consuming microbially contaminated water compared to households that use shallow tubewells.

Health effects of flooding in rural Bangladesh.

BACKGROUND: There is little information available on nontraumatic health risks as the result of floods, and on the factors that determine vulnerability to them (especially in low-income settings). We estimated the pattern of mortality, diarrhea, and acute respiratory infection following the 2004 floods in rural Bangladesh. METHODS: We conducted controlled interrupted time-series analysis of adverse health outcomes, from 2001 to 2007, in a cohort of 211,000 residents of the Matlab region classified as flooded or nonflooded in 2004. Ratios of mortality, diarrhea, and acute respiratory infection rates in flooded compared with nonflooded areas were calculated by week for mortality and diarrhea, and by month for acute respiratory infection. We controlled for baseline differences as well as normal seasonal patterns in the flooded and nonflooded areas. Variations in flood-related health risks were examined by age, income level, drinking-water source, latrine type, and service area. RESULTS: After fully controlling for pre-flood rate differences and for seasonality, there was no clear evidence of excesses in mortality or diarrhea risk during or after flooding. For acute respiratory infection, we found no evidence of excess risk during the flood itself but a moderate increase in risk during the 6 months after the flood (relative risk = 1.25 [95% confidence interval = 1.06-1.47]) and the subsequent 18 months. CONCLUSIONS: We found little evidence of increased risk of diarrhea or mortality following the floods, but evidence of a moderate elevation in risk of acute respiratory infection during the 2 years after flooding. The discrepancies between our results and the apparent excesses for mortality and diarrhea reported in other situations, using less- controlled estimates, emphasize the importance of stringent confounder control.

Effects of prenatal micronutrient and early food supplementation on maternal hemoglobin, birth weight, and infant mortality among children in Bangladesh: the MINIMat randomized trial.

CONTEXT: Nutritional insult in fetal life and small size at birth are common in low-income countries and are associated with serious health consequences. OBJECTIVES: To test the hypothesis that prenatal multiple micronutrient supplementation (MMS) and an early invitation to food supplementation would increase maternal hemoglobin level and birth weight and decrease infant mortality, and to assess whether a combination of these interventions would further enhance these outcomes. DESIGN, SETTING, AND PARTICIPANTS: A randomized trial with a factorial design in Matlab, Bangladesh, of 4436 pregnant women, recruited between November 11, 2001, and October 30, 2003, with follow-up until June 23, 2009. INTERVENTIONS: Participants were randomized into 6 groups; a double-masked supplementation with capsules of 30 mg of iron and 400 µg of folic acid, 60 mg of iron and 400 µg of folic acid, or MMS containing a daily allowance of 15 micronutrients, including 30 mg of iron and 400 µg of folic acid, was combined with food supplementation (608 kcal 6 days per week) randomized to either early invitation (9 weeks' gestation) or usual invitation (20 weeks' gestation). MAIN OUTCOME MEASURES: Maternal hemoglobin level at 30 weeks' gestation, birth weight, and infant mortality. Under 5-year mortality was also assessed. RESULTS: Adjusted maternal hemoglobin level at 30 weeks' gestation was 115.0 g/L (95% CI, 114.4-115.5 g/L), with no significant differences among micronutrient groups. Mean maternal hemoglobin level was lower in the early vs usual invitation groups (114.5 vs 115.4 g/L; difference, -0.9 g/L; 95% CI, -1.7 to -0.1; P = .04). There were 3625 live births out of 4436 pregnancies. Mean birth weight among 3267 singletons was 2694 g (95% CI, 2680-2708 g), with no significant differences among groups. The early invitation with MMS group had an infant mortality rate of 16.8 per 1000 live births vs 44.1 per 1000 live births for usual invitation with 60 mg of iron and 400 µg of folic acid (hazard ratio [HR], 0.38; 95% CI, 0.18-0.78). Early invitation with MMS group had an under 5-year mortality rate of 18 per 1000 live births (54 per 1000 live births for usual invitation with 60 mg of iron and 400 µg of folic acid; HR, 0.34; 95% CI, 0.18-0.65). Usual invitation with MMS group had the highest incidence of spontaneous abortions and the highest infant mortality rate. CONCLUSION: Among pregnant women in poor communities in Bangladesh, treatment with multiple micronutrients, including iron and folic acid combined with early food supplementation, vs a standard program that included treatment with iron and folic acid and usual food supplementation, resulted in decreased childhood mortality. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN16581394.

BRAVE: A Point of Care Adaptive Leadership Approach to Providing Patient-Centric Care in the Emergency Department.

The practice of emergency medicine has reached its cross roads. Emergency physicians (EPs) are managing many more time-dependent conditions, initiating complex treatments in the emergency department (ED), handling ethical and end of life care discussions upfront, and even performing procedures which used to be done only in critical care settings, in the resuscitation room. EPs manage a wide spectrum of patients, 24 h a day, which reflects the community and society they practice in. Besides the medical and "technical" issues to handle, they have to learn how to resolve confounding elements which their patients can present with. These may include social, financial, cultural, ethical, relationship, and even employment matters. EPs cannot overlook these, in order to provide holistic care. More and more emphasis is also now given to the social determinants of health. We, from the emergency medicine fraternity, are proposing a unique "BRAVE model," as a mnemonic to assist in the provision of point of care, adaptive leadership at the bedside in the ED. This represents another useful tool for use in the current climate of the ED, where patients have higher expectations, need more patient-centric resolution and handling of their issues, looming against the background of a more complex society and world.

Neutrophil-lymphocyte ratio as a predictor of outcome following traumatic brain injury: Systematic review and meta-analysis.

Objectives: The neutrophil-to-lymphocyte ratio (NLR) is a simple and routinely performed hematological parameter; however, studies on NLR as a prognostic tool in traumatic brain injury (TBI) have yielded contradictory results. Materials and Methods: This systematic review and meta-analysis was conducted according to the Preferred Reporting Items in the Systematic Review and Meta-Analysis guidelines 2020. Electronic databases of PubMed, Cochrane Library, Web of Science, and Scopus were searched. The population consisted of TBI patients in the absence of moderate and severe extracranial injury. Day 1 NLR was taken for the analysis. The outcomes evaluated were mortality and the Glasgow Outcome Scale (GOS). No restrictions were placed on the language, year and country of publication, and duration of follow-up. Animal studies were excluded from the study. Studies, where inadequate data were reported for the outcomes, were included in the qualitative synthesis but excluded from the quantitative synthesis. Study quality was evaluated using the Newcastle-Ottawa scale (NOS). The risk of bias was estimated using the Cochrane RoBANS risk of bias tool. Results: We retrieved 7213 citations using the search strategy and 2097 citations were excluded based on the screening of the title and abstract. Full text was retrieved for 40 articles and subjected to the eligibility criteria, of which 28 were excluded from the study. Twelve studies were eligible for the synthesis of the systematic review while seven studies qualified for the meta-analysis. The median score of the articles was 8/9 as per NOS. The risk of selection bias was low in all the studies while the risk of detection bias was high in all except one study. Ten studies were conducted on adult patients, while two studies reported pediatric TBI. A meta-analysis for GOS showed that high NLR predicted unfavorable outcomes at ≥6 months with a mean difference of -5.18 (95% confidence interval: -10.04, -0.32); P = 0.04; heterogeneity (I2), being 98%. The effect estimates for NLR and mortality were a mean difference of -3.22 (95% confidence interval: -7.12, 0.68), P = 0.11, and an I2 of 85%. Meta-analysis for Area under the curve (AUC) receiver operating characteristic of the included studies showed good predictive power of NLR in predicting outcomes following TBI with AUC 0.706 (95% CI: 0.582-0.829). Conclusion: A higher admission NLR predicts an increased mortality risk and unfavorable outcomes following TBI. However, future research will likely address the existing gaps.