High Rates of Placental Inflammation Among Samples Collected by the MOMI Consortium.

BACKGROUND: The Multi-Omics for Mothers and Infants (MOMI) consortium aims to improve birth outcomes. Preterm birth is a major obstetric complication globally causing significant infant and childhood morbidity and mortality. OBJECTIVES: We analyzed placental samples (basal plate, placenta/chorionic villi and/or the chorionic plate) collected by the 5 MOMI sites: The Alliance for Maternal and Newborn Health Improvement (AMANHI) Bangladesh, AMANHI Pakistan, AMANHI Tanzania, The Global Alliance to Prevent Prematurity and Stillbirth (GAPPS) Bangladesh and GAPPS Zambia. The goal was to analyze the morphology and gene expression of samples collected from preterm and uncomplicated term births. STUDY DESIGN: The teams provided biopsies from 166 singleton preterm (<37 weeks) and 175 term (≥37 weeks) deliveries. They were formalin-fixed and paraffin embedded. Tissue sections from these samples were stained with hematoxylin and eosin and subjected to morphological analyses. Other placental biopsies (n = 35 preterm, 21 term) were flash frozen, which enabled RNA purification for bulk transcriptomics. RESULTS: The morphological analyses revealed a surprisingly high rate of inflammation involving the basal plate, placenta/chorionic villi and/or the chorionic plate. The rate in chorionic villus samples, likely attributable to chronic villitis, ranged from 25% (Pakistan site) to 60% (Zambia site) of cases. Leukocyte infiltration in this location vs. the basal plate or chorionic plate correlated with preterm birth. Our transcriptomic analyses identified 267 genes as differentially expressed (DE) between placentas from preterm vs. term births (123 upregulated, 144 downregulated). Mapping the DE genes onto single cell RNA-seq data from human placentas suggested that all the component cell types, either singly or in subsets, contributed to the observed dysregulation. Consistent with the histopathological findings, GO (Gene Ontology) analyses highlighted leukocyte infiltration/activation and inflammatory responses in both the fetal and maternal compartments. CONCLUSION: The relationship between placental inflammation and preterm birth is appreciated in developed countries. Here, we show that this link also exists in developing geographies. Also, among the participating sites, we found geographic- and/or population-based differences in placental inflammation and preterm birth, suggesting the importance of local factors.

Measuring the effectiveness of an integrated intervention package to improve the level of infection prevention and control: a multi-centre study in Bangladesh.

BACKGROUND: Infection prevention and control (IPC) is a critical component of delivering safe, effective and high-quality healthcare services, and eliminating avoidable healthcare-associated infections (HAIs) in health facilities, predominantly in population-dense settings such as Bangladesh. AIM: Our study aimed to assess the effect of an integrated intervention package in improving the IPC level of the health facilities in Bangladesh. METHODS: We conducted a pre-post intervention study in six district hospitals (DHs) and 13 Upazila Health Complexes (UHCs) in the six districts of Bangladesh. Baseline and endline assessments were conducted between March and December 2021 using the adapted World Health Organization Infection Prevention and Control Assessment Framework (WHO-IPCAF) tool. The IPCAF score, ranging from 0-800, was calculated by adding the scores of eight components, and the IPC promotion and practice level was categorized as Inadequate (0-200), Basic (201-400), Intermediate (401-600) and Advanced (601-800). The integrated intervention package including IPC committee formation, healthcare provider training, logistics provision, necessary guidelines distribution, triage/flu corners establishment, and infrastructure development was implemented in all facilities. RESULTS: The average IPCAF score across all the facilities showed a significant increase from 16% (95% CI: 11.5-20.65%) to 54% (95% CI: 51.4-57.1%). Overall, the IPCAF score increased by 34 percentage points (P<0.001) in DHs and 40 percentage points (P<0.001) in UHCs. Following the intervention, 12 (three DHs, nine UHCs) of 19 facilities progressed from inadequate to intermediate, and another three DHs upgraded from basic to intermediate in terms of IPC level. CONCLUSION: The integrated intervention package improved IPCAF score in all facilities.

Vitamin D deficiency in pregnancy and the risk of preterm birth: a nested case-control study.

BACKGROUND: Each year, an estimated 15 million babies are born preterm. Micronutrient deficiencies, including vitamin D deficiency (VDD), are common in many low- and middle-income countries (LMICs), and these conditions are often associated with adverse pregnancy outcomes. Bangladesh experiences a high prevalence of VDD. The country also has a high preterm birth (PTB) rate. Using data from a population-based pregnancy cohort, we estimated the burden of VDD during pregnancy and its association with PTB. METHODS: Pregnant women (N = 3,000) were enrolled after ultrasound confirmation of gestational age at 8-19 weeks of gestation. Trained health workers prospectively collected phenotypic and epidemiological data at scheduled home visits. Trained phlebotomists collected maternal blood samples at enrollment and 24 -28 weeks of gestation. Aliquots of serum were stored at -800 C. We conducted a nested case-control study with all PTB (n = 262) and a random sample of term births (n = 668). The outcome, PTB, was defined as live births < 37 weeks of gestation, based on ultrasound. The main exposure was vitamin D concentrations of 24-28 weeks maternal blood samples. The analysis was adjusted for other PTB risk factors. Women were categorized as VDD (lowest quartile of 25(OH)D; < = 30.25 nmol/L) or not deficient (upper-three quartiles of 25(OH)D; > 30.25 nmol/L). We used logistic regression to determine the association of VDD with PTB, adjusting for potential confounders. RESULTS: The median and interquartile range of serum 25(OH)D was 38.0 nmol/L; 30.18 to 48.52 (nmol/L). After adjusting for co-variates, VDD was significantly associated with PTB [adjusted odds ratio (aOR) = 1.53, 95% confidence interval (CI) = 1.10 - 2.12]. The risk of PTB was also higher among women who were shorter (aOR = 1.81, 95% CI: 1.27-2.57), primiparous (aOR = 1.55, 95% CI = 1.12 - 2.12), passive smokers (aOR = 1.60, 95% CI = 1.09 - 2.34), and those who received iron supplementation during pregnancy (aOR = 1.66, 95% CI: 1.17, 2.37). CONCLUSION: VDD is common in Bangladeshi pregnant women and is associated with an increased risk of PTB.

Multiomic signals associated with maternal epidemiological factors contributing to preterm birth in low- and middle-income countries.

Preterm birth (PTB) is the leading cause of death in children under five, yet comprehensive studies are hindered by its multiple complex etiologies. Epidemiological associations between PTB and maternal characteristics have been previously described. This work used multiomic profiling and multivariate modeling to investigate the biological signatures of these characteristics. Maternal covariates were collected during pregnancy from 13,841 pregnant women across five sites. Plasma samples from 231 participants were analyzed to generate proteomic, metabolomic, and lipidomic datasets. Machine learning models showed robust performance for the prediction of PTB (AUROC = 0.70), time-to-delivery (r = 0.65), maternal age (r = 0.59), gravidity (r = 0.56), and BMI (r = 0.81). Time-to-delivery biological correlates included fetal-associated proteins (e.g., ALPP, AFP, and PGF) and immune proteins (e.g., PD-L1, CCL28, and LIFR). Maternal age negatively correlated with collagen COL9A1, gravidity with endothelial NOS and inflammatory chemokine CXCL13, and BMI with leptin and structural protein FABP4. These results provide an integrated view of epidemiological factors associated with PTB and identify biological signatures of clinical covariates affecting this disease.

Implementation and Delivery of Oral Cholera Vaccination Campaigns in Humanitarian Crisis Settings among Rohingya Myanmar nationals in Cox's Bazar, Bangladesh.

BACKGROUND: Over 700,000 Myanmar nationals known as the 'Rohingyas' fled into Cox's Bazar, Bangladesh, in late 2017. Due to this huge displacement into unhygienic areas, these people became vulnerable to communicable diseases including cholera. Assessing the risk, the Government of Bangladesh (GoB), with the help of the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B) and other international partners, decided to take preventive measures, one of which is the execution of oral cholera vaccination (OCV) campaigns. This paper describes the implementation and delivery of OCV campaigns during humanitarian crises in Bangladesh. METHODS: Seven rounds of OCV campaigns were conducted between October 2017 and December 2021. The OCV campaigns were conducted by applying different strategies. RESULTS: Approximately 900,000 Rohingya Myanmar nationals (RMNs) and the host population (amounting to 528,297) received OCV across seven campaigns. In total, 4,661,187 doses of OCVs were administered, which included 765,499 doses for RMNs, and 895,688 doses for the host community. The vaccine was well accepted, and as a result, a high level of coverage was achieved, ranging from 87% to 108% in different campaigns. CONCLUSIONS: After successful pre-emptive campaigns in Cox's Bazar humanitarian camps, no cholera outbreaks were detected either in the RMN or host communities.

Acute Watery Diarrhea Surveillance During the Rohingya Crisis 2017-2019 in Cox's Bazar, Bangladesh.

BACKGROUND: Forcibly Displaced Myanmar Nationals (FDMNs) fled into Cox's Bazar, Bangladesh due to internal conflict. Considering the public health situation, a surveillance network was established to identify the enteric pathogens and early detection of cholera epidemics. The purpose of this manuscript is to report the clinical, epidemiological determinants of cholera and other enteric pathogens among hospitalized diarrheal patients from FDMNs and host community. METHODS: A total of 11 sentinel surveillance sites were established around the camps in Ukhia and Teknaf Upazila, Cox's Bazar. Rapid diagnostic testing was conducted for immediate detection of cholera cases. Stool samples were transferred to the Infectious Diseases Division, International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b) laboratory for culture. RESULTS: A total of 8134 participants with diarrhea were enrolled from 2017 to 2019: 4881 were FDMNs and 3253 were from the Bangladeshi host community. Among the FDMNs, the proportion of Vibrio cholerae was 0.7%, the proportion of enterotoxigenic Escherichia coli (ETEC) was 4.9%, and the proportion of Shigella was 1.5%. The distributions from host community were 1.2% V cholerae, 1.8% ETEC, and 1.1% Shigella. Similar risk factors have been identified for the diarrheal pathogens for both communities. CONCLUSIONS: This surveillance helped to monitor the situation of diarrheal diseases including cholera in refugee camps as well as in the neighboring host community. These findings lead policymakers to take immediate preventive measures.

Cholera outbreak in Forcibly Displaced Myanmar National (FDMN) from a small population segment in Cox's Bazar, Bangladesh, 2019.

BACKGROUND: Bangladesh experienced a sudden, large influx of forcibly displaced persons from Myanmar in August 2017. A cholera outbreak occurred in the displaced population during September-December 2019. This study aims to describe the epidemiologic characteristics of cholera patients who were hospitalized in diarrhea treatment centers (DTCs) and sought care from settlements of Forcibly Displaced Myanmar Nationals (FDMN) as well as host country nationals during the cholera outbreak. METHODS: Diarrhea Treatment Center (DTC) based surveillance was carried out among the FDMN and host population in Teknaf and Leda DTCs hospitalized for cholera during September-December 2019. RESULTS: During the study period, 147 individuals with cholera were hospitalized. The majority, 72% of patients reported to Leda DTC. Nearly 65% sought care from FDMN settlements. About 47% of the cholera individuals were children less than 5 years old and 42% were aged 15 years and more. Half of the cholera patients were females. FDMN often reported from Camp # 26 (45%), followed by Camp # 24 (36%), and Camp # 27 (12%). Eighty-two percent of the cholera patients reported watery diarrhea. Some or severe dehydration was observed in 65% of cholera individuals. Eighty-one percent of people with cholera received pre-packaged ORS at home. About 88% of FDMN cholera patients reported consumption of public tap water. Pit latrine without water seal was often used by FDMN cholera individuals (78%). CONCLUSION: Vigilance for cholera patients by routine surveillance, preparedness, and response readiness for surges and oral cholera vaccination campaigns can alleviate the threats of cholera.

Diarrhea treatment center (DTC) based diarrheal disease surveillance in settlements in the wake of the mass influx of forcibly displaced Myanmar national (FDMN) in Cox's Bazar, Bangladesh, 2018.

BACKGROUND: In August 2017, after a large influx of forcibly displaced Myanmar nationals (FDMN) in Cox's Bazar, Bangladesh diarrhea treatment centers (DTCs) were deployed. This study aims to report the clinical, epidemiological, and laboratory characteristics of the hospitalized patients. METHODS: The study followed cross-sectional design. In total 1792 individuals were studied. Other than data, a single, stool specimen was subjected to one step rapid visual diagnostic test for Vibrio cholerae. The provisionally diagnosed specimens of cholera cases were inoculated into Cary-Blair Transport Medium; then sent to the laboratory of icddr,b in Dhaka to isolate the colony as well as perform antibiotic susceptibility tests. Data were analyzed by STATA and analyses included descriptive as well as analytic methods. RESULTS: Of the total 1792 admissions in 5 DTCs, 729 (41%) were from FDMN settlements; children <5 years contributed the most (n = 981; 55%). Forty percent (n = 716) were aged 15 years and above, and females were predominant (n = 453; 63%). Twenty-eight percent (n = 502) sought treatment within 24h of the onset of diarrhea. FDMN admissions within 24h were low compared to host hospitalization (n = 172, 24% vs. n = 330, 31%; p<0.001). Seventy-two percent (n = 1295) had watery diarrhea; more common among host population than FDMN (n = 802; 75% vs. n = 493; 68%; p<0.001). Forty-four percent admissions (n = 796) had some or severe dehydration, the later was common in FDMN (n = 46; 6% vs. n = 36; 3%, p = 0.005). FDMN often used public taps (n = 263; 36%), deep tube-well (n = 243; 33%), and shallow tube well (n = 188; 26%) as the source of drinking water. Nearly 96% (n = 698) of the admitted FDMN used pit latrines as opposed to 79% (n = 842) from the host community (p<0.001). FDMN children were often malnourished. None of the FDMN reported cholera. CONCLUSION: No diarrhea outbreak was detected, but preparedness for surges and response readiness are warranted in this emergency and crisis setting.

The CYCLIN-DEPENDENT KINASE Module of the Mediator Complex Promotes Flowering and Reproductive Development in Pea.

Control of flowering time has been a major focus of comparative genetic analyses in plant development. This study reports on a forward genetic approach to define previously uncharacterized components of flowering control pathways in the long-day legume, pea (Pisum sativum). We isolated two complementation groups of late-flowering mutants in pea that define two uncharacterized loci, LATE BLOOMER3 (LATE3) and LATE4, and describe their diverse effects on vegetative and reproductive development. A map-based comparative approach was employed to identify the underlying genes for both loci, revealing that that LATE3 and LATE4 are orthologs of CYCLIN DEPENDENT KINASE8 (CDK8) and CYCLIN C1 (CYCC1), components of the CDK8 kinase module of the Mediator complex, which is a deeply conserved regulator of transcription in eukaryotes. We confirm the genetic and physical interaction of LATE3 and LATE4 and show that they contribute to the transcriptional regulation of key flowering genes, including the induction of the florigen gene FTa1 and repression of the floral repressor LF Our results establish the conserved importance of the CDK8 module in plants and provide evidence for the function of CYCLIN C1 orthologs in the promotion of flowering and the maintenance of normal reproductive development.

Expansion of syndromic vaccine preventable disease surveillance to include bacterial meningitis and Japanese encephalitis: evaluation of adapting polio and measles laboratory networks in Bangladesh, China and India, 2007-2008.

BACKGROUND: Surveillance for acute flaccid paralysis with laboratory confirmation has been a key strategy in the global polio eradication initiative, and the laboratory platform established for polio testing has been expanded in many countries to include surveillance for cases of febrile rash illness to identify measles and rubella cases. Vaccine-preventable disease surveillance is essential to detect outbreaks, define disease burden, guide vaccination strategies and assess immunization impact. Vaccines now exist to prevent Japanese encephalitis (JE) and some etiologies of bacterial meningitis. METHODS: We evaluated the feasibility of expanding polio-measles surveillance and laboratory networks to detect bacterial meningitis and JE, using surveillance for acute meningitis-encephalitis syndrome in Bangladesh and China and acute encephalitis syndrome in India. We developed nine syndromic surveillance performance indicators based on international surveillance guidelines and calculated scores using supervisory visit reports, annual reports, and case-based surveillance data. RESULTS: Scores, variable by country and targeted disease, were highest for the presence of national guidelines, sustainability, training, availability of JE laboratory resources, and effectiveness of using polio-measles networks for JE surveillance. Scores for effectiveness of building on polio-measles networks for bacterial meningitis surveillance and specimen referral were the lowest, because of differences in specimens and techniques. CONCLUSIONS: Polio-measles surveillance and laboratory networks provided useful infrastructure for establishing syndromic surveillance and building capacity for JE diagnosis, but were less applicable for bacterial meningitis. Laboratory-supported surveillance for vaccine-preventable bacterial diseases will require substantial technical and financial support to enhance local diagnostic capacity.

The feasibility of identifying children with primary immunodeficiency disorders: preparation for the polio post-eradication era in Bangladesh.

BACKGROUND: Persons with primary immunodeficiency disorders (PIDD) who receive oral poliovirus vaccine (OPV) or are household contacts of OPV recipients are at risk of excreting immunodeficiency-associated vaccine-derived polioviruses (iVDPVs). iVDPVs can be transmitted and cause paralytic polio. The objective of this study was to determine the feasibility of identifying infants and young children with PIDD in Bangladesh, and among those identified, to estimate the proportion excreting iVDPVs. METHODS: Patients admitted at 5 referral and teaching hospitals from the hospital catchment area were screened for PIDD using a standardized clinical case definition. PIDD was confirmed using results of testing for age-specific quantitative immunoglobulins (QIGs) levels. Stool specimens were collected according to WHO guidelines from children with confirmed PIDD. RESULTS: During February-July 2009, 13 patients were identified who met the clinical case definition for PIDD; their median age was 1.4 years (range: 2 months to 10 years). Six (46%) of the patients had age-specific QIG results that confirmed PIDD. Stool specimens from four patients tested negative for polio vaccine viruses. All four had received OPV between 50 and 264 days prior to study recruitment. CONCLUSION: Identifying children with PIDD at referral and teaching hospitals in Bangladesh is feasible, but a larger number of patients is needed to estimate the risk for iVDPV excretion. The national polio eradication program should expand surveillance for PIDD case-patients and regularly test persons with PIDD for poliovirus excretion. These efforts will be essential for developing effective prevention and control strategies following OPV cessation, especially for densely populated and tropical countries like Bangladesh where even a minimal iVDPV risk could have significant public health consequences.

Stability of the age distribution of measles cases over time during outbreaks in Bangladesh, 2004-2006.

Despite recommendations from WHO to conduct measles outbreak response vaccination campaigns based on the age distribution of cases at the beginning of an outbreak, few data exist to specifically examine whether the age distribution of cases remains constant over time in a measles outbreak. This analysis explores this question with use of measles outbreak surveillance data from Bangladesh from the period 2004-2006. Pearson χ(2) tests were conducted of age distributions over 2 periods during 41 large laboratory-confirmed measles outbreaks. Statistically significant changes in age distribution over time were observed in 24% of the outbreaks. No single pattern was detected in the shifts in age distribution; however, an increase in the proportion of cases occurring among infants <9 months of age was evident in 6 outbreaks. These findings suggest a need to consider the possibility of a shift in the age distribution over time when planning an outbreak response vaccination campaign.