Preparation and Characterization of Spray-Dried Hybrid Nanocrystal-Amorphous Solid Dispersions (HyNASDs) for Supersaturation Enhancement of a Slowly Crystallizing Drug.

We prepared hybrid nanocrystal-amorphous solid dispersions (HyNASDs) to examine their supersaturation capability in the release of a poorly soluble drug, itraconazole (ITZ), a slow crystallizer during dissolution. The HyNASD formulations included a polymer (HPC: hydroxypropyl cellulose, Sol: Soluplus, or VA64: Kollidon-VA64) and a surfactant (SDS: sodium dodecyl sulfate). Additionally, the dissolution performance of the HyNASDs and ASDs was compared. To this end, wet-milled aqueous nanosuspensions containing a 1:5 ITZ:polymer mass ratio with/without SDS as well as solutions of the same ratio without SDS in dichloromethane were spray-dried. XRPD-DSC confirmed that ASDs were formed upon spray drying the solution-based feeds, whereas HyNASDs (~5-30% amorphous) were formed with the nanosuspension-based feeds. SDS aided to stabilize the ITZ nanosuspensions and increase the amorphous content in the spray-dried powders. During dissolution, up to 850% and 790% relative supersaturation values were attained by HyNASDs with and without SDS, respectively. Due to the stronger molecular interaction between ITZ-Sol than ITZ-HPC/VA64 and micellar solubilization by Sol, Sol-based HyNASDs outperformed HPC/VA64-based HyNASDs. While the ASD formulations generated greater supersaturation values (≤1670%) than HyNASDs (≤790%), this extent of supersaturation from a largely nanocrystalline formulation (HyNASD) has not been achieved before. Overall, HyNASDs could boost drug release from nanoparticle-based formulations and may render them competitive to ASDs.

Association of diabetes, smoking, and alcohol use with subclinical-to-symptomatic spectrum of tuberculosis in 16 countries: an individual participant data meta-analysis of national tuberculosis prevalence surveys.

Background: Non-communicable diseases (NCDs) and NCD risk factors, such as smoking, increase the risk for tuberculosis (TB). Data are scarce on the risk of prevalent TB associated with these factors in the context of population-wide systematic screening and on the association between NCDs and NCD risk factors with different manifestations of TB, where ∼50% being asymptomatic but bacteriologically positive (subclinical). We did an individual participant data (IPD) meta-analysis of national and sub-national TB prevalence surveys to synthesise the evidence on the risk of symptomatic and subclinical TB in people with NCDs or risk factors, which could help countries to plan screening activities. Methods: In this systematic review and IPD meta-analysis, we identified eligible prevalence surveys in low-income and middle-income countries that reported at least one NCD (e.g., diabetes) or NCD risk factor (e.g., smoking, alcohol use) through the archive maintained by the World Health Organization and by searching in Medline and Embase from January 1, 2000 to August 10, 2021. The search was updated on March 23, 2023. We performed a one-stage meta-analysis using multivariable multinomial models. We estimated the proportion of and the odds ratio for subclinical and symptomatic TB compared to people without TB for current smoking, alcohol use, and self-reported diabetes, adjusted for age and gender. Subclinical TB was defined as microbiologically confirmed TB without symptoms of current cough, fever, night sweats, or weight loss and symptomatic TB with at least one of these symptoms. We assessed heterogeneity using forest plots and I2 statistic. Missing variables were imputed through multi-level multiple imputation. This study is registered with PROSPERO (CRD42021272679). Findings: We obtained IPD from 16 national surveys out of 21 national and five sub-national surveys identified (five in Asia and 11 in Africa, N = 740,815). Across surveys, 15.1%-56.7% of TB were subclinical (median: 38.1%). In the multivariable model, current smoking was associated with both subclinical (OR 1.67, 95% CI 1.27-2.40) and symptomatic TB (OR 1.49, 95% CI 1.34-1.66). Self-reported diabetes was associated with symptomatic TB (OR 1.67, 95% CI 1.17-2.40) but not with subclinical TB (OR 0.92, 95% CI 0.55-1.55). For alcohol drinking ≥ twice per week vs no alcohol drinking, the estimates were imprecise (OR 1.59, 95% CI 0.70-3.62) for subclinical TB and OR 1.43, 95% CI 0.59-3.46 for symptomatic TB). For the association between current smoking and symptomatic TB, I2 was high (76.5% (95% CI 62.0-85.4), while the direction of the point estimates was consistent except for three surveys with wide CIs. Interpretation: Our findings suggest that current smokers are more likely to have both symptomatic and subclinical TB. These individuals can, therefore, be prioritised for intensified screening, such as the use of chest X-ray in the context of community-based screening. People with self-reported diabetes are also more likely to have symptomatic TB, but the association is unclear for subclinical TB. Funding: None.

Stress Biomarkers and Child Development in Young Children in Bangladesh.

Background: Hundreds of millions of children in low-and middle-income countries are exposed to chronic stressors, such as poverty, poor sanitation and hygiene, and sub-optimal nutrition. These stressors can have physiological consequences for children and may ultimately have detrimental effects on child development. This study explores associations between biological measures of chronic stress in early life and developmental outcomes in a large cohort of young children living in rural Bangladesh. Methods: We assessed physiologic measures of stress in the first two years of life using measures of the hypothalamic-pituitary-adrenal (HPA) axis (salivary cortisol and glucocorticoid receptor gene methylation), the sympathetic-adrenal-medullary (SAM) system (salivary alpha-amylase, heart rate, and blood pressure), and oxidative status (F2-isoprostanes). We assessed child development in the first two years of life with the MacArthur-Bates Communicative Development Inventories (CDI), the WHO gross motor milestones, and the Extended Ages and Stages Questionnaire (EASQ). We compared development outcomes of children at the 75th and 25th percentiles of stress biomarker distributions while adjusting for potential confounders (hereafter referred to as contrasts) using generalized additive models, which are statistical models where the outcome is predicted by a potentially non-linear function of predictor variables. Results: We analyzed data from 684 children (49% female) at both 14 and 28 months of age; we included an additional 765 children at 28 months of age. We observed 135 primary contrasts of the differences in child development outcomes at the 75 th and 25 th percentiles of stress biomarkers, where we detected significant relationships in 5 out of 30 contrasts (17%) of HPA axis activity, 1 out of 30 contrasts (3%) of SAM activity, and 3 out of 75 contrasts (4%) of oxidative status. These findings revealed that measures of HPA axis activity were associated with poor development outcomes. We did not find consistent evidence that markers of SAM system activity or oxidative status were associated with developmental status. Conclusions: Our observations reveal associations between the physiological evidence of stress in the HPA axis with developmental status in early childhood. These findings add to the existing evidence exploring the developmental consequences of early life stress.

Micronutrient status during pregnancy is associated with child immune status in rural Bangladesh.

Background: Poor immune function increases children's risk of infection and mortality. Several maternal factors during pregnancy may affect infant immune function during the postnatal period. Objectives: We aimed to evaluate whether maternal micronutrients, stress, estriol, and immune status during the first or second trimester of pregnancy were associated with child immune status in the first two years after birth. Methods: We conducted observational analyses within the water, sanitation, and hygiene (WASH) Benefits Bangladesh randomized controlled trial. We measured biomarkers in 575 pregnant women and postnatally in their children. Maternal biomarkers measured during the first and second trimester of pregnancy included nutrition status via vitamin D (25-hydroxy-D [25(OH)D]), ferritin, soluble transferrin receptor (sTfR), and retinol-binding protein (RBP); cortisol; estriol. Immune markers were assessed in pregnant women at enrollment and their children at ages 14 and 28 mo, including C-reactive protein (CRP), alpha-1-acid glycoprotein (AGP), and 13 cytokines (including IFN-γ). We generated a standardized sum score of log-transformed cytokines. We analyzed IFN-γ individually because it is a critical immunoregulatory cytokine. All outcomes were prespecified. We used generalized additive models and reported the mean difference and 95% confidence intervals at the 25th and 75th percentiles of exposure distribution. Results: At child age 14 mo, concentrations of maternal RBP were inversely associated with the cytokine sum score in children (-0.34 adjusted difference between the 25th and 75th percentile [95% confidence interval -0.61, -0.07]), and maternal vitamin A deficiency was positively associated with the cytokine sum score in children (1.02 [0.13, 1.91]). At child age of 28 mo, maternal RBP was positively associated with IFN-γ in children (0.07 [0.01, 0.14]), whereas maternal vitamin A deficiency was negatively associated with child AGP (-0.07 [-0.13, -0.02]). Maternal iron deficiency was associated with higher AGP concentrations in children at age 14 mo (0.13 [0.04, 0.23]), and maternal sTfR concentrations were positively associated with child CRP concentrations at age 28 mo (0.18 [0, 0.36]). Conclusion: Maternal deficiencies in vitamin A or iron during the first 2 trimesters of pregnancy may shape the trajectory of a child's immune status.

Interactive SARS-CoV-2 dashboard for real-time geospatial visualisation of sewage and clinical surveillance data from Dhaka, Bangladesh: a tool for public health situational awareness.

Throughout the COVID-19 pandemic, many dashboards were created to visualise clinical case incidence. Other dashboards have displayed SARS-CoV-2 sewage data, largely from countries with formal sewage networks. However, very few dashboards from low-income and lower-middle-income countries integrated both clinical and sewage data sets. We created a dashboard to track in real-time both COVID-19 clinical cases and the level of SARS-CoV-2 virus in sewage in Dhaka, Bangladesh. The development of this dashboard was a collaborative iterative process with Bangladesh public health stakeholders to include specific features to address their needs. The final dashboard product provides spatiotemporal visualisations of COVID-19 cases and SARS-CoV-2 viral load at 51 sewage collection sites in 21 wards in Dhaka since 24 March 2020. Our dashboard was updated weekly for the Bangladesh COVID-19 national task force to provide supplemental data for public health stakeholders making public policy decisions on mitigation efforts. Here, we highlight the importance of working closely with public health stakeholders to create a COVID-19 dashboard for public health impact. In the future, the dashboard can be expanded to track trends of other infectious diseases as sewage surveillance is increased for other pathogens.

Comparison of Tumor Control and Skin Damage in a Mouse Model after Ultra-High Dose Rate Irradiation and Conventional Irradiation.

Recent studies suggest ultra-high dose rate radiation treatment (UHDR-RT) reduces normal tissue damage compared to conventional radiation treatment (CONV-RT) at the same dose. In this study, we compared first, the kinetics and degree of skin damage in wild-type C57BL/6 mice, and second, tumor treatment efficacy in GL261 and B16F10 dermal tumor models, at the same UHDR-RT and CONV-RT doses. Flank skin of wild-type mice received UHDR-RT or CONV-RT at 25 Gy and 30 Gy. Normal skin damage was tracked by clinical observation to determine the time to moist desquamation, an endpoint which was verified by histopathology. Tumors were inoculated on the right flank of the mice, then received UHDR-RT or CONV-RT at 1 × 11 Gy, 1 × 15, 1 × 25, 3 × 6 and 3 × 8 Gy, and time to tumor tripling volume was determined. Tumors also received 1 × 11, 1 × 15, 3 × 6 and 3 × 8 Gy doses for assessment of CD8+/CD4+ tumor infiltrate and genetic expression 96 h postirradiation. All irradiations of the mouse tumor or flank skin were performed with megavoltage electron beams (10 MeV, 270 Gy/s for UHDR-RT and 9 MeV, 0.12 Gy/s for CONV-RT) delivered via a clinical linear accelerator. Tumor control was statistically equal for similar doses of UHDR-RT and CONV-RT in B16F10 and GL261 murine tumors. There were variable qualitative differences in genetic expression of immune and cell damage-associated pathways between UHDR and CONV irradiated B16F10 tumors. Compared to CONV-RT, UHDR-RT resulted in an increased latent period to skin desquamation after a single 25 Gy dose (7 days longer). Time to moist skin desquamation did not significantly differ between UHDR-RT and CONV-RT after a 30 Gy dose. The histomorphological characteristics of skin damage were similar for UHDR-RT and CONV-RT. These studies demonstrated similar tumor control responses for equivalent single and fractionated radiation doses, with variable difference in expression of tumor progression and immune related gene pathways. There was a modest UHDR-RT skin sparing effect after a 1 × 25 Gy dose but not after a 1 × 30 Gy dose.

Evaluation of the transmission of SARS-CoV-2 through breast milk: a case series.

Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted through breast milk remains controversial. This study aimed to determine the presence of SARS-CoV-2 in breast milk and assess its transmissibility to the child in infancy. Eleven samples were obtained from nine mothers with coronavirus disease 2019 (COVID-19). All but one sample had negative results on a reverse transcription-quantitative polymerase chain reaction. Among nine children, five were diagnosed with COVID-19, including one child whose mother's milk tested positive. Although SARS-CoV-2 RNA was detected in breast milk, its possible transmission via breastfeeding could not be established. Thus, we conclude that the physical attachment between mother and child is a conceivable transmission route.

The Effects of Yogurt Supplementation and Nutritional Education on Malnourished Infants: A Pilot RCT in Dhaka's Slums.

Our objective was to quantify the effects of yogurt supplementation and nutrition education over three months on the linear growth of infants at risk of stunting. We conducted a three-arm pilot randomized controlled trial: (1) nutrition education for mothers; (2) nutrition education plus a daily yogurt supplement (50 g) for the index child; and (3) usual care (control). Dyads of children aged 4-6 months and at risk of stunting [length-for-age z-score (LAZ) ≤ -1 SD and >-2 SD] and their mothers with ≤10 years of education were eligible for the study. Participants were recruited from five slum areas in Dhaka, Bangladesh. Intention-to-treat (N = 162) and complete-case analyses (N = 127) showed no between-group statistically significant differences in LAZ or weight-for-age (WAZ). However, the yogurt group showed greater change in linear growth compared to the control (LAZ: mean difference 0.20, 95% CI: -0.06, 0.47, p-value 0.13), which was also slightly greater than the education-only group. Children in the yogurt plus group were five times (95% CI: 0.80, 31.80, p-value 0.09) more likely to meet the minimum dietary diversity (MDD) score compared to the control. A 3-month follow-up of this pilot study did not demonstrate that yogurt was beneficial to linear growth. However, there were encouraging trends that merit replication of the intervention with larger samples and longer follow-ups.

Monitoring SARS-CoV-2 variants in wastewater of Dhaka City, Bangladesh: approach to complement public health surveillance systems.

BACKGROUND: Wastewater-based epidemiological surveillance has been considered a powerful tool for early detection and monitoring of the dynamics of SARS-CoV-2 and its lineages circulating in a community. This study is aimed to investigate the complexity of SARS-CoV-2 infection dynamics in Dhaka city by examining its genetic variants in wastewater. Also, the study seeks to determine a connection between the SARS-CoV-2 variations detected in clinical testing and those found in wastewater samples. RESULTS: Out of 504 samples tested in RT-qPCR, 185 (36.7%) tested positive for SARS-CoV-2 viral RNA. The median log10 concentration of SARS-CoV-2 N gene copies/Liter of wastewater (gc/L) was 5.2, and the median log10 concentration of ORF1ab was 4.9. To further reveal the genetic diversity of SARS-CoV-2, ten samples with ORF1ab real-time RT-PCR cycle threshold (Ct) values ranging from 28.78 to 32.13 were subjected to whole genome sequencing using nanopore technology. According to clade classification, sequences from wastewater samples were grouped into 4 clades: 20A, 20B, 21A, 21J, and the Pango lineage, B.1, B.1.1, B.1.1.25, and B.1.617.2, with coverage ranging from 94.2 to 99.8%. Of them, 70% belonged to clade 20B, followed by 10% to clade 20A, 21A, and 21J. Lineage B.1.1.25 was predominant in Bangladesh and phylogenetically related to the sequences from India, the USA, Canada, the UK, and Italy. The Delta variant (B.1.617.2) was first identified in clinical samples at the beginning of May 2021. In contrast, we found that it was circulating in the community and was detected in wastewater in September 2020. CONCLUSION: Environmental surveillance is useful for monitoring temporal and spatial trends of existing and emerging infectious diseases and supports evidence-based public health measures. The findings of this study supported the use of wastewater-based epidemiology and provided the baseline data for the dynamics of SARS-CoV-2 variants in the wastewater environment in Dhaka, Bangladesh.

Food safety policy enforcement and associated actions reduce lead chromate adulteration in turmeric across Bangladesh.

Turmeric adulterated with lead chromate pigment has been previously identified as a primary source of lead exposure in Bangladesh. This study assesses the impact of a multi-faceted intervention between 2017 and 2021 to reduce lead-tainted turmeric in Bangladesh. The intervention involved: i) disseminating findings from scientific studies via news media that identified turmeric as a source of lead poisoning, ii) educating consumers and businesspeople about the risks of lead chromate in turmeric via public notices and face-to-face meetings, and iii) collaborating with the Bangladesh Food Safety Authority to utilize a rapid lead detection technology to enforce policy disallowing turmeric adulteration. Before and after the intervention, evidence of lead chromate turmeric adulteration was assessed at the nation's largest turmeric wholesale market and at turmeric polishing mills across the country. Blood lead levels of workers at two mills were also assessed. Forty-seven interviews were conducted with consumers, businesspeople, and government officials to assess changes in supply, demand, and regulatory capacity. The proportion of market turmeric samples containing detectable lead decreased from 47% pre-intervention in 2019 to 0% in 2021 (n = 631, p < 0.0001). The proportion of mills with direct evidence of lead chromate adulteration (pigment on-site) decreased from 30% pre-intervention in 2017 to 0% in 2021 (n = 33, p < 0.0001). Blood lead levels dropped a median of 30% (IQR: 21-43%), while the 90th percentile dropped 49% from 18.2 µg/dL to 9.2 µg/dL 16 months after the intervention (n = 15, p = 0.033). Media attention, credible information, rapid lead detection tools and swift government action to enforce penalties all contributed to the intervention's success. Subsequent efforts should evaluate if this is an example of an effective intervention that can be replicated to reduce lead chromate adulteration of spices globally.

How does women's empowerment relate to antenatal care attendance? A cross-sectional analysis among rural women in Bangladesh.

BACKGROUND: In South Asia, roughly half of women attend at least four antenatal care visits with skilled health personnel, the minimum number recommended by the World Health Organization for optimal birth outcomes. A much greater proportion of women attend at least one antenatal care visit, suggesting that a key challenge is ensuring that women initiate antenatal care early in pregnancy and continue to attend after their first visit. One critical barrier to antenatal care attendance may be that women do not have sufficient power in their relationships, households, or communities to attend antenatal care when they want to. The main goals of this paper were to 1) understand the potential effects of intervening on direct measures of women's empowerment-including household decision making, freedom of movement, and control over assets-on antenatal care attendance in a rural population of women in Bangladesh, and 2) examine whether differential associations exist across strata of socioeconomic status. METHODS: We analyzed data on 1609 mothers with children under 24 months old in rural Bangladesh and employed targeted maximum likelihood estimation with ensemble machine learning to estimate population average treatment effects. RESULTS: Greater women's empowerment was associated with an increased number of antenatal care visits. Specifically, among women who attended at least one antenatal care visit, having high empowerment was associated with a greater probability of ≥ 4 antenatal care visits, both in comparison to low empowerment (15.2 pp, 95% CI: 6.0, 24.4) and medium empowerment (9.1 pp, 95% CI: 2.5, 15.7). The subscales of women's empowerment driving the associations were women's decision-making power and control over assets. We found that greater women's empowerment is associated with more antenatal care visits regardless of socioeconomic status. CONCLUSIONS: Empowerment-based interventions, particularly those targeting women's involvement in household decisions and/or facilitating greater control over assets, may be a valuable strategy for increasing antenatal care attendance. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04111016, Date First Registered: 01/10/2019.

Can oral sex be performed safely among men who have sex with men (MSM) and transgender women in Bangladesh? Challenges, complexities and the way forward.

Introduction: There is currently ample research and intervention initiatives addressing anal sex and sexually transmitted infections (STIs) among gender and sexually diverse people (i.e., men who have sex with men (MSM) and transgender women). However, oral sex and oral STIs are not prioritized to the same extent, despite their concerning implications. This article aimed to delineate the underlying contexts of unprotected oral sex and the management challenges of oral STIs. Methodology: This qualitative study constituted 30 in-depth interviews, 14 focus group discussions, and 10 key-informant interviews with gender and sexually diverse people, service providers of HIV interventions and sexuality researchers. Thematic analysis conventions were applied. Results: Findings revealed various contexts of unprotected oral sex. In particular, we found a discordance between pleasure and protected sex where participants believed the two phenomena were mutually exclusive, therefore they did not want to compromise their pleasure by using condoms. Moreover, their low awareness, risk perception, and unchallenged misconceptions about the harms of unprotected oral sex fueled their hesitancy to use condoms during oral sex. Compared to anal sex and STIs, oral sex and STIs were less prioritized in the current HIV intervention modalities, where healthcare providers lacked adequate knowledge and training about oral sex and oral STIs, as well as their complexities. Conclusions: In Bangladesh and several other settings, oral sex is considered a taboo, thus imbuing silence about this issue and its complexities. In this context, it is integral to eradicate the taboos and silence surrounding oral sex and oral STIs in order to strengthen the overall STI management strategy. Therefore, HIV/STI prevention programs and mainstream healthcare facilities need to underscore oral STI interventions, otherwise this issue would remain under-prioritized.

Engineered Yeast Displaying Specific Norovirus-Binding Nanobodies for the Concentration and Detection of Human Norovirus in Food Matrix.

Human noroviruses pose grave threats to public health and economy. In this study, we genetically engineered yeast (Saccharomyces cerevisiae EBY100) to display specific norovirus-binding nanobodies (Nano-26 and Nano-85) on cell surface to facilitate the concentration of noroviruses for improved detection. Binding of norovirus virus-like particles (VLPs) to these nanobody-displaying yeasts was confirmed and characterized using confocal microscopy and flow cytometry. The ability of our engineered yeasts to capture norovirus VLPs can reach up to 91.3%. Furthermore, this approach was applied to concentrate and detect norovirus VLPs in a real food matrix. A wide linear detection range (1-104 pg/g) was observed, and the detection limit on spiked spinach was calculated as low as 0.071 pg/g. Overall, our engineered yeasts could be a promising approach to concentrate and purify noroviruses in food samples for easy detection, which allows us to prevent the spread of food-borne virus in the food supply chain.

The 2022 dengue outbreak in Bangladesh: hypotheses for the late resurgence of cases and fatalities.

Bangladesh reported the highest number of annual deaths (n = 281) related to dengue virus infection in 2022 since the virus reappeared in the country in 2000. Earlier studies showed that >92% of the annual cases occurred between the months of August and September. The 2022 outbreak is characterized by late onset of dengue cases with unusually higher deaths in colder months, that is, October-December. Here we present possible hypotheses and explanations for this late resurgence of dengue cases. First, in 2022, the rainfall started late in the season. Compared to the monthly average rainfall for September and October between 2003 and 2021, there was 137 mm of additional monthly rainfall recorded in September and October 2022. Furthermore, the year 2022 was relatively warmer with a 0.71°C increased temperature than the mean annual temperature of the past 20 yr. Second, a new dengue virus serotype, DENV-4, had recently reintroduced/reappeared in 2022 and become the dominant serotype in the country for a large naïve population. Third, the post-pandemic return of normalcy after 2 yr of nonpharmaceutical social measures facilitates extra mosquito breeding habitats, especially in construction sites. Community engagement and regular monitoring and destruction of Aedes mosquitoes' habitats should be prioritized to control dengue virus outbreaks in Bangladesh.

Implementing a group-based multi-component early child development intervention through the government health system in rural Bangladesh: A feasibility study.

Children in low- and middle-income countries face an increased risk of impaired cognitive development due to contaminated environments, poor nutrition, and inadequate responsive stimulation from caregivers. Implementing multi-component, community-level interventions may reduce these risks; however, there is little evidence supporting implementation of these interventions at scale. We assessed the feasibility of implementing a group-based intervention that included responsive stimulation, maternal and child nutrition, water and sanitation, and childhood lead exposure prevention through the government health system in Chatmohar, Bangladesh. After implementation, we conducted 17 in-depth interviews with frontline health service providers and 12 key informant interviews with their supervisors and managers to explore the facilitators and difficulties implementing such a complex programme within the health system. Factors facilitating implementation included: high quality training and skill level of providers, support from community members, family, and supervisors, positive relationships between providers and participants, and provision of children's toys and books free of cost. Difficulties included increased workload of the providers, complicated group-based yet stage-specific delivery where providers had to manage a large group of mother-child dyads representing many different child age-groups at once, and logistics difficulties in providing toys and books through a centralised health system process. Key informants made suggestions to ensure effective government-level scale-up including engaging relevant NGOs as partners, identifying feasible ways to make toys available, and offering providers meaningful even if non-monetary rewards. These findings can be used to shape the design and delivery of multi-component child development interventions to be delivered through the health system.

Geographic pair-matching in large-scale cluster randomized trials.

Custer randomized trials are often used to study large-scale public health interventions. In large trials, even small improvements in statistical efficiency can have profound impacts on the required sample size and cost. Pair matched randomization is one strategy with potential to increase trial efficiency, but to our knowledge there have been no empirical evaluations of pair-matching in large-scale, epidemiologic field trials. Location integrates many socio-demographic and environmental characteristics into a single feature. Here, we show that geographic pair-matching leads to substantial gains in statistical efficiency for 14 child health outcomes that span growth, development, and infectious disease through a re-analysis of two large-scale trials of nutritional and environmental interventions in Bangladesh and Kenya. We estimate relative efficiencies ≥ 1.1 for all outcomes assessed and relative efficiencies regularly exceed 2.0, meaning an unmatched trial would have needed to enroll at least twice as many clusters to achieve the same level of precision as the geographically pair-matched design. We also show that geographically pair-matched designs enable estimation of fine-scale, spatially varying effect heterogeneity under minimal assumptions. Our results demonstrate broad, substantial benefits of geographic pair-matching in large-scale, cluster randomized trials.

Characterization of a diode dosimeter for UHDR FLASH radiotherapy.

BACKGROUND: Ultra-high dose rate (UHDR) FLASH beams typically deliver dose at rates of  >40 Gy/sec. Characterization of these beams with respect to dose, mean dose rate, and dose per pulse requires dosimeters which exhibit high temporal resolution and fast readout capabilities. PURPOSE: A diode EDGE Detector with a newly designed electrometer has been characterized for use in an UHDR electron beam and demonstrated appropriateness for UHDR FLASH radiotherapy dosimetry. METHODS: Dose linearity, mean dose rate, and dose per pulse dependencies of the EDGE Detector were quantified and compared with dosimeters including a W1 scintillator detector, radiochromic film, and ionization chamber that were irradiated with a 10 MeV UHDR beam. The dose, dose rate, and dose per pulse were controlled via an in-house developed scintillation-based feedback mechanism, repetition rate of the linear accelerator, and source-to-surface distance, respectively. Depth-dose profiles and temporal profiles at individual pulse resolution were compared to the film and scintillation measurements, respectively. The radiation-induced change in response sensitivity was quantified via irradiation of ∼5kGy. RESULTS: The EDGE Detector agreed with film measurements in the measured range with varying dose (up to 70 Gy), dose rate (nearly 200 Gy/s), and dose per pulse (up to 0.63 Gy/pulse) on average to within 2%, 5%, and 1%, respectively. The detector also agreed with W1 scintillation detector on average to within 2% for dose per pulse (up to 0.78 Gy/pulse). The EDGE Detector signal was proportional to ion chamber (IC) measured dose, and mean dose rate in the bremsstrahlung tail to within 0.4% and 0.2% respectively. The EDGE Detector measured percent depth dose (PDD) agreed with film to within 3% and per pulse output agreed with W1 scintillator to within -6% to +5%. The radiation-induced response decrease was 0.4% per kGy. CONCLUSIONS: The EDGE Detector demonstrated dose linearity, mean dose rate independence, and dose per pulse independence for UHDR electron beams. It can quantify the beam spatially, and temporally at sub millisecond resolution. It's robustness and individual pulse detectability of treatment deliveries can potentially lead to its implementation for in vivo FLASH dosimetry, and dose monitoring.

Feasibility and acceptability of home-based neonatal hyperbilirubinemia screening by community health workers using transcutaneous bilimeters in Bangladesh.

BACKGROUND: Universal screening for neonatal hyperbilirubinemia risk assessment is recommended by the American Academy of Pediatrics to reduce related morbidity. In Bangladesh and in many low- and middle-income countries, there is no screening for neonatal hyperbilirubinemia. Furthermore, neonatal hyperbilirubinemia may not be recognized as a medically significant condition by caregivers and community members. We aimed to evaluate the acceptability and operational feasibility of community health worker (CHW)-led, home-based, non-invasive neonatal hyperbilirubinemia screening using a transcutaneous bilimeter in Shakhipur, a rural subdistrict in Bangladesh. METHODS: We employed a two-step process. In the formative phase, we conducted eight focus group discussions with parents and grandparents of infants and eight key informant interviews with public and private healthcare providers and managers to explore their current knowledge, perceptions, practices, and challenges regarding identification and management of neonatal hyperbilirubinemia. Next, we piloted a prenatal sensitization intervention and home-based screening by CHWs using transcutaneous bilimeters and evaluated the acceptability and operational feasibility of this approach through focus group discussions and key informant interviews with parents, grandparents and CHWs. RESULTS: Formative findings identified misconceptions regarding neonatal hyperbilirubinemia causes and health risks among caregivers in rural Bangladesh. CHWs were comfortable with adoption, maintenance and use of the device in routine home visits. Transcutaneous bilimeter-based screening was also widely accepted by caregivers and family members due to its noninvasive technique and immediate display of findings at home. Prenatal sensitization of caregivers and family members helped to create a supportive environment in the family and empowered mothers as primary caregivers. CONCLUSION: Adopting household neonatal hyperbilirubinemia screening in the postnatal period by CHWs using a transcutaneous bilimeter is an acceptable approach by both CHWs and families and may increase rates of screening to prevent morbidity and mortality.

Retrospective comparison of clinical outcomes of ultrasound-guided percutaneous cholecystostomy in patients with and without coagulopathy: a single center's experience.

PURPOSE: To compare the complication rate and clinical outcomes for percutaneous cholecystostomy (PC) in patients with or without coagulopathy. MATERIALS AND METHODS: We retrospectively reviewed electronic medical chart of patients who underwent ultrasound-guided PC with a 8.5-F drainage tube for acute cholecystitis between November 2003 and March 2017. We divided the patients into two groups: patients with coagulopathy (international normalized ratio > 1.5 or platelet count < 50 × 109/L or with a history of anticoagulant medication in preceding 5 days) and patients without coagulopathy. Duration of drainage, duration of hospital stay, 30-day mortality and complication rates were compared between these two groups. Student's t test, Chi-square test or Fisher's exact test was used for bivariate analyses. Age, age-adjusted Charlson Comorbidity Index (ACCI) and sepsis-adjusted complication rates were also compared. RESULTS: In total, 141 patients had PC (mean age was 73.3 years [SD 13.3]; range 33-96 years; 94 men and 47 women). Fifty-two patients (36.9%) had coagulopathy and 89 patients (63.1%) were without any history of coagulopathy. Hemorrhagic complication rate was 3.5% (5 out of 141 patients, including 4 with coagulopathy and 1 without). One patient with coagulopathy died due to the hemorrhage. Duration of drainage was longer in patients with coagulopathy than patients without coagulopathy (20.0 days vs. 14.8 days; P = 0.033). No significant difference was observed with regard to duration of hospital stay (32.3 days vs. 25.6 days; P = 0.103) and 30-day mortality (7.7% vs. 1.1%; P = 0.062). The overall complication rate did not significantly differ (9.6% and 11.2%; P = 0.763), nor did age, ACCI or sepsis-adjusted complications. CONCLUSION: Clinical outcomes and complications rates after PC did not statistically differ between patients with and without coagulopathy, but there was a tendency of higher risk of hemorrhage in coagulopathy patients. Therefore, the indication of this procedure should be carefully determined.