Characteristics and outcomes of children 2-23 months of age with prolonged diarrhoea: A secondary analysis of data from the 'Antibiotics for Children with Diarrhea' trial.

Background: Approximately 12% of all diarrhoeal episodes last for 7-13 days. As such, they are termed prolonged diarrhoea, and are associated with over two-thirds of all diarrhoeal deaths. Due to a lack of robust data, we aimed to evaluate a comparative background characteristics of young children with acute and prolonged diarrhoea, and their outcomes at day 90 follow-up. Methods: We performed a secondary analysis of data from the Antibiotics for Children with Diarrhea (ABCD) trial. Children aged 2-23 months were enrolled between July 2017 and July 2019 from seven Asian and sub-Saharan African countries. For this analysis, we divide diarrhoea into two categories: acute diarrhoea (duration <7 days) and prolonged diarrhoea (duration ≥7-13 days). We used logistic regression to observe baseline crude and adjusted associations and linear regression to compare post-discharge outcomes. Results: We analysed data on 8266 children, of whom 756 (9%) had prolonged diarrhoea and 7510 (91%) had acute diarrhoea. Pakistan had the highest proportion of children with prolonged diarrhoea (n/N = 178/1132, 16%), while Tanzania had the lowest (n/N = 12/1200, 1%). From an analysis that adjusted for sex, breastfeeding, nutritional status, clinical presentation, housing, water supply, sanitation, and country, we observed that presentation at a health facility with prolonged diarrhoea was associated with low age (2-12 months) (adjusted odds ratio (aOR) = 1.25; 95% confidence interval (CI) = 1.02, 1.53; P = 0.028), presence of three or more under-five children in the family (aOR = 1.54; 95% CI = 1.26, 1.87; P < 0.001), maternal illiteracy (aOR = 1.45; 95% CI = 1.21, 1.74, P < 0.001), moderate underweight (aOR = 1.25; 95% CI = 1.01, 1.55; P = 0.042) and pathogen (Campylobacter) (aOR = 1.27; 95% CI = 1.12, 1.44; P < 0.001). At day 90 follow-up, children with prolonged diarrhoea had significantly lower weight-for-age z-score compared to children with acute diarrhoea (-1.62, standard deviation (SD) = 1.11 vs -1.52, SD = 1.20; P = 0.032), as well as significantly higher frequency of hospital admission (6.1% vs 4.5%; P = 0.042). Conclusions: Prolonged diarrhoea was more common in children of younger age, those who were moderately underweight, those with Campylobacter in stool, those with three or more under-five children in a family, and those with illiterate mothers compared to those who had acute diarrhoea. Children with prolonged diarrhoea more often required hospitalisation during the three-month follow-up period compared to their counterparts.

Experiences, acceptability and barriers to calcium supplementation during pregnancy in Dar es Salaam, Tanzania.

Calcium supplementation in pregnancy is recommended in contexts with low dietary calcium intake to reduce the risk of pre-eclampsia and its complications. The World Health Organisation suggested high-dose calcium supplementation (1500-2000 mg/day), divided into three doses and taken at different times from daily iron-folic supplements. We conducted a mixed methods evaluation study to assess experiences, acceptability and barriers to high-dose calcium supplementation from the perspectives of pregnant women and antenatal health care providers at two public health facilities in Dar es Salaam, Tanzania. Descriptive statistics and thematic analysis were used to characterise acceptability, barriers and overall experiences of using high-dose calcium supplementation. Pregnant women in the cohort were aged 19-41 years, with 32.4% being primiparous. The proportion of pregnant women who liked calcium supplements 'a lot' decreased from 50.2% at the first visit to 31.8% at the last antenatal follow-up visit. Adherence was 71.3% (interquartile range: 50.5%, 89.3%), with only 24.0% of the participants taking 90% or more of the required supplements. Although participants expressed positive attitudes towards using calcium supplements, they also voiced concerns about the large size, side effects, the potential to forget and the burden of taking calcium supplements three times per day. Antenatal health care providers also affirmed the high burden of taking calcium supplements in addition to iron-folic acid supplements. Participants expressed the acceptability of using calcium supplements during pregnancy, but adherence to three doses per day posed challenges to pregnant women. Reducing the number of calcium supplement doses per day may improve adherence.

Effects of Vitamin D-3 Supplementation During Pregnancy and Lactation on Maternal and Infant Biomarkers of Environmental Enteric Dysfunction, Systemic Inflammation, and Growth: A Secondary Analysis of a Randomized Controlled Trial.

BACKGROUND: Environmental enteric dysfunction (EED) is an acquired, subclinical state of intestinal inflammation common in children and adults in low-income and middle-income countries. Although vitamin D-3 supplementation has purported anti-inflammatory properties, its ability to ameliorate biomarkers of EED remains unclear. OBJECTIVES: This study aimed to examine the effects of maternal vitamin D-3 supplementation during pregnancy and lactation on biomarkers of EED, systemic inflammation, and growth in women living with HIV and their infants in Dar es Salaam, Tanzania. METHODS: We conducted subgroup analyses among randomly selected mothers (n = 720) and infants (n = 365 at 6 wk of age, and n = 266 at 6 mo of age) who participated in a randomized, triple-blind, placebo-controlled trial of daily maternal 3000 IU vitamin D-3 supplementation from the second trimester of pregnancy until 1 y postpartum. Biomarkers of EED (soluble CD14 and intestinal fatty acid-binding protein), systemic inflammation (C-reactive protein and α1-acid glycoprotein), and growth factors (insulin-like growth factor 1 and fibroblast growth factor 21) were measured via the Micronutrient and Environmental Enteric Dysfunction Assessment Tool. Anti-flagellin and anti-lipopolysaccharide immunoglobulins were measured via enzyme-linked immunosorbent assay. Comparisons by randomized treatment arm were performed using ordinary least squares regression models with log2-transformed biomarkers. RESULTS: At 32 wk of gestation, intestinal fatty acid-binding protein (ß: -0.19; P = 0.03) and α1-acid glycoprotein (ß:-0.11; P = 0.04) were significantly lower in mothers in the vitamin D-3 group than those in mothers in the placebo group. At 6 wk of age, insulin-like growth factor 1 (ß:-0.31; P = 0.03) was significantly lower in infants whose mothers were in the vitamin D-3 group than that in infants whose mothers were in the placebo group. CONCLUSIONS: Vitamin D-3 supplementation during pregnancy and lactation reduced selected EED and systemic inflammation biomarkers among women living with HIV. While the effects of maternal vitamin D-3 supplementation do not appear to extend to infants, there may be an effect on growth factors. This trial was registered at clinicaltrials.gov as NCT02305927 (https://clinicaltrials.gov/study/NCT02305927).

Proposed Nutrition Competencies for Medical Students and Physician Trainees: A Consensus Statement.

Importance: In 2022, the US House of Representatives passed a bipartisan resolution (House of Representatives Resolution 1118 at the 117th Congress [2021-2022]) calling for meaningful nutrition education for medical trainees. This was prompted by increasing health care spending attributed to the growing prevalence of nutrition-related diseases and the substantial federal funding via Medicare that supports graduate medical education. In March 2023, medical education professional organizations agreed to identify nutrition competencies for medical education. Objective: To recommend nutrition competencies for inclusion in medical education to improve patient and population health. Evidence Review: The research team conducted a rapid literature review to identify existing nutrition-related competencies published between July 2013 and July 2023. Additional competencies were identified from learning objectives in selected nutrition, culinary medicine, and teaching kitchen curricula; dietetic core competencies; and research team-generated de novo competencies. An expert panel of 22 nutrition subject matter experts and 15 residency program directors participated in a modified Delphi process and completed 4 rounds of voting to reach consensus on recommended nutrition competencies, the level of medical education at which they should be included, and recommendations for monitoring implementation and evaluation of these competencies. Findings: A total of 15 articles met inclusion criteria for competency extraction and yielded 187 competencies. Through review of gray literature and other sources, researchers identified 167 additional competencies for a total of 354 competencies. These competencies were compiled and refined prior to voting. After 4 rounds of voting, 36 competencies were identified for recommendation: 30 at both undergraduate and graduate levels, 2 at the undergraduate level only, and 4 at the graduate level only. Competencies fell into the following nutrition-related themes: foundational nutrition knowledge, assessment and diagnosis, communication skills, public health, collaborative support and treatment for specific conditions, and indications for referral. A total of 36 panelists (97%) recommended nutrition competencies be assessed as part of licensing and board certification examinations. Conclusions and Relevance: These competencies represent a US-based effort to use a modified Delphi process to establish consensus on nutrition competencies for medical students and physician trainees. These competencies will require an iterative process of institutional prioritization, refinement, and inclusion in current and future educational curricula as well as licensure and certification examinations.

Achieving Enteral Autonomy in Children with Intestinal Failure Following Inpatient Admission: A Case Series.

We describe cases of intestinal failure wherein inpatient admission was critical toward enteral autonomy. We performed a retrospective chart review of 6 children with long-term parenteral nutrition dependence who were weaned from parenteral nutrition after admission. Admissions included feeding and medication titration, interdisciplinary care, and a home parenteral nutrition team consultation.

Performance of pan-enteroscopy in children with intestinal failure due to short bowel syndrome: A single-center retrospective study.

OBJECTIVES: In pediatric patients with intestinal failure (IF) due to short bowel syndrome (SBS), we hypothesized that young children, those with shorter residual small bowel and those with congenital malrotation of the bowel would be more likely to undergo pan-enteroscopy. We aimed to determine the feasibility and diagnostic yield of pan-enteroscopy in this cohort. METHODS: We performed a single-center, retrospective study of pediatric patients with IF due to SBS who had undergone at least one GI endoscopic evaluation between January 1, 2018 and January 1, 2023. RESULTS: A pan-enteroscopy might have been possible in 381 of the 431 procedures (206 patients) reviewed. Forty-four (21%) patients underwent 54 pan-enteroscopies. Children with a residual bowel length <35 cm had higher odds of undergoing pan-enteroscopy (odds ratio [OR] 3.72, 95% confidence interval [CI] [1.32, 10.48], p = 0.01), as did patients with periprocedural glucagon-like peptide 2 (GLP-2) analog use (OR 4.30, 95% CI [1.24, 14.95], p = 0.02). Patients with diagnoses other than necrotizing enterocolitis (NEC) tended to be more likely to achieve a pan-enteroscopy (OR 2.73, 95% CI [0.95,7.88], p = 0.06). Evidence of gross and histopathologic abnormalities were found in 77.8% and 78% of the procedures, respectively. No complications were identified. CONCLUSION: In a large cohort of children with SBS, pan-enteroscopy was successfully performed in 14.2% of the procedures and microscopic abnormalities were common. Shorter residual bowel length, underlying diagnoses of non-NEC, and GLP-2 analog use were generally associated with successful pan-enteroscopy, independent of age and several other factors. These data suggest that pan-enteroscopy is feasible and of high-yield in a subset of patients with SBS.

Fetal, neonatal, and infant death among offspring of pregnant women living with HIV in Tanzania.

OBJECTIVE: Assess the risk of death for offspring of pregnant women living with HIV (PWLHIV) and the association with sociodemographic, pregnancy, HIV-related, and birth factors. DESIGN: We conducted a prospective cohort study of PWLHIV on antiretroviral therapy (ART) and their offspring in urban Tanzania who were enrolled in a vitamin D trial conducted from June 2015 to October 2019. METHODS: We described rates of fetal, neonatal, and infant death and assessed risk factors for these outcomes with generalized estimating equations. We also estimated population-attributable risk percentages for the contribution of prematurity and small-for-gestational age (SGA) to neonatal and infant mortality. RESULTS: Among 2,299 PWLHIV, there were a total of 136 fetal deaths (5.6%) and the stillbirth rate was 42.0 per 1,000 total births. Among 2,167 livebirths, there were 57 neonatal deaths (26.3 per 1,000 livebirths) and 114 infant deaths (52.6 per 1,000 livebirths). Twin birth was associated with neonatal death, while maternal CD4 T-cell count <350 cells/µL in pregnancy was associated with infant death (p-values < 0.05). As compared to term-appropriate-for-gestational age (AGA) births, the relative risks for neonatal mortality for term-SGA, preterm-AGA, and preterm-SGA infants were 2.07 (95% CI: 1.00-4.28), 2.87 (95% CI 1.54-5.35) and 7.15 (95% CI: 2.11-24.30), respectively. We estimated that 42.7% of neonatal and 29.4% of infant deaths were attributable to prematurity and SGA in the cohort. CONCLUSIONS: The risk of death is high for offspring of PWLHIV in Tanzania and the combination of prematurity and fetal growth restriction may account for nearly half of neonatal deaths.

Derivation and Internal Validation of a Novel Risk Assessment Tool to Identify Infants and Young Children at Risk for Post-Discharge Mortality in Dar es Salaam, Tanzania and Monrovia, Liberia.

OBJECTIVE: To derive and validate internally a novel risk assessment tool to identify young children at risk for all-cause mortality ≤60 days of discharge from hospitals in sub-Saharan Africa. STUDY DESIGN: We performed a prospective observational cohort study of children aged 1-59 months discharged from Muhimbili National Hospital in Dar es Salaam, Tanzania and John F. Kennedy Medical Center in Monrovia, Liberia (2019-2022). Caregivers received telephone calls up to 60 days after discharge to ascertain participant vital status. We collected socioeconomic, demographic, clinical, and anthropometric data during hospitalization. Candidate variables with P < .20 in bivariate analyses were included in a multivariable logistic regression model with best subset selection to identify risk factors for the outcome. We internally validated our tool using bootstrapping with 500 repetitions. RESULTS: There were 1933 young children enrolled in the study. The median (IQR) age was 11 (4, 23) months and 58.7% were males. In total, 67 (3.5%) died during follow-up. Ten variables contributed to our tool (total possible score 82). Cancer (aOR 10.6, 95% CI 2.58, 34.6), pedal edema (aOR 6.94, 95% CI 1.69, 22.6), and leaving against medical advice (aOR 6.46, 95% CI 2.46, 15.3) were most predictive of post-discharge mortality. Our risk assessment tool demonstrated good discriminatory value (optimism corrected area under the receiver operating characteristic curve 0.77), high precision, and sufficient calibration. CONCLUSIONS: After validation, this tool may be used to identify young children at risk for post-discharge mortality to direct resources for follow-up of high-risk children.

Preoperative Malnutrition Increases Risk of In-Hospital Mortality, Major Infection, and Longer Intensive Care Unit Stay After Ventricular Septal Defect Closure.

BACKGROUND: High energy requirements and poor feeding can lead to growth failure in patients with ventricular septal defect (VSD), but effects of preoperative malnutrition on surgical outcomes are poorly understood, especially in low-resource settings. METHODS AND RESULTS: We analyzed a cohort of children <5 years of age undergoing VSD closure at 60 global centers participating in the International Quality Improvement Collaborative for Congenital Heart Disease, 2015 to 2020. We calculated adjusted odds ratios (ORs) for in-hospital death and major infection and adjusted coefficients for duration of intensive care unit stay for 4 measures of malnutrition: severe wasting (weight-for-height Z score, <-3), moderate wasting (-3

Morbidity and unplanned healthcare encounters after hospital discharge among young children in Dar es Salaam, Tanzania and Monrovia, Liberia.

BACKGROUND: Researchers and healthcare providers have paid little attention to morbidity and unplanned healthcare encounters for children following hospital discharge in low- and middle-income countries. Our objective was to compare symptoms and unplanned healthcare encounters among children aged <5 years who survived with those who died within 60 days of hospital discharge through follow-up phone calls. METHODS: We conducted a secondary analysis of a prospective observational cohort of children aged <5 years discharged from neonatal and paediatric wards of two national referral hospitals in Dar es Salaam, Tanzania and Monrovia, Liberia. Caregivers of enrolled participants received phone calls 7, 14, 30, 45, and 60 days after hospital discharge to record symptoms, unplanned healthcare encounters, and vital status. We used logistic regression to determine the association between reported symptoms and unplanned healthcare encounters with 60-day post-discharge mortality. RESULTS: A total of 4243 participants were enrolled and had 60-day vital status available; 138 (3.3%) died. For every additional symptom ever reported following discharge, there was a 35% greater likelihood of post-discharge mortality (adjusted odds ratio [aOR] 1.35, 95% confidence interval [CI] 1.10 to 1.66; p=0.004). The greatest survival difference was noted for children who had difficulty breathing (2.1% among those who survived vs 36.0% among those who died, p<0.001). Caregivers who took their child home from the hospital against medical advice during the initial hospitalisation had over eight times greater odds of post-discharge mortality (aOR 8.06, 95% CI 3.87 to 16.3; p<0.001) and those who were readmitted to a hospital had 3.42 greater odds (95% CI 1.55 to 8.47; p=0.004) of post-discharge mortality than those who did not seek care when adjusting for site, sociodemographic factors, and clinical variables. CONCLUSION: Surveillance for symptoms and repeated admissions following hospital discharge by healthcare providers is crucial to identify children at risk for post-discharge mortality.

Clinical and nutritional correlates of bacterial diarrhoea aetiology in young children: a secondary cross-sectional analysis of the ABCD trial.

OBJECTIVE: The objective was to assess the association between nutritional and clinical characteristics and quantitative PCR (qPCR)-diagnosis of bacterial diarrhoea in a multicentre cohort of children under 2 years of age with moderate to severe diarrhoea (MSD). DESIGN: A secondary cross-sectional analysis of baseline data collected from the AntiBiotics for Children with Diarrhoea trial (NCT03130114). PATIENTS: Children with MSD (defined as >3 loose stools within 24 hours and presenting with at least one of the following: some/severe dehydration, moderate acute malnutrition (MAM) or severe stunting) enrolled in the ABCD trial and collected stool sample. STUDY PERIOD: June 2017-July 2019. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Likely bacterial aetiology of diarrhoea. Secondary outcomes included specific diarrhoea aetiology. RESULTS: A total of 6692 children with MSD had qPCR results available and 28% had likely bacterial diarrhoea aetiology. Compared with children with severe stunting, children with MAM (adjusted OR (aOR) (95% CI) 1.56 (1.18 to 2.08)), some/severe dehydration (aOR (95% CI) 1.66 (1.25 to 2.22)) or both (aOR (95% CI) 2.21 (1.61 to 3.06)), had higher odds of having likely bacterial diarrhoea aetiology. Similar trends were noted for stable toxin-enterotoxigenic Escherichia coli aetiology. Clinical correlates including fever and prolonged duration of diarrhoea were not associated with likely bacterial aetiology; children with more than six stools in the previous 24 hours had higher odds of likely bacterial diarrhoea (aOR (95% CI) 1.20 (1.05 to 1.36)) compared with those with fewer stools. CONCLUSION: The presence of MAM, dehydration or high stool frequency may be helpful in identifying children with MSD who might benefit from antibiotics.

The Association Between Breastfeeding and Growth Among Infants with Moderately Low Birth Weight: A Prospective Cohort Study.

OBJECTIVE: To assess the association between breastfeeding competency, as determined by Latch, Audible swallowing, Type of nipple, Comfort, and Hold (LATCH) and Preterm Infant Breastfeeding Behavior Scale (PIBBS) scores, and exclusive breastfeeding and growth among infants with low birth weight (LBW) in India, Malawi, and Tanzania. STUDY DESIGN: We conducted LATCH and PIBBS assessments among mother-infant dyads enrolled in the Low Birthweight Infant Feeding Exploration (LIFE) observational study of infants with moderately LBW (1500g-2499 g) in India, Malawi, and Tanzania. We analyzed feeding and growth patterns among this cohort. RESULTS: We observed 988 infants. We found no association between LATCH or PIBBS scores and rates of exclusive breastfeeding at 4 or 6 months. Higher week 1 LATCH and PIBBS scores were associated with increased likelihood of regaining birth weight by 2 weeks of age [LATCH: aRR 1.42 (95% CI 1.15, 1.76); PIBBS: aRR 1.15 (95% CI 1.07, 1.23); adjusted for maternal age, parity, education, residence, delivery mode, LBW type, number of offspring, and site]. Higher PIBBS scores at 1 week were associated with improved weight gain velocity (weight-for-age z-score change) at 1, 4, and 6 months [adjusted beta coefficient: 1 month 0.04 (95% CI 0.01, 0.06); 4 month 0.04 (95% CI 0.01, 0.06); and 6 month 0.04 (95% CI 0.00, 0.08)]. CONCLUSION: Although week 1 LATCH and PIBBS scores were not associated with rates of exclusive breastfeeding, higher scores were positively associated with growth metrics among infants with LBW, suggesting that these tools may be useful to identify dyads who would benefit from early lactation support.

Identifying neonates at risk for post-discharge mortality in Dar es Salaam, Tanzania, and Monrovia, Liberia: Derivation and internal validation of a novel risk assessment tool.

INTRODUCTION: The immediate period after hospital discharge carries a large burden of childhood mortality in sub-Saharan Africa. Our objective was to derive and internally validate a risk assessment tool to identify neonates discharged from the neonatal ward at risk for 60-day post-discharge mortality. METHODS: We conducted a prospective observational cohort study of neonates discharged from Muhimbili National Hospital in Dar es Salaam, Tanzania, and John F Kennedy Medical Centre in Monrovia, Liberia. Research staff called caregivers to ascertain vital status up to 60 days after discharge. We conducted multivariable logistic regression analyses with best subset selection to identify socioeconomic, demographic, clinical, and anthropometric factors associated with post-discharge mortality. We used adjusted log coefficients to assign points to each variable and internally validated our tool with bootstrap validation with 500 repetitions. RESULTS: There were 2344 neonates discharged and 2310 (98.5%) had post-discharge outcomes available. The median (IQR) age at discharge was 8 (4, 15) days; 1238 (53.6%) were male. In total, 71 (3.1%) died during follow-up (26.8% within 7 days of discharge). Leaving against medical advice (adjusted OR [aOR] 5.62, 95% CI 2.40 to 12.10) and diagnosis of meconium aspiration (aOR 6.98, 95% CI 1.69 to 21.70) conferred the greatest risk for post-discharge mortality. The risk assessment tool included nine variables (total possible score=63) and had an optimism corrected area under the receiver operating characteristic curve of 0.77 (95% CI 0.75 to 0.80). A score of ≥6 was most optimal (sensitivity 68.3% [95% CI 64.8% to 71.5%], specificity 72.1% [95% CI 71.5% to 72.7%]). CONCLUSIONS: A small number of factors predicted all-cause, 60-day mortality after discharge from neonatal wards in Tanzania and Liberia. After external validation, this risk assessment tool may facilitate clinical decision making for eligibility for discharge and the direction of resources to follow-up high risk neonates.

Factors associated with D-lactic acidosis in pediatric intestinal failure: A case-control study.

BACKGROUND: D-lactic acidosis (DLA) is a serious complication of short bowel syndrome (SBS) in children with intestinal failure (IF). Malabsorbed carbohydrates are metabolized by bacteria in the intestine to D-lactate which can lead to metabolic acidosis and neurologic symptoms. METHODS: A retrospective chart review was performed in children ≤18 years old with SBS who had one of the following criteria: unexplained metabolic acidosis, neurologic signs or symptoms, history of antibiotic therapy for small bowel bacterial overgrowth, or high clinical suspicion of DLA. Cases had serum D-lactate concentration >0.25 mmol/L; controls with concentrations ≤0.25 mmol/L. RESULTS: Of forty-six children, median age was 3.16 (interquartile range (IQR): 1.98, 5.82) years, and median residual bowel length was 40 (IQR: 25, 59) cm. There were 23 cases and 23 controls. Univariate analysis showed that cases had significantly lower median bicarbonate (19 vs. 24 mEq/L, p = 0.001), higher anion gap (17 vs. 14 mEq/L, p < 0.001) and were less likely to be receiving parenteral nutrition, compared with children without DLA. Multivariable analysis identified midgut volvulus, history of intestinal lengthening procedure, and anion gap as significant independent risk factors. Midgut volvulus was the strongest independent factor associated with DLA (adjusted odds ratio = 17.1, 95% CI: 2.21, 133, p = 0.007). CONCLUSION: DLA is an important complication of pediatric IF due to SBS. Patients with IF, particularly those with history of midgut volvulus, having undergone intestinal lengthening, or with anion gap acidosis, should be closely monitored for DLA.

Risk factors for moderate acute malnutrition among children with acute diarrhoea in India and Tanzania: a secondary analysis of data from a randomized trial.

BACKGROUND: Moderate acute malnutrition (MAM) affects over 30 million children aged < 5 years worldwide. MAM may confer a greater risk of developing severe malnutrition and even mortality in children. Assessing risk factors for MAM may allow for earlier recognition of children at risk of deleterious health outcomes. OBJECTIVE: To determine risk factors associated with the prevalence and development of MAM among children aged 6 to 59 months with acute diarrhoea who received treatment with oral rehydration solution and zinc supplementation. METHODS: We conducted a secondary analysis of data from a randomized, dose-finding trial of zinc among children with acute diarrhoea in India and Tanzania. We used regression models to assess risk factors for prevalent MAM at the start of diarrhoea treatment and to identify risk factors associated with the development of MAM at 60 days. MAM was defined as weight for length (or height) Z score ≤-2 and > -3 or mid-upper arm circumference < 12.5 and ≥ 11.5 cm. RESULTS: A total of 4,500 children were enrolled; 593 (13.2%) had MAM at the baseline. MAM at baseline was significantly less common among children in Tanzania than in India (adjusted risk ratio [aRR] 0.37, 95% confidence interval [CI]: 0.30, 0.44, P < 0.001), in children aged 24- < 60 months versus 6- < 12 months (aRR 0.46, 95% CI: 0.38, 0.56, P < 0.001), and in families with household wealth index higher than the median (aRR 0.79, 95% CI: 0.68, 0.92, P = 0.002). Sixty days after outpatient treatment and follow-up, 87 (2.5%) children developed MAM. When compared to children aged 6- < 12 months, children aged 24- < 60 months had a 52% lower risk of developing MAM. Every one unit increase in weight for length (or height) Z score at enrolment was associated with a 93% lower risk of developing MAM during follow-up. CONCLUSIONS: Among children with diarrhoea, younger children and those from households with lower wealth were at greater risk of MAM. These children may benefit from targeted interventions focusing on feeding (targeted nutrition support for at-risk households) and follow up in order to reduce the occurrence of MAM and its consequences.

Two Randomized Trials of Low-Dose Calcium Supplementation in Pregnancy.

BACKGROUND: The World Health Organization recommends 1500 to 2000 mg of calcium daily as supplementation, divided into three doses, for pregnant persons in populations with low dietary calcium intake in order to reduce the risk of preeclampsia. The complexity of the dosing scheme, however, has led to implementation barriers. METHODS: We conducted two independent randomized trials of calcium supplementation, in India and Tanzania, to assess the noninferiority of a 500-mg daily dose to a 1500-mg daily dose of calcium supplementation. In each trial, the two primary outcomes were preeclampsia and preterm birth, and the noninferiority margins for the relative risks were 1.54 and 1.16, respectively. RESULTS: A total of 11,000 nulliparous pregnant women were included in each trial. The cumulative incidence of preeclampsia was 3.0% in the 500-mg group and 3.6% in the 1500-mg group in the India trial (relative risk, 0.84; 95% confidence interval [CI], 0.68 to 1.03) and 3.0% and 2.7%, respectively, in the Tanzania trial (relative risk, 1.10; 95% CI, 0.88 to 1.36) - findings consistent with the noninferiority of the lower dose in both trials. The percentage of live births that were preterm was 11.4% in the 500-mg group and 12.8% in the 1500-mg group in the India trial (relative risk, 0.89; 95% CI, 0.80 to 0.98), which was within the noninferiority margin of 1.16; in the Tanzania trial, the respective percentages were 10.4% and 9.7% (relative risk, 1.07; 95% CI, 0.95 to 1.21), which exceeded the noninferiority margin. CONCLUSIONS: In these two trials, low-dose calcium supplementation was noninferior to high-dose calcium supplementation with respect to the risk of preeclampsia. It was noninferior with respect to the risk of preterm live birth in the trial in India but not in the trial in Tanzania. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT03350516; Clinical Trials Registry-India number, CTRI/2018/02/012119; and Tanzania Medicines and Medical Devices Authority Trials Registry number, TFDA0018/CTR/0010/5).

Stress Ulcer Prophylaxis Versus Placebo-A Blinded Pilot Randomized Controlled Trial to Evaluate the Safety of Two Strategies in Critically Ill Infants With Congenital Heart Disease.

OBJECTIVES: The routine use of stress ulcer prophylaxis (SUP) in infants with congenital heart disease (CHD) in the cardiac ICU (CICU) is controversial. We aimed to conduct a pilot study to explore the feasibility of performing a subsequent larger trial to assess the safety and efficacy of withholding SUP in this population (NCT03667703). DESIGN, SETTING, PATIENTS: Single-center, prospective, double-blinded, parallel group (SUP vs. placebo), pilot randomized controlled pilot trial (RCT) in infants with CHD admitted to the CICU and anticipated to require respiratory support for greater than 24 hours. INTERVENTIONS: Patients were randomized 1:1 (stratified by age and admission type) to receive a histamine-2 receptor antagonist or placebo until respiratory support was discontinued, up to 14 days, or transfer from the CICU, if earlier. MEASUREMENTS AND MAIN RESULTS: Feasibility was defined a priori by thresholds of screening rate, consent rate, timely drug allocation, and protocol adherence. The safety outcome was the rate of clinically significant upper gastrointestinal (UGI) bleeding. We screened 1,426 patients from February 2019 to March 2022; of 132 eligible patients, we gained informed consent in 70 (53%). Two patients did not require CICU admission after obtaining consent, and the remaining 68 patients were randomized to SUP (n = 34) or placebo (n = 34). Ten patients were withdrawn early, because of a change in eligibility (n = 3) or open-label SUP use (n = 7, 10%). Study procedures were completed in 58 patients (89% protocol adherence). All feasibility criteria were met. There were no clinically significant episodes of UGI bleeding during the pilot RCT. The percentage of patients with other nonserious adverse events did not differ between groups. CONCLUSIONS: Withholding of SUP in infants with CHD admitted to the CICU was feasible. A larger multicenter RCT designed to confirm the safety of this intervention and its impact on incidence of UGI bleeding, gastrointestinal microbiome, and other clinical outcomes is warranted.

Azithromycin for Bacterial Watery Diarrhea: A Reanalysis of the AntiBiotics for Children With Severe Diarrhea (ABCD) Trial Incorporating Molecular Diagnostics.

BACKGROUND: Bacterial pathogens cause substantial diarrhea morbidity and mortality among children living in endemic settings, yet antimicrobial treatment is only recommended for dysentery or suspected cholera. METHODS: AntiBiotics for Children with severe Diarrhea was a 7-country, placebo-controlled, double-blind efficacy trial of azithromycin in children 2-23 months of age with watery diarrhea accompanied by dehydration or malnutrition. We tested fecal samples for enteric pathogens utilizing quantitative polymerase chain reaction to identify likely and possible bacterial etiologies and employed pathogen-specific cutoffs based on genomic target quantity in previous case-control diarrhea etiology studies to identify likely and possible bacterial etiologies. RESULTS: Among 6692 children, the leading likely etiologies were rotavirus (21.1%), enterotoxigenic Escherichia coli encoding heat-stable toxin (13.3%), Shigella (12.6%), and Cryptosporidium (9.6%). More than one-quarter (1894 [28.3%]) had a likely and 1153 (17.3%) a possible bacterial etiology. Day 3 diarrhea was less common in those randomized to azithromycin versus placebo among children with a likely bacterial etiology (risk difference [RD]likely, -11.6 [95% confidence interval {CI}, -15.6 to -7.6]) and possible bacterial etiology (RDpossible, -8.7 [95% CI, -13.0 to -4.4]) but not in other children (RDunlikely, -0.3% [95% CI, -2.9% to 2.3%]). A similar association was observed for 90-day hospitalization or death (RDlikely, -3.1 [95% CI, -5.3 to -1.0]; RDpossible, -2.3 [95% CI, -4.5 to -.01]; RDunlikely, -0.6 [95% CI, -1.9 to .6]). The magnitude of risk differences was similar among specific likely bacterial etiologies, including Shigella. CONCLUSIONS: Acute watery diarrhea confirmed or presumed to be of bacterial etiology may benefit from azithromycin treatment. CLINICAL TRIALS REGISTRATION: NCT03130114.