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Background: Monitoring of various clinical outcomes and parameters, such as lipid levels, is recommended in transgender individuals undergoing hormone therapies. However, comprehensive data to inform these recommendations is scarce., Objective: This study aims to conduct a systematic review and meta-analysis to synthesize evidence from existing literature on the effect of exogenous hormone therapy on clinical and biochemical outcomes for transgender adolescents and adults., Methods: We will search multiple electronic databases and will include prospective and retrospective observational studies with and without a control group. The study population will include transgender individuals undergoing hormone therapy with testosterone or estrogen. Comparisons will include age-matched, cisgender individuals and changes from baseline. Primary outcomes include changes in or the development of abnormal lipid parameters. Secondary outcomes include BMI, weight, height, and blood pressure for age, serum testosterone or estrogen levels, and development of disease including hypertension, diabetes, fatty liver disease, obesity, adverse cardiac events, as well as all-cause mortality. The meta-analysis will pool the studies where applicable, and meta-regressions will be conducted to evaluate effect modifiers. The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach will be used to evaluate the overall certainty of evidence., Results: We will summarize the selection of the eligible studies using a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flowchart. The results will be presented in a table summarizing the evidence. Data collection is ongoing, and the paper is expected to be published in Spring 2025., Conclusions: This systematic review will summarize and evaluate the evidence of the clinical and biochemical outcomes associated with hormone therapies for transgender individuals., Trial Registration: PROSPERO CRD42024483138; https://tinyurl.com/yc4sfvnb., International Registered Report Identifier (irrid): PRR1-10.2196/57931., (©Emily Sattora, Karen Teelin, Christopher Prendergast, Abigail Smith, James Evans, Aamer Imdad. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 12.11.2024.)

Background/Objectives : Sickle cell disease (SCD) impacts about 100,000 people in the US. SCD increases the risk of cholelithiasis and microvascular ischemia, which could increase the risk of acute pancreatitis (AP). Abdominal pain is a common presenting symptom of AP and sickle cell vaso-occlusive crisis. The purpose of our systematic review is to estimate the prevalence and determine the severity of AP in individuals with SCD compared to the general population. Methods : Multiple electronic databases were searched. We included studies that included children and adults (population) and addressed the association of SCD (exposure) with AP (outcome) compared to the same population without SCD (control). Two authors screened titles and abstracts independently, and data were abstracted in duplication from included studies. We registered this protocol in PROSPERO-CRD42023422397. Results : Out of 296 studies screened from multiple electronic databases, we identified 33 studies. These studies included 17 case reports, one case series, and 15 retrospective cohort studies, and 18 studies included children. Eight of the AP case reports were in patients with HbSS genotype, two with sickle beta thalassemia, and one with HbSoArab, and in six case reports, a genotype was not specified. Complications were reported in 11 cases-respiratory complication (in at least four cases), splenic complications (three cases), pancreatic pseudocyst (two cases) and death from AP (one case). Of the four AP cases in the case series, three had HbSS genotype, and two cases had complications and severe pancreatitis. AP prevalence in SCD was estimated to be 2% and 7% in two retrospective studies, but they lacked a comparison group. In retrospective studies that evaluated the etiology of AP in children, biliary disease caused mostly by SCD was present in approximately 12% and 34%, respectively. Conclusions: Data on the prevalence of AP in individuals with SCD are limited. Prospectively designed studies aiming to proactively evaluate AP in individuals with SCD who present with abdominal pain are needed to improve timely diagnosis of AP in SCD and outcomes.

The recent shortage of pediatric formulas in the United States, caused by supply chain issues and contamination of formula products in 1 of the major manufacturing plants, led many families to seek an alternate formula for their children. The Food and Drug Administration (FDA) allowed import of infant formulas from selected European and non-European countries. The European infant formulas differ from those produced in the United States regarding the primary source of the formula, age category, mixing instructions, labeling requirements, and formula composition in terms of macronutrients and micronutrients. Although most European infant formulas are nutritionally adequate, pediatricians and families need to be aware of the differences between the European and FDA-regulated formulas for their correct use and preparation for infants and young children. Supplementation with cow milk is recommended for children beyond infancy, and older infant formulas are not recommended for otherwise healthy growing children. However, pediatric formulas have been used to support the nutrition needs of children with feeding difficulties, especially those dependent on tube feeding and with certain medical conditions. The FDA does not regulate the production of pediatric formulas beyond infant formula, and significant variations exist in their composition. The pediatric formulas are available as polymeric (intact), hydrolyzed, elemental, or food-based blenderized formulas. The plant-based nonformula (milk) drinks are being used increasingly for children. These products might not be nutritionally complete and should be avoided in infants and children dependent on liquid nutrition., (© American Academy of Pediatrics, 2024. All rights reserved.)

Objectives: Breast milk is the recommended nutritional source for newborns and has been associated with decreased morbidity in low-birth-weight and preterm infants. In situations where breast milk is not available, donor breast milk is an alternative. Milk banking is becoming increasingly common worldwide to meet this need. Although the benefits of donor breast milk for the recipient infant are well established, the health impact on the breast milk donor and the infant of the breast milk donor is an area of current research. We aim to synthesize and evaluate the available evidence regarding the impact of donating breast milk on the health, lactation, and well-being of the breast milk donor, and the health and growth of the infant of the breast milk donor., Methods: We will search electronic databases, grey literature, and the websites of relevant international organizations. We will include studies that involve lactating women and their infants, healthy or with health conditions, who donate breast milk, without restrictions on study date, language, or study design. If sufficient homogeneity exists between studies, we will complete meta-analyses. We will evaluate the risk of bias using the Risk of Bias tool or the Cochrane Risk of Bias in Non-Randomized Studies tool. We will evaluate the overall certainty of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach., Conclusion: In this systematic review and meta-analysis, we will summarize the current literature regarding the effects of human milk donation on human milk donors and their infants., Competing Interests: Dr. Tarah Colaizy is the research director of the research committee of the Human Milk Banking Association of North America (HMBANA). She contributes to this position on a volunteer basis and has never received any honorarium from HMBANA. This proposal was not discussed in the research committee of HMBANA, and HMBANA did not have any role in the design of this study. The remaining authors declare no conflict of interest., (© 2024 The Author(s). JPGN Reports published by Wiley Periodicals LLC on behalf of The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objectives: Human milk has been shown to reduce severe morbidity in preterm/low-birth-weight infants and is therefore the recommended nutritional source. When infants cannot receive maternal milk, donor human milk (DHM) is recommended. The use of human milk banking facilities is increasing to meet the need for DHM. DHM is unique compared to maternal milk as it must be processed and stored. The processing and storage of animal milk has been more rigorously studied than human milk and can serve as proxy to create DHM banking guidelines., Methods and Analysis: We will search electronic databases, grey literature, and the websites of relevant international organizations. We will include studies that evaluated the impact of storage, handling, and treatment on the nutritional quality and safety of animal milk. We will not restrict study date, language, or design. If sufficient homogeneity exists between studies, we will conduct a meta-analysis. We will evaluate the methodological quality of each study using the SYRCLE's (Systematic Review Centre for Laboratory Animal Experimentation) risk of bias tool. (1) We will evaluate the overall certainty of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach., Conclusion: In this systematic review and meta-analysis, commissioned by the World Health Organization, we will synthesize the available literature regarding the impact of various storage, handling, and treatment practices on the nutritional quality and safety of animal milk., Competing Interests: Dr. Colaizy is the research director of the research committee of the Human Milk Banking Association of North America (HMBANA). She contributes to this position on a volunteer basis and has never received any honorarium from HMBANA. This proposal was not discussed in the research committee of HMBANA, and HMBANA did not have any role in the design of this study. The remaining authors declare no conflict of interest., (© 2024 The Author(s). JPGN Reports published by Wiley Periodicals LLC on behalf of The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Introduction: The underdevelopment of preterm infants can lead to delayed progression through key early milestones. Demonstration of safe oral feeding skills, constituting proper suck-swallow reflex are requirements for discharge from the neonatal intensive care unit (NICU) to ensure adequate nutrition acquisition. Helping an infant develop these skills can be draining and emotional for both families and healthcare staff involved in the care of preterm infants with feeding difficulties. Currently, there are no systematic reviews evaluating both family and healthcare team perspectives on aspects of oral feeding. Thus, we first aim to evaluate the current knowledge surrounding the perceptions, experiences and needs of families with preterm babies in the context of oral feeding in the NICU. Second, we aim to evaluate the current knowledge surrounding the perceptions, experiences and needs of healthcare providers (physicians, advanced practice providers, nurses, dietitians, speech-language pathologists and occupational therapists) in the context of oral feeding in the NICU., Methods and Analysis: A literature search will be conducted in multiple electronic databases from their inception, including PubMed, CINHAL, Embase, the Cochrane Central Register for Controlled Trials and PsycINFO. No restrictions will be applied based on language or data of publication. Two authors will screen the titles and abstracts and then review the full text for the studies' inclusion in the review. The data will be extracted into a pilot-tested data collection sheet by three independent authors. To evaluate the quality, reliability and relevance of the included studies, the Critical Appraisal Skills Programme checklist will be used. The overall evidence will be assessed using the Grading of Recommendation Assessment, Development and Evaluation criteria. We will report the results of the systematic review by following the Enhancing Transparency in Reporting the synthesis of Qualitative research checklist., Ethics and Dissemination: Ethical approval of this project is not required as this is a systematic review using published and publicly available data and will not involve contact with human subjects. Findings will be published in a peer-reviewed journal., Prospero Registration Number: CRD42023479288., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Chronic constipation is a common condition in pediatric patients worldwide and is associated with decreased quality of life. Inpatient management of constipation is required when outpatient therapy fails and a child becomes obstipated, and unable to pass stool or gas. There is a growing body of evidence regarding different management strategies for pediatric obstipation. This scoping review aims to map the existing literature regarding inpatient management of pediatric obstipation and identify gaps in knowledge., Methods: We will follow the methodology described by the Joanna Briggs Institute and outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines. The search strategy will include Embase, PubMed, CINAHL, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Web of Science, Scopus, and gray literature sources. Two independent reviewers will complete screening for eligible studies in two steps: a scan of the title and abstracts followed by a full-text review. Studies regarding inpatient management of pediatric obstipation, with experimental or cohort design, and with full text available in English will be included. Systematic reviews will also be included. Two independent reviewers will extract data using a standardized form. Extracted data will be presented in visual and narrative formats, including an evidence map to meet the objectives of this scoping review. This protocol is registered at Open Science Framework., Conclusion: In this scoping review, we will outline the current evidence available regarding the efficacy and safety of various hospital interventions for the treatment of pediatric obstipation., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. JPGN Reports published by Wiley Periodicals LLC on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Introduction: Gastrointestinal hospitalisations in the USA cause over US$130 billion in expenditures, and acute pancreatitis is a leading cause of these hospitalisations. Adequate pain control is one of the primary treatment goals for acute pancreatitis. Though opioids are commonly used for analgesia in these patients, there have been concerns about short-term and long-term side effects of using opioids. Recently, non-opioid medications have been studied to treat pain in patients with acute pancreatitis. This systematic review and network meta-analysis aims to assess the comparative efficacy of analgesic medication for non-severe, acute pancreatitis., Methods and Analysis: We will search multiple electronic databases for randomised controlled trials that study pain management in patients with non-severe, acute pancreatitis. The intervention will be any analgesic for acute pancreatitis in the hospital setting. The comparison group will be patients who received a placebo or other active interventions for pain management. The primary outcomes of interest include pain scores and the need for supplementary analgesia. The secondary outcomes will be serious adverse events, local complications, progression to severe pancreatitis, transfer to the intensive care unit, length of hospitalisation, time to start enteral feeds, 30-day all-cause mortality and Quality of Life Scale scores. If sufficient homogeneity exists among included studies, the findings will be pooled using a traditional pairwise and network meta-analysis. The risk of bias in randomised control trials will be evaluated using the Cochrane Risk of Bias Tool 2.0. The Grading of Recommendations, Assessment, Development, and Evaluation approach will be used to report the certainty of evidence., Ethics and Dissemination: This systematic review will not involve direct contact with human subjects. The findings of this review will be published in a peer-reviewed journal. They will give healthcare providers a better awareness of the optimal analgesic medication for pain treatment in non-severe, acute pancreatitis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: Fecal microbiota-based therapies include conventional fecal microbiota transplant and US Food and Drug Administration-approved therapies, fecal microbiota live-jslm and fecal microbiota spores live-brpk. The American Gastroenterological Association (AGA) developed this guideline to provide recommendations on the use of fecal microbiota-based therapies in adults with recurrent Clostridioides difficile infection; severe to fulminant C difficile infection; inflammatory bowel diseases, including pouchitis; and irritable bowel syndrome., Methods: The guideline was developed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) framework to prioritize clinical questions, identify patient-centered outcomes, and conduct an evidence synthesis. The guideline panel used the Evidence-to-Decision framework to develop recommendations for the use of fecal microbiota-based therapies in the specified gastrointestinal conditions and provided implementation considerations for clinical practice., Results: The guideline panel made 7 recommendations. In immunocompetent adults with recurrent C difficile infection, the AGA suggests select use of fecal microbiota-based therapies on completion of standard of care antibiotics to prevent recurrence. In mildly or moderately immunocompromised adults with recurrent C difficile infection, the AGA suggests select use of conventional fecal microbiota transplant. In severely immunocompromised adults, the AGA suggests against the use of any fecal microbiota-based therapies to prevent recurrent C difficile. In adults hospitalized with severe or fulminant C difficile not responding to standard of care antibiotics, the AGA suggests select use of conventional fecal microbiota transplant. The AGA suggests against the use of conventional fecal microbiota transplant as treatment for inflammatory bowel diseases or irritable bowel syndrome, except in the context of clinical trials., Conclusions: Fecal microbiota-based therapies are effective therapy to prevent recurrent C difficile in select patients. Conventional fecal microbiota transplant is an adjuvant treatment for select adults hospitalized with severe or fulminant C difficile infection not responding to standard of care antibiotics. Fecal microbiota transplant cannot yet be recommended in other gastrointestinal conditions., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: Probiotic supplementation has been proposed as a therapeutic intervention to improve growth outcomes in children with undernutrition. The objective of this review is to synthesize the current evidence on probiotic supplementation for promotion of growth in undernourished children., Methods: We searched MEDLINE, Cochrane CENTRAL, CINAHL, Embase, LILACS, and Scopus for randomized controlled trials (RCTs) that administered probiotics or eligible comparators to undernourished children below 5 years of age. Our primary outcomes of interest were weight-for-age, height-for-age, and weight-for-height at the longest follow-up points reported. Random-effects meta-analysis was used to calculate standardized mean differences (SMD) for continuous outcomes and risk ratios for dichotomous outcomes. The Grading of Recommendations Assessment, Development and Evaluation criteria were used to assess certainty of the evidence., Results: Nine RCTs with 5295 children in total were included. Durations of treatment ranged from 1 month to 1 year. Pooled analyses from 7 studies showed that probiotics may have little to no effect on weight-for-age (SMD 0.05 standard deviation [SD], 95% CI: -0.04 to 0.13, n = 2115 children; low-certainty evidence) and height-for-age (SMD -0.04 SD, 95% CI: -0.14 to 0.07, n = 1357 children; low-certainty evidence). The evidence was very uncertain about the effect on weight-for-height., Conclusions: Probiotics may have little to no effect on anthropometry in undernourished children, though there is considerable heterogeneity among the trials reviewed thus far. The interaction between gut microbiota and human nutrition is complex, and further research is needed to determine how the gut microbiome may contribute to undernutrition and how probiotics may affect growth in this vulnerable population., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

In pregnancies complicated by sickle cell disease (SCD), the maternal-fetal dyad is at high risk for mortality and morbidity. In healthy pregnancies, maternal nutritional status is a critical factor for the healthy growth and development of the fetus. However, there are no reviews of the current research on the nutritional status of pregnant women with SCD and pregnancy outcomes. First, we aim to assess the burden of malnutrition in pregnant women with SCD. Next, we aim to systematically evaluate if pregnant women with SCD who have poor nutritional status are at increased risk for adverse birth outcomes compared to pregnant women with sickle cell disease and normal nutritional status. We will systematically search multiple electronic databases. Our exposure is pregnant women with SCD and poor nutritional status. The primary outcomes of interest include low birth weight (categorical) and birth weight z-scores (continuous). We will also evaluate maternal and perinatal outcomes as secondary outcomes. We will evaluate the risk of bias and overall certainty of evidence with Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I), and the overall evidence will be assessed using Grading of Recommendation Assessment, Development, and Evaluation (GRADE) criteria. We will pool findings with a meta-analysis if sufficient homogeneity exists among studies. Findings will be published in a peer-reviewed journal and disseminated to SCD advocacy groups. PROSPERO registration number: 429412.

Abstract: Gastroesophageal reflux (GER) is a common physiologic occurrence in infants, children, and adolescents and can develop into a pathological process (GERD) with associated complications. Gastroesophageal reflux is reported in approximately 30% of healthy infants, with a peak age of 3 to 4 months and is a common concern from families presenting to the emergency department. Evaluation and diagnosis of GER/GERD is primarily clinical and requires a detailed history, a complete physical examination, and exclusion of more severe extraesophageal pathologies. A high index of suspicion for GERD should be considered in patients with recurrent respiratory symptoms, difficulty with weight gain, and children with medically complex conditions who would be at higher risk for these complications. This review will briefly discuss diagnostic studies for the evaluation of GER/GERD; however, these are not helpful in the acute care setting and should be reserved for evaluation by a subspecialist. Management of GER/GERD includes nonmedication management with reflux precautions and dietary/lifestyle modifications; medication management with proton-pump inhibitors, H2 blockers, antacids, or prokinetics, as well as surgical management for refractory or high-risk cases., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Suboptimal complementary feeding practices remain highly prevent. This review aims to comprehensively synthesize new emerging evidence on a set of topics related to the selection and consumption of complementary foods. We synthesized evidence related to five key topics focused on nutritional interventions that target the complementary feeding period, based on four systematic reviews that include updated evidence to February 2022. While there have been many studies examining interventions during the complementary feeding period, there is an overall lack of relevant information through which to draw conclusions on the ideal feeding schedule by food type. Similarly, few studies have examined the effects of animal milk versus infant formula for non-breastfed infants (6-11 months), though those that did found a greater risk of anemia among infants who were provided cow's milk. This review highlights a number of interventions that are successful at improving micronutrient status and anthropometry during the complementary feeding period, including fortified blended foods, locally and commercially produced supplementary foods, and small-quantity lipid-based nutrient supplements. Complementary feeding education for caregivers can also be used to improve nutrition outcomes among infants in both food secure and insecure populations.

This study was a systematic review and meta-analysis that assessed the risk of aspiration pneumonia in children with laryngeal penetration or tracheal aspiration via a video-fluoroscopic study (VFSS) and compared the results to those for children with neither condition. Systematic searches were conducted using databases, including PubMed, Cochrane Library, and Web of Science. Meta-analysis was used to obtain summary odds ratios (OR) and 95% confidence intervals (CI). The overall quality of evidence was assessed using the grading of recommendations, assessment, development, and evaluation (GRADE) criteria. In total, 13 studies were conducted with 3159 participants. Combined results from six studies showed that laryngeal penetration on VFSS may be associated with aspiration pneumonia compared to no laryngeal penetration; however, the summary estimate was imprecise and included the possibility of no association (OR 1.44, 95% CI 0.94, 2.19, evidence certainty: low). Data from seven studies showed that tracheal aspiration might be associated with aspiration pneumonia compared to no tracheal aspiration (OR 2.72, 95% CI 1.86, 3.98, evidence certainty: moderate). The association between aspiration pneumonia and laryngeal penetration through VFSS seems to be weaker than that for tracheal aspiration. Prospective cohort studies with clear definitions of laryngeal penetration and that measure clinical and patient reported outcomes are needed to further define the association between laryngeal penetration and aspiration pneumonia.

Introduction: Chronic idiopathic constipation (CIC) is a common disorder associated with significant impairment in quality of life. This clinical practice guideline, jointly developed by the American Gastroenterological Association and the American College of Gastroenterology, aims to inform clinicians and patients by providing evidence-based practice recommendations for the pharmacological treatment of CIC in adults., Methods: The American Gastroenterological Association and the American College of Gastroenterology formed a multidisciplinary guideline panel that conducted systematic reviews of the following agents: fiber, osmotic laxatives (polyethylene glycol, magnesium oxide, lactulose), stimulant laxatives (bisacodyl, sodium picosulfate, senna), secretagogues (lubiprostone, linaclotide, plecanatide), and serotonin type 4 agonist (prucalopride). The panel prioritized clinical questions and outcomes and used the Grading of Recommendations Assessment, Development, and Evaluation framework to assess the certainty of evidence for each intervention. The Evidence to Decision framework was used to develop clinical recommendations based on the balance between the desirable and undesirable effects, patient values, costs, and health equity considerations., Results: The panel agreed on 10 recommendations for the pharmacological management of CIC in adults. Based on available evidence, the panel made strong recommendations for the use of polyethylene glycol, sodium picosulfate, linaclotide, plecanatide, and prucalopride for CIC in adults. Conditional recommendations were made for the use of fiber, lactulose, senna, magnesium oxide, and lubiprostone., Discussion: This document provides a comprehensive outline of the various over-the-counter and prescription pharmacological agents available for the treatment of CIC. The guidelines are meant to provide a framework for approaching the management of CIC; clinical providers should engage in shared decision making based on patient preferences as well as medication cost and availability. Limitations and gaps in the evidence are highlighted to help guide future research opportunities and enhance the care of patients with chronic constipation., (Copyright © 2023 by The American College of Gastroenterology and the American Gastroenterological Association.)

Introduction: Chronic idiopathic constipation (CIC) is a common disorder associated with significant impairment in quality of life. This clinical practice guideline, jointly developed by the American Gastroenterological Association and the American College of Gastroenterology, aims to inform clinicians and patients by providing evidence-based practice recommendations for the pharmacological treatment of CIC in adults., Methods: The American Gastroenterological Association and the American College of Gastroenterology formed a multidisciplinary guideline panel that conducted systematic reviews of the following agents: fiber, osmotic laxatives (polyethylene glycol, magnesium oxide, lactulose), stimulant laxatives (bisacodyl, sodium picosulfate, senna), secretagogues (lubiprostone, linaclotide, plecanatide), and serotonin type 4 agonist (prucalopride). The panel prioritized clinical questions and outcomes and used the Grading of Recommendations Assessment, Development, and Evaluation framework to assess the certainty of evidence for each intervention. The Evidence to Decision framework was used to develop clinical recommendations based on the balance between the desirable and undesirable effects, patient values, costs, and health equity considerations., Results: The panel agreed on 10 recommendations for the pharmacological management of CIC in adults. Based on available evidence, the panel made strong recommendations for the use of polyethylene glycol, sodium picosulfate, linaclotide, plecanatide, and prucalopride for CIC in adults. Conditional recommendations were made for the use of fiber, lactulose, senna, magnesium oxide, and lubiprostone., Discussion: This document provides a comprehensive outline of the various over-the-counter and prescription pharmacological agents available for the treatment of CIC. The guidelines are meant to provide a framework for approaching the management of CIC; clinical providers should engage in shared decision making based on patient preferences as well as medication cost and availability. Limitations and gaps in the evidence are highlighted to help guide future research opportunities and enhance the care of patients with chronic constipation., (Copyright © 2023. Published by Elsevier Inc.)

Objective: This systematic review commissioned by WHO aimed to synthesise evidence from current literature on the effects of systematically given, routine use of antibiotics for infants under 6 months of age with growth failure/faltering., Settings: Low-income and middle-income countries., Participants: The study population was infants less than 6 months of age with growth failure/faltering., Intervention: The intervention group was infants who received no antibiotics or antibiotics other than those recommended in 2013 guidelines by WHO to treat childhood severe acute malnutrition. The comparison group was infants who received antibiotics according to the aforementioned guidelines., Primary and Secondary Outcomes: The primary outcome was all-cause mortality, and secondary outcomes: clinical deterioration, antimicrobial resistance, recovery from comorbidity, adverse events, markers of intestinal inflammation, markers of systemic inflammation, hospital-acquired infections and non-response. The Grading of Recommendations Assessment, Development and Evaluation approach was considered to report the overall evidence quality for an outcome., Results: We screened 5137 titles and abstracts and reviewed the full text of 157 studies. None of the studies from the literature search qualified to answer the question for this systematic review., Conclusions: There is a paucity of evidence on the routine use of antibiotics for the treatment of malnutrition in infants less than 6 months of age. Future studies with adequate sample sizes are needed to assess the potential risks and benefits of antibiotics in malnourished infants under 6 months of age., Prospero Registration Number: CRD42021277073., Competing Interests: Competing interests: None declared., (© World Health Organization 2023. Licensee BMJ.)

Background: Inflammatory bowel disease (IBD) is a chronic, relapsing disease of the gastrointestinal (GI) tract that is thought to be associated with a complex interplay between the immune system, the GI tract lining, the environment, and the gut microbiome, leading to an abnormal inflammatory response in genetically susceptible individuals. An altered composition of the gut's native microbiota, known as dysbiosis, may have a major role in the pathogenesis of ulcerative colitis (UC) and Crohn disease (CD), two subtypes of IBD. There is growing interest in the correction of this underlying dysbiosis using fecal microbiota transplantation (FMT)., Objectives: To evaluate the benefits and safety profile of FMT for treatment of IBD in adults and children versus autologous FMT, placebo, standard medication, or no intervention., Search Methods: We searched CENTRAL, MEDLINE, Embase, two clinical trial registries, and the reference sections of published trials through 22 December 2022., Selection Criteria: We included randomized controlled trials that studied adults and children with UC or CD. Eligible intervention arms used FMT, defined as the delivery of healthy donor stool containing gut microbiota to a recipient's GI tract, to treat UC or CD., Data Collection and Analysis: Two review authors independently screened studies for inclusion. Our primary outcomes were: 1. induction of clinical remission, 2. maintenance of clinical remission, and 3. serious adverse events. Our secondary outcomes were: 4. any adverse events, 5. endoscopic remission, 6. quality of life, 7. clinical response, 8. endoscopic response, 9. withdrawals, 10. inflammatory markers, and 11. microbiome outcomes. We used the GRADE approach to assess the certainty of evidence., Main Results: We included 12 studies with 550 participants. Three studies were conducted in Australia; two in Canada; and one in each of the following: China, the Czech Republic, France, India, the Netherlands, and the USA. One study was conducted in both Israel and Italy. FMT was administered in the form of capsules or suspensions and delivered by mouth, nasoduodenal tube, enema, or colonoscopy. One study delivered FMT by both oral capsules and colonoscopy. Six studies were at overall low risk of bias, while the others had either unclear or high risk of bias. Ten studies with 468 participants, of which nine studies focused on adults and one focused on children, reported induction of clinical remission in people with UC at longest follow-up (range 6 to 12 weeks) and showed that FMT may increase rates of induction of clinical remission in UC compared to control (risk ratio (RR) 1.79, 95% confidence interval (CI) 1.13 to 2.84; low-certainty evidence). Five studies showed that FMT may increase rates of induction of endoscopic remission in UC at longest follow-up (range 8 to 12 weeks); however, the CIs around the summary estimate were wide and included a possible null effect (RR 1.45, 95% CI 0.64 to 3.29; low-certainty evidence). Nine studies with 417 participants showed that FMT may result in little to no difference in rates of any adverse events (RR 0.99, 95% CI 0.85 to 1.16; low-certainty evidence). The evidence was very uncertain about the risk of serious adverse events (RR 1.77, 95% CI 0.88 to 3.55; very low-certainty evidence) and improvement in quality of life (mean difference (MD) 15.34, 95% CI -3.84 to 34.52; very low-certainty evidence) when FMT was used to induce remission in UC. Two studies, of which one also contributed data for induction of remission in active UC, assessed maintenance of remission in people with controlled UC at longest follow-up (range 48 to 56 weeks). The evidence was very uncertain about the use of FMT for maintenance of clinical remission (RR 2.97, 95% CI 0.26 to 34.42; very low-certainty evidence) and endoscopic remission (RR 3.28, 95% CI 0.73 to 14.74; very low-certainty evidence). The evidence was also very uncertain about the risk of serious adverse events, risk of any adverse events, and improvement in quality of life when FMT was used to maintain remission in UC. None of the included studies assessed use of FMT for induction of remission in people with CD. One study with 21 participants reported data on FMT for maintenance of remission in people with CD. The evidence was very uncertain about the use of FMT for maintenance of clinical remission in CD at 24 weeks (RR 1.21, 95% CI 0.36 to 4.14; very low-certainty evidence). The evidence was also very uncertain about the risk of serious or any adverse events when FMT was used to maintain remission in CD. None of the studies reported data on use of FMT for maintenance of endoscopic remission or improvement in quality of life in people with CD., Authors' Conclusions: FMT may increase the proportion of people with active UC who achieve clinical and endoscopic remission. The evidence was very uncertain about whether use of FMT in people with active UC impacted the risk of serious adverse events or improvement in quality of life. The evidence was also very uncertain about the use of FMT for maintenance of remission in people with UC, as well as induction and maintenance of remission in people with CD, and no conclusive statements could be made in this regard. Further studies are needed to address the beneficial effects and safety profile of FMT in adults and children with active UC and CD, as well as its potential to promote longer-term maintenance of remission in UC and CD., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Clostridioides difficile (formerly known as Clostridium difficile) is a bacterium that can cause potentially life-threatening diarrheal illness in individuals with an unhealthy mixture of gut bacteria, known as dysbiosis, and can cause recurrent infections in nearly a third of infected individuals. The traditional treatment of recurrent C difficile infection (rCDI) includes antibiotics, which may further exacerbate dysbiosis. There is growing interest in correcting the underlying dysbiosis in rCDI using of fecal microbiota transplantation (FMT); and there is a need to establish the benefits and harms of FMT for the treatment of rCDI based on data from randomized controlled trials., Objectives: To evaluate the benefits and harms of donor-based fecal microbiota transplantation for the treatment of recurrent Clostridioides difficile infection in immunocompetent people., Search Methods: We used standard, extensive Cochrane search methods. The latest search date was 31 March 2022., Selection Criteria: We considered randomized trials of adults or children with rCDI for inclusion. Eligible interventions must have met the definition of FMT, which is the administration of fecal material containing distal gut microbiota from a healthy donor to the gastrointestinal tract of a person with rCDI. The comparison group included participants who did not receive FMT and were given placebo, autologous FMT, no intervention, or antibiotics with activity against C difficile., Data Collection and Analysis: We used standard Cochrane methods. Our primary outcomes were 1. proportion of participants with resolution of rCDI and 2. serious adverse events. Our secondary outcomes were 3. treatment failure, 4. all-cause mortality, 5. withdrawal from study, 6. rate of new CDI infection after a successful FMT, 7. any adverse event, 8. quality of life, and 9. colectomy. We used the GRADE criteria to assess certainty of evidence for each outcome., Main Results: We included six studies with 320 participants. Two studies were conducted in Denmark, and one each in the Netherlands, Canada, Italy, and the US. Four were single-center and two were multicenter studies. All studies included only adults. Five studies excluded people who were severely immunocompromised, with only one study including 10 participants who were receiving immunosuppressive therapy out of the 64 enrolled; these were similarly distributed between the FMT arm (4/24 or 17%) and comparison arms (6/40 or 15%). The route of administration was the upper gastrointestinal tract via a nasoduodenal tube in one study, two studies used enema only, two used colonoscopic only delivery, and one used either nasojejunal or colonoscopic delivery, depending on a clinical determination of whether the recipient could tolerate a colonoscopy. Five studies had at least one comparison group that received vancomycin. The risk of bias (RoB 2) assessments did not find an overall high risk of bias for any outcome. All six studies assessed the efficacy and safety of FMT for the treatment of rCDI. Pooled results from six studies showed that the use of FMT in immunocompetent participants with rCDI likely leads to a large increase in resolution of rCDI in the FMT group compared to control (risk ratio (RR) 1.92, 95% confidence interval (CI) 1.36 to 2.71; P = 0.02, I 2 = 63%; 6 studies, 320 participants; number needed to treat for an additional beneficial outcome (NNTB) 3; moderate-certainty evidence). Fecal microbiota transplantation probably results in a slight reduction in serious adverse events; however, the CIs around the summary estimate were wide (RR 0.73, 95% CI 0.38 to 1.41; P = 0.24, I² = 26%; 6 studies, 320 participants; NNTB 12; moderate-certainty evidence). Fecal microbiota transplantation may result in a reduction in all-cause mortality; however, the number of events was small, and the CIs of the summary estimate were wide (RR 0.57, 95% CI 0.22 to 1.45; P = 0.48, I 2 = 0%; 6 studies, 320 participants; NNTB 20; low-certainty evidence). None of the included studies reported colectomy rates., Authors' Conclusions: In immunocompetent adults with rCDI, FMT likely leads to a large increase in the resolution of recurrent Clostridioides difficile infection compared to alternative treatments such as antibiotics. There was no conclusive evidence regarding the safety of FMT for the treatment of rCDI as the number of events was small for serious adverse events and all-cause mortality. Additional data from large national registry databases might be required to assess any short-term or long-term risks with using FMT for the treatment of rCDI. Elimination of the single study that included some immunocompromised people did not alter these conclusions. Due to the low number of immunocompromised participants enrolled, conclusions cannot be drawn about the risks or benefits of FMT for rCDI in the immunocompromised population., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Zinc deficiency is prevalent in low- and middle-income countries, and is considered a significant risk factor for morbidity, mortality, and linear growth failure. The effectiveness of preventive zinc supplementation in reducing prevalence of zinc deficiency needs to be assessed., Objectives: To assess the effects of zinc supplementation for preventing mortality and morbidity, and for promoting growth, in children aged 6 months to 12 years., Search Methods: A previous version of this review was published in 2014. In this update, we searched CENTRAL, MEDLINE, Embase, five other databases, and one trials register up to February 2022, together with reference checking and contact with study authors to identify additional studies., Selection Criteria: Randomized controlled trials (RCTs) of preventive zinc supplementation in children aged 6 months to 12 years compared with no intervention, a placebo, or a waiting list control. We excluded hospitalized children and children with chronic diseases or conditions. We excluded food fortification or intake, sprinkles, and therapeutic interventions., Data Collection and Analysis: Two review authors screened studies, extracted data, and assessed the risk of bias. We contacted study authors for missing information and used GRADE to assess the certainty of evidence. The primary outcomes of this review were all-cause mortality; and cause-specific mortality, due to all-cause diarrhea, lower respiratory tract infection (LRTI, including pneumonia), and malaria. We also collected information on a number of secondary outcomes, such as those related to diarrhea and LRTI morbidity, growth outcomes and serum levels of micronutrients, and adverse events., Main Results: We included 16 new studies in this review, resulting in a total of 96 RCTs with 219,584 eligible participants. The included studies were conducted in 34 countries; 87 of them in low- or middle-income countries. Most of the children included in this review were under five years of age. The intervention was delivered most commonly in the form of syrup as zinc sulfate, and the most common dose was between 10 mg and 15 mg daily. The median duration of follow-up was 26 weeks. We did not consider that the evidence for the key analyses of morbidity and mortality outcomes was affected by risk of bias. High-certainty evidence showed little to no difference in all-cause mortality with preventive zinc supplementation compared to no zinc (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.84 to 1.03; 16 studies, 17 comparisons, 143,474 participants). Moderate-certainty evidence showed that preventive zinc supplementation compared to no zinc likely results in little to no difference in mortality due to all-cause diarrhea (RR 0.95, 95% CI 0.69 to 1.31; 4 studies, 132,321 participants); but probably reduces mortality due to LRTI (RR 0.86, 95% CI 0.64 to 1.15; 3 studies, 132,063 participants) and mortality due to malaria (RR 0.90, 95% CI 0.77 to 1.06; 2 studies, 42,818 participants); however, the confidence intervals around the summary estimates for these outcomes were wide, and we could not rule out a possibility of increased risk of mortality. Preventive zinc supplementation likely reduces the incidence of all-cause diarrhea (RR 0.91, 95% CI 0.90 to 0.93; 39 studies, 19,468 participants; moderate-certainty evidence) but results in little to no difference in morbidity due to LRTI (RR 1.01, 95% CI 0.95 to 1.08; 19 studies, 10,555 participants; high-certainty evidence) compared to no zinc. There was moderate-certainty evidence that preventive zinc supplementation likely leads to a slight increase in height (standardized mean difference (SMD) 0.12, 95% CI 0.09 to 0.14; 74 studies, 20,720 participants). Zinc supplementation was associated with an increase in the number of participants with at least one vomiting episode (RR 1.29, 95% CI 1.14 to 1.46; 5 studies, 35,192 participants; high-certainty evidence). We report a number of other outcomes, including the effect of zinc supplementation on weight and serum markers such as zinc, hemoglobin, iron, copper, etc. We also performed a number of subgroup analyses and there was a consistent finding for a number of outcomes that co-supplementation of zinc with iron decreased the beneficial effect of zinc., Authors' Conclusions: Even though we included 16 new studies in this update, the overall conclusions of the review remain unchanged. Zinc supplementation might help prevent episodes of diarrhea and improve growth slightly, particularly in children aged 6 months to 12 years of age. The benefits of preventive zinc supplementation may outweigh the harms in regions where the risk of zinc deficiency is relatively high., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Refugees, immigrants, and migrants (RIM) in the United States (US) have been identified as an underimmunized population prior to the COVID-19 pandemic. Vaccine acceptance is critical to combat the public health threat incited by COVID-19 and other vaccine-preventable disease. To better understand escalating vaccine hesitancy among US RIM, a comprehensive evaluation of the problem and solutions is necessary. In this systematic review, we included 57 studies to describe vaccination rates, barriers, and interventions addressing vaccine hesitancy over the past decade. Meta-analysis was performed among 22 studies, concluding that RIM represent an underimmunized population compared to the general US population. Narrative synthesis and qualitative methods were used to identify critical barriers, including gaps in knowledge, poor access to medical care, and heightened distrust of the medical system. Our results demonstrate the need for effective, evidence-based interventions to increase vaccination rates among diverse RIM populations.

The optimal dose of iron in ready-to-use therapeutic foods (RUTF) used to treat uncomplicated severe acute malnutrition (SAM) in community settings is not well established. The objective of this systematic review was to assess if an increased iron dose in RUTF, compared with the standard iron dose in the World Health Organization (WHO)-recommended peanut-based RUTF, improved outcomes in children aged six months or older. We searched multiple electronic databases and only included randomized controlled trials. We pooled the data in a meta-analysis to obtain relative risk (RR) and reported it with a 95% confidence interval (CI). Three studies, one each from Zambia, the Democratic Republic of Congo, and Malawi, were included. In all studies, the RUTF used in the intervention group was milk-free soya-maize-sorghum-based RUTF. The pooled results showed that, compared to the control group, a high iron content in RUTF may lead to increase in hemoglobin concentration (mean difference 0.33 g/dL, 95% CI: 0.02, 0.64, two studies, certainty of evidence: low) and a decrease in any anemia (RR 0.66, 95% CI: 0.48, 0.91, two studies, certainty of evidence: low), but also decrease recovery rates (RR 0.91, 95% CI: 0.84, 0.99, three studies, certainty of evidence: low) and increase mortality (RR 1.30, 95% CI: 0.87, 1.95, three studies, certainty of evidence: moderate). However, the CIs were imprecise for the latter outcome. Future studies with large sample sizes are needed to confirm the beneficial versus harmful effects of high iron content in RUTF in treating uncomplicated SAM in children aged 6-59 months in community settings.

Introduction: Antibiotics have been used as an adjunct in treating children with severe acute malnutrition 6-59 months of age; however, the data for infants less than 6 months are scarce. The WHO recently started guideline development for preventing and treating wasting, including growth failure/faltering in infants less than 6 months. This systematic review commissioned by WHO aims to synthesise evidence from current literature on the effectiveness of antibiotics for infants less than 6 months of age with growth failure/faltering., Methods and Analysis: We will conduct a systematic review and meta-analysis for studies that assessed the effect of antibiotics in the treatment of infants with growth faltering. We will search multiple electronic databases. We will include randomised control trials and non-randomised studies with a control arm. The study population is infants less than 6 months of age with growth failure. The intervention group will be infants who received no antibiotics or antibiotics other than recommended in 2013 guidelines by WHO to treat severe acute malnutrition in children. The comparison group will be infants who received antibiotics according to the 2013 guideline by WHO. We will consider the following outcomes: mortality, clinical deterioration, antimicrobial resistance, recovery from comorbidity, adverse events, markers of intestinal inflammation, markers of systemic inflammation, hospital-acquired infections, non-response. We will use the meta-analysis to pool the studies where applicable. We will use the Grading of Recommendations Assessment, Development, and Evaluation approach to reporting the overall evidence quality for an outcome., Ethics and Dissemination: This is a systematic review and will not involve contact with a human subject. The findings of this review will be published in a peer-review journal and will guide the WHO's recommendation for the use of antibiotics in infants less than 6 months of age with growth failure., Prospero Registration Number: CRD42021277073., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Vitamin A deficiency (VAD) is a major public health problem in low- and middle-income countries, affecting 190 million children under five years of age and leading to many adverse health consequences, including death. Based on prior evidence and a previous version of this review, the World Health Organization has continued to recommend vitamin A supplementation (VAS) for children aged 6 to 59 months. The last version of this review was published in 2017, and this is an updated version of that review., Objectives: To assess the effects of vitamin A supplementation (VAS) for preventing morbidity and mortality in children aged six months to five years., Search Methods: We searched CENTRAL, MEDLINE, Embase, six other databases, and two trials registers up to March 2021. We also checked reference lists and contacted relevant organisations and researchers to identify additional studies., Selection Criteria: Randomised controlled trials (RCTs) and cluster-RCTs evaluating the effect of synthetic VAS in children aged six months to five years living in the community. We excluded studies involving children in hospital and children with disease or infection. We also excluded studies evaluating the effects of food fortification, consumption of vitamin A rich foods, or beta-carotene supplementation., Data Collection and Analysis: For this update, two review authors independently assessed studies for inclusion resolving discrepancies by discussion. We performed meta-analyses for outcomes, including all-cause and cause-specific mortality, disease, vision, and side effects. We used the GRADE approach to assess the quality of the evidence., Main Results: The updated search identified no new RCTs. We identified 47 studies, involving approximately 1,223,856 children. Studies were set in 19 countries: 30 (63%) in Asia, 16 of these in India; 8 (17%) in Africa; 7 (15%) in Latin America, and 2 (4%) in Australia. About one-third of the studies were in urban/periurban settings, and half were in rural settings; the remaining studies did not clearly report settings. Most studies included equal numbers of girls and boys and lasted about one year. The mean age of the children was about 33 months. The included studies were at variable overall risk of bias; however, evidence for the primary outcome was at low risk of bias. A meta-analysis for all-cause mortality included 19 trials (1,202,382 children). At longest follow-up, there was a 12% observed reduction in the risk of all-cause mortality for VAS compared with control using a fixed-effect model (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.83 to 0.93; high-certainty evidence). Nine trials reported mortality due to diarrhoea and showed a 12% overall reduction for VAS (RR 0.88, 95% CI 0.79 to 0.98; 1,098,538 children; high-certainty evidence). There was no evidence of a difference for VAS on mortality due to measles (RR 0.88, 95% CI 0.69 to 1.11; 6 studies, 1,088,261 children; low-certainty evidence), respiratory disease (RR 0.98, 95% CI 0.86 to 1.12; 9 studies, 1,098,538 children; low-certainty evidence), and meningitis. VAS reduced the incidence of diarrhoea (RR 0.85, 95% CI 0.82 to 0.87; 15 studies, 77,946 children; low-certainty evidence), measles (RR 0.50, 95% CI 0.37 to 0.67; 6 studies, 19,566 children; moderate-certainty evidence), Bitot's spots (RR 0.42, 95% CI 0.33 to 0.53; 5 studies, 1,063,278 children; moderate-certainty evidence), night blindness (RR 0.32, 95% CI 0.21 to 0.50; 2 studies, 22,972 children; moderate-certainty evidence), and VAD (RR 0.71, 95% CI 0.65 to 0.78; 4 studies, 2262 children, moderate-certainty evidence). However, there was no evidence of a difference on incidence of respiratory disease (RR 0.99, 95% CI 0.92 to 1.06; 11 studies, 27,540 children; low-certainty evidence) or hospitalisations due to diarrhoea or pneumonia. There was an increased risk of vomiting within the first 48 hours of VAS (RR 1.97, 95% CI 1.44 to 2.69; 4 studies, 10,541 children; moderate-certainty evidence)., Authors' Conclusions: This update identified no new eligible studies and the conclusions remain the same. VAS is associated with a clinically meaningful reduction in morbidity and mortality in children. Further placebo-controlled trials of VAS in children between six months and five years of age would not change the conclusions of this review, although studies that compare different doses and delivery mechanisms are needed. In populations with documented VAD, it would be unethical to conduct placebo-controlled trials., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Introduction: The current standard of care for children with severe acute malnutrition (SAM) involves using ready-to-use therapeutic food (RUTF) to promote growth; however, the precise formulation to achieve optimal recovery remains unclear. Emerging research suggests that alternative RUTF formulations may be more effective in correcting SAM-related complications such as anaemia and iron deficiency. This systematic review commissioned by the WHO aims to synthesise the most recent research on the iron content in RUTF and related products in the community-based treatment of uncomplicated severe malnutrition in children aged 6 months and older., Methods and Analysis: We will search multiple electronic databases. We will include randomised controlled trials and non-randomised studies with a control arm. The intervention group will be infants who received RUTF treatments other than the current recommended guidelines set forth by the WHO. The comparison group is children receiving RUTF containing iron at the current WHO-recommended level of 1.9 mg/100 kcal (10-14 mg/100 g). The primary outcomes of interest include blood haemoglobin concentration, any anaemia, severe anaemia, iron-deficiency anaemia, recovery from SAM and any adverse outcomes. We will use meta-analysis to pool findings if sufficient homogeneity exists among included studies. The risk of bias in studies will be evaluated using the Cochrane risk of bias-2. We will use the Grading of Recommendations Assessment, Development, and Evaluation(GRADE) approach to examine the overall certainty of evidence., Ethics and Dissemination: This is a systematic review and will not involve direct contact with human subjects. The findings of this review will be published in a peer-reviewed journal and will guide the WHO's recommendation on the optimal iron content in RUTFs for the treatment of SAM in children aged 6-59 months., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Many infants do not receive breastmilk for the recommended 2-year duration. Instead, alternative milk beverages are often used, including infant formula and raw animal milk products. The purpose of this systematic review was to summarize the effect of animal milk consumption, compared to infant formula, on health outcomes in non-breastfed or mixed-fed infants aged 6-11 months. We searched multiple databases and followed Cochrane guidelines for conducting the review. The primary outcomes were anemia, gastrointestinal blood loss, weight-for-age, length-for-age, and weight-for-length. Nine studies were included: four randomized controlled trials (RCT) and five cohort studies. All studies, except one, were conducted in high income countries. There was a low certainty of evidence that cow's milk increased the risk of anemia compared to formula milk (Cohort studies RR: 2.26, 95% CI: 1.15, 4.43, RCTs: RR: 4.03, 95% CI: 1.68, 9.65) and gastrointestinal blood loss (Cohort study RR: 1.52, 95% CI: 0.73, 3.16, RCTs: RR: 3.14, 95% CI: 0.98, 10.04). Additionally, there was low certainty evidence that animal milk consumption may not have a differential effect on weight and length-for-age compared to formula milk. Overall, the evidence was of low certainty and no solid conclusions can be drawn from this data. Further studies are needed from low- and middle-income countries to assess optimal milk type in non-breastfed infants aged 6-11 months.

Probiotics are commonly prescribed to promote a healthy gut microbiome in children. Our objective was to investigate the effects of probiotic supplementation on growth outcomes in children 0-59 months of age. We conducted a systematic review and meta-analysis which included randomized controlled trials (RCTs) that administered probiotics to children aged 0-59 months, with growth outcomes as a result. We completed a random-effects meta-analysis and calculated a pooled standardized mean difference (SMD) or relative risk (RR) and reported with a 95% confidence interval (CI). We included 79 RCTs, 54 from high-income countries (HIC), and 25 from low- and middle-income countries (LMIC). LMIC data showed that probiotics may have a small effect on weight (SMD: 0.26, 95% CI: 0.11-0.42, grade-certainty = low) and height (SMD 0.16, 95% CI: 0.06-0.25, grade-certainty = moderate). HIC data did not show any clinically meaningful effect on weight (SMD: 0.01, 95% CI: -0.04-0.05, grade-certainty = moderate), or height (SMD: -0.01, 95% CI: -0.06-0.04, grade-certainty = moderate). There was no evidence that probiotics affected the risk of adverse events. We conclude that in otherwise healthy children aged 0-59 months, probiotics may have a small but heterogenous effect on weight and height in LMIC but not in children from HIC.

Introduction: Dysphagia affects several children in USA and around the globe. Videofluoroscopic Swallow Study (VFSS) and Fiberoptic Endoscopic Evaluation of Swallowing (FEES) are the most objective studies to define swallowing function. The presence of tracheal aspiration during VFSS or FEES in children with dysphagia is associated with an increased risk of aspiration pneumonia. However, the association of laryngeal penetration with aspiration pneumonia remains unclear. This systematic review aims to assess the risk of aspiration pneumonia in children with dysphagia with laryngeal penetration on VFSS/FEES and compare it with children with tracheal aspiration and children with neither tracheal aspiration nor laryngeal penetration., Methods and Analysis: This study will be a systematic review and meta-analysis. Systematic electronic searches will be conducted on PubMed, EMBASE, Web of Science, CINHAL, Scopus, Cochrane CENTRAL, LILACS and WHO Global Index Medicus. We will include studies published through 6 October 2021. Primary outcome will be the incidence of aspiration pneumonia. Secondary outcomes will be incidence of hospitalisation, paediatric intensive care unit admission, enteral tube requirement, growth, symptoms improvement and mortality. The Cochrane Risk of Bias In Non-Randomised Studies of Interventions tool will be used to assess the risk of bias. Meta-analysis will be used to pool the studies. We will pool dichotomous outcomes to obtain an odd ratio (OR) and report with 95% CI. Continuous outcomes will be pooled to obtain mean difference and reported with 95% CI. Overall grade of evidence will be assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria, and findings will be presented in a summary of findings table., Ethics and Dissemination: This study is a systematic review without contact with patients. Therefore, IRB approval is not required. Authors consent to publishing this review. Data will be kept for review by editors and peer reviewers. Data will be available to general public on request., Prospero Registration Number: CRD42020222145., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Haemolytic uraemic syndrome (HUS) is a common cause of acquired kidney failure in children and rarely in adults. The most important risk factor for development of HUS is a gastrointestinal infection by Shiga toxin-producing Escherichia coli (STEC). This review addressed the interventions aimed at secondary prevention of HUS in patients with diarrhoea who were infected with a bacteria that increase the risk of HUS., Objectives: Our objective was to evaluate evidence regarding secondary preventative strategies for HUS associated with STEC infections. In doing so, we sought to assess the effectiveness and safety of interventions as well as their potential to impact the morbidity and death associated with this condition., Search Methods: We searched the Cochrane Kidney and Transplant Register of Studies up to 12 November 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov., Selection Criteria: Studies were considered based on the methods, participants, and research goals. Only randomised controlled trials were considered eligible for inclusion. The participants of the studies were paediatric and adult patients with diarrhoeal illnesses due to STEC. The primary outcome of interest was incidence of HUS., Data Collection and Analysis: We used standard methodological procedures as recommended by Cochrane. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach., Main Results: We identified four studies (536 participants) for inclusion that investigated four different interventions including antibiotics (trimethoprim-sulfamethoxazole), anti-Shiga toxin antibody-containing bovine colostrum, Shiga toxin binding agent (Synsorb Pk: a silicon dioxide-based agent), and a monoclonal antibody against Shiga toxin (urtoxazumab). The overall risk of bias was unclear for selection, performance and detection bias and low for attrition, reporting and other sources of bias. It was uncertain if trimethoprim-sulfamethoxazole reduced the incidence of HUS compared to no treatment (47 participants: RR 0.57, 95% CI 0.11-2.81, very low certainty evidence). Adverse events relative to this review, need for acute dialysis, neurological complication and death were not reported. There were no incidences of HUS in either the bovine colostrum group or the placebo group. It was uncertain if bovine colostrum caused more adverse events (27 participants: RR 0.92, 95% CI 0.42 to 2.03; very low certainty evidence). The need for acute dialysis, neurological complications or death were not reported. It is uncertain whether Synsorb Pk reduces the incidence of HUS compared to placebo (353 participants: RR 0.93, 95% CI 0.39 to 2.22; very low certainty evidence). Adverse events relevant to this review, need for acute dialysis, neurological complications or death were not reported. One study compared two doses of urtoxazumab (3.0 mg/kg and 1.0 mg/kg) to placebo. It is uncertain if either 3.0 mg/kg urtoxazumab (71 participants: RR 0.34, 95% CI 0.01 to 8.14) or 1.0 mg/kg urtoxazumab (74 participants: RR 0.95, 95% CI 0.79 to 1.13) reduced the incidence of HUS compared to placebo (very low certainty evidence). Low certainty evidence showed there may be little or no difference in the number of treatment-emergent adverse events with either 3.0 mg/kg urtoxazumab (71 participants: RR 1.00, 95% CI 0.84 to 1.18) or 1.0 mg/kg urtoxazumab (74 participants: RR 0.95, 95% CI 0.79 to 1.13) compared to placebo. There were 25 serious adverse events reported in 18 patients: 10 in the placebo group, and 9 and 6 serious adverse events in the 1.0 mg/kg and 3.0 mg/kg urtoxazumab groups, respectively. It is unclear how many patients experienced these adverse events in each group, and how many patients experienced more than one event. It is uncertain if either dose of urtoxazumab increased the risk of neurological complications or death (very low certainty evidence). Need for acute dialysis was not reported., Authors' Conclusions: The included studies assessed antibiotics, bovine milk, and Shiga toxin inhibitor (Synsorb Pk) and monoclonal antibodies (Urtoxazumab) against Shiga toxin for secondary prevention of HUS in patients with diarrhoea due to STEC. However, no firm conclusions about the efficacy of these interventions can be drawn given the small number of included studies and the small sample sizes of those included studies. Additional studies, including larger multicentre studies, are needed to assess the efficacy of interventions to prevent development of HUS in patients with diarrhoea due to STEC infection., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Almost two billion people who are deficient in vitamins and minerals are women and children in low- and middle-income countries (LMIC). These deficiencies are worsened during pregnancy due to increased energy and nutritional demands, causing adverse outcomes in mother and child. To reduce micronutrient deficiencies, several strategies have been implemented, including diet diversification, large-scale and targeted fortification, staple crop bio-fortification and micronutrient supplementation., Objectives: To evaluate and summarize the available evidence on the effects of micronutrient supplementation during pregnancy in LMIC on maternal, fetal, child health and child development outcomes. This review will assess the impact of single micronutrient supplementation (calcium, vitamin A, iron, vitamin D, iodine, zinc, vitamin B12), iron-folic acid (IFA) supplementation, multiple micronutrient (MMN) supplementation, and lipid-based nutrient supplementation (LNS) during pregnancy., Search Methods: We searched papers published from 1995 to 31 October 2019 (related programmes and good quality studies pre-1995 were limited) in CAB Abstracts, CINAHL, Cochrane Central Register of Controlled Trials, Embase, International Initiative for Impact Evaluations, LILACS, Medline, POPLINE, Web of Science, WHOLIS, ProQuest Dissertations & Theses Global, R4D, WHO International Clinical Trials Registry Platform. Non-indexed grey literature searches were conducted using Google, Google Scholar, and web pages of key international nutrition agencies., Selection Criteria: We included randomized controlled trials (individual and cluster-randomized) and quasi-experimental studies that evaluated micronutrient supplementation in healthy, pregnant women of any age and parity living in a LMIC. LMIC were defined by the World Bank Group at the time of the search for this review. While the aim was to include healthy pregnant women, it is likely that these populations had one or more micronutrient deficiencies at baseline; women were not excluded on this basis., Data Collection and Analysis: Two authors independently assessed studies for inclusion and risk of bias, and conducted data extraction. Data were matched to check for accuracy. Quality of evidence was assessed using the GRADE approach., Main Results: A total of 314 papers across 72 studies (451,723 women) were eligible for inclusion, of which 64 studies (439,649 women) contributed to meta-analyses. Seven studies assessed iron-folic acid (IFA) supplementation versus folic acid; 34 studies assessed MMN vs. IFA; 4 studies assessed LNS vs. MMN; 13 evaluated iron; 13 assessed zinc; 9 evaluated vitamin A; 11 assessed vitamin D; and 6 assessed calcium. Several studies were eligible for inclusion in multiple types of supplementation. IFA compared to folic acid showed a large and significant (48%) reduction in the risk of maternal anaemia (average risk ratio (RR) 0.52, 95% CI 0.41 to 0.66; studies = 5; participants = 15,540; moderate-quality evidence). As well, IFA supplementation demonstrated a smaller but significant, 12% reduction in risk of low birthweight (LBW) babies (average RR 0.88, 95% CI 0.78 to 0.99; studies = 4; participants = 17,257; high-quality evidence). MMN supplementation was defined as any supplement that contained at least 3 micronutrients. Post-hoc analyses were conducted, where possible, comparing the differences in effect of MMN with 4+ components and MMN with 3 or 4 components. When compared to iron with or without FA, MMN supplementation reduced the risk of LBW by 15% (average RR 0.85, 95% CI 0.77 to 0.93; studies = 28; participants = 79,972); this effect was greater in MMN with >4 micronutrients (average RR 0.79, 95% CI 0.71 to 0.88; studies = 19; participants = 68,138 versus average RR 1.01, 95% CI 0.92 to 1.11; studies = 9; participants = 11,834). There was a small and significant reduction in the risk of stillbirths (average RR 0.91; 95% CI 0.86 to 0.98; studies = 22; participants = 96,772) and a small and significant effect on the risk of small-for-gestational age (SGA) (average RR 0.93; 95% CI 0.88 to 0.98; studies = 19; participants = 52,965). For stillbirths and SGA, the effects were greater among those provided MMN with 4+ micronutrients. Children whose mothers had been supplemented with MMN, compared to IFA, demonstrated a 16% reduced risk of diarrhea (average RR 0.84; 95% CI 0.76 to 0.92; studies = 4; participants = 3,142). LNS supplementation, compared to MMN, made no difference to any outcome; however, the evidence is limited. Iron supplementation, when compared to no iron or placebo, showed a large and significant effect on maternal anaemia, a reduction of 47% (average RR 0.53, 95% CI 0.43 to 0.65; studies = 6; participants = 15,737; moderate-quality evidence) and a small and significant effect on LBW (average RR 0.88, 95% CI 0.78 to 0.99; studies = 4; participants = 17,257; high-quality evidence). Zinc and vitamin A supplementation, each both compared to placebo, had no impact on any outcome examined with the exception of potentially improving serum/plasma zinc (mean difference (MD) 0.43 umol/L; 95% CI -0.04 to 0.89; studies = 5; participants = 1,202) and serum/plasma retinol (MD 0.13 umol/L; 95% CI -0.03 to 0.30; studies = 6; participants = 1,654), respectively. When compared to placebo, vitamin D supplementation may have reduced the risk of preterm births (average RR 0.64; 95% CI 0.40 to 1.04; studies = 7; participants = 1,262), though the upper CI just crosses the line of no effect. Similarly, calcium supplementation versus placebo may have improved rates of pre-eclampsia/eclampsia (average RR 0.45; 95% CI 0.19 to 1.06; studies = 4; participants = 9,616), though the upper CI just crosses 1., Authors' Conclusions: The findings suggest that MMN and vitamin supplementation improve maternal and child health outcomes, including maternal anaemia, LBW, preterm birth, SGA, stillbirths, micronutrient deficiencies, and morbidities, including pre-eclampsia/eclampsia and diarrhea among children. MMN supplementation demonstrated a beneficial impact on the most number of outcomes. In addition, MMN with >4 micronutrients appeared to be more impactful than MMN with only 3 or 4 micronutrients included in the tablet. Very few studies conducted longitudinal analysis on longer-term health outcomes for the child, such as anthropometric measures and developmental outcomes; this may be an important area for future research. This review may provide some basis to guide continual discourse around replacing IFA supplementation with MMN along with the use of single micronutrient supplementation programs for specific outcomes., Competing Interests: 5.33A post‐hoc analysis was conducted to examine if any effect estimates were influenced by studies where a conflict of interest was declared. Five studies reported a conflict of interest (Ashorn et al., 2015; Dewey et al., 2009; Osrin et al., 2005; West et al., 2014; Zeng et al., 2008), and exclusion of these studies did not significant affect the findings for the reported outcomes., (© 2021 The Authors. Campbell Systematic Reviews published by John Wiley & Sons Ltd on behalf of The Campbell Collaboration.)

Malnutrition-consisting of undernutrition, overweight and obesity, and micronutrient deficiencies-continues to afflict millions of women and children, particularly in low-income and middle-income countries (LMICs). Since the 2013 Lancet Series on maternal and child nutrition, evidence on the ten recommended interventions has increased, along with evidence of newer interventions. Evidence on the effectiveness of antenatal multiple micronutrient supplementation in reducing the risk of stillbirths, low birthweight, and babies born small-for-gestational age has strengthened. Evidence continues to support the provision of supplementary food in food-insecure settings and community-based approaches with the use of locally produced supplementary and therapeutic food to manage children with acute malnutrition. Some emerging interventions, such as preventive small-quantity lipid-based nutrient supplements for children aged 6-23 months, have shown positive effects on child growth. For the prevention and management of childhood obesity, integrated interventions (eg, diet, exercise, and behavioural therapy) are most effective, although there is little evidence from LMICs. Lastly, indirect nutrition strategies, such as malaria prevention, preconception care, water, sanitation, and hygiene promotion, delivered inside and outside the health-care sector also provide important nutritional benefits. Looking forward, greater effort is required to improve intervention coverage, especially for the most vulnerable, and there is a crucial need to address the growing double burden of malnutrition (undernutrition, and overweight and obesity) in LMICs., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The last two decades have seen a significant decrease in mortality for children <5 years of age in low and middle-income countries (LMICs); however, neonatal (age, 0-28 days) mortality has not decreased at the same rate. We assessed three neonatal nutritional interventions that have the potential of reducing morbidity and mortality during infancy in LMICs., Objectives: To determine the efficacy and effectiveness of synthetic vitamin A, dextrose oral gel, and probiotic supplementation during the neonatal period., Search Methods: We conducted electronic searches for relevant studies on the following databases: PubMed, CINAHL, LILACS, SCOPUS, and CENTRAL, Cochrane Central Register for Controlled Trials, up to November 27, 2019., Selection Criteria: We aimed to include randomized and quasi-experimental studies. The target population was neonates in LMICs. The interventions included synthetic vitamin A supplementation, oral dextrose gel supplementation, and probiotic supplementation during the neonatal period. We included studies from the community and hospital settings irrespective of the gestational age or birth weight of the neonate., Data Collection and Analysis: Two authors screened the titles and extracted the data from selected studies. The risk of bias (ROB) in the included studies was assessed according to the Cochrane Handbook of Systematic Reviews. The primary outcome was all-cause mortality. The secondary outcomes were neonatal sepsis, necrotizing enterocolitis (NEC), prevention and treatment of neonatal hypoglycaemia, adverse events, and neurodevelopmental outcomes. Data were meta-analyzed by random effect models to obtain relative risk (RR) and 95% confidence interval (CI) for dichotomous outcomes and mean difference with 95% CI for continuous outcomes. The overall rating of evidence was determined by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach., Main Results: Sixteen randomized studies (total participants 169,366) assessed the effect of vitamin A supplementation during the neonatal period. All studies were conducted in low- and middle-income (LMIC) countries. Thirteen studies were conducted in the community setting and three studies were conducted in the hospital setting, specifically in neonatal intensive care units. Studies were conducted in 10 different countries including India (four studies), Guinea-Bissau (three studies), Bangladesh (two studies), and one study each in China, Ghana, Indonesia, Nepal, Pakistan, Tanzania, and Zimbabwe. The overall ROB was low in most of the included studies for neonatal vitamin A supplementation. The pooled results from the community based randomized studies showed that there was no significant difference in all-cause mortality in the vitamin A (intervention) group compared to controls at 1 month (RR, 0.99; 95% CI, 0.90-1.08; six studies with 126,548 participants, statistical heterogeneity I 2 0%, funnel plot symmetrical, grade rating high), 6 months (RR, 0.98; 95% CI, 0.89-1.07; 12 studies with 154,940 participants, statistical heterogeneity I 2 43%, funnel plot symmetrical, GRADE quality high) and 12 months of age (RR, 1.04; 95% CI, 0.94-1.14; eight studies with 118,376 participants, statistical heterogeneity I 2 46%, funnel plot symmetrical, GRADE quality high). Neonatal vitamin A supplementation increased the incidence of bulging fontanelle by 53% compared to control (RR, 1.53; 95% CI, 1.12-2.09; six studies with 100,256 participants, statistical heterogeneity I 2 65%, funnel plot symmetrical, GRADE quality high). We did not identify any experimental study that addressed the use of dextrose gel for the prevention and/or treatment of neonatal hypoglycaemia in LMIC. Thirty-three studies assessed the effect of probiotic supplementation during the neonatal period (total participants 11,595; probiotics: 5854 and controls: 5741). All of the included studies were conducted in LMIC and were randomized. Most of the studies were done in the hospital setting and included participants who were preterm (born < 37 weeks gestation) and/or low birth weight (<2500 g birth weight). Studies were conducted in 13 different countries with 10 studies conducted in India, six studies in Turkey, three studies each in China and Iran, two each in Mexico and South Africa, and one each in Bangladesh, Brazil, Colombia, Indonesia, Nepal, Pakistan, and Thailand. Three studies were at high ROB due to lack of appropriate randomization sequence or allocation concealment. Combined data from 25 studies showed that probiotic supplementation reduced all-cause mortality by 20% compared to controls (RR, 0.80; 95% CI, 0.66-0.96; total number of participants 10,998, number needed to treat 100, statistical heterogeneity I 2 0%, funnel plot symmetrical, GRADE quality high). Twenty-nine studies reported the effect of probiotics on the incidence of NEC, and the combined results showed a relative reduction of 54% in the intervention group compared to controls (RR, 0.46; 95% CI, 0.35-0.59; total number of participants 5574, number needed to treat 17, statistical heterogeneity I 2 24%, funnel plot symmetrical, GRADE quality high). Twenty-one studies assessed the effect of probiotic supplementation during the neonatal period on neonatal sepsis, and the combined results showed a relative reduction of 22% in the intervention group compared to controls (RR, 0.78; 95% CI, 0.70-0.86; total number of participants 9105, number needed to treat 14, statistical heterogeneity I 2 23%, funnel plot symmetrical, GRADE quality high)., Authors' Conclusions: Vitamin A supplementation during the neonatal period does not reduce all-cause neonatal or infant mortality in LMICs in the community setting. However, neonatal vitamin A supplementation increases the risk of Bulging Fontanelle. No experimental or quasi-experimental studies were available from LMICs to assess the effect of dextrose gel supplementation for the prevention or treatment of neonatal hypoglycaemia. Probiotic supplementation during the neonatal period seems to reduce all-cause mortality, NEC, and sepsis in babies born with low birth weight and/or preterm in the hospital setting. There was clinical heterogeneity in the use of probiotics, and we could not recommend any single strain of probiotics for wider use based on these results. There was a lack of studies on probiotic supplementation in the community setting. More research is needed to assess the effect of probiotics administered to neonates in-home/community setting in LMICs., (© 2021 The Authors. Campbell Systematic Reviews published by John Wiley & Sons Ltd on behalf of The Campbell Collaboration.)

Introduction: Prevalence rates of breastfeeding remain low even though the World Health Organization (WHO) and the American Academy of Pediatrics recommend exclusive breast feeding for the first 6 months of life in combination with appropriate complementary feeding beyond six 6 months of age. There have been several studies that address the implication of drinking animal milk and/or infant formula on children's health and development when breast feeding is not offered during the first year of life. Vast improvements have been made in infant formula design, which may increase its benefits compared with animal's milk. The objective of this review is therefore to synthesise the most recent evidence on the effects of the consumption of animal milk compared with infant formula in non-breastfed or mixed breastfed infants aged 6-11 months., Methods and Analysis: We will conduct a systematic review and meta-analysis of studies that assessed the effect of animal milk compared with formula or mixed-fed (breastmilk and formula) on infants aged 6-11 months. The primary outcomes of interest include anaemia, gastrointestinal blood loss, weight for age, height for age and weight for height. We will include randomised and non-randomised studies with a control group. We will use the Cochrane risk of bias tools to assess the risk of bias. We will use meta-analysis to pool findings if the identified studies are conceptually homogenous and data are available from more than one study. We will assess the overall quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach., Ethics and Dissemination: This is a systematic review, so no patients will be directly involved in the design or development of this study. The findings from this systematic review will be disseminated to relevant patient populations and caregivers and will guide the WHO's recommendations on formula consumption versus animal milk in infants aged 6-11 months., Trial Registration Number: CRD42020210925., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Acute gastroenteritis (AGE) is a major cause of morbidity and mortality in children aged less than 5 years in low- and middle-income countries where limited access to potable water, poor sanitation, deficient hygiene, and food product contamination are prevalent. Research on the changing etiology of AGE and associated risk factors in Latin America, including Colombia, is essential to understand the epidemiology of these infections. The primary objectives of this study were to describe etiology of moderate to severe AGE in children less than 5 years of age from Bucaramanga, Colombia, a middle-income country in Latin American, and to identify the presence of emerging E. coli pathotypes., Methodology/principal Findings: This was a prospective, matched for age, case-control study to assess the etiology of moderate to severe AGE in children less than 5 years of age in Bucaramanga, Colombia, South America. We tested for 24 pathogens using locally available diagnostic testing, including stool culture, polymerase chain reaction, microscopy and enzyme-linked immunoassay. Adjusted attributable fractions were calculated to assess the association between AGE and each pathogen in this study population. The study included 861 participants, 431 cases and 430 controls. Enteric pathogens were detected in 71% of cases and in 54% of controls (p = <0.001). Co-infection was identified in 28% of cases and in 14% of controls (p = <0.001). The adjusted attributable fraction showed that Norovirus GII explained 14% (95% CI: 10-18%) of AGE, followed by rotavirus 9.3% (6.4-12%), adenovirus 3% (1-4%), astrovirus 2.9% (0.6-5%), enterotoxigenic Escherichia coli (ETEC) 2.4% (0.4-4%), Cryptosporidium sp. 2% (0.5-4%), Campylobacter sp. 2% (0.2-4%), and Salmonella sp.1.9% (0.3 to 3.5%). Except for Cryptosporidium, all parasite infections were not associated with AGE. Three emergent diarrheagenic E. coli pathotypes were identified in cases (0.7%), including an enteroaggregative/enterotoxigenic E.coli (EAEC/ETEC), an enteroaggregative/enteropathogenic E.coli (EAEC/EPEC), and an emergent enteroinvasive E. coli with a rare O96:H19. No deaths were reported among cases or controls., Conclusions/significance: Norovirus and rotavirus explained the major proportion of moderate to severe AGE in this study. Higher proportion of infection in cases, in the form of single infections or co-infections, showed association with AGE. Three novel E. coli pathotypes were identified among cases in this geographic region., Competing Interests: The authors have no conflicts of interest to disclose.

Background: Suboptimal nutritional status of a newborn is a risk factor for short- and long-term morbidity and mortality. The objectives of this review were to assess the efficacy and effectiveness of neonatal synthetic vitamin A supplementation, dextrose gel and probiotic supplementation for prevention of morbidity and mortality during infancy in low and middle-income countries. Methods: We included randomized trials. Primary outcome was all-cause mortality. We conducted electronic searches on multiple databases. Data were meta-analyzed to obtain relative risk (RR) and 95% confidence interval (CI). Studies for vitamin A and Probiotics were analyzed separately. No studies were found for dextrose gel supplementation during neonatal period. The overall rating of evidence was determined by Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Results: Sixteen studies assessed the effect of vitamin A supplementation during the neonatal period. Based on pooled data from community-based studies only, there was no significant effect of vitamin A on all-cause mortality at age 1 month (RR 0.99, 95% CI 0.90, 1.08), 6 months (RR 0.98; 95% CI 0.89-1.08) and 12 months (RR 1.04, 95% CI 0.94, 1.14) but increased risk of bulging fontanelle (RR 1.53, 95% CI 1.12, 2.09). The overall quality of evidence was high for the above outcomes. Thirty-three studies assessed the effect of probiotic supplementation during the neonatal period and were mostly conducted in the hospital setting. Probiotics reduced the risk of all-cause mortality (RR 0.80, 95% CI 0.66, 0.96), necrotizing enterocolitis (RR 0.46, 95% CI 0.35, 0.59) and neonatal sepsis (RR 0.78, 95% CI 0.70, 0.86). The grade ratings for the above three outcomes were high. Conclusions: Vitamin A supplementation during the neonatal period does not reduce all-cause neonatal or infant mortality in low and middle-income countries in the community setting. Probiotic supplementation during the neonatal period seems to reduce all-cause mortality, NEC, and sepsis in babies born low birth weight and/or preterm in the hospital setting.

Competing Interests: Dr. Bhutta was involved in study on neonatal vitamin A supplementation. He will not be involved in data extraction for this study to avoid the bias in quality assessment of the study.

Autoimmune enteropathy (AIE) is a complex disease affecting both children and adults. Although associated with significant morbidity and mortality, the pathophysiology of the disease and its treatment have not been well characterized. This study aims to review the medical literature available on this rare but clinically significant ailment, to help establish a better understanding of its pathophysiology and enumerate the available diagnostic and treatment modalities. A literature search was conducted on PubMed using key terms related to autoimmune enteropathy and intractable diarrhea, with no restrictions on the date of publication or language. We found a total of 98 reports of AIE published in the form of case reports and case series. The evidence reviewed suggests that AIE is a multifaceted disorder that requires a high index of suspicion in the appropriate clinical setting to be able to make an early diagnosis. Current evidence supports the use of supportive care to correct nutritional and metabolic deficiencies, and immunosuppressives and immunomodulators as directed therapies. Hematopoietic stem cell transplant is an aggressive, but successful curative modality for patients with AIE as part of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Cumulative clinical experience with management of AIE has allowed improved outcomes in transplanted and non-transplanted AIE patients even though morbidity and mortality with are still high in patients with this condition. More research is needed to further define the role of new therapies for AIE, and a central registry with participation of multiple institutions might help share and standardize care of patients with this rare but serious condition.

Background: Inflammatory bowel disease (IBD) is a chronic, relapsing disease of the gastrointestinal tract that is thought to be associated with a complex interplay between microbes and the immune system, leading to an abnormal inflammatory response in genetically susceptible individuals. Dysbiosis, characterized by the alteration of the composition of the resident commensal bacteria in a host compared to healthy individuals, is thought to play a major role in the pathogenesis of ulcerative colitis (UC) and Crohn's disease (CD), two subtypes of IBD. There is growing interest to correct the underlying dysbiosis through the use of fecal microbiota transplantation (FMT) for the treatment of IBD., Objectives: The objective of this systematic review was to assess the efficacy and safety of FMT for the treatment of IBD., Search Methods: We searched the MEDLINE, Embase, Cochrane Library, and Cochrane IBD Group Specialized Register databases from inception to 19 March 2018. We also searched ClinicalTrials.gov, ISRCTN metaRegister of Controlled Trials, and the Conference Proceedings Citation Index., Selection Criteria: Only randomized trials or non-randomized studies with a control arm were considered for inclusion. Adults or pediatric participants with UC or CD were eligible for inclusion. Eligible interventions were FMT defined as the administration of fecal material containing distal gut microbiota from a healthy donor to the gastrointestinal tract of a someone with UC or CD. The comparison group included participants who did not receive FMT and were given placebo, autologous FMT, or no intervention., Data Collection and Analysis: Two authors independently screened the titles and extracted data from the included studies. We used the Cochrane risk of bias tool to assess study bias. The primary outcomes were induction of clinical remission, clinical relapse, and serious adverse events. Secondary outcomes included clinical response, endoscopic remission and endoscopic response, quality of life scores, laboratory measures of inflammation, withdrawals, and microbiome outcomes. We calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI) for dichotomous outcomes and the mean difference and 95% CI for continuous outcomes. Random-effects meta-analysis models were used to synthesize effect sizes across trials. The overall certainty of the evidence supporting the primary and selected secondary outcomes was rated using the GRADE criteria., Main Results: Four studies with a total of 277 participants were included. These studies assessed the efficacy of FMT for treatment of UC in adults; no eligible trials were found for the treatment of CD. Most participants had mild to moderate UC. Two studies were conducted in Australia, one study was conducted in Canada, and another in the Netherlands. Three of the included studies administered FMT via the rectal route and one study administered FMT via the nasoduodenal route. Three studies were rated as low risk of bias. One study (abstract publication) was rated as unclear risk of bias. Combined results from four studies (277 participants) suggest that FMT increases rates of clinical remission by two-fold in patients with UC compared to controls. At 8 weeks, 37% (52/140) of FMT participants achieved remission compared to 18% (24/137) of control participants (RR 2.03, 95 % CI, 1.07 to 3.86; I² = 50%; low certainty evidence). One study reported data on relapse at 12 weeks among participants who achieved remission. None of the FMT participants (0/7) relapsed at 12 weeks compared to 20% of control participants (RR 0.28, 95% CI 0.02 to 4.98, 17 participants, very low certainty evidence). It is unclear whether there is a difference in serious adverse event rates between the intervention and control groups. Seven per cent (10/140) of FMT participants had a serious adverse event compared to 5% (7/137) of control participants (RR 1.40, 95% CI 0.55 to 3.58; 4 studies; I² = 0%; low certainty evidence). Serious adverse events included worsening of UC necessitating intravenous steroids or surgery; infection such as Clostridium difficile and cytomegalovirus, small bowel perforation and pneumonia. Adverse events were reported by two studies and the pooled data did not show any difference between the study groups. Seventy-eight per cent (50/64) of FMT participants had an adverse event compared to 75% (49/65) of control participants (RR 1.03, 95% CI 0.81 to 1.31; I² = 31%; moderate certainty evidence). Common adverse events included abdominal pain, nausea, flatulence, bloating, upper respiratory tract infection, headaches, dizziness, and fever. Four studies reported on clinical response at 8 weeks. Forty-nine per cent (68/140) of FMT participants had a clinical response compared to 28% (38/137) of control participants (RR 1.70, 95% CI 0.98 to 2.95, I² = 50%, low certainty evidence). Endoscopic remission at 8 weeks was reported by three studies and the combined results favored FMT over the control group. Thirty per cent (35/117) of FMT participants achieved endoscopic remission compared to 10% (11/112) of control participants (RR 2.96, 95 % CI 1.60 to 5.48, I² = 0%; low certainty evidence)., Authors' Conclusions: Fecal microbiota transplantation may increase the proportion of participants achieving clinical remission in UC. However, the number of identified studies was small and the quality of evidence was low. There is uncertainty about the rate of serious adverse events. As a result, no solid conclusions can be drawn at this time. Additional high-quality studies are needed to further define the optimal parameters of FMT in terms of route, frequency, volume, preparation, type of donor and the type and disease severity. No studies assessed efficacy of FMT for induction of remission in CD or in pediatric participants. In addition, no studies assessed long-term maintenance of remission in UC or CD. Future studies are needed to address the therapeutic benefit of FMT in CD and the long-term FMT-mediated maintenance of remission in UC or CD.

Background: Diarrheagenic Escherichia coli (DEC) is an important cause of acute gastroenteritis in children; however, there is limited information available on the epidemiology, phylogenetics, serotyping and antibiotic susceptibility of DEC in children in the United States. The aim of this study was to determine the molecular epidemiology of DEC among children with and without acute gastroenteritis in Davidson County, Tennessee., Methods: This prospective, frequency matched, case-control study recruited subjects 15 days to 17 years of age and detected DEC with polymerase chain reaction from stool samples. Additional testing was done to define phylogenetics and antibiotics resistance., Results: Among 1267 participants, 857 cases and 410 controls, 5.5% were positive for at least one subtype of DEC. Enteroaggregative E. coli [n = 32 (45%)] was the most common subtype followed by enteropathogenic E. coli (EPEC) [n = 30 (43%)], Shiga toxin-producing E. coli [n = 4 (6%)] and diffusely adherent E. coli [n = 4 (6%)]. No significant difference in prevalence of DEC was found between cases (5%) and controls (7%) [odds ratio: 0.66 (95% confidence interval: 0.4-1.07)], and results were similar when data were stratified by subtypes and adjusted for age, sex, race and ethnicity. Substantial diversity was found among DEC isolates in terms of phylotypes and serotypes, and a large proportion was resistant to, at least, one antibiotic., Conclusions: Enteroaggregative E. coli and enteropathogenic E. coli were frequently found in both cases and controls in this study population. DNA-based methods for detection of these subtypes need further investigation to help differentiate between pathogenic and colonizing strains.

Background: Culture-independent diagnostic tests (CIDTs) are increasingly used to identify enteric pathogens. However, foodborne illness surveillance systems have relied upon culture confirmation to estimate disease burden and identify outbreaks through molecular subtyping. This study examined the impacts of CIDT and estimated costs for culture verification of Shigella, Salmonella, Shiga toxin-producing Escherichia coli (STEC), and Campylobacter at the Tennessee Department of Health Public Health Laboratory (PHL)., Methods: This observational study included laboratory and epidemiological surveillance data collected between years 2013-2016 from patients with the reported enteric illness. We calculated pathogen recovery at PHL based on initial diagnostic test type reported at the clinical laboratory. Adjusted prevalence ratios (PRs) and 95% confidence intervals (CIs) were estimated with modified Poisson regression. Estimates of cost were calculated for pathogen recovery from CIDT-positive specimens compared to recovery from culture-derived isolates., Results: During the study period, PHL received 5553 specimens from clinical laboratories from patients with the enteric illness. Pathogen recovery was 57% (984/1713) from referred CIDT-positive stool specimens and 95% (3662/3840) from culture-derived isolates (PR, 0.61 [95% CI, .56-.66]). Pathogen recovery from CIDT-positive specimens varied based on pathogen type: Salmonella (72%), Shigella (64%), STEC (57%), and Campylobacter (26%). Compared to stool culture-derived isolates, the cost to recover pathogens from 100 CIDT-positive specimens was higher for Shigella (US $6192), Salmonella (US $18373), and STEC (US $27783)., Conclusions: Pathogen recovery was low from CIDT-positive specimens for enteric bacteria. This has important implications for the current enteric disease surveillance system, outbreak detection, and costs for public health programs.

Background: Pneumonia is a leading cause of childhood mortality from infectious disease, responsible for an estimated 1.3 million deaths annually in children under five years of age, many of which are in low-income countries. The World Health Organization recommends intravenous antibiotics for five days as first-line treatment for children with severe pneumonia. Although controversy exists regarding the specific clinical features used to diagnose pneumonia, the criteria for diagnosis of severe pneumonia are better defined and are widely used to triage children for referral and second-line therapy.In 2011 it was estimated that approximately 120 million new cases of pneumonia occur globally each year in children under five years of age, of which 14 million become severe episodes. Hospitalisation for severe pneumonia in children places a significant burden on both patients and their families, including substantial expense, loss of routine, and decrease in quality of life. By reducing the duration of hospital treatment, healthcare burdens could potentially be reduced and treatment compliance may improve.This is an update of a review published in 2015., Objectives: To evaluate the efficacy of short-course (two to three days) versus long-course (five days) intravenous therapy (alone or in combination with oral antibiotics) with the same antibiotic for severe community-acquired pneumonia in children aged two months to 59 months., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 12), MEDLINE (1966 to December week 3, 2016), Embase (1974 to 22 December 2016), and four trials registers (23 August 2017), together with reference checking of all relevant trials and reviews., Selection Criteria: Randomised controlled trials evaluating the efficacy of short-course (two to three days) versus long-course (five days) intravenous antibiotic therapy (alone or in combination with oral antibiotics) for severe pneumonia in children aged two months to 59 months. We excluded children with any other debilitating disease, including those infected with HIV. We also excluded children who had developed pneumonia during their hospital stay (i.e. with nosocomial infection). There was no restriction on the type of antibiotic used, the dose, or the frequency of dosing., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane., Main Results: Our searches identified 4295 records, however no studies met our predefined inclusion criteria., Authors' Conclusions: We identified no randomised controlled trials comparing a short course (two to three days) of intravenous antibiotics compared to a long course (five days) for severe pneumonia in children aged two months to 59 months that met our inclusion criteria.

Background: Vitamin A deficiency (VAD) is a major public health problem in low- and middle-income countries, affecting 190 million children under five years of age and leading to many adverse health consequences, including death. Based on prior evidence and a previous version of this review, the World Health Organization has continued to recommend vitamin A supplementation for children aged 6 to 59 months. There are new data available from recently published randomised trials since the previous publication of this review in 2010, and this update incorporates this information and reviews the evidence., Objectives: To assess the effects of vitamin A supplementation (VAS) for preventing morbidity and mortality in children aged six months to five years., Search Methods: In March 2016 we searched CENTRAL, Ovid MEDLINE, Embase, six other databases, and two trials registers. We also checked reference lists and contacted relevant organisations and researchers to identify additional studies., Selection Criteria: Randomised controlled trials (RCTs) and cluster-RCTs evaluating the effect of synthetic VAS in children aged six months to five years living in the community. We excluded studies involving children in hospital and children with disease or infection. We also excluded studies evaluating the effects of food fortification, consumption of vitamin A rich foods, or beta-carotene supplementation., Data Collection and Analysis: For this update, two reviewers independently assessed studies for inclusion and abstracted data, resolving discrepancies by discussion. We performed meta-analyses for outcomes, including all-cause and cause-specific mortality, disease, vision, and side effects. We used the GRADE approach to assess the quality of the evidence., Main Results: We identified 47 studies (4 of which are new to this review), involving approximately 1,223,856 children. Studies took place in 19 countries: 30 (63%) in Asia, 16 of these in India; 8 (17%) in Africa; 7 (15%) in Latin America, and 2 (4%) in Australia. About one-third of the studies were in urban/periurban settings, and half were in rural settings; the remaining studies did not clearly report settings. Most of the studies included equal numbers of girls and boys and lasted about a year. The included studies were at variable overall risk of bias; however, evidence for the primary outcome was at low risk of bias. A meta-analysis for all-cause mortality included 19 trials (1,202,382 children). At longest follow-up, there was a 12% observed reduction in the risk of all-cause mortality for vitamin A compared with control using a fixed-effect model (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.83 to 0.93; high-quality evidence). This result was sensitive to choice of model, and a random-effects meta-analysis showed a different summary estimate (24% reduction: RR 0.76, 95% CI 0.66 to 0.88); however, the confidence intervals overlapped with that of the fixed-effect model. Nine trials reported mortality due to diarrhoea and showed a 12% overall reduction for VAS (RR 0.88, 95% CI 0.79 to 0.98; 1,098,538 participants; high-quality evidence). There was no significant effect for VAS on mortality due to measles, respiratory disease, and meningitis. VAS reduced incidence of diarrhoea (RR 0.85, 95% CI 0.82 to 0.87; 15 studies; 77,946 participants; low-quality evidence) and measles (RR 0.50, 95% CI 0.37 to 0.67; 6 studies; 19,566 participants; moderate-quality evidence). However, there was no significant effect on incidence of respiratory disease or hospitalisations due to diarrhoea or pneumonia. There was an increased risk of vomiting within the first 48 hours of VAS (RR 1.97, 95% CI 1.44 to 2.69; 4 studies; 10,541 participants; moderate-quality evidence)., Authors' Conclusions: Vitamin A supplementation is associated with a clinically meaningful reduction in morbidity and mortality in children. Therefore, we suggest maintaining the policy of universal supplementation for children under five years of age in populations at risk of VAD. Further placebo-controlled trials of VAS in children between six months and five years of age would not change the conclusions of this review, although studies that compare different doses and delivery mechanisms are needed. In populations with documented vitamin A deficiency, it would be unethical to conduct placebo-controlled trials.

Introduction: Acute diarrheal disease (ADD) is a common cause of morbidity and mortality in children under 5 years of age. Understanding of the etiology of ADD is lacking in most low and middle income countries because reference laboratories detect limited number of pathogens . The objective of this study was to determine the feasibility to conduct a comprehensive case-control study to survey diarrheal pathogens among children with and without moderate-to-severe ADD., Materials and Methods: Microbiology and molecular-based techniques were used to detect viral, bacterial, and parasitic enteropathogens. The study was conducted in Bucaramanga, Colombia, after Institutional Review Board approval was obtained., Results: Ninety children less than 5 years of age were recruited after a written informed consent was obtained from parents or guardians. Forty-five subjects served as cases with ADD and 45 as controls. Thirty-six subjects out of 90 (40.0%) were positive for at least one enteropathogen, that is, 20 (44.4%) cases and 16 (35.5%) controls., Conclusions: The three most common enteric pathogens were enteroaggregative E. coli (10.0%), Norovirus (6.7%), and Salmonella spp. (5.6%). The E. coli pathogens were 18.8% of all infections making them the most frequent pathogens. Half of ADD cases were negative for any pathogens.

Background: Vitamin A deficiency is a significant public health problem in low- and middle-income countries. Vitamin A supplementation provided to infants less than six months of age is one of the strategies to improve the nutrition of infants at high risk of vitamin A deficiency and thus potentially reduce their mortality and morbidity., Objectives: To evaluate the effect of synthetic vitamin A supplementation in infants one to six months of age in low- and middle-income countries, irrespective of maternal antenatal or postnatal vitamin A supplementation status, on mortality, morbidity and adverse effects., Search Methods: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 2), MEDLINE via PubMed (1966 to 5 March 2016), Embase (1980 to 5 March 2016) and CINAHL (1982 to 5 March 2016). We also searched clinical trials databases, conference proceedings and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials., Selection Criteria: Randomised or quasi-randomised, individually or cluster randomised trials involving synthetic vitamin A supplementation compared to placebo or no intervention provided to infants one to six months of age were eligible., Data Collection and Analysis: Two review authors assessed the studies for eligibility and assessed their risk of bias and collected data on outcomes., Main Results: The review included 12 studies (reported in 22 publications). The included studies assigned 24,846 participants aged one to six months to vitamin A supplementation or control group. There was no effect of vitamin A supplementation for the primary outcome of all-cause mortality based on seven studies that included 21,339 (85%) participants (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.89 to 1.25; I 2 = 0%; test for heterogeneity: P = 0.79; quality of evidence: moderate). Also, there was no effect of vitamin A supplementation on mortality or morbidity due to diarrhoea and respiratory tract infection. There was an increased risk of bulging fontanelle within 24 to 72 hours of supplementation in the vitamin A group compared to control (RR 3.10, 95% CI 1.89 to 5.09; I 2 = 9%, test for heterogeneity: P = 0.36; quality of evidence: high). There was no reported subsequent increased risk of death, convulsions or irritability in infants who developed bulging fontanelle after vitamin A supplementation, and it resolved in most cases within 72 hours. There was no increased risk of other adverse effects such as vomiting, irritability, diarrhoea, fever and convulsions in the vitamin A supplementation group compared to control. Vitamin A supplementation did not have any statistically significant effect on vitamin A deficiency (RR 0.86, 95% CI 0.70 to 1.06; I 2 = 27%; test for heterogeneity: P = 0.25; quality of evidence: moderate)., Authors' Conclusions: There is no convincing evidence that vitamin A supplementation for infants one to six months of age results in a reduction in infant mortality or morbidity in low- and middle-income countries. There is an increased risk of bulging fontanelle with vitamin A supplementation in this age group; however, there were no reported subsequent complications because of this adverse effect.

Background: Pneumonia remains the single leading cause of childhood mortality, causing an estimated 1.3 million childhood deaths each year in children under the age of five years. The greater burden of disease occurs in low-income countries, where medical resources and hospital-based management are poor. The World Health Organization (WHO) current evidence summaries recommend intravenous antibiotics for five days as first-line treatment for severe pneumonia. Although there is controversy around the specificity of clinical features in the diagnosis of pneumonia, the criteria for the diagnosis of severe pneumonia are better defined and widely used to triage children for referral and second-line therapy.Approximately 120 million new cases of pneumonia occur globally each year in children under five years of age, of which 14 million progress to severe episodes. Hospitalisation for severe pneumonia in children places a significant burden on both patients and their families, including substantial expense, loss of routine and decrease in quality of life. By reducing the duration of treatment in the hospital, this burden could potentially be lessened and possibly lead to better treatment compliance., Objectives: To evaluate the efficacy of short-course (two to three days) versus long-course (five days) intravenous therapy with the same antibiotic for severe community-acquired pneumonia (CAP) in children aged two months to 59 months., Search Methods: We searched CENTRAL (2015, Issue 1), MEDLINE (1966 to January week 4, 2015) and EMBASE (1974 to February 2015)., Selection Criteria: Randomised controlled trials (RCTs) evaluating the efficacy of short-course (two to three days) versus long-course (five days) intravenous antibiotic therapy for severe pneumonia in children aged two months to 59 months. We excluded children with any other debilitating disease, including those infected with HIV and we excluded children with signs and symptoms of very severe pneumonia (i.e. unable to drink or breast feed, vomiting, lethargic, unconscious, convulsing, central cyanosis, severe respiratory distress or clinically severe malnutrition). We also excluded children who had developed pneumonia during their hospital stay (i.e. with nosocomial infection). There was no restriction on the type of antibiotic used, the dose or the frequency of dosing., Data Collection and Analysis: We used the standard methodological procedures expected by The Cochrane Collaboration., Main Results: We identified 2352 studies, however none fulfilled our pre-defined inclusion criteria., Authors' Conclusions: We did not identify any RCTs comparing a short course (two to three days) of intravenous antibiotics compared to a long course (five days) for severe pneumonia in children aged two to 59 months.