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Background: Numerous studies have investigated the efficacy of probiotics in treating acute and persistent diarrhoea. However, probiotics have not been established as a recommended management option for diarrhoeal illness by the World Health Organization (WHO). Therefore, we conducted a systematic review of randomised controlled trials to assess the efficacy of probiotics for the management of acute and persistent diarrhoea in children., Methods: A systematic search on PubMed, CINAHL, Wiley Cochrane Library, Scopus, Clinicaltrials.gov, and WHO International Clinical Trials Registry Platform (ICTRP) was performed. All studies published in the year 2000 and onwards that assessed the use of probiotics in the management of acute and persistent diarrhoea in children aged 0-10 years were included. The risk of bias was assessed using the Cochrane Risk of Bias II (RoB-2) tool and the quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach. This review was commissioned by WHO for revision of their guidelines for childhood diarrhoea management., Results: The review included 98 studies with a total of 17 236 participants. Studies were categorised based on the WHO definition of diarrhoea or author-specified definition. In studies considering the WHO definition of diarrhoea, the probiotics group was more likely to achieve clinical cure (risk ratio = 1.12 (95% confidence interval (CI) = 1.01, 1.24, studies = 14)) and reduce the duration of diarrhoea (mean difference = -13.27 hours (95% CI = -16.72, -9.83, studies = 33)) than the control group in children with acute diarrhoea. However, the effect size was small, and statistical heterogeneity was very high, leading to low certainty of evidence. In children with persistent diarrhoea, probiotics reduced the duration of diarrhoea by 95 hours (mean difference = -96.45 (95% CI = -110.53, -82.37, studies = 2)), but the certainty of the evidence was very low., Conclusions: The results from this systematic review suggest low certainty of evidence for the effect of probiotics on clinical cure and duration of diarrhoea in children. There was significant diversity in the genus, species, dosages, and duration of treatment in the trial and administration. High levels of heterogeneity reduced the certainty of evidence. Large-scale randomised clinical trials are needed to evaluate specific probiotic strains and doses. In addition, cost-effective analysis studies are needed to be explored in future research., Registration: The protocol for this review was registered with the International Prospective Register of Systematic Reviews (PROSPERO: CRD42023449200)., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests. YBN is a staff member of the World Health Organization. The authors alone are responsible for the views expressed in this article, and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated., (Copyright © 2024 by the Journal of Global Health. All rights reserved.)

Background: Zinc is a micronutrient that plays a role in immune system strengthening and regulation of intestinal epithelial cells, and can reduce the duration and severity of diarrhoea. We conducted a systematic review of randomised controlled trials (RCTs) to assess the effectiveness of zinc compared to no zinc for the management of acute and persistent diarrhoea in children., Methods: We searched PubMed, the Cochrane Library, Scopus, CINAHL, ClinicalTrials.gov, and World Health Organization (WHO) International Clinical Trials Registry Platform from inception until 31 July 2023 for studies published from year 2000 onwards that assessed the use of zinc in the management of acute and persistent diarrhoea in children aged less than 10 years. We conducted the meta-analysis in Cochrane's RevMan software, determined risk of bias in individual studies using the Risk of Bias 2 (RoB 2) tool, and assessed the quality of evidence through the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. This review was commissioned by the WHO for revision of their guidelines for childhood diarrhoea management., Results: We included 38 RCTs in this systematic review. Our findings suggest that, in children with acute diarrhoea, zinc supplementation resulted in a greater proportion of children who recovered from diarrhoea at last follow-up (risk ratio (RR) = 1.07; 95% confidence interval (CI) = 1.03, 1.1; moderate certainty of evidence) and a reduction in the duration of diarrhoea (mean difference (MD) = -13.27 hours; 95% CI = -17.66, -8.89; moderate certainty of evidence) when compared to placebo. A significant number of children in the zinc group compared to placebo experienced vomiting (RR = 1.46; 95% CI = 1.22, 1.76; moderate certainty of evidence), however, there were few vomiting episodes in low-dose zinc group compared to high-dose (RR = 0.80; 95% CI = 0.72, 0.89; moderate certainty of evidence). In children with persistent diarrhoea, zinc supplementation led to a greater proportion of children who recovered from diarrhoea (RR = 1.75; 95% CI = 1.34, 2.30; low certainty of evidence). The low certainty of evidence ratings were mostly due to high heterogeneity among the studies., Conclusions: Zinc should continue to be recommended in children under the age of 10 years with acute or persistent diarrhoea, but moderate certainty of evidence concludes that the dose of zinc should be reduced. However, further multi-country randomised clinical trials are required with a direct comparison to assess the appropriate dosage, duration and adverse effects., Registration: PROSPERO: CRD42023439028., Competing Interests: Disclosure of interests: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose the following activities and/or relationships: YBN is staff member of the World Health Organization., (Copyright © 2024 by the Journal of Global Health. All rights reserved.)

Background: Oral rehydration solution (ORS) is crucial in the management of diarrhoea. Until the early 2000s, the standard formulation of glucose-based ORS with a total osmolarity of 311 mmol/L was being used for this purpose. However, due to concerns about sodium levels and cases of hypernatremia, a low-osmolarity ORS solution (LORS) with an osmolarity of 245mmol/L or less was developed to replace the standard ORS. With this systematic review, we aimed to assess the effectiveness of LORS compared to standard ORS for the treatment of acute and persistent diarrhoea., Methods: We comprehensively searched PubMed, CINAHL, the Cochrane Library, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform, and Scopus until 20 July 2023 for studies published after 1990 assessing the efficacy of LORS in acute and persistent diarrhoea in children under 10 years of age. Meta-analysis was conducted using the RevMan software. We performed log approximation for all the values for an outcome when studies reported arithmetic and geometric means per the Cochrane Handbook. We otherwise used the Cochrane Risk of Bias II tool to assess the risk of bias in individual studies, and assessed the quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluations approach. This review was commissioned by the WHO for revision of guidelines for childhood diarrhoea., Results: For the comparison of LORS to standard ORS in acute diarrhoea, our findings suggest that there was a significant decrease in the duration of diarrhoea (mean difference (MD) = -0.28; 95% confidence interval (CI) = -0.41, -0.15; moderate certainty of evidence), stool output (MD = -0.25; 95% CI = -0.35, -0.16; very low certainty of evidence), and ORS intake (MD = -0.18; 95% CI = -0.28, -0.07; moderate certainty of evidence) in patients receiving LORS. There was a comparable effect on the number of patients cured within five days, treatment failure, and frequency of unscheduled intravenous therapy (risk ratio (RR) = 0.77; 95% CI = 0.72, 9.38; low certainty of evidence). For persistent diarrhoea, there was a significant decrease in duration of diarrhoea (MD = -30.60; 95% CI = -48.95, -12.25), stool output (MD = -14.00; 95% CI = -26.63, -1.37), and ORS intake (MD = -21.40; 95% CI = -41.01, -1.79), while there was a comparable effect on the number of patients cured., Conclusion: Our findings suggest that LORS should continue to be recommended in children under the age of 10 years with acute watery or persistent diarrhoea and upholds the current WHO recommendations., Registration: PROSPERO: CRD42023438762., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose the following activities and/or relationships: YBN is staff member of the World Health Organization., (Copyright © 2024 by the Journal of Global Health. All rights reserved.)

Background: The use of antibiotics in the treatment of acute and persistent watery diarrhoea has long been a subject of contention. While the advantages of using antimicrobials are acknowledged, concerns remain regarding potential adverse effects and antibiotic resistance. Therefore, we conducted a systematic review and meta-analysis to assess the efficacy of antibiotics compared to placebos for the treatment of diarrhoea., Methods: We searched PubMed, CINAHL, the Cochrane Library, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform, and Scopus from inception until 20 July 2023 for studies published after the year 2000 assessing antibiotics vs placebo in acute and persistent diarrhoea and/or blood in stools in children less than 10 years of age. We conducted a meta-analysis for the included studies, assessed them using the Risk of Bias 2 tool, and evaluated their quality of evidence through the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. This review was commissioned by WHO for revision of their guidelines for childhood diarrhoea management., Results: We included five randomised controlled trials (RCTs) for acute watery diarrhoea and no study for bloody diarrhoea. Our findings suggest that there is a significant increase in clinical cure (risk ratio (RR) = 2.28; 95% confidence interval (CI) = 1.52, 3.41; low certainty evidence) and parasitological cure (RR = 2.86; 95% CI = 1.72 to 4.74; low certainty evidence) among children with acute watery diarrhoea in the antibiotic group when compared to the placebo group. The duration of diarrhoea (in hours) was significantly reduced (mean difference = -24.90; 95% CI = -34.09, -15.71; low certainty evidence) in the intervention group, while the effect on all-cause mortality (RR = 0.71; 95% CI = 0.40, 1.27; moderate certainty evidence) and the need for intravenous fluid infusion (RR = 0.50; 95% CI = 0.05, 5.17; very low certainty evidence) were comparable between the two groups., Conclusions: In children under 10 years of age suffering from acute watery or persistent diarrhoea, antibiotics led to an apparent increase in cure rates. However, considering the low certainty of evidence, low number of studies with small sample sizes, and the fact that most studies were conducted in a single country, further investigation and cautious interpretation are warranted, as is a large multi-country RCT that would allow for firmer conclusions., Registration: PROSPERO: CRD42023447133., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose the following activities and/or relationships: YBN is staff member of the World Health Organization., (Copyright © 2024 by the Journal of Global Health. All rights reserved.)

Background: The existing World Health Organization (WHO) pneumonia case management guidelines rely on clinical symptoms and signs for identifying, classifying, and treating pneumonia in children up to 5 years old. We aimed to collate an individual patient-level data set from large, high-quality pre-existing studies on pneumonia in children to identify a set of signs and symptoms with greater validity in the diagnosis, prognosis, and possible treatment of childhood pneumonia for the improvement of current pneumonia case management guidelines., Methods: Using data from a published systematic review and expert knowledge, we identified studies meeting our eligibility criteria and invited investigators to share individual-level patient data. We collected data on demographic information, general medical history, and current illness episode, including history, clinical presentation, chest radiograph findings when available, treatment, and outcome. Data were gathered separately from hospital-based and community-based cases. We performed a narrative synthesis to describe the final data set., Results: Forty-one separate data sets were included in the Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) database, 26 of which were hospital-based and 15 were community-based. The PREPARE database includes 285 839 children with pneumonia (244 323 in the hospital and 41 516 in the community), with detailed descriptions of clinical presentation, clinical progression, and outcome. Of 9185 pneumonia-related deaths, 6836 (74%) occurred in children <1 year of age and 1317 (14%) in children aged 1-2 years. Of the 285 839 episodes, 280 998 occurred in children 0-59 months old, of which 129 584 (46%) were 2-11 months of age and 152 730 (54%) were males., Conclusions: This data set could identify an improved specific, sensitive set of criteria for diagnosing clinical pneumonia and help identify sick children in need of referral to a higher level of care or a change of therapy. Field studies could be designed based on insights from PREPARE analyses to validate a potential revised pneumonia algorithm. The PREPARE methodology can also act as a model for disease database assembly., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and declare the following activities and relationships: YBN is staff member of the World Health Organization., (Copyright © 2022 by the Journal of Global Health. All rights reserved.)

Background: Puerperal sepsis (PP sepsis) is a leading cause of maternal mortality globally. The majority of maternal sepsis cases and deaths occur at home and remain undiagnosed and under-reported. In this paper, we present findings from a nested case-control study in Bangladesh and Pakistan which sought to assess the validity of community health worker (CHW) identification of PP sepsis using a clinical diagnostic algorithm with physician assessment and classification used as the gold standard., Methods: Up to 300 postpartum women were enrolled in each of the 3 sites 1) Sylhet, Bangladesh (n = 278), 2) Karachi, Pakistan (n = 278) and 3) Matiari, Pakistan (n = 300). Index cases were women with suspected PP Sepsis as diagnosed by CHWs clinical assessment of one or more of the following signs and symptoms: temperature (recorded fever ≥38.1°C, reported history of fever, lower abdominal or pelvic pain, and abnormal or foul-smelling discharge. Each case was matched with 3 control women who were diagnosed by CHWs to have no infection. Cases and controls were assessed by trained physicians using the same algorithm implemented by the CHWs. Using physician assessment as the gold standard, Kappa statistics for reliability and diagnostic validity (sensitivity and specificity) are presented with 95% CI. Sensitivity and specificity were adjusted for verification bias., Results: The adjusted sensitivity and specificity of CHW identification of PP sepsis across all sites was 82% (Karachi: 78%, Matiari: 78%, Sylhet: 95%) and 90% (Karachi: 95%, Matiari: 85%, Sylhet: 90%) respectively. CHW-Physician agreement was highest for moderate and high fever (range across sites: K = 0.84-0.97) and lowest for lower abdominal pain (K = 0.30-0.34). The clinical signs and symptoms for other conditions were reported infrequently, however, the CHW-physician agreement was high for all symptoms except severe headache/ blurred vision (K = 0.13-0.38) and reported "lower abdominal pain without fever" (K = 0.39-0.57)., Conclusion: In all sites, CHWs with limited training were able to identify signs and symptoms and to classify cases of PP sepsis with high validity. Integrating postpartum infection screening into existing community-based platforms and post-natal visits is a promising strategy to monitor women for PP sepsis - improving delivery of cohesive maternal and child health care in low resource settings., Competing Interests: Competing interests: The authors completed the ICMJE Declaration of Interest Form (available upon request from the corresponding author), and declare no conflicts of interest., (Copyright © 2021 by the Journal of Global Health. All rights reserved.)

Background: In 2013, an estimated 2.8 million newborns died and 2.7 million were stillborn. A much greater number suffer from long term impairment associated with preterm birth, intrauterine growth restriction, congenital anomalies, and perinatal or infectious causes. With the approaching deadline for the achievement of the Millennium Development Goals (MDGs) in 2015, there was a need to set the new research priorities on newborns and stillbirth with a focus not only on survival but also on health, growth and development. We therefore carried out a systematic exercise to set newborn health research priorities for 2013-2025., Methods: We used adapted Child Health and Nutrition Research Initiative (CHNRI) methods for this prioritization exercise. We identified and approached the 200 most productive researchers and 400 program experts, and 132 of them submitted research questions online. These were collated into a set of 205 research questions, sent for scoring to the 600 identified experts, and were assessed and scored by 91 experts., Results: Nine out of top ten identified priorities were in the domain of research on improving delivery of known interventions, with simplified neonatal resuscitation program and clinical algorithms and improved skills of community health workers leading the list. The top 10 priorities in the domain of development were led by ideas on improved Kangaroo Mother Care at community level, how to improve the accuracy of diagnosis by community health workers, and perinatal audits. The 10 leading priorities for discovery research focused on stable surfactant with novel modes of administration for preterm babies, ability to diagnose fetal distress and novel tocolytic agents to delay or stop preterm labour., Conclusion: These findings will assist both donors and researchers in supporting and conducting research to close the knowledge gaps for reducing neonatal mortality, morbidity and long term impairment. WHO, SNL and other partners will work to generate interest among key national stakeholders, governments, NGOs, and research institutes in these priorities, while encouraging research funders to support them. We will track research funding, relevant requests for proposals and trial registers to monitor if the priorities identified by this exercise are being addressed.