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Background There is limited data on antibiotic treatment in hospitalized neonates in low- and middle-income countries (LMICs). We aimed to describe patterns of antibiotic use, pathogens, and clinical outcomes, and to develop a severity score predicting mortality in neonatal sepsis to inform future clinical trial design. Methods and findings Hospitalized infants Conclusion Antibiotic regimens used in neonatal sepsis commonly diverge from WHO guidelines, and trials of novel empiric regimens are urgently needed in the context of increasing antimicrobial resistance (AMR). The baseline NeoSep Severity Score identifies high mortality risk criteria for trial entry, while the NeoSep Recovery Score can help guide decisions on regimen change. NeoOBS data informed the NeoSep1 antibiotic trial (ISRCTN48721236), which aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis. Trial registration ClinicalTrials.gov, (NCT03721302). James Neal Russell and colleagues report a global neonatal sepsis observational cohort study (NeoOBS) exploring patterns of antibiotic use, pathogens and prediction of mortality in hospitalised neonates and young infants with sepsis. Author summary Why was this study done? Increasing trends in antimicrobial resistance (AMR) disproportionately affect neonates and young infants with sepsis in LMIC settings and undermine the effectiveness of WHO-recommended antibiotics. Despite this, longitudinal data on antibiotic management strategies and outcomes of hospitalized neonates and young infants with sepsis in low- and middle-income country (LMIC) settings are extremely limited, impeding the design of robust antibiotic trials. There is limited data to define risk stratification, inclusion, and escalation criteria in trials of sepsis in hospitalized neonates and young infants. What did the researchers do and find? In this large global, prospective, hospital-based observational study across 4 continents, including LMIC settings, there was a high mortality among infants with culture positive sepsis (almost 1 in 5), and a significant burden of antibiotic resistance. This study highlights wide variations in standard of care (SOC) for sepsis in neonates and young infants, with more than 200 different antibiotic combinations, significant divergence from WHO-recommended regimens, and frequent switching of antibiotics. A NeoSep Severity Score that defined patterns of mortality risk at baseline was developed from 4 non-modifiable and 6 modifiable factors that are feasible to measure across a range of LMIC hospital contexts. A NeoSep Recovery Score including the same modifiable factors (with the addition of cyanosis) predicted mortality on the following day during treatment. What do these findings mean? These data demonstrate that patterns of routine antibiotic use are now markedly divergent from global guidance. There is an urgent need for large pragmatic randomized controlled trials to address optimal empiric first- and second-line antibiotic treatment strategies in LMIC hospital settings with a significant AMR burden. The wide range of multiple antibiotic regimens routinely used as SOC suggests the need for novel trial designs. The NeoSep Severity Score and NeoSep Recovery Score informed inclusion and escalation criteria in the NeoSep1 antibiotic trial (ISRCTN48721236) that aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis.

Neonatal sepsis is a significant cause of mortality and morbidity in low- and middle-income countries. To deliver high-quality data studies and inform future trials, it is crucial to understand the challenges encountered when managing global multi-centre research studies and to identify solutions that can feasibly be implemented in these settings. This paper provides an overview of the complexities faced by diverse research teams in different countries and regions, together with actions implemented to achieve pragmatic study management of a large multi-centre observational study of neonatal sepsis. We discuss specific considerations for enrolling sites with different approval processes and varied research experience, structures, and training. Implementing a flexible recruitment strategy and providing ongoing training were necessary to overcome these challenges. We emphasize the attention that must be given to designing the database and monitoring plans. Extensive data collection tools, complex databases, tight timelines, and stringent monitoring arrangements can be problematic and might put the study at risk. Finally, we discuss the complexities added when collecting and shipping isolates and the importance of having a robust central management team and interdisciplinary collaborators able to adapt easily and make swift decisions to deliver the study on time and to target. With pragmatic approaches, appropriate training, and good communication, these challenges can be overcome to deliver high-quality data from a complex study in challenging settings through a collaborative research network.

Abstract Background Progress has been made in the reduction of under-five mortality in India; however, neonatal mortality is reducing at a slower rate. Efforts are required to bring down neonatal mortality in order to attain the Sustainable Development Goal-3. Prevention of sepsis among the high-risk, vulnerable low birth weight neonates by a newer intervention with probiotic supplementation is promising. Methods A phase III, multicenter, randomized, double-blind, placebo-controlled study is being conducted at six sites in India. A total of 6144 healthy low birth weight (LBW) infants fulfilling the eligibility criteria would be enrolled within the first week of life, after obtaining written informed consent from the parents of the infant. Randomization in 1:1 ratio, stratified by site, sex, and birth weight, would be done through an interactive web response system (IWRS) using a standard web browser and email service. Vivomixx®, a probiotic containing a mix of 8 strains of bacteria, in a suspension form standardized to deliver 10 billion CFU/ml, or an organoleptically similar placebo would be fed to enrolled infants in a 1-ml/day dose for 30 days. The follow-up of enrolled infants for 60 days would take place as per a pre-specified schedule for recording morbidities and outcome assessments at the six participating sites. Screening for morbidities would be conducted by trained field workers in the community, and sick infants would be referred to designated clinics/hospitals. A physician would examine the referred infants presenting with complaints and clinical signs, and blood samples would be collected from sick infants for diagnosis of neonatal sepsis by performing sepsis screen and blood culture. Appropriate treatment would be provided as per hospital protocol. The study would be implemented as per the MRC guideline for the management of Global Health Trials in accordance with ICH-GCP and Indian Regulatory guidelines. A contract research organization would be engaged for comprehensive monitoring and quality assurance. The final analysis would be conducted in a blinded manner as per the statistical analysis plan (SAP) to estimate the primary outcomes of sepsis, possible serious bacterial infection (PSBI), and secondary outcomes. The codes will be broken after DMC permission. The protocol has been reviewed by the Research Ethics Committee of the Liverpool School of Tropical Medicine (REC-LSTM), from Research Ethics Committees of the six subject recruitment participating sites. Discussion This adequately powered and well-designed trial would conclusively answer the question whether probiotics can prevent neonatal sepsis in the high-risk group of low birth weight infants as indicated by a pilot study in 1340 LBW infants, evidence from systematic reviews of hospital-based studies, and a primary study on healthy newborns in Orissa. Results of the study would be generalizable to India and other low–middle-income countries. Trial registration Clinical Trial Registry of India (CTRI) CTRI/2019/05/019197 . Registered on 16 May 2019

Mother's milk is the ideal food for a neonate. When mother's milk is unavailable for any reason, pasteurised donor human milk (PDHM) is the next best option. This quality improvement (QI) project aimed at improving voluntary donation in a public human milk bank (HMB) in South India. Between January 2018 and June 2019, the HMB received an average of 15 L of donor milk per month (0.5 L/day). Our aim was to increase voluntary donation by 50% from the baseline over a period of 8 months from July 2019 to March 2020 using QI methods. Two plan-do-study-act (PDSA) cycles were done during the intervention period (4 months). Interventions included the formation of micro teams in postnatal wards to promote exclusive breastfeeding and to liaison with the core QI team. We created a milk expression area in the postnatal ward, counseled postnatal mothers, and addressed supply chain issues like sterile pumping accessories. The average daily voluntary milk donation to HMB increased from 0.83 L/day in the baseline phase to 1.16 and 1.14 L per day in the intervention and postintervention phases, respectively. The mean (SD) monthly donated volumes increased from 28.2 (6.1) L to 34.1 (3.7) L; mean difference (95% CI) 5.9 (0.33–11.4); P = 0.03. The volume of PDHM disbursed from HMB increased from 26.6 (3.2) L/month to 32.2 (9.2) L/month, although not statistically significant (p = 0.15). The number of mothers donating milk did not increase during the study period. A multipronged QI intervention effort focusing on exclusive breastfeeding improved voluntary milk donation in HMB bank. Multiple micro-teams and local networking facilitated the QI initiative. [ABSTRACT FROM AUTHOR]

Introduction: Vitamin D endocrine system is a potential immune system modulator and has been implicated in the pathogenesis of several autoimmune diseases including Type 1 Diabetes Mellitus (T1DM). Studies have demonstrated an inverse risk relationship between T1DM and Vitamin D levels and also, shown a reduced risk of the disease with its supplementation. Aim: To evaluate the role of Vitamin D as an adjuvant in improving glycaemic control and residual pancreatic beta-cell function. Primary outcome was the mean change in HbA1c levels over a period of six months. Materials and Methods: This double-blinded randomized controlled trial was done in a tertiary care hospital, Southern India and included 52 children aged 1-18 years with T1DM, with 26 participants each in the intervention and standard of care arm. Oral Vitamin D therapy was administered once a month for six months in addition to insulin in intervention arm while only insulin was continued for other arm. Plasma HbA1c, serum 25- Hydroxy vitamin D (25OHD), insulin dose and C-peptide were measured at baseline and repeated after 6 months. Results: Prevalence of Vitamin D deficiency was as high as 63.5% i.e., 33 of total 52 children with T1DM. The mean C-peptide levels were significantly high in intervention arm as compared to standard of care after six months. However, there was no significant difference in HbA1c, and insulin requirement at six months between the two groups. No adverse events due to Vitamin D therapy were noted. Conclusion: Oral Vitamin D may serve as an adjuvant to insulin therapy for children with T1DM by augmenting residual beta-cell function and improving insulin secretion. However, a significant decrease in HbA1c level and requirement for exogenous insulin was not achieved in our study.