Inflammation and epithelial repair predict mortality, hospital readmission, and growth recovery in complicated severe acute malnutrition.

Severe acute malnutrition (SAM) is the most high-risk form of undernutrition, particularly when children require hospitalization for complications. Complicated SAM is a multisystem disease with high inpatient and postdischarge mortality, especially in children with comorbidities such as HIV; however, the underlying pathogenesis of complicated SAM is poorly understood. Targeted multiplex biomarker analysis in children hospitalized with SAM (n = 264) was conducted on plasma samples, and inflammatory markers were assessed on stool samples taken at recruitment, discharge, and 12 to 24 and 48 weeks after discharge from three hospitals in Zimbabwe and Zambia. Compared with adequately nourished controls (n = 173), we found that at baseline, complicated SAM was characterized by systemic, endothelial, and intestinal inflammation, which was exacerbated by HIV infection. This persisted over 48 weeks despite nutritional recovery and was associated with children's outcomes. Baseline plasma concentrations of vascular endothelial growth factor, glucagon-like peptide-2, and intestinal fatty acid-binding protein were independently associated with lower mortality or hospital readmission over the following 48 weeks. Following principal components analysis of baseline biomarkers, higher scores of a component representing growth factors was associated with greater weight-for-height z score recovery and lower mortality or hospital readmission over the 48 weeks. Conversely, components representing higher gut and systemic inflammation were associated with higher mortality or hospital readmission. These findings highlight the interplay between inflammation, which damages tissues, and growth factors, which mediate endothelial and epithelial regeneration, and support further studies investigating interventions to reduce inflammation and promote epithelial repair as an approach to reducing mortality and improving nutritional recovery.

A pilot study using hospital surveillance and a birth cohort to investigate enteric pathogens and malnutrition in children, Dili, Timor-Leste.

In low-to-middle-income countries (LMICs), enteric pathogens contribute to child malnutrition, affecting nutrient absorption, inducing inflammation, and causing diarrhoea. This is a substantial problem in LMICs due to high disease burden, poor sanitation and nutritional status, and the cyclical nature of pathogen infection and malnutrition. This relationship remains understudied in Timor-Leste. In our pilot study of enteric pathogens and malnutrition in Dili, Timor-Leste (July 2019-October 2020), we recruited 60 infants in a birth cohort from Hospital Nacional Guido Valadares (HNGV) with up to four home visits. We collected faecal samples and details of demographics, anthropometrics, diet and food practices, and animal husbandry. Additionally, we collected faecal samples, diagnostics, and anthropometrics from 160 children admitted to HNGV with a clinical diagnosis of severe diarrhoea or severe acute malnutrition (SAM). We tested faeces using the BioFire® FilmArray® Gastrointestinal Panel. We detected high prevalence of enteric pathogens in 68.8% (95%CI 60.4-76.2%) of infants at home, 88.6% of SAM cases (95%CI 81.7-93.3%) and 93.8% of severe diarrhoea cases (95%CI 67.7-99.7%). Diarrhoeagenic Escherichia coli and Campylobacter spp. were most frequently detected. Pathogen presence did not significantly differ in birth cohort diarrhoeal stool, but hospital data indicated associations between Salmonella and Shigella and diarrhoea. We observed wasting in 18.4% (95%CI 9.2-32.5%) to 30.8% (95%CI 17.5-47.7%) of infants across home visits, 57.9% (95%CI 34.0-78.9%) of severe diarrhoea cases, and 92.5% (95%CI 86.4-96.2%) of SAM cases. We associated bottle feeding with increased odds of pathogen detection when compared with exclusive breastfeeding at home (OR 8.3, 95%CI 1.1-62.7). We detected high prevalence of enteric pathogens and signs of malnutrition in children in Dili. Our pilot is proof of concept for a study to fully explore the risk factors and associations between enteric pathogens and malnutrition in Timor-Leste.

NUTRITIONAL STATUS AND RISK FACTORS ASSOCIATED WITH SEVERE ACUTE MALNUTRITION AMONG HIV-INFECTED CHILDREN ENROLLED IN THE PAEDIATRIC HIV CLINIC, KORLE BU TEACHING HOSPITAL, ACCRA, GHANA.

Background: Malnutrition remains a common problem among Human Immunodeficiency Virus (HIV)-infected children even while receiving antiretroviral therapy leading to disease progression and reduced survival. Aim: To assess the nutritional status and risk factors associated with severe acute malnutrition (SAM) among HIV-infected children aged 1 to 15 years attending the Paediatric HIV Clinic at Korle Bu Teaching Hospital (KBTH), Accra. Methods: A cross-sectional study was conducted from October 2018 to January 2019 at the Clinic during which 150 participants aged 15 to 179 months were systematically recruited. A structured interview, physical examination, including anthropometric measurements, data extraction from hospital records, and laboratory investigations were conducted. Weight-for- age, weight-for-length/height, length/height-for-age, body mass index Z scores, and mid-upper arm circumference-for-age were obtained. Logistic regression models were used to assess the crude and adjusted odds of the nutritional status on the socio-demographic, clinical, and HIV-related characteristics of the participants at alpha= 0.05. Results: The prevalence of SAM, moderate acute malnutrition and normal nutrition were 4.0% (6/149), 13.4% (20/149) and 80.5% (120/149), respectively, whilst 1.3% (2/149) were overweight and 0.7% (1/149) obese. Stunting and severe stunting were 18.1% (27/149) and 6.7% (10/149) prevalent, respectively. SAM was significantly associated with oral thrush among participants in the adjusted model. The prevalence of mild-, moderate- and severe-anaemia were 23.7% (33/139), 38.8% (54/139) and 1.4% (2/139), respectively. Conclusion: Malnutrition is prevalent among HIV-infected children on antiretroviral therapy at KBTH. SAM is associated with oral thrush.

Growth and Body Composition 5 y After Treatment for Severe Acute Malnutrition: A 5-y Prospective Matched Cohort Study in Ethiopian Children.

BACKGROUND: Short-term anthropometric outcomes are well documented for children treated for severe acute malnutrition (SAM). However, anthropometric recovery may not indicate restoration of healthy body composition. OBJECTIVES: This study aimed to evaluate long-term associations of SAM with growth and body composition of children 5 y after discharge from community-based management of acute malnutrition (CMAM). METHODS: We conducted a 5-y prospective cohort study, enrolling children aged 6 to 59 mo discharged from CMAM (post-SAM) (n = 203) and nonmalnourished matched controls (n = 202) from Jimma Zone, Ethiopia in 2013. Anthropometry and body composition (bioelectrical impedance) were assessed. Multiple linear regression models tested differences in height-for-age (HAZ), weight-for-age (WAZ), and body mass index-for-age (BAZ) z-scores; height-adjusted fat-free mass index (FFMI); and FM index (FMI) between groups. RESULTS: Post-SAM children had higher stunting prevalence than controls at discharge (82.2% compared with 36.0%; P < 0.001), 1 y (80.2% compared with 53.7%; P < 0.001), and 5 y postdischarge (74.2% compared with 40.8%; P < 0.001). Post-SAM children remained 5 cm shorter throughout follow-up, indicating no HAZ catch-up. No catch-up in WAZ or BAZ was observed. Post-SAM children had lower hip (-2.05 cm; 95% CI: -2.73, -1.36), waist (-0.92 cm; CI: -1.59, -0.23) and mid-upper arm (-0.64 cm; CI: -0.90, -0.42) circumferences and lower-limb length (-1.57 cm; 95% CI: -2.21, -0.94) at 5 y postdischarge. They had larger waist-hip (0.02 cm; 95% CI: 0.008, 0.033) and waist-height (0.013 cm; 95% CI: 0.004, 0.021) ratios, and persistent deficits in FFMI at discharge and 6 mo and 5 y postdischarge (P < 0.001 for all). No difference was detected in head circumference, sitting height, or FMI. CONCLUSIONS: Five y after SAM treatment, children maintained deficits in HAZ, WAZ, BAZ, and FFMI, with preservation of FMI, sitting height, and head circumference at the expense of lower-limb length, indicating a "thrifty growth" pattern. Research is urgently needed to identify effective clinical and public health interventions to mitigate these consequences of malnutrition.

Risk factors for inpatient mortality among children with severe acute malnutrition in Zimbabwe and Zambia.

BACKGROUND/OBJECTIVES: Malnutrition underlies 45% of deaths in children under-5 years annually. Children hospitalised with complicated severe acute malnutrition (SAM) have unacceptably high mortality. We aimed to identify variables from early hospital admission (baseline factors) independently associated with inpatient mortality in this cohort to identify those most at risk. SUBJECTS/METHODS: Observational study of 745 children aged 0-59 months admitted with complicated SAM at three hospitals in Zimbabwe/Zambia. Children underwent anthropometry and clinical assessment by a study physician within 72 h of enrolment, and caregivers provided sociodemographic data. Children were followed-up daily until discharge/death. A multivariable survival analysis identified the baseline factors independently associated with mortality. RESULTS: 70/745 (9.4%) children died in hospital. Age between 6-23 months [aHR 6.53, 95%CI 2.24-19.02], higher mid-upper arm circumference [aHR 0.73, 95%CI 0.59-0.89], presence of oedema [aHR 2.22, 95%CI 1.23-4.05], shock [aHR 8.18, 95%CI 3.79-17.65], sepsis [aHR 3.13, 95%CI 1.44-6.80], persistent diarrhoea [aHR 2.27, 95%CI 1.18-4.37], lack of a toilet at home [aHR 4.35, 95%CI 1.65-11.47], and recruitment at one Harare site [aHR 0.38, 95%CI 0.18-0.83] were all independently associated with inpatient mortality. Oedematous children had a significantly higher birthweight [2987 g vs 2757 g, p < 0.001] than those without oedema; higher birthweight was weakly associated with mortality [aHR 1.50 95%CI 0.97-2.31]. CONCLUSIONS: Children with oedema, low MUAC, baseline infections, shock and lack of home sanitation had a significantly increased risk of inpatient mortality following hospitalisation for complicated SAM. Children with high-risk features may require additional care. A better understanding of the pathophysiology of SAM is needed to identify adjunctive interventions.

Feasibility trial for the management of severe acute malnutrition in older children with sickle cell anemia in Nigeria.

Children with sickle cell anemia (SCA) living in Nigeria are at an increased risk of malnutrition, which contributes to increased morbidity and mortality. However, evidence-based guidelines for managing malnutrition in children with SCA are lacking. To address this gap, we conducted a multicenter, randomized controlled feasibility trial to assess the feasibility and safety of treating children with SCA aged from 5 to 12 years and having uncomplicated severe acute malnutrition (body mass index z score of <-3.0). Children with SCA and uncomplicated severe acute malnutrition were randomly allocated to receive supplemental ready-to-use therapeutic food (RUTF) with or without moderate-dose hydroxyurea therapy (20 mg/kg per day). Over a 6-month enrollment period, 3190 children aged from 5 to 12 years with SCA were evaluated for eligibility, and 110 of 111 children who were eligible were enrolled. During the 12-week trial, no participants withdrew or missed visits. One participant died of unrelated causes. Adherence was high for hydroxyurea (94%, based on pill counts) and RUTF (100%, based on the number of empty sachets returned). No refeeding syndrome event or hydroxyurea-related myelosuppression occurred. At the end of the trial, the mean change in body mass index z score was 0.49 (standard deviation = 0.53), and 39% of participants improved their body mass index z score to ≥-3.0. Our findings demonstrate the feasibility, safety, and potential of outpatient treatment for uncomplicated severe acute malnutrition in children with SCA aged from 5 to 12 years in a low-resource setting. However, RUTF sharing with household and community members potentially confounded the response to malnutrition treatment. This trial was registered at clinicaltrials.gov as #NCT03634488.

Nutritional Recovery of Children With HIV and Severe Acute Malnutrition Attending an Outpatient Therapeutic Care Program.

BACKGROUND: Despite significant morbidity and mortality from HIV and severe acute malnutrition (SAM) among children in sub-Saharan Africa, research is lacking in these children. We describe the proportion of children living with HIV with SAM achieving recovery, the factors associated with recovery, and time to recovery in an outpatient therapeutic care program. SETTING AND METHODS: This is a retrospective observational study of children with SAM and HIV on antiretroviral therapy (6 months-15 years), enrolled in outpatient therapeutic care from 2015 to 2017 at a pediatric HIV clinic in Kampala, Uganda. SAM diagnosis and recovery by 120 days after enrollment were determined per World Health Organization guidelines. Cox-proportional hazards models were used to determine predictors of recovery. RESULTS: Data from 166 patients were analyzed (mean age 5.4 years, SD 4.7). Outcomes showed 36.1% recovered, 15.6% were lost to follow-up, 2.4% died, and 45.8% failed. Average time to recovery was 59.9 days (SD 27.8). Patients 5 years or older were less likely to recover (crude hazard ratio [CHR] = 0.33, 95% CI: 0.18 to 0.58). In multivariate analysis, febrile patients were less likely to recover (adjusted hazard ratio = 0.53, 95% CI: 0.12 to 0.65). Patients with CD4 count of 200 or less at enrollment were less likely to recover (CHR = 0.46, 95% CI: 0.22 to 0.96). CONCLUSIONS: Despite treatment with antiretroviral therapy for children living with HIV, we observed poor rates of recovery from SAM, below the international target of >75%. Moreover, patients 5 years and older, fever, or low CD4 at diagnosis of SAM may require more intense therapy or closer monitoring than their counterparts.

Probiotics for children with uncomplicated severe acute malnutrition (PruSAM study): A randomized controlled trial in the Democratic Republic of Congo.

BACKGROUND: Severe acute malnutrition (SAM) contributes to nearly 1 million deaths annually worldwide, with diarrhea and pneumonia being the common morbidity associated with mortality. OBJECTIVES: To assess the effect of probiotics on diarrhea, pneumonia, and nutritional recovery in children with uncomplicated SAM. METHODS: A randomized, double-blind, placebo-controlled study was conducted involving 400 children with uncomplicated SAM randomly assigned to ready-to-use therapeutic food (RUTF) either with (n = 200) or without (n = 200) probiotics. Patients received 1 mL daily dose of a blend of Lacticasebacillus rhamnosus GG and Limosilactobacillus reuteri DSM 17938 (dosage, 2 billion colony-forming units; 50:50) or placebo during 1 mo. They were simultaneously fed with the RUTF for 6 to 12 wk, depending on patients' recovery rates. The primary outcome was the duration of diarrhea. Secondary outcomes included diarrheal and pneumonic incidence, nutritional recovery, and transfer to inpatient care rate. RESULTS: For children with diarrhea, the number of days of disease was lower in the probiotic group (4.11; 95% CI: 3.37, 4.51) than that in the placebo group (6.68; 95% CI: 6.26, 7.13; P < 0.001). For children aged 16 mo or older, the risk of diarrhea was lower in the probiotic group (75.6%; 95% CI: 66.2, 82.9) than that in the placebo group (95.0%; 95% CI: 88.2, 97.9; P < 0.001), but no significant difference of the risk for the youngest. In the probiotic group, nutritional recovery happened earlier: at the 6th wk, 40.6% of the infants were waiting for nutritional recovery, contrasting with 68.7% of infants in the placebo group; but the nutritional recovery rate at the 12th wk was similar between the groups. Probiotics had no effect on pneumonic incidence and transfer to inpatient care. CONCLUSIONS: This trial supports using probiotics for the treatment of children with uncomplicated SAM. Its effect on diarrhea could positively affect nutritional programs in resource-limited settings. This trial was registered https://pactr.samrc.ac.za as PACTR202108842939734.

Efficacy of dopamine, epinephrine and blood transfusion for treatment of fluid refractory shock in children with severe acute malnutrition or severe underweight and cholera or other dehydrating diarrhoeas: protocol for a randomised controlled clinical trial.

INTRODUCTION: Diarrhoea is one of the leading causes of under-5 childhood mortality and accounts for 8% of 5.4 million global under-5 deaths. In severely malnourished children, diarrhoea progresses to shock, where the risk of mortality is even higher. At icddr,b Dhaka Hospital, the fatality rate is as high as 69% in children with severe malnutrition and fluid refractory septic shock. To date, no study has evaluated systematically the effects of inotrope or vasopressor or blood transfusion in children with dehydrating diarrhoea (eg, in cholera) and severe acute malnutrition (SAM) or severe underweight who are in shock and unresponsive to WHO-recommended fluid therapy. To reduce the mortality of severely malnourished children presenting with diarrhoea and fluid refractory shock, we aim to compare the efficacy of blood transfusion, dopamine and epinephrine in fluid refractory shock in children who do not respond to WHO-recommended fluid resuscitation. METHODS AND ANALYSIS: In this randomised, three-arm, controlled, non-masked clinical trial in children 1-59 months old with SAM or severe underweight and fluid refractory shock, we will compare the efficacy of dopamine or epinephrine administration versus blood transfusion in children who failed to respond to WHO-recommended fluid resuscitation. The primary outcome variable is the case fatality rate. The effect of the intervention will be assessed by performing an intention-to-treat analysis. Recruitment and data collection began in July 2021 and are now ongoing. Results are expected by May 2023. ETHICS AND DISSEMINATION: This study has been approved by the icddr,b Institutional Review Board. We adhere to the 'Declaration of Helsinki' (2000), guidelines for Good Clinical Practice. Before enrolment, we collect signed informed consent from the parents or caregivers of the children. We will publish the results in a peer-reviewed journal and will arrange a dissemination seminar. TRIAL REGISTRATION NUMBER: NCT04750070.

Prevalence, severity, and predictors of malnutrition in Indian children with cerebral palsy and their impact on health-related quality of life.

Although several studies have shown that undernutrition is frequent in children with cerebral palsy (CP), studies determining predictors of undernutrition and its impact on health-related quality of life (HRQoL) are scarce. This study aimed to assess the prevalence, severity, and predictors of malnutrition in children with CP and its impact on quality of life. This prospective study was performed between August 2019 and December 2021 in children with a clinical diagnosis of CP aged 2-18 years. We also intended to determine the socio-demographic and clinical predictors of undernutrition in these children and its impact on HRQoL, measured by the cerebral palsy quality of life (CPQoL)-Primary Caregiver reported version. Out of 569 (5.4 ± 2.8 years of age, 74% boys) children with CP, 71%, 44%, and 72% children were underweight, wasted, and stunted respectively, whereas 22%, 11%, and 21% were severely underweight, wasted and stunted respectively. Lower socioeconomic status, higher Gross Motor Function Classification System, and Manual Ability Classification System level were found to be significantly associated with the severity of stunting and underweight (p < 0.05), but not with wasting. CPQoL score in children with CP aged > 4 years was lower in patients with severe wasting, stunting, and underweight, as compared to their rest of the counterparts when adjusted for socio-demographic and other clinical variables (p < 0.05).  Conclusion: Chronic undernutrition is more common than severe acute malnutrition in children with CP. The severity of undernutrition is an important predictor of impaired HRQoL in children with CP. What is Known: • Several studies have shown that undernutrition is frequent in children with cerebral palsy; however, studies determining predictors of undernutrition and its impact on health-related quality of life are scarce. What is New: • Our study identifies that lower socioeconomic status, higher Gross Motor Function Classification System, and Manual Ability Classification System level are significantly associated with the severity of stunting and being underweight. • Chronic undernutrition is more common than severe acute malnutrition in children with cerebral palsy. Its severity is an important predictor of impaired health-related quality of life in children with cerebral palsy.

Antibiotic use and resistance in children with severe acute malnutrition and human immunodeficiency virus infection.

Severe acute malnutrition (SAM) and human immunodeficiency virus (HIV) infection underlie a major proportion of the childhood disease burden in low- and middle-income countries. These diseases commonly co-occur and lead to higher risk of other endemic infectious diseases, thereby compounding the risk of mortality and morbidity. The widespread use of antibiotics as treatment and prophylaxis in childhood SAM and HIV infections, respectively, has reduced mortality and morbidity but canlead to increasing antibiotic resistance. Development of antibiotic resistance could render future infections untreatable. This review summarises the endemic co-occurrence of undernutrition, particularly SAM, and HIV in children, and current treatment practices, specifically WHO-recommended antibiotic usage. The risks and benefits of antibiotic treatment, prophylaxis and resistance are reviewed in the context of patients with SAM and HIV and associated sub-populations. Finally, the review highlights possible research areas and populations where antibiotic resistance progression can be studied to best address concerns associated with the future impact of resistance. Current antibiotic usage is lifesaving in complicated SAM and HIV-infected populations; nevertheless, increasing baseline resistance and infection remain a significant concern. In conclusion, antibiotic usage currently addresses the immediate needs of children in SAM and HIV endemic regions; however, it is prudent to evaluate the impact of antibiotic use on resistance dynamics and long-term child health.

Long-term health after Severe Acute Malnutrition in children and adults- the role of the Pancreas (SAMPA): Protocol.

Background: Prenatal growth retardation may increase the risk of later chronic non-communicable diseases (NCDs), including diabetes; however, long-term effects of wasting malnutrition in childhood or adulthood are less studied. Pancreatic exocrine and endocrine functions, both critical for nutrition and NCD aetiology, may not fully recover following malnutrition. However, the evidence and mechanistic information is piecemeal. We hypothesise that wasting malnutrition at any age has long-term detrimental effects on endocrine and exocrine pancreatic structure and function. Methods: The SAMPA international research programme will assess pancreatic structure and function in 3700 participants from ongoing observational nutrition cohorts, two adolescent and four adult, in Zambia, Tanzania, Philippines, and India. Pancreas size, structure, and calcification will be assessed by ultrasound and computed tomography (CT) scan; exocrine function by faecal elastase and serum lipase; and endocrine function by haemoglobin A1c (HbA1c) and blood glucose, insulin and C-peptide concentrations during an oral glucose tolerance test (OGTT). In-depth hormonal analyses of incretins, glucagon, proinsulin and trypsinogen during OGTT and intravenous glucose tolerance tests will be done in subsets of adult participants. Pancreatic size and function outcomes will be compared between people with and without prior wasting malnutrition. Analyses will investigate effect modification by sex, current age, time since malnutrition, current body mass index and dietary patterns. Mathematical modelling of OGTT data will be used to estimate the relative contribution to glucose dysregulation of decreased insulin production, changes in insulin clearance and increased insulin resistance. Proinsulin/insulin ratio will be analysed in archived samples from the Tanzanian cohort using a nested case-control design to investigate whether abnormal values precede diabetes. Conclusions: SAMPA, a large-scale multi-centre research programme using data from people with or without prior wasting malnutrition to assess several aspects of pancreatic phenotype, will provide coherent evidence for future policies and programmes for malnutrition and diabetes.

Post-discharge morbidity and mortality in children admitted with severe anaemia and other health conditions in malaria-endemic settings in Africa: a systematic review and meta-analysis.

BACKGROUND: Severe anaemia is associated with high in-hospital mortality among young children. In malaria-endemic areas, surviving children also remain at increased risk of mortality for several months after hospital discharge. We aimed to compare the risks of morbidity and mortality among children discharged from hospital after recovery from severe anaemia versus other health conditions in malaria-endemic settings in Africa. METHODS: Following PRISMA guidelines, we searched PubMed, Scopus, Web of Science, and Cochrane Central from inception to Nov 30, 2021, without language restrictions, for prospective or retrospective cohort studies and randomised controlled trials that followed up children younger than 15 years for defined periods after hospital discharge in malaria-endemic countries in Africa. We excluded the intervention groups in trials and studies or subgroups involving children with sickle cell anaemia, malignancies, or surgery or trauma, or those reporting follow-up data that were combined with the in-hospital period. Two independent reviewers extracted the data and assessed the quality and risk of bias using the Newcastle Ottawa Scale or the Cochrane Collaboration's tool. The coprimary outcomes were all-cause death and all-cause readmissions 6 months after discharge. This study is registered with PROSPERO, CRD42017079282. FINDINGS: Of 2930 articles identified in our search, 27 studies were included. For children who were recently discharged following hospital admission with severe anaemia, all-cause mortality by 6 months was higher than during the in-hospital period (n=5 studies; Mantel-Haenszel odds ratio 1·72, 95% CI 1·22-2·44; p=0·0020; I2=51·5%) and more than two times higher than children previously admitted without severe anaemia (n=4 studies; relative risk [RR] 2·69, 95% CI 1·59-4·53; p<0·0001; I2=69·2%). Readmissions within 6 months of discharge were also more common in children admitted with severe anaemia than in children admitted with other conditions (n=1 study; RR 3·05, 1·12-8·35; p<0·0001). Children admitted with severe acute malnutrition (regardless of severe anaemia) also had a higher 6-month mortality after discharge than those admitted for other reasons (n=2 studies; RR=3·12, 2·02-4·68; p<0·0001; I2=54·7%). Other predictors of mortality after discharge included discharge against medical advice, HIV, bacteraemia, and hypoxia. INTERPRETATION: In malaria-endemic settings in Africa, children admitted to hospital with severe anaemia and severe acute malnutrition are at increased risk of mortality in the first 6 months after discharge compared with children admitted with other health conditions. Improved strategies are needed for the management of these high-risk groups during the period after discharge. FUNDING: Research Council of Norway and US Centers for Disease Control and Prevention.

Simplifying and optimising the management of uncomplicated acute malnutrition in children aged 6-59 months in the Democratic Republic of the Congo (OptiMA-DRC): a non-inferiority, randomised controlled trial.

BACKGROUND: Global access to acute malnutrition treatment is low. Different programmes using different nutritional products manage cases of severe acute malnutrition and moderate acute malnutrition separately. We aimed to assess whether integrating severe acute malnutrition and moderate acute malnutrition treatment into one programme, using a single nutritional product and reducing the dose as the child improves, could achieve similar or higher individual efficacy, increase coverage, and minimise costs compared with the current programmes. METHODS: We conducted an open-label, non-inferiority, randomised controlled trial in the Democratic Republic of the Congo. Acutely malnourished children aged 6-59 months with a mid-upper-arm circumference (MUAC) of less than 125 mm or oedema were randomly assigned (1:1), using specially developed software and random blocks (size was kept confidential), to either the current standard strategy (one programme for severe acute malnutrition using ready-to-use therapeutic food [RUTF] at an increasing dose as weight increased, another for moderate acute malnutrition using a fixed dose of ready-to-use supplementary food [RUSF]) or the OptiMA strategy (a single programme for both severe acute malnutrition and moderate acute malnutrition using RUTF at a decreasing dose as MUAC and weight increased). The primary endpoint was a favourable outcome at 6 months, defined as being alive, not acutely malnourished as per the definition applied at inclusion, and with no further episodes of acute malnutrition throughout the 6-month observation period; the endpoint was analysed in the intention-to-treat (all children) and per-protocol populations (participants who had a minimum prescription of 4 weeks' RUTF, received at least 90% of the total amount of RUTF they were supposed to receive as per the protocol, or were prescribed RUSF rations for a minimum of 4 weeks [ie, minimum of 28 RUSF sachets], and had a maximum interval of 6 weeks between any two visits in the 6-month follow-up). The non-inferiority analysis (margin 10%) was to be followed by a superiority analysis (margin 0%) if non-inferiority was concluded. This trial is registered at ClinicalTrials.gov, NCT03751475, and is now closed. FINDINGS: Between July 22 and Dec 6, 2019, 912 children were randomly assigned; after 16 were excluded, 896 were analysed (446 in the standard group and 450 in the OptiMA group). In the intention-to-treat analysis, 282 (63%) of 446 children in the standard group and 325 (72%) of 450 children in the OptiMA group had a favourable outcome (difference -9·0%, 95% CI -15·9 to -2·0). In the per protocol analysis, 161 (61%) of 264 children in the standard group and 291 (74%) of 392 children in the OptiMA group had a favourable outcome (-13·2%, -21·6 to -4·9). INTERPRETATION: In this non-inferiority trial treating children with MUAC of less than 125 mm or oedema, decreasing RUTF dose according to MUAC and weight increase proved to be a superior strategy to the standard protocol in the Democratic Republic of the Congo. These results demonstrate the safety and benefits of an approach that could substantially increase access to treatment for millions of children with acute malnutrition in sub-Saharan Africa. FUNDING: Innocent Foundation and European Civil Protection and Humanitarian Aid Operations. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Liver fat in adult survivors of severe acute malnutrition.

The association between severe acute malnutrition (SAM) in early childhood and liver fat in adults is unknown. We hypothesized that exposure to SAM, especially severe wasting, is associated with fatty liver later in life. In this observational study, abdominal CT was used to quantify mean liver attenuation (MLA) and liver:spleen attenuation ratio (L/S). Birth weight (BW), serum lipids, insulin resistance (homeostatic model assessment), anthropometry and intrabdominal fat were collected. Mean differences between diagnostic groups were tested and hierarchical regression analysis determined the best predictors of liver fat. We studied 88 adult SAM survivors and 84 community participants (CPs); age 29.0 ± 8.4 years, BMI 23.5 ± 5.0 kg/m2 (mean ± SDs). SAM survivors had less liver fat than CPs (using L/S) (p = 0.025). Severe wasting survivors (SWs) had lower BW (-0.51 kg; p = 0.02), were younger, thinner and had smaller waist circumference than oedematous malnutrition survivors (OMs). In the final regression model adjusting for age, sex, birth weight and SAM phenotype (i.e., oedematous malnutrition or severe wasting), SWs had more liver fat than OMs (using MLA) (B = 2.6 ± 1.3; p = 0.04) but similar liver fat using L/S (p = 0.07) and lower BW infants had less liver fat (MLA) (B = -1.8 ± 0.8; p = 0.03). Greater liver fat in SWs than OMs, despite having less body fat, supports our hypothesis of greater cardiometabolic risk in SWs. Other postnatal factors might influence greater liver fat in survivors of severe wasting, suggesting the need to monitor infants exposed to SAM beyond the acute episode.

Optimal iron content in ready-to-use therapeutic foods for the treatment of severe acute malnutrition in the community settings: a protocol for the systematic review and meta-analysis.

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.

The effect of wasting and stunting during severe acute malnutrition in infancy on insulin sensitivity and insulin clearance in adult life.

Adults who had non-edematous severe acute malnutrition (SAM) during infancy (i.e., marasmus) have worse glucose tolerance and beta-cell function than survivors of edematous SAM (i.e., kwashiorkor). We hypothesized that wasting and/or stunting in SAM is associated with lower glucose disposal rate (M) and insulin clearance (MCR) in adulthood.We recruited 40 nondiabetic adult SAM survivors (20 marasmus survivors (MS) and 20 kwashiorkor survivors (KS)) and 13 matched community controls. We performed 150-minute hyperinsulinaemic, euglycaemic clamps to estimate M and MCR. We also measured serum adiponectin, anthropometry, and body composition. Data on wasting (weight-for-height) and stunting (height-for-age) were abstracted from the hospital records.Children with marasmus had lower weight-for-height z-scores (WHZ) (-3.8 ± 0.9 vs. -2.2 ± 1.4; P < 0.001) and lower height-for-age z-scores (HAZ) (-4.6 ± 1.1 vs. -3.4 ± 1.5; P = 0.0092) than those with kwashiorkor. As adults, mean age (SD) of participants was 27.2 (8.1) years; BMI was 23.6 (5.0) kg/m2. SAM survivors and controls had similar body composition. MS and KS and controls had similar M (9.1 ± 3.2; 8.7 ± 4.6; 6.9 ± 2.5 mg.kg-1.min-1 respectively; P = 0.3) and MCR. WHZ and HAZ were not associated with M, MCR or adiponectin even after adjusting for body composition.Wasting and stunting during infancy are not associated with insulin sensitivity and insulin clearance in lean, young, adult survivors of SAM. These data are consistent with the finding that glucose intolerance in malnutrition survivors is mostly due to beta-cell dysfunction.

Time to develop severe acute malnutrition and its predictors among children living with HIV in the era of test and treat strategies at South Gondar hospitals, northwest, Ethiopia, 2021: a multicentre retrospective cohort study.

BACKGROUND: Although severe acute malnutrition is a major public issue among HIV infected children, there is no prior evidence in Ethiopia. Hence, this study aims to assess the time to develop severe acute malnutrition and its predictors among children living with human immunodeficiency virus in Ethiopia, 2012. METHODS: An institution based retrospective cohort study was conducted in South Gondar hospitals among 363 HIV infected children from February 10, 2014, to January 7, 2021. Epi-data version 3.1 was used to enter data, which was then exported to STATA version 14 for analysis. Besides, WHO (World Health Organization) Anthro Plus software was used to assess the nutritional status of the children. A standardized data extraction tool was used to collect the data. The Kaplan Meier survival curve was used to estimate the median survival time. The Cox-proportional hazard model assumption was checked via the Schoenfeld residual ph test and a stph plot. Bivariable and multivariable Cox proportional hazard models were employed at 95% confidence intervals (CI). A variable having a p-value < 0.05 was considered a statistically significant predictor of severe acute malnutrition. RESULTS: A total of 363 children living with HIV, 97 (26.72%) developed severe acute malnutrition during the follow-up period. The overall incidence rate was 5.4 (95% CI: 4.7-5.9) person per year with a total of 21, 492 months or 1791 years of observation. Moreover, the median survival time was 126 months. Treatment failure [AHR =3.4 (95% CI: 2.05-5.75)], CD4 count below threshold [AHR =2.5 (95% CI: 1.64-3.95)], and WHO stage III & IV [AHR =2.9 (95% CI: 1.74-4.73)] were all significant predictors of severe acute malnutrition. CONCLUSION: The time to develop severe acute malnutrition was found to be very low. Treatment failure, CD4 count below threshold, and WHO stage III were all significant predictors of severe acute malnutrition. Hence, emphasizing those predictor variables is essential for preventing and controlling the occurrence of severe acute malnutrition among HIV infected children.

Use of TaqMan Array Cards to investigate the aetiological agents of diarrhoea among young infants with severe acute malnutrition.

OBJECTIVE: Studies involving less sensitive conventional microscopy and culture-based approaches have identified distinct differences in diarrhoeal aetiology in childhood malnutrition. Our study involved the use of an advanced molecular biology technique, the TaqMan Array Cards (TAC), to elucidate the diarrhoeal aetiology among young infants with severe acute malnutrition (SAM). METHOD: A total of 113 faecal samples was collected from SAM infants, aged 2-6 months, upon admission to the Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) with complications of diarrhoea and related comorbidities. We used TAC for the detection of 29 different diarrhoeal enteropathogens from a single faecal sample. For comparison, we also analysed 25 diarrhoeal samples from well-nourished infants of similar age. RESULTS: Higher odds of detection of all bacterial enteropathogens were associated with diarrhoea among SAM infants. In particular, the detection of Aeromonas sp (aOR: 25.7, p = 0.011), Campylobacter sp (aOR: 9.6, p < 0.01) and ETEC (aOR: 5.2, p = 0.022) was significantly associated with diarrhoea among SAM infants in comparison to well-nourished infants. 80% higher odds of detection of rotavirus and norovirus GII were associated with diarrhoea among well-nourished infants in comparison to SAM infants (aOR: 0.2, p < 0.05). CONCLUSION: Our study findings demonstrate a difference in diarrhoeal aetiology among SAM and well-nourished young infants, which may be useful in providing an evidence-based logic for possible revision of treatment guidelines for treatment of young diarrhoeal infants with SAM in the early management of the menace of antimicrobial resistance.

Metabolomic changes in severe acute malnutrition suggest hepatic oxidative stress: a secondary analysis.

Severe acute malnutrition (SAM), due to poor energy and/or protein intake, is associated with poor growth, depressed immune function, and long-term impacts on metabolic function. As the liver is a major metabolic organ and malnutrition poses metabolic stress, we hypothesize that SAM will be associated with alterations in the hepatic metabolome reflective of oxidative stress, gluconeogenesis, and ketogenesis. Thus, the purpose of this secondary analysis was to understand how SAM alters hepatic metabolism using a piglet model. Weanling piglets were feed either a reference (REF) or protein-energy deficient diet (MAL) for 5 weeks. After dietary treatment MAL piglets were severely underweight (weight-for-age Z-score of -3.29, Welch's t test, P = .0007), moderately wasted (weight-for-length Z-score of-2.49, Welch's t test, P = .003), and tended toward higher hepatic triglyceride content (Welch's t test, P = .07). Hematologic and blood biochemical measurements were assessed at baseline and after dietary treatment. The hepatic metabolome was investigated using 1H-NMR spectroscopy. Hepatic concentrations of betaine, cysteine, and glutathione tended to be lower in MAL (Welch's t test with FDR correction, P < .1), while inosine, lactate, and methionine sulfoxide concentrations were higher in MAL (inosine: P = .0448, lactate: P = .0258, methionine sulfoxide: P = .0337). These changes suggest that SAM is associated with elevated hepatic oxidative stress, increased gluconeogenesis, and alterations in 1-carbon metabolism.