A protocol for a proof-of-concept randomized control trial testing increased protein quantity and quality in ready-to-use therapeutic food in improving linear growth among 6-23-month-old children with severe wasting in Malawi

Introduction: Ready-to-use therapeutic foods (RUTFs) have successfully promoted recovery from severe wasting and increased treatment coverage. However, RUTFs do not sufficiently improve linear growth, leaving many survivors of severe wasting at risk of persistent stunting, which is associated with high mortality risk, poor child development and non-communicable diseases in adulthood. High protein quantity and quality can stimulate linear growth. Aim: The trial aims to assess whether higher-protein-RUTF leads to higher concentrations of markers of linear growth compared to standard RUTF among 6–23 months old children with severe wasting. Methods: We designed a higher protein quantity and quality RUTF for a proof-of-concept (PoC) double-blind randomized controlled trial. Outcomes: The primary outcome is a change in insulin-like growth factor-1 (IGF-1), a hormone positively associated with linear growth after four weeks of treatment. Secondary outcomes include changes in ponderal and linear growth and in body composition from baseline to eight weeks later; plasma amino acid profile at four weeks; acceptability and safety. Implications: These findings will help in informing the potential impact of increased protein in RUTF on linear growth when treating severe wasting towards conducting a larger clinical trial. Trial registration: The trial has been registered on clinicaltrial.gov (NCT05737472)

Intestinal disturbances associated with mortality of children with complicated severe malnutrition

Background: Children admitted to hospital with complicated severe malnutrition (CSM) have high mortality despite compliance with standard WHO management guidelines. Limited data suggests a relationship between intestinal dysfunction and poor prognosis in CSM, but this has not been explicitly studied. This study aimed to evaluate the role of intestinal disturbances in CSM mortality. Methods: A case-control study nested within a randomized control trial was conducted among children hospitalized with CSM in Kenya and Malawi. Children who died (cases, n = 68) were compared with those who were discharged, propensity matched to the cases on age, HIV and nutritional status (controls, n = 68) on fecal metabolomics that targeted about 70 commonly measured metabolites, and enteropathy markers: fecal myeloperoxidase (MPO), fecal calprotectin, and circulating intestinal fatty acid binding protein (I-FABP). Results: The fecal metabolomes of cases show specific reductions in amino acids, monosaccharides, and microbial fermentation products, when compared to controls. SCFA levels did not differ between groups. The overall fecal metabolomics signature moderately differentiates cases from controls (AUC = 0.72). Enteropathy markers do not differ between groups overall, although serum I-FABP is elevated in cases in a sensitivity analysis among non-edematous children. Integrative analysis with systemic data suggests an indirect role of intestinal inflammation in the causal path of mortality. Conclusions: Intestinal disturbances appear to have an indirect association with acute mortality. Findings of the study improve our understanding of pathophysiological pathways underlying mortality of children with CSM

New approaches and technical considerations in detecting outlier measurements and trajectories in longitudinal children growth data

Background Growth studies rely on longitudinal measurements, typically represented as trajectories. However, anthropometry is prone to errors that can generate outliers. While various methods are available for detecting outlier measurements, a gold standard has yet to be identified, and there is no established method for outlying trajectories. Thus, outlier types and their effects on growth pattern detection still need to be investigated. This work aimed to assess the performance of six methods at detecting different types of outliers, propose two novel methods for outlier trajectory detection and evaluate how outliers affect growth pattern detection. Methods We included 393 healthy infants from The Applied Research Group for Kids (TARGet Kids!) cohort and 1651 children with severe malnutrition from the co-trimoxazole prophylaxis clinical trial. We injected outliers of three types and six intensities and applied four outlier detection methods for measurements (model-based and World Health Organization cut-offs-based) and two for trajectories. We also assessed growth pattern detection before and after outlier injection using time series clustering and latent class mixed models. Error type, intensity, and population affected method performance. Results Model-based outlier detection methods performed best for measurements with precision between 5.72-99.89%, especially for low and moderate error intensities. The clustering-based outlier trajectory method had high precision of 14.93-99.12%. Combining methods improved the detection rate to 21.82% in outlier measurements. Finally, when comparing growth groups with and without outliers, the outliers were shown to alter group membership by 57.9 -79.04%. Conclusions World Health Organization cut-off-based techniques were shown to perform well in few very particular cases (extreme errors of high intensity), while model-based techniques performed well, especially for moderate errors of low intensity. Clustering-based outlier trajectory detection performed exceptionally well across all types and intensities of errors, indicating a potential strategic change in how outliers in growth data are viewed. Finally, the importance of detecting outliers was shown, given its impact on children growth studies, as demonstrated by comparing results of growth group detection

Bacterial Disease and Antimicrobial Susceptibility Patterns in HIV-Infected, Hospitalized Children: A Retrospective Cohort Study

The orginal version is available at www.plosone.orgBackground: Serious bacterial infections are a major source of morbidity and mortality in HIV-infected children. The spectrum of disease is wide, and responsible organisms vary according to setting. The use of antibiotic prophylaxis and the emergence of multi-drug resistant bacteria necessitate examination of responsible organisms and their antibiotic susceptibility. Methodology/Principal Findings: A retrospective cohort study of all HIV-positive pediatric admissions at an urban public sector hospital in Cape Town between January 2002 and June 2006 was conducted. Children between the ages of one month and nine years with laboratory confirmed HIV status, serious bacterial infection, and a hospital length of stay of 5 days or more, were eligible for inclusion. Organisms isolated from blood, urine, and cerebral spinal fluid cultures and their antimicrobial susceptibility were examined, and compared according to timing of isolation to distinguish nosocomial versus community-acquired. One hundred and forty-one children were identified (median age 1.2 years), 39% of whom were on antiretrovirals started before or during this hospitalization. Bacterial infections involved all organ systems, however pneumonia was most common (67%). S. pneumoniae and S. aureus were the most common gram positive and K. pneumoniae was the most common gram negative organism. K pneumoniae isolates were resistant to many first and second line antibiotics, and were all considered nosocomial. All S. aureus isolates were methicillin resistant, some of which were community-acquired. Conclusions/Significance: Bacterial infections are an important source of co-morbidity in HIV-infected children in resourcelimited settings. Clinicians should have a low threshold to initiate antibiotics in children requiring hospitalization. Broadspectrum antibiotics should be used judiciously. Clinicians caring for HIV-infected children should be cognizant of the most common organisms affecting such children, and of their local antimicrobial susceptibilities, when treating empirically for serious bacterial infections.Publisher's versio

A reduced-carbohydrate and lactose-free formulation for stabilization among hospitalized children with severe acute malnutrition: A double-blind, randomized controlled trial

BackgroundChildren with medically complicated severe acute malnutrition (SAM) have high risk of inpatient mortality. Diarrhea, carbohydrate malabsorption, and refeeding syndrome may contribute to early mortality and delayed recovery. We tested the hypothesis that a lactose-free, low-carbohydrate F75 milk would serve to limit these risks, thereby reducing the number of days in the stabilization phase.Methods and findingsIn a multicenter double-blind trial, hospitalized severely malnourished children were randomized to receive standard formula (F75) or isocaloric modified F75 (mF75) without lactose and with reduced carbohydrate. The primary endpoint was time to stabilization, as defined by the World Health Organization (WHO), with intention-to-treat analysis. Secondary outcomes included in-hospital mortality, diarrhea, and biochemical features of malabsorption and refeeding syndrome. The trial was registered at clinicaltrials.gov (NCT02246296). Four hundred eighteen and 425 severely malnourished children were randomized to F75 and mF75, respectively, with 516 (61%) enrolled in Kenya and 327 (39%) in Malawi. Children with a median age of 16 months were enrolled between 4 December 2014 and 24 December 2015. One hundred ninety-four (46%) children assigned to F75 and 188 (44%) to mF75 had diarrhea at admission. Median time to stabilization was 3 days (IQR 2–5 days), which was similar between randomized groups (0.23 [95% CI −0.13 to 0.60], P = 0.59). There was no evidence of effect modification by diarrhea at admission,age, edema, or HIV status. Thirty-six and 39 children died before stabilization in the F75 and in mF75 arm, respectively (P = 0.84). Cumulative days with diarrhea (P = 0.27), enteral (P = 0.42) or intravenous fluids (P = 0.19), other serious adverse events before stabilization, and serum and stool biochemistry at day 3 did not differ between groups. The main limitation was that the primary outcome of clinical stabilization was based on WHO guidelines, comprising clinical evidence of recovery from acute illness as well as metabolic stabilization evidenced by recovery of appetite. ConclusionsEmpirically treating hospitalized severely malnourished children during the stabilization phase with lactose-free, reduced-carbohydrate milk formula did not improve clinical outcomes. The biochemical analyses suggest that the lactose-free formulae may still exceed a carbohydrate load threshold for intestinal absorption, which may limit their usefulness in the context of complicated SAM

Iron Deficiency and Acute Seizures: Results from Children Living in Rural Kenya and a Meta-Analysis

There are conflicting reports on whether iron deficiency changes susceptibility to seizures. We examined the hypothesis that iron deficiency is associated with an increased risk of acute seizures in children in a malaria endemic area

Modified F75 formula for stabilisation among hospitalised children with severe acute malnutrition: double blind, randomised controlled trial

In a multi-centre double-blind trial, hospitalised severely malnourished children were randomised to receive standard formula (F75) or isocaloric modified F75 (mF75) without lactose and with reduced carbohydrate. The primary endpoint was time to stabilisation, as defined by the World Health Organisation, with intention-to-treat analysis. Secondary outcomes included in-hospital mortality, diarrhea, and biochemical features of malabsorption and refeeding syndrome. The trial was registered at clinicaltrials.gov (NCT02246296). </p