Loss of functional peroxisomes leads to increased mitochondrial biogenesis and reduced autophagy that preserve mitochondrial function.

Peroxisomes are essential for mitochondrial health, as the absence of peroxisomes leads to altered mitochondria. However, it is unclear whether the changes in mitochondria are a function of preserving cellular function or a response to cellular damage caused by the absence of peroxisomes. To address this, we developed conditional hepatocyte-specific Pex16 deficient (Pex16 KO) mice that develop peroxisome loss and subjected them to a low-protein diet to induce metabolic stress. Loss of PEX16 in hepatocytes led to increased biogenesis of small mitochondria and reduced autophagy flux but with preserved capacity for respiration and ATP capacity. Metabolic stress induced by low protein feeding led to mitochondrial dysfunction in Pex16 KO mice and impaired biogenesis. Activation of PPARα partially corrected these mitochondrial disturbances, despite the absence of peroxisomes. The findings of this study demonstrate that the absence of peroxisomes in hepatocytes results in a concerted effort to preserve mitochondrial function, including increased mitochondrial biogenesis, altered morphology, and modified autophagy activity. Our study underscores the relationship between peroxisomes and mitochondria in regulating the hepatic metabolic responses to nutritional stressors.

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.

Role of Pediatricians in Promoting and Supporting Breastfeeding: A Position Paper of the International Pediatric Association Strategic Advisory Group on Infant, Child, and Adolescent Nutrition.

BACKGROUND: Promoting and supporting breastfeeding is an important public health intervention with multiple benefits for both infants and mothers. Even modest increases in the prevalence and duration of breastfeeding could significantly reduce healthcare costs and improve maternal and child health outcomes. However, widespread adoption of breastfeeding recommendations remains poor in most settings, which contributes to widening health and social inequalities. Pediatricians have a duty to advocate for improving child health, including promoting and supporting breastfeeding. SUMMARY: This paper, from the International Pediatric Association Special Advisory Group on Nutrition, considers common barriers to breastfeeding and addresses how pediatricians can better promote and support breastfeeding, both at an individual level and by influencing practice and policy. All pediatricians need to understand the basics of breastfeeding, including lactation physiology, recognize common breastfeeding problems, and advise mothers or refer them for appropriate support; training curricula for general pediatricians and all pediatric subspecialties should reflect this. Even in the situation where their day-to-day work does not involve direct contact with mothers and infants, pediatricians can have an important influence on policy and practice. They should support colleagues who work directly with mothers and infants, ensuring that systems and environments are conducive to breastfeeding and, where appropriate, milk expression. Pediatricians and pediatric organizations should also promote policies aimed at promoting and supporting breastfeeding at local, regional, national, and international levels. KEY MESSAGES: Pediatricians have a duty to promote and support breastfeeding, regardless of their day-to-day role and responsibilities. Pediatric training curricula should ensure that all trainees acquire a good understanding of breastfeeding so they are able to effectively support mothers in their personal practice but also influence breastfeeding practice and policy at a local, regional, national, and international level.

The association between parents' stress and parental feeding practices and feeding styles: Systematic review and meta-analysis of observational studies.

In the extended UNICEF framework of early childhood nutrition, parents' stress is associated with parental feeding style. However, no comprehensive review has examined the association between parents' stress and feeding styles and practices. The objective of our review was to synthesise the current literature examining the association between parents' stress and their feeding practices and/or styles, among parents of children ≤ 5 years old. We searched; MEDLINE, EMBASE, PSYCHINFO and CINAHL from 2019 to 2021. Two investigators independently extracted relevant data and assessed the study quality and the certainty of evidence. Data were pooled using generic inverse variance with fixed effects (<5 comparisons) or random effects (≥5 comparisons) and expressed as correlation coefficients with 95% confidence intervals (CI). Between study heterogeneity was assessed using Cochran's Q and quantified with I2 . We identified 6 longitudinal and 11 cross-sectional studies, of which 4 studies provided sufficient data to be pooled. A very small correlation between general stress and restrictive feeding practices was observed (r = 0.06 [95% CI: 0.01-0.12]; no substantial heterogeneity (I2 = 0.00%, PQ < 0.85, very low certainty). No correlation between general stress and feeding pressure was identified (r = 0.06 [95% CI: -0.02 to 0.15]). Results showed that both general and parenting stress were associated with suboptimal breastfeeding practices and unresponsive feeding styles. Conclusion: This study demonstrated a low-to-moderate quality of literature for the inclusion of parents' stress in the extended UNICEF care model of child nutrition. Future research needs to explore this relationship longitudinally and in ethnic diverse populations to inform tailored interventions that promote responsive feeding practices.

Minimally Invasive Postmortem Intestinal Tissue Sampling in Malnourished and Acutely Ill Children Is Feasible and Informative.

BACKGROUND: Intestinal disorders such as environmental enteric dysfunction (EED) are prevalent in low- and middle-income countries (LMICs) and important contributors to childhood undernutrition and mortality. Autopsies are rarely performed in LMICs but minimally invasive tissue sampling is increasingly deployed as a more feasible and acceptable procedure, although protocols have been devoid of intestinal sampling to date. We sought to determine (1) the feasibility of postmortem intestinal sampling, (2) whether autolysis precludes enteric biopsies' utility, and (3) histopathologic features among children who died during hospitalization with acute illness or undernutrition. METHODS: Transabdominal needle and endoscopic forceps upper and lower intestinal sampling were conducted among children aged 1 week to 59 months who died while hospitalized in Blantyre, Malawi. Autolysis ratings were determined for each hematoxylin and eosin slide, and upper and lower intestinal scoring systems were adapted to assess histopathologic features and their severity. RESULTS: Endoscopic and transabdominal sampling procedures were attempted in 28 and 14 cases, respectively, with >90% success obtaining targeted tissue. Varying degrees of autolysis were present in all samples and precluded histopathologic scoring of 6% of 122 biopsies. Greater autolysis in duodenal samples was seen with longer postmortem interval (Beta = 0.06, 95% confidence interval, 0.02-0.11). Histopathologic features identified included duodenal Paneth and goblet cell depletion. Acute inflammation was absent but chronic inflammation was prevalent in both upper and lower enteric samples. Severe chronic rectal inflammation was identified in children as young as 5.5 weeks. CONCLUSIONS: Minimally invasive postmortem intestinal sampling is feasible and identifies histopathology that can inform mortality contributors.

Predicting the risk of mortality during hospitalization in sick severely malnourished children using daily evaluation of key clinical warning signs.

BACKGROUND: Despite adherence to WHO guidelines, inpatient mortality among sick children admitted to hospital with complicated severe acute malnutrition (SAM) remains unacceptably high. Several studies have examined risk factors present at admission for mortality. However, risks may evolve during admission with medical and nutritional treatment or deterioration. Currently, no specific guidance exists for assessing daily treatment response. This study aimed to determine the prognostic value of monitoring clinical signs on a daily basis for assessing mortality risk during hospitalization in children with SAM. METHODS: This is a secondary analysis of data from a randomized trial (NCT02246296) among 843 hospitalized children with SAM. Daily clinical signs were prospectively collected during ward rounds. Multivariable extended Cox regression using backward feature selection was performed to identify daily clinical warning signs (CWS) associated with time to death within the first 21 days of hospitalization. Predictive models were subsequently developed, and their prognostic performance evaluated using Harrell's concordance index (C-index) and time-dependent area under the curve (tAUC). RESULTS: Inpatient case fatality ratio was 16.3% (n=127). The presence of the following CWS during daily assessment were found to be independent predictors of inpatient mortality: symptomatic hypoglycemia, reduced consciousness, chest indrawing, not able to complete feeds, nutritional edema, diarrhea, and fever. Daily risk scores computed using these 7 CWS together with MUAC<10.5cm at admission as additional CWS predict survival outcome of children with SAM with a C-index of 0.81 (95% CI 0.77-0.86). Moreover, counting signs among the top 5 CWS (reduced consciousness, symptomatic hypoglycemia, chest indrawing, not able to complete foods, and MUAC<10.5cm) provided a simpler tool with similar prognostic performance (C-index of 0.79; 95% CI 0.74-0.84). Having 1 or 2 of these CWS on any day during hospitalization was associated with a 3 or 11-fold increased mortality risk compared with no signs, respectively. CONCLUSIONS: This study provides evidence for structured monitoring of daily CWS as recommended clinical practice as it improves prediction of inpatient mortality among sick children with complicated SAM. We propose a simple counting-tool to guide healthcare workers to assess treatment response for these children. TRIAL REGISTRATION: NCT02246296.

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

BACKGROUND: Children 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 FINDINGS: In 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. CONCLUSIONS: Empirically 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. TRIAL REGISTRATION: ClinicalTrials.gov NCT02246296.

Online education for gluten-free diet teaching: Development and usability testing of an e-learning module for children with concurrent celiac disease and type 1 diabetes.

BACKGROUND AND OBJECTIVE: Celiac disease (CD), the most common genetically-based food intolerance, affects 3% to 16% of children with type 1 diabetes (T1D). Treatment involves lifelong adherence to a gluten-free diet (GFD). Individualized dietary education is resource-intensive. We, therefore, sought to develop and test the usability of an e-learning module aimed at educating patients and caregivers regarding implementation of the GFD in children with concurrent CD and T1D. METHODS: An interactive e-learning module was developed based on extensive review of CD, T1D, and educational literature. A mixed-methods usability testing approach was used to refine and evaluate the module, using qualitative semi-structured interviews, observations, and satisfaction and knowledge questionnaires in two iterative cycles. The module was refined based on themes identified from each usability cycle. RESULTS: Eighteen patients (8 in cycle 1, 10 in cycle 2) and 15 caregivers (7 in cycle 1, 8 in cycle 2) participated. Patient participants had CD and T1D for a mean (SD) of 6.1 ± 5.1 and 8.3 ± 5.5 years, respectively. Their mean age was 13.5 ± 4.5 years. Thematic analysis of usability interviews showed the module to be appealing and resulted in minor module revisions after each cycle to improve usability. Mean satisfaction scores post-module completion were high (4.67 ± 0.54), indicating participants were "very satisfied" with the education. Knowledge test scores increased significantly from pre- to post-module completion (P = 0.001). CONCLUSION: A multifaceted user-centered usability approach demonstrated that an innovative, interactive e-learning module is effective in knowledge retention and can provide comprehensive and accessible information in the implementation of the GFD teaching in children with CD and T1D.

The Relation Between Malnutrition and the Exocrine Pancreas: A Systematic Review.

OBJECTIVE: The relation between malnutrition and exocrine pancreatic insufficiency (EPI) has been described previously, but it is unclear if malnutrition leads to EPI or vice versa. We systematically synthesized current evidence evaluating the association between malnutrition and EPI in children. METHODS: Pubmed, Embase, and Cochrane databases were searched from inception until February 2017. We included cohort or case-controlled studies in children reporting on prevalence or incidence of EPI and malnutrition. Data generation was performed independently by 2 authors. Quality was assessed by using quality assessment tools from the National Heart, Lung, and Blood Institute. RESULTS: Nineteen studies were divided into 2 groups: 10 studies showing EPI leading to malnutrition, and 9 studies showing malnutrition leading to EPI. Because of heterogeneity in design, definitions, and outcome measures, pooling of results was impossible. Quality was good in 4 of 19 studies. Pancreatic insufficiency was linked to decreased nutritional status in 8 of 10 articles, although this link was not specified properly in most articles. In malnourished children, improvement was seen in pancreatic function in 7 of 9 articles after nutritional rehabilitation. The link between the 2 was not further specified. Heterogeneity exists with respect to definitions, outcome measures, and study design. CONCLUSIONS: There is sufficient evidence for an association between EPI and malnutrition. We could not confirm whether there is a correlation or causality between EPI or malnutrition. It was therefore not possible to draw firm conclusions from this systematic review on underlying pathophysiological mechanisms between EPI and malnutrition. More observational clinical trials are crucially needed.

Pancreatic Enzyme Replacement Therapy in Children with Severe Acute Malnutrition: A Randomized Controlled Trial.

OBJECTIVE: To assess the benefits of pancreatic enzyme replacement therapy (PERT) in children with complicated severe acute malnutrition. STUDY DESIGN: We conducted a randomized, controlled trial in 90 children aged 6-60 months with complicated severe acute malnutrition at the Queen Elizabeth Central Hospital in Malawi. All children received standard care; the intervention group also received PERT for 28 days. RESULTS: Children treated with PERT for 28 days did not gain more weight than controls (13.7 ± 9.0% in controls vs 15.3 ± 11.3% in PERT; P = .56). Exocrine pancreatic insufficiency was present in 83.1% of patients on admission and fecal elastase-1 levels increased during hospitalization mostly seen in children with nonedematous severe acute malnutrition (P <.01). Although the study was not powered to detect differences in mortality, mortality was significantly lower in the intervention group treated with pancreatic enzymes (18.6% vs 37.8%; P < .05). Children who died had low fecal fatty acid split ratios at admission. Exocrine pancreatic insufficiency was not improved by PERT, but children receiving PERT were more likely to be discharged with every passing day (P = .02) compared with controls. CONCLUSIONS: PERT does not improve weight gain in severely malnourished children but does increase the rate of hospital discharge. Mortality was lower in patients on PERT, a finding that needs to be investigated in a larger cohort with stratification for edematous and nonedematous malnutrition. Mortality in severe acute malnutrition is associated with markers of poor digestive function. TRIAL REGISTRATION: ISRCTN.com: 57423639.

Starved Guts: Morphologic and Functional Intestinal Changes in Malnutrition.

Malnutrition contributes significantly to death and illness worldwide and especially to the deaths of children younger than 5 years. The relation between intestinal changes in malnutrition and morbidity and mortality has not been well characterized; however, recent research indicates that the functional and morphologic changes of the intestine secondary to malnutrition itself contribute significantly to these negative clinical outcomes and may be potent targets of intervention. The aim of this review was to summarize current knowledge of experimental and clinically observed changes in the intestine from malnutrition preclinical models and human studies. Limited clinical studies have shown villous blunting, intestinal inflammation, and changes in the intestinal microbiome of malnourished children. In addition to these findings, experimental data using various animal models of malnutrition have found evidence of increased intestinal permeability, upregulated intestinal inflammation, and loss of goblet cells. More mechanistic studies are urgently needed to improve our understanding of malnutrition-related intestinal dysfunction and to identify potential novel targets for intervention.

Effectiveness of three commonly used transition phase diets in the inpatient management of children with severe acute malnutrition: a pilot randomized controlled trial in Malawi.

BACKGROUND: The case fatality rate of severely malnourished children during inpatient treatment is high and mortality is often associated with diarrhea. As intestinal carbohydrate absorption is impaired in severe acute malnutrition (SAM), differences in dietary formulations during nutritional rehabilitation could lead to the development of osmotic diarrhea and subsequently hypovolemia and death. We compared three dietary strategies commonly used during the transition of severely malnourished children to higher caloric feeds, i.e., F100 milk (F100), Ready-to-Use Therapeutic Food (RUTF) and RUTF supplemented with F75 milk (RUTF + F75). METHODS: In this open-label pilot randomized controlled trial, 74 Malawian children with SAM aged 6-60 months, were assigned to either F100, RUTF or RUTF + F75. Our primary endpoint was the presence of low fecal pH (pH ≤ 5.5) measured in stool collected 3 days after the transition phase diets were introduced. Secondary outcomes were duration of hospital stay, diarrhea and other clinical outcomes. Chi-square test, two-way analysis of variance and logistic regression were conducted and, when appropriate, age, sex and initial weight for height Z-scores were included as covariates. RESULTS: The proportion of children with acidic stool (pH ≤5.5) did not significantly differ between groups before discharge with 30, 33 and 23% for F100, RUTF and RUTF + F75, respectively. Mean duration of stay after transitioning was 7.0 days (SD 3.4) with no differences between the three feeding strategies. Diarrhea was present upon admission in 33% of patients and was significantly higher (48%) during the transition phase (p < 0.05). There was no significant difference in mortality (n = 6) between diets during the transition phase nor were there any differences in other secondary outcomes. CONCLUSIONS: This pilot trial does not demonstrate that a particular transition phase diet is significantly better or worse since biochemical and clinical outcomes in children with SAM did not differ. However, larger and more tightly controlled efficacy studies are needed to confirm these findings. TRIAL REGISTRATION: ISRCTN13916953 Registered: 14 January 2013.

Malnutrition-associated liver steatosis and ATP depletion is caused by peroxisomal and mitochondrial dysfunction.

BACKGROUND & AIMS: Severe malnutrition in young children is associated with signs of hepatic dysfunction such as steatosis and hypoalbuminemia, but its etiology is unknown. Peroxisomes and mitochondria play key roles in various hepatic metabolic functions including lipid metabolism and energy production. To investigate the involvement of these organelles in the mechanisms underlying malnutrition-induced hepatic dysfunction we developed a rat model of malnutrition. METHODS: Weanling rats were placed on a low protein or control diet (5% or 20% of calories from protein, respectively) for four weeks. Peroxisomal and mitochondrial structural features were characterized using immunofluorescence and electron microscopy. Mitochondrial function was assessed using high-resolution respirometry. A novel targeted quantitative proteomics method was applied to analyze 47 mitochondrial proteins involved in oxidative phosphorylation, tricarboxylic acid cycle and fatty acid ß-oxidation pathways. RESULTS: Low protein diet-fed rats developed hypoalbuminemia and hepatic steatosis, consistent with the human phenotype. Hepatic peroxisome content was decreased and metabolomic analysis indicated peroxisomal dysfunction. This was followed by changes in mitochondrial ultrastructure and increased mitochondrial content. Mitochondrial function was impaired due to multiple defects affecting respiratory chain complex I and IV, pyruvate uptake and several ß-oxidation enzymes, leading to strongly reduced hepatic ATP levels. Fenofibrate supplementation restored hepatic peroxisome abundance and increased mitochondrial ß-oxidation capacity, resulting in reduced steatosis and normalization of ATP and plasma albumin levels. CONCLUSIONS: Malnutrition leads to severe impairments in hepatic peroxisomal and mitochondrial function, and hepatic metabolic dysfunction. We discuss the potential future implications of our findings for the clinical management of malnourished children. LAY SUMMARY: Severe malnutrition in children is associated with metabolic disturbances that are poorly understood. In order to study this further, we developed a malnutrition animal model and found that severe malnutrition leads to an impaired function of liver mitochondria which are essential for energy production and a loss of peroxisomes, which are important for normal liver metabolic function.

Both Exocrine Pancreatic Insufficiency and Signs of Pancreatic Inflammation Are Prevalent in Children with Complicated Severe Acute Malnutrition: An Observational Study.

OBJECTIVES: To assess whether pancreatic function is impaired in children with severe acute malnutrition, is different between edematous vs nonedematous malnutrition, and improves by nutritional rehabilitation. STUDY DESIGN: We followed 89 children with severe acute malnutrition admitted to Queen Elizabeth Central Hospital in Blantyre, Malawi. Stool and blood samples were taken on admission and 3 days after initial stabilization to determine exocrine pancreatic function via fecal elastase-1 (FE-1) and serum trypsinogen and amylase levels. RESULTS: A total of 33 children (37.1%) had nonedematous severe acute malnutrition, whereas 56 (62.9%) had edematous severe acute malnutrition. On admission, 92% of patients showed evidence of pancreatic insufficiency as measured by FE-1 <200 µg/g of stool. Patients with edematous severe acute malnutrition were more likely to have low FE-1 (98% vs 82.8%, P = .026). FE-1 levels remained low in these individuals throughout the assessment period. Serum trypsinogen was elevated (>57 ng/mL) in 28% and amylase in 21% (>110 U/L) of children, suggesting pancreatic inflammation. CONCLUSION: Exocrine pancreatic insufficiency is prevalent in children with severe acute malnutrition and especially in children with edematous severe acute malnutrition. In addition, biochemical signs suggestive of pancreatitis are common in children with severe acute malnutrition. These results have implications for standard rehabilitation treatment of children with severe acute malnutrition who may benefit from pancreatic enzyme replacement therapy. TRIAL REGISTRATION: ISRCTN.com: 13916953.

A low-protein diet combined with low-dose endotoxin leads to changes in glucose homeostasis in weanling rats.

Severe malnutrition is a leading cause of global childhood mortality, and infection and hypoglycemia or hyperglycemia are commonly present. The etiology behind the changes in glucose homeostasis is poorly understood. Here, we generated an animal model of severe malnutrition with and without low-grade inflammation to investigate the effects on glucose homeostasis. Immediately after weaning, rats were fed diets containing 5 [low-protein diet (LP)] or 20% protein [control diet (CTRL)], with or without repeated low-dose intraperitoneal lipopolysaccharide (LPS; 2 mg/kg), to mimic inflammation resulting from infections. After 4 wk on the diets, hyperglycemic clamps or euglycemic hyperinsulinemic clamps were performed with infusion of [U-(13)C6]glucose and [2-(13)C]glycerol to assess insulin secretion, action, and hepatic glucose metabolism. In separate studies, pancreatic islets were isolated for further analyses of insulin secretion and islet morphometry. Glucose clearance was reduced significantly by LP feeding alone (16%) and by LP feeding with LPS administration (43.8%) compared with control during the hyperglycemic clamps. This was associated with a strongly reduced insulin secretion in LP-fed rats in vivo as well as ex vivo in islets but signficantly enhanced whole body insulin sensitivity. Gluconeogenesis rates were unaffected by LP feeding, but glycogenolysis was higher after LP feeding. A protein-deficient diet in young rats leads to a susceptibility to low-dose endotoxin-induced impairment in glucose clearance with a decrease in the islet insulin secretory pathway. A protein-deficient diet is associated with enhanced peripheral insulin sensitivity but impaired insulin-mediated suppression of hepatic glycogenolysis.

Weight gain during nutritional rehabilitation post-childhood malnutrition may influence the associations between adulthood desaturases activity and anthro-cardiometabolic risk factors.

BACKGROUNDS & AIMS: Childhood malnutrition is a major global health problem with long-term sequelae, including non-communicable diseases (NCDs). Mechanisms are unknown but may involve metabolic programming, resulting from "short-term" solutions to optimise survival by compromising non-priority organs. As key players in lipid metabolism, desaturases have been shown to be predictive of NCDs. We hypothesised that the association between specific desaturase activities and NCD risk determinants (including body composition, serum glucose, insulin levels, and blood pressure) are influenced by childhood post-malnutrition weight gain. METHODS: 278 Afro-Caribbean adults with well-documented clinical history of severe malnutrition in childhood were studied. Extensive metabolic analyses including body composition (DXA), fasting serum glucose and lipidomics (n = 101), and fasting serum insulin (n = 83) were performed in malnutrition survivors and matched community controls (n = 90). Established lipid ratios were used as proxies of desaturase activities: CE 16:1/CE 16:0 for stearoyl-CoA desaturase (SCD1), LysoPC 20:4/20:3 for fatty acid desaturase 1 (FADS1), and LysoPC 20:3/18:2 for FADS2. RESULTS: Compared to community controls, adult malnutrition survivors (mean ± SD) age 28.3 ± 7.8 and BMI 23.6 ± 5.2 had higher SCD1 and FADS1 activity, (B ± SE) 0.07 ± 0.02 and 0.7 ± 0.08, respectively, but lower FADS2 activities (B ± SE) -0.05 ± 0.01, adjusted for sex and age (p < 0.0005). SCD1 was positively associated with adult BMI and body fat percentage, and negatively associated with lean mass and height. Stratification based on weight gain during nutritional rehabilitation among malnutrition survivors might signal the potential associations between weight gain during that critical period, desaturase activities, and some of adult metabolic parameters, with the lowest tertiles (slowest catch-up weight gain) performing more similarly to controls. CONCLUSIONS: In adult survivors of early-life severe acute malnutrition, desaturase activity is associated with markers of NCD risk, especially adiposity. These associations seem to be strengthened by faster weight gain during nutritional rehabilitation.

Upregulated pexophagy limits the capacity of selective autophagy.

Selective autophagy is an essential process to maintain cellular homeostasis through the constant recycling of damaged or superfluous components. Over a dozen selective autophagy pathways mediate the degradation of diverse cellular substrates, but whether these pathways can influence one another remains unknown. We address this question using pexophagy, the autophagic degradation of peroxisomes, as a model. We show in cells that upregulated pexophagy impairs the selective autophagy of both mitochondria and protein aggregates by exhausting the autophagy initiation factor, ULK1. We confirm this finding in cell models of the pexophagy-mediated form of Zellweger Spectrum Disorder, a disease characterized by peroxisome dysfunction. Further, we extend the generalizability of limited selective autophagy by determining that increased protein aggregate degradation reciprocally reduces pexophagy using cell models of Parkinson's Disease and Huntington's Disease. Our findings suggest that the degradative capacity of selective autophagy can become limited by an increase in one substrate.

Development of the Pediatric Integrated Nutrition Pathway for Acute Care (P-INPAC) using a modified Delphi technique.

One in three hospitalized children have disease-related malnutrition (DRM) upon admission to hospital, and all children are at risk for further nutritional deterioration during hospital stay; however, systematic approaches to detect DRM in Canada are lacking. To standardise and improve hospital care, the multidisciplinary pediatric working group of the Canadian Malnutrition Taskforce aimed to develop a pediatric, inpatient nutritional care pathway based on available evidence, feasibility of resources, and expert consensus. The working group (n = 13) undertook a total of four meetings: an in-person meeting to draft the pathway based on existing literature and modelled after the Integrated Nutrition Pathway for Acute Care (INPAC) in adults, followed by three online surveys and three rounds of online Delphi consensus meetings to achieve agreement on the draft pathway. In the first Delphi survey, 32 questions were asked, whereas in the second and third rounds 27 and 8 questions were asked, respectively. Consensus was defined as any question/issue in which at least 80% agreed. The modified Delphi process allowed the development of an evidence-informed, consensus-based pathway for inpatients, the Pediatric Integrated Nutrition Pathway for Acute Care (P-INPAC). It includes screening <24 h of admission, assessment with use of Subjective Global Nutritional Assessment (SGNA) <48 h of admission, as well as prevention, and treatment of DRM divided into standard, advanced, and specialized nutrition care plans. Research is necessary to explore feasibility of implementation and evaluate the effectiveness by integrating P-INPAC into clinical practice.

Dermatological changes in a prospective cohort of acutely ill, hospitalised Malawian children, stratified according to nutritional status.

RATIONALE: Since the first documentation of skin changes in malnutrition in the early 18th century, various hair and skin changes have been reported in severely malnourished children globally. We aimed to describe the frequency and types of skin conditions in children admitted with acute illness to Queen Elizabeth Central Hospital, Blantyre, Malawi across a spectrum of nutritional status and validate an existing skin assessment tool. METHODS: Children between 1 week and 23 months of age with acute illness were enrolled and stratified by anthropometry. Standardised photographs were taken, and three dermatologists assessed skin changes and scored each child according to the SCORDoK tool. RESULTS: Among 103 children, median age of 12 months, 31 (30%) had severe wasting, 11 (11%) kwashiorkor (nutritional oedema), 20 (19%) had moderate wasting, 41 (40%) had no nutritional wasting and 18 (17%) a positive HIV antibody test. Six (5.8%) of the included patients died. 51 (50%) of children presented with at least one skin change. Pigmentary changes were the most common, observed in 35 (34%), with hair loss and bullae, erosions and desquamation the second most prevalent skin condition. Common diagnoses were congenital dermal melanocytosis, diaper dermatitis, eczema and postinflammatory hyperpigmentation. Severe skin changes like flaky paint dermatosis were rarely identified. Inter-rater variability calculations showed only fair agreement (overall Fleiss' kappa 0.25) while intrarater variability had a fair-moderate agreement (Cohen's kappa score of 0.47-0.58). DISCUSSION: Skin changes in hospitalised children with an acute illness and stratified according to nutritional status were not as prevalent as historically reported. Dermatological assessment by means of the SKORDoK tool using photographs is less reliable than expected.

Development of machine learning models predicting mortality using routinely collected observational health data from 0-59 months old children admitted to an intensive care unit in Bangladesh: critical role of biochemistry and haematology data.

INTRODUCTION: Treatment in the intensive care unit (ICU) generates complex data where machine learning (ML) modelling could be beneficial. Using routine hospital data, we evaluated the ability of multiple ML models to predict inpatient mortality in a paediatric population in a low/middle-income country. METHOD: We retrospectively analysed hospital record data from 0-59 months old children admitted to the ICU of Dhaka hospital of International Centre for Diarrhoeal Disease Research, Bangladesh. Five commonly used ML models- logistic regression, least absolute shrinkage and selection operator, elastic net, gradient boosting trees (GBT) and random forest (RF), were evaluated using the area under the receiver operating characteristic curve (AUROC). Top predictors were selected using RF mean decrease Gini scores as the feature importance values. RESULTS: Data from 5669 children was used and was reduced to 3505 patients (10% death, 90% survived) following missing data removal. The mean patient age was 10.8 months (SD=10.5). The top performing models based on the validation performance measured by mean 10-fold cross-validation AUROC on the training data set were RF and GBT. Hyperparameters were selected using cross-validation and then tested in an unseen test set. The models developed used demographic, anthropometric, clinical, biochemistry and haematological data for mortality prediction. We found RF consistently outperformed GBT and predicted the mortality with AUROC of ≥0.87 in the test set when three or more laboratory measurements were included. However, after the inclusion of a fourth laboratory measurement, very minor predictive gains (AUROC 0.87 vs 0.88) resulted. The best predictors were the biochemistry and haematological measurements, with the top predictors being total CO2, potassium, creatinine and total calcium. CONCLUSIONS: Mortality in children admitted to ICU can be predicted with high accuracy using RF ML models in a real-life data set using multiple laboratory measurements with the most important features primarily coming from patient biochemistry and haematology.