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HIV infection affects up to 30% of children presenting with severe acute malnutrition (SAM) in Africa and is associated with increased mortality. Children with SAM are treated similarly regardless of HIV status, although mechanisms of nutritional recovery in HIV and/or SAM are not well understood. We performed a secondary analysis of a clinical trial and plasma proteomics data among children with complicated SAM in Kenya and Malawi. Compared to children with SAM without HIV (n = 113), HIV-infected children (n = 54) had evidence (false discovery rate (FDR) corrected p < 0.05) of metabolic stress, including enriched pathways related to inflammation and lipid metabolism. Moreover, we observed reduced plasma levels of zinc-α-2-glycoprotein, butyrylcholinesterase, and increased levels of complement C2 resembling findings in metabolic syndrome, diabetes and other non-communicable diseases. HIV was also associated (FDR corrected p < 0.05) with higher plasma levels of inflammatory chemokines. Considering evidence of biomarkers of metabolic stress, it is of potential concern that our current treatment strategy for SAM regardless of HIV status involves a high-fat therapeutic diet. The results of this study suggest a need for clinical trials of therapeutic foods that meet the specific metabolic needs of children with HIV and SAM.

Current scores for predicting sepsis outcomes are limited by generalizability, complexity, and electronic medical record (EMR) integration. Here, we validate a simple EMR-based score for sepsis outcomes in a large multi-centre cohort. A simple electronic medical record-based predictor of illness severity in sepsis (SEPSIS) score was developed (4 additive lab-based predictors) using a population-based retrospective cohort study. Internal medicine services across four academic teaching hospitals in Toronto, Canada from April 2010-March 2015 (primary cohort) and 2015-2019 (secondary cohort). We identified patients admitted with sepsis based upon receipt of antibiotics and positive cultures. The primary outcome was in-hospital mortality and secondary outcomes were ICU admission at 72 hours, and hospital length of stay (LOS). We calculated the area under the receiver operating curve (AUROC) for the SEPSIS score, qSOFA, and NEWS2. We then evaluated the SEPSIS score in a secondary cohort (2015-2019) of hospitalized patients receiving antibiotics. Our primary cohort included 1,890 patients with a median age of 72 years (IQR: 56-83). 9% died during hospitalization, 18.6% were admitted to ICU, and mean LOS was 12.7 days (SD: 21.5). In the primary and secondary (2015-2019, 4811 patients) cohorts, the AUROCs of the SEPSIS score for predicting in-hospital mortality were 0.63 and 0.64 respectively, which were similar to NEWS2 (0.62 and 0.67) and qSOFA (0.62 and 0.68). AUROCs for predicting ICU admission at 72 hours, and length of stay > 14 days, were similar between scores, in the primary and secondary cohorts. All scores had comparable calibration for predicting mortality. An EMR-based SEPSIS score shows a similar ability to predict important clinical outcomes compared with other validated scores (qSOFA and NEWS2). Because of the SEPSIS score's simplicity, it may prove a useful tool for clinical and research applications.

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

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. Plain Language Summary Malnourished children are at a high risk of dying when exposed to an acute illness. They often have symptoms like diarrhea that indicate their gut is not working properly. It is unclear whether these gut problems contribute to their deaths. Feces contain numerous small molecules processed by the gut that reflect gut health. We compare these fecal molecules between malnourished children who died during hospitalization to those who survived, and relate them to signs of inflammation in the body. We show that the fecal molecules are different between children who died and those who survived. These differences reveal that poor gut health could increase risk of death, potentially by perturbing the body’s defensive response to an acute illness. These findings underscore that treatment for ill severely malnourished children should focus on improving gut health. Wen et al. investigate associations between intestinal disturbances and mortality in children hospitalized with complicated severe malnutrition. Differences are seen in the fecal metabolome of children who die compared with those who are discharged, with integrative analyses suggesting an indirect role for intestinal inflammation in mortality.

In vitro and in vivo studies suggest that selected Bifidobacterium bifidum strains sustain intestinal homeostasis. This study aimed to examine whether the administration of B. bifidum MIMBb75 (BB75) attenuates Citrobacter rodentium infection, a murine model for enteric infection and inflammatory bowel disease in humans. C57Bl6/J mice were randomized to receive BB75 daily starting before or after C. rodentium infection. BB75 load and infection kinetics were monitored. On day 10 post-infection (p.i.), histological parameters of the large intestine were assessed. Barrier integrity was evaluated by pathogen translocation to secondary organs and in vivo permeability test. Fecal C. rodentium load peaked at 1010 CFU/g at day 10 p.i., with clearance at day 24 p.i., regardless of probiotic treatment. BB75 administration resulted in 107 cells/g of feces with no effect of timing of administration. BB75 treatment did not attenuate C. rodentium-induced crypt hyperplasia nor inflammation. C. rodentium and BB75 can co-exist in the gut with no mutual displacement. However, BB75 cannot counteract C. rodentium pathology. Our findings provide insight for the understanding of probiotics behavior and their clinical relevance in intestinal inflammation.

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.

Children admitted to hospitals with severe malnutrition are exceptionally vulnerable to death and account for a large proportion of early childhood mortality globally. In low- and middle- income countries, inpatient mortality rates of severely malnourished children remain high, despite implementation of the empirical management guidelines developed by the World Health Organization. Upon hospital admission, this group of children often present with a wide range of life-threatening illnesses and complications, making risk stratification and identification of underlying causes challenging. Severe malnutrition is also associated with concurrences of subclinical conditions, such as metabolic defects and enteric dysfunctions, that may not be clinically addressed but contribute to mortality. However, very few studies have investigated the pathophysiological pathways involved in the mortality of these children.Using medical records and biological samples among children hospitalized with severe malnutrition in African countries, Malawi and Kenya, the present research aimed to (1) identify clinical warning signs associated with inpatient mortality and evaluate their values in monitoring risks over the course of hospitalization, (2) define systemic pathways associated with mortality employing a multi-omic approach, and (3) evaluate the role of intestinal disturbances in mortality.It was found that monitoring the clinical warning signs: hypoglycemia, reduced consciousness, chest indrawing, not able to complete feeds, nutritional edema, diarrhea, and fever, can serve as a valuable tool for assessing children’s mortality risks during hospitalization. Compared to children who were discharged alive, children who died had distinct biomolecular profiles at admission, indicating that altered energy metabolism and systemic inflammation are associated with inpatient death. Furthermore, enteropathy was found to have a partial contributory role in the mortality of severely malnourished children.These findings alter our thinking around management of children hospitalized with severe malnutrition with important implications in providing novel evidence for guideline optimization to ultimately improve survival outcome of vulnerable children.

Current scores for predicting sepsis outcomes are limited by generalizability, complexity, and electronic medical record (EMR) integration. Here, we validate a simple EMR-based score for sepsis outcomes in a large multi-centre cohort. A simple electronic medical record-based predictor of illness severity in sepsis (SEPSIS) score was developed (4 additive lab-based predictors) using a population-based retrospective cohort study. Internal medicine services across four academic teaching hospitals in Toronto, Canada from April 2010-March 2015 (primary cohort) and 2015-2019 (secondary cohort). We identified patients admitted with sepsis based upon receipt of antibiotics and positive cultures. The primary outcome was in-hospital mortality and secondary outcomes were ICU admission at 72 hours, and hospital length of stay (LOS). We calculated the area under the receiver operating curve (AUROC) for the SEPSIS score, qSOFA, and NEWS2. We then evaluated the SEPSIS score in a secondary cohort (2015-2019) of hospitalized patients receiving antibiotics. Our primary cohort included 1,890 patients with a median age of 72 years (IQR: 56-83). 9% died during hospitalization, 18.6% were admitted to ICU, and mean LOS was 12.7 days (SD: 21.5). In the primary and secondary (2015-2019, 4811 patients) cohorts, the AUROCs of the SEPSIS score for predicting in-hospital mortality were 0.63 and 0.64 respectively, which were similar to NEWS2 (0.62 and 0.67) and qSOFA (0.62 and 0.68). AUROCs for predicting ICU admission at 72 hours, and length of stay > 14 days, were similar between scores, in the primary and secondary cohorts. All scores had comparable calibration for predicting mortality. An EMR-based SEPSIS score shows a similar ability to predict important clinical outcomes compared with other validated scores (qSOFA and NEWS2). Because of the SEPSIS score's simplicity, it may prove a useful tool for clinical and research applications.

Citrobacter rodentium is a murine pathogen causing transmissible colonic hyperplasia and colitis with a pathogenic mechanism similar to foodborne enterohaemorrhagic Escherichia coli in humans. Mechanisms underlying intestinal responses to C. rodentium infection are incompletely understood. We identified 24 colonic microRNAs (miRNAs) as significantly deregulated in response to C. rodentium, including miR-7a, -17, -19a, -20a, -20b, -92a, -106a, -132, -200a, and -2137; most of these miRNAs belong to the oncogenic miR-17-92 clusters. Pathways involved in cell cycle, cancers, and immune responses were enriched among the predicted targets of these miRNAs. We further demonstrated that an apoptosis facilitator, Bim, is a candidate gene target of miRNA-mediated host response to the infection. These findings suggest that host miRNAs participate in C. rodentium pathogenesis and may represent novel treatment targets.