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Variants in the UNC45A cochaperone have been recently associated with a syndrome combining diarrhea, cholestasis, deafness, and bone fragility. Yet the mechanism underlying intestinal failure in UNC45A deficiency remains unclear. Here, biallelic variants in UNC45A were identified by next-generation sequencing in 6 patients with congenital diarrhea. Corroborating in silico prediction, variants either abolished UNC45A expression or altered protein conformation. Myosin VB was identified by mass spectrometry as client of the UNC45A chaperone and was found misfolded in [UNC45A.sup.KO] Caco-2 cells. In keeping with impaired myosin VB function, [UNC45A.sup.KO] Caco-2 cells showed abnormal epithelial morphogenesis that was restored by full-length UNC45A, but not by mutant alleles. Patients and [UNC45A.sup.KO] 3D organoids displayed altered luminal development and microvillus inclusions, while 2D cultures revealed Rab11 and apical transporter mislocalization as well as sparse and disorganized microvilli. All those features resembled the subcellular abnormalities observed in duodenal biopsies from patients with microvillus inclusion disease. Finally, microvillus inclusions and shortened microvilli were evidenced in enterocytes from unc45a-deficient zebrafish. Taken together, our results provide evidence that UNC45A plays an essential role in epithelial morphogenesis through its cochaperone function of myosin VB and that UNC45A loss causes a variant of microvillus inclusion disease., Introduction Congenital diarrhea disorders (CDDs) are rare monogenic diseases characterized by chronic, life-threatening diarrhea starting early in life (1, 2). Depending on the mechanism, diarrhea can be the only symptom [...]

Background: Infants with intestinal failure (IF) are at increased risk of malnutrition and require adapted nutrition support. Optimal weight gain during nutrition rehabilitation should occur at the velocity of statural age (adjusted to the 50th percentile of height) and not chronological age. The aim of this study was to assess the relationship between weight gain during catch-up growth, nonprotein energy intake (NPEI) provided by total parenteral nutrition (TPN), and resting energy expenditure (REE) in children with severe malnutrition due to IF.Materials and Methods: This retrospective study included all infants with severe malnutrition treated with TPN for IF between January 1, 2010, and December 31, 2013. They all had no or minimal oral intake (<10% REE). The REE was calculated using the Schofield equations.Results: Seventeen children were included (11 boys) with a mean age at TPN onset of 5 mo. They were followed for a mean duration of 39 days. On admission, body weight and height were -3.1 ± 0.9 and -3.3 ± 1.3 SD, respectively. The indications for TPN were short bowel syndrome (n = 10), congenital enteropathy (microvillous inclusion disease, n = 6) and chronic intestinal pseudo-obstruction syndrome (n = 1). After 28 days of nutrition rehabilitation with full NPEI from TPN, the observed weight gain was 110 ± 5% of optimal weight gain for statural age. The mean NPEI from TPN was 104.3 ± 8.0 kcal/kg/d. The mean ratio of NPEI over REE was 2.1 ± 0.2.Conclusion: Optimal weight gain was achieved with NPEI from TPN twice the REE in severely malnourished infants with IF. NPEI values were adequate and not excessive for age. [ABSTRACT FROM AUTHOR]

Background: Catheter-related bloodstream infections (CRBSIs) remain a major issue in patients who are receiving home parenteral nutrition (HPN). The aim of this interventional study was to assess the impact of a new strategy using taurolidine-citrate (T-C) prophylactic locks on the CRBSI rate in children with intestinal failure who are receiving HPN., Methods: The rate of CRBSIs was monitored every calendar year in a prospective cohort of 195 children with intestinal failure. T-C locks were initiated from October 2011 in children with recurring CRBSIs (≥2 episodes per year)., Results: In the whole cohort, the median annual CRBSI rate per 1000 catheter days decreased significantly from 2.07 in 2008 to 2010 to 1.23 in 2012 to 2014 (P < .05). T-C locks were used in 40 patients. No adverse events were reported. In taurolidine-treated patients, the CRBSI rate per 1000 catheter days decreased from 4.16 to 0.25 (P < .0001). The cumulative percentage of patients free of CRBSI at 18 months was 92% (95% confidence interval [CI]: 71-98) on T-C lock vs 61% (95% CI: 49-72) in controls (P = .01). In multivariate analysis, factors associated with CRBSI were immune deficiency (adjusted hazard ratio 3.49; 95% CI: 1.01-12.17) and the young age of the parents (adjusted hazard ratio 4.79, 95% CI: 2.16-10.62), whereas T-C locks were protective (adjusted hazard ratio 0.22, 95% CI: 0.06-0.74)., Conclusion: This study confirms the efficacy of T-C catheter locks in decreasing the incidence of CRBSIs in children with intestinal failure who are receiving HPN., (© 2018 American Society for Parenteral and Enteral Nutrition.)