Molecular basis of ClC-6 function and its impairment in human disease.

ClC-6 is a late endosomal voltage-gated chloride-proton exchanger that is predominantly expressed in the nervous system. Mutated forms of ClC-6 are associated with severe neurological disease. However, the mechanistic role of ClC-6 in normal and pathological states remains largely unknown. Here, we present cryo-EM structures of ClC-6 that guided subsequent functional studies. Previously unrecognized ATP binding to cytosolic ClC-6 domains enhanced ion transport activity. Guided by a disease-causing mutation (p.Y553C), we identified an interaction network formed by Y553/F317/T520 as potential hotspot for disease-causing mutations. This was validated by the identification of a patient with a de novo pathogenic variant p.T520A. Extending these findings, we found contacts between intramembrane helices and connecting loops that modulate the voltage dependence of ClC-6 gating and constitute additional candidate regions for disease-associated gain-of-function mutations. Besides providing insights into the structure, function, and regulation of ClC-6, our work correctly predicts hotspots for CLCN6 mutations in neurodegenerative disorders.

Central Sleep Apnea Syndrome Can Complicate Neuromyelitis Optica Spectrum Disorder: A Case Report.

Neuromyelitis optica spectrum disorder is a rare, relapsing autoimmune disease of the central nervous system. Various initial presentations can delay diagnosis and treatment. A 14-year-old girl was admitted to the emergency department owing to respiratory insufficiency. Repeated history-taking and neuroimaging revealed an area postrema syndrome. A diagnosis of neuromyelitis optica spectrum disorder with positive aquaporin-4 antibodies has finally been established. The patient improved significantly with immunosuppressive therapy. However, her 3-year follow-up still showed sleep-disordered breathing requiring nocturnal bilevel positive airway pressure therapy. We report an original case of NMOSD leading to persistent central sleep apnea syndrome.

Is a semi-elemental diet better than a polymeric diet after congenital heart surgery?

A retrospective observational study has been set up in order to compare feeding tolerance and energy delivery in children fed with a semi-elemental diet or a polymeric diet after congenital heart surgery. The study took place in the intensive care unit of a tertiary children's hospital. One hundred children were included: 56 received a semi-elemental diet and 44 received a polymeric diet. Patients were aged between 2 days and 6 years. Data from patients were obtained from medical files between February 2014 and May 2016. The feeding protocol was changed in March 2015 when a semi-elemental diet was substituted for the polymeric diet. Primary outcome was the feeding tolerance. Feeding intolerance occurs if the patient has more than two episodes of emesis or more than four liquid stools per day. Feeding tolerance in the semi-elemental and polymeric diet groups was comparable: emesis occurred in 14.3% versus 6.8% of patients, respectively (p = 0.338); diarrhea occurred in 3.6% versus 4.5% (p = 1000); post-pyloric feeding was necessary in 14% versus 9% (p = 0.542). Energy delivery was also comparable in the two groups: on postoperative day 2, the semi-elemental diet group reached 50% of the caloric target versus 52% in the polymeric diet group (p = 0.283); on day 5, 76% versus 85% (p = 0.429); and on day 10, 105% versus 125% (p = 0.397). Energy delivery was insufficient on postoperative days 2 and 5, but nutritional goals were achieved by day 10. No patient developed necrotizing enterocolitis in our population.Conclusion: the present study suggests that the feeding tolerance to a semi-elemental or a polymeric diet is similar after CHS.What is Known:•Nutrition can modify prognosis in PICU•Different types of diet have been tested in children with intestinal disorders or with congenital heart disease. None of these diets have shown to be superior in terms of feeding tolerance.What is New:•Semi elemental and polymeric diets seem to have the same feeding tolerance in PICU after cardiac surgery for congenital heart disease.

Shoshin Beriberi and Severe Accidental Hypothermia as Causes of Heart Failure in a 6-Year-Old Child: A Case Report and Brief Review of Literature.

Severe accidental hypothermia has been demonstrated to affect ventricular systolic and diastolic functions, and rewarming might be responsible of cardiovascular collapse. Until now, there have been only a few reports on severe accidental hypothermia, none of which involved children. Herein, we describe here a rare case of heart failure in a 6-year-old boy admitted to the emergency unit owing to severe hypothermia and malnutrition. After he was warmed up (core temperature of 27.2°C at admission), he developed cardiac arrest, requiring vasoactive amines administration, and veno-arterial extracorporeal membrane oxygenation. Malnutrition and refeeding syndrome might have caused the thiamine deficiency, commonly known as beriberi, which contributed to heart failure as well. He showed remarkable improvement in heart failure symptoms after thiamine supplementation. High-dose supplementation per os (500 mg/day) after reconstitution of an adequate electrolyte balance enabled the patient to recover completely within 2 weeks, even if a mild diastolic cardiac dysfunction persisted longer. In conclusion, we describe an original pediatric case of heart failure due to overlap of severe accidental hypothermia with rewarming, malnutrition, and refeeding syndrome with thiamine deficiency, which are rare independent causes of cardiac dysfunction. The possibility of beriberi as a cause of heart failure and adequate thiamine supplementation should be considered in all high-risk patients, especially those with malnutrition. Refeeding syndrome requires careful management, including gradual electrolyte imbalance correction and administration of a thiamine loading dose to prevent or correct refeeding-induced thiamine deficiency.

Impact of vancomycin protein binding on target attainment in critically ill children: back to the drawing board?

Objectives: The objectives of this observational study were to investigate plasma protein binding and to evaluate target attainment rates of vancomycin therapy in critically ill children. Patients and methods: Paediatric ICU patients, in whom intravenous intermittent dosing (ID) or continuous dosing (CD) with vancomycin was indicated, were included. Covariates on unbound vancomycin fraction and concentration were tested using a linear mixed model analysis and attainment of currently used pharmacokinetic/pharmacodynamic (PK/PD) targets was evaluated. Clinicaltrials.gov: NCT02456974. Results: One hundred and eighty-eight plasma samples were collected from 32 patients. The unbound vancomycin fraction (median = 71.1%; IQR = 65.4%-79.7%) was highly variable within and between patients and significantly correlated with total protein and albumin concentration, which were both decreased in our population. Total trough concentration (ID) and total concentration (CD) were within the aimed target concentrations in 8% of patients. The targets of AUC/MIC ≥400 and f AUC/MIC ≥200 were achieved in 54% and 83% of patients, respectively. Unbound vancomycin concentrations were adequately predicted using the following equation: unbound vancomycin concentration (mg/L) = 5.38 + [0.71 × total vancomycin concentration (mg/L)] - [0.085 × total protein concentration (g/L)]. This final model was externally validated using 51 samples from another six patients. Conclusions: The protein binding of vancomycin in our paediatric population was lower than reported in non-critically ill adults and exhibited large variability. Higher target attainment rates were achieved when using PK/PD indices based on unbound concentrations, when compared with total concentrations. These results highlight the need for protein binding assessment in future vancomycin PK/PD research.