Comparison of the Lipidomic Signature of Fatty Liver in Children and Adults: A Cross-Sectional Study.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is an increasingly common condition in children characterised by insulin resistance and altered lipid metabolism. Affected patients are at increased risk of cardiovascular disease (CVD) and children with NAFLD are likely to be at risk of premature cardiac events. Evaluation of the plasma lipid profile of children with NAFLD offers the opportunity to investigate these perturbations and understand how closely they mimic the changes seen in adults with cardiometabolic disease. METHODS: We performed untargeted liquid chromatography-mass spectrometry (LC-MS) plasma lipidomics on 287 children: 19 lean controls, 146 from an obese cohort, and 122 NAFLD cases who had undergone liver biopsy. Associations between lipid species and liver histology were assessed using regression adjusted for age and sex. Results were then replicated using data from 9500 adults with metabolic phenotyping. RESULTS: More severe paediatric NAFLD was associated with lower levels of long chain, polyunsaturated phosphatidylcholines (pC) and triglycerides (TG). Similar trends in pC and TG chain length and saturation were seen in adults with hepatic steatosis; however, many of the specific lipids associated with NAFLD differed between children and adults. Five lipids replicated in adults (including PC(36:4)) have been directly linked to death and cardiometabolic disease, as well as indirectly via genetic variants. CONCLUSION: These findings suggest that, whilst similar pathways of lipid metabolism are perturbed in paediatric NAFLD as in cardiometabolic disease in adults, the specific lipid signature in children is different.JPM is supported by a Wellcome Trust fellowship (216329/Z/19/Z), a European Society for Paediatric Research (ESPR) Young Investigator Award, and a Children’s Liver Disease Foundation Grant. EU-PNAFLD Registry is supported by a European Association for Study of the Liver (EASL) Registry Grant. MZ is supported by a New Investigator Research Grant from the MRC (MR/T001917/1). BK is supported by grants from Van den Broek Lohman Foundation, Virtutis Opus Foundation and For Wishdom Foundation. SF, SGS & AK are supported by the BBSRC (BB/M027252/1 & BB/P028195/1), BJJ & AK are supported by the National Institute for Health Research (NIHR146281)

Health Care for Mitochondrial Disorders in Canada: A Survey of Physicians

Background: An improved understanding of diagnostic and treatment practices for patients with rare primary mitochondrial disorders can support benchmarking against guidelines and establish priorities for evaluative research. We aimed to describe physician care for patients with mitochondrial diseases in Canada, including variation in care. Methods: We conducted a cross-sectional survey of Canadian physicians involved in the diagnosis and/or ongoing care of patients with mitochondrial diseases. We used snowball sampling to identify potentially eligible participants, who were contacted by mail up to five times and invited to complete a questionnaire by mail or internet. The questionnaire addressed: personal experience in providing care for mitochondrial disorders; diagnostic and treatment practices; challenges in accessing tests or treatments; and views regarding research priorities. Results: We received 58 survey responses (52% response rate). Most respondents (83%) reported spending 20% or less of their clinical practice time caring for patients with mitochondrial disorders. We identified important variation in diagnostic care, although assessments frequently reported as diagnostically helpful (e.g., brain magnetic resonance imaging, MRI/MR spectroscopy) were also recommended in published guidelines. Approximately half (49%) of participants would recommend mitochondrial cocktails for all or most patients, but we identified variation in responses regarding specific vitamins and cofactors. A majority of physicians recommended studies on the development of effective therapies as the top research priority. Conclusions: While Canadian physicians\u27 views about diagnostic care and disease management are aligned with published recommendations, important variations in care reflect persistent areas of uncertainty and a need for empirical evidence to support and update standard protocols

Leefstijlinterventie voor kinderen met obesitas:Hoe jonger, hoe beter

Doel Het doel van deze studie was om de prevalentie van gewichtsgerelateerde comorbiditeit bij schoolkinderen met obesitas in kaart te brengen en deze prevalentie en het effect van gecombineerde leefstijlinterventie gedurende een jaar te vergelijken tussen kinderen van basisschool- en middelbare-schoolleeftijd en tussen jongens en meisjes. Opzet Cross-sectionele analyse en quasi-experimentele gecombineerde leefstijlinterventie. Methode Het gewichtsgerelateerde gezondheidsrisico en comorbiditeit werden onderzocht bij 149 kinderen van de basisschoolleeftijd en 150 kinderen van middelbare-schoolleeftijd met obesitas. Het effect van een gecombineerde leefstijlinterventie, die werd aangeboden vanuit een domein-overstijgend netwerk, werd onderzocht bij 82 kinderen van de basisschoolleeftijd en 75 kinderen van middelbare-schoolleeftijd. Resultaten Bij kinderen van de basisschoolleeftijd zagen we al vaak insulineresistentie (37%), gestoorde glucosetolerantie (3%), dyslipidemie (48%), hypertensie (7%) en verhoogde leverenzymwaarden (54%). Alleen glomerulaire hyperfiltratie en insulineresistentie kwamen vaker voor bij kinderen van middelbare-schoolleeftijd. Gestoorde glucosetolerantie kwam vaker voor bij meisjes dan bij jongens. De afname in de BMI-z-score na interventie was groter bij kinderen van de basisschoolleeftijd dan bij kinderen van middelbare-schoolleeftijd, net als de daling in LDL-cholesterolconcentratie en de verbetering van de z-score voor systolische bloeddruk. Bij jongens daalde de BMI-z-score sterker dan bij meisjes, maar de verbetering van de overige gezondheidsparameters verschilde niet. Conclusie Bij kinderen met obesitas komt comorbiditeit al op de basisschoolleeftijd frequent voor. Het effect van de gecombineerde leefstijlinterventie op comorbiditeit was groter bij kinderen van de basisschoolleeftijd dan bij kinderen van middelbare-schoolleeftijd. Deze resultaten benadrukken het belang van vroege preventie en interventies die het ontstaan van obesitas en gezondheidsgevolgen beogen te voorkomen

Developments in evidence creation for treatments of inborn errors of metabolism

Inborn errors of metabolism (IEM) represent the first group of genetic disorders, amenable to causal therapies. In addition to traditional medical diet and cofactor treatments, new treatment strategies such as enzyme replacement and small molecule therapies, solid organ transplantation, and cell-and gene-based therapies have become available. Inherent to the rare nature of the single conditions, generating high-quality evidence for these treatments in clinical trials and under real-world conditions has been challenging. Guidelines developed with standardized methodologies have contributed to improve the practice of care and long-term clinical outcomes. Adaptive trial designs allow for changes in sample size, group allocation and trial duration as the trial proceeds. n-of-1 studies may be used in small sample sized when participants are clinically heterogeneous. Multicenter observational and registry-based clinical trials are promoted via international research networks. Core outcome and standard data element sets will enhance comparative analysis of clinical trials and observational studies. Patient-centered outcome-research as well as patient-led research initiatives will further accelerate the development of therapies for IEM