The Avoidant Restrictive Food Intake Disorder - Genes and Environment (ARFID-GEN) study is a study of genetic and environmental factors that contribute to risk for developing ARFID in children and ...adults.
A total of 3,000 children and adults with ARFID from the United States will be included. Parents/guardians and their children with ARFID (ages 7 to 17) and adults with ARFID (ages 18 +) will complete comprehensive online consent, parent verification of child assent (when applicable), and phenotyping. Enrolled participants with ARFID will submit a saliva sample for genotyping. A genome-wide association study of ARFID will be conducted.
ARFID-GEN, a large-scale genetic study of ARFID, is designed to rapidly advance the study of the genetics of eating disorders. We will explicate the genetic architecture of ARFID relative to other eating disorders and to other psychiatric, neurodevelopmental, and metabolic disorders and traits. Our goal is for ARFID to deliver "actionable" findings that can be transformed into clinically meaningful insights.
ARFID-GEN is a registered clinical trial: clinicaltrials.gov NCT05605067.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Weight gain and nutritional rehabilitation are essential first steps to achieve medical stabilization in anorexia nervosa, and frequent resistance to weight gain requires patients to consume high ...kilocalorie loads. Adaptive hypometabolism is common when patients begin treatment, and rebound hypermetabolism is suspected to be a significant barrier to weight gain. The aim of this review was to summarize existing data describing metabolic changes in anorexia nervosa during weight restoration. The reported findings challenge current hypotheses of weight gain resistance and highlight key areas for future research.
Using scoping review guidelines, three databases were searched for studies investigating metabolic changes in anorexia nervosa before and after renourishment. Two reviewers systematically screened the titles and abstracts of 447 articles, and full-text versions of 106 studies were assessed for eligibility. A total of 36 studies were included for review. Data regarding the study description, sample population (including age, weight, BMI, duration of treatment, and caloric intake), and metabolic variable descriptions were extracted.
Female patients with anorexia nervosa from studies across 13 countries were included. Across the studies, average BMI increased from 13.7 kg/m
at admission to 17.57 kg/m
. Patients presented to treatment with clinically reduced energy expenditure levels. After varying levels of nutritional rehabilitation and weight restoration, measured energy expenditure increased significantly in 76% of the studies. Energy expenditure values at the second timepoint increased to the standard range for normal weight female teenagers and adults. Despite these increases, the studies do not indicate the presence of a hypermetabolic state during renourishment. Additionally, all studies including both measured and predicted energy expenditure reported that predicted energy expenditure overestimated measured values.
This study provides a detailed evaluation of the literature investigating energy expenditure and metabolic rate in patients with anorexia nervosa before and following a period of renourishment. The findings from this review identify important gaps in the current beliefs of energy expenditure in anorexia nervosa and highlight a need for further exploration of metabolic alterations during weight restoration.
Despite the substantial burden of asthma-related emergency department (ED) visits, there have been no recent multicenter efforts to characterize this high-risk population.
We aimed to characterize ...patients with asthma according to their frequency of ED visits and to identify factors associated with frequent ED visits.
A multicenter chart review study of 48 EDs across 23 US states. We identified ED patients ages 18 to 54 years with acute asthma during 2011 and 2012. Primary outcome was frequency of ED visits for acute asthma in the past year, excluding the index ED visit.
Of the 1890 enrolled patients, 863 patients (46%) had 1 or more (frequent) ED visits in the past year. Specifically, 28% had 1 to 2 visits, 11% had 3 to 5 visits, and 7% had 6 or more visits. Among frequent ED users, guideline-recommended management was suboptimal. For example, of patients with 6 or more ED visits, 85% lacked evidence of prior evaluation by an asthma specialist, and 43% were not treated with inhaled corticosteroids. In a multivariable model, significant predictors of frequent ED visits were public insurance, no insurance, and markers for chronic asthma severity (all P < .05). Stronger associations were found among those with a higher frequency of asthma-related ED visits (eg, 6 or more ED visits).
This multicenter study of US adults with acute asthma demonstrated many frequent ED users and suboptimal preventive management in this high-risk population. Future reductions in asthma morbidity and associated health care utilization will require continued efforts to bridge these major gaps in asthma care.
Background
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. COPD patients with cachexia or weight loss have increased risk of death independent of body mass ...index (BMI) and lung function. We tested the hypothesis genetic variation is associated with weight loss in COPD using a genome‐wide association study approach.
Methods
Participants with COPD (N = 4308) from three studies (COPDGene, ECLIPSE, and SPIROMICS) were analysed. Discovery analyses were performed in COPDGene with replication in SPIROMICS and ECLIPSE. In COPDGene, weight loss was defined as self‐reported unintentional weight loss > 5% in the past year or low BMI (BMI < 20 kg/m2). In ECLIPSE and SPIROMICS, weight loss was calculated using available longitudinal visits. Stratified analyses were performed among African American (AA) and Non‐Hispanic White (NHW) participants with COPD. Single variant and gene‐based analyses were performed adjusting for confounders. Fine mapping was performed using a Bayesian approach integrating genetic association results with linkage disequilibrium and functional annotation. Significant gene networks were identified by integrating genetic regions associated with weight loss with skeletal muscle protein–protein interaction (PPI) data.
Results
At the single variant level, only the rs35368512 variant, intergenic to GRXCR1 and LINC02383, was associated with weight loss (odds ratio = 3.6, 95% confidence interval = 2.3–5.6, P = 3.2 × 10−8) among AA COPD participants in COPDGene. At the gene level in COPDGene, EFNA2 and BAIAP2 were significantly associated with weight loss in AA and NHW COPD participants, respectively. The EFNA2 association replicated among AA from SPIROMICS (P = 0.0014), whereas the BAIAP2 association replicated in NHW from ECLIPSE (P = 0.025). The EFNA2 gene encodes the membrane‐bound protein ephrin‐A2 involved in the regulation of developmental processes and adult tissue homeostasis such as skeletal muscle. The BAIAP2 gene encodes the insulin‐responsive protein of mass 53 kD (IRSp53), a negative regulator of myogenic differentiation. Integration of the gene‐based findings participants with PPI data revealed networks of genes involved in pathways such as Rho and synapse signalling.
Conclusions
The EFNA2 and BAIAP2 genes were significantly associated with weight loss in COPD participants. Collectively, the integrative network analyses indicated genetic variation associated with weight loss in COPD may influence skeletal muscle regeneration and tissue remodelling.
Kinesin motor proteins transport intracellular cargo, including mRNA, proteins, and organelles. Pathogenic variants in kinesin-related genes have been implicated in neurodevelopmental disorders and ...skeletal dysplasias. We identified de novo, heterozygous variants in KIF5B, encoding a kinesin-1 subunit, in four individuals with osteogenesis imperfecta. The variants cluster within the highly conserved kinesin motor domain and are predicted to interfere with nucleotide binding, although the mechanistic consequences on cell signaling and function are unknown.
To understand the in vivo genetic mechanism of KIF5B variants, we modeled the p.Thr87Ile variant that was found in two patients in the C. elegans ortholog, unc-116, at the corresponding position (Thr90Ile) by CRISPR/Cas9 editing and performed functional analysis. Next, we studied the cellular and molecular consequences of the recurrent p.Thr87Ile variant by microscopy, RNA and protein analysis in NIH3T3 cells, primary human fibroblasts and bone biopsy.
C. elegans heterozygous for the unc-116 Thr90Ile variant displayed abnormal body length and motility phenotypes that were suppressed by additional copies of the wild type allele, consistent with a dominant negative mechanism. Time-lapse imaging of GFP-tagged mitochondria showed defective mitochondria transport in unc-116 Thr90Ile neurons providing strong evidence for disrupted kinesin motor function. Microscopy studies in human cells showed dilated endoplasmic reticulum, multiple intracellular vacuoles, and abnormal distribution of the Golgi complex, supporting an intracellular trafficking defect. RNA sequencing, proteomic analysis, and bone immunohistochemistry demonstrated down regulation of the mTOR signaling pathway that was partially rescued with leucine supplementation in patient cells.
We report dominant negative variants in the KIF5B kinesin motor domain in individuals with osteogenesis imperfecta. This study expands the spectrum of kinesin-related disorders and identifies dysregulated signaling targets for KIF5B in skeletal development.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Physical therapy efficacy relies on patient compliance and motivation. However, the monotony, intensity, and expense of most therapy routines do not promote engagement. Technology-based ...rehabilitation has the potential to provide engaging and cost-effective treatment, leading to better compliance and mobility outcomes. We present an interactive rehabilitation robot (iRebot) as an affordable, gesture-controlled vehicle that can provide a form of entertainment while conducting physical therapy. Healthy participants (n=11) executed a test maze with the iRebot for six repeated trials, three with each hand. Survey scores and quantitative metrics were evaluated to assess system usability and baseline motor performance, respectively. Wrist mobility across participants was evaluated, with an active range of motion of 39.7± 13° and 72.8± 18° for pitch and roll, respectively. In the course of conducting a single trial (time duration=87.2±67 sec), the participants performed on average 30 full wris t motion repetitions (e.g., flexion/extension). Participants rated the system's usability as excellent (survey score: 85 ± 13), and all participants indicated they would prefer iRebot over standard therapy. The iRebot demonstrated potential as an evidence-based rehabilitation tool based on excellent user ratings and the ability to monitor at- home compliance and motor performance.
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