An integrated gene-to-outcome multimodal database for metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the commonest cause of chronic liver disease worldwide and represents an unmet precision medicine challenge. We established a retrospective national cohort of 940 histologically defined patients (55.4% men, 44.6% women; median body mass index 31.3; 32% with type 2 diabetes) covering the complete MASLD severity spectrum, and created a secure, searchable, open resource (SteatoSITE). In 668 cases and 39 controls, we generated hepatic bulk RNA sequencing data and performed differential gene expression and pathway analysis, including exploration of gender-specific differences. A web-based gene browser was also developed. We integrated histopathological assessments, transcriptomic data and 5.67 million days of time-stamped longitudinal electronic health record data to define disease-stage-specific gene expression signatures, pathogenic hepatic cell subpopulations and master regulator networks associated with adverse outcomes in MASLD. We constructed a 15-gene transcriptional risk score to predict future hepatic decompensation events (area under the receiver operating characteristic curve 0.86, 0.81 and 0.83 for 1-, 3- and 5-year risk, respectively). Additionally, thyroid hormone receptor beta regulon activity was identified as a critical suppressor of disease progression. SteatoSITE supports rational biomarker and drug development and facilitates precision medicine approaches for patients with MASLD.

Effects of the exercise training on skeletal muscle oxygen consumption in heart failure patients with reduced ejection fraction.

AIMS: Skeletal muscle dysfunction is a systemic consequence of heart failure (HF) that correlates with functional capacity. However, the impairment within the skeletal muscle is not well established. We investigated the effect of exercise training on peripheral muscular performance and oxygenation in HF patients. METHODS AND RESULTS: HF patients with ejection fraction ≤40% were randomized 2:1 to exercise training or control for 12 weeks. Muscle tissue oxygen was measured noninvasively by near-infrared spectroscopy (NIRS) during rest and a symptom-limited cardiopulmonary exercise test (CPET) before and after intervention. Measurements included skeletal muscle oxygenated hemoglobin concentration, deoxygenated hemoglobin concentration, total hemoglobin concentration, VO2 peak, VE/VCO2 slope, and heart rate. Muscle sympathetic nerve activity by microneurography, and muscle blood flow by plethysmography were also assessed at rest pre and post 12 weeks. Twenty-four participants (47.5 ± 7.4 years, 58% men, 75% no ischemic) were allocated to exercise training (ET, n = 16) or control (CG, n = 8). At baseline, no differences between groups were found. Exercise improved VO2 peak, slope VE/VCO2, and heart rate. After the intervention, significant improvements at rest were seen in the ET group in muscle sympathetic nerve activity and muscle blood flow. Concomitantly, a significant decreased in Oxy-Hb (from 29.4 ± 20.4 to 15.7 ± 9.0 µmol, p = 0.01), Deoxi-Hb (from 16.3 ± 8.2 to 12.2 ± 6.0 µmol, p = 0.003) and HbT (from 45.7 ± 27.6 to 27.7 ± 13.4 µmol, p = 0.008) was detected at peak exercise after training. No changes were observed in the control group. CONCLUSION: Exercise training improves skeletal muscle function and functional capacity in HF patients with reduced ejection fraction. This improvement was associated with increased oxygenation of the peripheral muscles, increased muscle blood flow, and decreased sympathetic nerve activity.

Sleep and adjustment in preschool children: sleep diary reports by mothers relate to behavior reports by teachers.

Prior literature suggests that there may be relations between children's sleep disorders or inadequate amounts of sleep and behavioral adjustment. Most relevant studies concern clinical populations, however, and relatively few concern community populations. Moreover, previous studies have not addressed empirically the possible role of family functioning as a factor in the relation between children's sleep and adjustment. The present study, conducted in a predominantly low-income, community sample (N = 202), measured 4- to 5-year-old children's sleep patterns through daily logs kept by mothers, and measured family stress and parenting practices through detailed, multifaceted interviews and incidental observations of parent-child interactions. Children's adjustment, both positive and negative, was measured through preschool teacher reports on multiple occasions. A structural equation model showed that disrupted child sleep patterns (variability in reported amount of sleep, variability in bedtime, and lateness of bedtime) predicted less optimal adjustment in preschool, even after considering the roles of family stress and family management practices.