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High fat feeding impairs skeletal muscle metabolic flexibility and induces insulin resistance, whereas exercise training exerts positive effects on substrate handling and improves insulin sensitivity. To identify the genomic mechanisms by which exercise ameliorates some of the deleterious effects of high fat feeding, we investigated the transcriptional and epigenetic response of human skeletal muscle to 9 days of a high-fat diet (HFD) alone (Sed-HFD) or in combination with resistance exercise (Ex-HFD), using genome-wide profiling of gene expression and DNA methylation. HFD markedly induced expression of immune and inflammatory genes, which was not attenuated by Ex. Conversely, Ex markedly remodelled expression of genes associated with muscle growth and structure. We detected marked DNA methylation changes following HFD alone and in combination with Ex. Among the genes that showed a significant association between DNA methylation and gene expression changes were PYGM, which was epigenetically regulated in both groups, and ANGPTL4, which was regulated only following Ex. In conclusion, while short-term Ex did not prevent a HFD-induced inflammatory response, it provoked a genomic response that may protect skeletal muscle from atrophy. These epigenetic adaptations provide mechanistic insight into the gene-specific regulation of inflammatory and metabolic processes in human skeletal muscle.

Approximately 500 multi-PMTs (mPMTs) will be used as the photosensors for the Intermediate Water Cherenkov Detector (IWCD), a new near detector for the approved Hyper-Kamiokande experiment that will be built by 2025. The IWCD mPMT design has nineteen 3” PMTs enclosed in a water-tight pressure vessel, along with the associated electronics. The 3” PMTs provide excellent spatial imaging of the neutrino-induced Cherenkov light ring. This work will focus on the mechanical design of the mPMT vessel. In particular, design of the acrylic dome, use of optical gel to couple the dome to the PMTs, assembly procedures of dome and PMT sub-assembly (including the necessary jigs / fixtures), design of water-tight feed-through & plans for testing and results from several mPMT prototypes.

The Water Cherenkov Test Experiment (WCTE) is an experiment proposed at CERN to measure the response of a Water Cherenkov Detector for charged particles such as π ±, p+, e±, etc. The data obtained from WCTE will be used in future neutrino experiments. WCTE consists of a sealed cylindrical tank filled with ultrapure water. 128 multi-PhotoMultiplier Tubes (mPMTs) are mounted on a cylindrical support structure facing inwards to map out the Cherenkov radiation with high granularity. This work presents the mechanical design and analysis of the support structure for WCTE. It is designed to sustain the load of 128 mPMTs, arrangement of Photogrammetry system Cameras & lights and Calibration arm without significant change in the position / geometry of the structure. SS304 is identified as a suitable material to ensure the compatibility with the ultrapure water and Gd-loaded water. The structure is robust against stresses during handling and subsequent transport with and without water.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Skeletal muscle is a highly adaptable tissue and remodels in response to exercise training. Using short RNA sequencing, we determine the miRNA profile of skeletal muscle from healthy male volunteers before and after a 14-day aerobic exercise training regime. Among the exercise training-responsive miRNAs identified, miR-19b-3p was selected for further validation. Overexpression of miR-19b-3p in human skeletal muscle cells increases insulin signaling, glucose uptake, and maximal oxygen consumption, recapitulating the adaptive response to aerobic exercise training. Overexpression of miR-19b-3p in mouse flexor digitorum brevis muscle enhances contraction-induced glucose uptake, indicating that miR-19b-3p exerts control on exercise training-induced adaptations in skeletal muscle. Potential targets of miR-19b-3p that are reduced after aerobic exercise training include KIF13A , MAPK6 , RNF11 , and VPS37A . Amongst these, RNF11 silencing potentiates glucose uptake in human skeletal muscle cells. Collectively, we identify miR-19b-3p as an aerobic exercise training-induced miRNA that regulates skeletal muscle glucose metabolism. Exercise induces structural and functional adaptations in skeletal muscle that involve transcriptomic remodeling, including of miRNA expression. Here the authors examine the expression of miRNAs in human muscle following exercise training and investigate the functions of miR-19b-3p on glucose metabolism in cells and mouse muscle.

Innate circadian rhythms are critical for optimal tissue-specific functions, including skeletal muscle, a major insulin-sensitive tissue responsible for glucose homeostasis. We determined whether transcriptional oscillations are associated with CpG methylation changes in skeletal muscle. We performed rhythmicity analysis on the transcriptome and CpG methylome of circadian synchronized myotubes. We identified several transcripts and CpG-sites displaying oscillatory behavior, which were enriched with Gene Ontology terms related to metabolism and development. Oscillating CpG methylation was associated with rhythmic expression of 31 transcripts. Although circadian oscillations may be regulated by rhythmic DNA methylation, strong rhythmic associations between transcriptome and CpG methylation were not identified. This resource constitutes a transcriptomic/epigenomic atlas of skeletal muscle and regulation of circadian rhythms.

Importance Despite the benefits of goals-of-care (GOC) communication, many hospitalized individuals never communicate their goals or preferences to clinicians. Objective To assess whether a GOC video intervention delivered by palliative care educators (PCEs) increased the rate of GOC documentation. Design, Setting, and Participants This pragmatic, stepped-wedge cluster randomized clinical trial included patients aged 65 years or older admitted to 1 of 14 units at 2 urban hospitals in New York and Boston from July 1, 2021, to October 31, 2022. Intervention The intervention involved PCEs (social workers and nurses trained in GOC communication) facilitating GOC conversations with patients and/or their decision-makers using a library of brief, certified video decision aids available in 29 languages. Patients in the control period received usual care. Main Outcome and Measures The primary outcome was GOC documentation, which included any documentation of a goals conversation, limitation of life-sustaining treatment, palliative care, hospice, or time-limited trials and was obtained by natural language processing. Results A total of 10 802 patients (mean [SD] age, 78 [8] years; 51.6% male) were admitted to 1 of 14 hospital units. Goals-of-care documentation during the intervention phase occurred among 3744 of 6023 patients (62.2%) compared with 2396 of 4779 patients (50.1%) in the usual care phase (P < .001). Proportions of documented GOC discussions for Black or African American individuals (865 of 1376 [62.9%] vs 596 of 1125 [53.0%]), Hispanic or Latino individuals (311 of 548 [56.8%] vs 218 of 451 [48.3%]), non-English speakers (586 of 1059 [55.3%] vs 405 of 863 [46.9%]), and people living with Alzheimer disease and related dementias (520 of 681 [76.4%] vs 355 of 570 [62.3%]) were greater during the intervention phase compared with the usual care phase. Conclusions and Relevance In this stepped-wedge cluster randomized clinical trial of older adults, a GOC video intervention delivered by PCEs resulted in higher rates of GOC documentation compared with usual care, including among Black or African American individuals, Hispanic or Latino individuals, non-English speakers, and people living with Alzheimer disease and related dementias. The findings suggest that this form of patient-centered care delivery may be a beneficial decision support tool. Trial Registration ClinicalTrials.gov Identifier:NCT04857060

Whether addition of corticosteroids to antibiotic treatment benefits patients with community-acquired pneumonia who are not in intensive care units is unclear. We aimed to assess effect of addition of dexamethasone on length of stay in this group, which might result in earlier resolution of pneumonia through dampening of systemic inflammation. In our double-blind, placebo-controlled trial, we randomly assigned adults aged 18 years or older with confirmed community-acquired pneumonia who presented to emergency departments of two teaching hospitals in the Netherlands to receive intravenous dexamethasone (5 mg once a day) or placebo for 4 days from admission. Patients were ineligible if they were immunocompromised, needed immediate transfer to an intensive-care unit, or were already receiving corticosteroids or immunosuppressive drugs. We randomly allocated patients on a one-to-one basis to treatment groups with a computerised randomisation allocation sequence in blocks of 20. The primary outcome was length of hospital stay in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT00471640. Between November, 2007, and September, 2010, we enrolled 304 patients and randomly allocated 153 to the placebo group and 151 to the dexamethasone group. 143 (47%) of 304 enrolled patients had pneumonia of pneumonia severity index class 4–5 (79 [52%] patients in the dexamethasone group and 64 [42%] controls). Median length of stay was 6·5 days (IQR 5·0–9·0) in the dexamethasone group compared with 7·5 days (5·3–11·5) in the placebo group (95% CI of difference in medians 0–2 days; p=0·0480). In-hospital mortality and severe adverse events were infrequent and rates did not differ between groups, although 67 (44%) of 151 patients in the dexamethasone group had hyperglycaemia compared with 35 (23%) of 153 controls (p<0·0001). Dexamethasone can reduce length of hospital stay when added to antibiotic treatment in non-immunocompromised patients with community-acquired pneumonia. None.