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To evaluate the negative effect of physical restraint use on the hospital outcomes of older patients. A retrospective cohort study. Internal medicine wards of a tertiary medical center in Taiwan. Subjects aged 65 years and over who were admitted during April to Dec 2017 were recruited for study. Demographic data, geriatric assessments (polypharmacy, visual impairment, hearing impairment, activities of daily living before and after admission, risk of pressure sores, change in consciousness level, mood condition, history of falls in the previous year, risk of malnutrition and pain) and hospital conditions (admission route, department of admission, length of hospital stay and mortality) were collected for analysis. Overall, 4,352 participants (mean age 78.7±8.7 years, 60.2% = male) were enrolled and 8.3% had physical restraint. Results of multivariate logistic regression showed that subjects with physical restraints were at greater risk of functional decline (adjusted odds ratio 2.136, 95% confidence interval 1.322–3.451, p=0.002), longer hospital stays (adjusted odds ratio 5.360, 95% confidence interval 3.627–7.923, p<0.001) and mortality (adjusted odds ratio 4.472, 95% confidence interval 2.794–7.160, p<0.001) after adjustment for covariates. The use of physical restraints during hospitalization increased the risk of adverse hospital outcomes, such as functional decline, longer length of hospital stay and mortality.

Patients with end-stage kidney disease who are undergoing dialysis have reduced immune responses to COVID-19 vaccination. Frailty is extremely common among dialysis patients and may contribute to the impaired immunogenicity. This study aimed to determine the association between frailty and humoral immune responses following COVID-19 vaccination in hemodialysis patients. Adult hemodialysis patients without prior SARS-CoV-2 infection who received a priming dose of ChAdOx1 nCoV-19, an adenovirus-vectored vaccine, were assessed for eligibility. Participants were categorized as robust, pre-frail, or frail using the Fried frailty criteria. Humoral responses were assessed 28 days after vaccination by measuring titers of anti-spike IgG antibodies. The primary outcome was anti-spike antibody seroconversion, defined as antibody levels ≥50 AU/mL. Multivariable-adjusted logistic regression models were used to assess the association between frailty status and the primary outcome. A total of 206 participants (mean age 67 ± 13 years, 50% women) were included in the study, of whom 50 (24%) were characterized as frail, 86 (42%) were characterized as pre-frail, and 70 (34%) were characterized as robust. Anti-spike antibody levels were progressively lower with more advanced stages of frailty (P <0.001). Compared with robust patients, a significantly smaller proportion of pre-frail and frail patients developed anti-spike antibody seroconversion (87%, 66%, and 40%, respectively; P <0.001). Frailty was associated with the absence of humoral responses after adjustment for age, sex, body mass index, diabetes, coronary artery disease, serum albumin, and lymphocyte count (OR=0.25; 95% CI, 0.08–0.80). Frailty is independently associated with impaired humoral responses following COVID-19 vaccination among hemodialysis patients. Strategies aimed at preventing or attenuating frailty in the dialysis population are warranted.

This study aims to assess the effectiveness of a multidomain intervention program on the change in functional status of hospitalized older adults. This single-arm, prospective, non-randomized interventional study investigates the efficacy of a multidomain interventional program including cognitive stimulation activity, simple exercises, frailty education, and nutrition counseling. At a tertiary hospital in southern Taiwan, 352 eligible patients were sequentially enrolled. Included patients were aged ≥65 years (mean age, 79.6 ± 9.0 years; 62% male), scored 3–7 on the Clinical Frailty Scale (CFS), and were hospitalized in the geriatric acute ward. Those receiving standard care (physical rehabilitation and nutrition counseling) during January–July 2019 composed the historical control group. Those receiving the multidomain intervention during August–December 2019 composed the intervention group. The primary outcome was the change in activities of daily life (ADL) and frailty status, as assessed by Katz Index and Clinical Frailty Scale, with using the generalized estimating equation model. The length of hospital stay, medical costs, and re-admission rates were secondary outcomes. Participants undergoing intervention (n = 101; 27.9%) showed greater improvements in the ADL and CFS during hospitalization (ADL adjusted estimate, 0.61; 95% CI, 0.11–1.11; p = 0.02; CFS adjusted estimate, −1.11; 95% CI, −1.42–−0.80; p < 0.01), shorter length of hospital stay (adjusted estimate, -5.00; 95% CI, −7.99–−2.47; p < 0.01), lower medical costs (adjusted estimate, 0.58; 95% CI, 0.49–0.69; p < 0.01), and lower 30- and 90-day readmission rates (30-day adjusted OR [aOR], 0.12; 95% CI, 0.27–0.50; p < 0.01; 60-day aOR, 0.04; 95% CI, 0.01–0.33; p < 0.01) than did controls. Participation in the multidomain intervention program during hospitalization improved the functional status and decreased the hospital stay length, medical costs, and readmission rates of frail older people.

Muscle stem cell function has been suggested to be regulated by Acetyl-CoA and NAD+ availability, but the mechanisms remain unclear. Here we report the identification of two acetylation sites on PAX7 that positively regulate its transcriptional activity. Lack of PAX7 acetylation reduces DNA binding, specifically to the homeobox motif. The acetyltransferase MYST1 stimulated by Acetyl-CoA, and the deacetylase SIRT2 stimulated by NAD +, are identified as direct regulators of PAX7 acetylation and asymmetric division in muscle stem cells. Abolishing PAX7 acetylation in mice using CRISPR/Cas9 mutagenesis leads to an expansion of the satellite stem cell pool, reduced numbers of asymmetric stem cell divisions, and increased numbers of oxidative IIA myofibers. Gene expression analysis confirms that lack of PAX7 acetylation preferentially affects the expression of target genes regulated by homeodomain binding motifs. Therefore, PAX7 acetylation status regulates muscle stem cell function and differentiation potential to facilitate metabolic adaptation of muscle tissue. The acetyltransferase MYST1 stimulated by acetyl-CoA, and the deacetylase SIRT2 stimulated by NAD+, regulate PAX7 acetylation in muscle stem cells, which in turn, regulates stem cell self-renewal and regeneration following injury in mouse skeletal muscle.

Loss of dystrophin causes Duchenne Muscular Dystrophy (DMD), a neuromuscular disease characterized by muscle fragility and muscle stem cell (MuSC) impairment. Conventional understanding is that DMD manifests after birth from cumulative muscle damage. Here, examination of mdx mouse embryos lacking dystrophin reveals no impairment of the primary myogenic program. By contrast, histological and single cell RNA-sequencing analysis during secondary myogenesis uncovers an increase in the proportion of fetal (f) MuSCs and a marked reduction in myogenic progenitors and myocytes, leading to fewer smaller-caliber myofibers. Wild type fMuSCs express full-length dystrophin that interacts with MARK2, whereas mdx fMuSCs downregulate MARK2 and NUMB, exhibiting reduced PARD3 polarization. Strikingly, deletion of the Numb Associated Kinase, AAK1, rescues polarization of NUMB and myogenic progenitor generation in mdx fetal muscle. Together, our results elucidate an acute disease pathology during DMD fetal development and the potential for therapeutic intervention by targeting AAK1. In mdx mouse fetuses, the lack of dystrophin markedly impairs secondary myogenesis due to reduced muscle stem cell polarity. AAK1 deletion restores polarity and rescues secondary myogenesis, revealing fetal onset in Duchenne muscular dystrophy.

Satellite cells are required for the growth, maintenance, and regeneration of skeletal muscle. Quiescent satellite cells possess a primary cilium, a structure that regulates the processing of the GLI family of transcription factors. Here we find that GLI3 processing by the primary cilium plays a critical role for satellite cell function. GLI3 is required to maintain satellite cells in a G 0 dormant state. Strikingly, satellite cells lacking GLI3 enter the G Alert state in the absence of injury. Furthermore, GLI3 depletion stimulates expansion of the stem cell pool. As a result, satellite cells lacking GLI3 display rapid cell-cycle entry, increased proliferation and augmented self-renewal, and markedly enhanced regenerative capacity. At the molecular level, we establish that the loss of GLI3 induces mTORC1 signaling activation. Therefore, our results provide a mechanism by which GLI3 controls mTORC1 signaling, consequently regulating muscle stem cell activation and fate. Primary cilia regulate the processing of the GLI transcription factors and Hedgehog signaling. Here, the authors show that cilia-related GLI3 controls both the quiescence-to-activation transition and self-renewal in muscle stem cells.

To determine whether nutritional status can predict 3-year cognitive and functional decline, as well as 4-year all-cause mortality in older adults. Prospectively longitudinal cohort study. The study recruited 354 men aged 65 years and older in the veteran's retirement community. Baseline nutritional status was evaluated using the Mini-Nutritional Assessment-Short Form (MNA-SF). Cognitive function and Activities of Daily Living (ADL) function were determined by the Mini-Mental State Examination (MMSE) and the Barthel Index, respectively. Three-year cognitive and functional decline were respectively defined as a >3 point decrease in the MMSE scores and lower ADL scores than at baseline. Univariate and multivariable logistic regression analyses were conducted to identify nutritional status as a risk factor in poor outcome. The Kaplan-Meier method and Cox proportional regression models were used to estimate the effect of malnutrition risk on the mortality. According to MNS-SF, the prevalence of risk of malnutrition was 53.1% (188/354). Multivariate logistic regression found risk of malnutrition significantly associated with 3-year cognitive decline (Adjusted odds ratio [OR] 2.07, 95% Confidence Interval [CI] 1.05–4.08, P =0.036) and functional decline (Adjusted OR 1.83, 95% CI 1.01–3.34, P =0.047) compared with normal nutritional status. The hazard ratio (HR) for all-cause mortality was 1.8 times higher in residents at risk of malnutrition (Adjusted HR 1.82, 95% CI 1.19–2.79, P =0.006). Our results provide strong evidence that risk of malnutrition can predict not only cognitive and functional decline but also risk of all-cause mortality in older men living in a veteran retirement's community. Further longitudinal studies are needed to explore the causal relationship among nutrition, clinical outcomes, and the effect of an intervention for malnutrition.

Background Duchenne muscular dystrophy (DMD) is a devastating disease characterized by progressive muscle wasting that leads to diminished lifespan. In addition to the inherent weakness of dystrophin‐deficient muscle, the dysfunction of resident muscle stem cells (MuSC) significantly contributes to disease progression. Methods Using the mdx mouse model of DMD, we performed an in‐depth characterization of disease progression and MuSC function in dystrophin‐deficient skeletal muscle using immunohistology, isometric force measurements, transcriptomic analysis and transplantation assays. We examined the architectural and functional changes in mdx skeletal muscle from 13 and 52 weeks of age and following acute cardiotoxin (CTX) injury. We also studied MuSC dynamics and function under homeostatic conditions, during regeneration post‐acute injury, and following engraftment using a combination of histological and transcriptomic analyses. Results Dystrophin‐deficient skeletal muscle undergoes progressive changes with age and delayed regeneration in response to acute injury. Muscle hypertrophy, deposition of collagen and an increase in small myofibres occur with age in the tibialis anterior (TA) and diaphragm muscles in mdx mice. Dystrophic mdx mouse TA muscles become hypertrophic with age, whereas diaphragm atrophy is evident in 1‐year‐old mdx mice. Maximum tetanic force is comparable between genotypes in the TA, but maximum specific force is reduced by up to 38% between 13 and 52 weeks in the mdx mouse. Following acute injury, myofibre hyperplasia and hypotrophy and delayed recovery of maximum tetanic force occur in the mdx TA. We also find defective MuSC polarity and reduced numbers of myocytes in mdx muscle following acute injury. We observed a 50% and 30% decrease in PAX7+ and MYOG+ cells, respectively, at 5 days post CTX injury (5 dpi) in the mdx TA. A similar decrease in mdx progenitor cell proportion is observed by single cell RNA sequencing of myogenic cells at 5 dpi. The global expression of commitment‐related genes is also reduced at 5 dpi. We find a 46% reduction in polarized PARD3 in mdx MuSCs. Finally, mdx MuSCs exhibit elevated PAX7+ cell engraftment with significantly fewer donor‐derived myonuclei in regenerated myofibres. Conclusions Our study provides evidence that dystrophin deficiency in MuSCs and myofibres together contributes to progression of DMD. Ongoing muscle damage stimulates MuSC activation; however, aberrant intrinsic MuSC polarity and stem cell commitment deficits due to the loss of dystrophin impair muscle regeneration. Our study provides in vivo validation that dystrophin‐deficient MuSCs undergo fewer asymmetric cell divisions, instead favouring symmetric expansion.

Regeneration requires the precise integration of cues that initiate proliferation, direct differentiation, and ultimately re-pattern tissues to the proper size and scale. Yet how these processes are integrated with wounding responses remains relatively unknown. The freshwater planarian, Schmidtea mediterranea, is an ideal model to study the stereotyped proliferative and transcriptional responses to injury due to its high capacity for regeneration. Here, we characterize the effector of the Hippo signalling cascade, yorkie, during planarian regeneration and its role in restricting early injury responses. In yki(RNAi) regenerating animals, wound responses are hyper-activated such that both stem cell proliferation and the transcriptional wound response program are heighted and prolonged. Using this observation, we also uncovered novel wound-induced genes by RNAseq that were de-repressed in yki(RNAi) animals compared with controls. Additionally, we show that yki(RNAi) animals have expanded epidermal and muscle cell populations, which we hypothesize are the increased sources of wound-induced genes. Finally, we show that in yki(RNAi) animals, the sensing of the size of an injury by eyes or the pharynx is not appropriate, and the brain, gut, and midline cannot remodel or scale correctly to the size of the regenerating fragment. Taken together, our results suggest that yki functions as a key molecule that can integrate multiple aspects of the injury response including proliferation, apoptosis, injury-induced transcription, and patterning.

Sea salt aerosols (SSA) are dominant particles in the Arctic atmosphere and determine the polar radiative balance. SSA react with acidic pollutants that lead to changes in physical and chemical properties of their surface, which in turn alter their hygroscopic and optical properties. Transmission electron microscopy with energy-dispersive X-ray spectrometry was used to analyze morphology, composition, size, and mixing state of individual SSA at Ny-Ålesund, Svalbard, in summertime. Individual fresh SSA contained cubic NaCl coated by certain amounts of MgCl2 and CaSO4. Individual partially aged SSA contained irregular NaCl coated by a mixture of NaNO3, Na2SO4, Mg(NO3)2, and MgSO4. The comparison suggests the hydrophilic MgCl2 coating in fresh SSA likely intrigued the heterogeneous reactions at the beginning of SSA and acidic gases. Individual fully aged SSA normally had Na2SO4 cores and an amorphous coating of NaNO3. Elemental mappings of individual SSA particles revealed that as the particles ageing Cl gradually decreased, the C, N, O, and S content increased. 12C- mapping from nanoscale secondary ion mass spectrometry indicates that organic matter increased in the aged SSA compared with the fresh SSA. 12C- line scan further shows that organic matter was mainly concentrated on the aged SSA surface. These new findings indicate that this mixture of organic matter and NaNO3 on particle surfaces likely determines their hygroscopic and optical properties. These abundant SSA as reactive surfaces adsorbing inorganic and organic acidic gases can shorten acidic gas lifetime and influence the possible gaseous reactions in the Arctic atmosphere, which need to be incorporated into atmospheric chemical models in the Arctic troposphere.