Biomaterials for immunomodulation in wound healing.

The substantial economic impact of non-healing wounds, scarring, and burns stemming from skin injuries is evident, resulting in a financial burden on both patients and the healthcare system. This review paper provides an overview of the skin's vital role in guarding against various environmental challenges as the body's largest protective organ and associated developments in biomaterials for wound healing. We first introduce the composition of skin tissue and the intricate processes of wound healing, with special attention to the crucial role of immunomodulation in both acute and chronic wounds. This highlights how the imbalance in the immune response, particularly in chronic wounds associated with underlying health conditions such as diabetes and immunosuppression, hinders normal healing stages. Then, this review distinguishes between traditional wound-healing strategies that create an optimal microenvironment and recent peptide-based biomaterials that modulate cellular processes and immune responses to facilitate wound closure. Additionally, we highlight the importance of considering the stages of wounds in the healing process. By integrating advanced materials engineering with an in-depth understanding of wound biology, this approach holds promise for reshaping the field of wound management and ultimately offering improved outcomes for patients with acute and chronic wounds.

Unmet need for mental health care is common across insurance market segments in the United States.

A substantial proportion of individuals with depression in the United States do not receive treatment. While access challenges for mental health care have been documented, few recent estimates of unmet mental health needs across insurance market segments exist. Using nationally representative survey data with participant-reported depression symptom severity and mental health care use collected in Spring 2023, we assessed access to mental health care among individuals with similar levels of depression symptom severity with commercial, Medicare, Medicaid, and no insurance. Among individuals who reported symptoms consistent with moderately severe to severe depression, 37.8% did not have a diagnosis for depression (41.0%, 28.1%, 33.6%, and 56.3% with commercial, Medicare, Medicaid, and no insurance), 51.9% did not see a mental health specialist (49.7%, 51.7%, 44.9%, and 91.8%), and 32.4% avoided mental health care due to affordability in the past 12 months (30.2%, 34.0%, 21.1%, and 54.8%). There was substantial unmet need for mental health treatment in all insurance market segments, but especially among individuals without insurance.

Excess Intramyocellular Lipid Does Not Affect Muscle Fiber Biophysical Properties in Mice or People with Metabolically Abnormal Obesity.

Observational studies show correlations between intramyocellular lipid (IMCL) content and muscle strength and contractile function in people with "metabolically abnormal" obesity. However, a clear physiologic mechanism for this association is lacking and causation is debated. We combined immunofluorescent confocal imaging with force measurements on permeabilized muscle fibers from metabolically normal and metabolically abnormal mice and metabolically normal (defined as normal fasting plasma glucose and glucose tolerance) and metabolically abnormal (defined as pre-diabetes and type 2 diabetes) people with overweight/obesity to evaluate relationships among myocellular lipid droplet characteristics (droplet size and density) and biophysical (active contractile and passive viscoelastic) properties. The fiber type specificity of lipid droplet parameters varied between metabolically abnormal and normal mice and among metabolically normal and metabolically abnormal people. However, despite considerable quantities of IMCL in the metabolically abnormal groups, there were no significant differences in peak active tension or passive viscoelasticity between the metabolically abnormal groups and the control group in mice or people. Additionally, there were no significant relationships among IMCL parameters and biophysical variables. Thus, we conclude that IMCL accumulation per se does not impact muscle fiber biophysical properties or physically impede contraction.

Medicare Advantage growth and skilled nursing facility finances.

OBJECTIVE: To examine the relationship between growth in Medicare Advantage (MA) enrollment and changes in finances at skilled nursing facilities (SNFs). DATA SOURCES: Medicare SNF cost reports, LTCFocus.org data, and county MA penetration rates. STUDY DESIGN: We used ordinary least squares regression with SNF and year fixed effects. Our primary outcomes were SNF revenues, expenses, profits, and occupancy. Our primary independent variable was the yearly county Medicare Advantage penetration. DATA COLLECTION/EXTRACTION: We linked facility-year data from 2012 to 2019 obtained from cost reports and LTCFocus.org to county-year MA penetration. PRINCIPAL FINDINGS: A 10 percentage point increase in county MA enrollment was associated with a $213,883.89 (95% Confidence Interval [CI]: -296,869.08, -130,898.71) decrease in revenue, a $132,456.19 (95% CI: -203,852.28, -61,060.10) decrease in expenses, and a 0.59 percentage point (95% CI: -0.97, -0.21) decrease in profit margin. A 10 percentage point increase in county MA enrollment was associated with a decline (-318.93; 95% CI: -468.84, -169.02) in the number of resident-days (a measure of occupancy) as well as a decline in the revenue per resident day ($4.50; 95% CI: -6.81, -2.20), potentially because of lower prices in MA. There was also a decline in expenses per patient day (-2.35; 95% CI: -4.76, 0.05), though this was only statistically significant at the 10% level. While increased MA enrollment was associated with a substantial decline in the number of Medicare resident days (487.53; 95% CI: -588.70, -386.37), this was partially offset by an increase in other payer (e.g., private pay) resident days (285.91; 95% CI: 128.18, 443.63). Increased MA enrollment was not associated with changes in the number of Medicaid resident days or a decrease in staffing per resident day. CONCLUSION: SNFs in counties with more MA growth had substantially greater relative declines in revenue, expenses, and profit margins. The continued growth of MA may result in significant changes in the SNF industry.

Job Flows Into and Out of Health Care Before and After the COVID-19 Pandemic.

Importance: Anecdotal evidence suggests that health care employers have faced increased difficulty recruiting and retaining staff in the wake of the COVID-19 pandemic. Empirical research is needed to understand the magnitude and persistence of these changes, and whether they have disproportionate implications for certain types of workers or regions of the country. Objective: To quantify the number of workers exiting from and entering into the health care workforce before and after the pandemic and to examine variations over time and across states and worker demographics. Design, Setting, and Participants: This cohort study used US Census Bureau state unemployment insurance data on job-to-job flows in the continental US to construct state-level quarterly exit and entry rates for the health care industry from January 2018 through December 2021 (Arkansas, Mississippi, and Tennessee were omitted due to missing data). An event study design was used to compute quarterly mean adjusted rates of job exit from and entry into the health care sector as defined by the North American Industry Classification System. Data were examined from January to June 2023. Exposure: The COVID-19 pandemic. Main Outcomes and Measures: The main outcomes were the mean adjusted health care worker exit and entry rates in each quarter by state and by worker demographics (age, gender, race and ethnicity, and education level). Results: In quarter 1 of 2020, there were approximately 18.8 million people (14.6 million females [77.6%]) working in the health care sector in our sample. The exit rate for health care workers increased at the onset of the pandemic, from a baseline quarterly mean of 5.9 percentage points in 2018 to 8.0 (95% CI, 7.7-8.3) percentage points in quarter 1 of 2020. Exit rates remained higher than baseline levels through quarter 4 of 2021, when the health care exit rate was 7.7 (95% CI, 7.4-7.9) percentage points higher than the 2018 baseline. In quarter 1 of 2020, the increase in health care worker exit rates was dominated by an increase in workers exiting to nonemployment (78% increase compared with baseline); in contrast, by quarter 4 of 2021, the exit rate was dominated by workers exiting to employment in non-health care sectors (38% increase compared with baseline). Entry rates into health care also increased in the postpandemic period, from 6.2 percentage points at baseline to 7.7 percentage points (95% CI, 7.4-7.9 percentage points) in the last quarter of 2021, suggesting increased turnover of health care staff. Compared with prepandemic job flows, the share of workers exiting health care after the pandemic who were female was disproportionately larger, and the shares of workers entering health care who were female or Black was disproportionately smaller. Conclusions and Relevance: Results of this cohort study suggest a substantial and persistent increase in health care workforce turnover after the pandemic, which may have long-lasting implications for workers' willingness to remain in health care jobs. Policymakers and health care organizations may need to act to prevent further losses of experienced staff.

Profile of Older Dual-Enrollees Living in Areas with Managed Long-Term Services and Supports.

OBJECTIVES: Nearly half of all state Medicaid agencies in the United States have implemented managed long-term services and supports (MLTSS). Data gaps have inhibited our understanding of MLTSS experiences to date. We draw on a national survey with novel data linkages to develop a profile of older dual-enrollees with significant LTSS needs by MLTSS program presence. DESIGN: Cross-sectional observational study using the 2015 round of the National Health and Aging Trends Study (NHATS), a longitudinal study of a nationally representative sample of Medicare beneficiaries aged 65 years and older. SETTING AND PARTICIPANTS: The sample comprised 275 participants who self-reported Medicaid enrollment and met our definition of significant LTSS need as defined by receiving help with 2 or more self-care or mobility activities (eating, bathing, toileting, dressing, bed transfer, indoor mobility). METHODS: Bivariate analyses were used to comparatively examine differences in demographic, health, and care circumstances by MLTSS, as defined by living in a county with MLTSS program presence. RESULTS: Among approximately 1 million (weighted sample) older dual-enrollees with significant LTSS needs, 56.2% (weighted percentage) lived in counties with MLTSS and 43.7% lived in counties with mandatory MLTSS enrollment in 2015. Those living in areas with MLTSS were much more likely to be of Hispanic or other race and ethnicity (50.5% vs 15.1%, P < .001) yet less likely to live in a rural location (8.7% vs 31.4%, P < .05) or in a residential care facility or nursing home (18.4% vs 34.7%, P < .05). The majority (78.5%) received assistance from 2 or more helpers and received more than 70 hours of care per week. CONCLUSIONS AND IMPLICATIONS: Our findings reinforce the growing reach of MLTSS programs and importance of filling evidence gaps about who these programs are serving.

Health Care Staff Turnover and Quality of Care at Nursing Homes.

Importance: Turnover in health care staff may disrupt patient care and create operational and organizational challenges, and nursing home staff turnover rates are particularly high. Empirical evidence on the association between turnover and quality of care is limited and has typically relied on low-quality measures of turnover, small and selected samples of facilities, and comparisons across facilities that are highly susceptible to residual confounding. Objective: To quantify the association between nursing home staff turnover and quality of care using within-facility variation over time in reliable turnover measures available for virtually all US nursing homes. Design, Setting, and Participants: In this cross-sectional study, data from the Centers for Medicare & Medicaid Services on health inspection citations and quality measures at US nursing homes were combined with turnover measures constructed from daily staffing payroll data for quarter 2 of 2017 (April 1 to June 30) to quarter 4 of 2019 (October 1 to December 31), covering 1.06 billion shifts for 7.48 million employment relationships at 15 869 facilities. A 2-way fixed-effects design was used to estimate the association between staff turnover (direct care nursing staff and administrators) and quality-of-care outcomes based on how the same facility performed differently in times of low and high turnover. Data analysis was performed from September 2022 to August 2023. Exposures: Facility turnover, defined as the share of hours worked in a period by staff hired within the last 90 days. Main Outcomes and Measures: Number, type, scope, and severity of health inspection citations, overall health inspection scores, and Nursing Home Compare quality measures. Results: The study sample included 1.45 million facility-weeks between April 1, 2017, and December 31, 2019, corresponding to 13 826 unique facilities. During an average facility-week, 15.0% of nursing staff and 11.6% of administrators were new hires due to recent turnover. After both administrator turnover and the overall staffing level were controlled for, an additional 10 percentage points in nursing staff turnover in the 2 weeks before a health inspection was associated with an additional 0.241 (95% CI, 0.084-0.399) citations in that inspection, compared with a mean of 5.98 citations. An additional 10 percentage points in nursing staff turnover was associated with a mean decrease of 0.035 (95% CI, 0.023-0.047) SDs in assessment-based quality measures and 0.020 (95% CI, 0.001-0.038) SDs in claims-based quality measures, with the strongest associations found for measures related to patient functioning. Conclusions and Relevance: Within-facility variation in staff turnover was associated with decreased quality of care. These findings suggest that efforts to monitor and reduce staff turnover may be able to improve patient outcomes.

Occupational models from 42 million unstructured job postings.

Structuring jobs into occupations is the first step for analysis tasks in many fields of research, including economics and public health, as well as for practical applications like matching job seekers to available jobs. We present a data resource, derived with natural language processing techniques from over 42 million unstructured job postings in the National Labor Exchange, that empirically models the associations between occupation codes (estimated initially by the Standardized Occupation Coding for Computer-assisted Epidemiological Research method), skill keywords, job titles, and full-text job descriptions in the United States during the years 2019 and 2021. We model the probability that a job title is associated with an occupation code and that a job description is associated with skill keywords and occupation codes. Our models are openly available in the sockit python package, which can assign occupation codes to job titles, parse skills from and assign occupation codes to job postings and resumes, and estimate occupational similarity among job postings, resumes, and occupation codes.

Site-1 protease inhibits mitochondrial respiration by controlling the TGF-ß target gene Mss51.

The mitochondrial response to changes in cellular energy demand is necessary for cellular adaptation and organ function. Many genes are essential in orchestrating this response, including the transforming growth factor (TGF)-ß1 target gene Mss51, an inhibitor of skeletal muscle mitochondrial respiration. Although Mss51 is implicated in the pathophysiology of obesity and musculoskeletal disease, how Mss51 is regulated is not entirely understood. Site-1 protease (S1P) is a key activator of several transcription factors required for cellular adaptation. However, the role of S1P in muscle is unknown. Here, we identify S1P as a negative regulator of muscle mass and mitochondrial respiration. S1P disruption in mouse skeletal muscle reduces Mss51 expression and increases muscle mass and mitochondrial respiration. The effects of S1P deficiency on mitochondrial activity are counteracted by overexpressing Mss51, suggesting that one way S1P inhibits respiration is by regulating Mss51. These discoveries expand our understanding of TGF-ß signaling and S1P function.

Tenotomy-induced muscle atrophy is sex-specific and independent of NFκB.

The nuclear factor-κB (NFκB) pathway is a major thoroughfare for skeletal muscle atrophy and is driven by diverse stimuli. Targeted inhibition of NFκB through its canonical mediator IKKß effectively mitigates loss of muscle mass across many conditions, from denervation to unloading to cancer. In this study, we used gain- and loss-of-function mouse models to examine the role of NFκB in muscle atrophy following rotator cuff tenotomy - a model of chronic rotator cuff tear. IKKß was knocked down or constitutively activated in muscle-specific inducible transgenic mice to elicit a twofold gain or loss of NFκB signaling. Surprisingly, neither knockdown of IKKß nor overexpression of caIKKß significantly altered the loss of muscle mass following tenotomy. This finding was consistent across measures of morphological adaptation (fiber cross-sectional area, fiber length, fiber number), tissue pathology (fibrosis and fatty infiltration), and intracellular signaling (ubiquitin-proteasome, autophagy). Intriguingly, late-stage tenotomy-induced atrophy was exacerbated in male mice compared with female mice. This sex specificity was driven by ongoing decreases in fiber cross-sectional area, which paralleled the accumulation of large autophagic vesicles in male, but not female muscle. These findings suggest that tenotomy-induced atrophy is not dependent on NFκB and instead may be regulated by autophagy in a sex-specific manner.

Muscle atrophy ­ the gradual loss of muscle mass ­ follows injuries to our muscles, tendons, or joints. During atrophy, muscles shrink and become weaker, which can interfere with everyday activities and, ultimately, decrease quality of life. Rotator cuff tears are a common example of such injuries. A rotator cuff is group of four muscles that come together as tendons to form a cuff that normally stabilises our shoulders and allows us to lift and move our arms over our heads. Rotator cuff tears can result from an injury or may be caused by ageing-related wear and tear of the tendon. A signalling protein, called NFκB, is thought to be involved in muscle atrophy. When the NFκB signal is switched on, it interacts with genes that are thought to speed up the loss of muscle mass. However, NFκB's precise role in atrophy and recovery after muscle injury is still poorly understood, particularly following injuries where a tendon is cut or torn. Meyer et al. therefore set out to determine whether or not NFκB played a role in the muscle atrophy following rotator cuff tears. Meyer et al. used genetically engineered mice in which NFκB's signal could be turned off at the time of rotator cuff injury, and specifically in muscle cells (but not other parts of the body). The experiments revealed that stopping NFκß signalling in these mice did not reduce muscle atrophy after a rotator cuff injury: the levels of atrophy, muscle performance, and muscle composition were the same regardless of whether the NFκß signal was active. The sex of the mice did, however, affect muscle atrophy, specifically the way in which they lost muscle mass. In male mice, the size of muscle cells decreased, while in female mice, the number of muscle cells decreased. Muscle cells in male mice (but not in females) also accumulated abnormally high amounts of protein, which is an indication of a mechanism of muscle breakdown called autophagy. These results shed new light on the way that we lose muscle mass after injury, and how that could vary depending on the individual. Meyer et al. hope that this study will help guide the development of new, more effective treatments for muscle atrophy, and ultimately contribute to therapies tailored to the characteristics of the patient and the type of injury.

Staffing Patterns in US Nursing Homes During COVID-19 Outbreaks.

Importance: Staff absences and departures at nursing homes may put residents at risk and present operational challenges. Objective: To quantify changes in nursing home facility staffing during and after a severe COVID-19 outbreak. Design Setting and Participants: In this cohort study, daily staffing payroll data were used to construct weekly measures of facility staffing, absences, departures, and use of overtime and contract staff among US nursing homes experiencing a severe COVID-19 outbreak that started between June 14, 2020, and January 1, 2021. Facility outbreaks were identified using COVID-19 case data. An event-study design with facility and week fixed effects was used to investigate the association of severe outbreaks with staffing measures. Exposures: Weeks since the beginning of a severe COVID-19 outbreak (4 weeks prior to 16 weeks after). Main Outcomes and Measures: Total weekly staffing hours, staff counts, staff absences, departures, new hires, overtime and contract staff hours measured for all nursing staff and separately by staff type (registered nurses, licensed practical nurses, certified nursing assistants), facility self-reported staff shortages, and resident deaths. Results: Of the included 2967 nursing homes experiencing severe COVID-19 outbreaks, severe outbreaks were associated with a statistically significant drop in nursing staffing levels owing to elevated absences and departures. Four weeks after an outbreak's start, around when average new cases peaked, staffing hours were 2.6% (95% CI, 2.1%-3.2%) of the mean below preoutbreak levels, despite facilities taking substantial measures to bolster staffing through increased hiring and the use of contract staff and overtime. Because these measures were mostly temporary, staffing declined further in later weeks; 16 weeks after an outbreak's start, staffing hours were 5.5% (95% CI, 4.5%-6.5%) of the mean below preoutbreak levels. Staffing declines were greatest among certified nursing assistants, primarily owing to smaller increases in new hires of this staff type compared with licensed practical nurses and registered nurses. Conclusions and Relevance: In this cohort study of nursing homes experiencing severe COVID-19 outbreaks, facilities experienced considerable staffing challenges during and after outbreaks. These results suggest the need for policy action to ensure facilities' abilities to maintain adequate staffing levels during and after infectious disease outbreaks.

Relationship between nursing home COVID-19 outbreaks and staff neighborhood characteristics.

The COVID-19 pandemic has been particularly deadly for residents of nursing homes and other long-term care facilities. This paper analyzes COVID-19 deaths at nursing homes during the first wave of the pandemic in the United States during the spring and early summer 2020. By combining data on facility-level COVID-19 deaths during this period with data on the neighborhoods where nursing home staff reside for a sample of eighteen states, this paper finds that staff neighborhood characteristics were a large and significant predictor of COVID-19 nursing home deaths. Even after controlling for the county where a facility is located, one standard deviation increases in average staff neighborhood (Census tract) population density, public transportation use, and non-white share were associated with 1.3 (p < .001), 1.4 (p < .001), and 0.9 (p < .001) additional deaths per 100 beds, respectively. These effects are larger than all facility management or quality variables, and larger than the effect of the nursing home's own neighborhood characteristics. These results suggest COVID-19 outbreaks in staff communities can have large consequences for the facilities where they work, even in highly-rated facilities, and that disparities in nursing home outbreaks may be related to differences in the types of neighborhoods nursing home staff live in.

Prospective Nasal Screening for Methicillin-Resistant Staphylococcus aureus in Critically Ill Patients With Suspected Pneumonia.

We carried out a prospective de-escalation study based on methicillin-resistant Staphylococcus aureus (MRSA) nasal cultures in intensive care unit patients with suspected pneumonia. Days of anti-MRSA therapy was significantly reduced in the intervention group (2 [0-3] days vs 1 [0-2] day; P < .01). Time to MRSA de-escalation was also shortened in the intervention group.

A unique sarcopenic progression in the mouse rotator cuff.

BACKGROUND: In response to chronic injury, the muscles of the rotator cuff (RC) experience a unique degeneration characterized by extensive fatty infiltration and loss of contractile function. Human studies suggest this degeneration is also a feature of RC sarcopenia and may precede RC injury. In this study, we investigated whether RC muscles exhibit a similar unique sarcopenia in the mouse. METHODS: Male and female mice were subdivided into four age groups: 3, 9, 18, and 24 months. The supraspinatus (SS) and infraspinatus muscles of the RC and the tibialis anterior (TA) muscle of the hindlimb were assessed. Muscle mass, contractile function, fibre cross-sectional areas and numbers, fatty infiltration, and fibrosis were assessed at each time point. Targeted transcriptional analyses were performed to assess the role of metabolic and inflammatory derangement in the pathology. RESULTS: The 24-month-aged female mice exhibited decreased mass (25% lower than at 9 and 18 months, P < 0.01) in all muscles tested. However, only RC muscles also exhibited decreased contractile tension at this time point (20% lower than at 18 months, P < 0.005). Similarly, only female RC muscles exhibited increased fatty infiltration at 24 months (20% higher than 9 months, P < 0.05) and had elevated transcriptional markers of adipogenesis (2.4-fold higher Pparg and 3.8-fold higher Adipoq expression compared with 9 months, P < 0.001). Unbiased metabolic transcriptional profiling identified up-regulation of the antigen presentation (Z scores of 2.3 and 1.9 for SS and TA, respectively) and cytokine and chemokine signalling (Z scores of 3.1 and 2.4 for SS and TA, respectively) pathways in 24 month female muscle compared with 9. Further transcriptional analysis supported increased expression of pro-adipogenic inflammatory signals (6.3-fold increase in Il6 and 5.0-fold increase in Anxa2, P < 0.01) and increased presence of fibro-adipogenic progenitors (2.5-fold) in the 24-month-aged female RC compared with 9 months that together exacerbate fatty infiltration. CONCLUSIONS: These data indicate that female mice replicate the unique sarcopenic pathology in the ageing human RC. Furthermore, they suggest that the exacerbated fatty infiltration is due to an interaction between higher resident fibro-adipogenic progenitor numbers and an elevated systemic inflammation in aged female mice. We conclude that female mouse RC muscle is a novel system to study both human RC degeneration and the signals that regulate sarcopenic fatty infiltration in general, which is prevalent in humans but largely absent from the rodent hindlimb.

Estimates of COVID-19 Cases and Deaths Among Nursing Home Residents Not Reported in Federal Data.

Importance: Federal data underestimate the impact of COVID-19 on US nursing homes because federal reporting guidelines did not require facilities to report case and death data until the week ending May 24, 2020. Objective: To assess the magnitude of unreported cases and deaths in the National Healthcare Safety Network (NHSN) and provide national estimates of cases and deaths adjusted for nonreporting. Design, Setting, and Participants: This is a cross-sectional study comparing COVID-19 cases and deaths reported by US nursing homes to the NHSN with those reported to state departments of health in late May 2020. The sample includes nursing homes from 20 states, with 4598 facilities in 12 states that required facilities to report cases and 7401 facilities in 19 states that required facilities to report deaths. Estimates of nonreporting were extrapolated to infer the national (15 397 facilities) unreported cases and deaths in both May and December 2020. Data were analyzed from December 2020 to May 2021. Exposures: Nursing home ownership (for-profit or not-for-profit), chain affiliation, size, Centers for Medicare & Medicaid Services star rating, and state. Main Outcomes and Measures: The main outcome was the difference between the COVID-19 cases and deaths reported by each facility to their state department of health vs those reported to the NHSN. Results: Among 15 415 US nursing homes, including 4599 with state case data and 7405 with state death data, a mean (SE) of 43.7% (1.4%) of COVID-19 cases and 40.0% (1.1%) of COVID-19 deaths prior to May 24 were not reported in the first NHSN submission in sample states, suggesting that 68 613 cases and 16 623 deaths were omitted nationwide, representing 11.6% of COVID-19 cases and 14.0% of COVID-19 deaths among nursing home residents in 2020. Conclusions and Relevance: These findings suggest that federal NHSN data understated total cases and deaths in nursing homes. Failure to account for this issue may lead to misleading conclusions about the role of different facility characteristics and state or federal policies in explaining COVID outbreaks.

SWELL1 regulates skeletal muscle cell size, intracellular signaling, adiposity and glucose metabolism.

Maintenance of skeletal muscle is beneficial in obesity and Type 2 diabetes. Mechanical stimulation can regulate skeletal muscle differentiation, growth and metabolism; however, the molecular mechanosensor remains unknown. Here, we show that SWELL1 (Lrrc8a) functionally encodes a swell-activated anion channel that regulates PI3K-AKT, ERK1/2, mTOR signaling, muscle differentiation, myoblast fusion, cellular oxygen consumption, and glycolysis in skeletal muscle cells. LRRC8A over-expression in Lrrc8a KO myotubes boosts PI3K-AKT-mTOR signaling to supra-normal levels and fully rescues myotube formation. Skeletal muscle-targeted Lrrc8a KO mice have smaller myofibers, generate less force ex vivo, and exhibit reduced exercise endurance, associated with increased adiposity under basal conditions, and glucose intolerance and insulin resistance when raised on a high-fat diet, compared to wild-type (WT) mice. These results reveal that the LRRC8 complex regulates insulin-PI3K-AKT-mTOR signaling in skeletal muscle to influence skeletal muscle differentiation in vitro and skeletal myofiber size, muscle function, adiposity and systemic metabolism in vivo.

Skeletal muscles ­ the force-generating tissue attached to bones ­ must maintain their mass and health for the body to work properly. It is therefore necessary to understand how an organism can regulate the way skeletal muscles form, grow and heal. A multitude of factors can control how muscles form, including mechanical signals. The molecules that can sense these mechanical stimuli, however, remain unknown. Mechanoresponsive ion channels provide possible candidates for these molecular sensors. These proteins are studded through the cell membranes, where they can respond to mechanical changes by opening and allowing the flow of ions in and out of a cell, or by changing interactions with other proteins. The SWELL1 protein is a component of an ion channel known as VRAC, which potentially responds to mechanical stimuli. This channel is associated with many biological processes such as cells multiplying, migrating, growing and dying, but it is still unclear how. Here, Kumar et al. first tested whether SWELL1 controls how skeletal muscle precursors mature into their differentiated and functional form. These experiments showed that SWELL1 regulates this differentiation process under the influence of the hormone insulin, as well as mechanical signals such as cell stretching. In addition, this work revealed that SWELL1 relies on an adaptor molecule called GRB2 to relay these signals in the cell. Next, Kumar et al. genetically engineered mice lacking SWELL1 only in skeletal muscle. These animals had smaller muscle cells, as well as muscles that were weaker and less enduring. When raised on a high-calorie diet, the mutant mice also got more obese and developed resistance to insulin, which is an important step driving obesity-induced diabetes. Together, these findings show that SWELL1 helps to regulate the formation and function of muscle cells, and highlights how an ion channel participates in these processes. Healthy muscles are key for overall wellbeing, as they also protect against obesity and obesity-related conditions such as type 2 diabetes or nonalcoholic fatty liver disease. This suggests that targeting SWELL1 could prove advantageous in a clinical setting.

Treatment Of Opioid Use Disorder Among Commercially Insured US Adults, 2008-17.

There is abundant literature on efforts to reduce opioid prescriptions and misuse, but comparatively little on the treatment provided to people with opioid use disorder (OUD). Using claims data representing 12-15 million nonelderly adults covered through commercial group insurance during the period 2008-17, we explored rates of OUD diagnoses, treatment patterns, and spending. We found three key patterns: The rate of diagnosed OUD nearly doubled during 2008-17, and the distribution has shifted toward older age groups; the likelihood that diagnosed patients will receive any treatment has declined, particularly among those ages forty-five and older, because of a reduction in the use of medication-assisted treatment (MAT) and despite clinical evidence demonstrating its efficacy; and treatment spending is lower for patients who choose MAT. These patterns suggest that policies supporting the use of MAT are critical to addressing the undertreatment of OUD among the commercially insured and that further research to assess the cost-effectiveness of treatment with versus without medication is needed.

Infiltration of intramuscular adipose tissue impairs skeletal muscle contraction.

KEY POINTS: Muscle infiltration with adipose tissue (IMAT) is common and associated with loss of skeletal muscle strength and physical function across a diverse set of pathologies. Whether the association between IMAT and muscle weakness is causative or simply correlative remains an open question that needs to be addressed to effectively guide muscle strengthening interventions in people with increased IMAT. In the present studies, we demonstrate that IMAT deposition causes decreased muscle strength using mouse models. These findings indicate IMAT is a novel therapeutic target for muscle dysfunction. ABSTRACT: Intramuscular adipose tissue (IMAT) is associated with deficits in strength and physical function across a wide array of conditions, from injury to ageing to metabolic disease. Due to the diverse aetiologies of the primary disorders involving IMAT and the strength of the associations, it has long been proposed that IMAT directly contributes to this muscle dysfunction. However, infiltration of IMAT and reduced strength could both be driven by muscle disuse, injury and systemic disease, making IMAT simply an 'innocent bystander.' Here, we utilize novel mouse models to evaluate the direct effect of IMAT on muscle contraction. First, we utilize intramuscular glycerol injection in wild-type mice to evaluate IMAT in the absence of systemic disease. In this model we find that, in isolation from the neuromuscular and circulatory systems, there remains a muscle-intrinsic association between increased IMAT volume and decreased contractile tension (r2  > 0.5, P < 0.01) that cannot be explained by reduction in contractile material. Second, we utilize a lipodystrophic mouse model which cannot generate adipocytes to 'rescue' the deficits. We demonstrate that without IMAT infiltration, glycerol treatment does not reduce contractile force (P > 0.8). Taken together, this indicates that IMAT is not an inert feature of muscle pathology but rather has a direct impact on muscle contraction. This finding suggests that novel strategies targeting IMAT may improve muscle strength and function in a number of populations.