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Competing Interests: Competing interests: Work by all authors was supported by grants from either the US National Institutes of Health (NIH), National Center for Complementary and Integrative Health (NCCIH), the Office of Behavioral and Social Sciences Research (OBSSR) or the US Department of Defense. In all cases, funding was provided to institutions and not to individuals. No other competing interests to declare.

Goal: To document shifts in rural hospital service line offerings between 2010 and 2021 and to assess the resulting impacts on hospital profitability., Methods: We used annual Medicare cost report data for all rural hospitals that did not change payment classifications between 2010 and 2021. We documented changes in the percentages of hospitals offering each of the 37 inpatient or ancillary service lines included in the data. We then used panel event studies to assess effects on hospital operating margin for specific service lines that changed most prominently during this period., Principal Findings: Twelve service lines changed by more than 5% during our period of analysis. These are highlighted by hospitals adding rural health clinics (+32%) and CT scans (+20%) and removing delivery rooms (-21%) and skilled nursing facilities (-19%). Panel event studies demonstrated that the addition or subtraction of most services did not have statistically significant impacts on future hospital operating margins. Notable exceptions were the addition of rural health clinics and the removal of delivery services, both of which positively affected future operating margins. The addition of occupational therapy services had a positive effect on operating margin in the near term, but adding MRI services had a negative effect., Practical Applications: The finding that only a select few service line changes resulted in meaningful impacts to hospital operating margins suggests that hospital leaders should be wary of implementing such changes as a means of improving financial viability., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Foundation of the American College of Healthcare Executives.)

Aims: The aim of the present study was to assess the relationship between adolescent IQ and midlife alcohol use and to explore possible mediators of this relationship., Methods: Study data were from 6300 men and women who participated in the Wisconsin Longitudinal Study of high-school students graduating in 1957. IQ scores were collected during the participants' junior year of high school. In 2004, participants reported the number of alcoholic beverages consumed (past 30 days) and the number of binge-drinking episodes. A multinomial logistic regression was conducted to determine the relationship between adolescent IQ and future drinking pattern (abstainer, moderate drinker, or heavy drinker), and Poisson regression was used to examine the number of binge-drinking episodes. Two mediators-income and education-were also explored., Results: Every one-point increase in IQ score was associated with a 1.6% increase in the likelihood of reporting moderate or heavy drinking as compared to abstinence. Those with higher IQ scores also had significantly fewer binge-drinking episodes. Household income, but not education, partially mediated the relationship between IQ and drinking pattern., Conclusions: The present study suggests that higher adolescent IQ may predict a higher likelihood of moderate or heavy drinking in midlife, but fewer binge-drinking episodes. The study also suggests that this relationship is mediated by other psychosocial factors, specifically income, prompting future exploration of mediators in subsequent studies., (© The Author(s) 2024. Medical Council on Alcohol and Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Studies have examined floor-to-stand performance in varied adult populations both quantitatively and qualitatively. Despite an elevated risk of falls and inability to independently return to stand after a fall, few have examined the ability to stand from the floor in patients recovering from stroke. There were 2 objectives of the study: to identify the relationships between floor-to-stand performance using a timed supine-to-stand test (TSS) and physical performance measures of gait, balance, and balance confidence among persons in the subacute phase after stroke; and to analyze descriptive strategies used in the completion of the TSS., Methods: A cross-sectional design was implemented. Fifty-eight adults (mean age = 59.2 [standard deviation (SD) = 13.9] years; 34 [58.6%] men) who were in the subacute phase after ischemic or hemorrhagic stroke and who could stand from the floor with no more than supervision completed the TSS and physical performance assessments., Results: The median time to complete the TSS in our sample was 13.0 (interquartile range = 15.5) seconds. TSS time was significantly correlated with physical performance tests, including the Timed "Up & Go" Test (ρ = 0.70), gait speed (ρ = -0.67), Dynamic Gait Index (ρ = -0.52), and Activities-Specific Balance Confidence Scale (ρ = -0.43). Thirty-two percent of the variance in TSS time was attributed to Timed "Up & Go" Test time and the use of the quadruped position to transition to standing. Participants who used a gait device were more likely to use a chair during rise to stand., Conclusion: The TSS demonstrates concurrent validity with physical performance measures., Impact: Findings serve to improve functional mobility examination after stroke and to formulate effective treatment interventions to improve floor-to-stand performance., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: To determine whether community sociodemographic factors are associated with the survival or closure of rural hospitals at risk of financial distress between 2010 and 2019., Methods: We use a national sample of 985 rural hospitals at risk of financial distress to analyze the relationship between community sociodemographic characteristics and hospital survival or closure. We control for financial distress using the Financial Distress Index developed by the Sheps Center for Health Services Research. Community characteristics are retrieved from the Census and the Robert Wood Johnson Foundation. We first use Wilcoxon rank-sum tests to demonstrate annual sociodemographic differences between rural communities with financially distressed hospitals that closed between 2010 and 2019, and those that remained open. Multilevel Weibull proportional hazards regressions then uncover which sociodemographic factors are significantly associated with survival., Findings: Our initial results confirm that closures of rural hospitals at risk of financial distress disproportionately affect communities with certain sociodemographic characteristics. However, most of these characteristics are not associated with higher rates of closure in the multivariate survival analysis. The final results suggest that financially distressed hospitals are more likely to experience closure if their communities have higher rates of unemployment (Hazard Ratio = 1.36, P < .05) or uninsured residents under 65 (Hazard Ratio = 1.13, P < .05)., Conclusions: Among financially distressed rural hospitals, specific community-level sociodemographic characteristics (unemployment and uninsurance rates) are positively associated with the likelihood of closure. Social policies addressing these issues should emphasize their broader relationship with the local health sector., (© 2022 The Authors. The Journal of Rural Health published by Wiley Periodicals LLC on behalf of National Rural Health Association.)

Nonpharmacological treatments are considered first-line pain management strategies, but they remain clinically underused. For years, pain-focused pragmatic clinical trials (PCTs) have generated evidence for the enhanced use of nonpharmacological interventions in routine clinical settings to help overcome implementation barriers. The Pragmatic Explanatory Continuum Indicator Summary (PRECIS-2) framework describes the degree of pragmatism across 9 key domains. Among these, "flexibility in delivery" and "flexibility in adherence," address a key goal of pragmatic research by tailoring approaches to settings in which people receive routine care. However, to maintain scientific and ethical rigor, PCTs must ensure that flexibility features do not compromise delivery of interventions as designed, such that the results are ethically and scientifically sound. Key principles of achieving this balance include clear definitions of intervention core components, intervention monitoring and documentation that is sufficient but not overly burdensome, provider training that meets the demands of delivering an intervention in real-world settings, and use of an ethical lens to recognize and avoid potential trial futility when necessary and appropriate. PERSPECTIVE: This article presents nuances to be considered when applying the PRECIS-2 framework to describe pragmatic clinical trials. Trials must ensure that patient-centered treatment flexibility does not compromise delivery of interventions as designed, such that measurement and analysis of treatment effects is reliable., (Copyright © 2023 United States Association for the Study of Pain, Inc. All rights reserved.)

Pragmatic clinical trials (PCTs) are well-suited to address unmet healthcare needs, such as those arising from the dual public health crises of chronic pain and opioid misuse, recently exacerbated by the COVID-19 pandemic. These overlapping epidemics have complex, multifactorial etiologies, and PCTs can be used to investigate the effectiveness of integrated therapies that are currently available but underused. Yet individual pragmatic studies can be limited in their reach because of existing structural and cultural barriers to dissemination and implementation. The National Institutes of Health, Department of Defense, and Department of Veterans Affairs formed an interagency research partnership, the Pain Management Collaboratory. The partnership combines pragmatic trial design with collaborative tools and relationship building within a large network to advance the science and impact of nonpharmacological approaches and integrated models of care for the management of pain and common co-occurring conditions. The Pain Management Collaboratory team supports 11 large-scale, multisite PCTs in veteran and military health systems with a focus on team science with the shared aim that the "whole is greater than the sum of the parts." Herein, we describe this integrated approach and lessons learned, including incentivizing all parties; proactively offering frequent opportunities for problem-solving; engaging stakeholders during all stages of research; and navigating competing research priorities. We also articulate several specific strategies and their practical implications for advancing pain management in active clinical, "real-world," settings., (© The Association of Military Surgeons of the United States 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The aim of the study is to examine the relationship between electronic health record (EHR) use/functionality and hospital operating costs (divided into five subcategories), and to compare the results across rural and urban facilities., Methods: We match hospital-level data on EHR use/functionality with operating costs and facility characteristics to perform linear regressions with hospital- and time-fixed effects on a panel of 1,596 U.S. hospitals observed annually from 2016 to 2019. Our dependent variables are the logs of the various hospital operating cost categories, and alternative metrics for EHR use/functionality serve as the primary independent variables of interest. Data on EHR use/functionality are retrieved from the American Hospital Association's (AHA) Annual Survey of Hospitals Information Technology (IT) Supplement, and hospital operating cost and characteristic data are retrieved from the American Hospital Directory. We include only hospitals classified as "general medical and surgical," removing specialty hospitals., Results: Our results suggest, first, that increasing levels of EHR functionality are associated with hospital operating cost reductions. Second, that these significant cost reductions are exclusively seen in urban hospitals, with the associated coefficient suggesting cost savings of 0.14% for each additional EHR function. Third, that urban EHR-related cost reductions are driven by general/ancillary and outpatient costs. Finally, that a wide variety of EHR functions are associated with cost reductions for urban facilities, while no EHR function is associated with significant cost reductions in rural locations., Conclusion: Increasing EHR functionality is associated with significant hospital operating cost reductions in urban locations. These results do not hold across geographies, and policies to promote greater EHR functionality in rural hospitals will likely not lead to short-term cost reductions., Competing Interests: None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Introduction: Pragmatic clinical trials (PCTs) can overcome implementation challenges for bringing evidence-based therapies to people living with pain and co-occurring conditions, providing actionable information for patients, providers, health systems, and policy makers. All studies, including those conducted within health systems that have a history of advancing equitable care, should make efforts to address justice and equity., Methods: Drawing from collective experience within pragmatic pain clinical trials networks, and synthesizing relevant literature, our multidisciplinary working group examined challenges related to integrating justice and equity into pragmatic pain management research conducted in large, integrated health systems. Our analysis draws from military and veteran health system contexts but offers strategies to consider throughout the lifecycle of pragmatic research more widely., Results: We found that PCTs present a unique opportunity to address major influences on health inequities by occupying a space between research, healthcare delivery, and the complexities of everyday life. We highlight key challenges that require attention to support complementary advancement of justice and equity via pragmatic research, offering several strategies that can be pursued., Conclusions: Efforts are needed to engage diverse stakeholders broadly and creatively in PCTs, such as through dedicated health equity working groups and other collaborative relationships with stakeholders, to support robust and inclusive approaches to research design and implementation across study settings. These considerations, while essential to pain management research, offer important opportunities toward achieving more equitable healthcare and health systems to benefit people living with pain and co-occurring conditions., Competing Interests: The authors declares no conflicts of interest., (© 2021 The Authors. Learning Health Systems published by Wiley Periodicals LLC on behalf of University of Michigan.)

Background: Melasma is a common pigmentary disorder that responds well to treatment with oral and/or locally injected tranexamic acid but less so to topical application. We hypothesized that this may be due to an inability of some topical formulations of tranexamic acid to achieve robust therapeutic concentrations at the viable epidermal target site in the skin., Aims: To measure in vitro human epidermal and dermal skin concentrations of tranexamic acid following topical application of Fairence ® T-Complex, co-enhancer cream and a Japanese branded cream control ("branded") and compare these with estimates of tranexamic acid potency obtained from in vivo human pharmacokinetic and clinical studies and in vitro pharmacodynamic studies on inhibition of fibrinolysis., Methods: Static vertical Franz cells and human abdominal skin were used to measure stratum corneum, viable epidermal, and dermal concentrations of tranexamic acid using HPLC-MS-MS analysis at 6 and 24 hour periods after topical application., Results: Skin concentrations of tranexamic acid following application of the co-enhancer cream were robustly within the concentration range estimated to be required for efficacy at both 6 and 24 hours. Those from the branded cream control were within the lower range at 24 hours., Conclusions: These preclinical results support the benefits of conducting further studies, including a double-blind placebo-controlled clinical study, on Fairence ® T-Complex, co-enhancer cream in patients with melasma. It is hypothesized that a more robust and timely clinical response may be achieved especially in refractory patients., (© 2020 Wiley Periodicals, Inc.)

Despite efforts to promote diversity in the biomedical workforce, there remains a lower rate of funding of National Institutes of Health R01 applications submitted by African-American/black (AA/B) scientists relative to white scientists. To identify underlying causes of this funding gap, we analyzed six stages of the application process from 2011 to 2015 and found that disparate outcomes arise at three of the six: decision to discuss, impact score assignment, and a previously unstudied stage, topic choice. Notably, AA/B applicants tend to propose research on topics with lower award rates. These topics include research at the community and population level, as opposed to more fundamental and mechanistic investigations; the latter tend to have higher award rates. Topic choice alone accounts for over 20% of the funding gap after controlling for multiple variables, including the applicant's prior achievements. Our findings can be used to inform interventions designed to close the funding gap., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Previous research suggests that the endocrine disrupting chemical tolylfluanid (TF) may promote metabolic dysfunction and insulin resistance in humans. The potential impact of TF on skeletal muscle metabolism has yet to be fully investigated. The purpose of this study was to determine whether TF can promote insulin resistance and metabolic dysfunction in mammalian skeletal muscle cells. C2C12 murine skeletal myotubes were exposed to 1 ppm TF for 24 h. To examine the potential effect of cellular fatty acid levels on TF-dependent regulation of mitochondrial metabolism and insulin signaling, we treated skeletal myotubes with 0.25 mM or 1.0 mM oleic acid (OA) during TF exposure trials. Tolylfluanid (1-10 ppm) reduced lipid accumulation by approximately 20% in 0.25 and 1.0 mM OA treated cells. The addition of 0.25 mM OA completely inhibited the TF-dependent reduction in maximal mitochondrial oxygen consumption rate (OCR) while 1.0 mM OA exacerbated the TF-dependent reduction in mitochondrial OCR. Exposing skeletal myotubes to 1 ppm TF promoted an 80% reduction in mitochondrial membrane potential, which was completely inhibited by 0.25 mM OA and partially inhibited by1.0 mM OA. The addition of 0.25 mM OA promoted a TF-dependent increase in insulin-dependent P-Akt (Ser473). In contrast, the addition of 1.0 mM OA promoted a significant reduction in insulin-dependent P-Akt (Ser473). Further, the addition of 1 ppm TF significantly reduced insulin-dependent mTORC1 activity regardless of OA concentration. Finally, TF significantly reduced insulin-dependent protein synthesis in the 1 mM OA treated cells only. Our results demonstrate that the effect of 1 ppm TF on mitochondrial function and insulin-dependent protein synthesis in skeletal myotubes was largely dependent upon cellular fatty acid levels., (Copyright © 2018. Published by Elsevier Inc.)

Context: As today's rural hospitals have struggled with financial sustainability for the past 2 decades, it is critical to understand their value relative to alternatives, such as rural health clinics and private practices., Purpose: To estimate the willingness-to-pay for specific attributes of rural health care facilities in rural Kentucky to determine which services and operational characteristics are most valued by rural residents., Methodology: We fitted choice experiment data from 769 respondents in 10 rural Kentucky counties to a conditional logit model and used the results to estimate willingness-to-pay for attributes in several categories, including hours open, types of insurance accepted, and availability of health care professionals and specialized care., Findings: Acceptance of Medicaid/Medicare with use of a sliding fee scale versus acceptance of only private insurance was the most valued attribute. Presence of full diagnostic services, an emergency room, and 24-hour/7-day-per-week access were also highly valued. Conversely, the presence of specialized care, such as physical therapy, cancer care, or dialysis, was not valued. In total, respondents were willing to pay $225 more annually to support a hospital relative to a rural health clinic., Conclusion: Rural Kentuckians value the services, convenience, and security that rural hospitals offer, though they are not willing to pay more for specialized care that may be available in larger medical treatment centers. The results also inform which attributes might be added to existing rural health facilities to make them more valuable to local residents., (© 2014 National Rural Health Association.)

Our eyes are, both literally and figuratively, windows to the world, and ophthalmic approaches offer a tremendous space for conducting research to learn more. Male/female differences in ocular health and disease are prevalent but we know far too little about root causes to design and implement diagnostic, preventive, and treatment strategies to address sex- and gender-based disparities in eye health. Herein, we discuss several ophthalmic diseases and other conditions with ocular manifestations, with a focus upon those that disproportionately affect women. Because the vast majority of biomedical research in this area comes from studies of mixed-gender populations, or of male-predominant populations, there is a pressing need for sex- and/or gender-based research at various points along the basic to clinical biomedical research continuum. Moreover, the multitude of factors that affect eye health call for a balanced look at the influence of biology, culture, and societal contributors. As clinicians, we owe our patients the best care for their needs, and that care must be derived from research that shows what is effective, for whom, and under what conditions.