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While regular physical activity is a cornerstone of health, wellness, and vitality, the impact of endurance exercise training on molecular signaling within and across tissues remains to be delineated. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to characterize molecular networks underlying the adaptive response to exercise. Here, we describe the endurance exercise training studies undertaken by the Preclinical Animal Sites Studies component of MoTrPAC, in which we sought to develop and implement a standardized endurance exercise protocol in a large cohort of rats. To this end, Adult (6-mo) and Aged (18-mo) female (n = 151) and male (n = 143) Fischer 344 rats were subjected to progressive treadmill training (5 d/wk, ∼70%-75% VO2max) for 1, 2, 4, or 8 wk; sedentary rats were studied as the control group. A total of 18 solid tissues, as well as blood, plasma, and feces, were collected to establish a publicly accessible biorepository and for extensive omics-based analyses by MoTrPAC. Treadmill training was highly effective, with robust improvements in skeletal muscle citrate synthase activity in as little as 1-2 wk and improvements in maximum run speed and maximal oxygen uptake by 4-8 wk. For body mass and composition, notable age- and sex-dependent responses were observed. This work in mature, treadmill-trained rats represents the most comprehensive and publicly accessible tissue biorepository, to date, and provides an unprecedented resource for studying temporal-, sex-, and age-specific responses to endurance exercise training in a preclinical rat model.

Regular exercise promotes whole-body health and prevents disease, but the underlying molecular mechanisms are incompletely understood1-3. Here, the Molecular Transducers of Physical Activity Consortium4 profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome and immunome in whole blood, plasma and 18 solid tissues in male and female Rattus norvegicus over eight weeks of endurance exercise training. The resulting data compendium encompasses 9,466 assays across 19 tissues, 25 molecular platforms and 4 training time points. Thousands of shared and tissue-specific molecular alterations were identified, with sex differences found in multiple tissues. Temporal multi-omic and multi-tissue analyses revealed expansive biological insights into the adaptive responses to endurance training, including widespread regulation of immune, metabolic, stress response and mitochondrial pathways. Many changes were relevant to human health, including non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health and tissue injury and recovery. The data and analyses presented in this study will serve as valuable resources for understanding and exploring the multi-tissue molecular effects of endurance training and are provided in a public repository ( https://motrpac-data.org/ ).

BackgroundFalls are common in older adults and can lead to severe injuries. The Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) trial cluster-randomized 86 primary care practices across 10 health systems to a multifactorial intervention to prevent fall injuries, delivered by registered nurses trained as falls care managers, or enhanced usual care. STRIDE enrolled 5451 community-dwelling older adults age ≥70 at increased fall injury risk.MethodsWe assessed fall-related outcomes via telephone interviews of participants (or proxies) every 4 months. At baseline, 12 and 24 months, we assessed health-related quality of life (HRQOL) using the EQ-5D-5L and EQ-VAS. We used Poisson models to assess intervention effects on falls, fall-related fractures, fall injuries leading to hospital admission, and fall injuries leading to medical attention. We used hierarchical longitudinal linear models to assess HRQOL.ResultsFor recurrent event models, intervention versus control incidence rate ratios were 0.97 (95% confidence interval [CI], 0.93-1.00; p = 0.048) for falls, 0.93 (95% CI, 0.80-1.08; p = 0.337) for self-reported fractures, 0.89 (95% CI, 0.73-1.07; p = 0.205) for adjudicated fractures, 0.91 (95% CI, 0.77-1.07; p = 0.263) for falls leading to hospital admission, and 0.97 (95% CI, 0.89-1.06; p = 0.477) for falls leading to medical attention. Similar effect sizes (non-significant) were obtained for dichotomous outcomes (e.g., participants with ≥1 events). The difference in least square mean change over time in EQ-5D-5L (intervention minus control) was 0.009 (95% CI, -0.002 to 0.019; p = 0.106) at 12 months and 0.005 (95% CI, -0.006 to 0.015; p = 0.384) at 24 months.ConclusionsAcross a standard set of outcomes typically reported in fall prevention studies, we observed modest improvements, one of which was statistically significant. Future work should focus on patient-, practice-, and organization-level operational strategies to increase the real-world effectiveness of interventions, and improving the ability to detect small but potentially meaningful clinical effects.Clinicaltrialsgov identifier: NCT02475850.

BackgroundElectronic health record (EHR)-based readmission risk prediction models can be automated in real-time but have modest discrimination and may be missing important readmission risk factors. Clinician predictions of readmissions may incorporate information unavailable in the EHR, but the comparative usefulness is unknown. We sought to compare clinicians versus a validated EHR-based prediction model in predicting 30-day hospital readmissions.MethodsWe conducted a prospective survey of internal medicine clinicians in an urban safety-net hospital. Clinicians prospectively predicted patients' 30-day readmission risk on 5-point Likert scales, subsequently dichotomized into low- vs. high-risk. We compared human with machine predictions using discrimination, net reclassification, and diagnostic test characteristics. Observed readmissions were ascertained from a regional hospitalization database. We also developed and assessed a "human-plus-machine" logistic regression model incorporating both human and machine predictions.ResultsWe included 1183 hospitalizations from 106 clinicians, with a readmission rate of 20.8%. Both clinicians and the EHR model had similar discrimination (C-statistic 0.66 vs. 0.66, p = 0.91). Clinicians had higher specificity (79.0% vs. 48.9%, p

Background/objectivesIn the Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) study, a multifactorial intervention was associated with a nonsignificant 8% reduction in time to first serious fall injury but a significant 10% reduction in time to first self-reported fall injury relative to enhanced usual care. The effect of the intervention on other outcomes important to patients has not yet been reported. We aimed to evaluate the effect of the intervention on patient well-being including concern about falling, anxiety, depression, physical function, and disability.DesignPragmatic cluster-randomized trial of 5,451 community-living persons at high risk for serious fall injuries.SettingA total of 86 primary care practices within 10 U.S. healthcare systems.ParticipantsA random subsample of 743 persons aged 75 and older.MeasurementsThe well-being measures, assessed at baseline, 12 months, and 24 months, included a modified version of the Fall Efficacy Scale, Patient-Reported Outcomes Measurement Information System (PROMIS) anxiety and depression scales, and Late-Life Function and Disability Instrument.ResultsParticipants in the intervention (n = 384) and control groups (n = 359) were comparable in age: mean (standard deviation) of 81.9 (4.7) versus 81.8 (5.0) years. Mean scores were similar between groups at 12 and 24 months for concern about falling, physical function, and disability, whereas the intervention group's mean scores on anxiety and depression were .7 points lower (i.e., better) at 12 months and .6 to .8 points lower at 24 months. For each of these outcomes, differences between the groups' adjusted least square mean changes from baseline to 12 and 24 months, respectively, were quantitatively small. The overall difference in means between groups over 2 years was statistically significant only for depression, favoring the intervention: -1.19 (99% confidence interval, -2.36 to -.02), with 3.5 points representing a minimally important difference.ConclusionsSTRIDE's multifactorial intervention to reduce fall injuries was not associated with clinically meaningful improvements in patient well-being.

BackgroundLong-term acute care hospital (LTACH) use varies considerably across the U.S., which may reflect uncertainty about the effectiveness of LTACHs vs. skilled nursing facilities (SNF), the principal post-acute care alternative. Given that LTACHs provide more intensive care and thus receive over triple the reimbursement of SNFs for comparable diagnoses, we sought to compare outcomes and spending between LTACH versus SNF transfer.MethodsUsing Medicare claims linked to electronic health record (EHR) data from six Texas Hospitals between 2009 and 2010, we conducted a retrospective cohort study of patients hospitalized on a medicine service in a high-LTACH use region and discharged to either an LTACH or SNF and followed for one year. The primary outcomes included mortality, 60-day recovery without inpatient care, days at home, and healthcare spending RESULTS: Of 3503 patients, 18% were transferred to an LTACH. Patients transferred to LTACHs were younger (median 71 vs. 82 years), less likely to be female (50.5 vs 66.6%) and white (69.0 vs. 84.1%), but were sicker (24.3 vs. 14.2% for prolonged intensive care unit stay; median diagnosis resource intensity weight of 2.03 vs. 1.38). In unadjusted analyses, patients transferred to an LTACH vs. SNF were less likely to survive (59.1 vs. 65.0%) or recover (62.5 vs 66.0%), and spent fewer days at home (186 vs. 200). Adjusting for demographic and clinical confounders available in Medicare claims and EHR data, LTACH transfer was not significantly associated with differences in mortality (HR, 1.12, 95% CI, 0.94-1.33), recovery (SHR, 1.07, 0.93-1.23), and days spent at home (IRR, 0.96, 0.83-1.10), but was associated with greater Medicare spending ($16,689 for one year, 95% CI, $12,216-$21,162).ConclusionLTACH transfer for Medicare beneficiaries is associated with similar clinical outcomes but with higher healthcare spending compared to SNF transfer. LTACH use should be reserved for patients who require complex inpatient care and cannot be cared for in SNFs.

BackgroundInjuries from falls are major contributors to complications and death in older adults. Despite evidence from efficacy trials that many falls can be prevented, rates of falls resulting in injury have not declined.MethodsWe conducted a pragmatic, cluster-randomized trial to evaluate the effectiveness of a multifactorial intervention that included risk assessment and individualized plans, administered by specially trained nurses, to prevent fall injuries. A total of 86 primary care practices across 10 health care systems were randomly assigned to the intervention or to enhanced usual care (the control) (43 practices each). The participants were community-dwelling adults, 70 years of age or older, who were at increased risk for fall injuries. The primary outcome, assessed in a time-to-event analysis, was the first serious fall injury, adjudicated with the use of participant report, electronic health records, and claims data. We hypothesized that the event rate would be lower by 20% in the intervention group than in the control group.ResultsThe demographic and baseline characteristics of the participants were similar in the intervention group (2802 participants) and the control group (2649 participants); the mean age was 80 years, and 62.0% of the participants were women. The rate of a first adjudicated serious fall injury did not differ significantly between the groups, as assessed in a time-to-first-event analysis (events per 100 person-years of follow-up, 4.9 in the intervention group and 5.3 in the control group; hazard ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P = 0.25). The rate of a first participant-reported fall injury was 25.6 events per 100 person-years of follow-up in the intervention group and 28.6 events per 100 person-years of follow-up in the control group (hazard ratio, 0.90; 95% CI, 0.83 to 0.99; P = 0.004). The rates of hospitalization or death were similar in the two groups.ConclusionsA multifactorial intervention, administered by nurses, did not result in a significantly lower rate of a first adjudicated serious fall injury than enhanced usual care. (Funded by the Patient-Centered Outcomes Research Institute and others; STRIDE ClinicalTrials.gov number, NCT02475850.).

Exercise provides a robust physiological stimulus that evokes cross-talk among multiple tissues that when repeated regularly (i.e., training) improves physiological capacity, benefits numerous organ systems, and decreases the risk for premature mortality. However, a gap remains in identifying the detailed molecular signals induced by exercise that benefits health and prevents disease. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to address this gap and generate a molecular map of exercise. Preclinical and clinical studies will examine the systemic effects of endurance and resistance exercise across a range of ages and fitness levels by molecular probing of multiple tissues before and after acute and chronic exercise. From this multi-omic and bioinformatic analysis, a molecular map of exercise will be established. Altogether, MoTrPAC will provide a public database that is expected to enhance our understanding of the health benefits of exercise and to provide insight into how physical activity mitigates disease.

ObjectivesLong-term acute care (LTAC) hospitals provide extended complex post-acute care to more than 120 000 Medicare beneficiaries annually, with the goal of helping patients to regain independence and recover. Because little is known about patients' long-term outcomes, we sought to examine the clinical course after LTAC admission.DesignNationally representative 5-year cohort study using 5% Medicare data from 2009 to 2013.SettingLTAC hospitals.ParticipantsHospitalized Medicare fee-for-service beneficiaries 65 years of age or older who were transferred to an LTAC hospital.MeasurementsMortality, recovery (defined as achieving 60 consecutive days alive without inpatient care), time spent in an inpatient facility following LTAC hospital admission, receipt of an artificial life-prolonging procedure (feeding tube, tracheostomy, hemodialysis), and palliative care physician consultation.ResultsOf 14 072 hospitalized older adults transferred to an LTAC hospital, median survival was 8.3 months, and 1- and 5-year survival rates were 45% and 18%, respectively. Following LTAC admission, 53% never achieved a 60-day recovery. The median time of their remaining life a patient spent as an inpatient after LTAC admission was 65.6% (interquartile range = 21.4%-100%). More than one-third (36.9%) died in an inpatient setting, never returning home after the LTAC admission. During the preceding hospitalization and index LTAC admission, 30.9% received an artificial life-prolonging procedure, and 1% had a palliative care physician consultation.ConclusionHospitalized older adults transferred to LTAC hospitals have poor survival, spend most of their remaining life as an inpatient, and frequently undergo life-prolonging procedures. This prognostic understanding is essential to inform goals of care discussions and prioritize healthcare needs for hospitalized older adults admitted to LTAC hospitals. Given the exceedingly low rates of palliative care consultations, future research is needed to examine unmet palliative care needs in this population. J Am Geriatr Soc 67:2282-2288, 2019.

ObjectivesTo determine why non-mechanically ventilated hospitalized older adults are transferred to long-term acute care (LTAC) hospitals rather than remaining in the hospital.DesignObservational cohort.SettingNational Medicare data.ParticipantsNon-mechanically ventilated hospitalized adults aged 65 and older with fee-for-service Medicare in 2012 who were transferred to an LTAC hospital (n=1,831) or had a prolonged hospitalization without transfer (average hospital length of stay or longer of those transferred to an LTAC hospital) and had one of the 50 most common hospital diagnoses leading to LTAC transfer (N=12,875).MeasurementsWe assessed predictors of transfer using a multilevel model, adjusting for patient-, hospital-, and hospital referral region (HRR)-level factors. We estimated proportions of variance at each level and adjusted hospital- and HRR-specific LTAC transfer rates using sequential models.ResultsThe strongest predictor of transfer was being hospitalized near an LTAC hospital ( 33.6 miles, adjusted odds ratio=6.2, 95% confidence interval (CI)=4.2-9.1). After adjusting for case mix, differences between hospitals explained 15.4% of the variation in LTAC use and differences between regions explained 27.8%. Case mix-adjusted LTAC use was high in the South, where many HRRs had rates between 20.3% and 53.1%, whereas many HRRs were less than 5.4% in the Pacific Northwest, North, and New England. From our fully adjusted model, the median adjusted hospital LTAC transfer rate was 7.2% (interquartile range 2.8-17.5%), with substantial within-region variation (intraclass coefficient=0.25, 95% CI=0.21-0.30).ConclusionsNearly half of the variation in LTAC use is independent of illness severity and is explained by which hospital and what region the individual was hospitalized in. Because of the greater fragmentation of care and Medicare spending with LTAC transfers (because LTAC hospitals generate a separate bundled payment from the hospital), greater attention is needed to define the optimal role of LTAC hospitals in caring for older adults. J Am Geriatr Soc 66:2112-2119, 2018.

ObjectiveTo assess the projected effect of the Centers for Medicare and Medicaid Services new site-neutral payment policy, which aims to decrease unnecessary long-term acute care hospital (LTACH) admissions by reducing reimbursements for less-ill individuals by 2020.DesignObservational.SettingNational 5% Medicare data (2011-12).MeasurementsWe examined the proportion of site-neutral LTACH admissions. Regional LTACH market supply was defined as LTACH beds per 100,000 residents, categorized according to tertile. We conducted a hospital-level analysis to compare the projected effect of site-neutral payment on "propensity score" matched high- and low-LTACH-use hospitals.ResultsForty-one percent of LTACH admissions would be subjected to site-neutral payment. The proportion of site-neutral admissions was large, varied considerably according to LTACH (median 40%, interquartile range 22-60%), and was only modestly greater with greater market supply (Pearson correlation coefficient=0.23, p

BackgroundFall injuries are a major cause of morbidity and mortality among older adults. We describe the design of a pragmatic trial to compare the effectiveness of an evidence-based, patient-centered multifactorial fall injury prevention strategy to an enhanced usual care.MethodsStrategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) is a 40-month cluster-randomized, parallel-group, superiority, pragmatic trial being conducted at 86 primary care practices in 10 health care systems across United States. The 86 practices were randomized to intervention or control group using covariate-based constrained randomization, stratified by health care system. Participants are community-living persons, ≥70 years, at increased risk for serious fall injuries. The intervention is a comanagement model in which a nurse Falls Care Manager performs multifactorial risk assessments, develops individualized care plans, which include surveillance, follow-up evaluation, and intervention strategies. Control group receives enhanced usual care, with clinicians and patients receiving evidence-based information on falls prevention. Primary outcome is serious fall injuries, operationalized as those leading to medical attention (nonvertebral fractures, joint dislocation, head injury, lacerations, and other major sequelae). Secondary outcomes include all fall injuries, all falls, and well-being (concern for falling; anxiety and depressive symptoms; physical function and disability). Target sample size was 5,322 participants to provide 90% power to detect 20% reduction in primary outcome rate relative to control.ResultsTrial enrolled 5,451 subjects in 20 months. Intervention and follow-up are ongoing.ConclusionsThe findings of the STRIDE study will have important clinical and policy implications for the prevention of fall injuries in older adults.

Importance:Despite providing an overlapping level of care, it is unknown why hospitalized older adults are transferred to long-term acute care hospitals (LTACs) vs less costly skilled nursing facilities (SNFs) for postacute care. Objective:To examine factors associated with variation in LTAC vs SNF transfer among hospitalized older adults. Design, Setting, and Participants:We conducted this retrospective observational cohort study of hospitalized older adults (≥65 years) transferred to an LTAC vs SNF during fiscal year 2012 using national 5% Medicare data. Main Outcomes and Measures:Predictors of LTAC transfer were assessed using a multilevel mixed-effects model adjusting for patient-, hospital-, and region-level factors. We estimated variation partition coefficients and adjusted hospital- and region-specific LTAC transfer rates using sequential models. Results:Among 65 525 hospitalized older adults (42 461 [64.8%] women; 39 908 [60.9%] ≥85 years) transferred to an LTAC or SNF, 3093 (4.7%) were transferred to an LTAC. We identified 29 patient-, 3 hospital-, and 5 region-level independent predictors. The strongest predictors of LTAC transfer were receiving a tracheostomy (adjusted odds ration [aOR], 23.8; 95% CI, 15.8-35.9) and being hospitalized in close proximity to an LTAC (0-2 vs >42 miles; aOR, 8.4, 95% CI, 6.1-11.5). After adjusting for case-mix, differences between patients explained 52.1% (95% CI, 47.7%-56.5%) of the variation in LTAC use. The remainder was attributable to hospital (15.0%; 95% CI, 12.3%-17.6%), and regional differences (32.9%; 95% CI, 27.6%-38.3%). Case-mix adjusted LTAC use was very high in the South (17%-37%) compared with the Pacific Northwest, North, and Northeast (