Loss of transient receptor potential channel 5 causes obesity and postpartum depression.

Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified microdeletions on chromosome Xq23 disrupting the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals interpretable by the brain. Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression. As mothers, female knockin mice exhibited anhedonia and depression-like behavior with impaired care of offspring. Deletion of Trpc5 from oxytocin neurons in the hypothalamic paraventricular nucleus caused obesity in both sexes and postpartum depressive behavior in females, while Trpc5 overexpression in oxytocin neurons in knock-in mice reversed these phenotypes. We demonstrate that TRPC5 plays a pivotal role in mediating innate human behaviors fundamental to survival, including food seeking and maternal care.

Early clinical and quality impacts of the Age-Friendly Health System in a Veterans Affairs skilled nursing facility.

BACKGROUND: Skilled nursing facilities (SNFs) are an ideal setting to implement the Age-Friendly Health System (AFHS) approach, an initiative by the Institute for Healthcare Improvement (IHI) centered on the 4Ms: what matters, mobility, mentation, and medication. AFHS implementation has not been well studied in SNFs. METHODS: A 112-bed VA SNF implemented a facility-wide AFHS initiative including the following: (1) participating in a national IHI Age-Friendly Action Community; (2) establishing an AFHS workgroup centered on the 4Ms; (3) identifying meaningful clinical tools and frameworks for capturing each M; and (4) developing sustainment methods. Clinical (life-sustaining treatment, falls, disruptive behaviors, and medication deprescribing) and quality outcomes (rehospitalization, emergency department utilization, and discharge to the community) in addition to patient satisfaction were compared pre- and post-AFHS implementation (bed days of care [BDOC] 17413) to post-implementation (BDOC 20880). RESULTS: Clinical outcomes demonstrated improvements in the 4Ms, including: (1) what matters: 14% increase in life-sustaining treatment documentation (82%-96%; p < 0.01); (2) mobility: reduction in fall rate by 34% (8.15 falls/1000 BDOC to 5.41; p < 0.01); (3) mentation: decrease in disruptive behavior reporting system (DBRS) by 62% (5.11 DBRS/1000 BDOC to 1.96; p = 0.04); (4) medications: 53% increase in average potentially inappropriate medications (PIMs) deprescribing (0.38-0.80 interventions/patient; p < 0.01). Quality outcomes improved including rehospitalization (25.6%-17.9%) and emergency department utilization (5.3%-2.8%) within 30 days of admission. Patient satisfaction scores improved from a mean of 77.2 (n = 31, scale 1-100) to 81.3 (n = 42). CONCLUSIONS: Implementation of the AFHS initiative in a SNF was associated with improved clinical and quality outcomes and patient satisfaction. We describe here a sustainable, interprofessional approach to implementing the AFHS in a SNF.

Association Between Depression Symptoms and Disability Outcomes in Older Adults at Risk of Mobility Decline.

Objective: To assess the association between depression symptoms and physical functioning and participation in daily life over 2 years in older adults at risk of mobility decline. Design: A secondary analysis of 2-year observational data from the Boston Rehabilitative Impairment Study of the Elderly. Setting: Nine primary care clinics within a single health care system. Participants: Participants (N=432; mean age ± SD, 76.6±7.0y; range, 65-96y; 67.7% women) were community-dwelling adults (>65y) at risk of mobility decline. Interventions: Not applicable. Main Outcome Measures: Secondary data analyses of the Late Life Function and Disability Instrument (primary outcome), Short Physical Performance Battery (secondary outcome), and Patient Health Questionnaire-9 (PHQ-9) (predictor). Measures were administered at baseline, 12 months, and 24 months. Participants completed a self-report survey asking about 16 medical comorbidities, and demographic information was collected at baseline. Results: Participants had an average ± SD PHQ-9 score of 1.3±3.1, ranging from 0 to 24 at baseline. Twenty-nine percent of participants reported a history of depression. Greater depression symptoms were associated with lower physical functioning (unstandardized beta [B]=-0.14, SE=0.05, P=.011) and restricted participation (frequency subscale: B=-0.21, SE=0.11, P=.001; limitation subscale: B=-0.45, SE=0.04, P<.001) cross-sectionally over 2 years. PHQ-9 was not significantly associated with the rate of change in Late Life Function and Disability Instrument score over 2 years. Conclusions: Treating depression in primary care may be an important strategy for reducing the burden of functional limitations and participation restrictions at any 1 time. Further research is needed on treatment models to cotarget depression and physical functioning among at-risk older adults.

Feasibility and Preliminary Efficacy of Virtual Rehabilitation for Middle and Older Aged Veterans With Mobility Limitations: A Pilot Study.

Objective: To evaluate the feasibility and preliminary efficacy of the transition of an outpatient center-based rehabilitation program for middle and older aged Veterans with mobility limitations to a tele-health platform. Design: Non-randomized non-controlled pilot study including 10 treatment sessions over 8 weeks and assessments at baseline, 8, 16, and 24 weeks. Setting: VA Boston Healthcare System ambulatory care between August 2020 and March 2021. Participants: Veterans aged 50 years and older (n=178) were contacted via letter to participate, and 21 enrolled in the study. Intervention: Participants had virtual intervention sessions with a physical therapist who addressed impairments linked to mobility decline and a coaching program promoting exercise adherence. Main Outcome Measures: Ambulatory Measure for Post-Acute Care (AM-PAC), Phone-FITT, and Self-Efficacy for Exercise (SEE) scale. Results: Completers (n=14, mean age 74.9 years, 86% men) averaged 9.8 out of 10 visits. Changes in the Ambulatory Measure for Post-Acute Care (AM-PAC) exceeded clinically meaningful change after 8 and 24 weeks of treatment, at 4.1 units and 4.3 units respectively. Statistically significant improvements from baseline in AM-PAC and Phone-FITT were observed after 8 weeks of treatment and at 24 weeks. No significant changes were observed in exercise self-efficacy. Conclusions: In this group of veterans, telerehab was feasible and demonstrated preliminary efficacy in both mobility and physical activity, thus justifying further investigation in a larger scale clinical trial.

A Light-Responsive Neural Circuit Suppresses Feeding.

Light plays an essential role in a variety of physiological processes, including vision, mood, and glucose homeostasis. However, the intricate relationship between light and an animal's feeding behavior has remained elusive. Here, we found that light exposure suppresses food intake, whereas darkness amplifies it in male mice. Interestingly, this phenomenon extends its reach to diurnal male Nile grass rats and healthy humans. We further show that lateral habenula (LHb) neurons in mice respond to light exposure, which in turn activates 5-HT neurons in the dorsal Raphe nucleus (DRN). Activation of the LHb→5-HTDRN circuit in mice blunts darkness-induced hyperphagia, while inhibition of the circuit prevents light-induced anorexia. Together, we discovered a light-responsive neural circuit that relays the environmental light signals to regulate feeding behavior in mice.

5-HT Neurons Integrate GABA and Dopamine Inputs to Regulate Meal Initiation.

Obesity is a growing global health epidemic with limited effective therapeutics. Serotonin (5-HT) is one major neurotransmitter which remains an excellent target for new weight-loss therapies, but there remains a gap in knowledge on the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using a closed-loop optogenetic feeding paradigm, we showed that the 5-HTDRN→arcuate nucleus (ARH) circuit plays an important role in regulating meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HTDRN neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response to GABAergic inputs can be enhanced by hunger. Additionally, deletion of the GABAA receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the instrumental role of dopaminergic inputs via dopamine receptor D2 in 5-HTDRN neurons in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HTDRN neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, which allows for the initiation of a meal.

Primary care barriers and facilitators to nonpharmacologic treatments for low back pain: A qualitative pilot study.

BACKGROUND: Clinical practice guidelines encourage primary care providers (PCPs) to recommend nonpharmacologic treatment as first-line therapy for low back pain (LBP). However, the determinants of nonpharmacologic treatment use for LBP in primary care remain unclear, particularly in low-income settings. OBJECTIVE: To pilot a framework-informed interview guide and codebook to explore determinants of nonpharmacologic treatment use in primary care. METHODS: In this qualitative interview study, we enrolled PCPs and community health workers (CHWs) from four primary care clinics at a safety net hospital. A semistructured interview guide informed by the Consolidated Framework for Implementation Research (CFIR) guided inquiry on barriers/facilitators to nonpharmacologic treatments for LBP (eg, acupuncture, chiropractic care, physical therapy). We included questions on whether current CHW roles may address barriers to nonpharmacologic treatment use. Interviews were audio-recorded, transcribed verbatim, and independently coded by four investigators. An a priori codebook composed of CFIR determinants and known CHW roles guided deductive content analysis to identify major themes. RESULTS: Eight individuals (six PCPs, two CHWs; age range: 32-51 years, five female) participated in hour-long interviews. Half had worked at the hospital for ≥15 years and all reported seeing patients with LBP (range: 2-20 patients per week). All participants identified the following CFIR factors as barriers/facilitators: nonpharmacologic treatment characteristics (perceived cost, relative advantage compared to other treatments); outer setting (patient needs/resources, limited connections with community-based nonpharmacologic treatment) and PCP characteristics (attitudes/beliefs about nonpharmacologic treatments). Although participants indicated several CHW roles could be adapted to address barriers (eg, care coordination, resource linking, case management), other roles seemed less feasible (eg, targeted health education) in our health care system. CONCLUSIONS: Preliminary insight on key determinants of nonpharmacologic treatments for LBP should be further examined in large multisite studies. Future studies may also determine whether a CHW-led strategy can improve nonpharmacologic treatment access and clinical outcomes in primary care.

Research Protocol Adaptations During the COVID-19 Pandemic: A Process Evaluation.

In general, COVID-19-related adaptations that transitioned in-person assessments and interventions to a virtual format were not routinely evaluated. We aimed to conduct a process evaluation to examine the impact of COVID-19-related adaptations on a behavior change intervention designed to increase exercise adherence among Veterans with mobility difficulty. We used secondary data from a nonrandomized study to complete a process evaluation examining the intervention's reach, recruitment, fidelity, dose delivered by physical therapists, and the dose received by the 14 participating Veterans. The physical therapist delivered 95% (133/140) of the study's 10 sessions. Sessions with the lowest delivery dose included Sessions 1 and 10 (86%; n = 12/14). The elements with the lowest dose received included using an exercise journal and developing a postintervention plan (86%; n = 12/14). Our COVID-19 adaptations allowed us to provide our intervention to the majority (67%) of eligible participants without a negative impact on fidelity, dose delivered, or dose received.

Trends in Chiropractic Care and Physical Rehabilitation Use Among Adults with Low Back Pain in the United States, 2002 to 2018.

BACKGROUND: While nonpharmacologic treatments are increasingly endorsed as first-line therapy for low back pain (LBP) in clinical practice guidelines, it is unclear if use of these treatments is increasing or equitable. OBJECTIVE: Examine national trends in chiropractic care and physical rehabilitation (occupational/physical therapy (OT/PT)) use among adults with LBP. DESIGN/SETTING: Serial cross-sectional analysis of the National Health Interview Survey, 2002 to 2018. PARTICIPANTS: 146,087 adults reporting LBP in prior 3 months. METHODS: We evaluated the association of survey year with chiropractic care or OT/PT use in prior 12 months. Logistic regression with multilevel linear splines was used to determine if chiropractic care or OT/PT use increased after the introduction of clinical guidelines. We also examined trends in use by age, sex, race, and ethnicity. When trends were similar over time, we present differences by these demographic characteristics as unadjusted ORs using data from all respondents. RESULTS: Between 2002 and 2018, less than one-third of adults with LBP reported use of either chiropractic care or OT/PT. Rates did not change until 2016 when uptake increased with the introduction of clinical guidelines (2016-2018 vs 2002-2015, OR = 1.15; 95% CI: 1.10-1.19). Trends did not differ significantly by sex, race, or ethnicity (p for interactions > 0.05). Racial and ethnic disparities in chiropractic care or OT/PT use were identified and persisted over time. For example, compared to non-Hispanic adults, either chiropractic care or OT/PT use was lower among Hispanic adults (combined OR = 0.62, 95% CI: 0.65-0.73). By contrast, compared to White adults, Black adults had similar OT/PT use (OR = 0.98; 95% CI: 0.94-1.03) but lower for chiropractic care use (OR = 0.50; 95% CI: 0.47-0.53). CONCLUSIONS: Although use of chiropractic care or OT/PT for LBP increased after the introduction of clinical guidelines in 2016, only about a third of US adults with LBP reported using these services between 2016 and 2018 and disparities in use have not improved.

Defining Clinically Meaningful Cut Points for Leg Power Impairment Using Physical Performance in Older Adults: A Secondary Analysis From Boston RISE.

OBJECTIVE: To identify clinically meaningful thresholds of leg power impairment identified by the stair climb power test (SCPT). DESIGN: Cross-sectional analysis using the baseline data from an observational cohort study. SETTING: The Boston Rehabilitative Impairment Study of the Elderly. PARTICIPANTS: Community-dwelling older adults (N=413). MAIN OUTCOME MEASURES: SCPT and the Short Physical Performance Battery (SPPB). RESULTS: Using the receiver operating characteristic curves and Youden's J statistics, the optimal threshold for the SCPT associated with mobility limitation as defined by an SPPB score ≤9 was 3.07 Watts/kg for men with a sensitivity of 74%, a specificity of 73% and, an area under the curve (AUC) value of 0.78. For women, the optimal threshold was 2.59 Watts/kg with a sensitivity of 83%, a specificity of 69%, and an AUC value of 0.81. The classification and regression tree sensitivity analysis demonstrated similar thresholds, 2.88 Watts/kg and 2.53 Watts/kg for men and women, respectively. CONCLUSIONS: The study identified clinically meaningful thresholds of impairment for the SCPT for mobility limited older primary care patients. These thresholds may be used to inform rehabilitation care to improve functional mobility of older adults and should be validated in larger more representative clinical trials.

Defining and Measuring Preclinical Mobility Limitation: An Expert Consensus Exercise Informed by a Scoping Review.

BACKGROUND: Early change in function in older adults has been termed preclinical disability (PCD). PCD has been understudied compared to other stages of disability because it is unlikely to receive comparative priority in clinical settings. It has major implications for prevention and population health as it may be the optimal time to intervene to prevent further decline. A standardized approach to research in PCD, including a common definition and measurement approaches, is needed to advance this work. METHODS: The process to establish how PCD should be defined and measured was undertaken in 2 stages: (1) a scoping review of the literature, which was used to inform (2) a web-enabled consensus meeting with content experts. RESULTS: The scoping review and the consensus meeting support the use of the term preclinical mobility limitation (PCML) and that it should be measured using both patient-reported and performance-based measures. It was agreed that the definition of PCML should include modification of frequency and/or method of task completion, without overt disability, and that requisite mobility tasks include walking (distance and speed), stairs, and transfers. CONCLUSIONS: Currently, there are few standardized assessments that can identify PCML. PCML is the term that most clearly describes the stage where people experience a change in routine mobility tasks, without a perception of disability. Further evaluation into the reliability, validity, and responsiveness of outcome measures is needed to advance research on PCML.

Developing and Testing Implementation Strategies to support the Centers for Disease Control and Prevention's Initiative for Falls Risk Management in Outpatient Physical Therapy: A Protocol.

Objectives: To develop and test implementation strategies to support implementing the Centers for Disease Control and Preventions' Stopping Elderly Accidents, Deaths, and Injuries (STEADI) initiative for falls prevention and falls risk management in a novel setting, outpatient physical therapy. Design: A feasibility implementation study engaging key partners involved in or affected by the implementation throughout the study. Setting: Five outpatient physical therapy clinics embedded in a health system. Participants: Key partners (physical therapists, physical therapist assistants, referring physicians, administrative clinic staff, older adults, and caregivers) involved in or affected by the implementation (N=48) will participate in surveys and interviews to identify barriers and facilitators prior to implementation and post implementation. Twelve key partners representing at least 1 of each group will participate in evidence-based quality improvement panels to identify which barriers and facilitators are most important and feasible to address and to assist in choosing and designing implementation strategies to support the uptake of STEADI in outpatient rehabilitation. STEADI will be implemented in 5 outpatient physical therapy clinics as a standard of care for the ∼1200 older adults attending those clinics annually. Outcomes: Primary outcomes include clinic- and provider-level (physical therapists and physical therapist assistant) adoption and fidelity to STEADI screening, multifactorial assessment, and falls risk interventions for older adults (65 years or older) attending outpatient physical therapy. Key partners' perceived feasibility, acceptability, and appropriateness of STEADI in outpatient physical therapy will also be measured using validated implementation science questionnaires. Exploratory clinical outcomes of older adults' falls risk pre- and post rehabilitation will be investigated.

Anoctamin 4 channel currents activate glucose-inhibited neurons in the mouse ventromedial hypothalamus during hypoglycemia.

Glucose is the basic fuel essential for maintenance of viability and functionality of all cells. However, some neurons - namely, glucose-inhibited (GI) neurons - paradoxically increase their firing activity in low-glucose conditions and decrease that activity in high-glucose conditions. The ionic mechanisms mediating electric responses of GI neurons to glucose fluctuations remain unclear. Here, we showed that currents mediated by the anoctamin 4 (Ano4) channel are only detected in GI neurons in the ventromedial hypothalamic nucleus (VMH) and are functionally required for their activation in response to low glucose. Genetic disruption of the Ano4 gene in VMH neurons reduced blood glucose and impaired counterregulatory responses during hypoglycemia in mice. Activation of VMHAno4 neurons increased food intake and blood glucose, while chronic inhibition of VMHAno4 neurons ameliorated hyperglycemia in a type 1 diabetic mouse model. Finally, we showed that VMHAno4 neurons represent a unique orexigenic VMH population and transmit a positive valence, while stimulation of neurons that do not express Ano4 in the VMH (VMHnon-Ano4) suppress feeding and transmit a negative valence. Together, our results indicate that the Ano4 channel and VMHAno4 neurons are potential therapeutic targets for human diseases with abnormal feeding behavior or glucose imbalance.

Frailty and Time at Home After Post-Acute Care in Skilled Nursing Facilities.

OBJECTIVES: To examine the association of a claims-based frailty index with time at home, defined as the number of days alive and spent out of hospital or skilled nursing facility (SNF). DESIGN: Cohort Study. SETTING AND PARTICIPANTS: A 5% Medicare random sample of fee-for-service beneficiaries, who had continuous part A and B enrollment in the prior 6 months, that were discharged from a short SNF admission in 2014‒2016. METHODS: Frailty was measured with a validated claims-based frailty index (CFI) (range: 0‒1, higher scores indicating worse frailty) and categorized into nonfrail (CFI <0.25), mild frailty (CFI 0.25‒0.34), and moderate-to-severe frailty (CFI ≥0.35). We measured home time in the 6 months following SNF discharge (range: 0‒182 days with higher values representing more days at home and thus a better outcome). We used logistic regression to assess the association between frailty and short home time, defined as <173 days, adjusting for age, sex, race, region, a comorbidity index, clinical SNF admission characteristics in the Minimum Data Set, and SNF characteristics. RESULTS: In our sample of 144,708 beneficiaries (mean age, 80.8 years, 64.9% female, 85.9% white) who were discharged to community after SNF stay, the mean CFI was 0.26 (standard deviation, 0.07). The mean home time was 165.6 (38.1) days in nonfrail, 154.4 (47.4) days in mild frailty, 145.0 (52.0) days in moderate-to-severe frailty group. After full model adjustments, moderate to severe frailty was associated with a 1.71 (95% CI 1.65‒1.78) higher odds of having short time at home in the 6 months following SNF discharge. CONCLUSION AND IMPLICATIONS: Higher CFI is associated with short time at home in Medicare beneficiaries who are discharged to the community after post-acute SNF stay. Our results support the utility of CFI in identifying SNF patients who need additional resources and interventions to prevent health decline and poor quality of life.

Prevalence and Predictors of Ambulatory Care Physicians' Documentation of Mobility Limitations in Older Adults.

OBJECTIVE: To determine how often physicians document mobility limitations in visits with older adults, and which patient, physician, and practice characteristics associate with documented mobility limitations. DESIGN: We completed a cross-sectional analysis of National Ambulatory Medical Care Surveys, years 2012-2016. Multivariate analyses were conducted to identify patient, physician, and practice-level factors associated with mobility limitation documentation. SETTING: Ambulatory care visits. PARTICIPANTS: We analyzed visits with adults 65 years and older. Final sample size represented 1.3 billion weighted visits. INTERVENTION: Not applicable. MAIN OUTCOME MEASURE: We defined the presence/absence of a mobility limitation by whether any International Classification of Diseases (ICD)-9 or ICD-10 code related to mobility limitations, injury codes, or the patient's "reasons for visit" were documented in the visits. RESULTS: The overall prevalence of mobility limitation documentation was 2.4%. The most common codes were falls-related. Patient-level factors more likely to be associated with mobility limitation documentation were visits by individuals over 85 years of age, relative to 65-69 years, (odds ratio 2.32, 95% confidence interval 1.76-3.07]; with a comorbid diagnosis of arthritis (odds ratio 1.35, 1.18-2.01); and with a comorbid diagnosis of cerebrovascular disease (odds ratio 1.60, 1.13-2.26). Patient-level factors less likely to be associated with mobility limitation documentation were visits by men (odds ratio 0.80, 0.64-0.99); individuals with a cancer diagnosis (odds ratio 0.76, 0.58-0.99); and by individuals seeking care for a chronic problem (relative to a new problem [odds ratio 0.36, 0.29-0.44]). Physician-level factors associated with an increased likelihood of mobility limitation documentation were visits to neurologists (odds ratios 4.48, 2.41-8.32) and orthopedists (odds ratio 2.67, 1.49-4.79) compared with primary care physicians. At the practice-level, mobility documentation varied based on the percentage of practice revenue from Medicare. CONCLUSIONS: Mobility limitations are under-documented and may be primarily captured when changes in function are overt.

Changes in Mild Neurocognitive Disorder Status in Mobility Limited Older Primary Care Patients: Implications for Rehabilitative Care.

OBJECTIVE: The aim of the study is to identify potential rehabilitative treatment targets associated with participants' annual cognitive status. DESIGN: A cohort study patients with self-reported mobility limitation who completed neuropsychological, physical performance testing, and questionnaires at baseline to 2-year follow-up were categorized into three groups (persistently cognitively normal, nonpersistent mild neurocognitive disorder, and persistently mild neurocognitive disorder) based on their annual cognitive status using baseline, years 1 and 2 performance on Hopkins Verbal Learning, Trail Making, and Digit Symbol Substitution Tests. Repeated measures multinomial regression analysis was used to examine the differences between groups and associated characteristics. RESULTS: Study included 349 participants (mean age, 76 ± 7) with 57% of participants were persistently cognitively normal, 16% persistently mild neurocognitive disorder, and 27% nonpersistent mild neurocognitive disorder over 2 yrs of follow-up. Faster gait speed (relative risk reduction, 0.64-0.89) was associated with risk reduction and increase in depressive symptoms (relative risk reduction, 1.09-1.12) was associated with greater risk of being classified into the nonpersistent or persistently mild neurocognitive disorder compared with persistently cognitively normal. CONCLUSIONS: Variability across cognitive status over time was observed. Gait speed and depressive symptoms were modifiable risk factors associated with nonpersistent and persistent mild neurocognitive disorder status. This study reinforces the potential benefit of multifaceted rehabilitation for preventing and treating older adults with mobility and/or cognitive problems.

An innovative rehabilitation program for the veterans affairs post-acute skilled nursing setting: Preliminary results.

BACKGROUND: Skilled nursing rehabilitative care plays a critical role in older adults' functional recovery impacting post-discharge outcomes. Variations across post-acute rehabilitative care services and patient outcomes indicate a need to improve rehabilitative care in this setting. We adapted a successful outpatient care program (Live Long Walk Strong-LLWS) to address this need in post-acute care settings within the Veterans Health Administration. LLWS differs from standard PT care by treating impairments linked to functional decline that are not traditionally targeted by standard care, providing formalized coaching to optimize behavior change, and providing post-discharge case management to optimize long-term outcomes. The purpose was to adapt, refine and implement the LLWS program for the Community Living Center (CLC), determine its acceptability and feasibility, and evaluate its preliminary effectiveness among older adults. METHODS: The design of the program was adapted from the original outpatient LLWS program to the CLC setting through quality improvement methods and the Replicating Effective Programs (REP) framework. Primary outcomes included measures of feasibility and acceptability of >80% enrollment and completion of sessions as well as preliminary effectiveness using performance-based and patient-reported measures of function including the Short Physical Performance Battery (SPPB), AM-PAC, a Global Rating of Change questionnaire, and a satisfaction survey. RESULTS: After 18 months, 51 Veterans had enrolled in the LLWS program, with 94.1% maintaining enrollment. We observed >80% completion of the inpatient and home follow-up sessions. Most patients were highly satisfied with care. Improvements in the SPPB (2.3 (SD 2.2) points), gait speed (0.17 (0.14) m/s) and the AM-PAC (6.5 (SD 5.7)) surpassed clinically meaningful thresholds. CONCLUSIONS: This novel care program is feasible and acceptable to Veterans, demonstrating preliminary effectiveness with improving functional outcomes. Future research is needed to further examine the program's impact on other important outcomes relative to standard modes of care.

Hypothalamic Grb10 enhances leptin signalling and promotes weight loss.

Leptin acts on hypothalamic neurons expressing agouti-related protein (AgRP) or pro-opiomelanocortin (POMC) to suppress appetite and increase energy expenditure, but the intracellular mechanisms that modulate central leptin signalling are not fully understood. Here we show that growth factor receptor-bound protein 10 (Grb10), an adaptor protein that binds to the insulin receptor and negatively regulates its signalling pathway, can interact with the leptin receptor and enhance leptin signalling. Ablation of Grb10 in AgRP neurons promotes weight gain, while overexpression of Grb10 in AgRP neurons reduces body weight in male and female mice. In parallel, deletion or overexpression of Grb10 in POMC neurons exacerbates or attenuates diet-induced obesity, respectively. Consistent with its role in leptin signalling, Grb10 in AgRP and POMC neurons enhances the anorexic and weight-reducing actions of leptin. Grb10 also exaggerates the inhibitory effects of leptin on AgRP neurons via ATP-sensitive potassium channel-mediated currents while facilitating the excitatory drive of leptin on POMC neurons through transient receptor potential channels. Our study identifies Grb10 as a potent leptin sensitizer that contributes to the maintenance of energy homeostasis by enhancing the response of AgRP and POMC neurons to leptin.