Rehabilitation after surgery for hip fracture - the impact of prompt, frequent and mobilisation-focused physiotherapy on discharge outcomes: an observational cohort study.

PURPOSE: To determine the relationship between three postoperative physiotherapy activities (time to first postoperative walk, activity on the day after surgery, and physiotherapy frequency), and the outcomes of hospital length of stay (LOS) and discharge destination after hip fracture. METHODS: A cohort study was conducted on 437 hip fracture surgery patients aged ≥ 50 years across 36 participating hospitals from the Australian and New Zealand Hip Fracture Registry Acute Rehabilitation Sprint Audit during June 2022. Study outcomes included hospital LOS and discharge destination. Generalised linear and logistic regressions were used respectively, adjusted for potential confounders. RESULTS: Of 437 patients, 62% were female, 56% were aged ≥ 85 years, 23% were previously living in a residential aged care facility, 48% usually walked with a gait aid, and 38% were cognitively impaired prior to their injury. The median acute and total LOS were 8 (IQR 5-13) and 20 (IQR 8-38) days. Approximately 71% (n = 179/251) of patients originally living in private residence returned home and 29% (n = 72/251) were discharged to a residential aged care facility. Previously mobile patients had a higher total LOS if they walked day 2-3 (10.3 days; 95% CI 3.2, 17.4) or transferred with a mechanical lifter or did not get out of bed day 1 (7.6 days; 95% CI 0.6, 14.6) compared to those who walked day 1 postoperatively. Previously mobile patients from private residence had a reduced odds of return to private residence if they walked day 2-3 (OR 0.38; 95% CI 0.17, 0.87), day 4 + (OR 0.38; 95% CI 0.15, 0.96), or if they only sat, stood or stepped on the spot day 1 (OR 0.29; 95% CI 0.13, 0.62) when compared to those who walked day 1 postoperatively. Among patients from private residence, each additional physiotherapy session per day was associated with a -2.2 (95% CI -3.3, -1.0) day shorter acute LOS, and an increased log odds of return to private residence (OR 1.76; 95% CI 1.02, 3.02). CONCLUSION: Hip fracture patients who walked earlier, were more active day 1 postoperatively, and/or received a higher number of physiotherapy sessions were more likely to return home after a shorter LOS.

Barriers and facilitators to early mobilisation and weight-bearing as tolerated after hip fracture surgery among older adults in Saudi Arabia: a qualitative study.

OBJECTIVE: To explore the practice of prescribing and implementing early mobilisation and weight-bearing as tolerated after hip fracture surgery in older adults and identify barriers and facilitators to their implementation. METHODS: Semi-structured interviews were conducted with 20 healthcare providers (10 orthopaedic surgeons and 10 physiotherapists) from Saudi Arabian government hospitals. Data were analysed using inductive thematic analysis. RESULTS: While early mobilisation and weight-bearing as tolerated were viewed as important by most participants, they highlighted barriers to the implementation of these practices. Most participants advocated for mobility within 48 h of surgery, aligning with international guidance; however, the implementation of weight-bearing as tolerated was varied. Some participants stressed the type of surgery undertaken as a key factor in weight-bearing prescription. For others, local protocols or clinician preference was seen as most important, the latter partially influenced by where they were trained. Interdisciplinary collaboration between orthopaedic surgeons and physiotherapists was seen as a crucial part of postoperative care and weight-bearing. Patient and family member buy-in was also noted as a key factor, as fear of further injury can impact a patient's adherence to weight-bearing prescriptions. Participants noted a lack of standardised postoperative protocols and the need for routine patient audits to better understand current practices and outcomes. CONCLUSION: This study contributes to national and global discussions on the prescription of early mobilisation and weight-bearing as tolerated. It highlights the necessity for a harmonised approach, incorporating standardised, evidence-based protocols with patient-specific care, robust healthcare governance and routine audits and monitoring for quality assurance and better patient outcomes.

Factors associated with concerns about falling and activity restriction in older adults after hip fracture: a mixed-methods systematic review.

PURPOSE: To investigate factors contributing to concerns about falling and activity restriction in the community among older adults who had a hip fracture. METHODS: A mixed method systematic review with a convergent segregated approach. We searched Medline, Embase, PsycInfo, PEDRo, CINAHL and the Cochrane library. Results were synthesised narratively considering physical, psychological, environmental, care, and social factors and presented in tables. Critical appraisal was completed in duplicate. RESULTS: We included 19 studies (9 qualitative, 9 observational, 1 mixed methods) representing 1480 individuals and 23 factors related to concerns about falling and activity restriction. Physical factors included falls history, comorbidities, balance, strength, mobility and functionality. Psychological factors included anxiety and neuroticism scores, perceived confidence in/control over rehabilitation and abilities, and negative/positive affect about the orthopaedic trauma, pre-fracture abilities and future needs. Environmental factors included accessibility in the home, outdoors and with transport. Social and care factors related to the presence or absence of formal and informal networks, which reduced concerns and promoted activity by providing feedback, advice, encouragement, and practical support. CONCLUSION: These findings highlight that to improve concerns about falling and activity restriction after hip fracture, it is important to: improve physical and functional abilities; boost self-confidence; promote positive affect; involve relatives and carers; increase access to clinicians, and; enhance accessibility of the home, outdoors and transport. Most factors were reported on by a small number of studies of varying quality and require replication in future research.

The relationship between extent of mobilisation within the first postoperative day and 30-day mortality after hip fracture surgery.

OBJECTIVE: To determine the association between the extent of mobilisation within the first postoperative day and 30-day mortality after hip fracture. DESIGN: Cohort study. SETTING: Acute orthopaedic hospital ward. PARTICIPANTS: Consecutive sample of 701 patients, 65 years of age or older, 80% from own home, 49% with a trochanteric fracture, and 61% with an American Society of Anesthesiology grade > 2. INTERVENTION: n/a. MAIN MEASURES: Cumulated ambulation score (CAS) (0-6 points) on the first postoperative day and 30-day postoperative mortality. A CAS = 0 reflects no functional mobility (bedridden), while a CAS = 6 reflects independent out-of-bed-transfer, chair-stand, and indoor walking status. RESULTS: Overall, 86% of patients were mobilised to standing or seated in chair (CAS ≥ 1) on the first postoperative day. A CAS of 0, 1-3, and 4-6 was observed for 97 (14%), 519 (74%), and 85 (12%) patients, respectively. Overall, 61 (8.7%) patients died within 30 days with the highest mortality (23.7%, n = 23) seen for those not mobilised (CAS = 0). Only one patient (1.2%) with a CAS of 4-6 points died. Cox regression analysis adjusted for age, sex, residential status, pre-fracture CAS, fracture type, and American Society of Anesthesiology grade, showed that a one-unit increase in CAS was associated with a 38% lower risk of 30-day mortality (Hazard Ratio = 0.63, 95%Confidence Interval, 0.50-0.78). CONCLUSION: Mobility on the first postoperative day was associated with 30-day postoperative mortality, with a lower risk observed for those completing greater mobility. National registries may consider extending collection of mobility on the first postoperative day from a binary indicator to the CAS which captures the extent of mobility achieved.

Effectiveness of exercise rehabilitation interventions on depressive symptoms in older adults post hip fracture: a systematic review and meta-analysis.

This study determines the effectiveness of exercise rehabilitation interventions on depressive symptoms in older adults after hip fracture. Ovid MEDLINE, Embase, Global Health, APAPsych, CENTRAL, CIHAHL, PEDro and Open Grey were searched from database inception to June 10, 2022 for definitive, pilot or feasibility randomised controlled trials of rehabilitation interventions (versus any comparator) which reported depressive symptoms among older adults post hip fracture. Nonrandomised trials and those not published in English were excluded. Selection, quality appraisal (Cochrane Risk of Bias 2) and extraction in duplicate. Results were synthesised narratively and with meta-analysis (Hedge's g for intervention effect, I2 for heterogeneity). Eight trials (1146 participants) were included. Interventions were predominantly face-to-face exercise rehabilitation (range three to 56 sessions) at home versus usual care. Three trials were assigned overall low risk of bias, three some concerns and two high risk. The pooled effect of rehabilitation on depressive symptoms at intervention end favoured the intervention group (Hedges's g -0.43; 95% CI: -0.87, 0.01; four trials). Three trials demonstrated no between group difference following adjustment for baseline depressive symptoms. One trial found lower odds of depression when the intervention additionally included falls prevention, nutrition consultation and depression management. There is a potential benefit of exercise rehabilitation interventions on depressive symptoms after hip fracture. A mechanism for benefit may relate to baseline symptom severity, exercise frequency, frequency of health professional contacts, addition of a psychological component or of the quality of the underlying trials. To appropriately inform clinical guidelines, further appropriately powered trials with follow-up are warranted. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: CRD42022342099.

Therapeutic Potential of P110 Peptide: New Insights into Treatment of Alzheimer's Disease.

Mitochondrial degeneration in various neurodegenerative diseases, specifically in Alzheimer's disease, involves excessive mitochondrial fission and reduced fusion, leading to cell damage. P110 is a seven-amino acid peptide that restores mitochondrial dynamics by acting as an inhibitor of mitochondrial fission. However, the role of P110 as a neuroprotective agent in AD remains unclear. Therefore, we performed cell culture studies to evaluate the neuroprotective effect of P110 on amyloid-ß accumulation and mitochondrial functioning. Human SH-SY5Y neuronal cells were incubated with 1 µM and 10 µM of P110, and Real-Time PCR and Western blot analysis were done to quantify the expression of genes pertaining to AD and neuronal health. Exposure of SH-SY5Y cells to P110 significantly increased APP mRNA levels at 1 µM, while BACE1 mRNA levels were increased at both 1 µM and 10 µM. However, protein levels of both APP and BACE1 were significantly reduced at 10 µM of P110. Further, P110 treatment significantly increased ADAM10 and Klotho protein levels at 10 µM. In addition, P110 exposure significantly increased active mitochondria and reduced ROS in live SH-SY5Y cells at both 1 µM and 10 µM concentrations. Taken together, our results indicate that P110 might be useful in attenuating amyloid-ß generation and improving neuronal health by maintaining mitochondrial function in neurons.

Implementing an advanced physiotherapy outpatient triaging service as a model for improvement for patients recently discharged following surgical intervention for hip fracture.

Every year there are 1.3 million hip fractures globally; this is expected to rise to 6 million by 2050. Estimates of global cost is 1.75 million disability adjusted life years, and in established market economies, costs associated with hip fracture represent 1.4% of the total healthcare burden. New models of care will be required to meet this demand. Advance physiotherapy roles in elective arthroplasty across global settings have demonstrated benefit in safely reducing time burden on surgical teams and healthcare costs. The utility of similar roles in the care of hip fracture is unclear. This quality initiative (2020-2023) aimed to implement and evaluate a new model of care substituting a surgical registrar with an advanced physiotherapist in a post-discharge hip fracture clinic. Across many nonlinear, action/reflection cycles, a multi-disciplinary team engaged to operationalize key implementation strategies, mapped to the Expert Recommendations for Implementing Change (ERIC) project. Across the reporting period, 346 patients were seen by an advanced physiotherapist. Eighty-one patients seen by an advanced physiotherapist required informal discussion with the consultant surgeon. Fifteen patients required a formal consultant review. There were no patient complaints, critical incidents or other unintended consequences. The net surgical time realized over the three years was 110 hours.

Physiotherapists' perspectives of barriers and facilitators to effective community provision after hip fracture: a qualitative study in England.

PURPOSE: to investigate physiotherapists' perspectives of effective community provision following hip fracture. METHODS: qualitative semi-structured interviews were conducted with 17 community physiotherapists across England. Thematic analysis drawing on the Theoretical Domains Framework identified barriers and facilitators to implementation of effective provision. Interviews were complemented by process mapping community provision in one London borough, to identify points of care where suggested interventions are in place and/or could be implemented. RESULTS: four themes were identified: ineffective coordination of care systems, ineffective patient stratification, insufficient staff recruitment and retention approaches and inhibitory fear avoidance behaviours. To enhance care coordination, participants suggested improving access to social services and occupational therapists, maximising multidisciplinary communication through online notation, extended physiotherapy roles, orthopaedic-specific roles and seven-day working. Participants advised the importance of stratifying patients on receipt of referrals, at assessment and into appropriately matched interventions. To mitigate insufficient staff recruitment and retention, participants proposed return-to-practice streams, apprenticeship schemes, university engagement, combined acute-community rotations and improving job description advertisements. To reduce effects of fear avoidance behaviour on rehabilitation, participants proposed the use of patient-specific goals, patient and carer education, staff education in psychological strategies or community psychologist access. Process mapping of one London borough identified points of care where suggested interventions to overcome barriers were in place and/or could be implemented. CONCLUSION: physiotherapists propose that effective provision of community physiotherapy following hip fracture could be improved by refining care coordination, utilising stratification techniques, employing enhanced recruitment and retainment strategies and addressing fear avoidance behaviours.

Perioperative interventions to improve early mobilisation and physical function after hip fracture: a systematic review and meta-analysis.

BACKGROUND: Perioperative interventions could enhance early mobilisation and physical function after hip fracture surgery. OBJECTIVE: Determine the effectiveness of perioperative interventions on early mobilisation and physical function after hip fracture. METHODS: Ovid MEDLINE, CINAHL, Embase, Scopus and Web of Science were searched from January 2000 to March 2022. English language experimental and quasi-experimental studies were included if patients were hospitalised for a fractured proximal femur with a mean age 65 years or older and reported measures of early mobilisation and physical function during the acute hospital admission. Data were pooled using a random effect meta-analysis. RESULTS: Twenty-eight studies were included from 1,327 citations. Studies were conducted in 26 countries on 8,192 participants with a mean age of 80 years. Pathways and models of care may provide a small increase in early mobilisation (standardised mean difference [SMD]: 0.20, 95% confidence interval [CI]: 0.01-0.39, I2 = 73%) and physical function (SMD: 0.07, 95% CI 0.00 to 0.15, I2 = 0%) and transcutaneous electrical nerve stimulation analgesia may provide a moderate improvement in function (SMD: 0.65, 95% CI: 0.24-1.05, I2 = 96%). The benefit of pre-operative mobilisation, multidisciplinary rehabilitation, recumbent cycling and clinical supervision on mobilisation and function remains uncertain. Evidence of no effect on mobilisation or function was identified for pre-emptive analgesia, intraoperative periarticular injections, continuous postoperative epidural infusion analgesia, occupational therapy training or nutritional supplements. CONCLUSIONS: Perioperative interventions may improve early mobilisation and physical function after hip fracture surgery. Future studies are needed to model the causal mechanisms of perioperative interventions on mobilisation and function after hip fracture.

The role of depression in the association between physiotherapy frequency and duration and outcomes after hip fracture surgery: secondary analysis of the physiotherapy hip fracture sprint audit.

PURPOSE: It is not known whether the association between the frequency and duration of physiotherapy and patient outcomes varies for those with and without depression. This study aims to evaluate whether the associations between the frequency and duration of physiotherapy after hip fracture surgery and discharge home, surviving at 30 days post-admission, and being readmitted 30 days post discharge vary by depression diagnosis. METHODS: Data were from 5005 adults aged 60 and over included in the UK Physiotherapy Hip Fracture Sprint Audit who had undergone surgery for a nonpathological first hip fracture. Logistic regression models were used to estimate the unadjusted and adjusted odds ratios and their 95% confidence intervals for the associations between physiotherapy frequency and duration and outcomes. RESULTS: Physiotherapy frequency and duration were comparable between patients with and without depression (42.1% and 44.6%). The average adjusted odds for a 30-min increase in physiotherapy duration for those with and without depression for discharge home were 1.05 (95% CI 0.85-1.29) vs 1.16 (95% CI 1.05-1.28, interaction p = 0.36), for 30-day survival were 1.26 (95% CI 1.06-1.50) vs 1.11 (95% CI 1.05-1.17, interaction p = 0.45) and for readmission were 0.89 (95% CI 0.81-0.98) vs 0.97 (95% CI 0.93-1.00, interaction p = 0.09). None of the interaction tests reached formal significance, but the readmission models were close (p = 0.09). CONCLUSION: Results suggest physiotherapy duration may be negatively associated with readmission in those with depression but not those without depression, while no clear difference in the other outcomes was noted.

Frequency, duration, and type of physiotherapy in the week after hip fracture surgery - analysis of implications for discharge home, readmission, survival, and recovery of mobility.

PURPOSE: To examine the association between physiotherapy access after hip fracture and discharge home, readmission, survival, and mobility recovery. METHODS: A 2017 Physiotherapy Hip Fracture Sprint Audit was linked to hospital records for 5383 patients. Logistic regression was used to estimate the association between physiotherapy access in the first postoperative week and discharge home, 30-day readmission post-discharge, 30-day survival and 120-days mobility recovery post-admission adjusted for age, sex, American Society of Anesthesiology grade, Hospital Frailty Risk Score and prefracture mobility/residence. RESULTS: Overall, 73% were female and 40% had high frailty risk. Patients who received ≥2 hours of physiotherapy (versus less) had 3% (95% Confidence Interval: 0-6%), 4% (2-6%), and 6% (1-11%) higher adjusted probabilities of discharge home, survival, and outdoor mobility recovery, and 3% (0-6%) lower adjusted probability of readmission. Recipients of exercise (versus mobilisation alone) had 6% (1-12%), 3% (0-7%), and 11% (3-18%) higher adjusted probabilities of discharge home, survival, and outdoor mobility recovery, and 6% (2-10%) lower adjusted probability of readmission. Recipients of 6-7 days physiotherapy (versus 0-2 days) had 8% (5-11%) higher adjusted probability of survival. For patients with dementia, improved probability of survival, discharge home, readmission and indoor mobility recovery were observed with greater physiotherapy access. CONCLUSION: Greater access to physiotherapy was associated with a higher probability of positive outcomes. For every 100 patients, greater access could equate to an additional eight patients surviving to 30-days and six avoiding 30-day readmission. The findings suggest a potential benefit in terms of home discharge and outdoor mobility recovery. CONTRIBUTION OF THE PAPER.

Case management for integrated care of older people with frailty in community settings.

BACKGROUND: Ageing populations globally have contributed to increasing numbers of people living with frailty, which has significant implications for use of health and care services and costs. The British Geriatrics Society defines frailty as "a distinctive health state related to the ageing process in which multiple body systems gradually lose their inbuilt reserves". This leads to an increased susceptibility to adverse outcomes, such as reduced physical function, poorer quality of life, hospital admissions, and mortality. Case management interventions delivered in community settings are led by a health or social care professional, supported by a multidisciplinary team, and focus on the planning, provision, and co-ordination of care to meet the needs of the individual. Case management is one model of integrated care that has gained traction with policymakers to improve outcomes for populations at high risk of decline in health and well-being. These populations include older people living with frailty, who commonly have complex healthcare and social care needs but can experience poorly co-ordinated care due to fragmented care systems. OBJECTIVES: To assess the effects of case management for integrated care of older people living with frailty compared with usual care. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, Health Systems Evidence, and PDQ Evidence and databases from inception to 23 September 2022. We also searched clinical registries and relevant grey literature databases, checked references of included trials and relevant systematic reviews, conducted citation searching of included trials, and contacted topic experts. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared case management with standard care in community-dwelling people aged 65 years and older living with frailty. DATA COLLECTION AND ANALYSIS: We followed standard methodological procedures recommended by Cochrane and the Effective Practice and Organisation of Care Group. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: We included 20 trials (11,860 participants), all of which took place in high-income countries. Case management interventions in the included trials varied in terms of organisation, delivery, setting, and care providers involved. Most trials included a variety of healthcare and social care professionals, including nurse practitioners, allied healthcare professionals, social workers, geriatricians, physicians, psychologists, and clinical pharmacists. In nine trials, the case management intervention was delivered by nurses only. Follow-up ranged from three to 36 months. We judged most trials at unclear risk of selection and performance bias; this consideration, together with indirectness, justified downgrading the certainty of the evidence to low or moderate. Case management compared to standard care may result in little or no difference in the following outcomes. • Mortality at 12 months' follow-up (7.0% in the intervention group versus 7.5% in the control group; risk ratio (RR) 0.98, 95% confidence interval (CI) 0.84 to 1.15; I2 = 11%; 14 trials, 9924 participants; low-certainty evidence) • Change in place of residence to a nursing home at 12 months' follow-up (9.9% in the intervention group versus 13.4% in the control group; RR 0.73, 95% CI 0.53 to 1.01; I2 = 0%; 4 trials, 1108 participants; low-certainty evidence) • Quality of life at three to 24 months' follow-up (results not pooled; mean differences (MDs) ranged from -6.32 points (95% CI -11.04 to -1.59) to 6.1 points (95% CI -3.92 to 16.12) when reported; 11 trials, 9284 participants; low-certainty evidence) • Serious adverse effects at 12 to 24 months' follow-up (results not pooled; 2 trials, 592 participants; low-certainty evidence) • Change in physical function at three to 24 months' follow-up (results not pooled; MDs ranged from -0.12 points (95% CI -0.93 to 0.68) to 3.4 points (95% CI -2.35 to 9.15) when reported; 16 trials, 10,652 participants; low-certainty evidence) Case management compared to standard care probably results in little or no difference in the following outcomes. • Healthcare utilisation in terms of hospital admission at 12 months' follow-up (32.7% in the intervention group versus 36.0% in the control group; RR 0.91, 95% CI 0.79 to 1.05; I2 = 43%; 6 trials, 2424 participants; moderate-certainty evidence) • Change in costs at six to 36 months' follow-up (results not pooled; 14 trials, 8486 participants; moderate-certainty evidence), which usually included healthcare service costs, intervention costs, and other costs such as informal care. AUTHORS' CONCLUSIONS: We found uncertain evidence regarding whether case management for integrated care of older people with frailty in community settings, compared to standard care, improved patient and service outcomes or reduced costs. There is a need for further research to develop a clear taxonomy of intervention components, to determine the active ingredients that work in case management interventions, and identify how such interventions benefit some people and not others.

Effectiveness and Equity in Community-Based Rehabilitation on Pain, Physical Function, and Quality of Life After Unilateral Lower Limb Amputation: A Systematic Review.

OBJECTIVES: To synthesize evidence for (1) the effectiveness of exercise-based rehabilitation interventions in the community and/or at home after transfemoral and transtibial amputation on pain, physical function, and quality of life and (2) the extent of inequities (unfair, avoidable differences in health) in access to identified interventions. DATA SOURCES: Embase, MEDLINE, PEDro, Cinahl, Global Health, PsycINFO, OpenGrey, and ClinicalTrials.gov were systematically searched from inception to August 12, 2021, for published, unpublished, and registered ongoing randomized controlled trials. STUDY SELECTION: Three review authors completed screening and quality appraisal in Covidence using the Cochrane Risk of Bias Tool. Included were randomized controlled trials of exercise-based rehabilitation interventions based in the community or at home for adults with transfemoral or transtibial amputation that assessed effectiveness on pain, physical function, or quality of life. DATA EXTRACTION: Effectiveness data were extracted to templates defined a priori and the PROGRESS-Plus framework was used for equity factors. DATA SYNTHESIS: Eight completed trials of low to moderate quality, 2 trial protocols, and 3 registered ongoing trials (351 participants across trials) were identified. Interventions included cognitive behavioral therapy, education, and video games, combined with exercise. There was heterogeneity in the mode of exercise as well as outcome measures employed. Intervention effects on pain, physical function, and quality of life were inconsistent. Intervention intensity, time of delivery, and degree of supervision influenced reported effectiveness. Overall, 423 potential participants were inequitably excluded from identified trials (65%), limiting the generalizability of interventions to the underlying population. CONCLUSIONS: Interventions that were tailored, supervised, of higher intensity, and not in the immediate postacute phase showed greater promise for improving specific physical function outcomes. Future trials should explore these effects further and employ more inclusive eligibility to optimize any future implementation.

Inequity in exercise-based interventions for adults with rheumatoid arthritis: a systematic review.

Objectives: This systematic review describes the extent to which PROGRESS-Plus equity factors were considered in the eligibility criteria of trials of exercise interventions for adults with RA. Methods: Electronic databases were searched for published (Cinahl, Embase, Medline, Physiotherapy Evidence Database), unpublished (Opengrey) and registered ongoing (International Standard Randomized Controlled Trial Number registry) randomized controlled trials (RCTs) of exercise interventions for adults with RA. Two authors independently performed study selection and quality assessment (Cochrane risk of bias tool). Results: A total of 9696 records were identified. After screening, 50 trials were included. All trials had either some concerns or high risk of bias and reported at least one PROGRESS-Plus equity factor within the eligibility criteria; this included place of residence, personal characteristics (age and disability), language, sex, social capital, time-dependent factors or features of relationship factors. Where reported, this equated to exclusion of 457 of 1337 potential participants (34%) based on equity factors. Conclusion: This review identified the exclusion of potential participants within exercise-based interventions for people with RA based on equity factors that might affect health-care opportunities and outcomes. This limits the generalizability of results, and yet this evidence is used to inform management and service design. Trials need to optimize participation, particularly for people with cardiovascular conditions, older adults and those with cognitive impairments. Reasons for exclusions need to be justified. Further research needs to address health inequalities to improve treatment accessibility and the generalizability of research findings. PROSPERO registration: CRD42021260941.

The Degree of Adeno-Associated Virus-Induced Retinal Inflammation Varies Based on Serotype and Route of Delivery: Intravitreal, Subretinal, or Suprachoroidal.

Adeno-associated virus (AAV)-mediated gene therapy has great potential for treating a wide range of retinal degenerative diseases. However, some initial enthusiasm for gene therapy has been tempered by emerging evidence of AAV-associated inflammation, which in several instances has contributed to clinical trial discontinuation. Currently, there is a paucity of data describing the variable immune responses to different AAV serotypes, and similarly, little is known regarding how these responses differ depending on route of ocular delivery, including in animal models of disease. In this study, we characterize the severity and retinal distribution of AAV-associated inflammation in rats triggered by delivery of five different AAV vectors (AAV1, AAV2, AAV6, AAV8, and AAV9), each of which contained enhanced green fluorescent protein (eGFP) driven under control of the constitutively active cytomegalovirus promoter. We further compare the inflammation across three different potential routes (intravitreal, subretinal, and suprachoroidal) of ocular delivery. Compared to buffer-injected controls for each route of delivery, AAV2 and AAV6 induced the most inflammation across all routes of delivery of vectors tested, with AAV6 inducing the highest levels of inflammation when delivered suprachoroidally. AAV1-induced inflammation was highest when delivered suprachoroidally, whereas minimal inflammation was seen with intravitreal delivery. In addition, AAV1, AAV2, and AAV6 each induce infiltration of adaptive immune cells like T cells and B cells into the neural retina, suggesting an innate adaptive response to a single dose of virus. AAV8 and AAV9 induced minimal inflammation across all routes of delivery. Importantly, the degree of inflammation was not correlated with vector-mediated transduction and expression of eGFP. These data emphasize the importance of considering ocular inflammation when selecting AAV serotypes and ocular delivery routes for the development of gene therapy strategies.

Development and Validation of Multivariable Prediction Models for In-Hospital Death, 30-Day Death, and Change in Residence After Hip Fracture Surgery and the "Stratify-Hip" Algorithm.

BACKGROUND: To develop and validate the stratify-hip algorithm (multivariable prediction models to predict those at low, medium, and high risk across in-hospital death, 30-day death, and residence change after hip fracture). METHODS: Multivariable Fine-Gray and logistic regression of audit data linked to hospital records for older adults surgically treated for hip fracture in England/Wales 2011-14 (development n = 170 411) and 2015-16 (external validation, n = 90 102). Outcomes included time to in-hospital death, death at 30 days, and time to residence change. Predictors included age, sex, pre-fracture mobility, dementia, and pre-fracture residence (not for residence change). Model assumptions, performance, and sensitivity to missingness were assessed. Models were incorporated into the stratify-hip algorithm assigning patients to overall low (low risk across outcomes), medium (low death risk, medium/high risk of residence change), or high (high risk of in-hospital death, high/medium risk of 30-day death) risk. RESULTS: For complete-case analysis, 6 780 of 141 158 patients (4.8%) died in-hospital, 8 693 of 149 258 patients (5.8%) died by 30 days, and 4 461 of 119 420 patients (3.7%) had residence change. Models demonstrated acceptable calibration (observed:expected ratio 0.90, 0.99, and 0.94), and discrimination (area under curve 73.1, 71.1, and 71.5; Brier score 5.7, 5.3, and 5.6) for in-hospital death, 30-day death, and residence change, respectively. Overall, 31%, 28%, and 41% of patients were assigned to overall low, medium, and high risk. External validation and missing data analyses elicited similar findings. The algorithm is available at https://stratifyhip.co.uk. CONCLUSIONS: The current study developed and validated the stratify-hip algorithm as a new tool to risk stratify patients after hip fracture.

Characterization of a novel Pde6b-deficient rat model of retinal degeneration and treatment with adeno-associated virus (AAV) gene therapy.

In humans, mutations in the beta subunit of cGMP-phosphodiesterase type 6 (PDE6B) cause autosomal recessive retinitis pigmentosa (RP), which typically has an aggressive clinical course of early-onset severe vision loss due to rapid photoreceptor degeneration. In this study, we describe the generation of a novel Pde6b-deficient rat model using CRISPR-Cas9 genome editing. We characterize the model at multiple time points using clinical imaging modalities as well as histology with immunohistochemistry to show rapid photoreceptor degeneration compared to wild-type and heterozygous animals. We describe the manufacture of two different adeno-associated viral (AAV) vectors (AAV2/1, AAV2/5) under current Good Manufacturing Practices (cGMP) and demonstrate their ability to drive human PDE6B expression in vivo. We further demonstrate the ability of AAV-mediated subretinal gene therapy to delay photoreceptor loss in Pde6b-deficient rats compared to untreated controls. However, severe progressive photoreceptor loss was noted even in treated eyes, likely due to the aggressive nature of the disease. These data provide useful preclinical data to guide the development of potential human gene therapy for PDE6B-associated RP. In addition, the rapid photoreceptor degeneration of the Pde6b-deficient rat with intact inner retina may provide a useful model for the study of cell replacement strategies.