Consensus methods in patellofemoral pain: how rigorous are they? A scoping review.

OBJECTIVE: Clinicians treating patients with patellofemoral pain (PFP) rely on consensus statements to make the best practice recommendations in the absence of definitive evidence on how to manage PFP. However, the methods used to generate and assess agreement for these recommendations have not been examined. Our objective was to map the methods used to generate consensus-based recommendations for PFP and apply four novel questions to assess the rigour of consensus development. DESIGN: Scoping review. DATA SOURCES: We searched Medline, SPORTDiscus, CINAHL and Embase from inception to May 2022 to identify consensus-derived statements or practice guidelines on PFP. The Joanna Briggs Institute Manual for Evidence Synthesis was followed to map the existing evidence. We measured the consensus methods based on four sets of questions addressing the panel composition, application of the consensus method chosen, agreement process and the use of evidence mapping. ELIGIBILITY CRITERIA: All consensus statements or clinical guidelines on PFP were considered. RESULTS: Twenty-two PFP consensus statements were identified. Panel composition: 3 of the 22 (14%) consensus groups reported the panellists' experience, 2 (9%) defined a desired level of expertise, 10 (45%) reported panellist sex and only 2 (9%) included a patient. Consensus method: 7 of 22 (32%) reported using an established method of consensus measurement/development. Agreement process: 10 of 22 (45%) reported their consensus threshold and 2 (9%) acknowledged dissenting opinions among the panel. Evidence mapping: 6 of 22 (27%) reported using systematic methods to identify relevant evidence gaps. CONCLUSIONS: PFP consensus panels have lacked diversity and excluded key partners including patients. Consensus statements on PFP frequently fail to use recognised consensus methods, rarely describe how 'agreement' was defined or measured and often neglect to use systematic methods to identify evidence gaps.

Can exercise training promote better sleep and reduced fatigue in people with chronic stroke? A systematic review.

Poor sleep and chronic fatigue are common in people with chronic stroke (i.e. ≥ 6 months post-stroke). Exercise training is a viable, low-cost therapy for promoting sleep and reducing fatigue; however, the effects of exercise on sleep and fatigue in people with chronic stroke are unclear. Thus, we conducted a systematic review ascertaining the effects of exercise on sleep and fatigue in people with chronic stroke. We systematically searched EMBASE, MEDLINE, AgeLine, the Cochrane Database of Systematic Reviews, CINAHL, SPORTDiscus, SCOPUS, and reference lists of relevant reviews for articles that examined the effects of exercise on sleep or fatigue in chronic stroke. Search results were limited to adults ≥ 18 years, randomized controlled trials, non-randomized trials, and pre-post studies, which were published in English and examined the effects of exercise on sleep or fatigue in people with chronic stroke. We extracted study characteristics and information on the measurement of sleep and fatigue, and assessed study quality and risk of bias using the CONSORT criteria and Cochrane risk-of-bias tool, respectively. We found two studies that examined the effects of exercise on sleep, and two that examined the effects of exercise on fatigue. All studies reported positive effects of exercise training on sleep and fatigue; however, there were concerns of bias and study quality in all studies. There is preliminary evidence that exercise promotes sleep and reduces fatigue in people with chronic stroke; however, the extent to which exercise impacts these health parameters is unclear.

Establishing the minimal clinically important difference of the EQ-5D-3L in older adults with a history of falls.

PURPOSE: Establish the minimal clinically important difference (MCID) of a health-related quality of life (HRQoL) measure-the EuroQol EQ-5 Dimensions-3 Level (EQ-5D-3L)-in older adults with a history of falls. METHODS: This study is a secondary analysis of 255 complete cases who were enrolled in a 12-month randomized controlled trial (NCT01029171; NCT00323596); participants were randomized to the Otago Exercise Program (OEP; n = 126/172; Age:81.2 ± 6.2 years; 60.3% Female) or control (CON; n = 129/172; Age:81.7 ± 5.7 years; 70.5% Female). Participants completed the EQ-5D-3L and Visual Analogue Scale (VAS) at baseline and 1-year. The VAS was associated with HRQoL and was the health status anchor (VAS minimal improvement = 7 to 17, maximal improvement ≥ 18, minimal decline = - 7 to - 17, maximal decline ≤ - 18 points). We used four distinct approaches to estimate MCID ranges: (1) anchor-based change differences of the EQ-5D-3L (1-year minus baseline); (2) anchor-based beta coefficients from ordinary least squares regressions (OLS); (3) anchor-based receiver operating characteristic (ROC), and 4) distribution-based standard deviation and standardized effect size of 0.5. RESULTS: EQ-5D-3L MCID ranges for minimal improvements (OEP = 0.028 to 0.059; CON = 0.007 to 0.051), maximal improvements (OEP = 0.059 to 0.090; CON = 0.051 to 0.090), minimal declines (OEP = - 0.029 to - 0.105; CON = - 0.015 to - 0.051), and maximal declines (OEP = - 0.018 to - 0.072; CON = - 0.018 to - 0.082) were established using change difference, OLS, and distribution-based methods. The ROC area under the curve was poor, thus, it was not used to estimate the MCID. CONCLUSIONS: Our results will assist in the interpretation of changes in HRQoL, as measured by the EQ-5D-3L, in older adults with a history of falls.

Baseline health-related quality of life predicts falls: a secondary analysis of a randomized controlled trial.

PURPOSE: Among older adults, health-related quality of life (HRQoL) and falls are associated. Generic patient-reported outcomes measures (PROMs) assess individual's HRQoL. The role for PROMs, a potential tool for predicting subsequent falls, remains under-explored. Our primary aim was to determine whether a baseline PROMs assessment of HRQoL may be a useful tool for predicting future falls. METHODS: A secondary analysis of a 12-month randomized clinical trial (RCT) of a home-based exercise program among 344 adults (67% female), aged ≥ 70 years, with ≥ 1 falls in the prior year who were randomized (1:1) to either a home-based exercise program (n = 172) or usual care (n = 172). A negative binomial regression model with total falls count as the dependent variable evaluated the main effect of the independent variable-baseline HRQoL (measured by the Short-Form-6D)-controlling for total exposure time and experiment group (i.e., exercise or usual care) for the total sample. For the usual care group alone, the model controlled for total exposure time. RESULTS: For the total sample, the rate of subsequent total falls was significantly predicted by baseline HRQoL (IRR = 0.044; 95% CI [0.005-0.037]; p = .004). For the usual care group, findings were confirmed with wider confidence intervals and the rate of prospective total falls was significantly predicted by baseline HRQoL (IRR = 0.025; 95% CI [0.001-0.909]; p = .044). CONCLUSION: These findings suggest the ShortForm-6D should be considered as part of falls prevention screening strategies within a Falls Prevention Clinic setting. Trial Registrations ClinicalTrials.gov Protocol Registration System. Identifier: NCT01029171; URL: https://clinicaltrials.gov/ct2/show/NCT01029171 . Identifier: NCT00323596; URL: https://clinicaltrials.gov/ct2/show/NCT00323596 .

Minimal Clinically Important Difference of Executive Function Performance in Older Adults Who Fall: A Secondary Analysis of a Randomized Controlled Trial.

INTRODUCTION: Executive function is responsive to exercise and predictive of subsequent falls. Minimal clinically important differences (MCIDs) are critical for understanding whether observed changes are meaningful. However, MCIDs of many cognitive measures are not established. We aimed to determine MCIDs of the Digit Symbol Substitution Test ([DSST] processing speed measure), Stroop (inhibition measure), and Trail Making Test B-A (TMT; set-shifting measure), using anchor- and distribution-based approaches in older adults who have fallen and received the Otago Exercise Program (OEP) relative to usual care only (CON). Our secondary aim was to establish construct (convergent and divergent) validity of these measures. METHODS: Complete case analyses of cognitive outcomes (DSST, Stroop, TMT, and Montreal Cognitive Assessment [MoCA]) were acquired at baseline and 1 year (NCT01029171; NCT003235960); participants were randomized to the OEP (n = 114/172; Age: 80.6 ± 6.1 years; 64.9% Female) or CON (n = 128/172; Age: 82.3 ± 5.8 years; 71.9% Female)]. The MoCA was used as the anchor. We estimated MCIDs using anchor- and distribution-based approaches. Anchor-based executive function change differences ([CD] 1 year minus baseline) observed in participants with meaningful changes in the MoCA (≥3 or ≤ -3 points) receiving the OEP were subtracted from the CON. An anchor-based receiver operator characteristic (ROC) curve was employed to identify optimal cut-off scores of the 3 executive function measures. The distribution-based approach (DA) accounted for variability in baseline and follow-up data. MCID ranges were estimated using these approaches. We used Spearman's correlations to explore convergent validity between executive function measures and other measures involving the same construct (DSST, Stroop, TMT, MoCA, and Mini-Mental State Examination), and divergent validity between executive function measures and variables reflecting different constructs (Geriatric Depression Scale, Instrumental Activities of Daily Living, sex, and body mass index). RESULTS: Based on the 3 approaches, MCID improvement ranges were 3-5 symbols for the DSST (CD = 5; ROC = 2.5; DA = 3.3 symbols), and -11.5 to -26.0 s for the Stroop (CD = -26.0; ROC = -11.5; DA = -20.6 s). MCID decline ranges were -3 to -6 symbols for the DSST (CD = -5.2; ROC = -2.5; DA = -3.3 symbols) and 5.4-30.6 s for the Stroop (CD = 30.6; ROC = 5.4; DA = 20.6 s). MCIDs for the TMT were not meaningful due to high variability (Improvement: CD = -106.6; ROC = -18.4; DA = -69.1 s; Decline: CD = 69.1; ROC = 14.5; DA = 69.1 s). The executive function measures exhibited good convergent (r = -0.22 to r = 0.42) and divergent (r < -0.01 to r = 0.16) validity. CONCLUSIONS: These established MCIDs will allow clinicians to interpret meaningful changes in executive function following exercise amongst older adults who have fallen. The DSST, Stroop, and TMT demonstrated good construct validity, supporting their use in comprehensive fall-risk assessments in older adults who fall.

Sex Differences in Subsequent Falls and Falls Risk: A Prospective Cohort Study in Older Adults.

BACKGROUND: Sex differences for subsequent falls and falls risk factors in community-dwelling older adults who have fallen are unknown. Our aim was to: (1) compare the number of falls between sexes, (2) identify modifiable falls risk factors, and (3) explore the interaction of sex on falls risk factors in older adults who fall. METHODS: Four hundred sixty-two community dwellers seeking medical attention after an index fall were recruited from the Vancouver Falls Prevention Clinic and participated in this 12-month prospective cohort study. Ninety-six participants were part of a randomized controlled trial of exercise. Falls were tracked with monthly falls calendars. Demographics, falls risk measures, and the number of subsequent falls were compared between sexes. A principal component analysis (PCA) was employed to reduce the falls risk measures to a smaller set of factors. The PCA factors were used in negative binomial regression models to predict the number of subsequent falls. Age, exposure time (i.e., number of falls monitoring days), and prescribed exercise (yes/no) were used as covariates, and sex (male/female) and PCA factors were used as main effects. The interaction of sex by PCA factor was then included. RESULTS: Males fell more over 12 months (males: 2.80 ± 6.86 falls; females: 1.25 ± 2.63 falls) than females, and poorer executive function predicted falls in males. Four PCA factors were defined - impaired cognition and mobility, low mood and self-efficacy, mobility resilience, and perceived poor health - each predicted the number of falls. The sex by mobility resilience interaction suggested that mobility resilience was less protective of falls in males. CONCLUSION: Modifiable risk factors related to cognition, physical function, psychological wellbeing, and health status predicted subsequent falls. In males, better mobility was not as protective of falls compared with females. This may be due to males' poorer executive function, contributing to decreased judgement or slowed decision-making during mobility. These results may inform efficacious sex-specific falls prevention strategies.

International depiction of the cost of functional independence limitations among older adults living in the community: a systematic review and cost-of-impairment study.

BACKGROUND: Functional independence limitations restrict older adult self-sufficiency and can reduce quality of life. This systematic review and cost of impairment study examined the costs of functional independence limitations among community dwelling older adults to society, the health care system, and the person. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines this systematic review included community dwelling older adults aged 60 years and older with functional independence limitations. Databases (Cochrane Database of Systematic Reviews, EconLit, NHS EED, Embase, CINAHL, AgeLine, and MEDLINE) were searched between 1990 and June 2020. Two reviewers extracted information on study characteristics and cost outcomes including mean annual costs of functional independence limitations per person for each cost perspective (2020 US prices). Quality was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. RESULTS: 85 studies were included. The mean annual total costs per person (2020 US prices) were: $27,380.74 (95% CI: [$4075.53, $50,685.96]) for societal, $24,195.52 (95% CI: [$9679.77, $38,711.27]) for health care system, and $7455.49 (95% CI: [$2271.45, $12,639.53]) for personal. Individuals with cognitive markers of functional independence limitations accounts for the largest mean costs per person across all perspectives. Variations across studies included: cost perspective, measures quantifying functional independence limitations, cost items reported, and time horizon. CONCLUSIONS: This study sheds light on the importance of targeting cognitive markers of functional independence limitations as they accounted for the greatest costs across all economic perspectives.

Effects of exercise training on the cognitive function of older adults with different types of dementia: a systematic review and meta-analysis.

OBJECTIVES: To assess the effect of exercise training on the cognitive function of older adults living with different types of dementia, as well as potential moderators of exercise efficacy. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Cochrane Central, PsycINFO, Embase, Medline and CINAHL. ELIGIBILITY CRITERIA: Peer-reviewed, randomised controlled trials, in English (1990-present), which examined the effects of exercise training on the cognitive function of older adults living with dementia. STUDY APPRAISAL AND SYNTHESIS: Risk of bias and study quality were assessed (Cochrane Risk of Bias Tool 2.0 and Physiotherapy Evidence Database Scale). We performed random-effects models using robust variance estimation and tested moderators using the approximate Hotelling-Zhang test. RESULTS: Twenty-eight studies (n=2158) were included in the qualitative review and 25 in the meta-analysis. For all-cause dementia, a small effect of exercise training on cognitive function was observed (g=0.19; 95% CI 0.05 to 0.33; p=0.009). Type of dementia and exercise training characteristics did not moderate the effects of exercise training on cognitive function (p>0.05). Adherence to the intervention moderated the cognitive outcome effect size such that greater mean adherence was associated with greater cognitive outcome effect sizes (b=0.02; SE=0.01; p=0.005). CONCLUSION: Exercise training showed small benefits for the cognitive function of older adults living with all-cause dementia. More research and standardised reporting of exercise training characteristics can strengthen the evidence for what works best for which types of dementia. PROSPERO REGISTRATION NUMBER: CRD42020198716.

Cognitive Function and Functional Mobility Predict Exercise Adherence in Older Adults Who Fall.

INTRODUCTION: Strength and balance exercises prevent falls. Yet, exercise adherence is often low. To maximize the benefit of exercise on falls prevention, we aimed to identify baseline cognitive and mobility factors that predict adherence to the Otago Exercise Program (OEP) - a home-based exercise program proven to prevent falls. METHODS: We conducted a secondary longitudinal analysis of data from a randomized clinical trial (RCT) (OEP compared with usual care) among 172 participants who were assigned to the OEP intervention of the RCT. Adherence to the OEP was calculated as a percent score (i.e., [frequency of strength and balance retraining session per week/3 strength and balance retraining sessions per week] × 100). Executive function (i.e., mental flexibility) was measured using the Trail Making Tests (Part A and B: TMT B - TMT A) and the Digit Symbol Substitution Test (DSST). Short-term memory and encoding was measured using the Verbal Digits Forward test. Executive function (i.e., inhibition and working memory) was measured using the Stroop Color-Word Test and the Verbal Digits Forward minus Verbal Digits Backward test. Mobility was assessed using the Short Performance Physical Battery and the Timed Up and Go test. We used general estimation equations analysis to determine the predictors of adherence to the OEP. RESULTS: Better set shifting (ß = -0.06, z = -2.43, [SE = 0.02] p = 0.018] predicted greater OEP adherence. Greater attention and short-term memory (ß = -6.99, z = -2.37 [SE = 2.95]) predicted poorer OEP adherence. Response inhibition, processing speed, working memory, and mobility assessed by the SPPB were not associated with adherence. Poorer baseline Timed Up and Go (ß = 1.48 z = 1.94, [SE = 0.76]; p < 0.001), predicted better OEP adherence. CONCLUSION: Specific cognitive processes (i.e., executive function of set shifting, attention, and short-term memory) and functional mobility predicted exercise adherence. Further research needs to explore the pathways that explain why better attention and short-term memory predicted lower adherence and why poorer functional mobility led to better OEP adherence.

Sensorimotor, Cognitive, and Affective Functions Contribute to the Prediction of Falls in Old Age and Neurologic Disorders: An Observational Study.

OBJECTIVE: To determine whether impairments across cognitive and affective domains provide additional information to sensorimotor deficits for fall prediction among various populations. DESIGN: We pooled data from 5 studies for this observational analysis of prospective falls. SETTING: Community or low-level care facility. PARTICIPANTS: Older people (N=1090; 74.0±9.4y; 579 female); 500 neurologically intact (NI) older people and 3 groups with neurologic disorders (cognitive impairment, n=174; multiple sclerosis (MS), n=111; Parkinson disease, n=305). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Sensorimotor function was assessed with the Physiological Profile Assessment, cognitive function with tests of executive function, affect with questionnaires of depression, and concern about falling with falls efficacy questionnaires. These variables were associated with fall incidence rates, obtained prospectively over 6-12 months. RESULTS: Poorer sensorimotor function was associated with falls (incidence rate ratio [95% CI], 1.46 [1.28-1.66]). Impaired executive function was the strongest predictor of falls overall (2.91 [2.27-3.73]), followed by depressive symptoms (2.07 [1.56-2.75]) and concern about falling (2.02 [1.61-2.55]). Associations were similar among groups, except for a weaker relationship with executive impairment in NI persons and a stronger relationship with concern about falling in persons with MS. Multivariable analyses showed that executive impairment, poorer sensorimotor performance, depressive symptoms, and concern about falling were independently associated with falls. CONCLUSIONS: Deficits in cognition (executive function) and affect (depressive symptoms) and concern about falling are as important as sensorimotor function for fall prediction. These domains should be included in fall risk assessments for older people and clinical groups.

A theoretical framework to improve adherence among older adults to recommendations received at a falls prevention clinic: A narrative review.

BACKGROUND: Falls impose a prominent public health problem among older adults. Falls are preventable through multi-factorial interventions offered by a Falls Prevention Clinic. Yet, adherence to recommendations is often average or low, particularly for lifestyle recommendations. To achieve full health benefits from such a multifactorial intervention, improving adherence is critical. PURPOSE: Our primary objective was to conduct a narrative review to develop a theoretical framework, categorized by intrinsic and extrinsic factors that impact adherence to falls prevention interventions, considering a Falls Prevention Clinic setting. MATERIALS AND METHODS: We conducted a comprehensive literature review of all peer-reviewed manuscripts published between 1998 through August 2020 among older adults (i.e., aged 60 years and older) who fall. We used the following search engines: Pubmed, CINAHL, Embase, MedLine, Cochrane and Google Scholar. RESULTS: The theoretical framework categorizes two dominate factors (comprised of specific domains) that affect adherence among older adults who fall. Intrinsic factors comprised of three domains included: demographics (age, gender, ethnicity), individual factors (participation, control, behavioural habits) and health factors (physical health, mental state, perceived severity). Extrinsic factors comprised of four domains included: caregiver factors (family dynamics, miscarried helping) medication factors (availability, accessibility, drug handling, reliability), health system (costs, communication, relationship with doctors, attention) and environmental factors (public health policy interventions). Intrinsic factors such as high socioeconomic status, high health literacy, being married and extrinsic factors such as low healthcare cost, better communication and useful policy interventions were associated with greater adherence. CONCLUSION: This theoretical model elucidates priority factors to target for promoting adherence to reduce falls, decrease mortality and, lower fall-related healthcare costs.

Health-related quality of life in home care recipients after a falls prevention intervention: a 6-month follow-up.

BACKGROUND: Falls in older adults are an increasingly important public health concern due to the expanding older population and contribute considerably to the global burden of disease. Home care recipients have a high incidence of falls and a low level of health-related quality of life (HRQOL). In this understudied group of older adults, exercise interventions could prevent falls, promote HRQOL and enable healthy ageing in the longer term. METHODS: The study is a single-blinded parallel-group randomized controlled trial, lasting 3 months with a follow-up at 6 months, conducted in primary care. The objective was to explore the effects of a falls prevention exercise programme post-intervention at a 6-month follow-up in home care recipients 67+ years with a history of falls. The Otago Exercise Programme lasting 3 months was performed. The primary outcome was HRQOL measured by the Short Form 36 Health Survey (SF-36). Linear mixed regression models and structural equation models were employed. RESULTS: At 6-month follow-up, the intervention group scored significantly higher on SF-36's physical component summary compared with the controls; 3.0 points, 95% confidence interval (CI) = 0.4, 5.6. This effect was mediated by an increased probability of maintaining exercise in the post-intervention period; odds ratio = 2.3 (CI = 1.1, 5.1). Exercising was associated with a 7.1-point increase in physical component summary (CI = 3.2, 10.9). CONCLUSION: A falls prevention exercise programme can improve physical HRQOL in home care recipients post-intervention. The exercise programme also led to longer-term changes in exercise behaviour mediating this effect.

Correction: A pragmatic randomized controlled trial testing the effects of the international scientific SCI exercise guidelines on SCI chronic pain: protocol for the EPIC-SCI trial.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A pragmatic randomized controlled trial testing the effects of the international scientific SCI exercise guidelines on SCI chronic pain: protocol for the EPIC-SCI trial.

STUDY DESIGN: Protocol for a pragmatic randomized controlled trial (the Exercise guideline Promotion and Implementation in Chronic SCI [EPIC-SCI] Trial). PRIMARY OBJECTIVES: To test if home-/community-based exercise, prescribed according to the international SCI exercise guidelines, significantly reduces chronic bodily pain in adults with SCI. SECONDARY OBJECTIVES: To investigate: (1) the effects of exercise on musculoskeletal and neuropathic chronic pain; (2) if reduced inflammation and increased descending inhibitory control are viable pathways by which exercise reduces pain; (3) the effects of chronic pain reductions on subjective well-being; and (4) efficiency of a home-/community-based exercise intervention. SETTING: Exercise in home-/community-based settings; assessments in university-based laboratories in British Columbia, Canada. METHOD: Eighty-four adults with chronic SCI, reporting chronic musculoskeletal or neuropathic pain, and not meeting the current SCI exercise guidelines, will be recruited and randomized to a 6-month Exercise or Wait-List Control condition. Exercise will occur in home/community settings and will be supported through behavioral counseling. All measures will be taken at baseline, 3-months and 6-months. Analyses will consist of linear mixed effect models, multiple regression analyses and a cost-utility analysis. The economic evaluation will examine the incremental costs and health benefits generated by the intervention compared with usual care. ETHICS AND DISSEMINATION: The University of British Columbia Clinical Research Ethics Board approved the protocol (#H19-01650). Using an integrated knowledge translation approach, stakeholders will be engaged throughout the trial and will co-create and disseminate evidence-based recommendations and messages regarding the use of exercise to manage SCI chronic pain.

Antinociceptive activity of thiazole-containing cyclized DAMGO and Leu-(Met) enkephalin analogs.

Numerous studies demonstrate the promise of opioid peptides as analgesics, but poor oral bioavailability has limited their therapeutic development. This study sought to increase the oral bioavailability of opioid peptides by cyclization, using Hantzsch-based macrocyclization strategies to produce two new series of cyclized DAMGO and Leu/Met-enkephalin analogs. Opioid receptor affinity and selectivity for compounds in each series were assessed in vitro with radioligand competition binding assays. Compounds demonstrated modest affinity but high selectivity for the mu, delta, and kappa opioid receptors (MOR, DOR and KOR), while selectivity for mu opioid receptors varied by structure. Antinociceptive activity of each compound was initially screened in vivo following intracerebroventricular (i.c.v.) administration and testing in the mouse 55 °C warm-water tail-withdrawal test. The four most active compounds were then evaluated for dose- and time-dependent antinociception, and opioid receptor selectivity in vivo. Cyclic compounds 1924-10, 1936-1, 1936-7, and 1936-9 produced robust and long- lasting antinociception with ED50 values ranging from 0.32-0.75 nmol following i.c.v. administration mediated primarily by mu- and delta-opioid receptor agonism. Compounds 1924-10, 1936-1 and 1936-9 further displayed significant time-dependent antinociception after oral (10 mg kg-1, p.o.) administration. A higher oral dose (30 mg kg-1. p.o.) of all four cyclic peptides also reduced centrally-mediated respiration, suggesting successful penitration into the CNS. Overall, these data suggest cyclized opioid peptides synthesized by a Hantzsch-based macrocyclization strategy can retain opioid agonist activity to produce potent antinociception in vivo while conveying improved bioavailability following oral administration.

Evaluating a falls prevention intervention in older home care recipients: a comparison of SF-6D and EQ-5D.

PURPOSE: Health-related quality of life (HRQOL) is an important outcome in economic evaluations of health care interventions for older adults. The aim of this study was to compare two commonly used preference-based utility measures, SF-6D and EQ-5D, to provide knowledge on their applicability when evaluating falls prevention interventions in primary health care. METHODS: The study is a secondary analysis of longitudinal data from a randomised controlled trial, which included 155 older home care recipients participating in a falls prevention intervention in Norway. HRQOL was measured by SF-6D and EQ-5D. Physical function was measured by Berg Balance Scale, 4-m walk test, 30-s sit-to-stand and Falls Efficacy Scale International. Assessments were performed at baseline, 3 months and 6 months. The agreement between SF-6D and EQ-5D was examined using Bland-Altman plots and Spearman correlations. Elasticities from regression analysis were employed to compare the instruments' responsiveness. RESULTS: SF-6D and EQ-5D were strongly correlated (0.71), but there were differences in the instruments' agreement and domains of HRQOL covered. Participants with a higher mean HRQOL and/or better physical function scored generally higher on EQ-5D. Participants with a lower mean HRQOL and/or poorer physical function achieved a relatively higher score on SF-6D. EQ-5D was more responsive to changes in physical function compared to SF-6D. CONCLUSIONS: SF-6D and EQ-5D have both similarities and differences regarding sensitivity, domains covered and responsiveness to changes when evaluating a falls prevention intervention. Selecting the appropriate instrument depends on the characteristics of the participants and the intervention being evaluated.

Effect of a Home-Based Exercise Program on Subsequent Falls Among Community-Dwelling High-Risk Older Adults After a Fall: A Randomized Clinical Trial.

Importance: Whether exercise reduces subsequent falls in high-risk older adults who have already experienced a fall is unknown. Objective: To assess the effect of a home-based exercise program as a fall prevention strategy in older adults who were referred to a fall prevention clinic after an index fall. Design, Setting, and Participants: A 12-month, single-blind, randomized clinical trial conducted from April 22, 2009, to June 5, 2018, among adults aged at least 70 years who had a fall within the past 12 months and were recruited from a fall prevention clinic. Interventions: Participants were randomized to receive usual care plus a home-based strength and balance retraining exercise program delivered by a physical therapist (intervention group; n = 173) or usual care, consisting of fall prevention care provided by a geriatrician (usual care group; n = 172). Both were provided for 12 months. Main Outcomes and Measures: The primary outcome was self-reported number of falls over 12 months. Adverse event data were collected in the exercise group only and consisted of falls, injuries, or muscle soreness related to the exercise intervention. Results: Among 345 randomized patients (mean age, 81.6 [SD, 6.1] years; 67% women), 296 (86%) completed the trial. During a mean follow-up of 338 (SD, 81) days, a total of 236 falls occurred among 172 participants in the exercise group vs 366 falls among 172 participants in the usual care group. Estimated incidence rates of falls per person-year were 1.4 (95% CI, 0.1-2.0) vs 2.1 (95% CI, 0.1-3.2), respectively. The absolute difference in fall incidence was 0.74 (95% CI, 0.04-1.78; P = .006) falls per person-year and the incident rate ratio was 0.64 (95% CI, 0.46-0.90; P = .009). No adverse events related to the intervention were reported. Conclusions and Relevance: Among older adults receiving care at a fall prevention clinic after a fall, a home-based strength and balance retraining exercise program significantly reduced the rate of subsequent falls compared with usual care provided by a geriatrician. These findings support the use of this home-based exercise program for secondary fall prevention but require replication in other clinical settings. Trial Registration: ClinicalTrials.gov Identifiers: NCT01029171; NCT00323596.

Examining the Inter-relations of Depression, Physical Function, and Cognition with Subjective Sleep Parameters among Stroke Survivors: A Cross-sectional Analysis.

GOAL: Stroke survivors commonly experience depression as well as deficits in physical and cognition function. Emerging evidence also suggests sleep quality is compromised poststroke. Our primary objective was to examine the association of subjective sleep parameters (ie, total PSQI score) with depression, health related quality of life, physical function, and cognition among stroke survivors. MATERIALS AND METHODS: Cross-sectional analysis of 72 older adults with chronic stroke (≥6 months postischemic stroke) enrolled in a randomized controlled trial of exercise or cognitive enrichment. Subjective sleep parameters were assessed using the Pittsburgh Sleep Quality Index (PSQI). We report total PSQI score and specific PSQI parameter scores (ie, PSQI-subjective sleep quality, PSQI-sleep latency, PSQI-sleep duration, PSQI-habitual sleep efficiency, PSQI-sleep disturbances, PSQI-use of sleep medication, and PSQI-daytime dysfunction). Bivariate correlations and multivariate linear regression assessed associations between subjective sleep parameters and depression/health related quality of life, physical function, and cognition. FINDINGS: For bivariate correlations, depression was significantly associated with global PSQI, PSQI-subjective sleep quality, PSQI-habitual sleep efficiency, and PSQI-daytime dysfunction. Health related quality of life was significantly associated with PSQI-sleep medication. Physical function and health was significantly associated with PSQI-subjective sleep quality, PSQI-sleep latency, PSQI-sleep duration, and PSQI-daytime dysfunction. Multivariate linear regression demonstrated that PSQI-daytime dysfunction predicted depression and physical function; PSQI-subjective sleep quality predicted depression. No significant associations between global PSQI subjective sleep parameters with cognition were observed. CONCLUSION: Poor subjective sleep parameters and PSQI-subjective sleep quality among stroke survivors were associated with depression; PSQI-daytime dysfunction was associated with physical function. Thus, sleep should be considered in the management of those who have suffered a stroke to optimize poststroke rehabilitation outcomes.

Sex differences in exercise efficacy to improve cognition: A systematic review and meta-analysis of randomized controlled trials in older humans.

Exercise is a non-pharmacological strategy to mitigate the deleterious effects of aging on brain health. However, a large amount of variation exists in its efficacy. Sex of participants and exercise type are two possible factors contributing to this variation. To better understand this, we conducted a concurrent systematic review and meta-analysis of cognitively healthy older adults. Executive functions, episodic memory, visuospatial function, word fluency, processing speed and global cognitive function were examined for exercise- and sex-dependent effects. For executive functions, three types of exercise interventions - aerobic training, resistance training, and multimodal training (i.e., both aerobic and resistance training) - were associated with larger effect sizes in studies comprised of a higher percentage of women compared to studies with a lower percentage of women. This suggests that women's executive processes may benefit more from exercise than men. Regardless of sex, compared to control, all three exercise training approaches enhanced visuospatial function, but only multimodal training enhanced episodic memory. Overall, aerobic training led to greater benefits than resistance training in global cognitive function and executive functions, while multimodal combined training led to greater benefits than aerobic training for global cognitive function, episodic memory, and word fluency. Possible underlying mechanisms, including brain-derived neurotrophic factor and sex steroid hormones, are discussed.

Sex differences in aerobic exercise efficacy to improve cognition: A systematic review and meta-analysis of studies in older rodents.

Research in humans indicates that women may show greater cognitive benefits from aerobic training (AT) than men. To determine whether this sex difference extends to rodents, we conducted a systematic review and meta-analysis of studies in healthy, older rodents. Results indicate that compared to controls, AT improved hippocampus-dependent and -independent learning and memory. A sex difference was found with males showing larger benefits from AT on conditioned-avoidance and non-spatial memory tasks. AT also increased brain-derived neurotrophic factor compared to controls, with larger effects in females. As an exploratory analysis, sex differences in voluntary AT were examined separately from forced AT. Voluntary AT enhanced non-spatial memory to a greater extent in males. Forced AT enhanced hippocampus-dependent learning and memory more so in females. These findings suggest that sex is an important factor to consider, and studies directly assessing sex differences in the ability of exercise to improve brain function are needed.