Structure of the endosomal CORVET tethering complex.

Cells depend on their endolysosomal system for nutrient uptake and downregulation of plasma membrane proteins. These processes rely on endosomal maturation, which requires multiple membrane fusion steps. Early endosome fusion is promoted by the Rab5 GTPase and its effector, the hexameric CORVET tethering complex, which is homologous to the lysosomal HOPS. How these related complexes recognize their specific target membranes remains entirely elusive. Here, we solve the structure of CORVET by cryo-electron microscopy and revealed its minimal requirements for membrane tethering. As expected, the core of CORVET and HOPS resembles each other. However, the function-defining subunits show marked structural differences. Notably, we discover that unlike HOPS, CORVET depends not only on Rab5 but also on phosphatidylinositol-3-phosphate (PI3P) and membrane lipid packing defects for tethering, implying that an organelle-specific membrane code enables fusion. Our data suggest that both shape and membrane interactions of CORVET and HOPS are conserved in metazoans, thus providing a paradigm how tethering complexes function.

Family Involvement in the Care of Hospitalized Older Adults: Protocol for a Qualitative Evidence Synthesis.

BACKGROUND: Older adults are frequently hospitalized. Family involvement during these hospitalizations is incompletely characterized in the literature. OBJECTIVE: This study aimed to better understand how families are involved in the care of hospitalized older adults and develop a conceptual model describing the phenomenon of family involvement in the care of hospitalized older adults. METHODS: We describe the protocol of a qualitative evidence synthesis (QES), a systematic review of qualitative studies. We chose to focus on qualitative studies given the complexity and multifaceted nature of family involvement in care, a type of topic best understood through qualitative inquiry. The protocol describes our process of developing a research question and eligibility criteria for inclusion in our QES based on the SPIDER (Sample, Phenomenon of Interest, Design, Evaluation, and Research type) tool. It describes the development of our search strategy, which was used to search MEDLINE (via Ovid), Embase (via Elsevier), PsycINFO (via Ovid), and CINAHL Complete (via EBSCO). Title and abstract screening and full-text screening will occur sequentially. Purposive sampling may be used depending on the volume of studies identified as eligible for inclusion during our screening process. Descriptive data regarding included individual studies will be extracted and summarized in tables. The results from included studies will be synthesized using qualitative methods and used to develop a conceptual model. The conceptual model will be presented to community members via engagement panels for further refinement. RESULTS: As of September 2023, we have assembled a multidisciplinary team including physicians, nurses, health services researchers, a librarian, a social worker, and a health economist. We have finalized our search strategy and executed the search, yielding 8862 total citations. We are currently screening titles and abstracts and anticipate that full-text screening, data extraction, quality appraisal, and synthesis will be completed by summer of 2024. Conceptual model development will then take place with community engagement panels. We anticipate submitting our manuscript for publication in the fall of 2024. CONCLUSIONS: This paper describes the protocol for a QES of family involvement in the care of hospitalized older adults. We will use identified themes to create a conceptual model to inform further intervention development and policy change. TRIAL REGISTRATION: PROSPERO 465617; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023465617. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/53255.

Racial inequality in functional trajectories between Black and White U.S. veterans.

BACKGROUND: Racial inequality in functional trajectories has been well documented in the U.S. civilian population but has not been explored among Veterans. Our objectives were to: (1) assess how functional trajectories differed for Black and White Veterans aged ≥50 and (2) explore how socioeconomic, psychosocial, and health-related factors altered the relationship between race and function. METHODS: We conducted a prospective, longitudinal analysis using the 2006-2016 Health and Retirement Study. The study cohort included 3700 Veterans who self-identified as Black or White, responded to baseline psychosocial questionnaires, and were community-dwelling on first observation. We used stepwise and stratified linear mixed effects models of biannually assessed functional limitations. The outcome measure was as a count of functional limitations. Race was measured as respondent self-identification as Black or White. Demographic measures included gender and age. Socioeconomic resources included partnership status, education, income, and wealth. Psychosocial stressors included exposure to day-to-day and major discrimination, traumatic life events, stressful life events, and financial strain. Health measures included chronic and mental health diagnoses, smoking, rurality, and use of Veterans Affairs services. RESULTS: Black Veterans developed functional limitations at earlier ages and experienced faster functional decline than White Veterans between the ages of 50 and 70, with convergence occurring at age 85. Once we accounted for economic resources and psychosocial stressors in multivariable analyses, the association between race and the number of functional limitations was no longer statistically significant. Lower wealth, greater financial strain, and traumatic life events were significantly associated with functional decline. CONCLUSIONS: Health systems should consider how to track Veterans' function earlier in the life course to ensure that Black Veterans are able to get timely access to services that may slow premature functional decline. Providers may benefit from training about the role of economic resources and psychosocial stressors in physical health outcomes.

Virtual or In-Person: A Mixed Methods Survey to Determine Exercise Programming Preferences during COVID-19.

A survey was conducted to identify barriers and facilitators to engaging in virtual and in-person cancer-specific exercise during COVID-19. A theory-informed, multi-method, cross-sectional survey was electronically distributed to 192 individuals with cancer investigating preferences towards exercise programming during COVID-19. Respondents had previously participated in an exercise program and comprised two groups: those who had experience with virtual exercise programming ('Virtual') and those who had only taken part in in-person exercise ('In-Person'). Quantitative data were summarized descriptively. Qualitative data were thematically categorized using framework analysis and findings were mapped to an implementation model. The survey completion response rate was 66% (N = 127). All respondents identified barriers to attending in-person exercise programming during COVID-19 with concerns over the increased risk of viral exposure. Virtual respondents (n = 39) reported: (1) feeling confident in engaging in virtual exercise; and (2) enhanced motivation, accessibility and effectiveness as facilitators to virtual exercise. In-Person respondents (n = 88) identified: (1) technology as a barrier to virtual exercise; and (2) low motivation, accessibility and exercise effectiveness as barriers towards virtual exercise. Sixty-six percent (n = 58) of In-Person respondents reported that technology support would increase their willingness to exercise virtually. With appropriately targeted support, perceived barriers to accessing virtual exercise-including motivation, accessibility and effectiveness-may become facilitators. The availability of technology support may increase the engagement of individuals with cancer towards virtual exercise programming.

Psychological distress among medically complex veterans with a recent emergency department visit.

Medical complexity and psychological distress are associated with frequent emergency department (ED) use. Despite this known association, our understanding is limited about which patients are at risk for persistent psychological distress and what patterns of distress emerge over time. A secondary data analysis was used to examine self-reported psychological distress (defined as ≥14 unhealthy days due to poor mental health in the past month) at 30 and 180 days following enrollment in a randomized control trial of 513 medically complex Veterans after a nonpsychiatric ED visit. We used a multivariable ordered logistic regression model to examine the association of a priori factors [baseline psychological distress, age, race, income, health literacy, deficits in activities of daily living (ADL), and deficits in instrumental activities of daily living] with three psychological distress classifications (no/low, intermittent, and persistent). Among 513 Veterans, 40% reported at baseline that they had experienced high psychological distress in the previous month. Older age was associated with lower odds of high psychological distress (OR = 0.95; 95% CI: 0.94-0.97). Baseline factors associated with significantly higher odds of persistent psychological distress at 30 and 180 days assessments, included having the inadequate income (OR = 1.61; 95% CI: 1.02-2.55), having low health literacy (OR = 1.63; 95% CI: 1.01-2.62), and reporting at least one ADL deficit (OR = 1.94; 95% CI: 1.13-3.33). Psychological distress at follow-up was common among medically complex Veterans with a recent ED visit. Future research should explore interventions that integrate distress information into treatment plans and/or link to mental health referral services. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Walking All over COVID-19: The Rapid Development of STRIDE in Your Room, an Innovative Approach to Enhance a Hospital-Based Walking Program during the Pandemic.

Hospitalization is common among older adults. Prolonged time in bed during hospitalization can lead to deconditioning and functional impairments. Our team is currently working with Department of Veterans Affairs (VA) medical centers across the United States to implement STRIDE (assiSTed eaRly mobIlity for hospitalizeD older vEterans), a hospital-based walking program designed to mitigate the risks of immobility during hospitalization. However, the COVID-19 pandemic made in-person, or face-to-face, walking challenging due to social distancing recommendations and infection control concerns. In response, our team applied principles of implementation science, including stakeholder engagement, prototype development and refinement, and rapid dissemination and feedback, to create STRIDE in Your Room (SiYR). Consisting of self-guided exercises, light exercise equipment (e.g., TheraBands, stress ball, foam blocks, pedometer), the SiYR program provided safe alternative activities when face-to-face walking was not available during the pandemic. We describe the methods used in developing the SiYR program; present feedback from participating sites; and share initial implementation experiences, lessons learned, and future directions.

Preoperative Care Assessment of Need Scores Are Associated With Postoperative Mortality and Length of Stay in Veterans Undergoing Knee Replacement.

BACKGROUND: Care Assessment of Need (CAN) scores predicting 90-day mortality and hospitalization are automatically computed each week for patients receiving care at Veterans Health Administration facilities. While currently used only by primary care teams for care coordination, we explored their value as a perioperative risk stratification tool before major elective surgery. METHODS: We collected relevant demographic and perioperative data along with perioperative CAN scores for veterans who underwent total knee replacement between July 2014 and December 2015. We examined score distribution, relationships of preoperative CAN 1-year mortality scores with 1-year postoperative mortality and index hospital length of stay (LOS), and patterns of mortality. RESULTS: Among 8206 patients, 1-year mortality was 1.4% (110 patients), and CAN scores exhibited near-normal distribution. Median scores among survivors were significantly higher than those of in nonsurvivors (45 vs 75; P < .001). The Kaplan-Meier curves showed an approximately 4-fold higher rate of death at 1 year in the highest tercile for 1-year mortality CAN scores compared with those with lower scores (2.0% vs 0.5% respectively; P < .001). Locally estimated scatterplot smoothing curves revealed a significant and nonlinear increase in hospital LOS across preoperative CAN scores. CONCLUSIONS: Although designed for ambulatory care use, CAN scores can identify patients at high risk for mortality and extended hospital LOS in an elective surgery population. The CAN scores may prove valuable in supporting informed decision making and preoperative planning in high-risk and vulnerable populations. Further study is needed to confirm the validity of CAN scores and compare them to other more widely used surgical risk calculators.

Advancing the science of population-based measures of home-time.

The "home time" measure is gaining appeal in evaluating outcomes for multiple patient populations including post-surgery or intervention and the last 6 months of life. Advancing the science of home time measures will require obtaining the perspectives of patients and caregivers to arrive at a population-based measure of quality of life. Additionally, measure development requires considerations of what care settings denote time away from home, observation period, and thresholds that are clinically significant. We explore examples and challenges from current research and our own experience. Being able to advance such measures could also inform payment models and policy design.

Family Caregiver Skills Training to Improve Experiences of Care: a Randomized Clinical Trial.

OBJECTIVE: To evaluate the effectiveness of Helping Invested Families Improve Veterans' Experiences Study (HI-FIVES), a skills training program for caregivers of persons with functional or cognitive impairments. DESIGN: A two-arm RCT. SETTING: Single Veterans Affairs Medical Center. PARTICIPANTS: Patients and their primary caregivers referred in the past 6 months to home and community-based services or geriatrics clinic. INTERVENTION: All caregivers received usual care. Caregivers in HI-FIVES also received five training calls and four group training sessions. MAIN MEASURES: Cumulative patient days at home 12 months post-randomization, defined as days not in an emergency department, inpatient hospital, or post-acute facility. Secondary outcomes included patients' total VA health care costs, caregiver and patient rating of the patient's experience of VA health care, and caregiver depressive symptoms. RESULTS: Of 241 dyads, caregivers' (patients') mean age was 61 (73) years, 54% (53%) Black and 89% (4%) female. HI-FIVES was associated with a not statistically significant 9% increase in the rate of days at home (95% CI 0.72, 1.65; mean difference 1 day over 12 months). No significant differences were observed in health care costs or caregiver depressive symptoms. Model-estimated mean baseline patient experience of VA care (scale of 0-10) was 8.43 (95% CI 8.16, 8.70); the modeled mean difference between HI-FIVES and controls at 3 months was 0.29 (p = .27), 0.31 (p = 0.26) at 6 months, and 0.48 (p = 0.03) at 12 months. For caregivers, it was 8.34 (95% CI 8.10, 8.57); the modeled mean difference at 3 months was 0.28 (p = .18), 0.53 (p < .01) at 6 months, and 0.46 (p = 0.054) at 12 months. CONCLUSIONS: HI-FIVES did not increase patients' days at home; it showed sustained improvements in caregivers' and patients' experience of VA care at clinically significant levels, nearly 0.5 points. The training holds promise in increasing an important metric of care quality-reported experience with care.

Association of Sensory and Cognitive Impairment With Healthcare Utilization and Cost in Older Adults.

OBJECTIVES: To examine the association between self-reported vision impairment (VI), hearing impairment (HI), and dual-sensory impairment (DSI), stratified by dementia status, on hospital admissions, hospice use, and healthcare costs. DESIGN: Retrospective analysis. SETTING: Medicare Current Beneficiary Survey from 1999 to 2006. PARTICIPANTS: Rotating panel of community-dwelling Medicare beneficiaries, aged 65 years and older (N = 24 009). MEASUREMENTS: VI and HI were ascertained by self-report. Dementia status was determined by self-report or diagnosis codes in claims data. Primary outcomes included any inpatient admission over a 2-year period, hospice use over a 2-year period, annual Medicare fee-for-service costs, and total healthcare costs (which included information from Medicare claims data and other self-reported payments). RESULTS: Self-reported DSI was present in 30.2% (n = 263/871) of participants with dementia and 17.8% (n = 4112/23 138) of participants without dementia. In multivariable logistic regression models, HI, VI, or DSI was generally associated with increased odds of hospitalization and hospice use regardless of dementia status. In a generalized linear model adjusted for demographics, annual total healthcare costs were greater for those with DSI and dementia compared to those with DSI without dementia ($28 875 vs $3340, respectively). Presence of any sensory impairment was generally associated with higher healthcare costs. In a model adjusted for demographics, Medicaid status, and chronic medical conditions, DSI compared with no sensory impairment was associated with a small, but statistically significant, difference in total healthcare spending in those without dementia ($1151 vs $1056; P < .001) but not in those with dementia ($11 303 vs $10 466; P = .395). CONCLUSION: Older adults with sensory and cognitive impairments constitute a particularly prevalent and vulnerable population who are at increased risk of hospitalization and contribute to higher healthcare spending. J Am Geriatr Soc 67:1617-1624, 2019.

Comprehensive Support for Family Caregivers: Impact on Veteran Health Care Utilization and Costs.

This study aimed to examine the early impact of the Program of Comprehensive Assistance for Family Caregivers (PCAFC) on Veteran health care utilization and costs. A pre-post cohort design including a nonequivalent control group was used to understand how Veterans' use of Veteran Affairs health care and total health care costs changed in 6-month intervals up to 3 years after PCAFC enrollment. The control group was an inverse probability of treatment weighted sample of Veterans whose caregivers applied for, but were not accepted into, PCAFC. Veterans in PCAFC had similar acute care utilization postenrollment when compared with those in the control group, but significantly greater primary, specialty, and mental health outpatient care use at least 30, and up to 36, months postenrollment. Estimated total health care costs for PCAFC Veterans were $1,500 to $3,400 higher per 6-month interval than for control group Veterans. PCAFC may have increased Veterans' access to care.

An Interdisciplinary Academic Detailing Approach to Decrease Inappropriate Medication Prescribing by Physician Residents for Older Veterans Treated in the Emergency Department.

OBJECTIVE: To evaluate the impact of an academic detailing intervention delivered as part of a quality improvement project by a physician-pharmacist pair on (1) self-reported confidence in prescribing for older adults and (2) rates of potentially inappropriate medications (PIMs) prescribed to older adults by physician residents in a Veteran Affairs emergency department (ED). METHODS: This quality improvement project at a single site utilized a questionnaire that assessed knowledge of Beers Criteria, self-perceived barriers to appropriate prescribing in older adults, and self-rated confidence in ability to prescribe in older adults which was administered to physician residents before and after academic detailing delivered during their emergency medicine rotation. PIM rates in the resident cohort who received the academic detailing were compared to residents who did not receive the intervention. RESULTS: Sixty-three residents received the intervention between February 2013 and December 2014. At baseline, approximately 50% of the residents surveyed reported never hearing about nor using the Beers Criteria. A significantly greater proportion of residents agreed or strongly agreed in their abilities to identify drug-disease interactions and to prescribe the appropriate medication for the older adult after receiving the intervention. The resident cohort who received the educational intervention was less likely to prescribe a PIM when compared to the untrained resident cohort with a rate ratio of 0.73 ( P < .0001). CONCLUSION: Academic detailing led by a physician-pharmacist pair resulted in improved confidence in physician residents' ability to prescribe safely in an older adult ED population and was associated with a statistically significant decrease in PIM rates.

Systems-Based Practice to Improve Care Within and Beyond the Emergency Department.

There is evidence that an emergency department (ED) visit signifies a period of vulnerability for older adults. Transition between the ED and community care can be fraught with challenges. There are essential elements for improved care transition from the ED to the community. Starting a new program requires buy-in from leaders, clinical team, and community. Improving care within an ED requires looking beyond the ED. Following implementation science will increase the success of program implementation and dissemination. There are successful alternative approaches that can be learned from when striving to improve care and transitions.

Comprehensive Support for Family Caregivers of Post-9/11 Veterans Increases Veteran Utilization of Long-term Services and Supports: A Propensity Score Analysis.

Family caregivers are an important component of the long-term services and supports (LTSS) system. However, caregiving may have negative consequences for caregiver physical and emotional health. Connecting caregivers to formal short-term home- and community-based services (HCBS), through information resources and referrals, might alleviate family caregiver burden and delay nursing home entry for the patient. The aim of this study was to evaluate the early impact of the Program of Comprehensive Assistance for Family Caregivers (PCAFC) (established by P.L. 111-163 for family caregivers of seriously injured post-9/11 Veterans) on Veteran use of LTSS. A two-cohort pre-post design with a nonequivalent comparison group (treated n = 15 650; comparison n = 8339) was used to (1) examine the association between caregiver enrollment in PCAFC and any VA-purchased or VA-provided LTSS use among Veterans and (2) describe program-related trends in HCBS and institutional LTSS use. The comparison group was an inverse-propensity-score weighted sample of Veterans whose caregivers applied for, but were not accepted into, the program. From baseline through 24 months post application, use of any LTSS ranged from 13.1% to 17.8% for Veterans whose caregivers were enrolled in PCAFC versus from 3.8% to 5.3% for Veterans in the comparison group. Participation in PCAFC was associated with a statistically significant increased use of any LTSS from 1 to 24 months post application (over time odds ratios ranged from 2.71 [95% confidence interval: 2.31-3.17] to 4.86 [3.93-6.02]). Support for family caregivers may enhance utilization of LTSS for Veterans with physical, emotional, and/or cognitive conditions.

The Effect of Support and Training for Family Members on Access to Outpatient Services for Veterans with Posttraumatic Stress Disorder (PTSD).

The VA Program of Comprehensive Assistance for Family Caregivers (PCAFC) provides landmark support for family caregivers of post-9/11 veterans. This study examines PCAFC support for veterans with and without PTSD and assesses whether program effect differs by PTSD status using a pre-post, non-equivalent, propensity score weighted comparison group design (n = 24,280). Veterans with and without PTSD in PCAFC accessed more mental health, primary, and specialty care services than weighted comparisons. PCAFC participation had stronger effects on access to primary care for veterans with PTSD than for veterans without PTSD. For veterans with PTSD, PCAFC support might enhance health service use.

Early Mobility in the Hospital: Lessons Learned from the STRIDE Program.

Immobility during hospitalization is widely recognized as a contributor to deconditioning, functional loss, and increased need for institutional post-acute care. Several studies have demonstrated that inpatient walking programs can mitigate some of these negative outcomes, yet hospital mobility programs are not widely available in U.S. hospitals. STRIDE (assiSTed eaRly mobIlity for hospitalizeD older vEterans) is a supervised walking program for hospitalized older adults that fills this important gap in clinical care. This paper describes how STRIDE works and how it is being disseminated to other hospitals using the Replicating Effective Programs (REP) framework. Guided by REP, we define core components of the program and areas where the program can be tailored to better fit the needs and local conditions of its new context (hospital). We describe key adaptations made by four hospitals who have implemented the STRIDE program and discuss lessons learned for successful implementation of hospital mobility programs.

Internet Use and Technology-Related Attitudes of Veterans and Informal Caregivers of Veterans.

BACKGROUND: Healthcare systems are interested in technology-enhanced interventions to improve patient access and outcomes. However, there is uncertainty about feasibility and acceptability for groups who may benefit but are at risk for disparities in technology use. Thus, we sought to describe characteristics of Internet use and technology-related attitudes for two such groups: (1) Veterans with multi-morbidity and high acute care utilization and (2) informal caregivers of Veterans with substantial care needs at home. MATERIALS AND METHODS: We used survey data from two ongoing trials, for 423 Veteran and 169 caregiver participants, respectively. Questions examined Internet use in the past year, willingness to communicate via videoconferencing, and comfort with new technology devices. RESULTS: Most participants used Internet in the past year (81% of Veterans, 82% of caregivers); the majority of users (83% of Veterans, 92% of caregivers) accessed Internet at least a few times a week, and used a private laptop or computer (81% of Veterans, 89% of caregivers). Most were willing to use videoconferencing via private devices (77-83%). A majority of participants were comfortable attempting to use new devices with in-person assistance (80% of Veterans, 85% of caregivers), whereas lower proportions were comfortable "on your own" (58-59% for Veterans and caregivers). Internet use was associated with comfort with new technology devices (odds ratio 2.76, 95% confidence interval 1.70-4.53). CONCLUSIONS: Findings suggest that technology-enhanced healthcare interventions are feasible and acceptable for Veterans with multi-morbidity and high healthcare utilization, and informal caregivers of Veterans. In-person assistance may be important for those with no recent Internet use.

Risk stratification for return emergency department visits among high-risk patients.

OBJECTIVES: To compare 2 methods of identifying patients at high-risk of repeat emergency department (ED) use: high Care Assessment Need (CAN) score (≥90), derived from a model using Veterans Health Administration (VHA) data, and "Super User" status, defined as more than 3 ED visits within 6 months of the index ED visit. STUDY DESIGN: Retrospective cohort study. METHODS: Using McNemar's test, we compared rates of high-risk classification between CAN score and Super User status. We examined differences in patient characteristics and healthcare utilization across 4 levels of risk classification: high CAN and Super User status (n = 198), CAN <90 and non-Super User (n = 622), high CAN and non-Super User (n = 616), or Super User and CAN score <90 (n = 106). We used logistic regression to identify associations between risk classification and any ED visit within 90 days. RESULTS: Of 1542 veterans, 52.8% (n = 814) had a CAN score ≥90 and 19.7% (n = 304) were Super Users (P <.0001), indicating discrepant rates of high-risk classification. However, we found no differences in patient characteristics. Rates of subsequent ED use were high: 63.1% of patients had 1 or more ED visits. No levels of risk classification were associated with subsequent ED use within 90 days (P = .25). CONCLUSIONS: Among the VHA users with multimorbidity and 3 or more prior ED visits or hospitalizations, subsequent ED use was high. Although CAN scores have demonstrated utility for predicting hospitalizations and deaths, prior utilization and multimorbidity without further risk classification identified a high-risk group for repeat ED use.

Exercise, sleep and cancer-related fatigue: Are they related?

Cancer-related fatigue (CRF) is a commonly reported and debilitating side effect of cancer and/or cancer treatment. Sleep disorders are also highly reported in the cancer population; however it is unknown if sleep is associated with fatigue. In the general population, exercise has been shown to improve sleep, however in the cancer population this idea is under investigation. The primary purposes of this review were to: (i) review the prevalence and causes of sleep disorders in cancer patients and survivors, (ii) examine the relationship between sleep and CRF and (iii) review the impact of exercise interventions on sleep in cancer patients and survivors. A scoping review of the literature was conducted regarding exercise interventions in cancer patients and survivors with sleep as at least one outcome measure. A search of the literature revealed limited studies (n=21) assessing the effect of exercise on sleep disorders in the cancer population. Methodological issues are evident because assessing sleep is often not the main outcome of interest. The reviewed studies revealed that exercise positively impacts sleep quality and quantity. There seems to be possible relationship between sleep disorders, exercise and CRF. Further investigation of this relationship is necessary, specifically using objective measurement tools, in large, controlled studies, focusing on sleep as the primary outcome.

Neuromuscular fatigue during exercise: Methodological considerations, etiology and potential role in chronic fatigue.

The term fatigue is used to describe a distressing and persistent symptom of physical and/or mental tiredness in certain clinical populations, with distinct but ultimately complex, multifactorial and heterogenous pathophysiology. Chronic fatigue impacts on quality of life, reduces the capacity to perform activities of daily living, and is typically measured using subjective self-report tools. Fatigue also refers to an acute reduction in the ability to produce maximal force or power due to exercise. The classical measurement of exercise-induced fatigue involves neuromuscular assessments before and after a fatiguing task. The limitations and alternatives to this approach are reviewed in this paper in relation to the lower limb and whole-body exercise, given the functional relevance to locomotion, rehabilitation and activities of daily living. It is suggested that under some circumstances, alterations in the central and/or peripheral mechanisms of fatigue during exercise may be related to the sensations of chronic fatigue. As such, the neurophysiological correlates of exercise-induced fatigue are briefly examined in two clinical examples where chronic fatigue is common: cancer survivors and people with multiple sclerosis. This review highlights the relationship between objective measures of fatigability with whole-body exercise and perceptions of fatigue as a priority for future research, given the importance of exercise in relieving symptoms of chronic fatigue and/or overall disease management. As chronic fatigue is likely to be specific to the individual and unlikely to be due to a simple biological or psychosocial explanation, tailored exercise programmes are a potential target for therapeutic intervention.