IntroductionUsing tele-rehabilitation methods to deliver exercise, physical activity (PA) and behaviour change interventions for people with multiple sclerosis (pwMS) has increased in recent years, ...especially since the SARS-CoV-2 pandemic. This scoping review aims to provide an overview of the literature regarding adherence to therapeutic exercise and PA delivered via tele-rehabilitation for pwMS.Methods and analysisFrameworks described by Arksey and O’Malley and Levac et al underpin the methods. The following databases will be searched from 1998 to the present: Medline (Ovid), Embase (Ovid), CINAHL (EBSCOhost), Health Management Information Consortium Database, ProQuest Dissertations and Theses Global, Pedro, Cochrane Central Register of Controlled Trials, US National Library of Medicine Registry of Clinical Trials, WHO International Clinical Trials Registry Platform portal and The Cochrane Database of Systematic Reviews. To identify papers not included in databases, relevant websites will be searched. Searches are planned for 2023. With the exception of study protocols, papers on any study design will be included. Papers reporting information regarding adherence in the context of prescribed therapeutic exercise and PA delivered via tele-rehabilitation for pwMS will be included. Information relating to adherence may comprise; methods of reporting adherence, adherence levels (eg, exercise diaries, pedometers), investigation of pwMS’ and therapists’ experiences of adherence or a discussion of adherence. Eligibility criteria and a custom data extraction form will be piloted on a sample of papers. Quality assessment of included studies will use Critical Appraisal Skills Programme checklists. Data analysis will involve categorisation, enabling findings relating to study characteristics and research questions to be presented in narrative and tabular format.Ethics and disseminationEthical approval was not required for this protocol. Findings will be submitted to a peer-reviewed journal and presented at conferences. Consultation with pwMS and clinicians will help to identify other dissemination methods.
Background Adherence is an important factor contributing to the effectiveness of exercise-based rehabilitation. However, there appears to be a lack of reliable, validated measures to assess ...self-reported adherence to prescribed but unsupervised home-based rehabilitation exercises. Objectives A systematic review was conducted to establish what measures were available and to evaluate their psychometric properties. Data sources MEDLINE, EMBASE, PsycINFO CINAHL (June 2013) and the Cochrane library were searched (September 2013). Reference lists from articles meeting the inclusion criteria were checked to ensure all relevant papers were included. Study selection To be included articles had to be available in English; use a self-report measure of adherence in relation to a prescribed but unsupervised home-based exercise or physical rehabilitation programme; involve participants over the age of 18. All health conditions and clinical populations were included. Data extraction Descriptive data reported were collated on a data extraction sheet. The measures were evaluated in terms of eight psychometric quality criteria. Results 58 studies were included, reporting 61 different measures including 29 questionnaires, 29 logs, two visual analogue scales and one tally counter. Only two measures scored positively for one psychometric property (content validity). The majority of measures had no reported validity or reliability testing. Conclusions The results expose a gap in the literature for well-developed measures that capture self-reported adherence to prescribed but unsupervised home-based rehabilitation exercises.
Abstract
Background
Challenges of recruitment to randomized controlled trials (RCTs) and successful strategies to overcome them should be clearly reported to improve recruitment into future trials. ...REtirement in ACTion (REACT) is a United Kingdom-based multicenter RCT recruiting older adults at high risk of mobility disability to a 12-month group-based exercise and behavior maintenance program or to a minimal Healthy Aging control intervention.
Methods
The recruitment target was 768 adults, aged 65 years and older scoring 4–9 on the Short Physical Performance Battery (SPPB). Recruitment methods include the following: (a) invitations mailed by general practitioners (GPs); (b) invitations distributed via third-sector organizations; and (c) public relations (PR) campaign. Yields, efficiency, and costs were calculated.
Results
The study recruited 777 (33.9% men) community-dwelling, older adults (mean age 77.55 years (SD 6.79), mean SPPB score 7.37 (SD 1.56)), 95.11% white (n = 739) and broadly representative of UK quintiles of deprivation. Over a 20-month recruitment period, 25,559 invitations were issued. Eighty-eight percent of the participants were recruited via GP invitations, 5.4% via the PR campaign, 3% via word-of-mouth, and 2.5% via third-sector organizations. Mean recruitment cost per participant was £78.47, with an extra £26.54 per recruit paid to GPs to cover research costs.
Conclusions
REACT successfully recruited to target. Response rates were lower than initially predicted and recruitment timescales required adjustment. Written invitations from GPs were the most efficient method for recruiting older adults at risk of mobility disability. Targeted efforts could achieve more ethnically diverse cohorts. All trials should be required to provide recruitment data to enable evidence-based planning of future trials.
The REtirement in ACTion (REACT) study is a multi-centre, pragmatic, two-arm, parallel-group randomised controlled trial (RCT) with an internal pilot phase. It aims to test the effectiveness and ...cost-effectiveness of a community, group-based physical activity intervention for reducing, or reversing, the progression of functional limitations in older people who are at high risk of mobility-related disability.
A sample of 768 sedentary, community-dwelling, older people aged 65 years and over with functional limitations, but who are still ambulatory (scores between 4 and 9 out of 12 in the Short Physical Performance Battery test (SPPB)) will be randomised to receive either the REACT intervention, delivered over a period of 12 months by trained facilitators, or a minimal control intervention. The REACT study incorporates comprehensive process and economic evaluation and a nested sub-study which will test the hypothesis that the REACT intervention will slow the rate of brain atrophy and of decline in cognitive function assessed using magnetic resonance imaging (MRI). Outcome data will be collected at baseline, 6, 12 and 24 months for the main study, with MRI sub-study data collected at baseline, 6 and 12 months. The primary outcome analysis (SPPB score at 24 months) will be undertaken blinded to group allocation. Primary comparative analyses will be on an intention-to-treat (ITT) basis with due emphasis placed on confidence intervals.
REACT represents the first large-scale, pragmatic, community-based trial in the UK to target the non-disabled but high-risk segment of the older population with an intervention to reduce mobility-related disability. A programme that can successfully engage this population in sufficient activity to improve strength, aerobic capacity, coordination and balance would have a major impact on sustaining health and independence. REACT is also the first study of its kind to conduct a full economic and comprehensive process evaluation alongside the RCT. If effective and cost-effective, the REACT intervention has strong potential to be implemented widely in the UK and elsewhere.
ISRCTN, ID: ISRCTN45627165 . Retrospectively registered on 13 June 2016. Trial sponsor: University of Bath. Protocol Version 1.5.
Mobility limitations in old age can greatly reduce quality of life, generate substantial health and social care costs, and increase mortality. Through the Retirement in Action (REACT) trial, we aimed ...to establish whether a community-based active ageing intervention could prevent decline in lower limb physical functioning in older adults already at increased risk of mobility limitation.
In this pragmatic, multicentre, two-arm, single-blind, parallel-group, randomised, controlled trial, we recruited older adults (aged 65 years or older and who are not in full-time employment) with reduced lower limb physical functioning (Short Physical Performance Battery SPPB score 4–9) from 35 primary care practices across three sites (Bristol and Bath; Birmingham; and Devon) in England. Participants were randomly assigned to receive brief advice (three healthy ageing education sessions) or a 12-month, group-based, multimodal physical activity (64 1-h exercise sessions) and behavioural maintenance (21 45-min sessions) programme delivered by charity and community or leisure centre staff in local communities. Randomisation was stratified by site and adopted a minimisation approach to balance groups by age, sex, and SPPB score, using a centralised, online, randomisation algorithm. Researchers involved in data collection and analysis were masked but participants were not because of the nature of the intervention. The primary outcome was change in SPPB score at 24 months, analysed by intention to treat. This trial is registered with ISRCTN, ISRCTN45627165.
Between June 20, 2016, and Oct 30, 2017, 777 participants (mean age 77·6 SD 6·8 years; 66% female; mean SPPB score 7·37 1·56) were randomly assigned to the intervention (n=410) and control (n=367) groups. Primary outcome data at 24 months were provided by 628 (81%) participants (294 in the control group and 334 in the intervention group). At the 24-month follow-up, the SPPB score (adjusted for baseline SPPB score, age, sex, study site, and exercise group) was significantly greater in the intervention group (mean 8·08 SD 2·87) than in the control group (mean 7·59 2·61), with an adjusted mean difference of 0·49 (95% CI 0·06–0·92; p=0·014), which is just below our predefined clinically meaningful difference of 0·50. One adverse event was related to the intervention; the most common unrelated adverse events were heart conditions, strokes, and falls.
For older adults at risk of mobility limitations, the REACT intervention showed that a 12-month physical activity and behavioural maintenance programme could help prevent decline in physical function over a 24-month period.
National Institute for Health Research Public Health Research Programme (13/164/51).
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The prevention of mobility-related disability amongst adults is a global healthcare priority. Cost-effective community-based strategies to improve physical function and independence in older adults ...with mobility limitations are needed. This study investigated the effectiveness of the REtirement in ACTion (REACT) exercise intervention on individual markers of physical function at 6-and 12-months.
The REACT multicentre randomised controlled trial assigned 777 older adults (female, 514; male 263) (mean age 77·6 SD 6·8 years) with reduced lower limb physical functioning (Short Physical Performance Battery SPPB score 4-9) to receive brief healthy ageing advice or a 12-month, group-based, multimodal exercise programme delivered in local communities. Estimated differences in the three individual component scores of the SPPB (strength, balance, gait speed) and physical functional outcomes recorded at 6- and 12-months were assessed.
The intervention group demonstrated significant improvements in strength (OR = 1.88, 95% CI = 1.36-2.59,
< 0.001) and balance (OR = 1.96, 95% CI = 1.39-2.67, p < 0.001) at 12-months, but not in gait speed (OR = 1.32, 95% CI = 0.91-1.90,
= 0.139). In comparison to the control group, at six-and 12-months, the intervention group reported statistically significant improvements in Mobility Assessment Tool-Short Form (MAT-SF), physical component score from SF-36 questionnaire, and strength and endurance items of subjectively reported physical activity (PASE 10-item). Greater than 75% adherence (attending ≥48 of the 64 exercise sessions delivered in 12-months) was associated with superior functional outcomes.
The REACT exercise programme provides local, regional and national service providers with an effective solution to increase muscle strength and balance in older adults at risk of mobility disability.
Mobility limitations in older populations have a substantial impact on health outcomes, quality of life, and social care costs. The Retirement in Action (REACT) randomised controlled trial assessed a ...12-month community-based group physical activity and behaviour maintenance intervention to help prevent decline in physical functioning in older adults at increased risk of mobility limitation. We aimed to do an economic evaluation of the REACT trial to investigate whether the intervention is cost-effective.
In this health economic evaluation, we did cost-effectiveness and cost-utility analyses of the REACT programme versus standard care on the basis of resource use, primary outcome, and health-related quality-of-life data measured in the REACT trial. We also developed a decision analytic Markov model that forecasts the mobility of recipients beyond the 24-month follow-up of the trial and translated this into future costs and potential benefit to health-related quality of life using the National Health Service and Personal Social Services perspective. Participants completed questionnaire booklets at baseline, and at 6, 12, and 24 months after randomisation, which included a resource use questionnaire and the EQ-5D-5L and 36-item short-form survey (SF-36) health-related quality-of-life instruments. The cost of delivering the intervention was estimated by identifying key resources, such as REACT session leader time, time of an individual to coordinate the programme, and venue hire. EQ-5D-5L and SF-36 responses were converted to preference-based utility values, which were used to estimate quality-adjusted life-years (QALYs) over the 24-month trial follow-up using the area-under-the-curve method. We used generalised linear models to examine the effect of the REACT programme on costs and QALYs and adjust for baseline covariates. Costs and QALYs beyond 12 months were discounted at 3·5% per year. This is a pre-planned analysis of the REACT trial; the trial itself is registered with ISRCTN (ISRCTN45627165).
The 12-month REACT programme was estimated to cost £622 per recipient to deliver. The most substantial cost components are the REACT session leader time (£309 per participant), venue hire (£109), and the REACT coordinator time (£80). The base-case analysis of the trial-based economic evaluation showed that reductions in health and social care usage due to the REACT programme could offset the REACT delivery costs (£3943 in the intervention group vs £4043 in the control group; difference: –£103 95% CI −£695 to £489) with a health benefit of 0·04 QALYs (0·009–0·071; 1·354 QALYs in the intervention group vs 1·314 QALYs in the control group) within the 24-month timeframe of the trial.
The REACT programme could be considered a cost-effective approach for improving the health-related quality of life of older adults at risk of mobility limitations.
National Institute for Health Research Public Health Research Programme.
Background
Mobility limitation in older age reduces quality of life, generates substantial health- and social-care costs, and increases mortality.
Objective
The REtirement in ACTion (REACT) trial ...aimed to establish whether or not a community-based active ageing intervention could prevent decline in physical functioning in older adults already at increased risk of mobility limitation.
Design
A multicentre, pragmatic, two-arm, parallel-group randomised controlled trial with parallel process and health economic evaluations.
Setting
Urban and semi-rural locations across three sites in England.
Participants
Physically frail or pre-frail older adults (aged ≥ 65 years; Short Physical Performance Battery score of 4–9). Recruitment was primarily via 35 primary care practices.
Interventions
Participants were randomly assigned to receive brief advice (three healthy ageing education sessions) or a 12-month, group-based, multimodal exercise and behavioural maintenance programme delivered in fitness and community centres. Randomisation was stratified by site and used a minimisation algorithm to balance age, sex and Short Physical Performance Battery score. Data collection and analyses were blinded.
Main outcome measures
The primary outcome was change in lower limb physical function (Short Physical Performance Battery score) at 24 months, analysed using an intention-to-treat analysis. The economic evaluation adopted the NHS and Personal Social Services perspective.
Results
Between June 2016 and October 2017, 777 participants (mean age 77.6 years, standard deviation 6.8 years; 66% female; mean Short Physical Performance Battery score 7.37, standard deviation 1.56) were randomised to the intervention arm (
n
= 410) or the control arm (
n
= 367). Data collection was completed in October 2019. Primary outcome data at 24 months were provided by 628 (80.8%) participants. At the 24-month follow-up, the Short Physical Performance Battery score was significantly greater in the intervention arm (mean 8.08, standard deviation 2.87) than in the control arm (mean 7.59, standard deviation 2.61), with an adjusted mean difference of 0.49 (95% confidence interval 0.06 to 0.92). The difference in lower limb function between intervention and control participants was clinically meaningful at both 12 and 24 months. Self-reported physical activity significantly increased in the intervention arm compared with the control arm, but this change was not observed in device-based physical activity data collected during the trial. One adverse event was related to the intervention. Attrition rates were low (19% at 24 months) and adherence was high. Engagement with the REACT intervention was associated with positive changes in exercise competence, relatedness and enjoyment and perceived physical, social and mental well-being benefits. The intervention plus usual care was cost-effective compared with care alone over the 2 years of REACT; the price year was 2019. In the base-case scenario, the intervention saved £103 per participant, with a quality-adjusted life-year gain of 0.04 (95% confidence interval 0.006 to 0.074) within the 2-year trial window. Lifetime horizon modelling estimated that further cost savings and quality-adjusted life-year gains were accrued up to 15 years post randomisation.
Conclusion
A relatively low-resource, 1-year multimodal exercise and behavioural maintenance intervention can help older adults to retain physical functioning over a 24-month period. The results indicate that the well-established trajectory of declining physical functioning in older age is modifiable.
Limitations
Participants were not blinded to study arm allocation. However, the primary outcome was independently assessed by blinded data collectors. The secondary outcome analyses were exploratory, with no adjustment for multiple testing, and should be interpreted accordingly.
Future work
Following refinements guided by the process evaluation findings, the REACT intervention is suitable for large-scale implementation. Further research will optimise implementation of REACT at scale.
Trial registration
This trial is registered as ISRCTN45627165.
Funding
This project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme and will be published in full in
Public Health Research
; Vol. 10, No. 14. See the NIHR Journals Library website for further project information.
Pleomorphic xanthoastrocytoma (PXA) is an astrocytic neoplasm that is typically well circumscribed and can have a relatively favorable prognosis. Tumor progression to anaplastic PXA (WHO grade III), ...however, is associated with a more aggressive biologic behavior and worse prognosis. The factors that drive anaplastic progression are largely unknown. We performed comprehensive genomic profiling on a set of 23 PXAs from 19 patients, including 15 with anaplastic PXA. Four patients had tumor tissue from multiple recurrences, including two with anaplastic progression. We find that PXAs are genetically defined by the combination of CDKN2A biallelic inactivation and RAF alterations that were present in all 19 cases, most commonly as CDKN2A homozygous deletion and BRAF p.V600E mutation but also occasionally BRAF or RAF1 fusions or other rearrangements. The third most commonly altered gene in anaplastic PXA was TERT, with 47% (7/15) harboring TERT alterations, either gene amplification (n = 2) or promoter hotspot mutation (n = 5). In tumor pairs analyzed before and after anaplastic progression, two had increased copy number alterations and one had TERT promoter mutation at recurrence. Less commonly altered genes included TP53, BCOR, BCORL1, ARID1A, ATRX, PTEN, and BCL6. All PXA in this cohort were IDH and histone H3 wildtype, and did not contain alterations in EGFR. Genetic profiling performed on six regions from the same tumor identified intratumoral genomic heterogeneity, likely reflecting clonal evolution during tumor progression. Overall, anaplastic PXA is characterized by the combination of CDKN2A biallelic inactivation and oncogenic RAF kinase signaling as well as a relatively small number of additional genetic alterations, with the most common being TERT amplification or promoter mutation. These data define a distinct molecular profile for PXA and suggest additional genetic alterations, including TERT, may be associated with anaplastic progression.
Radiotherapy improves survival for common childhood cancers such as medulloblastoma, leukemia, and germ cell tumors. Unfortunately, long-term survivors suffer sequelae that can include secondary ...neoplasia. Gliomas are common secondary neoplasms after cranial or craniospinal radiation, most often manifesting as high-grade astrocytomas with poor clinical outcomes. Here, we performed genetic profiling on a cohort of 12 gliomas arising after therapeutic radiation to determine their molecular pathogenesis and assess for differences in genomic signature compared to their spontaneous counterparts. We identified a high frequency of
TP53
mutations,
CDK4
amplification or
CDKN2A
homozygous deletion, and amplifications or rearrangements involving receptor tyrosine kinase and Ras–Raf–MAP kinase pathway genes including
PDGFRA
,
MET
,
BRAF
, and
RRAS2
. Notably, all tumors lacked alterations in
IDH1
,
IDH2
,
H3F3A
,
HIST1H3B
,
HIST1H3C
,
TERT
(including promoter region), and
PTEN
, which genetically define the major subtypes of diffuse gliomas in children and adults. All gliomas in this cohort had very low somatic mutation burden (less than three somatic single nucleotide variants or small indels per Mb). The ten high-grade gliomas demonstrated markedly aneuploid genomes, with significantly increased quantity of intrachromosomal copy number breakpoints and focal amplifications/homozygous deletions compared to spontaneous high-grade gliomas, likely as a result of DNA double-strand breaks induced by gamma radiation. Together, these findings demonstrate a distinct molecular pathogenesis of secondary gliomas arising after radiation therapy and identify a genomic signature that may aid in differentiating these tumors from their spontaneous counterparts.
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