Accounting for Heterogeneity in Resource Allocation Decisions: Methods and Practice in UK Cancer Technology Appraisals.

OBJECTIVES: The availability of novel, more efficacious and expensive cancer therapies is increasing, resulting in significant treatment effect heterogeneity and complicated treatment and disease pathways. The aim of this study is to review the extent to which UK cancer technology appraisals (TAs) consider the impact of patient and treatment effect heterogeneity. METHODS: A systematic search of National Institute for Health and Care Excellence TAs of colorectal, lung and ovarian cancer was undertaken for the period up to April 2020. For each TA, the pivotal clinical studies and economic evaluations were reviewed for considerations of patient and treatment effect heterogeneity. The study critically reviews the use of subgroup analysis and real-world translation in economic evaluations, alongside specific attributes of the economic modeling framework. RESULTS: The search identified 49 TAs including 49 economic models. In total, 804 subgroup analyses were reported across 69 clinical studies. The most common stratification factors were age, gender, and Eastern Cooperative Oncology Group performance score, with 15% (119 of 804) of analyses demonstrating significantly different clinical outcomes to the main population; economic subgroup analyses were undertaken in only 17 TAs. All economic models were cohort-level with the majority described as partitioned survival models (39) or Markov/semi-Markov models. The impact of real-world heterogeneity on disease progression estimates was only explored in 2 models. CONCLUSION: The ability of current modeling approaches to capture patient and treatment effect heterogeneity is constrained by their limited flexibility and simplistic nature. This study highlights a need for the use of more sophisticated modeling methods that enable greater consideration of real-world heterogeneity.

Health-related quality of life assessment among people living with HIV in Rio de Janeiro, Brazil: a cross-sectional study.

PURPOSE: To assess health-related quality of life (HRQoL) and its associated factors among people living with HIV/AIDS (PLWHA) in Rio de Janeiro, Brazil. METHODS: A cross-sectional study including PLWHA receiving usual HIV-care at Instituto Nacional de Infectologia Evandro Chagas (INI/Fiocruz) was conducted between 2014 and 2016 in Rio de Janeiro, Brazil. The EQ-5D-3L assessed HRQoL; PHQ-2 and ASSIST were used for screening depression and substance use, respectively. Clinical variables were obtained from the INI/Fiocruz cohort database, and structured questions evaluated intimate partner violence, sexual abstinence and relationship status. Data were analysed using multivariable Tobit regression model. RESULTS: A total of 1480 PLWHA were included: 64.7% were male at birth (38.4% men who have sex with men [MSM], 24.3% heterosexual men and 2% transgender women [TGW]); median age was 43.1 years, and 95.8% were receiving antiretroviral therapy. The median EQ-5D-3L utility score was 0.801. Results showed that the following factors: MSM and women; older age; lower educational level; no engagement in a relationship; depression screening positive; polysubstance use; and, detectable viral load were independently associated with worse HRQoL. CONCLUSIONS: PLWHA under care at INI/Fiocruz presented good HRQoL. Polysubstance use, depression and lower educational level were among the factors negatively associated with HRQoL. This was the first time that the EQ-5D-3L utility scores were calculated for a considerable number of PLWHA in Brazil, which is a fundamental piece of information for future cost-effectiveness analysis.

Stated preferences for anti-malarial drug characteristics in Zomba, a malaria endemic area of Malawi.

BACKGROUND: The evidence on determinants of individuals' choices for anti-malarial drug treatments is scarce. This study sought to measure the strength of preference for adult antimalarial drug treatment attributes of heads of urban, rural and peri-urban households in a resource-limited malaria-endemic area of sub-Saharan Africa. METHODS: Discrete choice experiments were conducted with 508 heads of household interviewed face-to-face for a household population survey of health-seeking behavior in Zomba District, Malawi. The interviews were held in Chichewa and the choice experiment questions were presented with cartoon aids. The anti-malarial drug attributes included in the stated preference experiment were: speed of fever resolution, side effects (pruritus) risk, protection (duration of prophylactic effect), price, duration of treatment course and recommendation by a health professional. Sixteen treatment profiles from a fractional factorial design by orthogonal array were paired into choice scenarios, and scenarios were randomly assigned to participants so that each participant was presented with a series of eight pairwise choice scenarios. Respondents had the option to state indifference between the two profiles or decline to choose. Data were analysed in a mixed logit model, with normally distributed coefficients for all six attributes. RESULTS: The sex ratio was balanced in urban areas, whereas 63% of participants in rural areas were male. The proportion of individuals with no education was considerably higher in the rural group (25%) than in the urban (5%) and peri-urban (6%) groups. All attributes investigated had the expected influence, and traded-off in most respondents' choices. There were heterogeneous effects of price, pruritus risk, treatment recommendation by a professional, and duration of prophylaxis across respondents, only partly explained by their differences in education, household per capita expenditure, sex and age. Individuals' demand elasticity (simulated median, inter-quartile range) was highest (most responsive) to speed of symptom resolution (0.88, 0.80-0.89) and pruritus risk (0.25, 0.08-0.62). CONCLUSIONS: Most adult antimalarial users are willing to use treatments without recommendation from health professional, and may be influenced by price. Future studies should investigate the magnitude of differences in price and treatment attribute sensitivity between adult anti-malarial drug users in rural, peri-urban and urban areas in order to determine optimal price subsidies.

Clinical effectiveness and safety of adding a self-harm prevention app (BlueIce) to specialist mental health care for adolescents who repeatedly self-harm: A single blind randomised controlled trial (the BASH study).

No randomised controlled trials have evaluated whether the addition of a smartphone app to usual child and adolescent mental health care (CAMHS) can reduce self-harm in adolescents (<18 years) with repeated self-harm. We enrolled 170 participants aged 12-17, receiving CAMHS treatment who had self-harmed ≥2 in the past 12 months. Participants were randomised via an independent web-based system (1:1, minimised for gender, age, self-harm frequency, and depression severity) to treatment as usual (TAU) or treatment as usual plus BlueIce (TAU+BI). BlueIce is a self-harm prevention app that includes techniques from CBT and DBT that was co-designed with adolescents who self-harm. The primary outcome was change from baseline to 12-weeks on the self-harm scale of the Risk Taking and Self-Harm Inventory for Adolescents (RTSHIA), analysed by intention to treat (ITT). Emergency department attendances or admissions for self-harm were assessed over 6-months via a review of clinical records. Both groups improved but there were no statistically significant between group differences at 12 weeks or 6 months on the self-harm scale of the RTSHIA. There were fewer emergency department attendances and admissions in those who received the app, a finding that approached statistical significance. BlueIce can be helpful in some important aspects by contributing to fewer emergency department admissions and attendances. TRIAL REGISTRATION: Trial registration number ISRCTN10541045.

Acceptability, use and safety of the BlueIce self-harm prevention app: qualitative findings from the Beating Adolescent Self-Harm (BASH) randomised controlled trial.

BACKGROUND: Little is known about the social validity of self-harm prevention apps for young adolescents with severe mental health problems who repeatedly self-harm. OBJECTIVE: We assessed the acceptability, use and safety of BlueIce, a self-harm prevention app for young adolescents who self-harm. METHODS: Mixed methods study involving a content analysis of postuse interviews. Participants were a clinical group of 60 UK adolescents aged 12-17 with repeated self-harm, randomised to receive BlueIce. FINDINGS: BlueIce was used by 57/60 (95%) respondents with 47/57 (82%) using BlueIce when thinking about self-harm. 17/47 (36%) who were thinking about self-harm used it on more than six occasions with 36/47 (77%) reporting that BlueIce prevented at least one episode of self-harm. 33/47 (70%) reported occasions when they used the app but still went on to self-harm. Reasons why the app was not used or not helpful included feeling too distressed, a negative mindset, prior decision to self-harm or forgetting. BlueIce was rated 4.09 (SD=0.75) out of 5 stars, with high mean ratings out of 10 for ease of use (8.70, SD=1.37) and good for acceptability (7.68, SD=2.05) and helpfulness (6.77, SD=1.72). No respondent identified BlueIce as triggering any episode of self-harm. CONCLUSION: These findings are consistent with previous evaluations and highlight the acceptability, use and safety of BlueIce. Self-reports indicate that BlueIce prevented some episodes of self-harm. CLINICAL IMPLICATIONS: Our results highlight the acceptability of the BlueIce self-harm app for young adolescents who repeatedly self-harm.

Changes in the number of new takeaway food outlets associated with adoption of management zones around schools: A natural experimental evaluation in England.

By the end of 2017, 35 local authorities (LAs) across England had adopted takeaway management zones (or "exclusion zones") around schools as a means to curb proliferation of new takeaways. In this nationwide, natural experimental study, we evaluated the impact of management zones on takeaway retail, including unintended displacement of takeaways to areas immediately beyond management zones, and impacts on chain fast-food outlets. We used uncontrolled interrupted time series analyses to estimate changes from up to six years pre- and post-adoption of takeaway management zones around schools. We evaluated three outcomes: mean number of new takeaways within management zones (and by three identified sub-types: full management, town centre exempt and time management zones); mean number on the periphery of management zones (i.e. within an additional 100 m of the edge of zones); and presence of new chain fast-food outlets within management zones. For 26 LAs, we observed an overall decrease in the number of new takeaways opening within management zones. Six years post-intervention, we observed 0.83 (95% CI -0.30, -1.03) fewer new outlets opening per LA than would have been expected in absence of the intervention, equivalent to an 81.0% (95% CI -29.1, -100) reduction in the number of new outlets. Cumulatively, 12 (54%) fewer new takeaways opened than would have been expected over the six-year post-intervention period. When stratified by policy type, effects were most prominent for full management zones and town centre exempt zones. Estimates of intervention effects on numbers of new takeaways on the periphery of management zones, and on the presence of new chain fast-food outlets within management zones, did not meet statistical significance. Our findings suggest that management zone policies were able to demonstrably curb the proliferation of new takeaways. Modelling studies are required to measure the possible population health impacts associated with this change.

Changes in the number and outcome of takeaway food outlet planning applications in response to adoption of management zones around schools in England: A time series analysis.

Physical exposure to takeaway food outlets ("takeaways") is associated with poor diet and excess weight, which are leading causes of excess morbidity and mortality. At the end of 2017, 35 local authorities (LAs) in England had adopted takeaway management zones (or "exclusion zones"), which is an urban planning intervention designed to reduce physical exposure to takeaways around schools. In this nationwide, natural experimental study, we used interrupted time series analyses to estimate the impact of this intervention on changes in the total number of takeaway planning applications received by LAs and the percentage rejected, at both first decision and after any appeal, within management zones, per quarter of calendar year. Changes in these proximal process measures would precede downstream retail and health impacts. We observed an overall decrease in the number of applications received by intervention LAs at 12 months post-intervention (6.3 fewer, 95% CI -0.1, -12.5), and an increase in the percentage of applications that were rejected at first (additional 18.8%, 95% CI 3.7, 33.9) and final (additional 19.6%, 95% CI 4.7, 34.6) decision, the latter taking into account any appeal outcomes. This effect size for the number of planning applications was maintained at 24 months, although it was not statistically significant. We also identified three distinct sub-types of management zone regulations (full, town centre exempt, and time management zones). The changes observed in rejections were most prominent for full management zones (where the regulations are applied irrespective of overlap with town centres), where the percentage of applications rejected was increased by an additional 46.1% at 24 months. Our findings suggest that takeaway management zone policies may have the potential to curb the proliferation of new takeaways near schools and subsequently impact on population health.

Protocol for a pragmatic cluster randomised controlled trial assessing the clinical effectiveness and cost-effectiveness of Electronic RIsk-assessment for CAncer for patients in general practice (ERICA).

INTRODUCTION: The UK has worse cancer outcomes than most comparable countries, with a large contribution attributed to diagnostic delay. Electronic risk assessment tools (eRATs) have been developed to identify primary care patients with a ≥2% risk of cancer using features recorded in the electronic record. METHODS AND ANALYSIS: This is a pragmatic cluster randomised controlled trial in English primary care. Individual general practices will be randomised in a 1:1 ratio to intervention (provision of eRATs for six common cancer sites) or to usual care. The primary outcome is cancer stage at diagnosis, dichotomised to stage 1 or 2 (early) or stage 3 or 4 (advanced) for these six cancers, assessed from National Cancer Registry data. Secondary outcomes include stage at diagnosis for a further six cancers without eRATs, use of urgent referral cancer pathways, total practice cancer diagnoses, routes to cancer diagnosis and 30-day and 1-year cancer survival. Economic and process evaluations will be performed along with service delivery modelling. The primary analysis explores the proportion of patients with early-stage cancer at diagnosis. The sample size calculation used an OR of 0.8 for a cancer being diagnosed at an advanced stage in the intervention arm compared with the control arm, equating to an absolute reduction of 4.8% as an incidence-weighted figure across the six cancers. This requires 530 practices overall, with the intervention active from April 2022 for 2 years. ETHICS AND DISSEMINATION: The trial has approval from London City and East Research Ethics Committee, reference number 19/LO/0615; protocol version 5.0, 9 May 2022. It is sponsored by the University of Exeter. Dissemination will be by journal publication, conferences, use of appropriate social media and direct sharing with cancer policymakers. TRIAL REGISTRATION NUMBER: ISRCTN22560297.

A cluster randomised trial to evaluate the effectiveness of household alcohol-based hand rub for the prevention of sepsis, diarrhoea, and pneumonia in Ugandan infants (the BabyGel trial): a study protocol.

BACKGROUND: Infections are one of the leading causes of death in the neonatal period. This trial aims to evaluate if the provision of alcohol-based hand rub (ABHR) to pregnant women for postnatal household use prevents severe infections (including sepsis, diarrhoea, pneumonia, or death) among infants during the first three postnatal months. METHODS: Through a cluster-randomised trial in eastern Uganda, 72 clusters are randomised in a 2-arm design with rural villages as units of randomisation. We estimate to include a total of 5932 pregnant women at 34 weeks of gestation. All women and infants in the study are receiving standard antenatal and postnatal care. Women in the intervention group additionally receive six litres of ABHR and training on its use. Research midwives conduct follow-up visits at participants' homes on days 1, 7, 28, 42, and 90 after birth and telephone calls on days 14, 48, and 60 to assess the mother and infant for study outcomes. Primary analyses will be by intention to treat. DISCUSSION: This study will provide evidence on the effectiveness of a locally available and low-cost intervention in preventing neonatal sepsis and early infant infections. If ABHR is found effective, it could be implemented by adding it to birthing kits. TRIAL REGISTRATION: Pan African Clinical Trial Registry, PACTR202004705649428. Registered 1 April 2020, https://pactr.samrc.ac.za/ .

Clinical predictors of encephalitis in UK adults-A multi-centre prospective observational cohort study.

OBJECTIVES: Encephalitis, brain inflammation and swelling, most often caused by an infection or the body's immune defences, can have devastating consequences, especially if diagnosed late. We looked for clinical predictors of different types of encephalitis to help clinicians consider earlier treatment. METHODS: We conducted a multicentre prospective observational cohort study (ENCEPH-UK) of adults (> 16 years) with suspected encephalitis at 31 UK hospitals. We evaluated clinical features and investigated for infectious and autoimmune causes. RESULTS: 341 patients were enrolled between December 2012 and December 2015 and followed up for 12 months. 233 had encephalitis, of whom 65 (28%) had HSV, 38 (16%) had confirmed or probable autoimmune encephalitis, and 87 (37%) had no cause found. The median time from admission to 1st dose of aciclovir for those with HSV was 14 hours (IQR 5-50); time to 1st dose of immunosuppressant for the autoimmune group was 125 hours (IQR 45-250). Compared to non-HSV encephalitis, patients with HSV more often had fever, lower serum sodium and lacked a rash. Those with probable or confirmed autoimmune encephalitis were more likely to be female, have abnormal movements, normal serum sodium levels and a cerebrospinal fluid white cell count < 20 cells x106/L, but they were less likely to have a febrile illness. CONCLUSIONS: Initiation of treatment for autoimmune encephalitis is delayed considerably compared with HSV encephalitis. Clinical features can help identify patients with autoimmune disease and could be used to initiate earlier presumptive therapy.

Longitudinal realist evaluation of the Dementia PersonAlised Care Team (D-PACT) intervention: protocol.

BACKGROUND: Different dementia support roles exist but evidence is lacking on which aspects are best, for whom, and in what circumstances, and on their associated costs and benefits. Phase 1 of the Dementia PersonAlised Care Team programme (D-PACT) developed a post-diagnostic primary care-based intervention for people with dementia and their carers and assessed the feasibility of a trial. AIM: Phase 2 of the programme aims to 1) refine the programme theory on how, when, and for whom the intervention works; and 2) evaluate its value and impact. DESIGN & SETTING: A realist longitudinal mixed-methods evaluation will be conducted in urban, rural, and coastal areas across South West and North West England where low-income or ethnic minority populations (for example, South Asian) are represented. Design was informed by patient, public, and professional stakeholder input and phase 1 findings. METHOD: High-volume qualitative and quantitative data will be collected longitudinally from people with dementia, carers, and practitioners. Analyses will comprise the following: 1) realist longitudinal case studies; 2) conversation analysis of recorded interactions; 3) statistical analyses of outcome and experience questionnaires; 4a) health economic analysis examining costs of delivery; and 4b) realist economic analysis of high-cost events and 'near misses'. All findings will be synthesised using a joint display table, evidence appraisal tool, triangulation, and stakeholder co-analysis. CONCLUSION: The realist evaluation will describe how, why, and for whom the intervention does or does not lead to change over time. It will also demonstrate how a non-randomised design can be more appropriate for complex interventions with similar questions or populations.

Seafood safety: A need for greater awareness.

Although seafood consumption is recommended as part of a healthy diet, several marine biotoxins are present in seafood, which are associated with adverse health effects such as gastrointestinal and neurological symptoms and, therefore, pose unique food safety concerns. Given that global seafood consumption has increased and is expected to increase further along with increasing interest in reducing meat consumption also as part of commitments to climate change, oversight of seafood quality should be a priority to prevent future contamination. In this editorial, several measures are recommended that should be taken to ensure consumer seafood safety.

Women's priorities towards ovarian cancer testing: a best-worst scaling study.

OBJECTIVE: To investigate the importance of key characteristics relating to diagnostic testing for ovarian cancer and to understand how previous test experience influences priorities. DESIGN: Case 1 best-worst scaling embedded in an online survey. SETTING: Primary care diagnostic testing in England and Wales. PARTICIPANTS: 150 women with ovaries over 40 years old living in England and Wales. METHODS: We used best-worst scaling, a preference-based survey method, to elicit the relative importance of 25 characteristics relating to ovarian cancer testing following a systematic review. Responses were modelled using conditional logit regression. Subgroup analysis investigated variations based on testing history. MAIN OUTCOME MEASURES: Relative importance scores. RESULTS: 'Chance of dying from ovarian cancer' (0.380, 95% CI 0.26 to 0.49) was the most important factor to respondents, closely followed by 'test sensitivity' (0.308, 95% CI 0.21 to 0.40). In contrast, 'time away from usual activities' (-0.244, 95% CI -0.33 to -0.15) and 'gender of healthcare provider' (-0.243, 95% CI -0.35 to -0.14) were least important to respondents overall. Women who had previously undergone testing placed higher importance on certain characteristics including 'openness of healthcare providers' and 'chance of diagnosing another condition' at the expense of reduced emphasis on characteristics such as 'pain and discomfort' and 'time away from usual activities'. CONCLUSIONS: The results clearly demonstrated items at the extreme, which were most and least important to women considering ovarian cancer testing. Differences in priorities by testing history demonstrate an experience effect, whereby preferences adapt over time based on evidence and experience. Acknowledging these differences helps to identify underlying barriers and facilitators for women with no test experience as well as shortcomings of current service based on women with experience.

Attributes Used for Cancer Screening Discrete Choice Experiments: A Systematic Review.

BACKGROUND: Evidence from discrete choice experiments can be used to enrich understanding of preferences, inform the (re)design of screening programmes and/or improve communication within public campaigns about the benefits and harms of screening. However, reviews of screening discrete choice experiments highlight significant discrepancies between stated choices and real choices, particularly regarding willingness to undergo cancer screening. The identification and selection of attributes and associated levels is a fundamental component of designing a discrete choice experiment. Misspecification or misinterpretation of attributes may lead to non-compensatory behaviours, attribute non-attendance and responses that lack external validity. OBJECTIVES: We aimed to synthesise evidence on attribute development, alongside an in-depth review of included attributes and methodological challenges, to provide a resource for researchers undertaking future studies in cancer screening. METHODS: A systematic review was conducted to identify discrete choice experiments estimating preferences towards cancer screening, dated between 1990 and December 2020. Data were synthesised narratively. In-depth analysis of attributes led to classification into four categories: test specific, service delivery, outcomes and monetary. Attribute significance and relative importance were also analysed. The International Society for Pharmacoeconomics and Outcomes Research conjoint analysis checklist was used to assess the quality of reporting. RESULTS: Forty-nine studies were included at full text. They covered a range of cancer sites: over half (26/49) examined colorectal screening. Most studies elicited general public preferences (34/49). In total, 280 attributes were included, 90% (252/280) of which were significant. Overall, test sensitivity and mortality reduction were most frequently found to be the most important to respondents. CONCLUSIONS: Improvements in reporting the identification, selection and construction of attributes used within cancer screening discrete choice experiments are needed. This review also highlights the importance of considering the complexity of choice tasks when considering risk information or compound attributes. Patient and public involvement and stakeholder engagement are recommended to optimise understanding of unavoidably complex choice tasks throughout the design process. To ensure quality and maximise comparability across studies, further research is needed to develop a risk-of-bias measure for discrete choice experiments.

Incorporating Equity Concerns in Cost-Effectiveness Analyses: A Systematic Literature Review.

OBJECTIVE: The aim of this study was to review analytical methods that enable the incorporation of equity concerns within economic evaluation. METHODS: A systematic search of PubMed, Embase, and EconLit was undertaken from database inception to February 2021. The search was designed to identify methodological approaches currently employed to evaluate health-related equity impacts in economic evaluation studies of healthcare interventions. Studies were eligible if they described or elaborated on a formal quantitative method used to integrate equity concerns within economic evaluation studies. Cost-utility, cost-effectiveness, cost-benefit, cost-minimisation, and cost-consequence analyses, as well as health technology appraisals, budget impact analyses, and any relevant literature reviews were included. For each of the identified methods, we provided summaries of the scope of equity considerations covered, the methods employed and their key attributes, data requirements, outcomes, and strengths and weaknesses. A traffic light assessment of the practical suitability of each method was undertaken, alongside a worked example applying the different methods to evaluate the same decision problem. Finally, the review summarises the typical trade-offs arising in cost-effectiveness analyses and discusses the extent to which the evaluation methods are able to capture these. RESULTS: In total, 68 studies were included in the review. Methods could broadly be grouped into equity-based weighting (EBW) methods, extended cost-effectiveness analysis (ECEA), distributional cost-effectiveness analysis (DCEA), multi-criteria decision analysis (MCDA), and mathematical programming (MP). EBW and MP methods enable equity consideration through adjustment to incremental cost-effectiveness ratios, whereas equity considerations are represented through financial risk protection (FRP) outcomes in ECEA, social welfare functions (SWFs) in DCEA, and scoring/ranking systems in MCDA. The review identified potential concerns for EBW methods and MCDA with respect to data availability and for EBW methods and MP with respect to explicitly measuring changes in inequality. The only potential concern for ECEA related to the use of FRP metrics, which may not be relevant for all healthcare systems. In contrast, DCEA presented no significant concerns but relies on the use of SWFs, which may be unfamiliar to some audiences and requires societal preference elicitation. Consideration of typical cost-effectiveness and equity-related trade-offs highlighted the flexibility of most methods with respect to their ability to capture such trade-offs. Notable exceptions were trade-offs between quality of life and length of life, for which we found DCEA and ECEA unsuitable, and the assessment of lost opportunity costs, for which we found only DCEA and MP to be suitable. The worked example demonstrated that each method is designed with fundamentally different analytical objectives in mind. CONCLUSIONS: The review emphasises that some approaches are better suited to particular decision problems than others, that methods are subject to different practical requirements, and that significantly different conclusions can be observed depending on the choice of method and the assumptions made. Further, to fully operationalise these frameworks, there remains a need to develop consensus over the motivation for equity assessment, which should necessarily be informed with stakeholder involvement. Future research of this topic should be a priority, particularly within the context of equity evaluation in healthcare policy decisions.

Cost-effectiveness of a physical activity and behaviour maintenance programme on functional mobility decline in older adults: an economic evaluation of the REACT (Retirement in Action) trial.

BACKGROUND: 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. METHODS: 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). FINDINGS: 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. INTERPRETATION: 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. FUNDING: National Institute for Health Research Public Health Research Programme.

Effect of a physical activity and behaviour maintenance programme on functional mobility decline in older adults: the REACT (Retirement in Action) randomised controlled trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: National Institute for Health Research Public Health Research Programme (13/164/51).

Understanding primary care diagnosis and management of sleep disturbance for people with dementia or mild cognitive impairment: a realist review protocol.

INTRODUCTION: The increasingly ageing population is associated with greater numbers of people living with dementia (PLwD) and mild cognitive impairment (MCI). There are an estimated 55 million PLwD and approximately 6% of people over 60 years of age are living with MCI, with the figure rising to 25% for those aged between 80 and 84 years. Sleep disturbances are common for this population, but there is currently no standardised approach within UK primary care to manage this. Coined as a 'wicked design problem', sleep disturbances in this population are complex, with interventions supporting best management in context. METHODS AND ANALYSIS: The aim of this realist review is to deepen our understanding of what is considered 'sleep disturbance' in PLwD or MCI within primary care. Specifically, we endeavour to better understand how sleep disturbance is assessed, diagnosed and managed. To co-produce this protocol and review, we have recruited a stakeholder group comprising individuals with lived experience of dementia or MCI, primary healthcare staff and sleep experts. This review will be conducted in line with Pawson's five stages including the development of our initial programme theory, literature searches and the refinement of theory. The Realist and Meta-narrative Evidence Syntheses: Evolving Standards (RAMESES) quality and reporting standards will also be followed. The realist review will be an iterative process and our initial realist programme theory will be tested and refined in response to our data searches and stakeholder discussions. ETHICS AND DISSEMINATION: Ethical approval is not required for this review. We will follow the RAMESES standards to ensure we produce a complete and transparent report. Our final programme theory will help us to devise a tailored sleep management tool for primary healthcare professionals, PLwD and their carers. Our dissemination strategy will include lay summaries via email and our research website, peer-reviewed publications and social media posts. PROSPERO REGISTRATION NUMBER: CRD42022304679.