'ThinkCancer!' - Randomised feasibility trial of a novel practice-based early cancer diagnosis intervention.

BACKGROUND: UK cancer deaths remain high; primary care is key for earlier cancer diagnosis as half of avoidable delays occur here. Improvement is possible through lower referral thresholds, better guideline adherence, and better safety netting systems. Few interventions target whole practice teams. We developed a novel whole practice team intervention to address this. AIM: To test the feasibility and acceptability of a novel, complex behavioural intervention 'ThinkCancer!' for assessment in a subsequent Phase III trial. DESIGN & SETTING: Pragmatic, superiority pilot RCT with an embedded process evaluation and feasibility economic analysis in Welsh general practices. METHOD: Clinical outcome data were collected from practices (the unit of randomisation). Practice characteristics and cancer safety netting systems were assessed. Individual practice staff completed evaluation and feedback forms, and qualitative interviews. The intervention was adapted and refined. RESULTS: Trial recruitment and workshop deliveries took place between March 2020 to May 2021. Trial progression criteria for recruitment, intervention fidelity and routine data collection were met. Staff-level fidelity, retention and individual level data collection processes were reviewed and amended. Interviews highlighted positive participant views on all aspects of the intervention. All practices set out to liberalise referral thresholds appropriately, implement guidelines, and address safety netting plans in detail. CONCLUSION: 'ThinkCancer!' appears feasible and acceptable; the new iteration of the workshops was completed, and the Phase III trial has been funded to assess the effectiveness and cost effectiveness of this novel professional behaviour change intervention. Delivery at scale to multiple practices will likely improve fidelity and reach.

Elevated Na is a dynamic and reversible modulator of mitochondrial metabolism in the heart.

Elevated intracellular sodium Nai adversely affects mitochondrial metabolism and is a common feature of heart failure. The reversibility of acute Na induced metabolic changes is evaluated in Langendorff perfused rat hearts using the Na/K ATPase inhibitor ouabain and the myosin-uncoupler para-aminoblebbistatin to maintain constant energetic demand. Elevated Nai decreases Gibb's free energy of ATP hydrolysis, increases the TCA cycle intermediates succinate and fumarate, decreases ETC activity at Complexes I, II and III, and causes a redox shift of CoQ to CoQH2, which are all reversed on lowering Nai to baseline levels. Pseudo hypoxia and stabilization of HIF-1α is observed despite normal tissue oxygenation. Inhibition of mitochondrial Na/Ca-exchange with CGP-37517 or treatment with the mitochondrial ROS scavenger MitoQ prevents the metabolic alterations during Nai elevation. Elevated Nai plays a reversible role in the metabolic and functional changes and is a novel therapeutic target to correct metabolic dysfunction in heart failure.

Disrupting Na+ ion homeostasis and Na+/K+ ATPase activity in breast cancer cells directly modulates glycolysis in vitro and in vivo.

BACKGROUND: Glycolytic flux is regulated by the energy demands of the cell. Upregulated glycolysis in cancer cells may therefore result from increased demand for adenosine triphosphate (ATP), however it is unknown what this extra ATP turnover is used for. We hypothesise that an important contribution to the increased glycolytic flux in cancer cells results from the ATP demand of Na+/K+-ATPase (NKA) due to altered sodium ion homeostasis in cancer cells. METHODS: Live whole-cell measurements of intracellular sodium [Na+]i were performed in three human breast cancer cells (MDA-MB-231, HCC1954, MCF-7), in murine breast cancer cells (4T1), and control human epithelial cells MCF-10A using triple quantum filtered 23Na nuclear magnetic resonance (NMR) spectroscopy. Glycolytic flux was measured by 2H NMR to monitor conversion of [6,6-2H2]D-glucose to [2H]-labelled L-lactate at baseline and in response to NKA inhibition with ouabain. Intracellular [Na+]i was titrated using isotonic buffers with varying [Na+] and [K+] and introducing an artificial Na+ plasma membrane leak using the ionophore gramicidin-A. Experiments were carried out in parallel with cell viability assays, 1H NMR metabolomics of intracellular and extracellular metabolites, extracellular flux analyses and in vivo measurements in a MDA-MB-231 human-xenograft mouse model using 2-deoxy-2-[18F]fluoroglucose (18F-FDG) positron emission tomography (PET). RESULTS: Intracellular [Na+]i was elevated in human and murine breast cancer cells compared to control MCF-10A cells. Acute inhibition of NKA by ouabain resulted in elevated [Na+]i and inhibition of glycolytic flux in all three human cancer cells which are ouabain sensitive, but not in the murine cells which are ouabain resistant. Permeabilization of cell membranes with gramicidin-A led to a titratable increase of [Na+]i in MDA-MB-231 and 4T1 cells and a Na+-dependent increase in glycolytic flux. This was attenuated with ouabain in the human cells but not in the murine cells. 18FDG PET imaging in an MDA-MB-231 human-xenograft mouse model recorded lower 18FDG tumour uptake when treated with ouabain while murine tissue uptake was unaffected. CONCLUSIONS: Glycolytic flux correlates with Na+-driven NKA activity in breast cancer cells, providing evidence for the 'centrality of the [Na+]i-NKA nexus' in the mechanistic basis of the Warburg effect.

The mediating role of reflective functioning and general psychopathology in the relationship between childhood conduct disorder and adult aggression among offenders.

BACKGROUND: The nature of the pathway from conduct disorder (CD) in adolescence to antisocial behavior in adulthood has been debated and the role of certain mediators remains unclear. One perspective is that CD forms part of a general psychopathology dimension, playing a central role in the developmental trajectory. Impairment in reflective functioning (RF), i.e., the capacity to understand one's own and others' mental states, may relate to CD, psychopathology, and aggression. Here, we characterized the structure of psychopathology in adult male-offenders and its role, along with RF, in mediating the relationship between CD in their adolescence and current aggression. METHODS: A secondary analysis of pre-treatment data from 313 probation-supervised offenders was conducted, and measures of CD symptoms, general and specific psychopathology factors, RF, and aggression were evaluated through clinical interviews and questionnaires. RESULTS: Confirmatory factor analyses indicated that a bifactor model best fitted the sample's psychopathology structure, including a general psychopathology factor (p factor) and five specific factors: internalizing, disinhibition, detachment, antagonism, and psychoticism. The structure of RF was fitted to the data using a one-factor model. According to our mediation model, CD significantly predicted the p factor, which was positively linked to RF impairments, resulting in increased aggression. CONCLUSIONS: These findings highlight the critical role of a transdiagnostic approach provided by RF and general psychopathology in explaining the link between CD and aggression. Furthermore, they underscore the potential utility of treatments focusing on RF, such as mentalization-based treatment, in mitigating aggression in offenders with diverse psychopathologies.

Implementing and evaluating group interpersonal therapy for postnatal depression in Lebanon and Kenya-individually randomised superiority trial.

BACKGROUND: Depression ranks as the foremost mental health concern among childbearing women. Within low- and middle-income countries (LMICs), between 20 and 25% of women encounter depression during pregnancy or soon after delivery. This condition impacts not only the mothers but also their offspring. Offspring of women suffering from postnatal depression (PND) exhibit suboptimal cognitive development and increased emotional and behavioural issues throughout their growth. This scenario becomes more pronounced in LMICs, where numerous adversities further jeopardise children's developmental progress. Despite antenatal services providing a pivotal platform to address women's mental health needs, PND treatment remains inaccessible in many LMICs. The World Health Organization advocates interpersonal psychotherapy (IPT) for treating depression. While research from high-income countries has established the efficacy of IPT and group-IPT (g-IPT) for PND, its effectiveness within the LMIC context and its potential benefits for child development remain uncharted. This study seeks to gauge the potency of g-IPT for women with PND in two LMICs. METHODS: This multi-site randomised controlled trial is a continuation of two preceding phases-conceptual mapping and a feasibility study executed in Lebanon and Kenya. Insights gleaned from these phases underpin this comprehensive RCT, which contrasts the efficacy and cost-effectiveness of high-quality standard care (HQ-SC) augmented with g-IPT against HQ-SC in isolation. The trial, characterised as an individually randomised superiority assessment, targets women with postnatal depression in Beirut, Lebanon, and Nairobi, Kenya. It aims to determine if culturally tailored g-IPT, administered within community settings in both countries, outperforms HQ-SC in influencing child developmental outcomes, maternal depression, and the quality of the mother-child bond. DISCUSSION: The SUMMIT trial, designed with pragmatism, possesses the magnitude to evaluate g-IPT within two LMIC frameworks. It seeks to enlighten policymakers, service commissioners, professionals, and users about g-IPT's potential to alleviate maternal PND and bolster child developmental outcomes in LMICs. Additionally, the trial will generate valuable data on the clinical and economic merits of high-quality standard care. TRIAL REGISTRATION: ISRCTN, ISRCTN15154316. Registered on 27 September 2023, https://doi.org/10.1186/ISRCTN15154316.

Superiority and cost-effectiveness of monthly extended-release buprenorphine versus daily standard of care medication: a pragmatic, parallel-group, open-label, multicentre, randomised, controlled, phase 3 trial.

Background: Daily methadone maintenance or buprenorphine treatment is the standard-of-care (SoC) medication for opioid use disorder (OUD). Subcutaneously injected, extended-release buprenorphine (BUP-XR) may be more effective-but there has been no superiority evaluation. Methods: This pragmatic, parallel-group, open-label, multi-centre, effectiveness superiority randomised, controlled, phase 3 trial was conducted at five National Health Service community-based treatment clinics in England and Scotland. Participants (adults aged ≥ 18 years; all meeting DSM-5 diagnostic criteria for moderate or severe OUD at admission to their current maintenance treatment episode) were randomly assigned (1:1) to receive continued daily SoC (liquid methadone (usual dose range: 60-120 mg) or sublingual/transmucosal buprenorphine (usual dose range: 8-24 mg) for 24 weeks; or monthly BUP-XR (Sublocade;® two injections of 300 mg, then four maintenance injections of 100 mg or 300 mg, with maintenance dose selected by response and preference) for 24 weeks. In the intent-to-treat population (senior statistician blinded to blinded to treatment group allocation), and with a seven-day grace period after randomisation, the primary endpoint was the count of days abstinent from non-medical opioids between days 8-168 (i.e., weeks 2-24; range: 0-161 days). Safety was reported for the intention-to- treat population. Adopting a broad societal perspective inclusive of criminal justice, NHS and personal social service costs, a trial-based cost-utility analysis estimated the Incremental Cost-effectiveness Ratio (ICER) per quality-adjusted life year (QALY) of BUP-XR versus SoC at the National Institute for Health and Care Excellence threshold. The study was registered EudraCT (2018-004460-63) and ClinicalTrials.gov (NCT05164549), and is completed. Findings: Between Aug 9, 2019 and Nov 2, 2021, 314 participants were randomly allocated to receive SoC (n = 156) or BUP-XR (n = 158). Participants were abstinent from opioids for an adjusted mean of 104.37 days (standard error [SE] 9.89; range: 0-161 days) in the SoC group and an adjusted mean of 123.43 days (SE 4.76; range: 24-161 days) in the BUP-XR group (adjusted incident rate ratio [IRR] 1.18, 95% confidence interval [CI] 1.05-1.33; p-value 0.004). The incidence of any adverse event was higher in the BUP-XR group than the SoC group (128 [81.0%] of 158 participants versus 67 [42.9%] of 156 participants, respectively-most commonly rapidly-resolving (mild-moderate range) pain from drug administration in the BUP-XR group (121 [26.9%] of 450 adverse events). There were 11 serious adverse events (7.0%) in the 158 participants in the BUP-XR group, and 18 serious adverse events (11.5%) in the 156 participants in the SoC group-none judged to be related to study treatment. The BUP-XR treatment group had a mean incremental cost of £1033 (95% central range [CR] -1189 to 3225) and was associated with a mean incremental QALY of 0.02 (95% CR 0.00-0.05), and an ICER of £47,540 (0.37 probability of being cost-effective at the £30,000/QALY gained willingness-to-pay threshold). However, BUP-XR dominated the SoC among participants who were rated more severe at study baseline, and among participants in maintenance treatment for more that 28 days at study enrolment. Interpretation: Evaluated against the daily oral SoC, monthly BUP-XR is clinically superior, delivering greater abstinence from opioids, and with a comparable safety profile. BUP-XR was not cost-effective in a base case cost-utility analysis using the societal perspective, but it was more effective and less costly (dominant) among participants with more severe OUD, or those whose current treatment episode was longer than 28 days. Further trials are needed to evaluate if BUP-XR is associated with better clinical and health economic outcomes over the longer term. Funding: Indivior.

Discovery of a novel cardiac-specific myosin modulator using artificial intelligence-based virtual screening.

Direct modulation of cardiac myosin function has emerged as a therapeutic target for both heart disease and heart failure. However, the development of myosin-based therapeutics has been hampered by the lack of targeted in vitro screening assays. In this study we use Artificial Intelligence-based virtual high throughput screening (vHTS) to identify novel small molecule effectors of human ß-cardiac myosin. We test the top scoring compounds from vHTS in biochemical counter-screens and identify a novel chemical scaffold called 'F10' as a cardiac-specific low-micromolar myosin inhibitor. Biochemical and biophysical characterization in both isolated proteins and muscle fibers show that F10 stabilizes both the biochemical (i.e. super-relaxed state) and structural (i.e. interacting heads motif) OFF state of cardiac myosin, and reduces force and left ventricular pressure development in isolated myofilaments and Langendorff-perfused hearts, respectively. F10 is a tunable scaffold for the further development of a novel class of myosin modulators.

"Better Living with Non-memory-led Dementia": protocol for a feasibility randomised controlled trial of a web-based caregiver educational programme.

BACKGROUND: Non-memory-led dementias such as posterior cortical atrophy (PCA), primary progressive aphasia (PPA) and behavioural variant frontotemporal dementia (bvFTD) are low prevalent and often affect individuals under the age of 65. Tailored educational and support resources for caregivers of people living with these dementia phenotypes are scarce and unevenly distributed geographically. Web-based educational programmes are emerging as promising alternatives to improve caregiver self-efficacy and well-being. Here, we present the protocol of a study aiming to assess the feasibility of a co-produced online educational programme for caregivers of people living PCA, PPA and bvFTD: the Better Living with Non-memory-led Dementia programme. METHODS: A randomised controlled feasibility trial will be conducted on a sample of 30 caregivers of people living with PCA, PPA and bvFTD. Participants will be recruited among members of the support organisation Rare Dementia Support (based at UCL in the UK). The intervention group will be given access to an 8-week co-produced web-based educational programme consisting of 6 modules addressing education about PCA, PPA and bvFTD and support strategies for the person with dementia and for the caregiver. The control group will receive treatment as usual (TAU). Feasibility will be measured through feasibility of recruitment, clinical measurement tools and acceptability. Clinical measures will be used to assess preliminary efficacy and data on completion rates, missing data and variability used to decide on measures to be included in a full-scale trial. Allocation ratio will be 2:1 (intervention:control) stratified by diagnosis. Feasibility of recruitment and acceptability will be assessed. Clinical measures will be administered at baseline and 8-week and 3-month post-randomisation. The control group will be offered access to the intervention at the completion of data collection. Participants will be unblinded, and all measures will be self-reported online. DISCUSSION: Online-delivered educational programmes show potential for improving care competency of caregivers and may contribute to overcoming geographical inequalities in local provision of support services. This pilot study will inform a fully powered international trial to determine the effectiveness of Better Living with Non-memory-led Dementia. TRIAL REGISTRATION: This trial has been registered prospectively on the Clinical Trials Registry on 1st September 2022, registration number NCT05525377.

Development of an item pool for a patient reported outcome measure of resilience for people living with dementia.

BACKGROUND AND OBJECTIVES: Policies to support people living with dementia increasingly focus on strengths-based approaches, highlighting the importance of building resilience. This research responds to the lack of a suitable resilience measure for people with dementia. It develops a pool of items to inform a new measure of resilience for this population. METHODS: A conceptual model and associated data informed the item generation of the draft resilience measure. Regular meetings with professionals (n = 7) discussed response-scale formatting, content and face validity, leading to refinement and item reduction. Cognitive interviews with people living with dementia (n = 11) then examined the face and content validity of items and the suitability of response-scale formatting. These two phases informed subsequent revision and further item reduction of the resilience measure. RESULTS: The first item generation exercise led to 140 items. These were independently assessed by the professionals and this refinement reduced the measure to 63 items across 7 domains of the conceptual model (psychological strengths; practical approaches for adapting to life with dementia; continuing with hobbies, interests and activities; strong relationships with family and friends; peer support and education; participating in community activities; the role of professional support services). Cognitive interviews explored the 63 items with people living with dementia. Detailed feedback led to items removed due to difficulty with (a) understanding (N = 7); (b) answering (n = 11); (c) low preference for that item (n = 6); and (d) presence of a preferred item within a cluster of similar questions (n = 4). Items were amended to enhance clarity/conciseness (n = 19) leading to a final 37-item pool. CONCLUSION: Established methods for measurement development included the expertise of people with dementia and led to the generation of a set of items for a new resilience measure that were understandable and acceptable to this target population. This 37-item pool reflects the conceptual understanding of resilience in dementia as being derived across individual, community and societal level resources.

Single-centre, single-blinded, randomised, parallel group, feasibility study protocol investigating if mandibular advancement device treatment for obstructive sleep apnoea can reduce nocturnal gastro-oesophageal reflux (MAD-Reflux trial).

INTRODUCTION: Just under half of patients with obstructive sleep apnoea (OSA) also have gastro-oesophageal reflux disease (GORD). These conditions appear to be inter-related and continual positive airway pressure (CPAP) therapy, the gold standard treatment for OSA to prevent airway collapse, has been shown to reduce GORD. As the impact of mandibular advancement devices, a second-line therapy for OSA, on GORD has yet to be investigated, a feasibility study is needed prior to a definitive trial. METHODS: This will be a single-centre, single-blinded, tertiary-care based, interdisciplinary, parallel randomised controlled study. Potential OSA participants presenting to the sleep department will be pre-screened for GORD using validated questionnaires, consented and invited to receive simultaneous home sleep and oesophageal pH monitoring. Those with confirmed OSA and GORD (n=44) will be randomly allocated to receive either CPAP (n=22) or MAD therapy (n=22). Following successful titration and 3 weeks customisation period, participants will repeat the simultaneous sleep and oesophageal pH monitoring while wearing the device. The number of patients screened for recruitment, drop-out rates, patient feedback of the study protocol, costs of interventions and clinical information to inform a definitive study design will be investigated. ETHICS AND DISSEMINATION: Health Research Authority approval has been obtained from the Nottingham 2 Research Ethics Committee, ref:22/EM/0157 and the trial has been registered on ISRCTN (https://doi.org/10.1186/ISRCTN16013232). Definitive findings about the feasibility of doing 24 hour pH oesophageal monitoring while doing a home sleep study will be disseminated via clinical and research networks facilitating valuable insights into the simultaneous management of both conditions. TRIAL REGISTRATION NUMBER: ISRCTN Reg No: 16013232.

Promoting Activity, Independence, and Stability in Early Dementia and mild cognitive impairment (PrAISED): randomised controlled trial.

OBJECTIVE: To determine the effectiveness of an exercise and functional activity therapy intervention in adults with early dementia or mild cognitive impairment compared with usual care. DESIGN: Randomised controlled trial. SETTING: Participants' homes and communities at five sites in the United Kingdom. PARTICIPANTS: 365 adults with early dementia or mild cognitive impairment who were living at home, and family members or carers. INTERVENTION: The intervention, Promoting activity, Independence, and Stability in Early Dementia and mild cognitive impairment (PrAISED), was a specially designed, dementia specific, rehabilitation programme focusing on strength, balance, physical activity, and performance of activities of daily living, which was tailored and progressive and addressed risk and the psychological needs of people with dementia. Up to 50 therapy sessions were provided over 12 months. The control group received usual care plus a falls risk assessment. Procedures were adapted during the covid-19 pandemic. MAIN OUTCOME MEASURES: The primary outcome was score on the carer (informant) reported disability assessment for dementia scale 12 months after randomisation. Secondary outcomes were self-reported activities of daily living, physical activity, quality of life, balance, functional mobility, fear of falling, frailty, cognition, mood, carer strain, service use at 12 months, and falls between months 4 and 15. RESULTS: 365 patient participants were randomised, 183 to intervention and 182 to control. The median age of participants was 80 years (range 65-95), median Montreal cognitive assessment score was 20 out of 30 (range 13-26), and 58% (n=210) were men. Intervention participants received a median of 31 therapy sessions (interquartile range 22-40) and reported completing a mean 121 minutes of PrAISED exercise each week. Primary outcome data were available for 149 intervention and 141 control participants. Scores on the disability assessment for dementia scale did not differ between groups: adjusted mean difference -1.3, 95% confidence interval -5.2 to 2.6; Cohen's d effect size -0.06, 95% confidence interval -0.26 to 0.15; P=0.51). Upper 95% confidence intervals excluded small to moderate effects on any of the range of outcome measures. Between months 4 and 15 the intervention group experienced 79 falls and the control group 200 falls (adjusted incidence rate ratio 0.78, 95% confidence interval 0.5 to 1.3; P=0.3). CONCLUSION: The intensive PrAISED programme of exercise and functional activity training did not improve activities of daily living, physical activity, or quality of life; reduce falls; or improve any other secondary health status outcomes, despite good uptake. Future research should consider alternative approaches to maintaining ability and wellbeing in people with dementia. TRIAL REGISTRATION: ISRCTN Registry ISRCTN15320670.

"I felt like I had been put on the shelf and forgotten about" - lasting lessons about the impact of COVID-19 on people affected by rarer dementias.

BACKGROUND: The public health measures imposed in many countries to contain the spread of COVID-19 resulted in significant suspensions in the provision of support and care for people with dementia. The negative effects of these measures have been extensively reported. However, little is known about the specific impact on people with young onset, non-memory-led and inherited dementias. This group may have experienced different challenges compared to those with late onset dementia given their non-memory phenotypes and younger age. We explored the impact of the first COVID-19 lockdown on people living with familial Alzheimer's disease, behavioural variant frontotemporal dementia, familial frontotemporal dementia, dementia with Lewy bodies, posterior cortical atrophy and primary progressive aphasia and their carers in the UK and their self-reported strategies for coping. METHODS: This was a mixed methods study. An online survey was administered to people with dementia and family carers recruited via Rare Dementia Support. Free-text responses were analysed using framework analysis to identify key issues and themes. RESULTS: 184 carers and 24 people with dementia completed the survey. Overall, people with dementia experienced worsening of cognitive symptoms (70%), ability to do things (62%), well-being (57%) and changes to medication (26%) during lockdown. Carers reported a reduction in the support they received (55%) which impacted their own mental health negatively. Qualitative analysis of free-text responses shed light on how the disruption to routines, changes to roles and responsibilities, and widespread disconnection from friends, family and health and social care support varied according to phenotype. These impacts were exacerbated by a more general sense that precious time was being lost, given the progressive nature of dementia. Despite significant challenges, respondents demonstrated resilience and resourcefulness in reporting unexpected positives and strategies for adapting to confinement. CONCLUSIONS: This study has highlighted the specific impacts of the COVID-19 restrictions on people with young onset, non-memory-led and inherited dementias, including behavioural variant frontotemporal dementia, primary progressive aphasia and posterior cortical atrophy, and their carers. The specific challenges faced according to diagnosis and the self-reported strategies speak to the importance of - and may inform the development of - tailored support for these underrepresented groups more generally.

Group cognitive stimulation therapy versus usual care for people with intellectual disabilities and dementia (CST-IDD) in the UK: protocol for a mixed-methods feasibility randomised controlled trial.

INTRODUCTION: The prevalence of dementia is almost five times higher in people with intellectual disabilities compared with the general population. However, evidence-based treatments for this population are lacking, as most randomised controlled trials for dementia interventions have not included people with intellectual disabilities. Cognitive stimulation therapy (CST) has a robust evidence base in the general dementia population, consistently showing benefits to cognition, quality of life and being cost-effective. We are conducting a mixed-methods feasibility trial of group CST for people with intellectual disabilities and dementia, to determine if a future definitive randomised controlled trial is feasible. METHODS AND ANALYSIS: Fifty individuals with intellectual disabilities and dementia will be randomised to either the intervention arm (14 sessions of group CST plus treatment as usual) or the control arm (treatment as usual). Randomisation will occur after informed consent has been obtained and baseline assessments completed. Each arm will have 25 participants, with the intervention arm divided into five or more CST groups with three to five participants in each. The outcomes will be feasibility of recruitment, acceptability and adherence of the intervention, suitability of study outcome measures and feasibility of collecting resource use data. Quantitative and qualitative approaches, including semistructured interviews with group participants, carers and group facilitators, will be employed to assess these outcomes. ETHICS AND DISSEMINATION: This study has been approved by Essex REC (Ref: 21/EE/027) and the HRA ethical approval process through the Integrated Research Application System (IRAS ID: 306 756). We plan to publish the results in peer-reviewed journals and conferences as well as provide feedback to funders, sponsors and study participants. TRIAL REGISTRATION NUMBER: ISRCTN88614460.

The impact of different researchers to capture quality of life measures in a dementia randomised controlled trial.

BACKGROUND: Capturing changes in health and wellbeing within randomised controlled trials (RCTs) can be complex. The precision and accuracy of outcome scales to measure change is crucial, and therefore, consideration needs to be given to potential measurement errors when collecting these outcomes. Many RCTs use multiple researchers to collect data, which has the potential to introduce variation in measurements. This study aimed to identify if there was a measurable effect of using different researchers to collect repeated assessments of quality of life (QoL) at different time points. METHODS: A previously conducted study assessing the impact of reminiscence therapy on participants with dementia and carer (PwD-carer) dyads, 'REMCARE' (Reminiscence groups for people with dementia and their family caregivers), provided the platform for this exploratory secondary analysis. Data was categorised into two broad groups: those where the same researcher attended all assessments and those where different researchers undertook the assessments. ANCOVA (analysis of covariance) models used in the original REMCARE analysis with the addition of the 'researcher-continuity' variable were run on two QoL measures, the QoL-AD (Quality of Life in Alzheimer's Disease) and QCPR (Quality of the Caregiving Relationship). RESULTS: Three hundred thirty PwD-carer dyads were included in the analysis. For the PwD, a statistically significant effect was found on the researcher continuity variable for the QoL-AD and QCPR outcome measures at follow-up 1 but not at follow-up 2 signifying an impact of researcher attendance at the first follow-up but not follow-up 2. For the carer data, analyses revealed no statistically significant effects at follow-up 1; however, the QoL-AD measure at follow-up 2 was found to be statistically significant. CONCLUSIONS: These exploratory results indicate the possible impact of researcher continuity on QoL outcomes in dementia studies. Further research is required to explore this further and establish causality. If demonstrated, this would have implications for the planning of future empirical studies in dementia, in order to reduce this potential source of bias.

Earlier cancer diagnosis in primary care: a feasibility economic analysis of ThinkCancer!

BACKGROUND: UK cancer survival rates are much lower compared with other high-income countries. In primary care, there are opportunities for GPs and other healthcare professionals to act more quickly in response to presented symptoms that might represent cancer. ThinkCancer! is a complex behaviour change intervention aimed at primary care practice teams to improve the timely diagnosis of cancer. AIM: To explore the costs of delivering the ThinkCancer! intervention to expedite cancer diagnosis in primary care. DESIGN & SETTING: Feasibility economic analysis using a micro-costing approach, which was undertaken in 19 general practices in Wales, UK. METHOD: From an NHS perspective, micro-costing methodology was used to determine whether it was feasible to gather sufficient economic data to cost the ThinkCancer! INTERVENTION: Owing to the COVID-19 pandemic, ThinkCancer! was mainly delivered remotely online in a digital format. Budget impact analysis (BIA) and sensitivity analysis were conducted to explore the costs of face-to-face delivery of the ThinkCancer! intervention as intended pre-COVID-19. RESULTS: The total costs of delivering the ThinkCancer! intervention across 19 general practices in Wales was £25 030, with an average cost per practice of £1317 (standard deviation [SD]: 578.2). Findings from the BIA indicated a total cost of £34 630 for face-to-face delivery. CONCLUSION: Data collection methods were successful in gathering sufficient health economics data to cost the ThinkCancer! INTERVENTION: Results of this feasibility study will be used to inform a future definitive economic evaluation alongside a pragmatic randomised controlled trial (RCT).

Effects of an e-health intervention 'iSupport' for reducing distress of dementia carers: protocol for a randomised controlled trial and feasibility study.

INTRODUCTION: In the UK, National Health Service (NHS) guidelines recommend that informal carers of people living with dementia should be offered training to help them develop care skills and manage their own physical and mental health. The WHO recommends access to affordable, proven, well-designed, online technologies for education, skills training and support for dementia carers. In response to these recommendations, this multisite randomised controlled trial (RCT) is the first study in the UK to evaluate the clinical and cost-effectiveness of an online support programme developed by the WHO called 'iSupport for dementia carers'. METHODS AND ANALYSIS: 350 informal carers (age 18+ years) living in Britain who self-identify as experiencing stress and depression will be recruited. They will be randomised to receive 'iSupport', or standardised information about caring for someone with dementia (control-comparison). Data will be collected via videoconferencing (eg, Zoom) or telephone interview at baseline, 3 months and 6 months. Intention-to-treat analysis will ascertain effectiveness in the primary outcomes (distress and depression) and combined cost, and quality-adjusted life-year data will be used to assess cost-effectiveness compared with usual care from a public sector and wider societal perspective. A mixed-methods process evaluation with a subgroup of carers in the intervention (~N=50) will explore the barriers and facilitators to implementing 'iSupport'. A non-randomised feasibility study will adapt 'iSupport' for young carers (n=38 participants, age 11-17 years). ETHICS AND DISSEMINATION: The research plan was scrutinised by National Institute for Health Research reviewers ahead of funding being awarded. Ethical approval was granted by Bangor University's School of Health and Medical Sciences Academic Ethics Committee, reference number 2021-16915. Dissemination plans include delivering events for stakeholders, social media, a project website, developing policy briefings, presenting at conferences and producing articles for open access publications. TRIAL REGISTRATION NUMBER: ISRCTN17420703.

Extended-release pharmacotherapy for opioid use disorder (EXPO): protocol for an open-label randomised controlled trial of the effectiveness and cost-effectiveness of injectable buprenorphine versus sublingual tablet buprenorphine and oral liquid methadone.

BACKGROUND: Sublingual tablet buprenorphine (BUP-SL) and oral liquid methadone (MET) are the daily, standard-of-care (SOC) opioid agonist treatment medications for opioid use disorder (OUD). A sizable proportion of the OUD treatment population is not exposed to sufficient treatment to attain the desired clinical benefit. Two promising therapeutic technologies address this deficit: long-acting injectable buprenorphine and personalised psychosocial interventions (PSI). This study will determine (A) the effectiveness and cost-effectiveness - monthly injectable, extended-release (BUP-XR) in a head-to-head comparison with BUP-SL and MET, and (B) the effectiveness of BUP-XR with adjunctive PSI versus BUP-SL and MET with PSI. Safety, retention, craving, substance use, quality-adjusted life years, social functioning, and subjective recovery from OUD will be also evaluated. METHODS: This is a pragmatic, multi-centre, open-label, parallel-group, superiority RCT, with a qualitative (mixed-methods) evaluation. The study population is adults. The setting is five National Health Service community treatment centres in England and Scotland. At each centre, participants will be randomly allocated (1:1) to BUP-XR or SOC. At the London study co-ordinating centre, there will also be allocation of participants to BUP-XR with PSI or SOC with PSI. With 24 weeks of study treatment, the primary outcome is days of abstinence from non-medical opioids during study weeks 2-24 combined with up to 12 urine drug screen tests for opioids. For 90% power (alpha, 5%; 15% inflation for attrition), 304 participants are needed for the BUP-XR versus SOC comparison. With the same planning parameters, 300 participants are needed for the BUP-XR and PSI versus SOC and PSI comparison. Statistical and health economic analysis plans will be published before data-lock on the Open Science Framework. Findings will be reported in accordance with the Consolidated Standards of Reporting Trials and Consolidated Health Economic Evaluation Reporting Standards. DISCUSSION: This pragmatic randomised controlled trial is the first evaluation of injectable BUP-XR versus the SOC medications BUP-SL and MET, with personalised PSI. If there is evidence for the superiority of BUP-XR over SOC medication, study findings will have substantial implications for OUD clinical practice and treatment policy in the UK and elsewhere. TRIAL REGISTRATION: EU Clinical Trials register 2018-004460-63.

uSing rolE-substitutioN In care homes to improve ORal health (SENIOR): a study protocol.

BACKGROUND: Dental service provision in the care home sector is poor, with little emphasis on prevention. Emerging evidence suggests that the use of Dental Care Professionals (dental therapists and dental nurses) as an alternative to dentists has the potential to improve preventive advice, the provision of care and access to services within care homes. However, robust empirical evidence from definitive trials on how to successfully implement and sustain these interventions within care homes is currently lacking. The aim of the study is to determine whether Dental Care Professionals could reduce plaque levels of dentate older adults (65 + years) residing in care homes. METHODS: This protocol describes a two-arm cluster-randomised controlled trial that will be undertaken in care homes across Wales, Northern Ireland and England. In the intervention arm, the dental therapists will visit the care homes every 6 months to assess and then treat eligible residents, where necessary. All treatment will be conducted within their Scope of Practice. Dental nurses will visit the care homes every month for the first 3 months and then three-monthly afterwards to promulgate advice to improve the day-to-day prevention offered to residents by carers. The control arm will be 'treatment as usual'. Eligible care homes (n = 40) will be randomised based on a 1:1 ratio (20 intervention and 20 control), with an average of seven residents recruited in each home resulting in an estimated sample of 280. Assessments will be undertaken at baseline, 6 months and 12 months and will include a dental examination and quality of life questionnaires. Care home staff will collect weekly information on the residents' oral health (e.g. episodes of pain and unscheduled care). The primary outcome will be a binary classification of the mean reduction in Silness-Löe Plaque Index at 6 months. A parallel process evaluation will be undertaken to explore the intervention's acceptability and how it could be embedded in standard practice (described in a separate paper), whilst a cost-effectiveness analysis will examine the potential long-term costs and benefits of the intervention. DISCUSSION: This trial will provide evidence on how to successfully implement and sustain a Dental Care Professional-led intervention within care homes to promote access and prevention. TRIAL REGISTRATION: ISRCTN16332897 . Registered on 3 December 2021.

The Development of Videoconference-Based Support for People Living With Rare Dementias and Their Carers: Protocol for a 3-Phase Support Group Evaluation.

BACKGROUND: People living with rarer dementias face considerable difficulty accessing tailored information, advice, and peer and professional support. Web-based meeting platforms offer a critical opportunity to connect with others through shared lived experiences, even if they are geographically dispersed, particularly during the COVID-19 pandemic. OBJECTIVE: We aim to develop facilitated videoconferencing support groups (VSGs) tailored to people living with or caring for someone with familial or sporadic frontotemporal dementia or young-onset Alzheimer disease, primary progressive aphasia, posterior cortical atrophy, or Lewy body dementia. This paper describes the development, coproduction, field testing, and evaluation plan for these groups. METHODS: We describe a 3-phase approach to development. First, information and knowledge were gathered as part of a coproduction process with members of the Rare Dementia Support service. This information, together with literature searches and consultation with experts by experience, clinicians, and academics, shaped the design of the VSGs and session themes. Second, field testing involved 154 Rare Dementia Support members (people living with dementia and carers) participating in 2 rounds of facilitated sessions across 7 themes (health and social care professionals, advance care planning, independence and identity, grief and loss, empowering your identity, couples, and hope and dementia). Third, a detailed evaluation plan for future rounds of VSGs was developed. RESULTS: The development of the small groups program yielded content and structure for 9 themed VSGs (the 7 piloted themes plus a later stages program and creativity club for implementation in rounds 3 and beyond) to be delivered over 4 to 8 sessions. The evaluation plan incorporated a range of quantitative (attendance, demographics, and geography; pre-post well-being ratings and surveys; psycholinguistic analysis of conversation; facial emotion recognition; facilitator ratings; and economic analysis of program delivery) and qualitative (content and thematic analysis) approaches. Pilot data from round 2 groups on the pre-post 3-word surveys indicated an increase in the emotional valence of words selected after the sessions. CONCLUSIONS: The involvement of people with lived experience of a rare dementia was critical to the design, development, and delivery of the small virtual support group program, and evaluation of this program will yield convergent data about the impact of tailored support delivered to geographically dispersed communities. This is the first study to design and plan an evaluation of VSGs specifically for people affected by rare dementias, including both people living with a rare dementia and their carers, and the outcome of the evaluation will be hugely beneficial in shaping specific and targeted support, which is often lacking in this population. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/35376.

Neuropsychological evaluation and rehabilitation in multiple sclerosis (NEuRoMS): protocol for a mixed-methods, multicentre feasibility randomised controlled trial.

BACKGROUND: Cognitive problems affect up to 70% of people with multiple sclerosis (MS), which can negatively impact mood, ability to work, and quality of life. Addressing cognitive problems is a top 10 research priority for people with MS. Our ongoing research has systematically developed a cognitive screening and management pathway (NEuRoMS) tailored for people with MS, involving a brief cognitive evaluation and rehabilitation intervention. The present study aims to assess the feasibility of delivering the pathway and will inform the design of a definitive randomised controlled trial (RCT) to investigate the clinical and cost-effectiveness of the intervention and eventually guide its clinical implementation. METHODS: The feasibility study is in three parts. Part 1 involves an observational study of those who receive screening and support for cognitive problems, using routinely collected clinical data. Part 2 is a two-arm, parallel group, multicentre, feasibility RCT with a nested fidelity evaluation. This part will evaluate the feasibility of undertaking a definitive trial comparing the NEuRoMS intervention plus usual care to usual care only, amongst people with MS with mild cognitive problems (n = 60). In part 3, semi-structured interviews will be undertaken with participants from part 2 (n = 25), clinicians (n = 9), and intervention providers (n = 3) involved in delivering the NEuRoMS cognitive screening and management pathway. MS participants will be recruited from outpatient clinics at three UK National Health Service hospitals. DISCUSSION: Timely screening and effective management of cognitive problems in MS are urgently needed due to the detrimental consequences of cognitive problems on people with MS, the healthcare system, and wider society. The NEuRoMS intervention is based on previous and extant literature and has been co-constructed with relevant stakeholders. If effective, the NEuRoMS pathway will facilitate timely identification and management of cognitive problems in people with MS. TRIAL REGISTRATION: ISRCTN11203922 . Prospectively registered on 09.02.2021.