Bipolar disorder affects around 2% of the population and is linked with reduced life expectancy and socioeconomic burden. Depressive episodes are difficult to treat and typically more prevalent, enduring and burdensome than manic episodes. The use of antidepressants alone has limited effect and is associated with significant clinical risk through polarity switch. Current National Institute for Health and Care Excellence guidelines recommend quetiapine, olanzapine (with or without fluoxetine) and lamotrigine; however, these medications have limited efficacy, tolerability and acceptability. The ASCEnD study aims to assess the clinical and cost-effectiveness of aripiprazole plus sertraline compared with quetiapine, offering potential improvements for outcomes in bipolar depression. The study is funded by the National Institute for Health and Care Research Health Technology Assessment programme (NIHR132773).

ASCEnD is a prospective, two-arm, superiority, individually 1:1 randomised, controlled, pragmatic, parallel group, type A open-label clinical trial of aripiprazole/sertraline medication combination compared with quetiapine for bipolar depression. The study is conducted in the UK National Health Service setting with the aim of recruiting and randomising 270 participants followed-up for 24 weeks. Adults with bipolar disorder self-refer or are recruited through primary and secondary care services. The primary outcome is change in depressive symptoms 12–16 weeks after randomisation. Secondary outcomes include measures of symptom change, treatment satisfaction, tolerability, medication adherence, concomitant medication use, psychosocial functioning, quality of life and cost-effectiveness and informal carer measures of quality of life and costs of caring. The exploratory outcome is change in participant reward and punishment responsiveness. Analysis will follow a prespecified statistical analysis plan. A nested qualitative study is included to examine feasibility and acceptability of the trial design.

A Clinical Trial Authorisation from Medicines and Healthcare products Regulatory Agency, and approval from the Health Research Authority (IRAS 1007468) and North East – Newcastle and North Tyneside 1 Research Ethics Committee (23/NE/0132) were obtained. Results will be disseminated through peer-reviewed publications, conference presentations and lay summaries for participants and patient and public groups.

ISRCTN63917405.

Primary biliary cholangitis (PBC) is a rare chronic cholestatic disease that despite current therapy has significant ongoing unmet needs, including risks of cirrhosis and life-impairing symptoms. The current treatment approach is a step-up model, wherein first-line therapy, ursodeoxycholic acid (UDCA), is given for a minimum of 12 months before the addition of second-line therapy is considered for non-responding patients. This ‘waiting to fail’ approach, focused on the needs of low-risk patients, allows, we postulate, a key process of biliary epithelial cell (BEC) senescence to become established, driving accelerated bile duct loss and aggressive disease. Preclinical mouse modelling has shown that early use of the farnesoid X receptor agonist obeticholic acid (OCA), currently only used as second-line therapy following UDCA failure, reverses BEC senescence, changing the clinical course of disease. Here, we describe the design of the Optimising Primary thErapy in pRimAry biliary cholangitis (OPERA) trial. The aim of OPERA is to explore a new paradigm for disease-modifying treatment of PBC: risk-informed early treatment stratification, with patients at increased risk offered UDCA and OCA combination with the goal of complete biochemical remission.

OPERA is a multicentre, randomised, double-blind, placebo-controlled trial of OCA in combination with UDCA, as first-line treatment for high-risk PBC. This is a multicentre trial in England, which will be undertaken in specialist clinics in secondary/tertiary referral centres (or as per local set up). These centres will be specialists in the area of PBC management and will manage patients from across their local region. OPERA will recruit and randomise 106 adults, within 6 months of PBC diagnosis, who are at an enhanced risk of non-response to standard first-line therapy, between either: (1) UDCA and OCA or (2) UDCA and matched placebo in a 1:1 ratio. The primary efficacy outcome measure is the percentage of participants showing normalisation of serum alkaline phosphatase and total bilirubin values at 26 weeks (disease remission).

Favourable ethical opinion was received from London – Riverside Research Ethics Committee (reference: 22/LO/0878). Potential participants will be fully informed of their rights and the benefits and harms of the trial by the research team before giving informed consent to participate in the trial. Results will be disseminated in peer-reviewed publications, at national and international conferences, in peer-reviewed journals and to participants and the public (using lay language).

ISRCTN17176388.

Providing peer support can benefit youth peer support workers (peers)et by supporting self-determination, recovery and resilience to self-stigma. There is a need to clarify the role of the organisation in providing benefits for peers. We aimed to identify the organisational contexts and mechanisms that result in the creation of healthy workplaces for peers.

Rapid realist review guided by the Realist and Meta-Narrative Evidence Syntheses–Evolving Standards guidelines and Pawson’s iterative approach.

MEDLINE, CINAHL, PsycINFO, ERIC, SocINDEX, Google Scholar and Embase were searched from 1979 to 2025.

We included qualitative and quantitative peer-reviewed studies and grey literature that captured characteristics of organisational practices and employment considerations in youth peer support programmes.

Articles were screened independently by multiple reviewers. Inclusion criteria were adjusted to capture literature on organisational practices, and employment considerations for youth peer support programmes. Data were extracted and analysed retroductively to develop Context-Mechanism-Outcome Configurations (CMOCs).

Five employment-related risks to peer well-being were identified: (1) difficulty entering the job market, (2) lack of role clarity, (3) pressure to live up to ideals, (4) retraumatisation and (5) stigma. Six CMOCs were developed; all focused on the creation of equitable employment and supporting peer development and empowerment were developed.

Community-based mental health organisations can facilitate equitable peer employment through strategies that reduce professional stigma, enhance peer resilience and promote professional and personal development. Policy reform that addresses precarious work conditions is needed to support healthy work environments.

Returning research results that indicate risk of Alzheimer disease (AD) dementia—a disease for which no meaningful treatments or cure exist—to cognitively normal participants is controversial. AD is thought to begin many years before clinical signs and symptoms begin. During this time, individuals are cognitively normal but have biomarkers that indicate pathophysiological changes in the brain. With this study, we aim to evaluate the impact of returning research results on cognitively normal participants recruited from a longitudinal observational cohort on ageing at the Knight Alzheimer Disease Research Centre (Knight ADRC) at Washington University in St. Louis.

Our study uses a 2-year, delayed-start randomised clinical trial design. Participants are randomised to receive their research results either 2 weeks or 1 year after informed consent. This study was approved to recruit up to 450 participants with existing genetic and biomarker testing results from the Knight ADRC. During the study period, 260 individuals were eligible and approached for entry into the study. The primary cognitive outcomes are 1-year change in subjective cognitive score on the clinical dementia rating sum of box scores and the objective cognitive score on cognitive composite score. The primary psychosocial outcome is change in geriatric depression scale score 1 year after return of research results. The study was powered to answer primary outcomes with 140 participants (70 per study arm).

This study has been approved by the Washington University School of Medicine (WUSM) Institutional Review Board and the Human Research Protection Office. Results from these trials are shared through conferences and publications.

NCT04699786.

Glaucoma is the leading cause of irreversible blindness worldwide and the number of people with glaucoma is expected to increase to more than 112 million by the year 2040, making it a disease of public health interest. However, there is no consensus on public health indicators to monitor glaucoma care coverage. This scoping review aims to summarise published indicators for monitoring effective glaucoma care coverage globally, focusing on care needs, use of care services and outcomes achieved.

We will include studies that report the development and use of public health indicators for effective glaucoma care coverage in patients aged 18 years and older. Studies published from 1 January 2000, in all languages, will be included, provided they can be accurately and easily translated into English using Google Translate. Searches will be conducted by an information specialist on MEDLINE, Embase, Global Health and CENTRAL in the Cochrane Library. Two reviewers working independently will screen the search results, select studies for inclusion and extract data; any disagreements will be discussed with or resolved by a third reviewer. Data will be presented in tabular form, followed by a narrative synthesis based on the review objectives.

Ethical approval is not required as the review will use published data. Results will be published in a peer-reviewed journal, and summarised results will be available and contribute to the development of standardised glaucoma care indicators.

OSF registration on 19 May 2025: https://osf.io/zsyw9/

Parkinson’s disease (PD) is a common neurodegenerative disease, which has extensive pathology that critically includes the loss of midbrain dopaminergic neurons. This loss leads to debilitating motor features such as bradykinesia and rigidity, as well as some non-motor symptoms. Intracerebral dopamine cell transplants have been explored for many years as a new approach to treating PD and initially used human fetal ventral mesencephalic tissue with inconsistent results, related in part to major logistical challenges in sourcing enough tissue of the right quality and the limited possibilities for quality control and standardisation. Dopaminergic neurons can now be derived reliably from human stem cell sources, which may overcome some of the challenges associated with fetal tissue transplantations.

STEM-PD is a multi-centre, single-arm, dose-escalation, first-in-human advanced therapy investigational medicinal product (ATIMP) trial in Europe using a cell product that consists of dopaminergic neural progenitors derived from the RC17 human embryonic stem cell line. The aim of the study is to assess the safety, tolerability and feasibility of intraputamenal transplantation of this cell product in patients with moderately advanced PD. Eight participants will be recruited from two sites, Skånes University Hospital (Lund, Sweden) and Cambridge University Hospital (Cambridge, UK). The primary outcome of the trial is safety and tolerability, assessed by the number and nature of adverse events and serious adverse events, and the absence of space-occupying lesions on cranial MRI, in the first 12 months following transplantation. Secondary and exploratory outcomes, including clinical measures, changes in anti-Parkinson’s medication and measures of graft survival using positron emission tomography imaging, will be assessed at both 12 and 36 months post-grafting.

Ethical approval was obtained from the Swedish Ethical Review Authority (EPM dnr 2021-06945-01) and South Central - Oxford A Research Ethics Committee (reference 23/SC/0243). Clinical Trial Authorisation was given by the Swedish Medical Products Agency (Dnr: 5.1-2022-57953) and the Medicines and Healthcare products Regulatory Agency for clinical trials authorisation (reference CTA 40773/0001/001-0001). Authorisation for transfer to Clinical Trial Regulation (EU) 536/2014 was given by the Swedish Medical Products Agency (Dnr: 5.1.1-2024-100773). Potential participants will receive verbal and written information about the trial and written informed consent will be obtained prior to enrolment. A lay summary of the results of the trial will be uploaded to the trial website which is publicly accessible. Trial results will be published in peer-reviewed journals.

NCT05635409.

There is interest in using predictive models to address non-attendance of healthcare appointments without prior notification. Although several National Health Service (NHS) hospital trusts have piloted predictive models for non-attendance, there is a lack of published evidence in clinical settings.

This mixed-methods evaluation of the pilot of a predictive model intervention in outpatient services aimed to examine (1) the effect of the intervention on patient non-attendance and (2) staff engagement in the delivery of the intervention.

A mixed-methods study across two pilot phases. Quantitative data explored the use and impact of the predictive model on non-attendance. Z-tests were conducted to assess changes to non-attendance rates prepilot and in the two phases. Qualitative ethnographic work included 30 periods of observation and interviews with staff.

Nine outpatient services in an NHS Foundation Trust that volunteered to pilot the predictive model intervention. Qualitative participants were NHS clerical and administrative staff delivering the intervention and service managers.

An off-the-shelf predictive model, consisting of a cloud-based, random forest algorithm, produced a risk score of non-attendance by drawing on information from patients’ electronic health records. Staff in the pilot sites attempted to phone patients with a risk score to remind them of upcoming appointments.

Quantitative analysis showed that in phase 1, there were low volumes of intervention calls made across services, but three of nine outpatient services significantly reduced their non-attendance rate. There was a lower overall call rate in phase 2 among the four remaining participating services. One significantly reduced its non-attendance rate from 20.4% to 19.1% (p

The predictive model intervention was positioned as a simple solution to address a complex problem; however, there were challenges inherent in deployment within a dynamic healthcare setting. The sustainability of the intervention and its impact on patient experience warrants further exploration.

To translate and validate the HLS-Child-Q15, a relatively short questionnaire for assessing health literacy in children originally validated in German, into English to make it accessible to a large population of English-speaking children.

We translated the HLS-Child-Q15 into English following established methods, including forward and backward translation, using multiple translators. We incorporated clinician and consumer input into the translation process. We conducted a qualitative pre-test to assess comprehension and a validation to assess psychometric properties and test-retest reliability.

Perth Children’s Hospital, Perth, Western Australia

We recruited English-speaking children aged 8 to 15 years.

Qualitative analysis of pre-test interviews, Cronbach’s α coefficient for internal consistency and intraclass correlation coefficient for test-retest reliability.

The translation process yielded an acceptable translation. A qualitative pre-test conducted with 10 children demonstrated good comprehension of questionnaire items and resulted in small changes to increase item clarity. Validation with 207 participants demonstrated that questionnaire output score increased with age, school year, self-efficacy score, parental educational level and home literacy environment score. Internal consistency was assessed, with a Cronbach’s α coefficient of 0.854 (95% CI 0.812 to 0.887). Test-retest reliability was moderate, with an intraclass correlation coefficient of 0.612 (95% CI 0.402 to 0.761).

The translated HLS-Child-Q15 was well understood by children. Validation of the translated questionnaire demonstrated adequate psychometric properties, consistent with the original German questionnaire. The translated HLS-Child-Q15 is suitable for use with English-speaking children.

Data are available on reasonable request and in compliance with institutional ethics and governance requirements.

ACTRN12622001499774

Cognitive behavioural therapy (CBT) and interpersonal psychotherapy (IPT) are both efficacious treatments for depression, but it is less clear how both compare on outcome domains other than depression and in the longer term. Moreover, it is unclear which of these two psychotherapies works better for whom. This article describes the protocol for a systematic review and individual participant data (IPD) meta-analysis that aims to compare the efficacy of CBT and IPT for adults with depression on a range of outcomes in both the short and long term, and to explore moderators of the treatment effect. This study can enhance our understanding of treatments for depression and inform treatment personalisation.

Systematic literature searches will be conducted in PubMed, PsycINFO, EMBASE and the Cochrane Library from inception to 1 January 2026, to identify randomised clinical trials (RCTs) comparing CBT and IPT for adult depression. Researchers of eligible studies will be invited to contribute their participant-level data. One-stage IPD meta-analyses will be conducted with mixed-effects models to examine (a) treatment efficacy on all outcome measures that are assessed at post-treatment or follow-up in at least two studies, and (b) various baseline participant characteristics as potential moderators of depressive symptom level at treatment completion.

Ethical approval is not required for this study since it will be based on anonymised data from RCTs that have already been completed. The findings of the present study will be disseminated through a peer-reviewed journal or conference presentation.

Chronic pelvic pain, defined as persistent pain in the structures of the pelvis, is a condition that significantly impacts the health-related quality of life (HRQoL) of up to one-third of people worldwide, with substantial associated costs to both the individual and healthcare system/s. The present trial aims to establish the efficacy of e-hypnotherapy over relaxation and waitlist controls on pain, HRQoL and biopsychosocial outcomes, and evaluate cost-effectiveness.

A parallel-group, investigator-blinded, randomised controlled trial will be conducted. Eligible participants will be randomly allocated to either a 7-week online personalised e-hypnotherapy programme (n=44), a 7-week online personalised relaxation control (n=44) or waitlist control (n=44). The primary outcome will be self-reported pain level, and secondary outcomes will include psychological distress, QoL, pain catastrophising, self-efficacy, central sensitisation, somatic symptoms, fatigue and sleep. Cost-effectiveness will also be examined. Longitudinal qualitative interviews will be conducted with participants in the e-hypnotherapy (n=20) and relaxation (n=20) groups to understand meaningful change and barriers/facilitators for ongoing use.

This protocol has received ethics approval in Australia from the Deakin University Research Ethics Committee (DUREC ref. 2024-080). Findings will be disseminated through peer-reviewed publications and presentations at national and international conferences related to chronic pelvic pain and mind–body interventions.

Australian New Zealand Clinical Trials Registry ACTRN12623000368639p.

The objective of this scoping review is to elucidate contexts in which Flexible Assertive Community Treatment (FACT) has been utilised, which populations it has served, how it has been adapted and what outcomes it has achieved. FACT is a model of mental healthcare where patients are transitioned along a continuum of high-intensity outreach-based treatment and lower-intensity case management, according to need. Despite being adopted globally, a review of the evidence on the FACT model has not been conducted since 2014.

This study will follow the Joanna Briggs Institute’s (JBI) methodology for scoping reviews and the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews. A structured search of several electronic databases (MedLine, CINAHL, PsycINFO, Psychology & Behavioural Sciences, Embase, Scopus, Sociological Abstracts and ASSIA Social Sciences Index Abstracts) will be conducted to locate relevant studies addressing models of care that adhere to the core components of the FACT model and that were published in English or Dutch from 2003 (model conception date) to the present day. To explore the range of populations served by FACT, we will not limit participant populations by age or diagnosis. With respect to FACT adaptations, we will include articles that explore modifications to the structure of FACT such as staffing complement, caseloads or interface with other health and social services. Articles identified from our structured searches will be screened independently by two reviewers. Data from included articles will be extracted, analysed and presented on tables and visual graphs, and summarised in a narrative report.

Our scoping review does not require ethics approval as it does not involve human subjects and will draw evidence from published peer-reviewed articles. Our findings will be disseminated through journal publication, presentations at relevant conferences and distribution across our networks and those of our partners, including healthcare providers, researchers and other key stakeholders.

To compare costs and health consequences and to assess the cost-effectiveness of using low-dose oral long-acting morphine in people with chronic breathlessness.

Within-trial planned cost-consequences and cost-effectiveness analysis of data from a multisite, parallel-group, double-blind, randomised, placebo-controlled trial of low-dose, long-acting morphine.

11 hospital outpatients across the UK.

Consenting adults with chronic breathlessness due to long-term cardiorespiratory conditions.

5–10 mg two times a day oral long-acting morphine with a blinded laxative for 56 days.

Mean and SD of healthcare resource use (HRU) by trial arm; mean differences and 95% CI of costs between trial arms.

Mean differences in 28- and 56-day quality-adjusted life years (QALYs based on EuroQol five-dimension five-level score), Short Form-six dimensional scores and ICEpop CAPability-Supportive Care Measure scores; cost-utility of long-acting morphine for chronic breathlessness.

143 participants (75 morphine and 67 placebo) were randomised; 140 (90% power, males 66%, mean age 70.5 (SD 9.4)) formed the modified intention-to-treat population (participants receiving at least one dose of study medication). There were more inpatient and fewer outpatient services used by the morphine group versus the placebo. In the base-case analysis at 56 days, long-acting morphine was associated with similar mean per-patient costs and QALYs. There was an increase of £24 (95% CI –£395 to £552) and 0.002 (95% CI –0.004 to 0.008) QALYs. Hospitalisations were the main driver of cost differences. The corresponding incremental cost-effectiveness ratio was £12 000/QALY, with a probability of cost-effectiveness of 54% at a £20 000 willingness-to-pay threshold. In the scenario analysis that excluded costs of adverse events considered unrelated to long-acting morphine by site investigators and researchers, the probability of cost-effectiveness increased to 73%.

Oral morphine for chronic breathlessness is likely to be a cost-effective intervention provided adverse events are minimised, but the effect on outcome is small and cautious interpretation is warranted.

ISRCTN87329095.

Glaucoma is a leading cause of irreversible blindness worldwide. Early detection and continuous monitoring are essential to preventing vision loss, yet traditional diagnostic tools remain largely inaccessible in low-resource settings.

This scoping review aimed to map the existing evidence on the use of portable devices for the detection, diagnosis and monitoring of glaucoma.

We conducted a scoping review in accordance with the Joanna Briggs Institute Manual and Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines. A comprehensive search was performed across major databases to identify studies that evaluated handheld tonometers, portable fundus cameras and visual field testing devices. Data were extracted on study design, population characteristics, devices used, comparators and reported outcomes.

A total of 216 studies published between 1975 and 2024 were included. Most studies (90.3%) were method agreement studies, primarily focused on intraocular pressure (IOP) devices. Only two studies evaluated all three glaucoma assessment domains (IOP, visual fields and fundus imaging). Most studies were conducted in high-income countries, with a smaller number from low- and middle-income countries. Despite variability in performance, many devices demonstrated acceptable agreement with gold standard methods and were assessed in a range of clinical and community settings.

This review highlights the range and characteristics of portable glaucoma devices and their potential for enhancing access to diagnosis and monitoring, particularly in underserved settings. However, the predominance of method agreement studies and the limited integration of multimodal assessments point to gaps in the literature. Future research should focus on comprehensive diagnostic pathways using multiple portable tools and on expanding evaluations in low-resource settings to inform policy and service planning.

Home-based physiotherapy is a current approach to manage knee osteoarthritis (OA). However, adherence to physiotherapy is poor. Non-immersive virtual reality (VR) has shown promise in improving self-efficacy and adherence in other clinical conditions. A non-immersive VR-based home physiotherapy system named Sensor-based Physiotherapy Intervention with Virtual Reality (SPIN-VR) for knee OA has been developed, integrating physiotherapy exercises into engaging games that adjust in difficulty based on real-time performance. This approach aims to enhance exercise adherence by making physiotherapy more enjoyable and personalised. To evaluate the feasibility of this intervention, a randomised controlled trial is being conducted.

This single-centre, open-label, randomised controlled feasibility trial will evaluate the SPIN-VR system over 12 weeks compared with usual care physiotherapy for knee OA. 50 participants will be randomly assigned to either the SPIN-VR or usual care group, with follow-ups at 12 and 24 weeks post randomisation. The primary outcomes will be a description of feasibility of recruitment, patient willingness to be randomised, the completeness of outcome measures and patient adherence to the intervention. Secondary outcomes include evaluations of muscle strength, endurance, aerobic capacity, exercise technique, central pain processing and self-reported pain mechanisms and moderators. Participants in the intervention arm will be interviewed after 12 weeks to capture their experience in using the VR system.

This protocol was approved by the Wales Research Ethics Committee 3. Research findings will be disseminated in open-access peer-reviewed journals, to researchers and health professionals through conference presentations, to patients and the public by organising webinars and a seminar.

NCT06639867.