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.

To describe how care home staff experience bereavement and their perspectives on providing bereavement care within care home settings.

Qualitative descriptive study using focus groups analysed with the Framework Method.

Seven residential and nursing care homes for older adults in Scotland.

37 care home staff were recruited through the Enabling Research In Care Homes (ENRICH) Scotland research network. Participants included registered nurses, care workers, senior care workers, managers and ancillary workers with experience of resident death and bereavement practice.

Bereavement was woven through everyday care home life, understood as a tapestry of experiences, relationships and practices that involved staff, residents and their relatives. Three themes that connected to the tapestry metaphor were identified: Warps: structural threads grounding bereavement within the culture of homely living, where close bonds normalise death and dying, and pragmatic acceptance. Wefts: strengthening practices nurturing resilience, including relational trust, mutual support, rituals and follow-up with relatives. Moths: disruptions undermining bereavement practice include family secrecy, hospital deaths with withheld information, difficulty supporting residents with advanced dementia and dissatisfaction with online training.

Bereavement in care homes is collective, relational and embedded in routine practice. Organisational recognition of grief improved interservice communication. Tailored reflective support for staff is needed to sustain compassionate care. Further research should explore how residents experience repeated exposure to death and bereavement within communal living environments.

Self-harm represents a significant public health concern and is a common reason for contact with urgent and emergency care (UEC) services among young people. Although young people frequently interact with multiple components of the urgent care system following self-harm, there is limited system-level evidence describing patterns of service use, transitions between services and repeat emergency department (ED) attendance. An improved understanding of how young people use UEC services after self-harm is needed to inform the design of more effective and appropriate care pathways.

This protocol describes a prospective cohort study using an extract from the Centre for URgent and Emergency care research database (CUREd+) research database, which comprises routinely collected, linked healthcare data from the National Health Service 111 (NHS 111), ambulance services, urgent care centres, walk-in centres and EDs across Yorkshire and the Humber, England. The study population will include young people aged ≤25 years presenting to UEC services between April 2019 and March 2022 with self-harm coded as the reason for attendance. Analyses will describe the prevalence of self-harm presentations across UEC settings, quantify the proportion of NHS 111 and ambulance contacts resulting in ED attendance within 24 hours and examine factors associated with ED reattendance at 3 and 12 months. Mixed-effects logistic regression models will be used to account for repeated attendances, confounding variables and temporal variation, including changes related to the COVID-19 pandemic. Anticipated analysis period: January 2026–January 2027.

Ethical approval has been granted by the University of Leeds (MREC 22-079 Amd1) and the University of Sheffield (Ref 068194). The CUREd+ research database operates under Research Ethics Committee approval (23/YH/0079) and Confidentiality Advisory Group approval (18/CAG/0126). Individual consent is not required as all data are pseudonymised at source. Findings will be disseminated through peer-reviewed publications, conference presentations and public-facing outputs coproduced with patient and public involvement groups.

Shared decision-making is widely advocated in policy and practice, but how it is to be applied in a high-stakes clinical decision such as major lower limb amputation due to chronic limb-threatening ischaemia or diabetic foot is unclear. The aim of this study was to explore the communication, consent, risk prediction and decision-making process in relation to major lower limb amputation.

A qualitative study (done as part of a broader mixed-methods study) using semi-structured interviews. Interview transcriptions were analysed using thematic analysis.

Vascular centres in three large National Health Service hospitals in Wales and England, UK, between 1 October 2020 and 30 September 2022.

A purposive sample of 18 patients for whom major lower limb amputation was considered as a treatment option/carried out, with interviews conducted before or within 4 months of amputation and 4–6 months after amputation. A further purposive sample of 20 healthcare professionals (including eight surgeons) involved in supporting or conducting major lower limb amputation decision-making.

Five major categories were identified that highlighted the challenges of ensuring shared decision-making associated with major lower limb amputation: (i) patients’ limited understanding, (ii) variable patient attitudes to decision-making, (iii) healthcare professionals’ perceived challenges to sharing decision-making, (iv) surgeons’ paternalism and (v) patients’ and healthcare professionals’ decisional regret/possible consequences of challenges.

Amputation is a life-changing decision for both patients and healthcare professionals, with huge consequences. Despite being considered the gold standard, our findings highlight several challenges to effective shared decision-making for major lower limb amputation. Shared decision-making training for healthcare professionals is paramount if these limitations are to be addressed and patients are to feel confident in being adequately informed about the treatment decisions that they make.

NCT04903756.

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/

Declined donor organs and explanted recipient organs may hold considerable value for biomedical research, particularly in advancing knowledge of disease mechanisms and supporting drug development. However, public perceptions of such use, and preferences for how consent should be obtained, remain underexplored.

Four workshops were held across the UK to examine the views of organ donor families and transplant recipients regarding the use of human organs in research, with a focus on myocardial regeneration. Each workshop included three brief presentations on transplantation and cardiac regeneration, followed by facilitated small-group discussions. Observational notes were taken to capture participants’ perspectives on the use of organs unsuitable for transplantation. A follow-up survey generated both quantitative and qualitative data, the latter analysed using thematic analysis.

Participants expressed strong support for the use of declined donor and explanted recipient organs in research. Transplant recipients frequently cited a desire to give back to the National Health Service (NHS), while donor families viewed research use as a meaningful way to honour their loved ones when transplantation was not possible.

This exploratory study highlights widespread support for using non-transplantable organs in research among individuals with personal experience of transplantation. The findings suggest a need for further research into how best to support and inform potential donors and families. Participants emphasised the importance of sensitive communication, clear consent processes and transparency regarding the use of donated organs.

National Immunization Technical Advisory Groups (NITAGs) are multidisciplinary groups of national experts who provide independent advice to policy makers on issues related to immunisation and vaccines, based on evidence and the national context. On the other hand, academic institutions can be described as organisations dedicated to education and research. These include schools, colleges, universities and research centres that offer formal education, conduct scholarly research and contribute to knowledge in various fields. NITAGs can enhance their capacity by linking with academic institutions and leveraging scientific expertise in research, data analysis, modelling, resource procurement and management, and policy formulation. The proposed landscape analysis will explore the links between NITAGs and academic institutions, especially in the sub-Saharan African context, and, where such exist, document their characteristics and identify benefits, challenges and best practices for fostering such linkages.

This landscape analysis will use an adaptation of the WHO’s quick guide manual on ‘Performing a landscape analysis: Understanding health product research and development’. The planned landscape analysis will be conducted in two parts. The first part will entail a review of published literature to identify relevant documents on linkages between NITAGs and academic institutions. The second part will entail conducting key informant interviews with NITAG members, partners and other identified key stakeholders in two study countries: Ethiopia and Zambia. The transcribed scripts will be thematically analysed. The findings from both parts will be synthesised and presented as a descriptive landscape analysis report.

The protocol of the parent study has been reviewed and approved by the Human Research Ethics Committee of the University of Cape Town (Reference 417/2025). It has also been approved by the Biomedical Research Ethics Committee of the University of Zambia (REF. NO. 6760-2025) and the Ethiopian Public Health Association (EPHA/06/392/25). The landscape analysis report will be submitted to the commissioning funder (Gavi, the Vaccine Alliance) and will also be published in a peer-reviewed journal.

https://osf.io/vprka

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.

Frequent use of emergency departments (EDs) places a considerable burden on healthcare systems. Although frequent attenders are known to have complex physical, mental health and social needs, national-level evidence on their characteristics and patterns of attendance remains limited. This study aimed to provide a comprehensive, population-level description of frequent ED attendance in England, with a focus on age-based subgroups.

Retrospective cohort study.

EDs in England via the Hospital Episode Statistics and the Emergency Care Dataset data linked with primary care prescribing and mortality data, between March 2016 and March 2021.

The dataset received from National Health Service Digital contained approximately 150 million ED attendances by 30 million adult (>18 years) patients over the time period April 2016 to March 2021. A random sample of 5 million people was used for this analysis.

The primary outcome was the number of attendances in each financial year by frequent attenders compared with the remaining patients, split by age bands. Patients were classified as frequent attenders if they had ≥5 or ≥10 ED attendances within a rolling 12-month period. Secondary outcomes included demographic, diagnostic and prescribing characteristics, as well as the number of different ED sites visited.

A Gaussian mixture model was used to identify age-based subgroups. Descriptive statistics were used to summarise key features; 95% CIs were reported where applicable. Among 3.91 million unique adult ED attenders, there were 8.7 million attendances. Of these, 222 160 individuals (5.7%) had ≥5 attendances in a year, accounting for 12.6% of total attendances. A trimodal age distribution was identified, with three distinct peaks corresponding to ages 18–34, 35–64 and 65+. Frequent attenders were more likely to live in deprived areas and have a history of psychotropic or analgesic prescribing. Mental health diagnoses and polypharmacy were particularly common in the younger and middle-aged groups. Multisite attendance was uncommon, with over 80% of frequent attenders using only one ED site annually.

This national analysis reveals a trimodal age pattern among frequent ED attenders, with differing clinical and socio-demographic profiles across age groups. These findings highlight the need for age-tailored approaches to managing high-intensity ED use and inform targeted service development.

Aphasia is a language impairment that affects one-third of people who experience a stroke. Aphasia can impact all facets of language: speaking, understanding, reading and writing. Around 60% of people with aphasia have persistent language impairments 1 year after their stroke, requiring ongoing healthcare and support. In recent years, the internet has become a key resource for the self-management of chronic health conditions. Navigating web content, however, requires language use, and as such, people living with aphasia are more likely to be excluded from digital health and support services. Web Content Accessibility Guidelines exist; however, they do not fully address the unique and diverse needs of people with aphasia, and a significant proportion of websites (over 90%) do not fully adhere to them. This protocol paper describes the first two stages of the Bridging the Digital Divide project, which aims to codesign and develop (a) a web-browser extension to re-render webpages to an ‘aphasia-friendly’ (accessible) format, (b) training tools to help users and health professionals customise the web-browser extension and (c) guidelines for developing communication-accessible websites.

The research will be conducted using experience-based codesign. In Stage 1a, focus groups will be held with (1) people with aphasia, (2) family members or significant others and (3) health professionals working with people with aphasia. Participants will be asked to share their experiences of accessing (or supporting a person with aphasia to access) healthcare, information and support services on the web. The nominal group technique (NGT) will be used to identify priorities for improving web accessibility for people with aphasia. Focus group data will be analysed using reflexive thematic analysis, and prioritisation data will be analysed using inductive qualitative content analysis. In Stage 1b, eight codesign workshops will be held with representatives of the three key stakeholder groups to iteratively codesign and develop a web-browser extension, training tools and guidelines to support web accessibility.

Ethical clearance for Stage 1a and Stage 1b of this project has been approved by the University of Queensland Human Research Ethics Committee (Stage 1a approval number: 2023/HE000528, Stage 1b approval number: 2024/HE000721). The outcomes of this research will be disseminated in peer-reviewed journals and presented at national and international conferences. A dissemination and celebration event will be held at the completion of the project.

Food intolerances are prevalent in Europe and can cause considerable physical discomfort, dietary restrictions and psychosocial challenges. Among the prominent causes of food intolerance are defects in the digestion and/or transport of short-chain fermentable carbohydrates, fermentable oligo-, di-, monosaccharides and polyols (FODMAPs). A common diagnostic tool for food intolerance is the hydrogen breath test, which monitors the production of H₂ gas from the fermentation of ingested FODMAPs by colonic microbiota. However, this method is limited due to its relatively poor correlation with gastrointestinal (GI) symptoms experienced by patients. Diagnosis is complicated as food intolerance is often associated with functional GI disorders, while FODMAPs may exert their effects individually or in combination. Further research on the pathophysiology and the impact of intervention strategies for these conditions is required to improve the diagnosis of food intolerance.

The Lactobreath pilot study is a randomised, two-arm, double-blinded controlled study. 120 healthy, free-living adults will undergo 6-hour postprandial tests with lactose or glucose (control) to investigate the molecular composition of human exhaled breath (exhalome) as a potential source of biomarkers associated with clinical and metabolic traits of lactose malabsorption (Lactobreath profiles). This serves as a proof-of-concept for the future application of this technology in diagnosing food intolerance. We will use a sensitive, non-invasive, real-time measurement technique based on secondary electrospray ionisation coupled with high-resolution mass spectrometry to analyse the chemical profile of the postprandial exhalome after lactose ingestion. Symptoms of lactose intolerance will be assessed using a standardised questionnaire and mechanistically linked to specific key metabolites of the discriminating breath profile. In parallel, a solid-state sensor will measure postprandial hydrogen gas in breath samples, while GI gases (CH₄, H₂, O₂) and intestinal transit time will be monitored using a novel ingestible gas sensor (Atmo Gas capsule). Metabolites in urine, including lactose-derived metabolites, will be investigated using gas chromatography coupled with mass spectrometry. Postprandial bowel sounds will be recorded by wearable sensors (DigeHealth AG). Baseline assessments will be completed before the dietary challenge to capture usual dietary intake (repeated 24-hour recall), faecal microbiota (shallow shotgun sequencing) and to evaluate genetic polymorphisms using saliva samples (PCR analysis of selected penetrant single-nucleotide polymorphisms).

The Lactobreath study has been approved by the Ethics Committee of the Canton of Zurich, Switzerland (#2023-01639). The project results will be published in open-access journals, presented at national and international conferences and communicated to the public and other relevant stakeholders via the communication channels of all investigators and partners. All results derived from the study will be accessible, in line with the Swiss National Science Foundation open access policy.

NCT06177938.

Acute low back pain (LBP) is a prevalent condition with various non-surgical treatment options, yet no comprehensive network meta-analysis has systematically compared their relative efficacy for pain and disability. This study aims to fill that gap by synthesising available evidence on the efficacy of different types of non-surgical interventions for acute LBP, such as various medications, manual therapies and education-based therapies. Our coprimary objectives are to (1) compare each active treatment to an inert reference for measures of LBP and related disability and (2) rank the efficacy of treatments.

We will conduct a systematic search across multiple databases, including grey literature, to identify randomised controlled trials evaluating non-surgical treatments for acute LBP. Eligible studies must report on pain and/or disability outcomes in adults. The risk of bias will be assessed using the Risk of Bias tool, and the certainty of evidence will be graded using CINeMA (Confidence in Network Meta-Analysis). We will use a frequentist network meta-analysis to pool standardised mean differences in pain and disability, employing random-effects models to account for heterogeneity. A qualitative analysis will assess study characteristics and transitivity, while a quantitative analysis will evaluate efficacy and inconsistency. Results will be presented using network geometry, p-scores, forest plots, funnel plots, Egger’s test, Q-statistics and league tables to visualise both direct and indirect evidence and to identify potential biases.

This review protocol does not involve any primary research with human participants, animal subjects or medical record review. Consequently, this work did not require approval from an institutional review board or ethics committee. Results will be submitted to a peer-reviewed journal and presented at conference(s). De-identified data will be made available in a public repository.

International consensus guidelines support the initial administration of 30 mL/kg of intravenous fluids for haemodynamic resuscitation of newly diagnosed septic shock. Practice variation exists between the volume of fluids administered and timing of vasopressor commencement. The optimal approach in patients with septic shock is uncertain.

Australasian Resuscitation In Sepsis Evaluation: FLUid or vasopressors In emergency Department Sepsis is a 1000-participant multicentre, randomised, open-label, parallel group clinical trial conducted in patients with septic shock presenting to the emergency department in participating sites in Australia, New Zealand and Ireland. Participants are randomised (1:1) to either restricted fluids and early vasopressors or a larger initial intravenous fluid volume and later vasopressors. The primary outcome is days alive and out of hospital at day 90 postrandomisation. Secondary outcomes are all-cause mortality at day 90, time from randomisation until death (to day 90), days alive and at home at day 90 and ventilator-free, vasopressor-free and renal replacement-free days to day 28 postrandomisation and death or disability at 6-month and 12-month postrandomisation. Health-related quality of life will be assessed at day 180 and 12 months following randomisation.

The study was approved by Northern Sydney Local Health District Human Research Ethics Committee (HREC2020/ETH02874) on 21 January 2021. Patients will be enrolled under a waiver of prior consent. The patient or next-of-kin (or equivalent according to local jurisdiction) is approached at the first available opportunity and given a trial information sheet. According to local approvals, the patient or next-of-kin chooses to either continue in the trial or opt-out/decline continued participation. Results will be disseminated in peer-reviewed journals and presented at academic conferences.

NCT04569942