Introduction 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.Methods and analysis 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).Ethics and dissemination 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).Trial registration number ISRCTN17176388.

Digital pathology enables large multi-center studies of histological specimens, but differences in staining protocols and slide quality can compromise the comparability of quantitative results. We analyzed 686 PicroSirius Red-stained liver biopsies from 4 independent cohorts spanning more than 20 clinical sites to assess how stain variability affects automated fibrosis quantification and model uncertainty. An U-Net ensemble was trained to segment collagen and to estimate pixel- and tile-level predictive uncertainty. Across markedly heterogeneous staining conditions, the ensemble achieved strong segmentation performance (Dice 0.83–0.90) and produced informative uncertainty maps that identified artifacts and out-of-distribution regions. Epistemic uncertainty values were typically below 0.002, providing a practical criterion for flagging unreliable predictions. Our results demonstrate that ensemble-based uncertainty estimation complements stain-standardization efforts by quantifying prediction confidence directly from model outputs, improving the reliability and interpretability of collagen proportionate-area measurements across multi-center datasets. This framework supports more trustworthy and reproducible digital-pathology workflows for fibrosis assessment and other histological applications.

BACKGROUND:Liver transplantation (LT) for hepatic adenomas has been described, but there are no set criteria for patient selection. A Fixed Term Working Group (FTWG), set up by the NHS Blood and Transplant (NHSBT) Liver Advisory Group (LAG), advised systematic work-up and using strict selection criteria as a national guideline. METHODS:Opinions were sought from patient representatives, expert hepatologists, histopathologists, liver transplant and hepatobiliary surgeons, and radiologists, all with expertise in adenoma management and familiarity with UK transplant pathways. The group discussed the wide range of radiological, histological, and clinical characteristics of HAs and formulated a set of core questions that address the clinical scenarios requiring consideration of liver transplantation, and thus developing appropriate patient selection criteria, referral and transplant listing pathways were identified. RESULTS:This paper summarises the selection criteria for LT in United Kingdom for HAs, and highlights the investigation framework, the work-up needed prior to transplant assessment and the referral pathway for LT. CONCLUSION:This manuscript details the protocol for the work-up, referral, streamlined and standardised selection of patients with HAs for LT and represents a significant development in the management of HA patients.

Introduction Primary sclerosing cholangitis (PSC) is a rare immune-mediated hepatobiliary disease, characterised by progressive biliary fibrosis, cirrhosis, and end-stage liver disease. As yet, no licensed pharmacological therapy exists. While significant advancements have been made in our understanding of the pathophysiology, the exact aetiology remains poorly defined. Compelling evidence from basic science and translational studies implicates the role of T helper 17 cells (Th17) and the interleukin 17 (IL-17) pro-inflammatory signalling pathway in the pathogenesis of PSC. However, exploration of the safety and efficacy of inhibiting the IL-17 pathway in PSC is lacking.Methods and analysis This is a phase 2a, open-label, multicentre pilot study, testing the safety of brodalumab, a recombinant human monoclonal antibody that binds with high affinity to interleukin-17RA, in adults with PSC. This study will enrol 20 PSC patients across five large National Health Service tertiary centres in the UK. The primary outcome of the study relates to determining the safety and feasibility of administering brodalumab in early, non-cirrhotic PSC patients. Secondary efficacy outcomes include non-invasive assessment of liver fibrosis, changes in alkaline phosphatase values and other liver biochemical readouts, assessment of biliary metrics through quantitative MR cholangiography+, and quality of life evaluation on completion of follow-up (using the 5D-itch tool, the PSC-patient-reported outcome and PSC-specific Chronic Liver Disease Questionnaire).Ethics and dissemination Ethical approval for this study has been obtained from the London Bridge Research Ethics Committee (REC23/LO/0718). Written informed consent will be obtained from all trial participants prior to undertaking any trial-specific examinations or investigations. On completion of the study, results will be submitted for publication in peer-reviewed journals and presented at national and international hepatology meetings. A summary of the findings will also be shared with participants and PSC communities.Trial registration number ISRCTN15271834.