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Dysregulated immune proteins in plasma in the UK Biobank predict Multiple Myeloma 12 years before clinical diagnosis.

Bridging the generalisation gap: synthetic data generation for multi-site clinical model validation

Ensuring the generalisability of clinical machine learning (ML) models across diverse healthcare settings remains a significant challenge due to variability in patient demographics, disease prevalence, and institutional practices. Existing model evaluation approaches often rely on real-world datasets, which are limited in availability, embed confounding biases, and lack the flexibility needed for systematic experimentation. Furthermore, while generative models aim for statistical realism, they often lack transparency and explicit control over factors driving distributional shifts. In this work, we propose a novel structured synthetic data framework designed for the controlled benchmarking of model robustness, fairness, and generalisability. Unlike approaches focused solely on mimicking observed data, our framework provides explicit control over the data generating process, including site-specific prevalence variations, hierarchical subgroup effects, and structured feature interactions. This enables targeted investigation into how models respond to specific distributional shifts and potential biases. Through controlled experiments, we demonstrate the framework’s ability to isolate the impact of site variations, support fairness-aware audits, and reveal generalisation failures, particularly highlighting how model complexity interacts with site-specific effects. This work contributes a reproducible, interpretable, and configurable tool designed to advance the reliable deployment of ML in clinical settings.

Individualised treatment effects estimation with composite treatments and composite outcomes

Estimating individualised treatment effect (ITE) – that is the causal effect of a set of variables (also called exposures, treatments, actions, policies, or interventions), referred to as composite treatments, on a set of outcome variables of interest, referred to as composite outcomes, for a unit from observational data – remains a fundamental problem in causal inference with applications across disciplines, such as healthcare, economics, education, social science, marketing, and computer science. Previous work in causal machine learning for ITE estimation is limited to simple settings, like single treatments and single outcomes. This hinders their use in complex real-world scenarios; for example, consider studying the effect of different ICU interventions, such as beta-blockers and statins for a patient admitted for heart surgery, on different outcomes of interest such as atrial fibrillation and in-hospital mortality. The limited research into composite treatments and outcomes is primarily due to data scarcity for all treatments and outcomes. To address the above challenges, we propose a novel and innovative hypernetwork-based approach, called HLearner, to solve ITE estimation under composite treatments and composite outcomes, which tackles the data scarcity issue by dynamically sharing information across treatments and outcomes. Our empirical analysis with binary and arbitrary composite treatments and outcomes demonstrates the effectiveness of the proposed approach compared to existing methods. To address the above challenges, we propose a novel and innovative hypernetwork-based approach, called H-Learner, to solve ITE estimation under composite treatments and composite outcomes, which tackles the data scarcity issue by dynamically sharing information across treatments and outcomes. Our empirical analysis with binary and arbitrary composite treatments and outcomes demonstrates the effectiveness of the proposed approach compared to existing methods.

Application of large language models in medicine

Large language models (LLMs), such as ChatGPT, have received great attention owing to their capabilities for understanding and generating human language. Despite a trend in researching the application of LLMs in supporting different medical tasks (such as enhancing clinical diagnostics and providing medical education), a comprehensive assessment of their development, practical applications and outcomes in the medical space is still missing. Therefore, this Review aims to provide an overview of the development and deployment of LLMs in medicine, including the challenges and opportunities they face. In terms of development, we discuss the principles of existing medical LLMs, including their basic model structures, number of parameters, and sources and scales of data used for model development. In terms of deployment, we compare different LLMs across various medical tasks and with state-of-the-art lightweight models.

Individualised Treatment Effects Estimation with Composite Treatments and Composite Outcomes

A Survey of Large Language Models in Medicine: Progress, Application, and Challenge

Enhanced recovery programmes in knee arthroplasty: current concepts

The concept of a multimodal approach to improve the care of surgical patients was first proposed by Kehlet in the 1990s. Measures to optimise the surgical patient, and minimise perioperative stresses, aimed to improve postoperative outcomes. Although originally introduced in colorectal surgery, these ‘enhanced recovery programmes’ have now seen widespread uptake in multiple surgical specialities, including orthopaedics. Patients undergoing knee arthroplasty are well suited to an enhanced recovery approach. These programmes optimise the patient at each stage of the surgical journey, including preoperative optimisation of fitness, perioperative anaesthetic and surgical techniques and finally postoperative rehabilitation and discharge plans. The available evidence supports a number of improvements after programme introduction, including shorter length of stay, morbidity and economics. However, the impact on other outcomes is less clear. One of the issues in the field is a lack of consensus on what interventions an enhanced recovery programme should contain and the specifics of these interventions. As a result, individual units develop their own programmes, making the interpretation and comparison of their impact difficult. This article discusses interventions that could be considered for inclusion in an enhanced recovery programme for knee arthroplasty.

Higher surgeon volume reduces early failure in first time revision of non-infected total knee arthroplasty: An analysis using data from the United Kingdom National Joint Registry.

PURPOSE: Revision total knee replacement (RevKR) is an increasingly common procedure. It is hypothesised that higher surgical volume is linked to lower levels of adverse outcomes. The aim was to estimate the association of surgical volume on patient outcomes following first single-stage RevKR for non-infected indications. METHODS: This population-based cohort study used data from the United Kingdom National Joint Registry, Hospital Episode Statistics and National Patient Reported Outcome Measures. Patients undergoing procedures between 1 January 2009 and 30 June 2019 were included. The primary outcome measure was re-revision within 2 years; chosen to reflect the quality of the surgical provision. Fixed effect multivariable regression models were used to examine the association between surgeon and surgical unit annual caseload and the risk of adverse outcomes. RESULTS: A total of 8695 patients underwent first time single stage revision for aseptic loosening, instability, or malalignment across 389 surgical units and 1204 surgeons. Following adjustment for age, gender, ASA grade, year of surgery and operation funder, higher surgeon volume was associated with a lower risk of re-revision at 2 years. The risk of re-revision decreased amongst surgeons performing ≥9 annual revisions (OR 0.77, 95% CI 0.62-0.95, p-value = 0.02) compared to those performing <9 annual revisions. CONCLUSIONS: Annual surgeon case volume of ≥9 first single-stage RevKR for non-infected indications is independently associated with reductions in early re-revision. This evidence supports the setting of minimum volume targets to improve outcomes for patients. LEVEL OF EVIDENCE: Level III, retrospective cohort study of prospectively collected data.

Threaded rods versus arthrodesis nail as a static spacer for two-stage revision total knee arthroplasty.

INTRODUCTION: A spacer is required to maintain limb length and alignment and to provide a stable limb for mobilisation in two-stage revision total knee arthroplasty (rTKA) for periprosthetic joint infection (PJI). Static spacers are indicated in cases of massive bone loss, compromised soft tissues, and ligamentous and/or extensor mechanism insufficiency. The aim of this study was to compare the use of Ilizarov rods to arthrodesis nails for static spacer constructs in first-stage rTKA for PJI. METHODS: This was a retrospective cohort study of 40 patients who underwent two-stage rTKA for PJI between 2019 and 2022. Static spacers were used in all cases, constructed from Ilizarov rods 20 patients and nails in 20 patients. Data collected included number of previous revisions, patient age at first revision, comorbidities and identified organisms. Groups were compared based on outcome measures including complications, reoperations, length of stay and re-revision rates. RESULTS: The use of Ilizarov rods showed higher rates of intraoperative complications (5% vs. 0%), readmissions (55% vs. 5%), and interstage re-operations (50% vs. 10%). Spacer-related complications occurred in 10 of 20 cases (50%) in the Ilizarov rod group, all due to spacer fractures, compared to none in the nail group (0%) (p 

Improving the completeness and transparency of protocols and reports of randomized trials: SPIRIT 2025 and CONSORT 2025.

We developed SPIRIT 2025 and CONSORT 2025 together and in a similar manner. To ascertain new evidence to inform both updates we completed two scoping reviews. The results of the scoping reviews helped inform the SPIRIT and CONSORT Delphis. Following two Delphi rounds and an international online consensus meeting, draft checklists for both reporting guidelines were drafted. SPIRIT 2025 contains a 34-item checklist. Compared to the original SPIRT 2013 reporting guideline, SPIRIT 2025 include the addition of two new items, revisions to five, and the deletion or merging of five, alongside a new Open Science section. Emphasis on harm assessment, intervention description, and patient/public involvement was also strengthened. CONSORT 2025, compared to CONSORT 2010, is a 30-item checklist with seven new items, three revised, and one deleted, with content integrated from existing CONSORT extensions - Harms, Outcomes, Non-pharmacological Treatment, and TIDieR. As with SPIRIT 2025, CONSORT 2025 also includes a new open science section. Both reporting guidelines also include updated extensive explanation and elaboration papers meant to be pedagogical assistants to facilitate the use of both reporting guidelines. Widespread adoption of SPIRIT 2025 and CONSORT 2025 by investigators, funders, ethics committees, journals, and regulators should improve the quality and usability of research, ultimately benefiting patients and the broader research ecosystem.

An Integrated Education and Exercise Programme for Tamil People With Osteoarthritis Knee

<jats:title>ABSTRACT</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Osteoarthritis knee (OA knee) is a chronic joint condition associated with pain, disability and reduced quality of life. Guidelines recommend self‐management, patient education, behavioural support and tailored exercise as core components of non‐surgical treatment.</jats:p></jats:sec><jats:sec><jats:title>Purpose</jats:title><jats:p>To develop and evaluate an OA knee patient education booklet and a physiotherapist‐led integrated programme involving the core components of non‐surgical care to improve clinical outcomes in Tamil‐speaking people with OA knee of Tamil Nadu state (Population 72.1 million, 2011 census), India.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>A patient education booklet was developed through an iterative process and evaluated in 50 patients, carers, and physiotherapists. The impact of the integrated programme on knee pain, function, physical performance, and adherence was assessed at six weeks and during a follow‐up at six months.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The Tamil booklet was easy to read, useful and relevant. 31 patients (26 women; 5 men, average age 60.4 years) took part in the integrated programme. Improvements in pain, function and performance measures were statistically significant and clinically meaningful. The majority of them found the programme useful and satisfactory and reported that their condition improved. There were no adverse events.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Our Tamil OA knee education booklet was deemed relevant and useful. The integrated education and exercise programme was feasible and acceptable and our findings provided preliminary evidence on its clinical benefits in people with OA knee.</jats:p></jats:sec>

Molnupiravir or nirmatrelvir-ritonavir plus usual care versus usual care alone in patients admitted to hospital with COVID-19: a randomised, controlled, open-label, platform trial (RECOVERY)

Modifiable lifestyle factors and the risk of post-COVID-19 multisystem sequelae, hospitalization, and death.

Effective prevention strategies for post-COVID complications are crucial for patients, clinicians, and policy makers to mitigate their cumulative burden. This study evaluated the association of modifiable lifestyle factors (smoking, alcohol intake, BMI, physical activity, sedentary time, sleep duration, and dietary habits) with COVID-19 multisystem sequelae, death, and hospitalization in the UK Biobank cohort (n = 68,896). A favorable lifestyle (6-10 healthy factors; 46.4%) was associated with a 36% lower risk of multisystem sequelae (HR, 0.64; 95% CI, 0.58-0.69; ARR at 210 days, 7.08%; 95% CI, 5.98-8.09) compared to an unfavorable lifestyle (0-4 factors; 12.3%). Risk reductions spanned all 10 organ systems, including cardiovascular, coagulation, metabolic, gastrointestinal, kidney, mental health, musculoskeletal, respiratory disorders, and fatigue. This beneficial effect was largely attributable to direct lifestyle impacts independent of corresponding pre-infection comorbidities (71% for any sequelae). A favorable lifestyle was also related to the risk of post-COVID death (HR 0.59, 0.52-0.66) and hospitalization (HR 0.78, 0.73-0.84). These associations persisted across acute and post-acute infection phases, irrespective of hospitalization status, vaccination, or SARS-CoV-2 variant. These findings underscore the clinical and public health importance of adhering to a healthy lifestyle in mitigating long-term COVID-19 adverse impacts and enhancing future pandemic preparedness.

Relationship between HLA genetic variations, COVID-19 vaccine antibody response, and risk of breakthrough outcomes.

The rapid global distribution of COVID-19 vaccines, with over a billion doses administered, has been unprecedented. However, in comparison to most identified clinical determinants, the implications of individual genetic factors on antibody responses post-COVID-19 vaccination for breakthrough outcomes remain elusive. Here, we conducted a population-based study including 357,806 vaccinated participants with high-resolution HLA genotyping data, and a subset of 175,000 with antibody serology test results. We confirmed prior findings that single nucleotide polymorphisms associated with antibody response are predominantly located in the Major Histocompatibility Complex region, with the expansive HLA-DQB1*06 gene alleles linked to improved antibody responses. However, our results did not support the claim that this mutation alone can significantly reduce COVID-19 risk in the general population. In addition, we discovered and validated six HLA alleles (A*03:01, C*16:01, DQA1*01:02, DQA1*01:01, DRB3*01:01, and DPB1*10:01) that independently influence antibody responses and demonstrated a combined effect across HLA genes on the risk of breakthrough COVID-19 outcomes. Lastly, we estimated that COVID-19 vaccine-induced antibody positivity provides approximately 20% protection against infection and 50% protection against severity. These findings have immediate implications for functional studies on HLA molecules and can inform future personalised vaccination strategies.

Thalamic deep brain stimulation for central poststroke pain syndrome: an international multicenter study.

OBJECTIVE: The effectiveness and optimal stimulation site of deep brain stimulation (DBS) for central poststroke pain (CPSP) remain elusive. The objective of this retrospective international multicenter study was to assess clinical as well as neuroimaging-based predictors of long-term outcomes after DBS for CPSP. METHODS: The authors analyzed patient-based clinical and neuroimaging data of previously published and unpublished cohorts from 6 international DBS centers. DBS leads were reconstructed and normalized. A stimulation map was constructed on the basis of individual stimulation settings and associated outcomes. Furthermore, the authors projected the individual segmented stroke lesions and volumes of tissue activated (VTAs) of the stimulating electrode onto a normalized human connectome to obtain the connectivity profiles of the individual lesions and VTAs. RESULTS: The authors analyzed the data of 54 patients, of whom 15 were excluded from the final analysis due to a lack of imaging data. Among the remaining 39 patients from 6 different cohorts, the authors found 14 (35.9%) responders who were defined by pain relief of at least 50% at 12-month follow-up. Stimulation mapping identified areas in the posterior limb of the internal capsule, the sensorimotor thalamus, and the medial and intralaminar thalamus as effective for pain reduction. Baseline characteristics did not differ between responders and nonresponders. The stimulation sites of the responders showed significantly reduced structural connectivity to the sensory areas of the cerebral cortex compared to nonresponders. CONCLUSIONS: This comprehensive, multicenter analysis corroborates the efficacy of DBS in treating CPSP for a relevant number of patients. The posterior limb of the internal capsule and the sensorimotor thalamus emerged as potential stimulation sweet spots. The difference in structural connectivity between responders and nonresponders may constitute a biomarker of effective stimulation that can help guide surgical planning in future well-designed prospective trials.

Development of the rehabilitation interventions for people with an acute patellar dislocation in the Physiotherapy Rehabilitation Post Patellar Dislocation (PRePPeD) pilot randomized controlled trial.

AIMS: To develop the rehabilitation interventions for people with an acute patellar dislocation in the Physiotherapy Rehabilitation Post Patellar Dislocation (PRePPeD) pilot randomized controlled trial (RCT), and to describe how these interventions are delivered. METHODS: We developed the interventions drawing on a range of established intervention development approaches and frameworks. We selected intervention components after reviewing the existing evidence, clinical guidelines, UK NHS practice, and relevant scientific theory. We then created early versions of the interventions, and discussed these with clinical experts and patient and public partners. We finalized the interventions considering their feedback, findings from our preliminary study, and what would be acceptable and deliverable in the UK NHS. RESULTS: Upon randomization, all participants receive a workbook containing advice and initial exercises to implement before their first physiotherapy session. Self-managed rehabilitation then involves a single one-to-one session with a physiotherapist who provides advice, introduces a structured home exercise programme, and uses strategies to support exercise adherence. Participants then continue their recovery independently. Supervised rehabilitation involves four to six one-to-one physiotherapy sessions over a maximum of six months. Physiotherapists also provide advice, prescribe home exercise, and use exercise adherence strategies. Routine follow-up sessions enable physiotherapists to reassess participants and tailor the advice and exercises accordingly. CONCLUSION: The interventions were developed and are currently being assessed in the PRePPeD pilot RCT. This will determine whether a full-scale RCT comparing these interventions is feasible. Results are anticipated in Summer 2025.

The burden of hand trauma surgery on primary care in the United Kingdom: a nation-wide analysis of antibiotic and opioid prescriptions.

Although surgical site infection (SSI) risk after hand trauma surgery is around 5%, the severity of these infections is not known. The risk of superficial SSI in a cohort study was evaluated using NHS UK-wide primary care records (n = 641,223), using the Clinical Practice Research Datalink GOLD database. Within this cohort, a subcohort of those who had undergone a hand surgery operation for trauma were identified (n = 3,088). Antibiotic and analgesic prescriptions were analysed at 30 and 90 days postoperatively. By 30 days, 6.2% had been prescribed antibiotics appropriate for SSI, rising to 14.4% (CI [13.2 to 15.8]) by 90 days. By 30 days, 10% had been prescribed opioid analgaesia and by 90 days this had increased to 13.8%. Antibiotics prescriptions for SSI in primary care are substantially higher than the NICE estimate for SSI overall and the expected risk in hand trauma. The implications of this study are that many patients are receiving treatment for SSI in primary care and may be in more pain, for longer, than we expect. Further exploration of this is warranted and future research in hand trauma surgery should capture adverse events occurring outside of the hospital environment.Level of evidence: II.

Defining an ageing-related pathology, disease or syndrome: International Consensus Statement.

Around the world, individuals are living longer, but an increased average lifespan does not always equate to an increased health span. With advancing age, the increased prevalence of ageing-related diseases can have a significant impact on health status, functional capacity and quality of life. It is therefore vital to develop comprehensive classification and staging systems for ageing-related pathologies, diseases and syndromes. This will allow societies to better identify, quantify, understand and meet the healthcare, workforce, well-being and socioeconomic needs of ageing populations, whilst supporting the development and utilisation of interventions to prevent or to slow, halt or reverse the progression of ageing-related pathologies. The foundation for developing such classification and staging systems is to define the scope of what constitutes an ageing-related pathology, disease or syndrome. To this end, a consensus meeting was hosted by the International Consortium to Classify Ageing-Related Pathologies (ICCARP), on February 19, 2024, in Cardiff, UK, and was attended by 150 recognised experts. Discussions and voting were centred on provisional criteria that had been distributed prior to the meeting. The participants debated and voted on these. Each criterion required a consensus agreement of ≥ 70% for approval. The accepted criteria for an ageing-related pathology, disease or syndrome were (1) develops and/or progresses with increasing chronological age; (2) should be associated with, or contribute to, functional decline or an increased susceptibility to functional decline and (3) evidenced by studies in humans. Criteria for an ageing-related pathology, disease or syndrome have been agreed by an international consortium of subject experts. These criteria will now be used by the ICCARP for the classification and ultimately staging of ageing-related pathologies, diseases and syndromes.

T cell phenotypes in COVID-19 - a living review.

COVID-19 is characterized by profound lymphopenia in the peripheral blood, and the remaining T cells display altered phenotypes, characterized by a spectrum of activation and exhaustion. However, antigen-specific T cell responses are emerging as a crucial mechanism for both clearance of the virus and as the most likely route to long-lasting immune memory that would protect against re-infection. Therefore, T cell responses are also of considerable interest in vaccine development. Furthermore, persistent alterations in T cell subset composition and function post-infection have important implications for patients' long-term immune function. In this review, we examine T cell phenotypes, including those of innate T cells, in both peripheral blood and lungs, and consider how key markers of activation and exhaustion correlate with, and may be able to predict, disease severity. We focus on SARS-CoV-2-specific T cells to elucidate markers that may indicate formation of antigen-specific T cell memory. We also examine peripheral T cell phenotypes in recovery and the likelihood of long-lasting immune disruption. Finally, we discuss T cell phenotypes in the lung as important drivers of both virus clearance and tissue damage. As our knowledge of the adaptive immune response to COVID-19 rapidly evolves, it has become clear that while some areas of the T cell response have been investigated in some detail, others, such as the T cell response in children remain largely unexplored. Therefore, this review will also highlight areas where T cell phenotypes require urgent characterisation.

2023 EULAR recommendations for the management of fatigue in people with inflammatory rheumatic and musculoskeletal diseases.

OBJECTIVES: Fatigue is prevalent in people with inflammatory rheumatic and musculoskeletal diseases (I-RMDs) and recognised as one of the most challenging symptoms to manage. The existence of multiple factors associated with driving and maintaining fatigue, and the evidence about what improves fatigue has led to a multifaceted approach to its management. However, there are no recommendations for fatigue management in people with I-RMDs. This lack of guidance is challenging for those living with fatigue and health professionals delivering clinical care. Therefore, our aim was to develop EULAR recommendations for the management of fatigue in people with I-RMDs. METHODS: A multidisciplinary taskforce comprising 26 members from 14 European countries was convened, and two systematic reviews were conducted. The taskforce developed the recommendations based on the systematic review of evidence supplemented with taskforce members' experience of fatigue in I-RMDs. RESULTS: Four overarching principles (OAPs) and four recommendations were developed. OAPs include health professionals' awareness that fatigue encompasses multiple biological, psychological and social factors which should inform clinical care. Fatigue should be monitored and assessed, and people with I-RMDs should be offered management options. Recommendations include offering tailored physical activity and/or tailored psychoeducational interventions and/or, if clinically indicated, immunomodulatory treatment initiation or change. Patient-centred fatigue management should consider the individual's needs and preferences, their clinical disease activity, comorbidities and other psychosocial and contextual factors through shared decision-making. CONCLUSIONS: These 2023 EULAR recommendations provide consensus and up-to-date guidance on fatigue management in people with I-RMDs.