Queen Elizabeth Hospital King's Lynn NHS Foundation Trust

Megakaryocytes, the platelet precursors, have been known to populate tissues other than the bone marrow, most prominently the lung, but also the liver and spleen. Work in myeloproliferative neoplasms has established that dysplastic megakaryocytes are central organisers of the fibrosis in the bone marrow. In this commentary, we frame a hypothesis-gathering question as to whether megakaryocytes might analogously act as context-dependent contributors to organ fibrosis outside the marrow. In the lung, studies have identified resident/trafficking megakaryocytes with inflammatory properties, while in the liver, megakaryocytes-rich extramedullary foci often co-localise with periportal and perisinusoidal fibrosis. Approved agents for idiopathic pulmonary fibrosis act on broad growth-factor pathways across multiple cell types that may overlapwith the megakaryocytes/platelet secretome. It is thus possible that megakaryocytes may play a contributory role in organ fibrosis. We acknowledge that these observations are associative and preclinical, and that established epithelial-mesenchymal mechanisms remain central in organ fibrosis. We therefore do not assert that megakaryocytes are contributors of organ fibrosis. Rather, we pose this as a testable question prompted by converging yet incomplete evidence.

Background: Large language models (LLMs) now achieve performance comparable to senior postgraduate trainees on orthopaedic examinations and are increasingly trusted by clinicians to provide explanations for educational and decision-support purposes. However, correct answers do not necessarily indicate sound reasoning or reliable referencing. Current evaluations in this field emphasise accuracy alone, ignoring the quality and evidentiary reliability of the reasoning process.Aim: This study aimed to systematically evaluate the relationship between answer accuracy, reasoning quality, and reference reliability in the latest generation of LLMs applied to a standardised postgraduate orthopaedic examination.Methods: The 2024 Orthopaedic In-Training Examination (OITE; 203 questions) was administered to GPT-5 (OpenAI, San Francisco, CA, USA). The model was prompted to provide one answer, a brief rationale, and one supporting reference per question. Accuracy and percentile were recorded relative to official American Academy of Orthopaedic Surgeons (AAOS) data. A structured subsample of 88 responses (44 correct, 44 incorrect) underwent detailed validation of referencing and reasoning. GPT-5's reasoning was compared against official AAOS answer explanations for each question. Reasoning quality was scored using a three-point ordinal scale. References were categorised as fabricated, misrepresented, or accurate. Hallucination rates and reasoning scores were compared between correct and incorrect answers.Results: GPT-5 achieved 78.3% accuracy (159/203), exceeding the OITE pass threshold (67%) and the mean postgraduate year-5 (PGY-5) resident score (73%), the highest accuracy reported, to our knowledge, among peer-reviewed studies to date. In the subset of 88 responses, hallucinations occurred in 33% overall, significantly higher in incorrect (50%) than in correct answers (15.9%; p=0.001). Reasoning among correct answers was consistently high (median 2.0, IQR 0.0), with 95.5% scoring maximum points, indicating reasoning entirely concordant with the reasoning provided by AAOS. Image-based questions showed lower accuracy (44.7%) compared with text-based questions (54%), though this difference was not statistically significant (p=0.52).Conclusions: GPT-5 appears to exceed previously reported LLM performance on the OITE and achieved accuracy higher than published mean scores for senior trainees, but demonstrated poor reference reliability, with one in three answers citing fabricated or misrepresented evidence. Even correct answers frequently relied on flawed or unverifiable sources. Evaluation of LLMs in medical education should incorporate systematic reasoning and evidence validation, not accuracy alone.

The Terminally Ill Adults (End of Life) Bill, recently passed at the House of Commons, aims to legalise assisted dying for terminally ill adults with six months or less to live in England and Wales. While framed as a compassionate reform promoting autonomy and dignity, legalising assisted dying amidst widespread underfunding of palliative care risks institutionalising inequity and pressuring vulnerable patients towards premature death. The systemic failures, ranging from inconsistent end-of-life care access to limited psychological and logistical safeguards, undermine the notion of true choice. Moreover, assisted dying introduces moral strain for clinicians, potential biases in eligibility decisions, and long-term risks of legislative expansion. Until universal, high-quality palliative care is guaranteed, the bill may function less as a humane option and more as a symptom of an overstretched, under-resourced health system failing its most vulnerable.

Background: Subclinical magnesium deficiency has emerged as a potential modifiable factor in cardiovascular disease (CVD) risk. Although previous studies have examined its association with adverse cardiovascular outcomes, findings remain inconsistent. This systematic review and meta-analysis aimed to evaluate the association between subclinical magnesium deficiency and the risk of major cardiovascular events. Methods: A comprehensive literature search was conducted using PubMed, Scopus, Embase, and Web of Science from January 2000 to March 2024. Observational studies assessing the relationship between subclinical magnesium deficiency and outcomes including coronary heart disease (CHD), sudden cardiac death (SCD), stroke, and cardiovascular mortality were included. Data extraction, quality assessment (using NOS and AXIS tools), and meta-analysis were performed according to PRISMA guidelines. Pooled hazard ratios (HRs) or odds ratios (Ors) with 95% confidence intervals (Cis) were calculated using a random-effects model. Results: Three studies with a total of 56,448 participants met the inclusion criteria. Subclinical magnesium deficiency was significantly associated with an increased risk of CHD mortality (HR = 1.36, 95% CI: 1.09–1.69), sudden cardiac death (HR = 1.54, 95% CI: 1.12–2.11), cardiovascular mortality (HR = 2.01, 95% CI: 1.49–2.71), and stroke incidence (OR = 1.96, 95% CI: 1.55–2.49). Additionally, each standard deviation increase in serum magnesium level was associated with 21% lower odds of composite cardiovascular events (OR = 0.79, 95% CI: 0.70–0.89). The included studies exhibited low statistical heterogeneity, and funnel plots showed no significant publication bias. Conclusion: This meta-analysis provides strong evidence that subclinical magnesium deficiency is independently associated with elevated risk of major cardiovascular events. Routine assessment of magnesium status may serve as a cost-effective tool for early identification of at-risk individuals. Further randomized trials are warranted to evaluate the therapeutic impact of magnesium supplementation in cardiovascular prevention.

89 Background: Darolutamide has authorisation for treatment of metastatic hormone sensitive prostate cancer (MHSPC) in combination with docetaxel chemotherapy and androgen deprivation therapy (triplet therapy) based on ARASENS trial results. The RECOMMEND study is a prospective real-world evaluation (RWE) of clinical outcomes in patients with MHSPC treated with this regimen in the UK. Methods: 318 patients were enrolled from 21 UK centres over 20 months from November 2022. Data cut-off was 14 August 2024. Disease characteristics were evaluated. Descriptive statistics have been used for patient demographics and PSA changes with treatment were analysed. Results: Patients on the study had a median age of 67 (range 38-84) years. Majority of the patients were de novo metastatic (91.2%). 68.2% have a Gleason score ≥8. 76 patients (23.9%) had next generation imaging (NGI) at diagnosis. Performance score was 0 (62.7%) or 1 (37.3%). The distribution of metastases (%) were: bone (84.9), nodal (60.4), lung (12.6) and liver (2.5). The median PSA level was 134 (range 1 to 5628) ng/mL at diagnosis. At the end of docetaxel chemotherapy median PSA was 0.35 ng/mL. PSA response see in the 226 patients who had completed 6 cycles of docetaxel chemotherapy at the data cut-off, PSA 50 was seen in 87.6% (198/226) and PSA 90 in 53.2%. PSA responses in those who only completed 4/5 cycles of docetaxel (n=14) did not significantly differ compared to those who completed all 6 cycles (PSA 50 p=0.445 and PSA 90 p-0.664). At 6 months from darolutamide initiation, quality of life (QoL) data is currently available for 173 patients, of these 88.4% reported either stable or improved QoL and 11.6% had a decline in QoL at the end of chemotherapy. Conclusions: The tolerability and efficacy profile of treatment with ADT+Darolutamide+Docetaxel in MHSPC in the RECOmMEnD study is similar to that reported in the ARASENS trial. The QoL data available for 173 patients to date reports either stable or improved QoL at 6 months for 88.4% cases. This provides important prospective RWE data, enabling patients and clinical teams to make informed choices in this setting.