Salford Royal Hospital

BackgroundBrepocitinib is a first-in-class, oral, selective TYK2–JAK1 inhibitor that blocks cytokine signaling, which has been implicated in dermatomyositis.MethodsIn this phase 3, double-blind, randomized, placebo-controlled trial, adults with dermatomyositis were assigned in a 1:1:1 ratio to receive once-daily oral brepocitinib at a dose of 30 mg, brepocitinib at a dose of 15 mg, or placebo for 52 weeks. Standard therapies were continued, and glucocorticoids were tapered. The primary end point was the Total Improvement Score, a validated composite myositis index (with scores ranging from 0 to 100 and higher scores indicating greater improvement) at week 52. Key secondary end points, including skin disease activity, glucocorticoid tapering, and physical function, were tested in a multiplicity-controlled sequence.ResultsA total of 241 patients underwent randomization: 81 to receive brepocitinib 30 mg, 81 to receive brepocitinib 15 mg, and 79 to receive placebo. At week 52, the mean Total Improvement Score was 46.5, 37.5, and 31.2, respectively (difference with brepocitinib 30 mg vs. placebo, 15.3; 95% confidence interval [CI], 6.7 to 24.0; P<0.001; difference with brepocitinib 15 mg vs. placebo, 6.3; 95% CI, −2.4 to 14.9). Brepocitinib 30 mg was superior to placebo across all nine key secondary end points, including skin disease activity, systemic glucocorticoid tapering, and functional disability, with improvements observed as early as week 4. Serious infections were more frequent in the brepocitinib 30-mg group than in the placebo group (10% vs. 1%). No deaths occurred during the trial.ConclusionsIn adults with dermatomyositis that was resistant to previous therapy, the use of brepocitinib at a dose of 30 mg (but not at a dose of 15 mg) resulted in significant benefits with respect to a composite myositis index, skin disease severity, glucocorticoid tapering, and functional disability. (Funded by Priovant Therapeutics; ClinicalTrials.gov number, NCT05437263.)

As a group, patients with classic galactosemia (CG) demonstrate a high prevalence of long-term complications despite early detection and life-long dietary restriction of galactose, which is the current standard of care. Individual outcomes, however, vary widely. For decades, research teams have sought to identify potential environmental, metabolic, and/or galactose-1-phosphate uridylyltransferase (GALT) allelic differences that might explain this variability-with limited success. Among large cohorts, only severe brain-related disease in infancy has been associated with increased prevalence of complications, and only the presence of predicted or detected residual GALT activity has been associated with decreased prevalence. While significant, these factors fail to account for the majority of long-term outcome variability in CG. Here, we tested whether genetic factors, both inside and outside the GALT locus, might contribute to variability in speech/voice/language, cognitive, and/or motor outcomes among patients. Specifically, we compared outcomes among 66 sets of affected siblings who share both GALT genotype and genetic background, 54 unrelated CG patients who share GALT genotype (p.Gln188Arg/p.Gln188Arg) but not genetic background, and 52 unrelated CG patients who share neither GALT genotype nor genetic background. Heritability estimates for all three complications demonstrate substantial genetic contributions, with point estimates of 100% heritability for all three. Less than 8% of this heritability appears due to residual GALT activity from hypomorphic GALT alleles. Combined with prior data demonstrating clustering of all three outcomes, these results offer compelling evidence for the existence of genetic modifiers of developmental outcomes in CG beyond the GALT locus.

To assess the feasibility, in a clinical setting, of using a smartphone app that allows 'tracking' of SSc-related digital ulcers/lesions over time and to gauge patient opinion of the app's benefits, including a newly added lesion feedback function for patients. Patients with SSc with active digital ulcers/lesions were recruited and assessed twice: on study entry and at the point of lesion healing. Participants photographed their lesions and recorded patient-reported outcome measures (PROMs) with the app twice weekly. The lesion feedback function showed lesion size (measured from the photographs) over time. Ways in which feasibility was assessed included the number of photographs and PROMS recorded via the app, data from patient questionnaires and verbal feedback. A total of 10 patients were recruited: 9 (90%) female, median age 55 years, median disease duration 12 years. Nine (90%) completed the study. The median duration of study participation per 'lesion episode' was 39 days (range 18-140). A total of 210 images were returned, with a median of 12 (range 4-87) per episode, and 99 sets of visual analogue scale/pain scores were returned, with a median of 7 (range 3-24) per episode. On a scale of 1 (very easy/helpful) to 10 (very difficult/not helpful), the median score for ease of sending photographs was 1 (range 1-3) and for helpfulness of feedback it was 1.5 (range 1-8). All patients were keen to use the app again. The feasibility and benefits of using the smartphone app, including the feedback function, lend support to possible wider use of the app in routine clinical practice.

Type 2 diabetes mellitus (T2D) is associated with an increased burden of neuropsychiatric disorders, including cognitive decline, affective disorders, and substance use disorders. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), developed for glycemic control and weight reduction, have been hypothesized to confer neuroprotective and psychotropic benefits via central and peripheral mechanisms. However, evidence across individual studies remains inconsistent. We conducted a systematic review and meta-analysis (PROSPERO CRD420251025534) of randomized controlled trials (RCTs) and observational studies assessing the effect of GLP-1 RAs on neuropsychiatric outcomes. Searches were performed in MEDLINE, SCOPUS, CENTRAL, and Web of Science up to 30th October 2025. Eligible comparators included placebo, standard care, or alternative glucose-lowering agents. Data were synthesized using random-effects models, and risk of bias was assessed using RoB2 and ROBINS-I. Evidence certainty was graded using GRADE methodology. From 10,037 records, 82 studies were included. GLP-1 RAs were associated with a reduced risk of idiopathic Parkinson's disease (PD) (pooled HR 0.70, 95% CI: 0.53-0.92, I2 = 38%) but no improvements in motor symptoms in established PD (MDS-UPDRS Part III off-medication: mean difference -3.29, 95% CI: -7.84, 1.26, I2 = 80%). No consistent improvements in non-motor symptoms, quality of life, or dyskinesia scores were seen. GLP-1 RAs were associated with a reduced risk of cannabis use disorder (pooled HR 0.55, 95% CI: 0.39-0.77, I2 = 71%) but showed no significant effect on opioid use disorder (pooled HR 0.61, 95% CI: 0.24-1.52, I2 = 91%). Liraglutide reduced binge frequency in binge eating disorder (mean difference -1.28, 95% CI: -1.67, -0.89, I2 = 53%) compared to placebo. In observational studies versus non-user controls, GLP-1 RA use was associated with a lower reported risk of suicidality (pooled OR 0.34, 95% CI: 0.18-0.63, I2 = 99%), but no such association was seen with Semaglutide alone (pooled OR 0.71, 95% CI: 0.29-1.73, I2 = 99%), active-comparator studies (pooled HR 0.96, 95% CI: 0.81-1.15, I2=0%) or RCTs (pooled RR 1.13, 95% CI: 0.53-2.41, I2=0%). No associations were observed for depression or anxiety. For dementia, findings were mixed: no benefit versus SGLT2 inhibitors (pooled RR 1.07, 95% CI: 0.73-1.56, I2 = 78%), but there was a reduced risk of Alzheimer's disease when compared to unmatched or non-exposed controls (pooled RR 0.37, 95% CI: 0.14-0.96, I2 = 98%). Certainty of evidence ranged from moderate to very low. Current evidence, largely of low to very low certainty, suggests potential selective neuropsychiatric associations of GLP-1 RAs, particularly in Parkinson's disease risk reduction and binge eating disorder. Benefits for dementia risk reduction were observed primarily in comparisons with non-exposed or DPP4i, whereas no advantage was seen versus other active comparators, such as SGLT2 inhibitors. Our findings should be interpreted as hypothesis-generating due to significant heterogeneity and wide confidence intervals, indicating imprecision. Longer-term studies with neuropsychiatric outcomes as the primary endpoint are required.

Abstract X-ray imaging has found applications in many aspects of modern society. Highly sensitive imaging detectors with simple manufacturing methods can increase the deployment of detectors and enable low-dose imaging. In this work, we report on the impact of the solid-state synthesis conditions on the scintillator properties of the lead halide perovskite CsPbCl 3 :Yb. We optimize the synthesis conditions to maximize the light output when exposed to a radiography-relevant spectrum of x-rays. Using optimized conditions, we produced a scintillator powder with light output above 40,000 photons MeV −1 , rivaling commercially available radiography scintillators. The imaging characteristics are measured for scintillator screens comprised of powder dispersed in a polymer matrix and find the spatial resolution acceptable for general radiography. We conclude that CsPbCl 3 :Yb produced in this manner can be used for low frame rate radiography in conjunction with silicon photodetectors and has potential for much higher quantum efficiency imaging if used in conjunction with an NIR optimized photosensor.

Opioid use for chronic non-cancer pain remains common in the UK, despite limited evidence of long-term effectiveness. Delirium, a serious acute confusional state associated with increased mortality, is a known adverse effect of opioid use. Pharmacological differences between opioids may influence delirium risk, but comparative evidence is scarce. This study evaluated the association of opioid type and dosage with the risk of in-hospital delirium in non-cancer patients. We conducted a retrospective cohort study using electronic health records (EHRs) from a tertiary care hospital in northwest England (September 26, 2014-December 31, 2020). Adult (≥ 18 years) without cancer who were administered with opioids during admission were included. Delirium was identified using the 4 'A's Test or through a combination of ICD-10 codes and new-onset confusion scores (= 3) on the National Early Warning Score. Daily opioid doses were converted to daily morphine milligram equivalents (MME/day) to assess the effect of dose across different opioid types. Incidence rates were calculated by opioid type and opioid dosage. Cox regression models, adjusted for confounders, were used to evaluate delirium risk. Among 50,586 opioid-exposed patients (mean [SD] age, 55 [20] years; 53% female), 867 patients (1.7%) experienced delirium during their first hospital admission (mean [SD] age, 75.1 [16.7] years). Compared to codeine, oxycodone (hazard ratio [HR] 3.52, 95% CI 2.77-4.46), fentanyl (HR 2.45, 95% CI 1.71-3.51), buprenorphine (HR 2.43, 95% CI 1.54-3.82), combination opioids (HR 2.22, 95% CI 1.63-3.02), and morphine (HR 2.15, 95% CI 1.65-2.79) were associated with significantly higher delirium risk. No clear dose-response association was observed: doses of 50-119 MME/day were not associated with a significant increase in risk compared to < 50 MME/day (HR 0.96, 95% CI 0.66-1.39). Using in-hospital medication administration records to capture opioid exposure, we found that oxycodone, fentanyl, buprenorphine, morphine, and combinationopioids were associated with increased delirium risk compared with codeine. Oxycodone was associated with a higher riskof delirium compared with both codeine and morphine. These findings support personalised opioid prescribing in non-cancer pain and can inform shared clinical decision-making to prevent delirium in patientsprescribed opioids.

Currently there are no therapeutic agents that are effective against both vestibular schwannoma and meningioma, the two most common tumour types affecting patients with the rare tumour predisposition syndrome NF2-related schwannomatosis. This study aimed to characterise the similarities and differences in the tumour immune microenvironments of meningioma and vestibular schwannoma to identify potential therapeutic targets viable for both tumour types. Publicly available bulk Affymetrix expression data for both meningioma (n = 22) and vestibular schwannoma (n = 31) were used to compare gene expression and signalling pathways, and deconvolved to predict the abundance of the immune cell types present. Publicly available single cell RNA sequencing data for both meningioma (n = 6) and vestibular schwannoma (n = 15) was used to further investigate specific T cell and macrophage subtypes for their signalling pathways, gene expression, and drug targets for predicted drug repurposing in both tumour types. Immune cells comprised a larger proportion of the vestibular schwannoma tumour microenvironment compared to meningioma and included a significantly higher abundance of alternatively activated macrophages. However, these alternatively activated macrophages, alongside other immune cell subtypes such as CD8 + T cells and classically activated macrophages, were predicted to be more active in meningioma than vestibular schwannoma. Despite these differences, T cells and tumour associated macrophages of both vestibular schwannoma and meningioma shared drug-target kinases amenable to drug repurposing with Food and Drug Administration (FDA) drugs approved for other conditions. These include bosutinib, sorafenib, mitoxantrone, and nintedanib which are yet to be clinically investigated for vestibular schwannoma or meningioma. Drug repurposing may offer an expedited route to the clinical translation of approved drugs effective for treating both meningioma and vestibular schwannoma to benefit NF2-related schwannomatosis patients.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40478-025-02176-9.

Introduction: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic condition usually affecting small blood vessels, commonly causing kidney disease. It has a reported incidence of around 20–25 per million per year. AAV includes both granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Here, we describe the epidemiology of this condition at our renal centre over a 23-year period, compare GPA and MPA and compare the overall cohort by era of diagnosis. Methods: We identified all patients with AAV with renal involvement between January 2000 and December 2022 through our biopsy database and electronic patient record. The cohort after exclusions totaled 278. We collected demographic data, baseline laboratory values, treatment received and outcomes including progression to renal replacement therapy (RRT), relapse rates and mortality. We performed subgroup analysis comparing those with GPA and MPA, and created 4 groups by era of diagnosis. Results: Median age of the cohort was 63.5 years (interquartile range [IQR] 52–72), 52.5% were male and 92.4% White. GPA was seen in 49.3% and MPA in 42.1%. There was advanced renal disease at presentation with median eGFR 18 mL/min/1.73 m2 (IQR 9–38) and 54 (19.4%) required RRT at presentation. Relapse occurred in 23%, progression to RRT in 26.6% and 1-year mortality was 3.2%. Median follow-up duration was 54 months (IQR 22–98). Those with GPA were younger, had higher incidence of ENT disease at presentation, were more likely to relapse and had greater 1- and 5-year survival. Mortality rate per hundred person years improved from 2010 onwards. Conclusions: This is one of the largest retrospective observational studies conducted on AAV. We demonstrate that there were more cases of GPA (49.2%) compared to MPA (42.1%) presenting to our centre; comorbidity rates were high; there was advanced renal disease at presentation and mortality rate appeared to improve in the more recent eras.

IntroductionStroke is a major cause of global morbidity and mortality. Readability of educational material is critical for rapid clinical decision-making among healthcare professionals. UpToDate (UpToDate, Inc., Waltham, MA) is a widely used, peer-reviewed point-of-care clinical resource, while ChatGPT (OpenAI, San Francisco, CA) is an emerging AI-based educational support tool. However, a formal comparison of their linguistic accessibility has not been performed.ObjectiveTo compare the readability and linguistic complexity of educational material on stroke generated by ChatGPT (GPT-4o) versus content retrieved from UpToDate, using validated readability metrics.Design, setting, and participantsThis cross-sectional study was conducted between May 27 and June 4, 2025. ChatGPT (GPT-4o, accessed May 27, 2025) was prompted to generate educational content on stroke. A corresponding section from UpToDate (accessed May 27, 2025) was extracted. Only prose content was analyzed. Readability parameters assessed included total word count, sentence count, word/sentence ratio (average words per sentence), Flesch Reading Ease (FRE), Flesch-Kincaid Grade Level (FKGL), Simple Measure of Gobbledygook (SMOG) Index, difficult word count, and difficult word percentage. Data were analyzed using IBM SPSS v25 (IBM Corp., Armonk, NY) and R v4.3.2 (R Foundation for Statistical Computing, Vienna, Austria). The Mann-Whitney U test was used. P < 0.05 was considered statistically significant.ResultsUpToDate content was substantially longer (median = 2772 vs. 304 words; p = 0.008) and used more sentences (median = 134 vs. 23; p = 0.032) and difficult words (median = 857 vs. 88; p = 0.008) compared to ChatGPT. The word/sentence ratio (average words per sentence) was also higher (21.7 vs. 13.2; p = 0.008). However, no statistically significant differences were observed for FRE (p = 1.000), FKGL (p = 0.222), SMOG Index (p = 0.151), or difficult word percentage (p = 0.690).ConclusionsChatGPT produces shorter and more concise educational content on stroke while maintaining comparable readability to UpToDate. The lower linguistic density may enhance rapid orientation for trainees; however, the reduced depth indicates ChatGPT should supplement, not replace, established peer-reviewed resources. Future research should explore multiple medical topics, additional AI models, and assess the clinical applicability and accuracy of AI-generated content.