Manchester Academic Health Science Centre

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.)

Atrial fibrillation (AF) is the most common arrhythmia in older people, with an increasing prevalence of various geriatric conditions, such as multimorbidity, and frailty. A contemporary integrated approach is effective in reducing the risk of clinical adverse events, particularly when streamlined through the application of the Atrial Fibrillation Better Care (ABC) pathway, as proven in 2 non-European trials. The atrial fibrillation integrated approach in frail, multimorbid and polymedicated older people (AFFIRMO) trial, a European multicenter, open-label, cluster-randomized study, will examine whether a mobile-health integrated care approach based on the ABC pathway combined with a multidimensional Comprehensive Geriatric Assessment (CGA) can reduce the 12-month risk of unplanned all-cause hospitalizations in patients with AF ≥65 years with ≥1 concomitant chronic condition(s). The AFFIRMO trial enrolled 1,260 patients with AF (mean age 74 [SD 6] years; 44.4% female) across 6 European countries (Bulgaria, Denmark, Italy, Romania, Serbia, and Spain). At baseline, the median (IQR) CHA2DS2-VASc score was 4 (3-5), and the median (IQR) HAS-BLED score was 1 (1-2). Hypertension was reported in 992 (78.7%) patients, and diabetes mellitus in 369 (29.3%) patients. Among the enrolled patients, 507 (40.5%) were prefrail, and 171 (13.7%) were frail. Oral anticoagulants (OACs) were prescribed for 1,225 (97.2%) patients, with 1,149 (91.2%) patients receiving non-VKAs oral anticoagulants (NOACs). Follow-up is ongoing and planned to be completed in January 2026. The AFFIRMO trial will provide evidence on the efficacy of the ABC pathway in conjunction with the CGA approach in reducing the risk of unplanned all-cause hospitalizations and other clinical adverse events in older, multimorbid patients with AF. ClinicalTrials.gov identifier: NCT06775028.

RASopathies are clinically overlapping neurodevelopmental syndromes resulting from germline mutations in genes involved in the rat sarcoma/mitogen-activated protein kinases (RAS/MAPK) pathway. Historically, RASopathies have been described by clinical phenotypes, such as Noonan syndrome and Neurofibromatosis type I. There is emerging evidence of the association between Noonan syndrome spectrum disorders (NSSD) and systemic lupus erythematosus (SLE). Here, we present an SLE patient diagnosed with SOS1-associated Noonan Syndrome (c.806 T>C; p.Met269Thr) as part of a research study. Reviewing the literature, we identified further 16 cases of NSSD associated with SLE. Nine out of 16 cases (56%) had a confirmed molecular diagnosis, with pathogenic missense variants identified in KRAS, PTPN11, and SHOC2 genes, the majority in the last. Variants in SHOC2 are the cause of only a small proportion of all presentations of NSSD. Our case represents the first reported case of SLE in a patient with a SOS1 pathogenic variant. Compared to the general SLE population, SLE in the presence of NSSD develops at a younger age, with a similar prevalence among females and males, suggesting a contribution of the RAS/MAPK pathway in the development of SLE.

Many clinically used drugs are amphiphiles, yet the effect of their amphiphilicity on their therapeutic activity is poorly understood. As cell membranes are the first barrier a drug encounters on route to its site of action, we propose that an amphiphilic drug's membrane activity will impact its clinical efficacy. Comprehensive quantitative detail on the membrane interactions of the amphiphilic β-blocker drug, (±) propranolol has been investigated, using a synergistic combination of surface area-pressure measurements, ellipsometry, Brewster angle microscopy and selective H/D contrast variation neutron reflectometry, and using Langmuir monolayers comprising zwitterionic, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) alone and with 30mol% of negatively charged, 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-1'-rac-glycerol sodium (POPG). The interaction of propranolol with the lipid monolayers was resolved in terms of changes in lipid morphology, the extent of lipid loss from the membrane, and the drug's favoured location and orientation within the membrane. Propranolol is proposed to interact with the lipid monolayers in three stages: (1) electrostatic binding to the lipid head groups, (2) drug-mediated lipid loss from the membrane, and (3) the re-organisation of the drug's hydrophobic region within the membrane lipid chains. At steady state, and regardless of lipid packing, the monolayer contains more drug than lipid molecules. Further, the presence of negatively charged POPG does not enhance the cationic drug's interactions with the monolayer, most likely due to the differential solubilisation of membrane lipid in the aqueous subphase. Significantly, these results demonstrate how a drug's amphiphilic nature can determine its membrane activity and thereby impact its clinical efficacy.

Summary Background People with Type 2 diabetes mellitus (T2DM) are at increased risk of developing dementia. Evidence suggests that thiazolidinediones (TZDs) may be protective for dementia onset including Alzheimer's disease and vascular dementia, compared to other second-line antidiabetic medications (SAMs). However, causality remains uncertain due to methodological limitations. We examined the effect of TZD on the risk of vascular dementia and all-cause dementia in T2DM, compared to other second-line treatments. Methods We emulated a pragmatic randomised trial using UK primary care data, Clinical Practice Research Datalink Aurum, between 2003 and 2023 to estimate the comparative effectiveness of initiating a TZD, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, or sulfonylurea (SU) against incident dementia in T2DM adults on metformin therapy. Patients were followed for up to 5 years from 180 days after their first SAM prescription. We used overlap weighting to adjust for baseline confounding and fitted double robust Cox models to estimate adjusted hazard ratios (aHRs). Findings This study included 124,311 participants (mean age 63 years, 61% males, and 20% whites), of whom 595 developed vascular dementia and 1,678 developed all-cause dementia during follow-up. On top of metformin, 8,669 initiated TZD, 30,216 initiated DPP-4 inhibitors, 55,997 initiated SU and 29,429 initiated SGLT2 inhibitors. TZD were associated with a similar risk of vascular dementia compared with DPP-4 inhibitors (aHR 0.89;95% CI 0.36-2.23) and SU (0.58;0.24-1.42). SGLT2 inhibitors were associated with a lower risk of vascular dementia than TZD (0.29;0.09-0.94), DPP-4 inhibitors (0.25;0.10-0.64), and SU (0.17;0.07-0.40). Most patterns persisted in all-cause dementia: SGLT2 inhibitors vs DPP-4 inhibitors (0.51;0.26-0.99) and SGLT2 inhibitors vs SU (0.35;0.18-0.67), with no difference observed between SGLT2 inhibitors and TZDs. Interpretation Dementia risk was similar for TZDs, DPP-4 inhibitors and SUs but was significantly lower for SGLT2 inhibitors, a finding that warrants further investigation. Considering potential cognitive effects when selecting therapies for T2DM is important in an ageing population.

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.

Maerua edulis (Gilg & Gilg-Ben.) DeWolf) was traditionally used in the treatment and/ or management of various diseases, including cancer. However, limited studies have evaluated whether M. edulis can suppress the proliferation of cervical cancer cells, and its putative mechanism for antiproliferative activity remains unclear. Therefore, we conducted this study to evaluate the in-vitro antiproliferative and cytotoxic effects of M. edulis root extracts against human cervical cancer cells and their underlying mechanism of action. To achieve this goal, we performed MTT assay, microscopic analyses, and wound-healing assay to assess the antiproliferative activity of M. edulis extract and its fractions. Qualitative phytochemical and gas chromatography-mass spectrometry (GC-MS) analyses were performed to characterize the phytochemicals in bioactive extracts, and network pharmacology was utilized to predict putative molecular targets and the mechanism of action of the active extract's fractions. Target validation was accomplished through molecular docking and real-time PCR methods. Bioactive M. edulis extracts exhibited significant antiproliferative activity against HeLa cells, with hexane fraction (essential oil) and ethyl acetate extracts demonstrating IC50 values of 0.02% (v/v) and 47.42µg/mL, respectively. GC-MS analysis identified key phytochemicals such as methyl stearate, (8Z)-14-methylhexadec-8-enal, squalene, and stigmasta-3,5-diene, which were associated with the demonstrated bioactivities, possibly mechanistically through regulation of apoptosis and cell cycle-related genes (BCL2, CDK2, TP53). Interestingly, gene expression analysis revealed the modulation of these target genes. The results of our study suggest the potential therapeutic benefits of M. edulis in the treatment and management of cervical cancer. Further in-vivo studies are recommended to validate these findings and establish their safety profile.

Receiving a diagnosis of a vision-threatening eye condition is a psychologically salient event for many patients. Across ophthalmology, fear, uncertainty, and emotional distress are commonly observed at the time of diagnosis, often before substantial functional vision loss occurs. Although depression and anxiety are well documented in chronic eye disease, diagnosis-linked distress remains inconsistently recognised and is rarely addressed systematically within routine ophthalmic care. This article introduces post-visual diagnosis distress (PVDD) as a descriptive, nondiagnostic framework to characterise the predictable, loss-related emotional responses that may arise following the diagnosis of a vision-threatening or irreversible eye condition. PVDD is not proposed as a psychiatric disorder, but as a clinically meaningful construct that helps legitimise patient experience, supports empathetic communication, and facilitates timely recognition and appropriate signposting when distress is significant. Drawing on evidence from age-related macular degeneration, glaucoma, and other chronic eye diseases, and informed by multidisciplinary perspectives spanning ophthalmology, psychiatry, counselling, patient advocacy, and public health, the article argues that recognising PVDD may improve patient engagement, quality of life, and psychological outcomes.