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Background: The efficacy of icosapent ethyl among patients with very well-controlled baseline low-density lipoprotein cholesterol (LDL-C) is unknown., Methods: In this post hoc analysis of the REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) randomized clinical trial, statin-treated patients with high cardiovascular risk, elevated triglycerides (135-499 mg/dL), and baseline LDL-C of 41 to 100 mg/dL were included. Patients were randomized to icosapent ethyl (2 g twice daily) or placebo and then post hoc stratified by baseline LDL-C (<55 mg/dL versus ≥55 mg/dL). The primary composite end point included cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina., Results: Among 8175 patients with baseline LDL-C data, 7117 (87.1%) had LDL-C ≥55 mg/dL and 1058 (12.9%) had LDL-C <55 mg/dL. In patients with LDL-C <55 mg/dL, the rate of the primary composite end point was lower in the icosapent ethyl group (16.2% versus 22.8%) than in the placebo group (hazard ratio [HR], 0.66 [95% CI, 0.50-0.87]; absolute risk reduction, 6.6%; P =0.003). Among patients with LDL-C ≥55 mg/dL, a primary composite end point event occurred in a lower proportion of patients in the icosapent ethyl group (17.4% versus 21.9%) than in the placebo group (HR, 0.76 [95% CI, 0.69-0.85]; absolute risk reduction, 4.5%; P <0.0001). No significant interaction was observed between baseline LDL-C and treatment group ( P for interaction=0.40). Findings were consistent among secondary cardiovascular end points and in sensitivity analyses., Conclusions: Among statin-treated patients with elevated triglycerides and high cardiovascular risk, icosapent ethyl reduced the rate of cardiovascular end points irrespective of baseline LDL-C, including among eligible patients with optimal LDL-C control., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.

Computer-aided drug design has the potential to significantly reduce the astronomical costs of drug development, and molecular docking plays a prominent role in this process. Molecular docking is an in silico technique that predicts the bound 3D conformations of two molecules, a necessary step for other structure-based methods. Here, we describe version 1.3 of the open-source molecular docking software GNINA. This release updates the underlying deep learning framework to PyTorch, resulting in more computationally efficient docking and paving the way for seamless integration of other deep learning methods into the docking pipeline. We retrained our CNN scoring functions on the updated CrossDocked2020 v1.3 dataset and introduce knowledge-distilled CNN scoring functions to facilitate high-throughput virtual screening with GNINA. Furthermore, we add functionality for covalent docking, where an atom of the ligand is covalently bound to an atom of the receptor. This update expands the scope of docking with GNINA and further positions GNINA as a user-friendly, open-source molecular docking framework. GNINA is available at https://github.com/gnina/gnina .Scientific contributions: GNINA 1.3 is an open source a molecular docking tool with enhanced support for covalent docking and updated deep learning models for more effective docking and screening., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Objectives: The ACR-EULAR Myositis Response Criteria [Total Improvement Score (TIS)] is a composite measure calculated using changes in myositis core set measures. It is unclear if achieving improvement per TIS reflects improvement in any symptoms of patients with myositis. In this study, we examined the association between achieving TIS improvement and patient-centred outcome measures (PCOMs)., Methods: Adults with myositis were enrolled in a prospective study with baseline and 6-month visits. Six core set measures were collected at each visit along with the following PCOMs: fatigue [visual analogue scale (VAS) and short form 36 (SF36)], pain (VAS, SF36), health-related quality of life (SF-36), physical function (PROMIS-physical function, SF36, sit-to-stand, timed up-and-go and six-min walk) and physical activity (actigraphy). Mann-Whitney U was used to compare PCOMs between improvement groups. Spearman correlation and regression models were used for correlation and association between TIS and PCOMs, respectively., Results: Of 50 patients (six polymyositis, 24 dermatomyositis, nine necrotizing myopathy, 11 anti-synthetase syndrome) enrolled (mean age: 52, 60% female), 21 patients satisfied the TIS improvement criteria at 6 months. PCOMs including fatigue, pain, quality of life, physical activity and physical function demonstrated significantly greater improvement in patients who had minimal TIS improvement compared with those with no improvement. Greater PCOM improvements were seen with moderate-major TIS improvement. TIS had moderate-strong correlations with most PCOMs., Conclusion: Achieving improvement criteria was accompanied by significant clinical improvements in fatigue, pain, health-related quality of life, physical function, and physical activity. These results support the use of TIS as a clinically meaningful metric of improvement., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Renal impairment significantly affects morbidity and mortality rates of cirrhosis patients. Studies on glomerular filtration rate (eGFR) estimation did not include cirrhosis patients. These equations are erroneous and unreliable in cirrhosis due to sarcopenia. Further, the accuracy of eGFR equations varies across different ethnic groups. Measurement of GFR by iohexol clearance is a gold standard method of accurate determination of GFR. There is scarce data on iohexol GFR in cirrhosis and none in Indian population., Methodology: This was prospective observational study. Consecutive adult patients with cirrhosis with stable renal function for prior 1 month were included. Iohexol weight-based dosage was given and timed blood samples were taken to measure iohexol clearance. Plasma iohexol levels was measured by high performance liquid chromatography (HPLC) and Cystatin-C was measured by ELISA in plasma samples., Results: Thirty-five patients were enrolled in the study. Hepatitis B (n = 5), hepatitis C (n = 4); alcoholic liver disease (n = 20), metabolic dysfunctional associated steatotic liver disease (n = 2), others/overlap (n = 3). The average eGFR by MDRD4, MDRD6, CKD-EPI Creat, CKD EPI Cys C, CKD EPI Creat-Cys C, RFHand GRAIL formulae were 105.24(24.2),104.75(23.5),102.14(15.9),68.91(16.5),82.91(15.21), 67.27 (14.08) and 112.9 (19.5) ml/min ml/min/1.73m 2 , respectively. The average mGFR measured by iohexol method was 73.44 (16.8)ml/min/1.73 m 2 . 30% agreement with mGFR was found with eGFR by MDRD4 in 38.2% (n = 13), MDRD6 38.2% ((n = 13), CKD-EPI Creat in 35.2% (n = 12), CKD EPI Cys C in 79.41% (n = 27), CKD EPI Creat-Cys C in 76.42% (n = 26), RFH 76.4% (n = 26) and GRAIL 20.5% (n = 7)., Conclusion: The eGFR equations using creatinine are imprecise and less accurate in Indian patients with cirrhosis. All equations overestimate GFR. Equations especially developed for cirrhosis patients like MDRD6 are also not precise. Cystatin C based equations are better than creatinine-based equations. Further studies with large sample size are needed to establish an accurate method of GFR assessment in Indian patients with cirrhosis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (© 2024 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: Transcatheter aortic valve replacement (TAVR) is increasingly in demand for treating severe aortic stenosis in a variety of surgical risk profiles. This means increasing wait times and elevated morbidity and mortality on the waitlist. To address this, we developed the SWIFT TAVR algorithm to prioritize patients based on clinical risk and reduce wait times., Methods: The SWIFT algorithm, implemented in Microsoft Excel, calculates a clinical risk score from three parameters: left ventricular ejection fraction (LVEF), peak aortic valve gradient, and syncope. Scores categorize patients into four prioritisation profiles: high (9-10 points), intermediate (4-8 points), low (2-3 points), and minimal (0-1 point). The study prospectively applied the SWIFT algorithm to patients in 2022 (SWIFT group) and retrospectively to a 2021 cohort (CONTROL group). Outcomes measured were wait times from consultation to procedure and major adverse cardiac events (MACE) while awaiting TAVR., Results: A total of 228 patients were included (117 SWIFT, 111 CONTROL). There was no significant difference in baseline characteristics between groups (p > 0.05). Overall wait times were significantly shorter in the SWIFT group (21 vs 28 weeks, p < 0.001), particularly for high-risk patients (12 vs 31 weeks, p < 0.001). MACE rates were similar (9 % vs 10 %, p = 0.722)., Discussion: The SWIFT algorithm significantly reduced wait times, particularly for high-risk patients, without increasing MACE rates. This automated, risk-based prioritisation tool improves equity and efficiency in TAVR waitlist management and is globally applicable. Further randomized studies are warranted to validate these findings., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The federal government spends billions of dollars per year on payments to Medicare Advantage (MA) plans based, in part, on beneficiaries' risk scores. Despite this, little is known about the true burden of chronic medical conditions among MA beneficiaries compared with those in fee-for-service (FFS) Medicare., Objective: To determine whether the prevalence of chronic medical conditions is higher among MA compared with FFS beneficiaries., Design: Cross-sectional., Setting: Population based., Participants: Adults aged 65 years or older enrolled in MA or FFS Medicare., Measurements: Using direct physical examination and laboratory data from the National Health and Nutrition Examination Survey (2015 to 2018), we compared the age- and sex-standardized prevalence of obesity, hypertension, hyperlipidemia, diabetes, and chronic kidney disease between MA and FFS beneficiaries., Results: The unweighted study population included 2446 respondents corresponding to a weighted total of 45 426 711 adults (34.4% MA, 65.6% FFS Medicare). The prevalence of obesity (41.1% vs. 40.6%; standardized difference [SDiff], 0.48 percentage points [pp] [95% CI, -5.2 to 6.2 pp]), hypertension (70.9% vs. 71.0%; SDiff, -0.05 pp [CI, -5.8 to 5.7 pp]), hyperlipidemia (79.4% vs. 82.3%; SDiff, -2.86 pp [CI, -7.0 to 1.3 pp]), and chronic kidney disease (19.2% vs. 22.8%; SDiff, -3.48 pp [CI, -9.2 to 2.3 pp]) was not higher among MA beneficiaries compared with FFS beneficiaries. However, the prevalence of diabetes was higher in MA (33.3% vs. 26.3%; SDiff, 7.00 pp [CI, 3.3 to 10.7 pp])., Limitation: Differences in the severity of specific medical conditions between groups could not be assessed., Conclusion: In this nationally representative study from 2015 to 2018, the prevalence of obesity, hypertension, hyperlipidemia, and chronic kidney disease was not higher among MA compared with FFS beneficiaries; however, the prevalence of diabetes was higher among MA beneficiaries., Primary Funding Source: National Heart, Lung, and Blood Institute (NHLBI) and American Heart Association (AHA)., Competing Interests: Disclosures: Disclosure forms are available with the article online.

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease. Several studies have identified transcriptional subtypes of mCRPC, but comprehensive analysis of prognostic gene expression pathways has been limited. Therefore, we aggregated a cohort of 1012 mCRPC tissue samples from 769 patients and investigated the association of gene expression-based pathways with clinical outcomes and intrapatient and intratumor heterogeneity. Survival data were obtained for 272 patients. Pathway-level enrichment was evaluated using gene set variation analysis. scRNA-seq datasets from mCRPC tissue biopsies and circulating tumor cells were used to investigate heterogeneity of adverse pathways. We identified five pathway clusters: (a) Immune response/WNT/TGF-beta signaling, (b) AR signaling/luminal signatures, (c) mTOR signaling and glycolysis, (d) cell proliferation, and (e) neuroendocrine differentiation. Proliferation, AR signaling loss, and glycolysis/mTOR signaling were independently prognostic. Adverse prognostic pathway scores decreased on treatment with AR signaling inhibitors, but not at progression, suggesting failure to permanently target these pathways. scRNA-seq datasets from mCRPC tissue biopsies and circulating tumor cells were used to investigate heterogeneity of adverse pathways. Our results suggest loss of AR signaling, high proliferation, and a glycolytic phenotype as adverse prognostic pathways in mCRPC that could be used in conjunction with clinical factors to prognosticate for treatment decisions., (© 2025 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: Sodium-glucose co-transporter (SGLT)-2 inhibitors have shown consistent benefit in improving heart failure-related outcomes but not ischaemic cardiovascular events such as myocardial infarction or stroke. We assessed if the dual SGLT1/2 inhibitor sotagliflozin improves ischaemic outcomes., Methods: We did a prespecified secondary analysis of the SCORED trial, which was a double-blind, placebo-controlled, randomised clinical trial enrolling patients (aged ≥18 years) with type 2 diabetes, chronic kidney disease (estimated glomerular filtration rate [eGFR] 25-60 mL/min per 1·73 m 2 ), and additional cardiovascular risk factors. Patients at 750 sites in 44 countries were randomly assigned (1:1) to oral sotagliflozin or placebo via an interactive response technology system (block size of four; stratified by heart failure-related criteria and geographical region), with participants, investigators, and study staff, including those who assessed outcomes, masked to group assignment. Sotagliflozin treatment was prescribed at 200 mg once a day, with the dose increased to 400 mg once a day within the first 6 months if tolerated. Matching placebo was prescribed at the same treatment frequency as the intervention regimen. A prespecified secondary outcome was total major adverse cardiovascular events (MACE), which was defined as a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, assessed as first and subsequent events. Other outcomes included total myocardial infarction and total stroke (fatal and non-fatal events) as individual post-hoc endpoints. Outcomes were assessed by intention to treat with competing-risk proportional hazard models in the overall population, and, for total MACE, in prespecified subgroups stratified by baseline demographic and clinical features (sex, age, geographical region, heart failure-related criteria, eGFR, urine albumin-creatinine ratio, and cardiovascular disease history). The SCORED trial was registered at ClinicalTrials.gov, NCT03315143, and was ended early due to loss of funding., Findings: 10 584 patients were enrolled and randomly assigned to sotagliflozin (n=5292 [50·0%]) or placebo (n=5292 [50·0%]) between Dec 8, 2017 and Jan 20, 2020 (median age 69 years [IQR 63-74]; 4754 [44·9%] female patients and 5830 [55·1%] male patients). 5144 (48·6%) patients had a history of cardiovascular disease, of whom 2108 (19·9% of the total population) had a history of myocardial infarction, 946 (8·9%) had a history of stroke, and 2375 (22·4%) had a history of coronary revascularisation. Patients in the sotagliflozin group had a significantly lower rate of total MACE than those in the placebo group (4·8 events per 100 person-years vs 6·3 events per 100 person-years; hazard ratio [HR] 0·77 [95% CI 0·65-0·91]; p=0·0020). Interaction analyses suggested a consistent effect of sotagliflozin on total MACE among stratified subgroups without evidence of heterogeneity. Additionally, sotagliflozin significantly reduced the rate of myocardial infarction (1·8 events per 100 person-years vs 2·7 events per 100 person-years; HR 0·68 [0·52-0·89]; p=0·0041) and stroke (1·2 events per 100 person-years vs 1·8 events per 100 person-years; HR 0·66 [0·48-0·91]; p=0·012) compared with placebo., Interpretation: Sotagliflozin reduced MACE, with independent reductions in myocardial infarction and stroke, among patients with type 2 diabetes, chronic kidney disease, and additional cardiovascular risk. The ischaemic benefit on both myocardial infarction and stroke has not been previously observed with other SGLT inhibitors and warrants investigation of combined SGLT1 and SGLT2 inhibition as a possible underlying mechanism., Funding: Lexicon Pharmaceuticals., Competing Interests: Declaration of interests RA is involved in research funded by the Bristol Myers Squibb–Pfizer alliance, Novartis, Amarin, and Lexicon Pharmaceuticals. He has previously served as a consultant for Lexicon. DLB receives research funding from Lexicon Pharmaceuticals paid to the Icahn School of Medicine at Mount Sinai for his role as Chair of the SCORED trial and discloses the following relationships: advisory board membership for Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, E-Star Biotech, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Stasys; Board of Directors membership for the American Heart Association New York City, Angiowave, Bristol Myers Squibb, DRS.LINQ, and High Enroll (and holds stock or stock options with Angiowave, Bristol Myers Squibb, DRS.LINQ, and High Enroll); consulting for Broadview Ventures, GlaxoSmithKline, Hims, SFJ, and Youngene; data monitoring committee participation for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2 trial), Duke Clinical Research Institute, Mayo Clinic, Icahn School of Medicine at Mount Sinai (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; and for the ALLAY-HF trial, funded by Alleviant Medical), Novartis, Population Health Research Institute, and Rutgers University (for the MINT trial, funded by the US National Institutes of Health [NIH]); honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; and Chair, American College of Cardiology Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; for RE-DUAL PCI Clinical Trial Steering Committee membership funded by Boehringer Ingelheim; for AEGIS-II Executive Committee membership funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), the Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (American Heart Association lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor, Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (continuing medical education steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, the Population Health Research Institute (for the COMPASS Operations Committee, Publications Committee, Steering Committee, and US National Co-Leader, funded by Bayer), WebMD (continuing medical education steering committees), and Wiley (steering committee); other support from Clinical Cardiology (Deputy Editor); a patent for sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned the patent to Lexicon Pharmaceuticals; neither DLB nor Brigham and Women's Hospital receive any income from this patent); research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon Pharmaceuticals, Eli Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; royalties from Elsevier (Editor, Braunwald's Heart Disease); a role as site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; a role as Trustee of the American College of Cardiology; and unfunded research with FlowCo. MS serves as a consultant for and/or has received research support from Lexicon Pharmaceuticals, Amarin, NewAmsterdam, Silence, Sanofi, Regeneron, and Tourmaline. MS also receives salary support from CPC, a non-profit academic research organisation affiliated with the University of Colorado, that receives or has received research grant or consulting funding between July, 2021 and July, 2024 from the following organisations: Abbott Laboratories, Agios Pharmaceuticals, Alexion Pharma Godo Kaisha, Amgen, Anthos Therapeutics, ARCA biopharma, Arrowhead Pharmaceuticals, AstraZeneca Pharma India, AstraZeneca UK, Bayer, Bayer Aktiengesellschaft, Bayer Pharma, Beth Israel Deaconess Medical Center, Better Therapeutics, Boston Clinical Research Institute, Bristol Myers Squibb, Cleerly, Colorado Department of Public Health and Environment, Congress, Cook Regentec, CSL Behring, Eidos Therapeutics, EPG Communication Holdings, Esperion Therapeutics, Faraday Pharmaceuticals, HeartFlow, Insmed, Ionis Pharmaceuticals, IQVIA, Janssen Pharmaceuticals, Janssen Research & Development, Janssen Scientific Affairs, Lexicon Pharmaceuticals, Medpace, Medscape, Merck Sharp & Dohme, Nectero Medical, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, PPD Development, Prothena Biosciences, Regeneron, Regents of the University of Colorado (University of Colorado Denver), Sanifit Therapeutics, Sanofi, Silence Therapeutics, Stanford University, Stealth BioTherapeutics, Brigham and Women's Hospital, Thrombosis Research Institute, Tourmaline Bio, University of Colorado, University of Colorado Denver, University of Pittsburgh, VarmX, Verve Therapeutics, and WraSer. CPC has received research grants from Amgen, Better Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Merck, Novo Nordisk, and Pfizer; has received consulting fees from Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Eli Lilly, Janssen, Lexicon Pharmaceuticals, Merck, Pfizer, Rhoshan, and Sanofi; and has served on data and safety monitoring boards for Applied Therapeutics and Novo Nordisk. LAL has received research funding from, has provided continuing medical education on behalf of, and/or has acted an adviser to Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion, HLS Therapeutics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pfizer, and Sanofi. SEI has served as a consultant and member of clinical trial steering committees for Boehringer Ingelheim, AstraZeneca, Novo Nordisk, Merck, Pfizer, and Bayer; and has delivered lectures sponsored by Boehringer Ingelheim and AstraZeneca. RDL has received research grants or contracts from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi; has received funding for educational activities or lectures from Pfizer, Bristol Myers Squibb, Novo Nordisk, and AstraZeneca; and has received funding for consulting from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Novo Nordisk, and AstraZeneca. DKM has received research support for clinical trials leadership from Boehringer Ingelheim, Merck, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Eli Lilly, Lexicon Pharmaceuticals, CSL Behring, and NewAmsterdam Pharma; and has received honoraria for consultancy from Eli Lilly, Boehringer Ingelheim, Merck, Novo Nordisk, Applied Therapeutics, Altimmune, CSL Behring, Bayer, GlaxoSmithKline, and Intercept. JBL has received consultant fees from Sanofi. MCR has received honoraria for consulting from Adocia, Anji, Xeris, DalCor, and Theracos. MJD, AKC, and PB are employees of Lexicon Pharmaceuticals, and may hold stocks or stock options in the company. BAS reports institutional research grants to Brigham and Women's Hospital from Better Therapeutics, Merck, Novo Nordisk, and Pfizer; consulting fees from Allergan, Boehringer Ingelheim, Better Therapeutics, Elsevier Practice Update Cardiology, Esperion Therapeutics, Hanmi Pharmaceutical, Lexicon Pharmaceuticals, and Novo Nordisk; and equity in Health at Scale and Doximity. DZIC has received honoraria from Boehringer Ingelheim–Eli Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi Tanabe, AbbVie, Janssen, Amgen, Bayer, Prometic, Bristol Myers Squibb, Maze, Gilead, CSL Behring, Otsuka, Novartis, Youngene, Lexicon Pharmaceuticals, Inversago, GlaxoSmithKline, and Novo Nordisk, and has received operational funding for clinical trials from Boehringer Ingelheim–Eli Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL Behring, Novo Nordisk, and Bayer. SV holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; and reports receiving grants and/or research support and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, the Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Humber River Health, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, S & L Solutions Event Management, and Sanofi. JAU discloses advisory board roles for Boehringer Ingelheim, Novavax, Novo Nordisk, and Sanofi; speaker honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, and Eli Lilly; and research funding to his institution from Amgen, Bayer, Boehringer Ingelheim, and Novartis. RPM has received research funding or consulting fees from Amarin, Lexicon Pharmaceuticals, Esperion, and HLS Therapeutics. BP has received consulting fees from Lexicon Pharmaceuticals, Bayer, AstraZeneca, Boehringer Ingelheim, Merck, and Phasebio; has received consulting fees from and/or holds stock options from Viror, KBP Biosciences, Cereno Scientific, Tricida, scPharmaceuticals, SQ Innovation, G-3 Pharmaceuticals, Protonintel, and Brainstorm Medical; and holds a US patent (number 9931412) on site-specific delivery of eplerenone to the myocardium and US patent, pending (number 63/045,783) on histone-modulating agents for the protection and treatment of organ damage. PGS has received research grants from Amarin, Bayer, Sanofi, and Servier; has received speaker or consultant fees from Amarin, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen, Kowa, Idorsia, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, PhaseBio, Pfizer, Regeneron, Sanofi, and Servier; and is a Senior Associate Editor of Circulation. All other authors declare no competing interests., (Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose: Metastatic castration-resistant prostate cancer (mCRPC) has limited treatment options and a poor prognosis. Recently, PSMA-targeted alpha particle therapy agents using Actinium-225 (225Ac) have shown promising results for prostate cancer treatment, but a significant fraction of patients with advanced mCRPC demonstrate loss of PSMA expression. We have previously reported that PSMA-null and PSMA-positive tumors can be detected and treated effectively with CD46-targeted radiopharmaceuticals. This study evaluates the CD46-targeting PET imaging agent [89Zr]DFO-YS5 and the radioimmunotherapy agent [225Ac]Macropa-PEG4-YS5 in disseminated prostate cancer tumors., Experimental Design: Microtumor lesions, primarily observed in the liver, kidneys, and lungs, were successfully detected with [89Zr]DFO-YS5 PET imaging. We used disseminated 22Rv1 tumors for biodistribution studies, dosimetry assessments, and therapeutic efficacy evaluations of [225Ac]Macropa-PEG4-YS5., Results: Quantitative digital alpha-particle autoradiography revealed high radiation dose deposition from [225Ac]Macropa-PEG4-YS5 in microtumors compared to surrounding liver tissues, although in larger lesions (>1 mm diameter) the dose distribution was heterogeneous. Early treatment of smaller disseminated tumors with uniform radiation dose was more effective in ablating tumors and promoting survival. In late-stage lesions of large size, heterogeneous dose deposition limited therapeutic efficacy, requiring higher administered activity to achieve a complete response., Conclusions: Our findings highlight that [225Ac]Macropa-PEG4-YS5 holds the potential for clinical translation for metastatic prostate cancer and reinforces the value of microdosimetry in understanding the efficacy of and resistance to targeted alpha therapy.

Objectives: The phase 3 ProDERM study demonstrated intravenous immunoglobulin (IVIg) was safe and effective in patients with dermatomyositis (DM). This analysis assessed clinical and serological predictors of IVIg response in DM patients from ProDERM., Methods: ProDERM was a prospective, randomised, placebo-controlled study of DM patients. For Weeks 0-16, patients received 2.0 g/kg IVIg (Octagam, 10%) or placebo every 4 weeks. Eligible patients entered the open-label extension phase, where all received IVIg to week 40. Univariate and multivariate analyses examined associations between baseline variables and total improvement score (TIS), including myositis disease activity assessment tool (MDAAT; assessing different organ involvement), and myositis-specific and myositis-associated autoantibodies., Results: Ninety-five patients were enrolled. Univariate analyses found no significant association between TIS at week 16 or 40 and age; sex; ethnicity; disease duration/activity; cutaneous, skeletal, gastrointestinal or muscle disease activity; or previous failed or concomitant medications.Multivariate analysis found patients with higher MDAAT cutaneous scores had a better chance of at least minimal TIS improvement. Higher MDAAT pulmonary scores were associated with a lower, but still considerable, chance of improvement. Patients with TIF1-γ antibodies had a better TIS response; however, after controlling for cutaneous disease activity, there was no significant association between antibody classification (including anti-TIF1-γ) and efficacy outcome., Conclusion: IVIg was effective in treating DM patients regardless of demographic features and autoantibody status (for most autoantibodies). Patients with higher cutaneous disease activity and/or anti-TIF1-γ responded best to IVIg, while pulmonary disease activity predicted a lower, but still effective, IVIg response, warranting further investigation., Clinical Trial Registration: ClinicalTrials.gov, NCT02728752., (© The Author(s) 2025. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Introduction: Irreversible hydrocolloid (IHC) impression materials are widely used in dentistry for diagnostic impressions; however, they pose a risk of cross-contamination. Current cleaning methods such as rinsing with water may not be sufficient for effective disinfection. Incorporation of antimicrobial agents into IHC materials can reduce this risk. Chitosan, a biopolymer with proven antibacterial and antifungal properties, has potential as a self-disinfecting agent for IHC materials. This study aimed to evaluate the antibacterial and antifungal efficacy of chitosan nanoparticles (CHN) incorporated into IHC (alginate) impression materials., Materials and Methods: This cross-sectional study was conducted in the Department of Prosthodontics, at the Surendera Dental College and Research Institute, Sri Ganganagar, Rajasthan, India, with 20 dentulous patients. A 1% CHN was incorporated into the IHC impression material to serve as Group 1, while conventional alginate mixed with distilled water with a one-week interval between each impression served as Group 2. Impressions were made on patients' maxillary arches, with bacterial and fungal samples collected at 0- and 10-minute intervals after rinsing the impressions. The samples were cultured on nutrient agar and Sabouraud dextrose agar for bacteria and fungi, respectively. Colony counts were assessed and statistically analyzed., Results: The study found a significant reduction in both bacterial and fungal counts in impressions made with Group 1 compared with Group 2 at both 0- and 10-minute intervals (p<0.001). At 10 minutes, bacterial counts decreased significantly in Group 1 (from 75.50±34.56 to 26.00±16.03), and fungal counts were also reduced (from 2.70±1.22 to 0.55±0.69). The antibacterial and antifungal efficacy was increased at the 10-minute interval, compared to the 0-minute interval.  Conclusion: Incorporating 1% CHN into the IHC impression material significantly enhanced its antibacterial and antifungal properties, making it an effective self-disinfecting agent. This modification reduces the need for additional disinfection steps and offers a practical solution for improving cross-infection control in dental practice. CHN's biocompatibility and biodegradability further support its potential as an eco-friendly and sustainable alternative for dental materials., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Institutional Ethics Committee of Surendera Dental College and Research Institute issued approval SDRI/IEC/22/34. The study adhered to the principles outlined in the Declaration of Helsinki. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2025, Kumawat et al.)

Lineage plasticity and histologic transformation from prostate adenocarcinoma to neuroendocrine (NE) prostate cancer (NEPC) occur in up to 15% to 20% of patients with castration-resistant prostate cancer (CRPC) as a mechanism of treatment resistance and are associated with aggressive disease and poor prognosis. NEPC tumors typically display small cell carcinoma morphology with loss of androgen receptor (AR) expression and gain of NE lineage markers. However, there is a spectrum of phenotypes that are observed during the lineage plasticity process, and the clinical significance of mixed histologies or those that co-express AR and NE markers or lack all markers is not well defined. Translational research studies investigating NEPC have used variable definitions, making clinical trial design challenging. In this manuscript, we discuss the diagnostic workup of metastatic biopsies to help guide the reproducible classification of phenotypic CRPC subtypes. We recommend classifying CRPC tumors based on histomorphology (adenocarcinoma, small cell carcinoma, poorly differentiated carcinoma, other morphologic variant, or mixed morphology) and IHC markers with a priority for AR, NK3 homeobox 1, insulinoma-associated protein 1, synaptophysin, and cell proliferation based on Ki-67 positivity, with additional markers to be considered based on the clinical context. Ultimately, a unified workup of metastatic CRPC biopsies can improve clinical trial design and eventually practice., (©2024 American Association for Cancer Research.)

Idiopathic inflammatory myopathies (IIM), or myositis, are a heterogeneous group of systemic autoimmune disorders that are associated with significant morbidity and mortality. Conducting high-quality clinical trials in IIM is challenging due to the rare and variable presentations of disease. To address this challenge, the Myositis Clinical Trials Consortium (MCTC) was formed. MCTC is a collaborative international alliance dedicated to facilitating, promoting, coordinating and conducting clinical trials and related research in IIM. This partnership works to advance the discovery of effective evidence-based treatments for IIM by integrating a diverse group of clinical investigators, research professionals, medical centres, patient groups, and industry partners. The Steering Committee, Core Group, and Paediatric Subcommittee of MCTC are comprised of myositis experts and junior investigators from around the world, representing a diversity of genders, geographies, and subspecialties. MCTC works alongside other current myositis organisations to complement existing work by concentrating on the operationalisation of clinical trials. Our pilot Myositis Investigators' Information Survey gathered responses from 173 myositis investigators globally and found considerable variability in proficiency with outcome measures, geographic disparities in patient recruitment, and a significant disconnect between investigators' routine myositis patient load and clinical trial enrolment. MCTC will meet the need to support and diversify myositis clinical trials by facilitating trial planning, feasibility assessments, site selection, and the training and mentoring of junior investigators/centres to establish their readiness for clinical trial participation. Through experienced leadership, strategic collaborations, and interdisciplinary discussions, MCTC will establish standards for IIM clinical trial design, protocols, and outcome measures in myositis.

Dermatomyositis (DM) is a rare and debilitating, systemic, autoimmune disease. While heterogenous in presentation and severity, DM is primarily characterised by a spectrum of skin and muscle disease, which may include proximal muscle weakness and recalcitrant cutaneous eruptions. DM may also be associated with joint pain and stiffness, inflammatory arthritis, dysphagia, fatigue, and calcinosis. The current standard of care for DM includes glucocorticoids, immunosuppressants, and intravenous immunoglobulin (IVIg). Unfortunately, these medications are not uniformly effective and can lead to adverse events, particularly with chronic use, necessitating discontinuation of therapy. Therefore, a substantial unmet need exists for more tailored and efficacious therapies that target DM pathogenesis. Brepocitinib is an oral, once-daily, novel, and specific TYK2/JAK1 inhibitor. Brepocitinib's potent inhibition of TYK2 and JAK1 reduces the signalling of pro-inflammatory cytokines, including IFN-α/β, IL-12, IL-23, and IFNγ, that have been implicated in the pathogenesis of DM. Other JAK inhibitors have been used off-label in both case series and open-label clinical trials in patients with DM; and brepocitinib has demonstrated efficacy in phase 2 clinical trials of several other autoimmune diseases, including plaque psoriasis, psoriatic arthritis, Crohn's disease, hidradenitis suppurativa, and ulcerative colitis. Therefore, there is a strong scientific and clinical rationale for the utility and potential effectiveness of brepocitinib in the treatment of DM patients. Currently, the safety, tolerability, and efficacy of brepocitinib is being evaluated in the largest (n=225) double-blind placebo-controlled phase 3 trial in DM patients to date (VALOR - NCT0543726).

Background: Understanding pain in myositis remains challenging. This study aimed to assess patient-reported pain and its correlation with myositis core set measures (CSMs), patient-reported outcomes (PROs) and functional measures., Methods: Fifty subjects underwent baseline, 3-month and 6-month assessments, evaluating myositis CSMs, functional measures and PROs. Pain was measured using three methods: (i) a 10-cm visual analogue scale, (ii) the pain score from the HAQ Disability Index and (iii) the Short Form 36 survey pain questions. Correlations between disease activity measures and pain were examined at baseline, and changes in both were assessed at 6 months, along with longitudinal change of pain. The change in pain was also correlated with the published 2016 ACR/EULAR myositis response criteria, physician/patient's assessment of change., Results: Nearly half of patients (45%) reported moderate to severe pain in all three pain scales, with higher severity of pain in PM/necrotizing myopathy subset. At baseline, pain severity showed a strong correlation with most CSMs, PROs and functional outcomes in all three pain scales, and similar trends were noted for change in pain at the 6 months. On longitudinal analysis, the physical function scores and fatigue showed strong correlation with pain. Pain improved in myositis patients with improvement in disease activity over time., Conclusions: Pain is common in myositis and is associated with multiple measures of disease activity, PROs and functional outcomes in myositis. Most importantly pain improves with improvement in disease activity. SF-36 pain questions have good psychometric properties., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Roux-en-Y gastric bypass may present long-term complications that require revisional surgery or even reversal to normal anatomy. Data on the indications, surgical technique, and outcomes of RYGB reversal remain scarce., Methods: We identified 48 cases of RYGB reversals with complete 90-day follow-up within a multi-centric international retrospective database of elective secondary bariatric surgery. The operations were performed between 2010 and 2024 in high-volume referral centers in Europe and USA. Data were collected on body weight, associated diseases, and on surgical outcomes up to 1-year postoperatively., Results: Patients were mainly female (81.3%) with a median age of 50 years (IQR 39-56). RYGB reversal was performed 7 years (median) after primary RYGB in patients with a BMI of 23.9 kg/m 2 (IQR 20-27). Half of the patients underwent at least 1 bariatric revision before the reversal. Main indications for reversal were dumping syndrome (33.3%), excessive weight loss (29.2%), marginal ulcer (14.6%), malabsorption (12.5%), and abdominal pain (10.4%). Rate of conversion to open surgery was 8.3%, and the postoperative complications during the first year reached 50%, including 31.3% Clavien-Dindo grade I-II, 16.7% grade III-IV complications, and one death. At 1 year, the mean BMI of the cohort increased by 18% to 28.25 kg/m 2 ; only 1 patient reached pre-RYGB BMI., Conclusion: Although RYGB is a theoretically reversible procedure, normal anatomy is re-established only in selected cases which are refractory to medical therapy and often also to revisional bariatric surgery. RYGB reversals entail high morbidity, while the extent of recurrent weight gain at 1-year post-reversal seems to allow patients to remain below the threshold of severe obesity., Competing Interests: Declarations. Ethical Approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Swiss Cantonal Ethics Committees of Zurich, Vaud and Northwest- and Central Switzerland approved the creation and analysis of the Global Benchmarks in Secondary Bariatric Surgery database (BASEC-Nr. 2019–02145). Centers from the European Union complied with the General Data Protection Regulation (EU Regulation 2016/679). The Austrian co-authors additionally applied guidelines of the Austrian Data Protection Law (Österreichisches Datenschutzgesetz, DSG 2000). The co-authors from the United Kingdom complied with the NHS Health Research Agency decision making tool for data handling. Co-authors from the United States complied with the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Informed Consent: Only fully anonymized data without any patient identifiers (such as date of birth, date of operation, date of follow-up, name, social security number, address of patient) were transferred for data analysis, derived from patients who consented for further use of their health-related data for research purposes. Competing Interests: Prof. Bueter and Prof. Peterli report consulting fees from Johnson & Johnson and Medtronic, outside the submitted work. Dr. Dillemans reports consulting fees from Medtronic and Johnson & Johnson, outside the submitted work. Prof. Lannoo reports a non-restricted grant from Medtronic, outside the submitted work. Prof Pring and Dr Slater are also employed by Streamline Clinics Ltd, outside the scope of this work. The other authors have no commercial associations to disclose., (© 2025. The Author(s).)

Objectives: The objective of this study was to explore the prevalence, characteristics and risk factors of COVID-19 breakthrough infections (BIs) in idiopathic inflammatory myopathies (IIMs) using data from the COVID-19 Vaccination in Autoimmune Diseases (COVAD) study., Methods: A validated patient self-reporting e-survey was circulated by the COVAD study group to collect data on COVID-19 infection and vaccination in 2022. BIs were defined as COVID-19 occurring ≥14 days after two vaccine doses. We compared BI characteristics and severity among patients with IIMs, patients with other autoimmune rheumatic and non-rheumatic diseases (AIRD, nrAID), and healthy controls (HCs). Multivariable Cox regression models were used to assess the risk factors for BI, severe BI ,and hospitalizations among patients with IIMs., Results: Among the 9449 included responses, BIs occurred in 1447 respondents (15.3%). The median age was 44 years [interquartile range (IQR) 21], 77.4% were female, and 182 BIs (12.9%) occurred among the 1406 patients with IIMs. Multivariable Cox regression among the data for patients with IIMs showed increasing age to be a protective factor for BIs [hazard ratio (HR) = 0.98, 95% CI = 0.97-0.99], and HCQ and SSZ use were risk factors (HR = 1.81, 95% CI = 1.24-2.64, and HR = 3.79, 95% CI = 1.69-8.42, respectively). Glucocorticoid use was a risk factor for a severe BI (HR = 3.61, 95% CI = 1.09-11.8). Non-white ethnicity (HR = 2.61, 95% CI = 1.03-6.59) was a risk factor for hospitalization. Compared with other groups, patients with IIMs required more supplemental oxygen therapy (IIMs = 6.0% vs AIRDs = 1.8%, nrAIDs = 2.2% and HCs = 0.9%), intensive care unit admission (IIMs = 2.2% vs AIRDs = 0.6%, nrAIDs and HCs = 0%), advanced treatment with antiviral or monoclonal antibodies (IIMs = 34.1% vs AIRDs = 25.8%, nrAIDs = 14.6% and HCs = 12.8%) and had more hospitalization (IIMs = 7.7% vs AIRDs = 4.6%, nrAIDs = 1.1% and HCs = 1.5%)., Conclusion: Patients with IIMs are susceptible to severe COVID-19 BIs. Age and immunosuppressive treatments were related to the risk of BIs., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: There is an unmet need to develop patient-reported outcomes measures for idiopathic inflammatory myopathies (IIM). We aimed to investigate the feasibility, compliance and psychometric properties of the National Institutes of Health's Patient-Reported Outcomes Measurement Information System (PROMIS) physical function-20 (PF-20) in a large US IIM population., Methods: 'Myositis Patient Centered Tele-Research' (My PACER) is a multicentre prospective observational study of IIM patients, competitively recruited through traditional in-person clinic visits [centre-based cohort (CBC)], and remotely using smartphone- and web-based technology [tele-research cohort (TRC)]. The CBC was further randomly divided (1:1 ratio) into a traditional local subcohort and a remote subcohort. Data collected included patient-reported outcomes and other patient self-assessments monthly for 6 months. Clinician-reported outcomes were obtained at baseline and 6 months., Results: A total of 120 IIM patients were enrolled (82 TRC/38 CBC, mean ± s.d. age 55 ± 13.4 years, 75% females, 81% Caucasians), with similar demographics and mean PROMIS PF-20 score between cohorts. The PROMIS PF-20 score was not associated with age, sex or race. The compliance and completion rates were similar between TRC and CBC as well as subcohorts. PROMIS PF-20 showed strong test-retest reliability at 1 month. PROMIS PF-20 was significantly associated with all core set measures except extra-muscular global and creatine kinase, as well as with most symptoms, and function and physical activity measures. PROMIS PF-20 illustrated concordant change with myositis response criteria and patient assessment, with a large effect size., Conclusions: PROMIS PF-20 demonstrates favourable psychometric properties including reliability, validity and responsiveness in a large cohort of myositis patients, with similar adherence in local or remotely enrolled patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Edentulism is a significant global oral health concern, particularly among elderly individuals. Complete dentures are widely used to restore oral functionality, esthetics, and quality of life. The incorporation of soft liners into complete dentures has been proposed as a means of improving patient comfort and reducing the pressure on the oral mucosa. This study aimed to evaluate and compare the maximum bite force (MBF) in patients wearing complete dentures with and without soft liners for over six months., Materials and Methods: Forty-four completely edentulous patients participated in this prospective cohort study, divided into two groups: Group 1 (n=22) received complete dentures with long-term, heat-cured, plasticized acrylic liners (Permasoft, Dentsply International, York, PA, USA) and Group 2 (n=22) received conventional complete dentures without liners. MBF was recorded at two months (T0) and six months (T1) after denture delivery. Statistical analyses included paired t-tests for intragroup comparisons and independent t-tests for intergroup comparisons., Results: Group 1 demonstrated a significant increase in MBF, from 46.07±12.28 N at T0 to 66.34±13.81 newtons (N) at T1 (P=0.021). Similarly, Group 2 exhibited an increase in MBF, from 38.32±12.61 N at T0 to 49.41±10.89 N at T1 (P=0.001). Intergroup comparisons revealed significantly higher MBF in Group 1 than in Group 2 at both time points, with a mean difference of 16.93 N (P=0.001) at T1., Conclusion: The results indicated that the use of soft liners in complete dentures significantly increased MBF over six months compared with conventional dentures. These findings underscore the clinical value of soft liners in improving denture performance and patient outcomes., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Institutional Ethics Committee of Surendera Dental College and Research Institute issued approval SDRI/IEC/22/35. The study followed the principles of the Declaration of Helsinki. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2025, Singla et al.)

Background: Dermatomyositis is a chronic autoimmune disease with distinctive cutaneous eruptions and muscle weakness, and the pathophysiology is characterised by type I interferon (IFN) dysregulation. This study aims to assess the efficacy, safety, and target engagement of dazukibart, a potent, selective, humanised IgG1 neutralising monoclonal antibody directed against IFNβ, in adults with moderate-to-severe dermatomyositis., Methods: This multicentre, double-blind, randomised, placebo-controlled, phase 2 trial was conducted at 25 university-based hospitals and outpatient sites in Germany, Hungary, Poland, Spain, and the USA. Adults aged 18-80 years with skin-predominant dermatomyositis were enrolled during stages 1, 2, and 2a, and had to have a Cutaneous Dermatomyositis Disease Area and Severity Index-Activity (CDASI-A) score of 14 or more and at least one unsuccessful systemic treatment with standard of care; whereas those with muscle-predominant dermatomyositis were enrolled in stage 3 and had to have active moderate muscle involvement. Patients were randomly assigned using an interactive response technology system to dazukibart 600 mg or placebo in stage 1; dazukibart 600 mg, dazukibart 150 mg, or placebo in stage 2; dazukibart 600 mg then placebo, dazukibart 150 mg then placebo, placebo then dazukibart 600 mg, or placebo then dazukibart 150 mg in stage 2a; and dazukibart 600 mg then placebo or placebo then dazukibart 600 mg in stage 3. For stage 2a and stage 3, treatments were switched at week 12. Patients, investigators, outcome assessors, and funders were masked to the treatment assignment. Dazukibart and placebo were administered intravenously on day 1 every 4 weeks, up to and including week 8 (stages 1 and 2, and stages 2a and 3 for patients starting dazukibart), or on week 12 every 4 weeks, up to and including week 20 (stages 2a and 3 for patients who started placebo and switched to dazukibart). The primary outcome for the skin-predominant cohorts was the change from baseline in CDASI-A score at week 12 assessed in the full analysis set (FAS; stage 1) and the pooled skin FAS (stages 1, 2, and 2a), and safety in the muscle-predominant cohort. This study is registered with ClinicalTrials.gov, NCT03181893., Findings: Between Jan 23, 2018, and Feb 23, 2022, 125 adults were assessed and 50 were excluded. 75 patients were randomly assigned and treated (15 to dazukibart 150 mg, 37 to dazukibart 600 mg, and 23 to placebo). Most patients were female (53 [93%] of 57 in the skin-predominant cohort vs 13 [72%] of 18 in the muscle-predominant cohort and four [7%] vs five [28%] were male). In the FAS in stage 1 at week 12, the mean change from baseline in CDASI-A for dazukibart 600 mg was -18·8 (90% CI -21·8 to -15·8; placebo-adjusted difference -14·8 [-20·3 to -9·4]; p<0·0001). In the pooled skin FAS at week 12, the mean change from baseline in CDASI-A for the dazukibart 600 mg group was -19·2 (-21·5 to -16·8; placebo-adjusted difference -16·3 [-20·4 to -12·1]; p<0·0001), whereas the dazukibart 150 mg group was -16·6 (-19·8 to -13·4; placebo-adjusted difference -13·7 [-18·3 to -9·0]; p<0·0001). Treatment-emergent adverse events occurred in 12 (80%) of 15 patients in the dazukibart 150 mg group versus 30 (81%) of 37 in the dazukibart 600 mg group versus 18 (78%) of 23 in the placebo group, with the most common being infections and infestations (two [13%] vs 12 [32%] vs seven [30%]). Four (11%) patients in the dazukibart 150 mg group and one (4%) in the placebo group reported serious adverse events. One patient in stage 3 received dazukibart 600 mg then placebo and died during follow-up due to haemophagocytic lymphohistiocytosis and macrophage activation syndrome., Interpretation: Dazukibart resulted in a pronounced reduction in disease activity and was generally well tolerated, supporting IFNβ inhibition as a highly promising therapeutic strategy in adults with dermatomyositis., Funding: Pfizer., Competing Interests: Declaration of interests DF received grant support from Pfizer and EMD Serono; performs contracted research for Argenx, Kyverna, and IGM Biosciences; is a paid consultant for Pfizer, Bristol Myers Squibb, Argenx, Biogen, Janssen, Nuvig, and Priovant; and served on an advisory data and safety monitoring board panel for UCB and Amgen. ARM received grants or research support from Kyowa, Miragen, Regeneron, Corbus, Sun Pharma, Incyte, Pfizer, Merck, Priovant, Eli Lilly, Elorac, Novartis, Janssen, Soligenix, Argenx, Palvella, AbbVie, Bristol Myers Squibb, and Horizon; was a consultant for Nuvig, Kyowa, Eli Lilly, Momenta, UCB, Regeneron, Incyte, Phlecs, Soligenix, Clarivate, Argenx, Janssen, Bristol Myers Squibb, Boehringer Ingelheim, and Pfizer; and has two provisional and one filed intellectual property patents (Methods and materials for assessing and treating cutaneous squamous cell carcinoma [provisional 63–423254]; Use of oral JAKi in lichen planus [provisional 63/453,065]; and Topical ruxolitinib in lichen planus [wo2022072814a1]). VPW received grant support from Celgene, Janssen, Pfizer, Biogen, Gilead, Corbus, Genentech, AstraZeneca, Viela, Syntimmune, Amgen, Regeneron, Argenx, CSL Behring, Ventus, Q32 Bio, Bristol Myers Squibb, Horizon, Rome Pharmaceuticals, and Priovant; and consultant fees from Janssen, Lilly, Pfizer, Biogen, Bristol Myers Squibb, Gilead, Amgen, Nektar, Incyte, EMD Serono, CSL Behring, Crisalis, Viela, Argenx, Kwoya Kirin, Regeneron, AstraZeneca, AbbVie, Octapharma, GSK, Cugene, UCB, Corcept, Beacon Bioscience, Rome Pharmaceuticals, Horizon, Merck, Kezar, Sanofi, Bayer, Akari, Calyx, Cabaletta Bio, and Nuvig. LC-S received institutional grant support and consultant fees from Pfizer, Janssen, Corbus, Argenx, Bristol Myers Squibb, Horizon, Priovant, EMD Serono, Octapharma, Mallinkrodt, Galapagos, and Nuvig. AF received grant support and honoraria from Mallinckrodt and Novartis; honoraria from AbbVie and Bristol Myers Squibb; and is a principal investigator for Alexion. ACMM received honoraria from UpToDate. JCS received research grant support from Novartis, Merck, GSK, Regeneron, and Bristol Myers Squibb. LVG is a principal investigator in this trial and for Argenx, Biogen, and Regeneron. APF received speakers bureau fees from AbbVie, Bristol Myers Squibb, Mallinckrodt, and Kyowa; consulting fees from Biogen, Bristol Myers Squibb, and UCB; and received research grant support or served as a principal investigator for Pfizer, Alexion, and Priovant. RA received research grant support from Boehringer Ingelheim, Bristol Myers Squibb, EMD Serono, Janssen, Mallinckrodt, Pfizer, and Q32 Bio; and consulting fees from ActiGraph, Alexion, ANI Pharmaceuticals, Argenx, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cabaletta Bio, Capella, Corbus, CSL Behring, EMD Serono, Galapagos, Horizon Therapeutics, I-Cell, Janssen, Kezar, Kyverna, Merck, Novartis, Nuvig, Octapharma, Pfizer, Regeneron, Roivant, Sanofi, and Teva. KR received consulting fees from Pfizer. MC, KMP, XL, CH, NR, AS, BO, AB, MS, CB, SN, JSB, MSV, and EP are employees of Pfizer. JSB is a shareholder of Pfizer. RAV is a principal investigator in this trial and a paid consultant for ArgenX, Priovant, and Lilly., (Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background The medical education system periodically revises the teaching-learning strategies. Medical students find it difficult to cope with pre-clinical subjects due to limited patient exposure and traditional didactic lectures. This study introduced a jigsaw method for revising biochemistry topics and assessed first-year medical students' perceptions and feedback on its effectiveness and implementation in medical education. Materials and methods This cross-sectional study enrolled 80 students for a jigsaw exercise on the topic "carbohydrate chemistry." Students were divided into four groups guided by a moderator. Further subgroups were created in each group, and each student was assigned a subtopic in "carbohydrate chemistry." Students with common subtopics were regrouped to self-study the provided study material. Students then reassembled in their original subgroups to teach their respective subtopics to their peers. Thus, it enables all students of a subgroup to learn all subtopics of the main topic in a short time as an interactive team. In the end, students filled out a feedback form providing their opinion about the effectiveness of the exercise. Results Out of 80 students, 71 responded to the survey, yielding an 88.75% response rate. Most students opined that the jigsaw exercise enhanced their understanding (N = 59, 83.1%), clarified concepts (N = 54, 76.1%), improved retention (N = 55, 77.5%), and communication skills (N = 59, 83.1%) and that it is a good method to revise topics (N = 58, 81.7%). Most supported its inclusion in the medical curriculum (N = 56, 78.9%) and recommended frequent use (N = 49, 69%). Conclusion The jigsaw exercise seems promising for improving students' understanding, clearing doubts, enhancing retention and communication skills, and fast revision. The authors recommend its inclusion in the curriculum to facilitate self-directed active learning., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Institutional Ethics Committee of All India Institute of Medical Sciences, Bathinda issued approval IEC/AIIMS/BTI/306. The study was approved by the institutional ethics committee of our Institute on March 3, 2023. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2025, Nimesh et al.)

Background: Sudden cardiac death (SCD) in early adults aged 25 to 44 years represents an important and unexpected cause of death. We assessed trends in SCD-related mortality in the United States from 1999 to 2020 among early adults to determine differences by sex, ethnoracial groups, urbanization, and census region., Methods and Results: Mortality data were retrieved from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) data set from 1999 to 2020. Age-adjusted mortality rates were assessed using the Joinpoint regression modeling and expressed as estimated average annual percentage change with relative 95% CIs. Trends in prevalence of coronary artery disease/myocardial infarction, heart failure, and stroke, which may have contributed to SCD-related mortality over the same period, were obtained from the National Health and Nutrition Examination Survey. From 1999 to 2020, 10 516 US early adults aged 25 to 44 years had SCD (7832 men and 2684 women), resulting in 3.72 deaths per 1000 population, or a mean of 478 deaths annually. The relative age-adjusted mortality rate increased linearly (average annual percentage change: +1.0% [95% CI, 0.3-1.8]), without sex differences. The age-adjusted mortality rate increase was more pronounced in Black patients, Hispanic/Latinx patients, and residents of rural areas. Higher absolute numbers of SCDs were clustered in the South (47.6%). During the same period, the prevalence of coronary artery disease/myocardial infarction, heart failure, and stroke plateaued. SCD-related mortality associated with opioids/stimulants overdose significantly increased over the entire study period., Conclusions: SCD-related mortality among early adults has increased over the last 2 decades in the United States with notable racial and regional disparities.

Introduction: Olecranon fractures account for 5-7% of elbow fractures, making them a common injury. The majority of these fractures are treated surgically because they are intra-articular and can disrupt the elbow extensor mechanism. Mayo Type II fractures are displaced with a stable ulnohumeral joint, indicating intact ligamentous structures, particularly the anterior portion of the medial collateral ligament., Case Report: In our case report, a male in his 20's came to the outpatient department with complaints of pain in the right elbow since 1 day following a fall from a bike. He also reported that he was unable to fully extend his right elbow. After a plain radiograph, a right displaced comminuted olecranon fracture was suggested. He underwent a pre-anesthesia checkup and standard laboratory testing before being taken for surgery. Open reduction internal fixation with fragment-specific plates was done. An above-elbow slab in the extended position was applied post-surgery and continued for 14 days. Elbow range of motion physiotherapy was started in accordance with tolerance, and the patient responded favorably to surgery., Conclusion: To effectively categorize olecranon fractures according to displacement, comminution, and stability, the Mayo classification was developed. With appropriate computed tomography scan imaging and pre-operative planning, individual fragments of these comminuted fractures can be delineated, and fragment-specific implants can be used, resulting in good radiological and clinical outcome with minimal complications as compared to tension band wiring., Competing Interests: Conflict of Interest: Nil, (Copyright: © Indian Orthopaedic Research Group.)

The presence of an M-band in serum and/or urine electrophoresis is a crucial diagnostic indicator for multiple myeloma and other plasma cell dyscrasias. Conventionally, on serum protein electrophoresis (SPEP), the M-band is observed as a sharp spike (M-spike), typically in the gamma region, occasionally in the beta region, and rarely in the alpha region. However, the infrequency of M-bands in the alpha region raises the possibility of overlooking them when coexisting with normal bands. This study underscores the significance of considering the potential discovery of M-bands in unusual sites, particularly in the alpha-2 region. This retrospective study spanned three years and involved conducting serum and urine protein electrophoresis followed by serum and urine immunofixation electrophoresis on a semi-automated platform (Helena Biosciences, Europe) using agarose gel and serum protein 6-band format kits. We identified five cases of multiple myeloma presenting with a monoclonal band in the alpha-2 region on SPEP and UPEP. Subsequent immunofixation electrophoresis confirmed these bands to be monoclonal bands in the lambda lane. In suspected cases of multiple myeloma, even in the absence of an M-band in the gamma region, heightened prominence in the alpha or beta region warrants further investigation through immunofixation electrophoresis (IFE)., (© Indian Society of Hematology and Blood Transfusion 2024.)

This research aims to address the data gaps in freshwater ecotoxicological characterization factors (CFs) for per- and polyfluoroalkyl substances (PFASs). These CFs are essential for incorporating the ecotoxicity impacts of PFAS emissions into life cycle assessments (LCAs). This study has three primary objectives: first, to calculate a comprehensive set of experimental aquatic ecotoxicity CFs for PFASs utilizing the USEtox model (version 2.13); second, to compare these newly derived CFs with those generated using the PFAS-adapted USEtox model; and finally, to test the hypothesis concerning a potential correlation between CFs and effect factors (EFs) with the number of perfluorinated carbons in PFASs. In this study, 367 PFASs were selected from the CompTox Chemicals Dashboard PFAS suspect lists and REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) registration dossiers. Experimental ecotoxicity data were extracted from CompTox Version 2.1.1 and REACH. Using both the USEtox model (version 2.13) and the PFAS-adapted USEtox model, CFs were calculated for 367 PFASs. Of these, 237 CFs were newly calculated using the HC20EC10eq-based methodology, enriching the representation of PFASs in LCA studies. The analysis revealed no correlation between the number of perfluorinated carbons and the calculated EFs and CFs using the USEtox models. This study covers only a small portion of the extensive list of millions of PFASs in PubChem, primarily due to data constraints and scarcity. Discrepancies between CFs generated by USEtox and PFAS-adapted USEtox are attributed to variations in foundational fate and exposure factor calculation methodologies, whereas ecotoxicity factors remained consistent. Consequently, it is suggested that CFs for PFASs are dependent on the modeling approach and require regular updates with the latest data to ensure accuracy and relevance., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Society of Environmental Toxicology and Chemistry.)

Introduction: Kawasaki disease [KD] is a systemic disorder characterized by acute febrile illness due to widespread medium-vessel vasculitis, mainly affecting children. Despite the ongoing advanced research into the disease pathophysiology and molecular mechanisms, the exact etiopathogenesis of KD is still an enigma. Recently, single-cell RNA sequencing [scRNA-seq], has been utilized to elucidate the pathophysiology of KD at a resolution higher than that of previous methods., Area Covered: In the present article, we re-emphasize the pivotal role of this high-resolution technique, scRNA-seq, in the characterization of immune cell transcriptomic profile and signaling/response pathways in KD and explore the diagnostic, prognostic, and therapeutic potential of this new technique in KD. Using combinations of the search phrases 'KD, scRNA-seq, CAA, childhood vasculitis' a literature search was carried out on Scopus, Google Scholar, and PubMed until the beginning of 2024., Expert Opinion: scRNA-seq presents a transformative tool for dissecting KD at the cellular level. By revealing rare cell populations, gene expression alterations, and disease-specific pathways, scRNA-seq aids in understanding the intricacies of KD pathogenesis. This review will provide new insights into pathogenesis of KD and the field of applications of scRNA-seq in personalized therapeutics for KD in the future.

The Immunization and Vaccines-related Implementation Research Advisory Committee (IVIR-AC) is the primary advisory body of the World Health Organization conducting independent reviews of immunization-related implementation research, with a primary focus on transmission and economic modeling analyses that estimate the value and impact of vaccines. From 10 to 13th September 2024, IVIR-AC convened virtually for its second of two semi-annual meetings to provide feedback and recommendations across six sessions including: pneumococcal vaccination strategies that rely on indirect protection; vaccine impact modeling for chikungunya; The Lancet Commission on strengthening the use of epidemiological modeling of emerging and pandemic infectious diseases; methods for immunization coverage estimation; setting immunization research priorities in the South-East Asian Region; and modeling evidence related to typhoid conjugate vaccine schedules. This report summarizes the sessions, proceedings, and recommendations from that meeting., Competing Interests: Declaration of competing interest P. L. is supported financially by the Bill & Melinda Gates Foundation. S. S. was supported by the World Health Organization for this work. A. N. S. was financially supported by the World Health Organization for this work, and is additionally supported by the Bill & Melinda Gates Foundation, Gavi, the Vaccine Alliance, and the National Institutes of Health. M. K. is supported by the Bill & Melinda Gates Foundation. A. B. H. was supported by the Australian National Health and Medical Research Council for this work, is additionally supported by PATH, the World Health Organization, and Gavi, the Vaccine Alliance, and has received consulting fees from the Australian NSW Ministry of Health, WHO Europe and Asian Development Bank. A. P. is supported by Gavi, the Vaccine Alliance, Imperial College London, the Bill & Melinda Gates Foundation, and the World Health Organization. A. N. S. and A. B. H. report travel related support from the World Health Organization to attend previous IVIR-AC meetings. All other authors have no declarations., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)