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Objective: Idiopathic inflammatory myopathies (myositis, IIMs) are rare, systemic autoimmune disorders that lead to muscle inflammation, weakness, and extra-muscular manifestations, with a strong genetic component influencing disease development and progression. Previous genome-wide association studies identified loci associated with IIMs. In this study, we imputed data from two prior genome-wide myositis studies and analyzed the largest myositis dataset to date to identify novel risk loci and susceptibility genes associated with IIMs and its clinical subtypes., Methods: We performed association analyses on 14,903 individuals (3,206 cases and 11,697 controls) with genotypes and imputed data from the Trans-Omics for Precision Medicine (TOPMed) reference panel. Fine-mapping and expression quantitative trait locus co-localization analyses in myositis-relevant tissues indicated potential causal variants. Functional annotation and network analyses using the random walk with restart (RWR) algorithm explored underlying genetic networks and drug repurposing opportunities., Results: Our analyses identified novel risk loci and susceptibility genes, such as FCRLA, NFKB1, IRF4, DCAKD, and ATXN2 in overall IIMs; NEMP2 in polymyositis; ACBC11 in dermatomyositis; and PSD3 in myositis with anti-histidyl-tRNA synthetase autoantibodies (anti-Jo1). We also characterized effects of HLA region variants and the role of C4. Colocalization analyses suggested putative causal variants in DCAKD in skin and muscle, HCP5 in lung, and IRF4 in EBV-transformed lymphocytes, lung, and whole blood. RWR further prioritized additional candidate genes, including APP, CD74, CIITA, NR1H4, and TXNIP, for future investigation., Conclusion: Our study uncovers novel genetic regions contributing to IIMs, advancing our understanding of myositis pathogenesis and offering new insights for future research., (This article is protected by copyright. All rights reserved.)

Background: Beta-2 agonists play an important role in the management of asthma. Inhaled long-acting beta-2 agonists (LABAs) and short-acting beta-2 agonists (SABAs) cause bronchodilation by stimulating adrenoceptors. These receptors are also present in cardiac cells and, as a side effect, could also be stimulated by inhaled beta-2 agonists., Objective: This study aims to assess the effect of beta-2 agonists on heart rate (HR)., Methods: The data were retrieved from an observational study, the myAirCoach Quantification Campaign. Beta-2 agonist use was registered by self-reported monthly questionnaires and by smart inhalers. HR was monitored continuously with the Fitbit Charge HR tracker (Fitbit Inc). Patients (aged 18 years and older) were recruited if they had uncontrolled asthma and used inhalation medication. Our primary outcome was the difference in HR between LABA and non-LABA users. Secondary outcomes were the difference in HR on days SABAs were used compared to days SABAs were not used and an assessment of the timing of inhaler use during the day., Results: Patients using LABA did not have a clinically relevant higher HR (average 0.8 beats per minute difference) during the day. Around the moment of SABA inhalation itself, the HR does increase steeply, and it takes 138 minutes before it returns to the normal range., Conclusions: This study indicates that LABAs do not have a clinically relevant effect on HR. SABAs are instead associated with a short-term HR increase., Trial Registration: ClinicalTrials.gov NCT02774772; https://clinicaltrials.gov/study/NCT02774772., (©Rishi Jayant Khusial, Jacob K Sont, Omar S Usmani, Matteo Bonini, Kian Fan Chung, Stephen James Fowler, Persijn J Honkoop. Originally published in JMIR Cardio (https://cardio.jmir.org), 11.12.2024.)

Psoriasis (Ps) is a debilitating immune-mediated chronic skin condition. It affects about 1-3% of the world population, with an 8-11% prevalence in Northern European populations. Tyrosine kinase 2 (TYK2) is a newly identified target for Ps. An independent non-coding genetic association with Ps has been identified ~400 kb upstream of TYK2. The variants making up the credible Ps Single-Nucleotide Polymorphism (SNP) set were identified in their genomic context with the potential to influence TYK2 expression by interacting with regulatory elements involved in gene regulation. Previous evidence from our laboratory has suggested that credible SNP sets in intronic regions can be distal regulators of the genes of interest through long-range chromatin interactions. We hypothesise that SNPs at ILF3 are distal regulators of TYK2 expression via long-range chromatin interactions and Ps risk. The dysregulation of the TYK2 pathway in Ps may be mediated by a combination of GWAS risk SNPs at ILF3 and TYK2 and downstream genes. We investigated this by employing functional genomics and molecular biology methods. We developed a CD4 T cell model system with Jurkat-dCAS9-VP64 and Jurkat-dCAS9-KRAB cells using CRISPR activation and CRISPR inhibition of the risk variants rs892086 and rs7248205, selected from the latest Ps GWAS SNP set for their long-range interaction and light Linkage Disequilibrium (R 2 > 0.8), respectively. Using CRISPR activation, we demonstrate here that these risk SNPs, although distal to TYK2, do indeed regulate the TYK2 gene. Investigations into annotating the TYK2 pathway using RNA-seq analysis revealed differentially regulated genes, including VEGFA, C1R, ADORA1, GLUD2, NDUFB8, and FCGR2C, which are thought to be implicated in Ps. These genes were observed to be associated with conditions such as psoriatic arthritis, atopic dermatitis, and systemic sclerosis when compared using published databases, which confirms their relevance and importance in inflammatory conditions. With the developed cell model systems using CRISPR technology and differential gene regulation, we demonstrate here that these genes have the potential to define the TYK2/Ps pathway and our understanding of the disease biology.

Normal tissues adjacent to the tumor (NATs) may harbor early breast carcinogenesis events driven by field cancerization. Although previous studies have characterized copy-number (CN) and transcriptomic alterations, the evolutionary history of NATs in breast cancer (BC) remains poorly characterized. Utilizing whole-genome sequencing (WGS), methylation profiling, and RNA sequencing (RNA-seq), we analyzed paired germline, NATs, and tumor samples from 43 individuals with BC in Hong Kong (HK). We found that single-nucleotide variants (SNVs) were common in NATs, with one-third of NAT samples exhibiting SNVs in driver genes, many of which were present in paired tumor samples. The most frequently mutated genes in both tumor and NAT samples were PIK3CA, TP53, GATA3, and AKT1. In contrast, large-scale aberrations such as somatic CN alterations (SCNAs) and structural variants (SVs) were rarely detected in NAT samples. We generated phylogenetic trees to investigate the evolutionary history of paired NAT and tumor samples. They could be categorized into tumor only, shared, and multiple-tree groups, the last of which is concordant with non-genetic field cancerization. These groups exhibited distinct genomic and epigenomic characteristics in both NAT and tumor samples. Specifically, NAT samples in the shared-tree group showed higher number of mutations, while NAT samples belonging to the multiple-tree group showed a less inflammatory tumor microenvironment (TME), characterized by a higher proportion of regulatory T cells (Tregs) and lower presence of CD14 cell populations. In summary, our findings highlight the diverse evolutionary history in BC NAT/tumor pairs and the impact of field cancerization and TME in shaping the genomic evolutionary history of tumors., Competing Interests: Declaration of interests Authors have no competing interests to disclose., (Published by Elsevier Inc.)

Anti-Ro/SS-A antibodies are prevalent across systemic autoimmune rheumatic diseases (SARDs) and may signify a distinctive phenotype. This study aimed to identify protein biomarkers associated with symptom burden and health-related quality of life (HR-QoL), and use protein-based stratification to identify clinically meaningful clusters and inflammatory pathways implicated. Anti-Ro positive SARD patients were enrolled in a 6-month pilot study. HR-QoL was determined using a patient-reported visual analogue scale, and symptom burden was assessed with the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI). Proximity extension immunoassays measured normalized protein expression (NPX) across 92 inflammatory proteins. Linear regression identified proteins linked to patient outcomes. Unsupervised hierarchical clustering of baseline NPX identified patient clusters. Functional protein association networks were visualized using String V.12.0. Diagnostic groups showed no differences in HR-QoL or physician global assessment (PhGA). Poor HR-QoL and high symptom burden correlated with downregulated inflammatory proteins, while PhGA correlated with upregulated proteins. Two distinct clusters were identified; Cluster 1, 'low expression cluster' exhibited higher symptom burden and more impaired HR-QoL, while Cluster 2, 'high expression cluster' correlated with a higher physician global assessment (PhGA). Key hub proteins included TGF-β1, CXCL-8, and CCL-2. This study identified patient clusters across the Ro-positive SARD, linking symptom burden to specific proteomic profiles. Unraveling novel protein networks associated with symptom burden and poor HR-QoL may identify therapeutic targets, which address patient-reported outcome measures (PROMs) across several disease indications.

Introduction: Psoriasis in high-impact areas, including the scalp, nails, palms, and soles, can disproportionately impair patient quality of life. Here, we evaluate the 2-year efficacy of bimekizumab treatment in patients with moderate to severe plaque psoriasis in post hoc analyses of five phase 3/3b trials., Methods: High-impact area efficacy data were pooled through 2 years across five phase 3/3b trials: BE VIVID, BE READY, BE SURE, their ongoing open-label extension (OLE) BE BRIGHT, and BE RADIANT (including its double-blinded treatment period and the first year of its OLE). Complete clearance of psoriasis in high-impact areas is reported over 2 years using the scalp Investigator's Global Assessment (IGA), palmoplantar IGA, and modified Nail Psoriasis Severity Index (mNAPSI). Patients included in these analyses had baseline moderate to severe scalp or palmoplantar involvement (scalp or palmoplantar IGA score ≥ 3) or mNAPSI score > 10., Results: A total of 1107 patients were randomized to bimekizumab and entered the OLEs. Subsets of 821 patients had scalp IGA ≥ 3 at baseline, 377 had mNAPSI > 10, and 193 had palmoplantar IGA ≥ 3. Complete scalp clearance in patients with baseline scalp IGA ≥ 3 randomized to bimekizumab was achieved rapidly, with high responses sustained from first (86.4%) to second year (85.9%). Nail clearance responses in patients with baseline mNAPSI > 10 increased from 63.4% to 68.5% from first to second year. Palmoplantar clearance in patients with baseline palmoplantar IGA ≥ 3 was sustained from first (88.3%) to second year (89.8%). Similar trends were seen in the 374 patients who received bimekizumab 320 mg every 4 weeks (Q4W)/every 8 weeks (Q8W) initial/maintenance dosing., Conclusion: In these analyses pooled across 2 years, bimekizumab showed sustained efficacy in psoriasis in high-impact areas., Gov Trial Registration Numbers: NCT03370133, NCT03410992, NCT03412747, NCT03598790, NCT03536884., Competing Interests: Declarations. Conflicts of Interest: All details of authors’ affiliation or involvement in an organization or entity with a financial or nonfinancial interest in the subject matter or materials discussed in this manuscript are disclosed. Joseph F. Merola: A consultant and/or investigator for AbbVie, Amgen, Biogen, Bristol Myers Squibb, Dermavant, Eli Lilly, Janssen, LEO Pharma, Pfizer, Novartis, Regeneron, Sanofi, Sun Pharma, and UCB. Alice B. Gottlieb: Received honoraria as an advisory board member and consultant for Amgen, AnaptypsBio, Avotres Therapeutics, Bristol Myers Squibb, Boehringer Ingelheim, Dice Therapeutics, Eli Lilly, Janssen, Novartis, Sanofi, UCB, and Xbiotech; received research/educational grants from AnaptypsBio, Bristol Myers Squibb, Moonlake Immunotherapeutics, Novartis, and UCB; all funds paid to Mount Sinai School of Medicine. Andreas Pinter: Investigator and/or speaker and/or advisor for AbbVie, Almirall, Amgen, Biogen, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, GSK, Hexal, Janssen, LEO Pharma, MC2, Medac, Merck Serono, Mitsubishi Pharma, MSD, MoonLake Immunotherapeutics, Novartis, Pfizer, Regeneron, Roche, Sandoz, Schering-Plough, Tigercat Pharma, and UCB. Boni Elewski: Research support as funding to Case Western Reserve University from AbbVie, AnaptysBio, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Incyte, LEO Pharma, Menlo, Merck, Novartis, Pfizer, Regeneron, Sun Pharma, Valeant, and Vanda; Consultant (honoraria) from Arcutis, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, LEO Pharma, Menlo, Novartis, Pfizer, Sun Pharma, UCB, Valeant, and Verrica. Melinda Gooderham: Investigator, speaker, consultant, or advisory board member for AbbVie, Akros, Amgen, AnaptysBio, Arcutis, Aslan, Aristea, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Dermavant, Dermira, Eli Lilly, Galderma, GSK, Incyte, Janssen, Kyowa Kirin, MedImmune, Meiji, Merck, Moonlake Immunotherapeutics, Nimbus, Novartis, Pfizer, Regeneron, Reistone, Sanofi Genzyme, Sun Pharma, and UCB. Richard B. Warren: Consulting fees from AbbVie, Almirall, Amgen, Arena, Astellas, Avillion, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, GSK, Janssen, LEO Pharma, Novartis, Pfizer, Sanofi, and UCB; research grants to institution from AbbVie, Almirall, Janssen, LEO Pharma, Novartis, and UCB; honoraria from Astellas, DICE Therapeutics, GSK, and Union Therapeutics. Stefano Piaserico: Served as consultant and/or speaker for AbbVie, Almirall, Celgene, Eli Lilly, Janssen, LEO Pharma, Merck, Novartis, Pfizer, Sandoz, and UCB. Krista Wixted, Nancy Cross, Nicola Tilt, Susanne Wiegratz: Employees and shareholders of UCB. Ulrich Mrowietz: Advisor and/or clinical study investigator for, and/or received honoraria and/or grants from AbbVie, Aditxt, Almirall, Amgen, Aristea, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Dr. Reddy’s, Eli Lilly, Formycon, Immunic, Janssen-Cilag, LEO Pharma, Merck, MetrioPharm, Novartis, Phi-Stone, Sanofi-Aventis, Merck Sharp & Dohme, UCB, and Union Therapeutics. Ethical Approval: Reviewed and approved by the relevant IRBs. Clinicaltrials.gov trial registration: NCT03370133, NCT03410992, NCT03412747, NCT03598790, NCT03536884. Studies were conducted in accordance with the principles of the Declaration of Helsinki and approved by an independent review board and independent ethics committee. All participants provided informed written consent documented in accordance with local regulations. Written consent for the publication of recognizable patient photographs or other identifiable material was obtained by the authors and attested to at the time of article submission to the journal stating that all patients gave consent with the understanding that this information may be publicly available., (© 2024. The Author(s).)

Aims/hypothesis: The aim of this study was to investigate how diabetes mellitus affects longer term outcomes in individuals presenting to hospital with non-ST segment elevation myocardial infarction (NSTEMI)., Methods: We analysed data from 456,376 adults hospitalised between January 2005 and March 2019 with NSTEMI from the UK Myocardial Ischaemia National Audit Project (MINAP) registry, linked with Office for National Statistics death reporting. We compared outcomes and quality of care by diabetes status., Results: Individuals with diabetes were older (median age 74 vs 73 years), were more often of Asian ethnicity (13% vs 4%) and underwent revascularisation (percutaneous coronary intervention or coronary artery bypass graft surgery) (38% vs 40%) less frequently than those without diabetes. The mortality risk for those with diabetes compared with those without was significantly higher at 30 days (HR 1.19, 95% CI 1.15, 1.23), 1 year (HR 1.28, 95% CI 1.26, 1.31), 5 years (HR 1.36, 95% CI 1.34, 1.38) and 10 years (HR 1.39, 95% CI 1.36, 1.42). In individuals with diabetes, higher quality inpatient care, assessed by opportunity-based quality indicator (OBQI) score category ('poor', 'fair', 'good' or 'excellent'), was associated with lower mortality rates compared with poor care (good: HR 0.74, 95% CI 0.73, 0.76; excellent: HR 0.69, 95% CI 0.68, 0.71). In addition, compared with poor care, excellent care in the diabetes group was associated with the lowest mortality rates in the diet-treated and insulin-treated subgroups (diet-treated: HR 0.64, 95% CI 0.61, 0.68; insulin-treated: HR 0.69, CI 0.66, 0.72)., Conclusion/interpretation: Individuals with diabetes experience disparities during inpatient care following NSTEMI. They have a higher risk of long-term mortality than those without diabetes, and higher quality inpatient care may lead to better long-term survival., Competing Interests: Data availability: The data underlying this article were provided by the National Institute for Cardiovascular Outcomes Research (NICOR). Data will be shared on request to the corresponding author with the permission of NICOR. Funding: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. Authors’ relationships and activities: The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: All authors made substantial contributions to the conception or design of the work or the acquisition, analysis or interpretation of data; and drafting or reviewing the article critically for important intellectual content. All authors approved the final version to be published. MAM is responsible for the integrity of the work as a whole., (© 2024. The Author(s).)

Objectives: Sleep disturbance has been associated with chronic widespread pain (CWP), but their causal relationship remains unclear. We aimed to examine the causal relationship and direction between CWP and sleep traits, namely insomnia, sleep duration and chronotype, using Mendelian Randomization., Method: We used genetic association data from ~0.5 million individuals and up to 1.8 million controls from the UK Biobank (UKB). All traits were defined predominantly by self-report. Short sleep duration was defined as average ≤6 hours per 24 hours. Chronotype refers to the inclination to sleep at certain times where some wake and go to bed early ('morning' person), and others wake and go to sleep later ('evening' person). To permit use of the largest available genetic association data, we used the Causal Analysis Using Summary Effect estimates (CAUSE) method, which allows for sample overlap., Results: Insomnia (OR 1.009, 95% credible interval 1.005, 1.014; p = 0.018 that the causal model is a better fit than non-causal model) and short sleep duration (OR 1.060, 95%CrI 1.038, 1.083; p = 0.040) were causally associated with increased risk of CWP, with limited evidence for reverse causation. There was no evidence in support of long sleep duration or chronotype being associated with CWP., Conclusions: This study suggest that insomnia and short sleep duration (≤6 hours) are associated with an increased risk of CWP. Improving short sleep duration and insomnia, rather than chronotype, may be effective in reducing the risk of CWP, although these results should be replicated in epidemiological and interventional studies., Competing Interests: Declarations. Consent for publication: No external editing support or AI was used in our work. No part of this manuscript is copied or published elsewhere in whole or in part. Our work has not been published separately as a congress abstract at this time. Conflict of interest: The authors declare that they have no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Empirical evidence for a low normal or reference interval for serum prolactin (PRL) is lacking for men, while the implications of very low PRL levels for human health have never been studied. A clinical state of "PRL deficiency" has not been defined except in relation to lactation. Using data from the European Male Ageing Study (EMAS), we analyzed the distribution of PRL in 3,369 community-dwelling European men, aged 40-80 years at phase-1 and free from acute illnesses. In total, 2,948 and 2,644 PRL samples were collected during phase-1 and phase-2 (3 to 5.7 years later). All samples were analysed in the same centre with the same assay. After excluding individuals with known pituitary diseases, PRL ≥ 35 ng/ml, and PRL-altering drugs including antipsychotic agents, selective serotonin reuptake inhibitors, or dopamine agonists, 5,086 data points (2,845 in phase-1 and 2,241 in phase-2) were available for analysis. The results showed that PRL declined minimally with age (slope = -0.02) and did not correlate with BMI. The positively skewed PRL distribution was log-transformed to a symmetrical distribution (skewness reduced from 13.3 to 0.015). Using two-sigma empirical rule (2[]SD about the mean), a threshold at 2.5% of the lower end of the distribution was shown to correspond to a PRL value of 2.98ng/ml. With reference to individuals with PRL levels of 5-34.9 ng/ml (event rate = 6.3%), the adjusted risk of developing type 2 diabetes increased progressively in those with PRL levels of 3-4.9 ng/ml: event rate = 9.3%, OR (95% CI) 1.59 (0.93-2.71), and more so with PRL levels of 0.3-2.9 ng/ml: event rate = 22.7%, OR 5.45 (1.78-16.62). There was also an increasing trend in prediabetes and diabetes based on fasting blood glucose levels was observed with lower categories of PRL. However, PRL levels were not associated with cancer, cardiovascular diseases, depressive symptoms or mortality. Our findings suggest that a PRL level below 3 ng/ml (64 mlU/l) significantly identifies European men with a clinically-important outcome (of type 2 diabetes), offering a lower reference-value for research and clinical practice., Competing Interests: Declarations. Ethical approval: Ethical approval for the study was obtained in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the study. Conflict of interest: There is not conflict of interest., (© 2024. The Author(s).)

Insulin-like peptide 3 (INSL3) is a circulating biomarker for Leydig cell functional capacity in men, also indicating Leydig Cell Insufficiency (LCI) and potential primary hypogonadism. Using results from large cohort studies we explore sources of biological and technical variance, and establish a reference range for adult men. It is constitutively secreted with little within-individual variation and reflects testicular capacity to produce testosterone. The main INSL3 assays available indicate good concordance with low technical variance; there is no effect of ethnicity. INSL3 declines with age from 35 years at about 15% per decade. Like low calculated free testosterone, and to a lesser extent low total testosterone, reduced INSL3 is significantly associated with increasing age-related morbidity, including lower overall sexual function, reflecting LCI. Consequently, low INSL3 (≤0.4 ng/ml; ca. <2 SD from the population mean) might serve as an additional biochemical marker in the assessment of functional hypogonadism (late-onset hypogonadism, LOH) where testosterone is in the borderline low range. Excluding individuals with low LCI (INSL3 ≤ 0.4 ng/ml) leads to an age-independent (> 35 years) reference range (serum) for INSL3 in the eugonadal population of 0.4 - 2.3 ng/ml, with low INSL3 prospectively identifying individuals at risk of increased future morbidity.

Aim: In the global phase 3 POETYK PSO-1 and PSO-2 trials, significantly greater proportions of deucravacitinib-treated patients met the coprimary endpoints (PASI 75, sPGA 0/1) at Week 16 versus placebo or apremilast-treated patients. This analysis evaluated onset of action and maintenance of response in patients randomized to deucravacitinib and placebo only., Methods: Adults with moderate to severe plaque psoriasis at baseline were randomized 1:2:1 to oral placebo, deucravacitinib, or apremilast. Onset of action was determined through changes from baseline in mean PASI, BSA, BSA × sPGA, and DLQI. Maintenance of response was assessed using PASI 75, PASI 90, PASI 100, sPGA 0/1, and sPGA 0 response rates through Week 52 in patients who were treated continuously with deucravacitinib, crossed over from placebo to deucravacitinib at Week 16, or received deucravacitinib and achieved PASI 75 by Week 24., Results: Deucravacitinib showed significantly higher increases in mean percent change from baseline in PASI versus placebo by Week 1. Significant improvement versus placebo was observed in all other efficacy measures by Week 8. Efficacy with deucravacitinib was maintained through Week 52., Conclusion: Deucravacitinib displayed efficacy as early as 1 week and clinical responses were maintained over 52 weeks in patients with moderate to severe plaque psoriasis.

Objective: Treat-to-target is recommended in the management of rheumatoid arthritis (RA) but its implementation is suboptimal. We aimed to identify interventional strategies targeted at improving treat-to-target implementation in RA by systematically reviewing published evidence on barriers to, facilitators of, and interventions to support treat-to-target implementation., Methods: Systematic and scoping literature searches in PubMed/MEDLINE, BIOSIS Previews, Derwent Drug File, Embase, EMCare, International Pharmaceutical Abstracts, and SciSearch were conducted to identify barriers/facilitators and interventions relating to treat-to-target implementation in RA. The quality of included studies was assessed using Critical Appraisal Skills Programme (CASP) checklists. Data related to barriers/facilitators and interventions were extracted, grouped, and summarized descriptively, and a narrative synthesis was generated., Results: In total, 146 articles were analyzed, of which 123 (84%) included ≥50% of the items assessed by CASP checklists. Of the 146 studies, 76 evaluated treat-to-target barriers and facilitators, from which 329 relevant statements were identified and regrouped into 18 target areas, including health care professional (HCP) or patient knowledge or perceptions; patient-HCP communication or alignment; and time or resources. Overall, 56 interventions were identified from 70 studies across the 18 target areas; 54% addressed disease activity or patient-reported outcome assessments. Of the 56 interventions identified, 36 improved treat-to-target implementation and/or patient outcomes in RA., Conclusion: Despite long-established treat-to-target recommendations, there remain many barriers to its implementation. Interventions to improve treat-to-target should be developed further and assessed, with a particular focus on tailoring them to individual countries, regions, and health care settings., (© 2024 The Author(s). Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: Juvenile idiopathic arthritis (JIA)-associated uveitis (JIAU) is a serious JIA comorbidity that can result in vision impairment. This study aimed to identify genetic risk factors within the major histocompatibility complex for JIAU and evaluate their contribution for improving risk classification when combined with clinical risk factors., Methods: Data on single nucleotide polymorphisms, amino acids, and classical HLA alleles were available for 2,497 patients with JIA without uveitis and 579 patients with JIAU (female 2,060, male 1,015). Analysis was restricted to patients with inferred European ancestry. Forward conditional logistic regression identified genetic markers exceeding a Bonferroni-corrected significance (6 × 10 -6 ). Multivariable logistic regression estimated the effects of clinical and genetic risk factors, and a likelihood ratio test calculated the improvement in model fit when adding genetic factors. Uveitis risk classification performance of a model integrating genetic and clinical risk factors was estimated using area under the receiver operator characteristic curve and compared with a model of clinical risk factors alone., Results: Three genetic risk factors were identified, mapping to HLA-DRB1, HLA-DPB1, and HLA-A. These markers were statistically independent from clinical risk factors and significantly improved the fit of a model when included with clinical risk factors (P = 3.3 × 10 -23 ). The addition of genetic markers improved the classification of JIAU compared with a model of clinical risk factors alone (area under the curve 0.75 vs 0.71)., Conclusion: Integration of a genetic and clinical risk prediction model outperforms a model based solely on clinical risk factors. Future JIAU risk prediction models should include genetic risk factors., (© 2024 The Author(s). Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Rheumatic diseases, those that affect the musculoskeletal system, cause significant morbidity. Among risk factors of these diseases is a significant genetic component. Recent advances in high-throughput omics techniques now allow a comprehensive profiling of patients at a genetic level through genome-wide association studies. Without functional interpretation of variants identified through these studies, clinical insight remains limited. Strategies include statistical fine-mapping that refine the list of variants in loci associated with disease, whilst colocalization techniques attempt to attribute function to variants that overlap a genetically active chromatin annotation. Functional validation using genome editing techniques can be used to further refine genetic signals and identify key pathways in cell types relevant to rheumatic disease biology. Insight gained from the combination of genetic studies and functional validation can be used to improve precision medicine in rheumatic diseases by allowing risk prediction and drug repositioning., Competing Interests: Declaration of competing interest 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 paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: Safe and effective long-term treatments for moderate to severe plaque psoriasis are needed., Objective: To evaluate the long-term safety and efficacy of deucravacitinib through 3 years (week 148) in the randomized POETYK PSO-1, PSO-2, and nonrandomized long-term extension (LTE) trials., Design, Setting, and Participants: PSO-1/PSO-2 were global, 52-week, randomized, double-blinded phase 3 trials in patients with moderate to severe plaque psoriasis. After completing 52 weeks of treatment in PSO-1/PSO-2, patients could enroll in the prespecified, ongoing, nonrandomized LTE trial. The peak of the global COVID-19 pandemic coincided with the LTE trial. Patient enrollment in the LTE started August 12, 2019; safety and efficacy were assessed through June 15, 2022; and these data were analyzed through June 28, 2024., Interventions: The PSO-1/PSO-2 trials randomized patients 1:2:1 to oral placebo, deucravacitinib, 6 mg once daily, or apremilast, 30 mg twice daily. Patients enrolling in the LTE trial received open-label deucravacitinib, 6 mg once daily., Main Outcomes and Measures: Safety outcomes were evaluated in patients who received 1 or more doses of deucravacitinib. Efficacy outcomes included 75% or greater or 90% or greater reduction from baseline in Psoriasis Area and Severity Index (PASI 75/90) and static Physician Global Assessment scores of 0 (clear) or 1 (almost clear) (sPGA 0/1) and were assessed in patients who received deucravacitinib treatment from day 1 of the parent trials who continued in the LTE trial., Results: Of 1519 patients who received 1 or more doses of deucravacitinib, 513 received continuous deucravacitinib treatment from day 1 and entered the LTE trial. Exposure-adjusted incidence rates (EAIRs) per 100 person-years were decreased or similar in the 1-year vs 3-year cumulative periods, respectively, for adverse events (AEs) (229.2 vs 144.8; 95% CI, 215.4-243.9 vs 137.1-153.0), serious AEs (5.7 vs 5.5; 95% CI, 4.4-7.4 vs 4.7-6.4), discontinuations due to AEs (4.4 vs 2.4; 95% CI, 3.3-5.9 vs 2.0-3.0), and deaths (0.2 vs 0.3; 95% CI, 0.1-0.8 vs 0.2-0.6). Incidence rates of the most common AEs (EAIR per 100 person-years ≥5) during the 1-year and 3-year cumulative periods, respectively, were nasopharyngitis (26.1 vs 11.4; 95% CI, 23.0-29.8 vs 10.2-12.7), COVID-19 (0.5 vs 8.0; 95% CI, 0.2-1.2 vs 7.1-9.1), and upper respiratory tract infection (13.4 vs 6.2; 95% CI, 11.3-16.0 vs 5.4-7.2). EAIRs for AEs of interest, including herpes zoster, major adverse cardiovascular events, and malignant diseases, remained low and were decreased or comparable between the 1-year and 3-year cumulative periods. Clinical response rates were maintained through 3 years., Conclusions and Relevance: The findings of this integrated analysis of the phase 3 POETYK PSO-1, PSO-2, and nonrandomized LTE trials demonstrate a consistent safety profile and durable clinical response of continuous treatment with deucravacitinib through 3 years of treatment in patients with psoriasis., Trial Registration: ClinicalTrials.gov Identifiers: NCT03624127, NCT03611751, and NCT04036435.

Aim: The Assessment of Burden of ColoRectal Cancer (ABCRC)-tool is an integrated tool, developed in conjunction with colorectal cancer (CRC) patients, that measures the experienced burden of disease and lifestyle parameters and visualizes the results. To provide tailored follow-up care for watch-and-wait (WW) patients, in line with their specific needs and preferences, a WW module for the ABCRC-tool was developed. In this paper we describe the development and validation process of the WW module., Methods: This study followed a multistep approach. First, a three-round Delphi survey was conducted with both patients and healthcare professionals (HP). Participants were asked to score common RC outcomes that emerged from qualitative interviews with patients and a targeted literature review. Based on included items, appropriate questions were formulated. Reliability was tested by assessing test-retest reliability, defined by Intra Class Correlation. Construct validity was evaluated by hypothesis testing., Results: A total of 128 participants (75 patients and 53 HP) from four countries (UK, Brazil, Portugal and Netherlands) participated in the Delphi survey which included 41 items. After the consensus meeting seven outcomes and appropriate questions (including anxiety, fear of recurrence, fear of surgery, fear of stoma, fecal incontinence, urgency and happiness) were included in the WW module. Validity and reliability testing was completed by 50 Dutch WW patients. The ABCRC-WW module demonstrated sound construct validity and reliability., Conclusion: This study demonstrates good psychometric properties of the ABCRC-WW tool. This tool has the potential to facilitate patient-clinician communication, enhance patients' understanding of their condition, and enable individualized care through direct feedback., Competing Interests: Declaration of competing interest 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 paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: The lack of evidence under routine clinical settings limited the widespread adoption of adalimumab biosimilars for psoriasis treatment., Objective: This study compared the drug survival and safety of adalimumab biosimilars to Humira for psoriasis treatment., Methods: We conducted a prevalent new-user cohort study using data from the French National Health Data System (SNDS), the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR), and the Spanish Registry of Systemic Therapy in Psoriasis (BIOBADADERM). Adalimumab-naïve patients initiating adalimumab biosimilars (new users) were compared with Humira new users. Patients switching from Humira to biosimilars (switchers) were compared with those who continued Humira treatment. Patients were matched 1:1 based on previous adalimumab exposure time to create equal-sized cohorts of biosimilar and Humira users. Co-primary outcomes included drug discontinuation and serious adverse events (SAEs). Hazard ratios (HR) were calculated using Cox proportional hazard models. Meta-analyses using random effect models were performed to combine results from 3 databases., Results: 7387 biosimilar new users and 3654 switchers were matched and compared with Humira users. No differences in all-cause discontinuation were found between biosimilars and Humira new users (HR: 0.99, 95% CI: 0.94-1.04). Switching from Humira to biosimilars was associated with a higher discontinuation rate compared to remaining on Humira (HR: 1.35, 95% CI: 1.19-1.52). Similar results were observed for discontinuation due to ineffectiveness or adverse events. Risks of SAEs were similar between biosimilar new users and Humira new users (Incidence rate ratio IRR: 0.91, 95% CI: 0.80-1.05) or between switchers and continuous Humira users (IRR: 0.92, 95% CI: 0.83-1.01)., Conclusion: Adalimumab biosimilars can be considered viable alternatives to Humira for new patients with comparable effectiveness and safety. However, due to the higher likelihood of discontinuation, patients who switch from Humira to biosimilars may require closer monitoring and support., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Background: Elevated body mass index (BMI) ≥25 kg/m 2 is a major preventable cause of cancer. A single BMI measure does not capture the degree and duration of exposure to excess BMI. We investigate associations between adulthood overweight-years, incorporating exposure time to BMI ≥25 kg/m 2, and cancer incidence, and compare this with single BMI., Methods: In this cohort study and individual participant data meta-analysis, we obtained data from the ABACus 2 Consortium, consisting of four US cohorts: Atherosclerosis Risk in Communities (ARIC) study (1987-2015), Women's Health Initiative (WHI; 1991 to 2005 [main study], to 2010 [Extension 1], and to 2020 [Extension 2]), Prostate, Lung, Colorectal, Ovarian Cancer Screening (PLCO) Trial (1993-2009), NIH-AARP Diet and Health Study (1996-2011), and one European cohort, the European Prospective Investigation into Cancer and Nutrition (EPIC; participants enrolled in 1990 and administrative censoring was centre-specific). Participants with at least 3 BMI measurements and complete cancer follow-up data were included. We calculated overweight-years: degree of overweight (BMI ≥25 kg/m 2 ) multiplied by the duration of overweight (years). Using random effects two-stage individual participant data meta-analyses, associations between cancer and overweight-years, single BMI, cumulative overweight degree and duration, measured at the same time and captured over a median of 41 years in men and 39 years in women, were evaluated with Cox proportional hazards models. Models were age-adjusted or multivariable (MV) adjusted for baseline age, ethnicity, alcohol, smoking and hormone replacement therapy (HRT). Harrell's C-statistic of metrics were compared. This study is registered at PROSPERO, CRD42021238270., Findings: 720,210 participants, including 312,132 men and 408,078 women, were followed up for cancer incidence over a median 9.85 years (interquartile range (IQR) 8.03, 11.67) in men and 10.80 years (IQR 6.05, 15.55) in women. 12,959 men (4.15%) and 36,509 women (8.95%) were diagnosed with obesity-related cancer. Hazard ratios for obesity-related cancers in men, per 1 standard deviation (SD) overweight-years were 1.15 (95% CI: 1.14, 1.16, I 2 : 0) age-adjusted and 1.15 (95% CI: 1.13, 1.17, I 2 : 0%) MV-adjusted and per 1SD increment in single BMI were 1.17 (95% CI: 1.16, 1.18, I 2 : 0) age-adjusted and 1.16 (95% CI: 1.15, 1.18, I 2 : 0%) MV-adjusted. The HR for overweight-years in women per 1 SD increment was 1.08 (95% CI: 1.04, 1.13, I 2 : 82%) age-adjusted and 1.08 (95% CI: 1.04, 1.13, I 2 : 83%) MV-adjusted and per 1SD increment in single BMI was 1.10 (95% CI: 1.07, 1.14, I 2 : 72%) age-adjusted and 1.11 (95% CI: 1.07, 1.15, I 2 : 79%) MV-adjusted. C-statistics for overweight-years and single BMI for obesity-related cancers were 0.612 (95% CI: 0.578, 0.646) and 0.611 (95% CI: 0.578, 0.644) respectively for men and 0.566 (95% CI: 0.534, 0.598) and 0.573 (95% CI: 0.546, 0.600) for women., Interpretation: Adulthood degree and duration of excess BMI were associated with cancer risk. Both factors should be considered in cancer prevention strategies and policies. This study only focused on adulthood exposure to excess BMI, so the minimal differences in the predictive performance between adiposity metrics may be due to underestimation of cumulative excess BMI exposure., Funding: Cancer Research UK, the Manchester NIHR Biomedical Research Centre, the National Cancer Institute, the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, U.S. Department of Health and Human Services, the Intramural Research Program of the National Cancer Institute, the International Agency for Research on Cancer, Imperial College London, European Commission (DG-SANCO), the Danish Cancer Society, Ligue Contre le Cancer, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale, Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, German Federal Ministry of Education and Research, the Hellenic Health Foundation, Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council, Dutch Ministry of Public Health, Welfare, and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Dutch Zorg Onderzoek Nederland, World Cancer Research Fund, Statistics Netherlands, Health Research Fund, Instituto de Salud Carlos III, regional Spanish governments of Andalucía, Asturias, Basque Country, Murcia, and Navarra, the Catalan Institute of Oncology, Swedish Cancer Society, Swedish Scientific Council, and Region Skåne and Region Västerbotten, and the Medical Research Council., Competing Interests: NH, MS, GPM, RS, CEM, FR, AT, AKH, HF, MJG, and AGR declare no competing interests. EAP received a National Institutes of Health research grant; an award made to Johns Hopkins University for the manuscript. MN received funding for the paper from the National Heart Lung and Blood Institute, National Institutes of Health to the Institution (Fred Hutchinson Cancer Center). MN receives funding as the Deputy Editor of, Journal of Nutrition. CJ received the American Cancer Society's support for the present manuscript and the following grants or contracts to the institution, Johns Hopkins University, from the National Institutes of Health, Prostate Cancer Foundation, The Ralph Lauren Corporate Foundation, Department of Defense., (© 2024 The Authors.)

Pain is a common symptom in people with inflammatory arthritis (IA), which has far-reaching impacts on their lives. Recent electronic health record studies demonstrate that UK-based pain care in people with IA commonly involves the prescribing of long-term opioids and gabapentinoids, despite an absence of trial evidence for their efficacy. Patient surveys suggest that non-pharmacological pain management is underused. A UK-specific guideline on pain management for people with IA is required to resolve this. This scoping document outlines the context and prioritized clinical questions for the first British Society for Rheumatology (BSR) guideline on pain management for people with IA. The guideline aims to provide evidence-based recommendations on how pain can be best managed in people with IA (including its assessment, and pharmacological and non-pharmacological treatments), ensuring that people with IA in the UK are offered evidence-based pain management strategies. The guideline is for healthcare professionals involved in the care of people with IA of all ages and genders, people with IA and their families and carers, NHS managers and healthcare commissioners, and other relevant stakeholders such as patient organizations. It will be developed using the methods outlined in the BSR's 'Creating Clinical Guidelines' protocol., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: There are avoidable differences (i.e., inequities) in the prevalence and distribution of chronic pain across diverse populations, as well as in access to and outcomes of pain management services. Digital pain self-reporting tools have the potential to reduce or exacerbate these inequities. This study aimed to better understand how to optimise the health equity impact of digital pain self-reporting tools on people who are experiencing (or are at risk of) digital pain inequities., Methods: This was a qualitative study, guided by the Health Equity Impact Assessment tool-digital health supplement (HEIA-DH). We conducted three scoping focus groups with multiple stakeholders to identify the potential impacts of digital pain self-reporting tools and strategies to manage these impacts. Each group focused on one priority group experiencing digital pain inequities, including older adults, ethnic minorities, and people living in socio-economically deprived areas. A fourth consensus focus group was organised to discuss and select impact management strategies. Focus groups were audio-recorded, transcribed verbatim, and analysed using a framework approach. We derived codes, grouped them under four pre-defined categories from the HEIA-DH, and illustrated them with participants' quotes., Results: A total of fifteen people living with musculoskeletal pain conditions and thirteen professionals took part. Participants described how digital pain self-reports can have a positive health equity impact by better capturing pain fluctuations and enriching patient-provider communication, which in turn can enhance clinical decisions and self-management practices. Conversely, participants identified that incorrect interpretation of pain reports, lack of knowledge of pain terminologies, and digital (e.g., no access to technology) and social (e.g., gender stereotyping) exclusions may negatively impact on people's health equity. The participants identified 32 strategies, of which 20 were selected as being likely to mitigate these negative health equity impacts. Example strategies included, e.g., option to customise self-reporting tools in line with users' personal preferences, or resources to better explain how self-reported pain data will be used to build trust., Conclusion: Linked to people's personal and social characteristics, there are equity-based considerations for developing accessible digital pain self-reporting tools, as well as resources and skills to enable the adoption and use of these tools among priority groups. Future research should focus on implementing these equity-based considerations or strategies identified by our study and monitoring their impact on the health equity of people living with chronic pain., Competing Interests: Declarations Ethics approval and consent to participate The study received an ethical approval from the University of Manchester’s Research Ethics Committee (ref # 2022–14094-23756). Informed consent was obtained from all study participants. The study was conducted in accordance with the Declaration of Helsinki and its later amendments. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Irregular sleep duration may disrupt circadian rhythms and contribute to metabolic, behavioral, and mood changes, potentially increasing the risk for obesity. However, quantitative data on the relationship between sleep duration irregularity and weight change are lacking. In this prospective study, we analyzed data from 10,572 participants (mean age: 63 years) in the UK Biobank who wore accelerometers for a week between 2013-2015 and had two body mass index (BMI; kg/m 2 ) measurements on average 2.5 years apart. Irregular sleep duration was assessed by the within-person standard deviation (SD) of 7-night accelerometer-measured sleep duration. Participants with sleep duration SD >60 minutes versus ≤30 minutes had 0.24 kg/m 2 (95% CI: 0.08, 0.40) higher BMI change (kg/m 2 ), standardized to three-year intervals, and 80% (95% CI: 1.28, 2.52) higher risk for incident obesity, after adjusting for sociodemographic factors, shift work, and baseline BMI or follow-up period ( p -trend<0.02 for both). These associations remained consistent after adjusting for lifestyle, comorbidities, and other sleep factors, including sleep duration. Age, sex, baseline BMI, and genetic predisposition to higher BMI (measured with a polygenic risk score) did not appear to modify the association. Since irregular sleep duration is common, trials of interventions targeting sleep irregularity might lead to new public health strategies that tackle obesity., Competing Interests: Conflicts of Interest: MKR reports receiving consultancy fees from Eli Lilly and has modest stock ownership in GSK, unrelated to this work. The other authors have no conflicts of interest to declare.

Congenital heart defects (CHDs), the most common congenital anomalies, are considered to have a significant genetic component. However, despite considerable efforts to identify pathogenic genes in patients with CHDs, few gene variants have been proven as causal. The complexity of the genetic architecture underlying human CHDs likely contributes to this poor genetic discovery rate. However, several other factors are likely to contribute. For example, the level of patient phenotyping required for clinical care may be insufficient for research studies focused on mechanistic discovery. Although several hundred mouse gene knockouts have been described with CHDs, these are generally not phenotyped and described in the same way as CHDs in patients, and thus are not readily comparable. Moreover, most patients with CHDs carry variants of uncertain significance of crucial cardiac genes, further complicating comparisons between humans and mouse mutants. In spite of major advances in cardiac developmental biology over the past 25 years, these advances have not been well communicated to geneticists and cardiologists. As a consequence, the latest data from developmental biology are not always used in the design and interpretation of studies aimed at discovering the genetic causes of CHDs. In this Special Article, while considering other in vitro and in vivo models, we create a coherent framework for accurately modelling and phenotyping human CHDs in mice, thereby enhancing the translation of genetic and genomic studies into the causes of CHDs in patients., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Introduction: Biologic treatments have made complete skin clearance in moderate to severe plaque psoriasis a real possibility. Although clinical trials demonstrated the superiority of bimekizumab over secukinumab, adalimumab, and ustekinumab, direct comparisons with other biologics are not available. This systematic literature review (SLR) and network meta-analysis (NMA) aimed to evaluate the 1-year efficacy and safety of bimekizumab versus other biologic systemic therapies for moderate to severe plaque psoriasis., Methods: We conducted an SLR to retrieve published randomised controlled trials (RCTs) in patients with moderate to severe plaque psoriasis. We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews and PsycINFO on 13 January 2022. Two NMA types were used to analyse the long-term achievement of 100% improvement from baseline in Psoriasis Area and Severity Index (PASI 100): (1) NMA of cumulative clinical benefits, based on the area under the curve, from week 0 to 52; (2) multinomial NMA at weeks 44‒60. Binomial NMA was used to evaluate long-term serious adverse events (SAEs)., Results: The SLR identified 38 RCTs, of which 19 were included in the NMA. Bimekizumab 320 mg administered every 4 weeks to week 16 then every 8 weeks (Q4W/Q8W) showed a greater cumulative average number of days of PASI 100 response compared with all other biologics. These differences were statistically significant versus all biologics, except risankizumab 150 mg. The multinomial NMA demonstrated that interleukin (IL)-17 and IL-23 inhibitors were the most efficacious treatments. No significant differences were found in long-term occurrence of SAEs., Conclusion: Bimekizumab 320 mg Q4W/Q8W was superior to most other treatments in maintaining complete skin clearance during the first year of treatment. It demonstrated a greater cumulative average number of days with completely clear skin while displaying a comparable safety profile compared with all other biologics., Competing Interests: Declarations Conflict of Interest Richard B. Warren declares receiving consulting fees from AbbVie, Almirall, Amgen, Arena, Astellas, Avillion, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, GSK, Janssen, LEO Pharma, Novartis, Pfizer, Sanofi and UCB Pharma. He also declares receiving research grants to his institution from AbbVie, Almirall, Janssen, LEO Pharma, Novartis and UCB Pharma, and honoraria from Astellas, DiCE, GSK and Union Therapeutics. Richard B. Warren is an Editor-in-Chief of Dermatology and Therapy. Richard B. Warren was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Kerry Donnelly, Sandeep Kiri, Vanessa Taieb are employees and shareholders of UCB Pharma. Mahmoud Slim, Kyle Fahrbach, Marissa Betts, Binod Neupane are employed by Evidera, a part of Thermo Fisher Scientific. April Armstrong has served as a research investigator and/or scientific advisor to AbbVie, Almirall, Arcutis, ASLAN, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Dermira, Eli Lilly and Company, EPI, Incyte, Janssen, LEO Pharma, Nimbus, Novartis, Ortho Dermatologics, Pfizer, Regeneron, Sun Pharma, Sanofi and UCB Pharma. Ethical Approval This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors., (© 2024. The Author(s).)

There is important variation in the occurrence of Paget's disease in different regions and populations. There are though few data concerning the occurrence of clinically diagnosed disease in black and ethnic minority groups in the United Kingdom (UK). We undertook an anonymised search using an integrated primary and secondary care-based database in Greater Manchester, covering a population of over 3 million people. We looked also among those with a first positive COVID test, the influence of Paget's disease on subsequent admission to hospital within 28 days. Within our database, there were 534,571 people aged 60 years and over alive on 1 January 2020. The majority were white (84%) with 4.7% identifying as Asian or Asian British, and 1.27% Black or Black British. There were 931 with clinically diagnosed Paget's disease. Overall prevalence in the greater Manchester area was 0.174%. Prevalence was higher in men than women (0.195 vs 0.155%). Compared to the prevalence of Paget's in whites (0.179%) the prevalence was lower among those identifying as Asian or Asian British (0.048%) and higher among those identifying as Black or Black British (0.344%). Prevalence increased with increasing deprivation. Clinically diagnosed Paget's disease is uncommon affecting 0.174% of men and women aged 60 or more years. Within Greater Manchester, it was more common in those identifying as Black or Black British and less common in those identifying as Asian or Asian British., (© 2024. The Author(s).)

Background: Associations of waist circumferences (WC) and body mass index (BMI) measured once or over time, with cancer incidence were studied. WC is associated with some cancers independent of BMI. Analyses of cumulative central adiposity and cancer are lacking. We investigated associations between waist circumference-years, incorporating exposure time to WC ≥ 102 cm in men or ≥88 cm in women, and cancer, and compared this with single WC or BMI., Methods: Serial WC measurements taken over 9 years in the prospective Atherosclerosis Risk in Communities Study (ARIC) predicted yearly WC. Cox proportional hazards regression estimated hazard ratios (HRs) of cancer incidence for waist circumference-years, WC or BMI, measured in Visit 4. Harrell's C-statistic quantified metric predictive performances., Results: 10,172 participants were followed up from Visit 4 for cancer over a median 13.7 for men and 15.8 years for women. For obesity-related cancers, HRs per standard deviation waist circumference-years were 1.14 (95%CI:1.04,1.25) and 1.19 (95%CI:1.12,1.27), respectively. Differences in metric predictive performances were marginal., Discussion: This is the first study to identify positive associations between waist circumference-years and cancer. Waist circumference-years did not provide additional information on cancer risk beyond that of WC and BMI. BMI is routinely measured in clinic so it may be preferred over WC., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate The Institutional Review Boards at each study site approved the ARIC study protocol. Only participants who consented to research on chronic diseases such as cancer were included. Given the use of secondary cohort data, no ethical approval was required for the current analysis. Anonymous data was used and handled as per the data management plan and data transfer agreements [70]., (© 2024. The Author(s).)

Paget's disease of bone (PDB) is characterised by increased and disorganised bone remodelling leading to various complications, such as bone deformity, deafness, secondary osteoarthritis, and pathological fracture. Pain is the most common presenting symptom of PDB, but it is unclear to what extent this is due to increased metabolic activity of the disease, complications, or unrelated causes. We conducted a cross-sectional study of 168 people with PDB attending secondary care referral centres in the UK. We documented the presence of musculoskeletal pain and sought to determine its underlying causes. Musculoskeletal pain was reported by 122/168 (72.6%) individuals. The most common cause was osteoarthritis of joints distant from an affected PDB site in 54 (44.3%), followed by metabolically active PDB in 18 (14.7%); bone deformity in 14 (11.4%); osteoarthritis of a joint neighbouring an affected site in 11 (9.0%), neuropathic pain in 10 (8.2%), and various other causes in the remainder. Pain was more common in women (p<0.019) and in older individuals (p<0.001). Circulating concentrations of macrophage colony-stimulating factor (M-CSF) were significantly higher in those with pain (p = 0.008), but there was no difference between groups of patients with and without pain in concentrations of interleukin-6 (IL-6) or biochemical markers of bone turnover. Pain is a common symptom in PDB but is most often due to osteoarthritis at an unaffected site. The study illustrates the importance of fully evaluating people with PDB to determine the underlying cause of pain so that management can be tailored appropriately., (© 2024. The Author(s).)

Background and Objective: Randomized controlled trials (RCTs) inform health-care decisions. Unfortunately, some published RCTs contain false data, and some appear to have been entirely fabricated. Systematic reviews are performed to identify and synthesize all RCTs which have been conducted on a given topic. This means that any of these 'problematic studies' are likely to be included, but there are no agreed methods for identifying them. The INveStigating ProblEmatic Clinical Trials in Systematic Reviews (INSPECT-SR) project is developing a tool to identify problematic RCTs in systematic reviews of health care-related interventions. The tool will guide the user through a series of 'checks' to determine a study's authenticity. The first objective in the development process is to assemble a comprehensive list of checks to consider for inclusion., Methods: We assembled an initial list of checks for assessing the authenticity of research studies, with no restriction to RCTs, and categorized these into five domains: Inspecting results in the paper; Inspecting the research team; Inspecting conduct, governance, and transparency; Inspecting text and publication details; Inspecting the individual participant data. We implemented this list as an online survey, and invited people with expertise and experience of assessing potentially problematic studies to participate through professional networks and online forums. Participants were invited to provide feedback on the checks on the list, and were asked to describe any additional checks they knew of, which were not featured in the list., Results: Extensive feedback on an initial list of 102 checks was provided by 71 participants based in 16 countries across five continents. Fourteen new checks were proposed across the five domains, and suggestions were made to reword checks on the initial list. An updated list of checks was constructed, comprising 116 checks. Many participants expressed a lack of familiarity with statistical checks, and emphasized the importance of feasibility of the tool., Conclusion: A comprehensive list of trustworthiness checks has been produced. The checks will be evaluated to determine which should be included in the INSPECT-SR tool., Competing Interests: Declaration of competing interest J.W., CH, GAA., L.B., and J.J.K. declare funding from NIHR (NIHR203568) in relation to the current project. J.W. additionally declares Stats or Methodological Editor roles for BJOG, Fertility and Sterility, Reproduction and Fertility, Journal of Hypertension, and for Cochrane Gynecology and Fertility. C.H. declares a Statistical Editor role for Cochrane Colorectal. L.B. additionally declares a role as Academic Meta-Research Editor for PLoS Biology, and that The University of Colorado receives remuneration for service as Senior Research Integrity Editor, Cochrane. J.J.K. additionally declares a Statistical Editor role for The BMJ. A.A. declares that The Health Services Research Unit, University of Aberdeen, is funded by the Health and Social Care Directorates of the Scottish Government. V.B. is EiC of the Medical Journal of Australia and on the Editorial Board of Research Integrity and Peer Review. N.J.L.B. declares roles as Editorial Board member for International Review of Social Pyschology/Revue Internationale de Psychologie Sociale, Statistical Advisory Board member for Mental Health Science, and Advisory Board member for Meta-Psychology. M.C. declares that he is Co-ordinating Editor for the Cochrane Methodology Review Group, Editor in Chief, Journal of Evidence-Based Medicine, and Coordinating Editor, James Lind Library. E.F., S.G., and T.La. declare employment by Cochrane. E.F. additionally declares a role as Editorial Board member for Cochrane Synthesis and Methods. T.La. additionally declares authorship of a chapter in the Cochrane Handbook for Systematic Reviews of Interventions and that he is a developer of standards for Cochrane intervention reviews (MECIR). T.Li. is funded by the National Eye Institute, National Institutes of Health (Grant #UG1 EY020522). S.L. is funded by NHMRC (APP1195189), and holds general or methodological editor positions for Cochrane Gynecology and Fertility, Fertility and Sterility, and Human Reproduction. A.L. is on the editorial board of BMC Medical Ethics. B.W.M. declares roles as Editor for Cochrane Gynecology and Fertility and Sexually Transmitted Infections, and for Fertility and Sterility. S.L. declares roles as Associate Editor for Human Reproduction, Methodological Editor for Fertility and Sterility, and Editor for Cochrane Gynecology and Fertility. N.O.C. is a member of the Cochrane Editorial Board and holds an ERA-NET Neuron Cofund grant for a separate project. A.L.S. declares funding from Australian National Health and Medical Research Council Investigator Grants (GNT2009432). E.S. is a Sign-off Editor for the Cochrane Library. M.v.W. is coordinating editor of Cochrane Gynecology and Fertility and Cochrane Sexually Transmitted Infections, Methodological Editor of Human Reproduction Update and editorial Editor of Fertility and Sterility. There are no competing interests for any other author., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to assess 52-week efficacy and safety of bimekizumab in patients with active psoriatic arthritis (PsA) with or without concomitant methotrexate (+/-MTX) treatment at baseline., Methods: We conducted a post hoc analysis of patients in BE OPTIMAL (NCT03895203; biologic disease-modifying antirheumatic drug [bDMARD]-naïve), BE COMPLETE (NCT03896581; prior inadequate response or intolerance to tumor necrosis factor inhibitors [TNFi-IR]), and the BE VITAL open-label extension (NCT04009499) study. Patients were randomized to one of the following treatment groups: bimekizumab 160 mg every four weeks, placebo, or a reference drug (adalimumab 40 mg every two weeks; BE OPTIMAL only). From Week 16, placebo-randomized patients received bimekizumab. Missing data were imputed using non-responder imputation, multiple imputation, or worst-category imputation., Results: Through Week 52, similar proportions of bimekizumab-treated patients achieved American College of Rheumatology 50% (ACR50) response criteria for both +MTX and -MTX (BE OPTIMAL: 54.4% +MTX, 54.7% -MTX; BE COMPLETE: 56.3% +MTX, 48.0% -MTX). Similar proportions of bimekizumab-treated patients achieved complete skin clearance (Psoriasis Area and Severity Index 100% [PASI100] response) and minimal disease activity in both +MTX and -MTX groups. Similar trends were seen in placebo/bimekizumab-treated patients. Through Week 52, the proportion of bimekizumab-treated patients with ≥1 treatment-emergent adverse event were similar between the +MTX and -MTX groups (BE OPTIMAL 325 of 410 [79.3%] vs 230 of 292 [78.8%], BE COMPLETE 105 of 168 [62.5%] vs 138 of 220 [62.7%]). The safety profile was comparable between subgroups and consistent with the prior safety profile of bimekizumab., Conclusion: Treatment with bimekizumab demonstrated consistent, sustained efficacy to 52 weeks in bDMARD-naïve and TNFi-IR patients with PsA and was well tolerated, irrespective of concomitant MTX., (© 2024 UCB Pharma and The Author(s). ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: Inhibitors of the interleukin 13 (IL-13) pathway, such as dupilumab, are licensed for atopic dermatitis and asthma. Adverse events resembling psoriatic disease after dupilumab initiation have been reported, but evidence is limited to case reports with uncertain causality. We aimed to investigate whether genetically mimicked IL-13 inhibition (IL-13i) is associated with risk of psoriatic arthritis (PsA) and psoriasis., Methods: We instrumented IL-13i using a protein-coding variant in the IL13 gene, rs20541, that is associated with circulating eosinophil count (biomarker of IL-13i) at genome-wide significance in a study of 563,946 individuals. Outcome genetic data were taken from studies of PsA, psoriasis, and related spondyloarthritis traits in up to 10,588 cases and 209,287 controls. Colocalization analysis was performed to examine genetic confounding. We additionally used circulating IgE as a biomarker to test whether associations were replicated, both in the test and in an independent genetic dataset. We also replicated analyses using individual-level data from the UK Biobank., Results: Genetically proxied IL-13i was associated with increased risk of PsA (odds ratio [OR] 37.39; 95% confidence interval [95% CI] 11.52-121.34; P = 1.64 × 10 -9 ) and psoriasis (OR 20.08; 95% CI 4.38-92.01; P = 1.12 × 10 -4 ). No consistent associations were found for Crohn disease, ulcerative colitis, ankylosing spondylitis, or iritis. Colocalization showed no strong evidence of genetic confounding for psoriatic disease. Results were replicated using circulating IgE for the exposure, using independent outcome data and using individual-level data., Conclusion: We provide supportive genetic evidence that IL-13i is linked to increased risk of PsA and psoriasis. Physicians prescribing IL-13 inhibitors should be vigilant for these adverse events., (© 2024 The Author(s). Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

The exhaled breath represents an ideal matrix for noninvasive biomarker discovery, and exhaled metabolomics have the potential to be clinically useful in the era of precision medicine. In this concise translational review, we specifically address volatile organic compounds in the breath, with a view toward fulfilling the promise of these as actionable biomarkers, in particular, for lung diseases. We review the literature paying attention to seminal work linked to key milestones in breath research; discuss potential applications for breath biomarkers across disease areas and healthcare systems, including the perspectives of industry; and outline critical aspects of study design that will need to be considered for any pivotal research going forward if breath analysis is to provide robust validated biomarkers that meet the requirements for future clinical implementation.