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Intracellular trafficking involves an intricate machinery of motor complexes, including the dynein complex, to shuttle cargo for autophagolysosomal degradation. Deficiency in dynein axonemal chains, as well as cytoplasmic light and intermediate chains, have been linked with ciliary dyskinesia and skeletal dysplasia. The cytoplasmic dynein 1 heavy chain protein (DYNC1H1) serves as a core complex for retrograde trafficking in neuronal axons. Dominant pathogenic variants in DYNC1H1 have been previously implicated in peripheral neuromuscular disorders (NMD) and neurodevelopmental disorders (NDD). As heavy-chain dynein is ubiquitously expressed, the apparent selectivity of heavy chain dyneinopathy for motor neuronal phenotypes remains currently unaccounted for. Here, we aimed to evaluate the full DYNC1H1-related clinical, molecular and imaging spectrum, including multisystem features and novel phenotypes presenting throughout life. We identified 47 cases from 43 families with pathogenic heterozygous variants in DYNC1H1 (aged 0-59 years) and collected phenotypic data via a comprehensive standardized survey and clinical follow-up appointments. Most patients presented with divergent and previously unrecognized neurological and multisystem features, leading to significant delays in genetic testing and establishing the correct diagnosis. Neurological phenotypes include novel autonomic features, previously rarely described behavioral disorders, movement disorders and periventricular lesions. Sensory neuropathy was identified in nine patients (median age of onset 10.6 years), of which five were only diagnosed after the second decade of life, and three had a progressive age-dependent sensory neuropathy. Novel multisystem features included primary immunodeficiency, bilateral sensorineural hearing loss, organ anomalies and skeletal manifestations, resembling the phenotypic spectrum of other dyneinopathies. We also identified an age-dependent biphasic disease course with developmental regression in the first decade and, following a period of stability, neurodegenerative progression after the second decade of life. Of note, we observed several cases in whom neurodegeneration appeared to be prompted by intercurrent systemic infections with double-stranded DNA viruses (Herpesviridae) or single-stranded RNA viruses (Ross River fever, SARS-CoV-2). Moreover, the disease course appeared to be exacerbated by viral infections regardless of age and/or severity of neurodevelopmental disorder manifestations, indicating a role of dynein in anti-viral immunity and neuronal health. In summary, our findings expand the clinical, imaging and molecular spectrum of pathogenic DYNC1H1 variants beyond motor neuropathy disorders and suggest a life-long continuum and age-related progression due to deficient intracellular trafficking. This study will facilitate early diagnosis and improve counselling and health surveillance of affected patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: Our objective was to test the hypothesis, in a double-blind, placebo-controlled study that vipoglanstat, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1), which decreases prostaglandin E2 (PGE2) and increases prostacyclin biosynthesis, improves RP., Methods: Patients with SSc and ≥7 RP attacks during the last screening week prior to a baseline visit were randomized to 4 weeks treatment with vipoglanstat 120 mg or placebo. A daily electronic diary captured RP attacks (duration and pain) and Raynaud's Condition Score, with change in RP attacks/week as the primary end point. Cold challenge assessments were performed at baseline and end of treatment. Exploratory end points included patients' and physicians' global impression of change, Assessment of Scleroderma-associated Raynaud's Phenomenon questionnaire, mPGES-1 activity, and urinary excretion of arachidonic acid metabolites., Results: Sixty-nine subjects received vipoglanstat (n = 33) or placebo (n = 36). The mean weekly number of RP attacks [baseline; vipoglanstat 14.4 (S.D. 6.7), placebo 18.2 (12.6)] decreased by 3.4 (95% CI -5.8; -1.0) and 4.2 (-6.5; -2.0) attacks per week (P = 0.628), respectively. All patient-reported outcomes improved, with no difference between the groups. The mean change in recovery of peripheral blood flow after the cold challenge did not differ between the study groups. Vipoglanstat fully inhibited mPGES-1, resulting in 57% reduction of PGE2 and 50% increase of prostacyclin metabolites in the urine. Vipoglanstat was safe and well tolerated., Conclusion: Although vipoglanstat was safe, and well tolerated in a dose achieving full inhibition of mPGES-1, it was ineffective in SSc-related RP. Further development and evaluation of vipoglanstat will therefore be in other diseases where mPGES-1 plays a pathogenetic role., Trial Registration: ClinicalTrials.gov, https://www.clinicaltrials.gov, NCT0474420., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To perform a systematic literature review on definitions and instruments used to measure remission, relapse and disease activity in polymyalgia rheumatica (PMR), to inform an OMERACT project to endorse instruments for these outcomes., Methods: A search of Pubmed/MEDLINE, EMBASE, CINAHL, Cochrane and Epistemonikos was performed May 2021 and updated August 2023. Qualitative and quantitative studies published in English were included if they recruited people with isolated PMR regardless of treatment. Study selection and data extraction was performed independently by two investigators and disagreement was resolved through discussion. Data extracted encompassed definitions of disease activity, remission and relapse, and details regarding the instruments used to measure these outcomes., Results: From the 5718 records, we included 26 articles on disease activity, 36 on remission and 53 on relapse; 64 studies were observational and 15 interventional, and none used qualitative methods. Some heterogeneity was found regarding definitions and instruments encompassing the domains pain, stiffness, fatigue, laboratory markers (mainly acute phase reactants), and patient and physician global assessment of disease activity. However, instruments for clinical signs were often poorly described. Whilst measurement properties of the polymyalgia rheumatica activity score (PMR-AS) have been assessed, data to support its use for measurement of remission and relapse are limited., Conclusion: Remission, relapse and disease activity have been defined heterogeneously in clinical studies. Instruments to measure these disease states still need to be validated. Qualitative research is needed to better understand the concepts of remission and relapse in PMR., Review Registration: PROSPERO identification: CRD42021255925., (© 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: It is well-known that long-term osteoarthritis prognosis is not improved by corticosteroid treatments. Here we investigate what could underlie this phenomenon by measuring the short term corticosteroid response of osteoarthritic joint synovial macrophages (OA-Mf)., Methods: We determined the genome-wide transcriptomic response to corticosteroids of end-stage OA-Mf. This was compared with lipopolysaccharide-tolerized and β-glucan-trained circulating blood monocyte-derived macrophage models., Results: Upon corticosteroid stimulation, the trained and tolerized macrophages significantly altered the abundance of 201 and 257 RNA transcripts, respectively. By contrast, by the same criteria, OA-Mf had a very restricted corticosteroid response of only 12 RNA transcripts. Furthermore, while metalloproteinases 1, 2, 3 and 10 expression clearly distinguish OA-Mf from both the tolerized and trained macrophage models, OA-Mf IL-1, chemokine (CXCL) and cytokine (CCL) family member profiles resembled the tolerized macrophage model, with the exception that OA-Mf showed high levels of CCL20., Conclusion: Terminal osteoarthritis joints harbour macrophages with an inflammatory state that closely resembles the tolerized macrophage state, and this is compounded by a weak corticosteroid response capacity that may explain the lack of positive long-term effects of corticosteroid treatment for osteoarthritis patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Study Question: Do sexual, relational, and psychological functioning of male partners of women with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome differ from male partners of women without MRKH syndrome?, Summary Answer: Male partners of women with MRKH syndrome did not significantly differ in sexual functioning but reported higher relational satisfaction and less anxiety than the control group., What Is Known Already: To date, only a few studies have reported occasionally about sexual, psychological, and relational functioning of partners of women with MRKH syndrome. The results seem to suggest sexual satisfaction in these men, contrary to the more often reported insecurities in women with MRKH syndrome surrounding sexuality and relationships., Study Design, Size, Duration: In this case-control study, 42 male partners of women with MRKH syndrome and 40 partners of women without the condition were enrolled., Participants/materials, Setting, Methods: All participants were recruited through women with MRKH syndrome and age-matched women without the condition who participated in a previous case-control study on sexual, psychological, and relational functioning. Participants live in a heterosexual relationship for at least in the last 6 months and have a basic understanding of the Dutch language. They were administered a set of online questionnaires to assess sexual, relational, and psychological functioning., Main Results and the Role of Chance: Partners of women with MRKH syndrome did not differ significantly in overall sexual functioning and had similar percentages of sexual dysfunction and sexual distress as the control group. Partners of women with MRKH syndrome reported significantly less relational dissatisfaction (P = 0.01; Cohen's d = 0.6) than partners of women without the condition. There was no significant difference in overall psychological functioning or the presence of clinically relevant anxiety and depression, but the men in the MRKH group had a significantly lower anxiety score (P = 0.01; Cohen's d = 0.6)., Limitations, Reasons for Caution: We were not able to reach a sample size needed for enough power to detect small to medium effect sizes. Confounding factors and selection bias cannot be excluded., Wider Implications of the Findings: The study offers new knowledge on a perspective that remains underexposed so far, which makes comparison to previous literature difficult. More research is needed to apply the results in clinical practice., Study Funding/competing Interest(s): This research was supported by the Dutch Scientific Society of Sexology (Nederlandse Wetenschappelijke Vereniging Voor Seksuologie). There was no involvement in the conduct of the research, and the funding was unrestricted. There are no conflicts of interest to declare., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The objective of this study was to investigate the safety and effectiveness of disease activity-guided dose optimization of TNF inhibitors in RA over 10 years., Methods: The study involved an observational long-term extension of a randomized study of participants who completed the 3-year extension of the DRESS-study. After the randomized phase (months 0-18), disease activity-guided dose optimization was allowed for all. The main outcomes were mean time-weighted DAS28-CRP; biologic and targeted synthetic DMARD (b/tsDMARD) use per year, as proportion of daily defined dose; proportion of patients reaching discontinuation; durability and effectiveness of subsequent dose reduction attempts; and radiographic progression between years 3 and 10 using the Sharp-van der Heijde score., Results: A total of 170 patients were included, of whom 127 completed the 10-year follow-up. The mean disease activity remained low (DAS28-CRP 2.13, 95% CI 2.10-2.16), while the b/tsDMARD dose reduced from 97% at baseline (95% CI 96-99%, n = 170) to 56% at year 10 (95% CI 49-63%, n = 127). Of 161 participants with an optimization attempt, 119 (74%) reached discontinuation with a median duration of 7 months (interquartile range 3-33 months), and 25 participants never had to restart their b/tsDMARD (21%, 95% CI 14-29%). The mean dose reduction after dose optimization was 48% (n = 159) for the first optimization attempt, and 33% for a subsequent attempt (n = 86). Of the 86 participants, 41 (48%) had radiographic progression exceeding the smallest detectable change (5.7 units), and progression was associated with disease activity, not b/tsDMARD use., Conclusion: Long-term disease activity-guided dose optimization of TNF inhibitors in RA, including discontinuation and multiple tapering attempts, remains safe and effective., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Aims: The diagnostic performance of quantitative perfusion cardiac magnetic resonance (QP-CMR) imaging has scarcely been evaluated in patients with a history of coronary artery disease (CAD) and new onset chest pain. The present study compared the diagnostic performance of automated QP-CMR for the detection of fractional flow reserve (FFR) defined hemodynamically significant CAD with visual assessment of first-pass stress perfusion CMR (v-CMR) and quantitative [15O]H2O positron emission tomography (PET) imaging in a true head-to-head fashion in patients with prior CAD., Methods and Results: This PACIFIC-2 substudy included 145 symptomatic chronic coronary symptom patients with prior myocardial infarction and/or percutaneous coronary intervention. All patients underwent dual-sequence, single-bolus perfusion CMR, and [15O]H2O PET perfusion imaging followed by invasive coronary angiography with three-vessel FFR. Hemodynamically significant CAD was defined as an FFR ≤ 0.80. QP-CMR, v-CMR, and PET exhibited a sensitivity of 66, 67, and 80%, respectively, whereas specificity was 60, 62, and 63%. Sensitivity of QP-CMR was lower than that of PET (P = 0.015), whereas the specificity of QP-CMR and PET was comparable. Diagnostic accuracy and area under the curve of QP-CMR (64% and 0.66) was comparable to both v-CMR [66% (P = not significant [NS]) and 0.67 (P = NS)] and PET [74% (P = NS) and 0.78 (P = NS)]., Conclusion: In patients with prior myocardial infarction and/or percutaneous coronary intervention, the diagnostic performance of QP-CMR was comparable to visual assessment of first-pass stress perfusion CMR and quantitative [15O]H2O PET for the detection of hemodynamically significant CAD as defined by FFR., Competing Interests: Conflict of interest: Dr Knaapen has received research grants from Cleerly, Inc. and HeartFlow, Inc., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Complete non-culprit (NC) revascularisation may help reduce recurrent events after non-ST-segment elevation myocardial infarction (NSTEMI), especially if NC lesions would harbour high-risk plaque (HRP) features similar to ST-segment elevation myocardial infarction (STEMI). This study aimed to assess differences in fractional flow reserve (FFR)-negative NC plaque morphology in patients presenting with NSTEMI vs. STEMI and assess the association of HRP morphology and clinical outcome., Methods and Results: In the prospective PECTUS-obs study, 438 patients presenting with myocardial infarction (MI) underwent optical coherence tomography (OCT) of all FFR-negative intermediate NC lesions. The primary endpoint was the occurrence of major adverse cardiovascular events (MACE, composite of all-cause mortality, non-fatal MI or unplanned revascularisation) at 2-year follow-up. Four hundred and twenty patients had at least one analysable OCT, including 203 (48.3%) with NSTEMI and 217 (51.7%) with STEMI. The prevalence of HRPs, including thin-cap fibroatheromas, plaque rupture, and thrombus, was comparable between groups. MACE occurred in 29 (14.3%) NSTEMI patients and 16 (7.4%) STEMI patients (Puni-variable = 0.025 and Pmulti-variable = 0.270). Incidence of MACE was numerically higher among patients with HRP, irrespective of the clinical presentation at index (Pinteraction = 0.684). Among HRP criteria, plaque rupture was associated with MACE in both NSTEMI (P < 0.001) and STEMI (P = 0.020)., Conclusion: Presence of NC HRP is comparable between NSTEMI and STEMI and leads to numerically higher event rates in both. These results call for additional research on complete revascularisation in NSTEMI and treatment of HRP., Clinical Trial Registration: NCT03857971., Competing Interests: Conflict of interest: R.H.J.A.V. reported receiving grant funding from Abbott Vascular and Health~Holland during the conduct of the study. J.-Q.M. reported receiving grant funding from Abbott Vascular and Health~Holland during the conduct of the study. A.B. reported receiving speaker’s fees from Daiichi Sankyo Inc, travel fees from Novo Nordisk and Daiichi Sankyo, and is shareholder of Pfizer, outside the submitted work. R.S.H. reported receiving speaker fees from Amgen Inc, Angiocare, Edwards Lifesciences and Novartis AG outside the submitted work. R.M.O. reported receiving speaker fees from Abbott Vascular outside the submitted work. E.L. reported receiving grant funding from Abbott Laboratories outside the submitted work. C.C. reported receiving honorarium for organizing regional meetings from AstraZeneca outside the submitted work. P.D. reported receiving grant funding from Abbott Laboratories, AstraZeneca and Philips, ans consulting fees from Abbott Laboratories outside the submitted work. E.K. reported receiving grant funding from Abbott Laboratories and Medtronic, and proctorship honoraria from Abbott laboratories outside the submitted work. M.A.H.v.L. reported receiving grant funding from AstraZeneca, Top Sector Life Sciences & Health, Terumo Corporation, TOP Medical BV, and Abbott Laboratories and speakers’ fees and consulting from Terumo Corporation, Daiichi Sankyo Inc, and Abbott Laboratories outside the submitted work. R.-J.M.v.G. reported receiving grant funding from InfraRedx, and speaker fees from Amgen and Sanofi outside the submitted work. N.v.R. reported receiving grant funding and personal fees from Abbott Vascular and Health~Holland during the conduct of the study and grants from Philips, Biotronik, and Medtronic Inc, and speaker fees from Bayer AG, MicroPort, and RainMed Medical outside the submitted work., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: The 2022 European Society of Cardiology and European Respiratory Society (ESC/ERS) Guidelines for pulmonary arterial hypertension (PAH) recommend risk stratification to optimize management. However, the performance of generic PAH risk stratification tools in patients with systemic sclerosis (SSc)-associated PAH remains unclear. Our objective was to identify the most accurate approach for risk stratification at SSc-PAH diagnosis., Methods: In this multicentre, international cohort study from the European Scleroderma Trials and Research (EUSTAR) group database, we screened eleven risk stratification tools upon SSc-PAH diagnosis. We compared the performance of the three top-ranked tools to predict mortality with the ESC/ERS three-strata model, the currently recommended tool for baseline risk assessment. We also assessed the impact of incorporating SSc-specific characteristics into the tools. Kaplan-Meier analyses and Cox regression with area under the ROC curve (AUC) were conducted., Results: The ESC/ERS three-strata model had a lower ability to predict mortality than the ESC/ERS four-strata model, "SPAHR updated", and "REVEAL Lite 2". The ESC/ERS four-strata model divided "intermediate-risk" patients into two groups with significantly different long-term survival rates and is the easiest applicable tool. Incorporating SSc-specific characteristics did not significantly improve the predictive ability of any model, but a low DLCO was an independent predictor of mortality., Conclusion: Considering its ability to predict mortality, risk segregation capabilities, and clinical applicability, this study provides a rationale for using the simplified ESC/ERS four-strata model at SSc-PAH diagnosis as an alternative to the comprehensive ESC/ERS three-strata model. We propose considering DLCO as an individual prognostic marker in SSc-PAH., (© The Author(s) 2025. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Context: Radiofrequency ablation (RFA) is used as treatment for symptomatic thyroid nodules. Factors influencing the volume reduction ratio (VRR) at 12 months are not yet fully understood., Objective: The primary objective was evaluating the VRR at 12 months after RFA. Secondary objectives were the assessment of a learning curve and factors influencing the VRR at 12 months., Design: A retrospective observational cohort study., Setting: Three Dutch referral hospitals., Patients and Intervention: Patients who underwent RFA for symptomatic thyroid nodules with available ultrasound follow-up., Main Outcome Measures: Ultrasound based VRR at 12 months and chronologically numbered RFA procedures. All patients' baseline, treatment, and early follow-up factors were assessed for correlation with VRR at 12 months., Results: A total of 337 patients with 356 nodules were included in the learning curve analysis. VRR at 12 months increases for the first 20 treatments per center and stabilizes thereafter, indicating a plateau phase after a learning curve. These initial cases were removed from further analysis. In the remaining 299 nodules, median VRR at 3, 6 and 12 months was 57.1, 65.6 and 70.8%. Baseline nodule volume negatively correlated with VRR at 12 months but VRR was high for every volume category. Energy delivered per volume did not correlate to VRR., Conclusions: In RFA for thyroid nodules a stable treatment efficacy is achieved after 20 treatments, with a median VRR of 70.8%. Baseline nodule volume, energy delivered and prolonged follow-up 6 months after treatment may not be clinically relevant to predict treatment success., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.)

Invasive mould disease (IMD) has a high mortality in immunosuppressed patients. Invasive aspergillosis (IA) is the most common IMD. A guideline for preventing IA has been published jointly by the Centers for Diseases Control and Prevention, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. Use of high-efficiency particulate air filters, adequate air exchange rates, sealing of patient rooms, and preventing exposure to moulds by nursing patients in areas away from construction sites are recommended by the guideline. However, there is limited information in relation to the actions to be undertaken by infection prevention and control teams in the event of one or more cases of nosocomial aspergillosis. In this review, we describe a systematic approach to aspergillosis by defining possible and probable nosocomial acquisition based on the number of days since hospital admission. We advocate an incremental response to the investigation of nosocomial aspergillosis in patients in protective isolation taking into account the number of cases and the likelihood of nosocomial origin. For single cases of nosocomial IA, we suggest that infection control investigations should focus on case surveillance and walk-through inspection escalating in a step-wise manner to enhanced case surveillance, verification of environmental controls, environmental monitoring, genotyping of clinical and environmental isolates, and review of antifungal prophylaxis for multiple cases and outbreaks. Where applicable, the construction site should be inspected with the aim to reduce the dispersal of conidia. Surveillance systems need to be strengthened to better understand the epidemiology of IA., (© The Author(s) 2025. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Vitamin D deficiency is common in patients with chronic kidney disease (CKD) and associates with poor outcomes. Current clinical practice guidelines recommend supplementation with nutritional vitamin D as for the general population. However, recent large-scale, clinical trials in the general population failed to demonstrate a benefit of vitamin D supplementation on skeletal or non-skeletal outcomes, fueling a debate on the rationale for screening for and correcting vitamin D deficiency, both in non-CKD and CKD populations. In a collaboration between the European Renal Osteodystrophy initiative of the European Renal Association (ERA) and the European Society for Paediatric Nephrology (ESPN), an expert panel performed an extensive literature review and formulated clinical practice points on vitamin D supplementation in children and adults with CKD and after kidney transplantation. These were reviewed by a Delphi panel of members from relevant working groups of the ERA and ESPN. Key clinical practice points include recommendations to monitor for, and correct, vitamin D deficiency in children and adults with CKD and after kidney transplantation, targeting 25-hydroxyvitamin D levels >75 nmol/L (>30 ng/mL). While vitamin D supplementation appears well-tolerated and safe, it is recommended to avoid mega-doses (≥100 000 IU) and very high levels of 25 hydroxyvitamin D (>150-200 nmol/L, or 60-80 ng/mL) to reduce the risk of toxicity. Future clinical trials should investigate the benefit of vitamin D supplementation on patient-relevant outcomes in the setting of vitamin D deficiency across different stages of CKD., (© The Author(s) 2025. Published by Oxford University Press on behalf of the ERA.)

Background: Biologics are effective for the treatment of psoriasis, but little is known regarding patients treated with one biologic for an 'ultra-long' duration., Objectives: To explore the prevalence, patient and treatment characteristics, and treatment outcomes of ultra-long users of biologics for psoriasis., Methods: Data for patients with psoriasis who had received continuous treatment with the same biologic for ≥ 10 years were collected from the prospective, multicentre BioCAPTURE cohort. Baseline characteristics of these ultra-long users were determined and compared with the total BioCAPTURE population. The proportion of patients using concomitant systemic treatment and receiving dose adjustments, the trajectory of Psoriasis Area and Severity Index scores and drug survival rates beyond 10 years were also analysed., Results: Among the BioCAPTURE cohort, 30.5% of patients with the potential to achieve a treatment episode of ≥ 10 years reached this treatment duration. These patients were treated with ustekinumab, etanercept, adalimumab and infliximab. The proportion of ultra-long users was highest for ustekinumab (37.1%). The ultra-long user cohort had a slightly longer disease duration at registry entry, and a higher proportion of men and patients diagnosed with psoriatic arthritis (PsA) than the total BioCAPTURE population. Among the cohort, 69.5% of patients had at least one comorbidity and 66.1% used no additional systemic antipsoriatic treatment. Dose adjustments were often applied, varying from dose escalation (29.7%), dose reduction (40.7%) or both (13.6%); only 16.1% of patients consistently used the standard dose throughout their treatment. The median PASI score for ultra-long users from month 6 onwards was consistently < 3, with only a small proportion achieving complete clearance of their psoriasis (3.9-13.7% at the various timepoints). Drug survival analysis beyond 10 years showed that 62.3% of patients were still being treated with the same biologic after 15 years., Conclusions: Ultra-long use of the same biologic in patients with psoriasis was common in real-world practice but varied between biologics. The median PASI score was around 2.5 throughout the 10-year treatment course; complete clearance was often not achieved. Remarkably, ultra-long use was also recorded in patients with multiple comorbidities (including PsA). Dose adjustments of the biologic were applied in the majority of patients. These results provide clinicians with important evidence on ultra-long treatment with biologics, thereby improving psoriasis care and the management of treatment expectations., Competing Interests: Conflicts of interest: N.F.T.H. carries out a clinical trial for Janssen. The funding is not personal, but goes to the independent research fund of the Department of Dermatology, Radboud University Medical Centre (Radboudumc), Nijmegen, the Netherlands. M.E.O. has acted as consultant for Eli Lilly. J.M.P.A.R. carried out clinical trials for AbbVie, Celgene, Almirall and Janssen and has received speaking fees/attended advisory boards from AbbVie, Janssen, BMS, Almirall, LEO Pharma, Novartis, UCB and Eli Lilly and reimbursement for attending or chairing a symposium from Janssen, Pfizer, Celgene and AbbVie. All funding is not personal, but goes to the independent research fund of the Department of Dermatology, Radboud University Medical Centre (Radboudumc), Nijmegen, the Netherlands. E.M.G.J.J. has received research grants for the independent research fund of the Department of Dermatology, Radboud University Medical Centre (Radboudumc), Nijmegen, The Netherlands, from AbbVie, BMS, Janssen Pharmaceutica, Leo Pharma, Novartis and UCB for research on psoriasis and has acted as a consultant and/or paid speaker for and/or participated in research sponsored by companies that manufacture drugs used for the treatment of psoriasis or eczema, including AbbVie, Amgen, Almirall, Boehringer Ingelheim, BMS, Celgene, Galapagos, Janssen Pharmaceutica, LEO Pharma, Eli Lilly, Novartis, Sanofi and UCB. All funding is not personal, but goes directly to the Department of Dermatology, Radboud University Medical Centre (Radboudumc), Nijmegen, the Netherlands. R.R.M.C.K. has acted as a paid chairman for Janssen Immunology. P.P.M.L. has received funding from Wyeth for research and carried out clinical trials for Abbott and Janssen-Cilag; has received speaking and consulting fees from Wyeth and Schering-Plough; has received reimbursement for attending a symposium from Schering-Plough and Pfizer; and has attended advisory boards for AbbVie, LEO Pharma, Novartis and UCB. I.M.H. is a consultant, advisory board member and/or speaker for Sanofi Genzyme and Regeneron Pharmaceuticals, Pfizer, LEO Pharma, AbbVie, Janssen and Eli Lilly. S.R.P.D. has attended advisory boards for AbbVie, Janssen and Novartis. F.M.H. has acted as a consultant and/or paid speaker for AbbVie and LEO Pharma. M.B.A.D. is or recently was a speaker and/or adviser for and/or has received research funding from Novartis, AbbVie, Almirall, LEO Pharma, Sanofi, Janssen, UCB and BMS, outside the submitted work. M.T. has carried out clinical trials for AbbVie, Almirall, Cellgene, Eli Lilly, Incyte, LEO Pharma, Moonlake and Novartis. All trial funding is not personal, but goes to the independent research fund of the Department of Dermatology of Bravis Hospital Bergen op Zoom, the Netherlands. He has also received speaking fees/attended advisory boards from AbbVie, Novartis, Pfizer and UCB and reimbursement for attending a symposium from Almirall and UCB., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

A substantial number of patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) undergo a nephrectomy, especially in work-up for a kidney transplantation. Currently, there is no evidence-based algorithm to guide clinicians which patients should undergo nephrectomy, the optimal timing of this procedure, or the preferred surgical technique. This systematic review-based consensus statement aimed to answer important questions regarding nephrectomy in ADPKD. A literature review was performed and extended to a meta-analysis when possible. For this purpose, PubMed and EMBASE were searched up to May 2024. Fifty-four publications, describing a total of 2391 procedures, were included. In addition, an exploratory questionnaire was sent to urologists, nephrologists, and transplant-surgeons. These sources were used to develop practice points about indications, complications, mortality, timing, and technique of nephrectomy. In addition, data on renal embolization as a potential alternative to nephrectomy was explored and summarized. To reach consensus, practice points were defined and improved in three Delphi survey rounds by experts of the European Renal Association Working Group Genes & Kidney and the European Association of Urology Section of Transplantation Urology. A total of 23 practice points/statements were developed, all of which reached consensus. Among others, it was deemed that nephrectomy can be performed successfully for various indications and is an intermediate risk procedure with acceptable mortality and minimal impact on kidney graft function when performed before, in the same session or after transplantation. The complication rate seems to increase when the procedure is performed as an emergency. During the work-up for transplantation, patient complaints should be assessed routinely by questionnaires to indicate symptom burden. Deciding on the need for nephrectomy and exploring potential alternatives such as kidney embolization should be a process of shared decision making, preferably after multidisciplinary consultation., (© The Author(s) 2025. Published by Oxford University Press on behalf of the ERA.)

Introduction: Vasectomy is a widely used, safe, effective method of permanent contraception and contributes to healthy sexuality., Aims: We have conducted a 3-step observational clinical study to develop a vasectomy regret risk score and guide patients and clinicians when discussing a vasectomy., Methods: A 3-step approach has been followed. First, experts involved in male health have proposed risk factors for regret (remorse) after vasectomy, defined by a vasectomy reversal surgery or medically assisted reproduction. The selected factors were evaluated in 1200 patients vasectomized in the last 15 years. Finally, the expert panel has constructed a score for predicting regret after vasectomy., Results: Fifty-two international experts identified 17 risk factors for vasectomy regret. Five of the risk factors were significant: an age <35 years old, a high Barrat Impulsivity Score, a low level of education, and a patient who didn't understand that the vasectomy might not be reversible or for whom the contraception responsibility is ideally feminine, or no responsible partner. On multivariate analysis, 3 risk factors and 2 "sine qua non" conditions were used to build the decision algorithm. A risk score ≥ 4 required information on sperm cryopreservation before vasectomy, and those with a risk score ≥ 7 required extra time for reflection. The scoring system was proposed to 52 international experts and accepted with 86.7% strongly agreeing. The model's sensitivity and specificity were 0.98 and 0.53, respectively., Conclusion: A decisional algorithm was established to identify patients requiring information on sperm cryopreservation before vasectomy or additional time for reflection to reduce the risk of vasectomy regret. The algorithm contains 3 risk factors and 2 " sine qua non " conditions., Competing Interests: None declared., (© The Author(s) 2025. Published by Oxford University Press on behalf of The International Society for Sexual Medicine.)

Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency results in severe cortisol and aldosterone deficiency, leading to persistent adrenal stimulation and excess production of ACTH and adrenal androgens. This review examines the clinical considerations and challenges of balancing under- and overtreatment with glucocorticoids in adolescent and adult male individuals with CAH. Adolescents face many unique challenges that can hinder adherence, hormonal control, and transition to independence. Thus, patient education is critical during adolescence, especially in poorly controlled postpubertal males who lack obvious symptoms and may not recognize the long-term consequences of nonadherence, such as reduced final height, reduced reproductive health, poor bone health, obesity, and hypertension. The risk of subfertility/infertility begins early, especially in males with poor hormonal control, who often have reduced sperm counts, small testes, and benign tumors called testicular adrenal rest tumors (TARTs). Even males with good hormonal control can experience subfertility/infertility due to TARTs. In addition, several factors such as hypogonadism and long-term glucocorticoid treatment can predispose males with CAH to poor bone health (eg, low bone mineral density, increased risk of osteoporosis/osteopenia and fractures) and metabolic syndrome (eg, obesity, insulin resistance, dyslipidemia, and hypertension). Regular monitoring is recommended, with glucocorticoid dose optimization and prophylactic treatment to maximize future fertility potential and protect long-term bone health. Early implementation of lifestyle interventions and medical treatment are needed to address cardiometabolic consequences., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.)

In the modern era, cardiologists managing patients and families with cardiomyopathies need to be familiar with every stage of the diagnostic pathway from clinical phenotyping to the prescription and interpretation of genetic tests. This clinical consensus statement from the ESC Council for Cardiovascular Genomics aims to promote the integration of genetic testing into routine cardiac care of patients with cardiomyopathies, as recommended in the 2023 ESC guidelines for cardiomyopathies. The document describes the types of genetic tests currently available and provides advice on their prescription and for counselling after the return of genetic findings, including the approach in patients and families with variants of unknown significance., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. 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.)

Context: In adults, cortisol levels show a pronounced 24-hour rhythm with a peak in the early morning. It is unknown at what age this early-morning peak in cortisol emerges during infancy, hampering the establishment of optimal dosing regimens for hydrocortisone replacement therapy in infants with an inborn form of adrenal insufficiency., Objective: We aimed to characterize daily variation in salivary cortisol concentration across the first year of life., Methods: We conducted a systematic review followed by an individual participant data meta-analysis of studies reporting on spontaneous (ie, not stress-induced) salivary cortisol concentrations in healthy infants aged 0-1 year. A one-stage approach using linear mixed-effects modeling was used to determine the interaction between age and time of day on cortisol concentrations., Results: Through the systematic review, 54 eligible publications were identified, reporting on 29 177 cortisol observations. Individual participant data were obtained from 15 study cohorts, combining 17 079 cortisol measurements from 1904 infants. The morning/evening cortisol ratio increased significantly from 1.7 (95% CI: 1.3-2.1) at birth to 3.7 (95% CI: 3.0-4.5) at 6 to 9 months (P < .0001). Cosinor analysis using all available data revealed the gradual emergence of a 24-hour rhythm during infancy., Conclusion: The early-morning peak in cortisol secretion gradually emerges from birth onwards to form a stable morning/evening ratio from age 6 to 9 months. This might have implications for hydrocortisone replacement therapy in infants with an inborn form of adrenal insufficiency., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: Immune checkpoint inhibition (ICI) is highly effective for the treatment of melanoma, but intrinsic resistance is present in a subgroup of patients. TGF-β pathway activity may play a role in this resistance by preventing T-cells from entering the tumor microenvironment, causing immune escape. We investigated the association of TGF-β signal transduction pathway activity with resistance to ICI treatment in advanced melanoma. Furthermore, other pathway activities were analyzed to better understand their potential role in ICI resistance., Method: The activity of 8 signaling pathways (TGF-β, Hedgehog, MAPK, AR, NOTCH, PI3K, JAK/STAT1-2, and NFkB) was analyzed from tumor tissue from patients with advanced melanoma. Pathway activity scores (PAS) were explored for associations with survival and response to ICI in 34 patients (19 non-responders and 15 responders). A second, independent method to investigate the predictive value of TGF-β pathway activation was conducted by determining levels of phosphorylated SMAD2., Results: The mean TGF-β PAS of responders vs non-responders was 53.9 vs 56.8 (P = 0.265). No significant relation with progression-free survival was detected for TGF-β activity (P = 0.078). No association between pSMAD2 staining and treatment response or survival was identified. In contrast, Hedgehog scores of responders versus non-responders were 35.7 vs 41.6 (P = 0.038). High Hedgehog PAS was the sole significant predictor of resistance to ICI (OR 0.88, P = 0.033) and worse progression-free survival (HR 1-1.1, P = 0.012)., Conclusion: TGF-β pathway activation showed no significant relation with treatment response to ICI or survival in patients with advanced melanoma. Hedgehog PAS was identified as a possible biomarker associated with both treatment response and survival., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology.)

Background: Certain micronutrient levels have been associated with the risk of developing TB disease. We explored the possible association of selected at-risk micronutrient levels with the development of Mycobacterium tuberculosis (M.tb) infection., Methods: This cohort study in Bandung, Indonesia, followed Interferon Gamma Release Assay (IGRA) negative TB case contacts with a repeat IGRA test at 3 mo. At baseline, blood was analysed for haemoglobin, 25-hydroxyvitamin D, retinol-binding protein, C-reactive protein, alpha-1-acid glycoprotein, serum transferrin receptor (sTfR), ferritin, zinc and selenium. Total body iron was calculated using ferritin and sTfR status. Associations between case contact micronutrient concentration and IGRA conversion were estimated using Poisson regression., Results: Of 430 contacts, 115 (27%) underwent IGRA conversion. Ferritin concentration (adjusted for inflammation) was positively associated with risk of IGRA conversion (incidence rate ratio [IRR] for ferritin=1.17; 95% CI 1.01 to 1.35; p=0.03), but other select micronutrients were not. This association held for ferritin in the final multivariable model (IRR=1.27; 95% CI 1.09 to 1.47; p=0.002)., Conclusions: The risk of developing M.tb infection, as defined by IGRA conversion, is associated with increasing ferritin. Interventions in TB case contacts to temporarily reduce iron levels, including considering withholding any iron supplementation, may be worthy of evaluation., (© The Author(s) 2025. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Aims: Recent trials have shown that low-dose colchicine (0.5 mg once daily) reduces major cardiovascular events in patients with acute and chronic coronary syndromes. We aimed to estimate the cost-effectiveness of low-dose colchicine therapy in patients with chronic coronary disease when added to standard background therapy., Methods and Results: This Markov cohort cost-effectiveness model used estimates of therapy effectiveness, transition probabilities, costs, and quality of life obtained from the Low-Dose Colchicine 2 trial, as well as meta-analyses and public sources. In this trial, low-dose colchicine was added to standard of care and compared with placebo. The main outcomes were cardiovascular events, including myocardial infarction, stroke, and coronary revascularization, quality-adjusted life year (QALY), the cost per QALY gained (incremental cost-effectiveness ratio), and net monetary benefit. In the model, low-dose colchicine therapy yielded 0.04 additional QALYs compared with standard of care at an incremental cost of €455 from a societal perspective and €729 from a healthcare perspective, resulting in a cost per QALY gained of €12 176/QALY from a societal perspective and €19 499/QALY from a healthcare perspective. Net monetary benefit was €1414 from a societal perspective and €1140 from a healthcare perspective. Low-dose colchicine has a 96 and 94% chance of being cost-effective, from a societal and a healthcare perspective, respectively, when using a willingness to pay of €50 000/QALY. Net monetary benefit would decrease below zero when annual low-dose colchicine costs would exceed an annual cost of €221 per patient., Conclusion: Adding low-dose colchicine to standard of care in patients with chronic coronary disease is cost-effective according to commonly accepted thresholds in Europe and Australia and compares favourably in cost-effectiveness to other drugs used in chronic coronary disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background and Aims: Individuals with coronary artery disease have poorer mental health, health-related quality of life (HR-QoL), and cognition compared with (age-matched) controls. Exercise training may attenuate these effects. The aim is to systematically review and meta-analyse the effects of different exercise types and settings on brain structure/function, cognition, HR-QoL, mental health (e.g. depression, anxiety), and sleep in patients with coronary artery disease., Methods: A systematic search was conducted and a network meta-analysis compared (i) exercise types, high-intensity interval training (HIIT), HIIT + resistance (HIIT + R), moderate-intensity training (MIT), MIT + R and stretching-toning-balance training, and (ii) exercise settings, in-person and home-based., Results: A total of 42 randomized controlled trials with a parallel group design were identified, of which 36 were included in the meta-analysis. Few studies included cognition (n = 2), sleep (n = 2), and none brain structure/function (n = 0). Most studies examined HR-QoL (n = 30), depression (n = 15), and anxiety (n = 9), in which outcomes were meta-analysed. HIIT + R, HIIT, and MIT were associated with improved HR-QoL vs. no exercise (i.e. usual care) [standardized mean difference, SMD: 1.53 (95% confidence interval 0.83; 2.24), 0.44 (0.15; 0.73), and 0.44 (0.20; 0.67), respectively]. In-person exercise was associated with larger and significant improvements [HR-QoL SMD: 0.51 (0.28; 0.74), depressive SMD: -0.55 (-1.03; -0.07), and anxiety symptoms SMD: -1.16 (-2.05; -0.26)] compared with no exercise, whereas home-based programmes were not significantly associated with improvements in these outcomes. Findings were robust in secondary (i.e. intervention duration and volume) and sensitivity analyses excluding high risk of bias studies., Conclusions: Exercise training, especially in-person sessions, was associated with improved HR-QoL, depression and anxiety, independently of exercise type. However, this study raises concern about the effectiveness of home-based programmes in improving these outcomes.Study protocol was registered in PROSPERO (ID: CRD42023402569)., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Mid-level visual processing represents a crucial stage between basic sensory input and higher-level object recognition. The conventional model posits that fundamental visual qualities like color and motion are processed in specialized, retinotopic brain regions (e.g., V4 for color, MT/V5 for motion). Using atlas-based lesion-symptom mapping and disconnectome maps in a cohort of 307 ischemic stroke patients, we examined the neuroanatomical correlates underlying the processing of eight mid-level visual qualities. Contrary to the standard model's predictions, our results did not reveal consistent relationships between processing impairments and damage to traditionally associated brain regions. While we validated our methodology by confirming the established relationship between visual field defects and damage to primary visual areas (V1, V2, and V3), we found no reliable evidence linking processing deficits to specific regions in the posterior brain. These findings challenge the traditional modular view of visual processing and suggest that mid-level visual processing may be more distributed across neural networks than previously thought. This supports alternative models where visual maps represent constellations of co-occurring information rather than specific qualities., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain.)

There should be no assumption that an athlete is immune to coronary artery disease (CAD), even when traditional cardiovascular (CV) risk factors appear well-managed. Excelling in certain aspects of health does not equate to total CV protection. Recent data from cardiac imaging studies have raised the possibility that long-term, high-volume, high-intensity endurance exercise is associated with coronary atherosclerosis. Whilst the risk of CV events has not been shown to rise with athletic activity, the potential for CAD should not be overlooked as it is the leading cause of sudden cardiac death in athletes >35 years of age (i.e. 'Masters athletes'). Evaluating both traditional and non-traditional risk factors for CAD is the most important part of pre-participation evaluation in Masters athletes. When managing athletes at risk of CAD it is important to adopt a shared decision-making approach regarding lifestyle adaptation and lipid-lowering treatments. In the great majority of athletes, after excluding the presence of symptoms and inducible ischaemia, this advice should include encouragement to continue exercising as available data indicate that higher levels of fitness are associated with a markedly attenuated incidence of coronary events regardless of the severity of coronary disease. Future research is needed to establish the relationship between clinically relevant CAD outcomes and coronary artery calcification in Masters Athletes, the role of sex, as well as exploration of the mechanisms underpinning these unexpected CV adaptations., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Higher than standard doses of rifampicin could improve the treatment outcome of drug-susceptible tuberculosis without compromising the safety of patients., Methods: We performed a systematic review of prospective clinical studies including adults with pulmonary and extrapulmonary TB receiving rifampicin doses above 10mg/kg/day. We extracted the data on overall adverse events (AE), hepatic AE, sputum culture conversion (SCC) at week 8, recurrence, mortality, and pharmacokinetics. We performed a Bayesian network meta-analysis (NMA) using a random-effects model., Results: In 19 studies, 2033 out of 3654 participants received rifampicin doses higher than 10mg/kg/day. The NMA showed an increased risk of overall and hepatic AE for the 40mg/kg/day dose (RR 4.8, 95% CrI 1.1; 25, and 15.00, 95% CrI 1.1; 58.0, respectively), but no other doses, including 50mg/kg/day showed such an increase. Increasing doses improved sputum culture conversion at week 8 (RR 1.3, 95% CrI 1.1; 1.7 for SCC with 35mg/kg/day)., Conclusion: Optimal doses of rifampicin may be between 25 and 35mg/kg/day, but should be tailored at the individual or, at least, at the population level., (© The Author(s) 2025. Published by Oxford University Press on behalf of Infectious Diseases Society of America. 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.)

Treatment of classic congenital adrenal hyperplasia (CAH) is directed at replacing deficient hormones and reducing androgen excess. However, even in the era of early diagnosis and lifelong hormonal substitution, the presence of CAH is still associated with numerous complications and also with increased mortality. The aim of this article was to create an authoritative and balanced review concerning cardiometabolic risk in patients with CAH. The authors searched all major databases and scanned reference lists of all potentially eligible articles to find relevant articles. The risk was compared with that in other forms of adrenal insufficiency. The reviewed articles, most of which were published recently, provided conflicting results, which can be partially explained by differences in the inclusion criteria and treatment, small sample sizes, and gene-environment interactions. However, many studies showed that the presence of CAH is associated with an increased risk of weight gain, worsening of insulin sensitivity, high blood pressure, endothelial dysfunction, early atherosclerotic changes in the vascular wall, and left ventricular diastolic dysfunction. These complications were more consistently reported in patients with classic than nonclassic CAH and were in part related to hormonal and functional abnormalities associated with this disorder and/or to the impact of overtreatment and undertreatment. An analysis of available studies suggests that individuals with classic CAH are at increased cardiometabolic risk. Excess cardiovascular and metabolic morbidity is likely multifactorial, related to glucocorticoid overtreatment, imperfect adrenal hormone replacement therapy, androgen excess, and adrenomedullary failure. Cardiometabolic effects of new therapeutic approaches require future targeted studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: The growth hormone (GH) secretagogue receptor, encoded by GHSR, is expressed on somatotrophs of the pituitary gland. Stimulation with its ligand ghrelin, as well as its constitutive activity, enhances GH secretion. Studies in knock-out mice suggest that heterozygous loss-of-function of GHSR is associated with decreased GH response to fasting, but patient observations in small case reports have been equivocal., Objective: To establish the phenotype of GHSR haploinsufficiency and their growth response to GH treatment., Methods: This case series includes 26 patients with short stature and heterozygous GHSR variants. Pathogenicity was studied in vitro using total protein levels, cell surface expression, and receptor activity in basal, stimulated and inhibited states., Results: Ten different variants were identified, of which six were novel. Variants showed either partial or complete loss-of-function, primarily through loss of constitutive activity. Patients (4.0-15.1 years) had proportionate short stature (height -2.8±0.5 SDS), failure to thrive with low appetite (n=4), a mean serum insulin growth factor I (IGF-I) of -1.6±0.7 SDS, and a normal stimulated GH response. Nine patients received GH treatment, showing a height gain of 0.9±0.4 SDS after 1 year and 1.5±0.4 SDS after 2 years (n=5)., Conclusion: This study combines phenotypical and functional data in a uniquely large group of children with short stature carrying GHSR variants, and shows their good response to GH treatment. The results strengthen the hypothesis of GHSR's role in GH secretion., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.)

Objectives: Gastroesophageal reflux disease (GERD) is frequent in systemic sclerosis (SSc) and could predict progression of interstitial lung disease (ILD). We aimed to analyse (1) the prevalence of GERD among SSc-ILD patients, (2) its association with disease characteristics and (3) predictive factors for ILD progression in SSc-ILD patients with GERD., Methods: SSc patients from the EUSTAR database with ILD were included. GERD was labeled as present if reflux/dysphagia was reported at the baseline visit or before. Disease characteristics of patients with and without GERD were compared at baseline. ILD progression was defined as relative FVC decline ≥10% or relative FVC decline between 5-9% in association with relative DLCO decline of ≥ 15% over 12±3 months of follow-up. Prognostic factors for ILD progression, overall survival and progression-free survival in SSc-ILD patients with GERD were tested by multivariable Cox regression., Results: 5462 SSc-ILD patients were included, 4400 (80.6%) had GERD. Patients with GERD presented more frequently with diffuse cutaneous SSc (OR: 1.44 [1.22-1.69], p < 0.001) and more severe lung involvement with lower FVC (85.8±22.1 vs 90.2±20.1, p < 0.001), lower DLCO (60.8±19.7 vs 65.3±20.6, p < 0.001) and worse performance at the 6-minute walking test. Female sex (HR: 1.39 [1.07-1.80], p = 0.012) and older age (HR: 1.02 [1.01-1.03], p < 0.001) independently predicted ILD progression in SSc-ILD patients with GERD., Conclusion: SSc-ILD patients with GERD appear to suffer from a more severe SSc disease. In this population, female sex may be considered as risk factor for ILD progression., (© The Author(s) 2025. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Heligmosomoides polygyrus co-infection is reported to have protective antiviral effects against pulmonary viral infections. To investigate a potential underlying mechanism, we infected C57BL/6 mice with H. polygyrus larvae for two weeks. Bone marrow (BM)-derived plasmacytoid dendritic cells (pDCs) were generated and stimulated with TLR agonists. We found increased expression of type 1 interferon genes (Ifnα1, Ifnα4, Ifnβ1, Mx1, Isg15), increased TNF, IL-6, IL-10 secretion, and higher expression of antigen presentation markers in BM-derived-pDCs from infected mice compared to naïve control. Our findings may partly explain the mechanism of the antiviral protection previously reported in acute helminth infections., (© The Author(s) 2025. Published by Oxford University Press on behalf of Infectious Diseases Society of America. 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: The EASL cystic liver disease guideline states that drug penetration at the site of infection (liver cyst) is essential for successful treatment, but pharmacokinetic (PK) data on cyst penetration are limited., Objectives: This study aims to investigate tissue penetration of four antibiotics in non-infected liver cysts and explores influencing factors., Methods: We performed a prospective, randomized single-dose PK-study. Before percutaneous drainage of a non-infected liver cyst, an intravenous (IV) dose of either ciprofloxacin and piperacillin/tazobactam (group 1); or co-trimoxazole (trimethoprim/sulfamethoxazole) and doxycycline (group 2) was given. Cyst fluid was collected during drainage. Blood samples were obtained before, during and after drainage (within 12 h). Drug concentrations were measured with a validated LC-MS/MS. Primary outcome was liver cyst penetration, defined as the cyst-fluid-to-plasma concentration ratio (%) expressed as median (IQR)., Results: We included 20 patients, and 21 liver cysts were drained (group 1: n = 11, group 2: n = 10). Median drained cyst volume was 700 mL. Median time between infusion and drainage was 139 min (IQR 120-188 min). Median cyst-fluid-to-plasma concentration ratio was 4.2% (IQR 1.6%-8.9%) for ciprofloxacin, 0.3% (IQR 0.0%-1.3%) for piperacillin, 0.2% (IQR 0.0%-1.3%) for tazobactam, 12.2% (IQR 6.3%-16.1%) for trimethoprim, 0.4% (IQR 0.2%-3.8%) for sulfamethoxazole and 1.6% (IQR 0.9%-2.3%) for doxycycline. Time between trimethoprim infusion and cyst drainage was correlated with increased cyst-fluid-to-plasma concentration ratio (P < 0.01)., Conclusions: Trimethoprim and ciprofloxacin have the highest penetration ratios amongst antibiotics tested. We found that liver cyst penetration varies widely between drugs after a single IV dose., Clinical Trial Number: NTR8499The trial was originally registered in the Netherlands Trial Register (ID: NL7290), which was converted to the International Clinical Trials Registry Platform in 2022., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: Inflammatory bowel disease (IBD) is often diagnosed in young adults, and therefore frequently coincides with pregnancy. Patients may require surgery that includes (temporary) stoma placement. Literature on the occurrence of stoma-complications during pregnancy and the effect on pregnancy outcomes is limited. To evaluate stoma- complications peri- and postpartum, a retrospective study was performed in women who were pregnant while having a stoma., Methods: This multicentre cohort and survey study included all pregnant patients with IBD and a stoma who delivered between 2016 and 2023 from 5 Dutch university hospitals. Stoma-complications and pregnancy outcomes were retrospectively collected from electronic patient files. A questionnaire assessed patient-reported complications and long-term stoma-related complaints., Results: In total, 50 patients were included (median age at conception 31.0 years; 55.2% Crohn's disease and 44.8% ulcerative colitis), comprising 67 pregnancies, 5 of which ended in pregnancy loss. Stoma complications occurred in 44 full-term pregnancies (71.0%), most commonly obstruction (35.5%) and decreased output (29.0%). Surgery was required in four pregnancies due to obstruction (n = 3) and prolapse (n = 2). In the first-year postpartum, 7 patients required surgery for stoma-complications. Amongst 29 women who completed the questionnaire, 10 (34.5%) reported unresolved complications 6 months postpartum. Cesarean sections were performed in 31 (50.0%) pregnancies. Adverse pregnancy outcomes included prematurity (n = 9, 14.5%), low birth weight (n = 9, 14.5%), and dysmaturity (n = 5, 8.1%)., Conclusions: Pregnancy with a stoma is feasible, though manageable complications often occur. Counseling before pregnancy and close monitoring of symptoms during pregnancy and postpartum are essential for women with IBD and a stoma., (© 2025 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Echinocandin drugs are the current first-line therapy for fungal infections caused by Candida spp. Most patients require once-daily intravenous (IV) administration in a hospital or outpatient setting for treatment, which may negatively impact their quality of life and stress healthcare resources. Similar to other echinocandins, the novel FDA-, EMA-, and Medical and Healthcare Products Regulatory Agency-approved echinocandin, rezafungin (CD101), exhibited strong antifungal activity against several fungal pathogens and a low drug-drug interaction liability, which are important for medically complex patients. A pharmacometric-based approach has been adopted throughout the development of rezafungin, which contrasts with older echinocandins where dosing regimens were largely derived empirically, and only recently based on pharmacometric guidance. This state-of-the-art approach used model-based simulations incorporating pre-clinical and clinical data as it became available to optimize the dosing regimen for rezafungin. The enhanced stability of the molecular structure and the safety profile of rezafungin allow for the administration of once-weekly IV doses, compared to the daily dosing requirement for other echinocandin drugs, with this distinctive pharmacokinetic profile of rezafungin resulting in a front-loaded dosing regimen with high exposures early in therapy for enhanced fungal killing. The long shelf-life of rezafungin makes this echinocandin more flexible in terms of storage and manufacturing. Demonstrated across clinical development, rezafungin may provide patients with next-generation first-line antifungal treatment for the treatment of candidaemia and invasive candidiasis., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Objectives: Macrophages are key orchestrators of the osteoarthritis (OA)-associated inflammatory response. Macrophage phenotype is dependent on environmental cues like the inflammatory factor S100A8/A9. Here, we investigated how S100A9 exposure during monocyte-to-macrophage differentiation affects macrophage phenotype and function., Methods: OA synovium cellular composition was determined using flow cytometry and multiplex immunohistochemistry. Healthy donor monocytes were differentiated towards M1- and M2-like macrophages in the presence of S100A9. Macrophage markers were measured using flow cytometry, and phagocytic activity was determined using pHrodo Red Zymosan A BioParticles. Gene expression was determined using qPCR. Protein secretion was measured using Luminex multianalyte analysis and ELISA., Results: Macrophages were the dominant leucocyte subpopulation in OA synovium. They mainly presented with an M2-like phenotype, although the majority also expressed M1-like macrophage markers. Long-term exposure to S100A9 during monocyte-to-macrophage differentiation increased M2-like macrophage markers CD163 and CD206 in M1-like and M2-like differentiated cells. In addition, M1-like macrophage markers were increased in M1-like, but decreased in M2-like differentiated macrophages. In agreement with this mixed phenotype, S100A9 stimulation modestly increased expression and secretion of pro-inflammatory markers and catabolic enzymes, but also increased expression and secretion of anti-inflammatory/anabolic markers. In accordance with the upregulation of M2-like macrophage markers, S100A9 increased phagocytic activity. Finally, we indeed observed a strong association between S100A8 and S100A9 expression and the M2-like/M1-like macrophage ratio in end-stage OA synovium., Conclusion: Chronic S100A8/A9 exposure during monocyte-to-macrophage differentiation favours differentiation towards an M2-like macrophage phenotype. The properties of these cells could help explain the catabolic/anabolic dualism in established OA joints with low-grade inflammation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: The main objective was to develop and evaluate an artificial intelligence model for tooth segmentation in magnetic resonance (MR) scans., Methods: MR scans of 20 patients performed with a commercial 64-channel head coil with a T1-weighted 3D-SPACE (Sampling Perfection with Application Optimized Contrasts using different flip angle Evolution) sequence were included. Sixteen datasets were used for model training and 4 for accuracy evaluation. Two clinicians segmented and annotated the teeth in each dataset. A segmentation model was trained using the nnU-Net framework. The manual reference tooth segmentation and the inferred tooth segmentation were superimposed and compared by computing precision, sensitivity, and Dice-Sørensen coefficient. Surface meshes were extracted from the segmentations, and the distances between points on each mesh and their closest counterparts on the other mesh were computed, of which the mean (average symmetric surface distance) and 95th percentile (Hausdorff distance 95%, HD95) were reported., Results: The model achieved an overall precision of 0.867, a sensitivity of 0.926, a Dice-Sørensen coefficient of 0.895, and a 95% Hausdorff distance of 0.91 mm. The model predictions were less accurate for datasets containing dental restorations due to image artefacts., Conclusions: The current study developed an automated method for tooth segmentation in MR scans with moderate to high effectiveness for scans with respectively without artefacts., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Institute of Radiology and the International Association of Dentomaxillofacial Radiology.)

Study Question: What is the predictive value of oligomenorrhea and other PCOS diagnostic characteristics in adolescence (age 15-18 years) for future fertility and cardiovascular and metabolic health at adult age?, Summary Answer: Adolescents with oligomenorrhea are more often treated to conceive but are as likely to have as much children as those with regular periods, while persisting oligomenorrhea may associate more often with cardiovascular or metabolic problems., What Is Known Already: Adolescents with oligomenorrhea have a high risk for adult PCOS associated with subfertility due to ovulatory disorders and long-term health risks. Longitudinal studies to estimate the extent of these risks with input starting at adolescence and covering the complete reproductive lifespan are lacking., Study Design, Size, Duration: A 25-year prospective follow-up study based on a unique population-based adolescent study on menstrual irregularities performed between 1990 and 1997, the Pubertal Onset of Menstrual Cycle abnormalities, a Prospective study (POMP study). Of the 271 invited adults, 160 (59%) participated., Participants/materials, Setting, Methods: We contacted stratified samples of the POMP study cohort two decades after the initial study for a questionnaire assessing PCOS features, fertility history, pregnancy outcome, metabolic, and cardiovascular health. One hundred and sixty subjects completed the questionnaire. The mean adolescent age was 15.3 years, and the women were 39.6 years at the time of follow-up. One hundred and eight subjects had a regular menstrual cycle as adolescents and 52 were oligomenorrheic., Main Results and the Role of Chance: Of those with adolescent regular menstrual cycles 12 never tried to conceive, 4 tried but never conceived and 92 of 96 (96%) conceived, 89 of 96 (93%) delivering at least one living child. The median number of children was two. The mean time to pregnancy (TTP) was 8.4 months in the women with regular periods as adolescents and 13.2 months in case of oligomenorrhea (P = 0.08) and subfertility was present in respectively 18% and 26%. 47 of 52 adolescents with oligomenorrhea tried to conceive and 45 succeeded to have at least one live birth. Twenty-eight per cent of the subjects reported a change over time of their menstruation pattern. Fifty per cent of the girls with adolescent oligomenorrhea developed a regular cycle and 16% of those with regular periods changed to oligomenorrhea with significantly more reported subfertility (40%, P = 0.04). In case of persistent oligomenorrhea, a significant proportion (40%) underwent fertility treatment (P = 0.04). Adult BMI did not differ between groups. The risk for pregnancy-induced hypertension or pre-eclampsia was comparable between the groups. Gestational diabetes developed in three subjects each with persistent oligo amenorrhea. Adult diabetes, hypertension, and hypercholesterolemia were also mostly reported in case of persistent oligomenorrhea. In this group, the prevalence of combined cardiovascular and metabolic problems was 14% compared to 7% in the case of regular menstrual cycles as adolescent., Limitations, Reasons for Caution: The numbers in the study are small. However, the small difference between the percentage with a least one living child of those with adolescent oligomenorrhea versus those with adolescent regular menstrual cycles is reassuring. Time to pregnancy data may have been biased by early treatment of oligomenorrheic adults., Wider Implications of the Findings: Oligomenorrheic adolescents may be reassured that their chance to have a live birth is comparable with those with a regular menstrual cycle., Study Funding/competing Interest(s): This research received no external funding, J.S.E.L. received unrestricted research grants from the following companies (in alphabetical order): Ansh Labs, Ferring, Merck, and Roche Diagnostics. He received consultancy fees or royalties from Ansh Labs, Art pred, Ferring, Gedeon Richter, and Roche Diagnostics. He received presentation fees from Ferring and Roche Diagnostics as well as support for attending meetings and/or travel from Ferring and Roche Diagnostics and he participated in the advisory board of the LOCI Trial UK., Trial Registration Number: Dutch Trial Registry, NTR5871., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Background: Mycobacterium abscessus is a highly drug-resistant non-tuberculous mycobacterium (NTM) for which treatment is limited by the lack of active oral antimycobacterials and frequent adverse reactions. Epetraborole is a novel oral, boron-containing antimicrobial that inhibits bacterial leucyl-tRNA synthetase, an essential enzyme in protein synthesis, and has been shown to have anti-M. abscessus activity in preclinical studies., Objectives: To determine epetraborole MIC distribution for 147 recent M. abscessus isolates via broth microdilution., Methods: M. abscessus isolates collected in 2021 from the USA (n = 122) from pulmonary sources and during 2019-22 predominantly from Europe (n = 25) from pulmonary and extrapulmonary sources had MICs determined by broth microdilution according to CLSI guidelines for epetraborole and a panel of 12 other antimycobacterials. Descriptive analyses were done on the MIC values., Results: Of the 147 M. abscessus isolates, 101 were subspecies abscessus, 6 were bolletii and 40 were massiliense. Epetraborole MICs ranged from 0.03 to 0.25 mg/L and were consistent across subspecies. Epetraborole MIC50/MIC90 for all isolates were 0.06/0.12 mg/L. When stratified by subspecies, amikacin resistance, clarithromycin resistance and morphotype, the MIC50/MIC90 values remained 0.06/0.12 mg/L., Conclusions: Epetraborole demonstrated potent in vitro activity against M. abscessus with MICs from 0.03 to 0.25 mg/L and consistent activity against all subspecies, resistance phenotypes and morphotypes. These data support clinical evaluation of epetraborole as a therapeutic option for M. abscessus disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: Ovarian cancer is the leading cause of death among gynaecological cancers. The identification of the fallopian tube epithelium as the origin of most ovarian cancers introduces a novel prevention strategy by removing the fallopian tubes during an already indicated abdominal surgery for another reason, also known as an opportunistic salpingectomy. This preventive opportunity is evidence based, recommended and established at the time of gynaecologic surgery in many countries worldwide. To expand interest among surgeons in performing a salpingectomy during non-gynaecological surgery, the aim of this review is to identify knowledge gaps during those surgeries., Methods: A scoping review was performed following the PRISMA-Scoping Review (ScR) checklist. PubMed, Embase, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL) database and Cochrane Library were systematically searched from inception to November 2024. Trial registers were searched for ongoing trials. All studies reporting original data on salpingectomy during non-gynaecological surgery were included. Outcomes were provided narratively., Results: Eighteen studies were identified reporting on the implementation, surgical feasibility, patients' perspectives, physicians' knowledge and cost-effectiveness of an opportunistic salpingectomy during non-gynaecological surgery. Population-level data indicate that an opportunistic salpingectomy is rarely performed in non-gynaecological surgeries. High success rates and no complications of an opportunistic salpingectomy were observed during bariatric surgery and cholecystectomies. However, performing an additional salpingectomy appeared more time-consuming. Patients had strong interest in information on and willingness to undergo opportunistic salpingectomy. Cost-effectiveness analysis encourages opportunistic salpingectomy use, as models show reduced ovarian cancer incidence and mortality rate while being cost-effective., Conclusions: Opportunistic salpingectomy during non-gynaecologic surgery appears to be a promising method to prevent ovarian cancer. Implementing such a strategy will require education of multiple surgical disciplines, training and resolution of organizational issues., (© The Author(s) 2025. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Histoplasmosis poses a significant risk to HIV patients, particularly in regions with limited access to antiretroviral therapy. Antigen detection assays are crucial in these settings for timely diagnosis and treatment, which can reduce mortality. While commercial antigen detection kits have performed well in diagnosing histoplasmosis, their effectiveness in monitoring treatment remains unclear. This study aimed to evaluate the correlation between urine antigen levels and clinical response using the clarus Histoplasma Galactomannan (GM) enzyme immunoassays (EIA) kit. The study followed 27 HIV patients diagnosed with histoplasmosis over 24 weeks, measuring urinary Histoplasma antigen (Ag) levels and clinical outcomes. Patients received amphotericin B as induction therapy, followed by maintenance with itraconazole. Results showed a significant decrease in Ag levels over time, with clinical scores improving in correlation with the decline in Ag levels. Four patients exhibited atypical Ag patterns due to immune reconstitution inflammatory syndrome or issues with itraconazole bioavailability. Despite these challenges, all patients showed improvement by week 24. The findings suggest that the clarus Histoplasma GM EIA kit could be a valuable tool for monitoring and evaluating the response to antifungal therapy in histoplasmosis patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)