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Background Prognostic staging systems in transthyretin amyloid (ATTR) cardiomyopathy were developed before the introduction of disease‐modifying treatment. We therefore evaluated contemporary risk stratification according to different staging systems in patients with ATTR cardiomyopathy. Methods All patients with newly diagnosed ATTR cardiomyopathy and baseline biomarker measurements from 2019 to 2023 were included from Mayo Clinic, Rochester, MN. Prognostic outcomes were calculated with Kaplan–Meier analysis for 3e staging systems in the main analysis: the National Amyloidosis Centre (NAC) staging system; a modified Mayo staging system using hsTNT (high‐sensitivity troponin T) cutoff >65 ng/L; the extended NAC model with a fourth stage (NT‐proBNP [N‐terminal pro‐B‐type natriuretic peptide] >10 000 ng/L). Results The study population consisted of 441 patients with a median age of 76 years, 93% were men, 85% were initiated on tafamidis, and 94% had wild‐type ATTR. Median follow‐up was 3.4 years, and 109 deaths occurred during follow‐up. The 3‐year survival for the Mayo stages were 92.3% (88.7–95.9) for stage I, 71.6% (63.0–81.3) for stage II, and 43.5% (32.4–58.5) for stage III. For the NAC system, 3‐year survival were 92.0% (89.0–95.7), 67.5% (59.0–77.3), and 47.0% (34.7–63.5) for stages I, II, and III, respectively. The 3‐year survival by the extended NAC system was 92.0 (69.0–79.2), 69.0% (60.1–79.2), 53.2% (39.9–70.8) and 34.4% (17.4–68.0) for stages I, II, III, and IV, respectively. Conclusions In a contemporary cohort of patients with ATTR cardiomyopathy, the NAC and modified Mayo staging systems remained equally effective in delineating clinically meaningful prognostic groups, whereas the extended NAC system identified a stage IV subgroup with high mortality.

Marketing authorizations for oncology drugs are often based on single‐arm trials (SATs), and real‐world data‐based external comparator cohorts (ECCs) are increasingly explored to contextualize results. In retrospective studies, comparators may be identified by time of diagnosis but included based on time of relapse; such sampling strategies can introduce bias, potentially leading to erroneous efficacy conclusions. Simulated diffuse large B‐cell lymphoma (DLBCL) cohorts were generated using published time‐to‐relapse and post‐relapse survival distributions. Three ECC sampling strategies were evaluated: naïve (screening and inclusion periods coincide), delayed (inclusion period extends beyond screening), and displacement (screening and inclusion periods shifted relative to each other). Different sampling strategies caused significant changes in the time‐to‐relapse distribution in the ECC and, by proxy, the estimated 2‐year post‐relapse overall survival (22.5–52.2%). Naïve sampling consistently resulted in oversampling of early relapses, though bias was reduced with extended inclusion periods; in hypothetical trials, it produced inflated Type I errors (10.5–84.9%) despite α = 0.025. Delayed sampling reduced bias when the inclusion period was sufficiently extended to capture late relapses, yielding unbiased estimates under long delays (Type I error of 2.5% at a 6‐year delay). Displacement sampling depended strongly on the degree of shift: moderate shifts minimized bias, whereas long displacements introduced substantial distortion (Type I error of 2.7% and 0.0% at displacements of 2 and 5, respectively). Real‐world data‐based ECCs in relapsed/refractory oncology are susceptible to selection bias from sampling strategies, particularly through distortions in time‐to‐relapse, leading to erroneous efficacy conclusions; similar bias may occur in non‐oncology settings where time‐to‐treatment initiation is prognostic.

Abstract Aims Cardiogenic shock (CS) is characterized by impaired left ventricular (LV) mechanical performance and adverse remodelling. We evaluated whether transthoracic echocardiography (TTE)-derived modified cardiac efficiency (mCE), integrating stroke work and residual LV volume, is associated with short- and long-term mortality in CS and whether its prognostic value differs by shock aetiology. Methods and results In this retrospective cohort study, consecutive adults admitted with CS to the cardiac intensive care unit at Mayo Clinic (2007–2018) were included if TTE was performed within 24 h. mCE was calculated as (stroke volume × estimated LV end-systolic pressure) divided by LV end-systolic volume and categorized into quartiles. Primary outcome was in-hospital mortality; secondary outcome was 1-year mortality. Multivariable logistic and Cox models adjusted for illness severity, comorbidity burden, shock aetiology, cardiac arrest, vasoactive therapy, and mechanical circulatory support. Among 667 patients, median mCE was 48 mmHg (IQR 32–74). In-hospital mortality was 28% and increased stepwise across decreasing mCE quartiles. The lowest quartile had a 2.5-fold higher adjusted odds of in-hospital death (OR 2.53; 95%CI: 1.49–4.37; P < 0.001). One-year mortality was 41%; the lowest quartile had a two-fold higher adjusted hazard of death (HR 2.05; 95%CI: 1.45–2.89; P < 0.001). Associations were stronger in acute coronary syndrome-related CS (interaction P = 0.035 for in-hospital; P = 0.015 for 1-year). Within the lowest quartile, reduced systolic pressure further amplified mortality risk. Conclusion Early TTE-derived mCE was independently associated with short- and long-term mortality in CS, particularly in acute coronary syndrome-related CS, and captured the interaction between ventricular remodelling and mechanical performance underlying high-risk phenotypes.

Objectives To explore the outcomes among patients treated with TAVI (transcatheter aortic valve implantation) in the COMPARE-TAVI 1 trial by age groups and sex. Design Cohort study. Setting Three Danish university hospitals. Participants Patients treated with TAVI in the COMPARE-TAVI 1 trial (N=1030), 60 (5.8%), 337 (32.7%), 592 (57.5%) and 41 (4.0%) were in the four age groups, < 70, 70–79, 80–89 and 90+ years while 414 (40.2%) and 616 (59.8%) were of female and male sex. Interventions Transfemoral TAVI with balloon-expandable valves (Sapien or Myval) performed between June 2020 and November 2023. Outcome measures Post hoc analyses of trial secondary outcomes that include end-point committee-adjudicated outcomes. Results In the four age groups, 1-year mortality rates were 8.3%, 5.6%, 5.6% and 7.3% while it was 5.8% in both sexes. Across the four age groups, 1-year stroke rates were 6.7%, 1.8%, 3.2% and 4.9%, and 5.1% among females and 4.7% among males. In the four age groups, 1-year new pacemaker rates were 7.5%, 15%, 19% and 13% while it was 15% among females and 18% among males. Females had smaller annuli than males and their gradients were higher and the effective orifice area lower after TAVI but their frequency of prosthesis-patient mismatch was similar at 1 year. Conclusion While comorbidity levels varied between groups, clinical outcomes were similar across age groups and between sexes. Trial registration number NCT04443023 .

Abstract Since its introduction in 2002, left atrial appendage closure (LAAC) has rapidly expanded as an alternative to anticoagulation in patients with atrial fibrillation at high risk of stroke. Harmonized processes for data collection, analysis, and reporting in LAAC trials are essential to enhance research quality and improve clinical practice. The Left Atrial Appendage Academic Research Consortium (LAARC) initiative is an independent collaboration of academic research organizations, cardiology and neurology experts, clinical trialists, and regulatory authorities from the USA, Europe, and Asia. The consortium engaged clinical experts, regulators—including the US Food and Drug Administration (FDA), European Notified Bodies, and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA)—and industry leaders to define standardized study elements and endpoints for LAAC trials. Key considerations included alignment with prior Academic Research Consortium initiatives, procedural and mechanistic insights, and clinical relevance. Consensus definitions were proposed for mortality, stroke, bleeding, and device performance, along with composite endpoints for safety and effectiveness. The proposed LAARC consensus definitions aim to standardize endpoint reporting, improve comparability across studies, and support regulatory and clinical trial applications for this evolving therapy through broad dissemination in the peer-reviewed literature.

Abstract Unvetted scientific claims about vaccines can spread rapidly and undermine decades of progress in immunization and public trust. A recent non-peer-reviewed analysis, promoted at political hearings, in the documentary “An Inconvenient Study,” and on social media, has been used to suggest that vaccinated children experience higher rates of chronic illness than unvaccinated peers. Despite standard regression models, critical flaws - uncontrolled confounding, exposure misclassification, unequal follow-up, and outcome multiplicity, invalidate causal inference. An independent group of international experts critically appraises this analysis and contrast its claims with the consistent evidence confirming vaccine safety and effectiveness. We also show how poorly designed studies can distort public discourse, amplify misinformation, and fuel vaccine hesitancy. We outline actions to strengthen research integrity, such as transparent data sharing, labeling of non-peer-reviewed content, and evidence-based communication. Safeguarding public health demands that vaccine evidence be methodologically sound, reviewed, and interpreted by qualified experts.

Objectives Rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPA) are linked to disease activity, severity and cardiovascular risk in rheumatoid arthritis (RA). Since RA-related inflammation associates with cardiovascular disease, we investigated whether RF and ACPA status influence the relationship between RA activity and event risk. Methods We assessed 3952 cardiovascular disease-free patients with prevalent RA registered in an international observational consortium between 1985 and 2012. Main outcome was a first major adverse cardiovascular event (MACE) including myocardial infarction, stroke and cardiovascular death. Follow-up accrued from enrolment until first MACE or censoring. Multivariable Cox models stratified by centre risk evaluated disease activity, RF, ACPA and their interactions. Results We recorded 184 first MACE events over 22 981 patient-years. Disease activity associated with MACE (HR 1.18 (95% CI 1.03 to 1.35)), whereas RF (HR 1.26 (0.82 to 1.94)) and ACPA (HR 1.25 (0.85 to 1.83)) did not reach statistical significance, though CIs were wide and a clinically meaningful association cannot be excluded. A three-way interaction between disease activity, RF and ACPA on MACE (p for interaction=0.044) was observed. RA activity associated with MACE in seronegative and double seropositive (p≤0.047), but not single RF-positive or ACPA-positive patients. Among RF-negative participants, RA activity was linked to MACE in ACPA-negative but not positive ones (p for interaction=0.003). Among ACPA-positive patients, disease activity was linked to MACE in RF-positive but not RF-negative ones (p for interaction=0.040). Conclusions Disease activity may better discriminate inflammation-driven cardiovascular risk in seronegative and double seropositive than single RF-positive or ACPA-positive patients. Risk protection through lowering disease activity may be serostatus dependent.

Abstract Background Rare pediatric and young adult brain tumors pose major diagnostic and therapeutic challenges due to limited evidence and scattered expertise. The International Rare Brain Tumor Board was established to enable multidisciplinary case review, shared learning, and collaborative decision support. Methods Launched in February 2025, the Rare Brain Tumor Board is a monthly collaborative initiative led by Children’s National Hospital and the National Institutes of Health (NIH). Close partnership with the European Pediatric Rare CNS Tumor Board enhances transatlantic exchange and alignment of diagnostic and treatment recommendations. De-identified cases are presented with clinical history, neuroimaging, histopathology, and molecular profiling, including DNA methylation classification, available for the majority of cases. Sessions are structured to support integrated diagnosis and evidence-informed management recommendations through multidisciplinary discussion (neuropathology, neuroradiology, neurosurgery, radiation oncology, and pediatric as well as adult neuro-oncology). Findings Since its inception, 12 sessions have been held averaging 138 participants per session, reviewing a total of 32 cases (mean 3 cases/session; range 1–4) from 7 different countries and 3 different continents. Entities reviewed include DICER1-intracranial sarcoma (n = 5), astroblastoma (n = 4), FOXR2-activated neuroblastoma (n = 4), CNS tumors with BCOR internal tandem duplication (n = 3) and, BCOR-fused tumors (n = 3), CIC-rearranged-sarcoma (n = 3), intracranial mesenchymal tumor FET::CREB fusion positive (n = 3), MN1::PATZ1 fusion tumors (n = 2), undifferentiated sarcoma (n = 2), PLAG1-fusion tumor (n = 1), medullomyoblastoma (n = 1), and EZHIP-altered diffuse midline glioma (DMG) (n = 1). Multidisciplinary review has supported diagnostic clarification, strengthened familiarity with ultra-rare entities, and informed real-world treatment discussions in settings where prospective data are limited. Discussions have also increased awareness of rare brain tumor registries and opportunities for systematic case capture. Conclusion An international multidisciplinary rare brain tumor board is a feasible, scalable model to advance integrated diagnosis and collaborative management of ultra-rare pediatric and young adult brain tumors, while building a shared knowledge base across institutions.

Abstract Aims This study aimed to identify clinical factors associated with AVC in individuals with T2D. Methods and results This cross-sectional study is a pre-specified substudy of the multicentre randomized Steno INTEN-CT trial (Clinical Trials—INTEN-CT). Participants were eligible if they had T2D without ischaemic heart disease and were aged between 55–69 years (men) or 60–74 years (women). All participants underwent non-contrast cardiac computed tomography. AVC was measured in Agatston Units and categorized as 0, 0–300, ≥ 300. Of the 4570 participants, 46% had AVC &gt; 0. With increasing AVC, patients were older, predominantly males, and with significantly more comorbidities. In multivariable ordered logistic regression age (OR per SD 1.54, 95% CI 1.43–1.66), BMI (OR per SD 1.18, 95% CI 1.11–1.25), hypertension (OR 1.21, 95% CI 1.05–1.40), and chronic kidney disease (OR 1.18, 95% CI 1.03–1.36) were associated with higher AVC. Statin use was also associated with higher AVC (OR 1.50, 95% CI 1.27–1.78). Higher LDL cholesterol showed stronger associations with AVC in men than women (OR 1.39, 95% CI 1.24–1.56 vs. OR 1.16, 95% CI 1.02–1.31, P for interaction = 0.025). T2D severity (Haemoglobin A1c, T2D duration, and number of antidiabetic drugs) was not associated with AVC. Conclusion In individuals with T2D without cardiovascular disease, AVC is prevalent in nearly half of all individuals. Higher AVC was associated with T2D-related comorbidities, but not T2D severity.