Citations

Background: Journal editors influence the visibility and direction of scientific research and should have adequate gender and geographic representation. Research Question: Are there disparities in gender and institutional country affiliation among editors of highly cited cardiology and cardiovascular disease journals? Methods: In May 2025, we used Scimago Journal Rankings to identify the 50 top-cited cardiology and cardiovascular disease journals worldwide from 2022 to 2024. Due to the large volume of members, general editorial board listings without defined roles were excluded. Editors’ genders and country of institutional affiliation were extracted independently and in duplicate by eight sub-investigators. An additional sub-investigator resolved any discrepancies. Gender was determined using institutional profiles and publicly available pronouns on academic or professional platforms. Country affiliation was based on the editor’s primary institution and categorized by World Bank income classification 2025, which divides countries into high-income (HIC), upper-middle income (UMIC), lower-middle income (LMIC), and low-income countries (LIC). Key journal characteristics, such as country, impact factor, and article processing charges, were also extracted in duplicate. Results: All 50 top-cited cardiology and cardiovascular disease journals identified were based in HICs. A total of 1,762 editors were included. Most editorial positions were held by men (67%), with women accounting for 28%. One editor was identified as non-binary, and the gender of 91 editors (5%) could not be determined based on publicly available information (Table 1). Pronouns were identifiable for all EIC (n=52), out of which 87% were men (n=45) and 13% were women (n=7). Ninety-five percent of editors were affiliated with institutions based in HIC, while only 5% were based in UMIC (n=71), LMIC (n=16), or LIC (n=5). The most represented countries were the US (41%), Italy (8%), and the UK (7%) (Figure 2). All EICs (100%) were affiliated with institutions based in HICs, mainly the US (52%) and the UK (10%) (Figure 3). Conclusion: Editors of top-cited cardiology journals are predominantly men affiliated with HICs. Diverse editorial leadership in academic cardiology journals is needed to reflect global perspectives in research.

ABSTRACT Suicidality contributes substantially to global morbidity and mortality, yet despite its heritability, its biological etiology remains largely elusive. We conducted multi-ancestry genome-wide association study meta-analyses of suicidal ideation (259,747 cases), suicide attempt (64,993 cases), suicide death (9,197 cases), and suicidal behavior (suicide attempt/ death, 75,300 cases), across 54 cohorts (e.g., the Psychiatric Genomics Consortium, Million Veteran Program, UK Biobank). We identified 77 significant loci across meta-analyses, including 59 previously unreported for suicidality. SNP-based heritability ranged from 2.0-6.7% and there were strong, yet incomplete, genetic correlations between suicidality phenotypes (0.70-0.88). Fine-mapping prioritized putative causal SNPs and 20 credible genes. Enrichment analyses implicated synaptic pathways and neuronal populations predominantly in subcortical brain regions (e.g., amygdala excitatory, medium spiny, hippocampal CA1-3). Together, these findings establish suicidality as a polygenic set of traits with both shared and distinct genetic influences, providing a foundation for future studies of suicide biology and etiology.

Abstract Purpose: The role of tumor-infiltrating lymphocytes (TIL) remains unclear in hormone receptor (HR)–positive/HER2-negative breast cancer, particularly in young patients, whose immune microenvironment could be altered by age-related host and tumor differences. Experimental Design: Patients with stage I to III HR-positive/HER2-negative tumors were identified from a prospective cohort study of patients with breast cancer diagnosed at age ≤40 years. Multiplexed immunofluorescence and semiautomated quantitative software measured cytotoxic T, non–CD8 T, T regulatory, exhausted T, and PDL1+ cells in stroma and tumor. Univariate analyses assessed differences in clinicopathologic characteristics by high versus low immune infiltration, divided based on median. TIL subtypes were evaluated as a continuous variable per 10% increase in Cox regression analyses for invasive breast cancer–free survival, distant disease–free survival (DDFS), and overall survival, adjusted for clinicopathologic parameters. Results: Among 390 patients, high immune infiltration was associated with increasing age, Black race, grade 3 tumors, and metaplastic or micropapillary histologic subtypes. Over a median follow-up of 8 years, higher stromal and intratumoral non–CD8 T-cell infiltration, T regulatory–cell infiltration, and PDL1 expression were associated with improved invasive breast cancer–free survival. Higher intratumoral non–CD8 T-cell infiltration, T regulatory–cell infiltration, and PDL1 expression were associated with improved DDFS; higher stromal PDL1 expression was also associated with improved DDFS. Higher intratumoral cytotoxic T-cell infiltration and PDL1 expression were associated with improved overall survival. Conclusions: Characterization of immune subpopulations could help refine the prognostic value of TILs in young patients with HR-positive breast cancer, who may benefit from risk stratification for treatment individualization. See related commentary by Salgado and Kok, p. 2133

511 Background: Long-term survivorship care is essential for cancer patients, encompassing surveillance, symptom management, psychosocial effects, chronic condition care and health promotion. In low-resource settings such as Peru, financial toxicity (FT) is a pervasive challenge that may hinder access to these services. However, the extent of FT and its association with survivorship care gaps remains understudied in Latin America. Methods: A cross-sectional online survey was conducted among 218 adult cancer survivors in Peru (2024). FT was assessed using the validated COST-FACIT tool. Survivorship care was evaluated across five domains: (1) recurrence and new cancer surveillance, (2) physical effects, (3) psychosocial effects, (4) health promotion, and (5) chronic conditions. Data included demographics, cancer history, monthly income and type of insurance. Multivariable logistic regression identified predictors of severe FT, adjusting for demographics, income, insurance, and urban/rural residence. Results: Participants were predominantly female (78%), aged 45–64 (50.5%), and urban-dwelling (50.9% reside in the capital city). Breast (42.2%), cervical (18.3%), and ovarian (12.4%) cancers were most common. All respondents reported FT, with 66.5% severe and 30.3% moderate. Only 4.1% received care in all five domains. Gaps were highest in chronic condition care (20.2%) and health promotion (22.9%). Insurance coverage included public (70.7%), private (15.8%), and none (13.4%). In adjusted analysis, survivors reporting perceived adequate survivorship care (OR = 0.27, p = 0.002) and recurrence surveillance (OR = 0.30, p = 0.013) had lower odds of severe FT. Higher income was protective (OR = 0.15, p = 0.024). Conclusions: FT is universal among Peruvian cancer survivors and linked to critical gaps in survivorship care, particularly chronic disease and preventive health. The inverse association between comprehensive care and FT severity suggests that structured survivorship programs that integrate financial navigation, care coordination, and insurance expansion could mitigate FT. Findings underscore the urgency of policy reforms to reduce out-of-pocket costs and adapt survivorship models tested in low- and middle-income countries. While this cross-sectional study identifies strong associations, it cannot establish causality, and findings may be subject to selection bias inherent in online surveys.

Importance Advances in Alzheimer disease (AD) have shifted research focus to earlier disease stages, necessitating more scalable approaches to identify cognitively unimpaired individuals with amyloid β (Aβ) pathology. Objective To assess the utility of plasma phosphorylated tau 217 (p-tau217) for classifying Aβ status in cognitively unimpaired individuals, both as a stand-alone test and in a 2-step approach where positive plasma results were confirmed using a second modality (Aβ positron emission tomography [PET] or cerebrospinal fluid [CSF]). Design, Setting, and Participants This cross-sectional cohort study used data collected between June 2009 and March 2024. We included 2916 cognitively unimpaired participants from 12 international independent observational cohorts in the US, Europe, Australia, and Canada with available plasma p-tau217 levels and CSF or PET Aβ biomarkers. Performance comparisons between mass spectrometry and immunoassay-based p-tau217 measurements were also performed (n = 964). Exposures Plasma p-tau217 levels measured by immunoassay. Main Outcome and Measures Aβ status, determined by CSF or Aβ PET biomarkers. Results Participants had a mean (SD) age of 66.9 (9.9) years; 971 (33.3%) were Aβ positive by either CSF or PET, 1667 (57.2%) were women, and 1108 (38.1%) carried at least 1 APOE ε4 allele. As a stand-alone test, plasma p-tau217 achieved a positive predictive value (PPV) of 79% (95% CI, 74-84) and an overall accuracy of 81% (95% CI, 80-82). In a 2-step workflow, the PPV and accuracy significantly increased to 91% (95% CI, 86-95). While this approach required screening of 677 individuals with plasma p-tau217 to identify 100 Aβ-positive individuals, compared to 536 participants when using PET alone, it reduced the need for PET testing to 124. Immunoassays demonstrated comparable PPVs to mass spectrometry (80% [95% CI, 74-86] vs 85% [95% CI, 81-90]; P = .12) but significantly lower overall accuracy (82% [95% CI, 79-84]% vs 88 [95% CI, 86-90]; P < .001) and true Aβ-positive detection rate (49% [95% CI, 43-55] vs 69% [95% CI, 64-75]; P < .001). Conclusions and Relevance The findings highlight the potential of plasma p-tau217 as a stand-alone test—or when used in a sequential 2-step approach alongside PET or CSF testing—as a cost-effective, scalable, and minimally burdensome strategy for identifying preclinical AD. Tailored screening workflows that incorporate p-tau217 can improve efficiency in participant selection for preclinical AD trials and, in the future, help guide access to disease-modifying treatments.

Abstract Active learning strategies enhance medical education by fostering self‐directed learning, communication, and problem‐solving skills. The paper puzzle, a game‐based learning approach, provides an engaging way to reinforce anatomical knowledge and promote collaboration. This study assessed its impact on student performance and perceptions in clinical anatomy, comparing it to PowerPoint‐based imaging reviews and evaluating the role of Near Peer Teachers (NPTs). A prospective, longitudinal, quasi‐experimental study with a mixed‐methods approach was conducted on first‐year medical students enrolled in the Human Anatomy course. Surveys using a Likert scale assessed student and NPT perceptions, while focus groups and interviews provided qualitative insights. Thematic analysis identified key themes related to engagement, knowledge reinforcement, and effectiveness. A total of 907 medical students and 30 NPTs completed a survey, while 75 students and 10 NPTs participated in the qualitative phase. Students perceived the paper puzzle as an engaging and interactive review tool that reduced stress, increased involvement, and enhanced knowledge retrieval through collaboration and a structured gameplay loop. They also valued the emotional impact on learning. NPTs reported benefits for student motivation and teamwork but noted that time constraints limited content coverage. The activity's effectiveness was highly dependent on the NPT's facilitation, emphasizing the need for structured implementation. Findings suggested that game‐based learning strategies like the paper puzzle can improve motivation, teamwork, and content retrieving in anatomy education when carefully designed and effectively executed by NPTs.

Abstract Rationale High-attenuation area (HAA) is a computed tomography (CT) tool that correlates with lung inflammation and fibrosis. Systemic molecular correlates of HAA (e.g., plasma proteins) may inform biological processes involved in interstitial lung disease. Objectives To identify plasma proteins that associate with HAA and correlate with a higher probability of developing new-onset fibrotic or subpleural interstitial lung abnormalities (ILAs). Methods Plasma protein levels were measured using a semiquantitative aptamer-based platform in MESA (the Multi-Ethnic Study of Atherosclerosis; N = 5,486) and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study; N = 1,781). Linear regression models identified HAA-associated proteins after adjustment for demographic and socioeconomic factors, CT scanner parameters, study center, and batch. Associations of HAA-related proteins with new-onset fibrotic or subpleural ILAs were examined in MESA participants with ILA assessments on full-lung CT 10 years later. Immunohistochemical staining of select proteins was performed in lung tissue from pulmonary fibrosis cases. Measurements and Main Results There were 75 proteins detected that were significantly associated with HAA in MESA and SPIROMICS. Gene Ontology analysis of these proteins identified processes involved in immune cell chemotaxis and cellular growth and apoptosis. Seven proteins were associated with a higher probability of new-onset fibrotic or subpleural ILAs in MESA, and two of these, junctional adhesion molecule-like protein and GTP cyclohydrolase 1 feedback regulatory protein, stained in areas of fibrosis in lung tissue from patients with interstitial lung disease. Conclusions Plasma proteins associated with more HAA are involved in immune and cellular processes and associate with new-onset fibrotic-subpleural ILA.

Abstract Twenty percent of patients with follicular lymphoma relapse early with poor outcomes; however, the molecular mechanisms underlying this aggressive behavior are unknown. Using a multiomic approach, we show that patients with follicular lymphoma with elevated IRF4 expression (IRF4hi) have increased transformation risk, dysregulated immune signaling, and a suppressive tumor microenvironment. Loss- and gain-of-function experiments in IRF4hi lymphoma cells, along with chromatin profiling, demonstrate that IRF4 impairs their interaction with T cells by repressing antigen presentation and co-receptor gene modules while promoting the expression of cytokines that antagonize T-follicular helper cell and regulatory T-cell functions. Additionally, IRF4 rewires tumor metabolism and restricts glucose availability to immune cells. Silencing of IRF4 inhibits tumor cell growth and restores immune surveillance mechanisms, thus representing a promising target for therapy. Our data suggest that IRF4hi lymphoma cells co-opt a developmental mechanism used to exit the germinal center response in promoting a more aggressive cancer via engagement of multiple immune-evasive mechanisms. Significance: We show that IRF4 controls immune and metabolic signaling with functional effects on the cross-talk between B and T cells, resulting in a suppressive immune microenvironment when IRF4 is overexpressed in lymphoma. This underscores the importance of IRF4 as a pivotal therapeutic target to restore antitumor immunosurveillance for IRF4-associated lymphomas.

The translation of AI-generated brain metastases (BM) segmentation into clinical practice relies heavily on diverse, high-quality annotated medical imaging datasets. The BraTS-METS 2023 challenge has gained momentum for testing and benchmarking algorithms using rigorously annotated internationally compiled real-world datasets. This study presents the results of the segmentation challenge and characterizes the challenging cases that impacted the performance of the winning algorithms. Untreated brain metastases on standard anatomic MRI sequences (T1, T2, FLAIR, T1PG) from eight contributed international datasets were annotated in stepwise method: published UNET algorithms, student, neuroradiologist, final approver neuroradiologist. Segmentations were ranked based on lesion-wise Dice and Hausdorff distance (HD95) scores. False positives (FP) and false negatives (FN) were rigorously penalized, receiving a score of 0 for Dice and a fixed penalty of 374 for HD95. The mean scores for the teams were calculated. Eight datasets comprising 1303 studies were annotated, with 402 studies (3076 lesions) released on Synapse as publicly available datasets to challenge competitors. Additionally, 31 studies (139 lesions) were held out for validation, and 59 studies (218 lesions) were used for testing. Segmentation accuracy was measured as rank across subjects, with the winning team achieving a LesionWise mean score of 7.9. The Dice score for the winning team was 0.65 ± 0.25. Common errors among the leading teams included false negatives for small lesions and misregistration of masks in space. The Dice scores and lesion detection rates of all algorithms diminished with decreasing tumor size, particularly for tumors smaller than 100 mm3. In conclusion, algorithms for BM segmentation require further refinement to balance high sensitivity in lesion detection with the minimization of false positives and negatives. The BraTS-METS 2023 challenge successfully curated well- annotated, diverse datasets and identified common errors, facilitating the translation of BM segmentation across varied environments and providing the tools for future development of personalized volumetric reports to patients undergoing BM treatment.