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BACKGROUND: Intracranial atherosclerosis (ICAS) is associated with an increased risk of early recurrent ischemic stroke. We evaluated whether biomarkers of impaired distal perfusion—specifically, anterior circulation borderzone infarct, and hypoperfusion mismatch volume—were associated with recurrent ischemic stroke within 90 days. METHODS: The BIORISK ICAS (Biomarkers and Recurrence Risk in Symptomatic Intracranial Atherosclerosis) is a multicenter retrospective international study (35 sites) that included hospitalized patients with symptomatic ICAS (50%–99% luminal stenosis of the intracranial vertebral, basilar, distal internal carotid, or proximal middle cerebral artery) from January 2019 to June 2024. The primary outcome was recurrent ischemic stroke in the territory of the symptomatic artery within 90 days. In the primary analysis, the exposure was an acute anterior circulation borderzone infarct. In secondary analysis of the subset with presentation within 72 hours of last known normal and perfusion imaging completed, the exposure of interest was prespecified as hypoperfusion mismatch volume at T max (time to maximum) threshold of 6 seconds, dichotomized at the Youden index. We performed multivariable Cox regression to test associations between exposure variables and the outcome, adjusting for clinically relevant variables and those associated with the outcome ( P <0.1). RESULTS: Of 2050 patients with symptomatic ICAS, 1737 (84.7%) presented within 72 hours of symptom onset, among whom 509 (29.3%) underwent perfusion imaging. The primary analysis included 1891 patients; 174 (9.2%) patients had recurrent ischemic stroke in the symptomatic arterial territory. In adjusted Cox regression models, there was an association between anterior circulation borderzone infarct and recurrent ischemic stroke at 90 days (adjusted hazard ratio, 1.40 [95% CI, 1.02–1.93]). In the perfusion imaging analysis, hypoperfusion mismatch of ≥10 mL was associated with recurrent ischemic stroke (adjusted hazard ratio, 1.83 [95% CI, 1.03–3.28]). CONCLUSIONS: Biomarkers of impaired distal perfusion, anterior circulation borderzone infarct, and hypoperfusion mismatch were associated with increased risk of recurrent ischemic stroke. These findings support the use of perfusion imaging in ICAS as well as future trials investigating early reperfusion in high-risk patients with ICAS.

This cohort study evaluates the use of arterial spin labeling magnetic resonance imaging (ASL MRI) to quantify placental perfusion in pregnant individuals with a fetus with congenital heart disease.

Background A contemporary, comprehensive risk score for the prediction of in‐hospital fatal and nonfatal adverse events after percutaneous coronary intervention has been recently developed, albeit its external validation in patients with acute coronary syndrome is lacking. The objective of this study is to validate the Mayo Clinic integer risk score in a large cohort of patients with acute coronary syndrome undergoing percutaneous coronary intervention from the MATRIX (Minimizing Adverse Haemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox) trial. Methods The risk score is composed of a common set of 23 clinical and procedural variables (model A) and 18 preprocedural variables (model B). The primary objective was to appraise the receiver‐operator characteristics of both models for in‐hospital mortality, bleeding, contrast‐associated acute kidney injury, and stroke. The impact of risk score categories on 1‐year outcomes was also investigated. Results Among the 6724 patients undergoing percutaneous coronary intervention in the MATRIX trial, the receiver‐operator characteristics—area under the curves for in‐hospital mortality, bleeding, contrast‐associated acute kidney injury, and stroke were 0.88 (95% CI, 0.85–0.91), 0.66 (95% CI, 0.63–0.69), 0.70 (95% CI, 0.67–0.72), and 0.65 (95% CI, 0.52–0.78) for model A and 0.88 (95% CI, 0.84–0.92), 0.63 (95% CI, 0.60–0.66), 0.66 (95% CI, 0.63–0.69), and 0.65 (95% CI, 0.52–0.78) for model B, respectively. Mortality (model A), bleeding, and stroke risks were well calibrated, whereas mortality (model B) and contrast‐associated acute kidney injury risk were underestimated. There was a gradual risk increase for 1‐year mortality and bleeding as a function of the risk score tertile using both models. Conclusions The risk score identifies patients with acute coronary syndrome at incremental risk of in‐hospital mortality, bleeding, contrast‐associated acute kidney injury, and stroke, representing a valuable tool for mitigation of modifiable risk factors. Registration URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT01433627.

Abstract BRCA-associated homologous recombination deficiency (HRD) is present in ~ 50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤ 3 years, n = 42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n = 1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.

ABSTRACT Introduction Sinonasal sarcomas are exceedingly rare entities, constituting less than 7% of head and neck sarcomas. Their complex histology needs specialized treatment, which is often based on multimodal approaches including surgery, radiation therapy, and/or chemotherapy. This manuscript aims to gather expert opinions to establish common management principles for sinonasal sarcomas. Methods This international consensus followed a modified Delphi method in seven steps, including statements definition by the core group, expert panel recruitment, and a two‐round survey. Sixty‐two statements on sinonasal sarcoma management were developed. Experts from multiple continents participated, and results were anonymized and analyzed between March and May 2025. Results A total of 44 invited experts were recruited, 43.2% otorhinolaryngologists/head and neck surgeons, 31.8% medical oncologists, and 25% radiation oncologists. Participants varied in age and experience, representing Europe (70.5%), North America (18.2%), South America (6.8%), and Asia (4.5%). Among all histologies, biphenotypic sarcoma, chondrosarcoma, leiomyosarcoma, and myofibrosarcoma are principally treated with an upfront surgical management, differently from Ewing sarcoma and rhabdomyosarcoma in which chemotherapy, eventually associated with radiotherapy, is often chosen. In the remaining histologies (angiosarcoma, liposarcoma, malignant peripheral nerve sheath tumor [MPNST], osteosarcoma, and synovial sarcoma), a precise multimodal treatment is less standardized and needs to be discussed on a case‐by‐case basis. Conclusion Sinonasal sarcomas require a histology‐driven approach to determine upfront treatment, whether surgical, medical, or multimodal. Despite this structured strategy, prognosis remains highly variable across subtypes. Multidisciplinary evaluation and individualized management in referral centers are crucial to address the biological diversity and anatomical complexity of these rare malignancies.

Background A classification system describing clinical presentation before aortic valve replacement (AVR) has recently been proposed (stable valve syndrome [SVS]), mildly symptomatic (progressive valve syndrome), or with acute and severe signs and symptoms (acute valve syndrome [AVS]). We aimed to evaluate the clinical impact, health care costs, and resource use associated with the mode of clinical presentation at the time of AVR among patients presenting with aortic stenosis. Methods Using the Market Clarity database (2017–2023), patients >18 years old with aortic stenosis and undergoing AVR (transcatheter or surgical) were included. Patients were categorized as SVS, progressive valve syndrome, or AVS based on their clinical presentation during the 1 year before AVR. All‐cause death, heart failure hospitalization, total health care costs (index hospitalization plus 1‐year follow‐up), and resource use were compared across clinical presentation groups using adjusted regression models. Results Of the 24 075 patients undergoing AVR for aortic stenosis, 270 (1.1%) had SVS, 10 195 (42.3%) progressive valve syndrome, and 13 610 (56.5%) AVS. Compared with SVS, AVS presentation was associated with increased risk of 1‐year death (adjusted hazard ratio [aHR], 2.93 [95% CI, 1.1–7.8]; P =0.03) and heart failure hospitalization (aHR, 4.15 [95% CI, 1.6–11.1]; P <0.01) after AVR. The total costs of AVR and 1‐year follow‐up were significantly higher in both the progressive valve syndrome (difference $27 410 [$13 507–$41 314]) and AVS groups (difference $36 267 [$22 302–$50 232]) compared with patients with SVS. Conclusions AVS was frequent among patients undergoing AVR and was associated with increase in death, heart failure hospitalization, health care costs, and resource use 1 year after AVR, and SVS presentation was associated with the best clinical and economic outcomes.

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 &amp;lt; .001) and true Aβ-positive detection rate (49% [95% CI, 43-55] vs 69% [95% CI, 64-75]; P &amp;lt; .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.

IntroductionBipolar disorder (BD) is a chronic illness that can lead to severe functioning impairment, which can disrupt daily life. This study aims to compare overall functioning and clinical presentation associated with early onset (EO) and mid-life onset (MO) BD.ObjectivesThe objective of this study is to be able to predict the cognitive and functional impairment evolution of bipolar disorder based on the onset.MethodsA total of 154 BD patients (81 in euthymia and 51 in a depressive episode) participated in this cross-sectional study. We selected two groups of subjects based on age at onset of the first mood episode (EO: 0-20 years, n=117; MO: 20-40 years, n=37) and compared socio-demographic, clinical variables and functional impairment assessed by the World Health Organization Disability Assessment Schedule (WHODAS 2.0).Results75.2% of the patients with an EO were female, they had higher psychiatric comorbidities prevalence (76.1% vs. 43.2%; p<.001), being personality disorders the most significant (30.2% vs. 5.4%; p=.001), more suicide attempts (51.3% vs. 16.2%; p<.001), mood episodes (mdn=12, iqr=17 vs. mdn=6, iqr=9.5; p=.001), childhood abuse (93.5% vs. 73.9%; p=.014), being verbal (78.0% vs. 52.2%; p=.015) and physical abuse (51.6% vs. 21.7%; p=.009) higher compared to MO. Functionality was also affected, with higher dysfunction percentages in EO (mdn=47, iqr=34.7 vs. mdn=24, iqr=12.5; p<.001) affecting cognition (mdn=8.5, iqr=6 vs. mdn=4, iqr=7; p<.001), self-care (mdn=2, iqr=5 vs. mdn=0, iqr=1; p<.001), daily activities (mdn=12, iqr=13 vs. mdn=4, iqr=10; p<.001) and community participation (mdn=13, iqr=8.7 vs. mdn=8, iqr=7; p<.001).EO depressed patients (n=38; F: 30; M: 8), had more personality disorders (42.1% vs. 0%; p=.010), suicide attempts (60.5% vs. 0%; p<.001), mood episodes (mdn=12, iqr=12 vs. mdn=5.5, iqr=4.7; p=.001), lower overall functionality (mdn=57, iqr=41.5 vs. mdn=35, iqr=38.3; p=.009), cognition (mdn=10, iqr=6.5 vs. mdn=4, iqr=9; p=.023), self-care (mdn=4, iqr=6.2 vs. mdn=0, iqr=3; p=.008), oneself care (mdn=9, iqr =7 vs. mdn=5, iqr=8.5; p=.025), daily activities (mdn=15.5, iqr=14 vs. mdn=11, iqr=12.7; p=.037) and community participation (mdn= 15.5, iqr=8.2 vs. mdn=11.5, iqr=5.7; p=.030).EO euthymic patients (n=59; F: 42; M: 17) had more psychiatric comorbidities (74.6% vs. 33.3%; p=.001), physical abuse history (51.2% vs. 0%; p= .002), and lower functionality (mdn=7, iqr=7 vs. mdn=2, iqr=7; p=.004), cognition (mdn=7.5, iqr=7 vs. mdn=4, iqr=7; p=.033), daily activities (mdn=9, iqr=11 vs. mdn=3, iqr=8.5; p=.005) and community participation (mdn=10, iqr=9 vs. mdn= 7, iqr=7; p=.031).ConclusionsResults suggest that patients with an EO are more associated with severe psychosocial functioning impairment. Future studies are needed to clarify a more severe illness prediction between EO and MO.Disclosure of InterestNone Declared

ABSTRACT Objectives To explore the clinical impact of social determinants of health (SDoH) stress in bipolar disorder (BD) course of illness and to explore potential gender differences in SDoH stress endorsement. Methods 2280 individuals living with BD type I or II (62% women; 67.5% BD‐I) participating in the Mayo Clinic Bipolar Biobank who completed a questionnaire assessing positive and negative‐valent stressors in the 12 months prior to study enrollment were included for this analysis. Six negative stressors were used as proxies of SDoH. Generalized linear models were used to test the association between SDoH stressors and markers of illness severity as well as potential differences by sex by including an interaction term. Results After adjusting for age, sex, and recruitment site, SDoH‐related stressors were significantly associated with a more severe course of illness in both men and women. Except for unemployment rates, women reported more frequently SDoH‐related stress (i.e., lack of family support, financial problems, health coverage and access problems). Conclusions The study found significant gender differences in both the endorsement of specific SDoH stressors and in the prevalence of specific illness severity markers; however, it did not directly test the predictive relationship between gender differences in SDoH and illness severity markers. Future studies aiming to achieve health equity in mental health care should continue assessing social determinants of health stressors, incorporating a gender perspective to better understand their influence on bipolar disorder.