Citations

Abstract Objective To evaluate whether thyroid dysfunction, including hypothyroidism and hyperthyroidism, is associated with migraine across racial and age groups using a large, multinational electronic health record database. Background Thyroid disorders are highly prevalent worldwide, with hypothyroidism affecting over 200 million individuals and hyperthyroidism affecting approximately 2.5% of adults. Migraine is a leading cause of disability globally. Prior studies have suggested potential links between thyroid dysfunction and migraine, but evidence has been limited by small sample sizes, restricted population diversity, and inadequate control of confounding. Whether associations differ by thyroid subtype, race, or age remains unclear. Methods We performed two parallel retrospective cohort analyses within the TriNetX Global Collaborative Network, comprising over 200 million patients across 21 countries, using patient records from January 2004 to December 2024. Adults aged 18–100 years with hypothyroidism or hyperthyroidism, defined by ≥3 clinical encounters within 20 years, were identified. Individuals with psychiatric disorders (including mood, anxiety, and stress‐related disorders), sleep disorders, epilepsy or recurrent seizures, or known migraine‐related genetic mutations were excluded. Each thyroid cohort was compared with a control group without thyroid disease, with groups balanced on key demographic and clinical characteristics including age, sex, and hypertension; beta‐blocker use was additionally considered in the hyperthyroidism cohort. The primary outcome was diagnosis of migraine (International Classification of Diseases, 10th Revision, code G43) within 5 years of index date. Subgroup analyses were conducted by race (Caucasian, African American/Black, Asian) and age (18–40, 40–65, 65–100 years). Sensitivity analyses assessed robustness to alternative visit thresholds and expanded covariate adjustment. Results A total of 33,327,750 patients were included in the hypothyroidism analysis and 28,182,377 in the hyperthyroidism analysis. Baseline differences between groups were minimized after cohort balancing. Hypothyroidism was associated with higher odds of migraine across all racial groups, strongest among African American/Black (odds ratio [OR] 2.04; 95% confidence interval [CI] 1.91–2.17), followed by White (OR 1.93; 95% CI 1.89–1.96) and Asian (OR 1.83; 95% CI 1.69–1.98). Hyperthyroidism was similarly associated with increased migraine odds, most prominently among White (OR 1.64; 95% CI 1.59–1.70), with smaller but significant associations in African American/Black (OR 1.28; 95% CI 1.14–1.44) and Asian (OR 1.18; 95% CI 1.07–1.29). Elevated odds were observed across all age strata, generally increasing with age. Findings were consistent in sensitivity analyses. Conclusion In this large, multinational real‐world study, both hypothyroidism and hyperthyroidism were independently associated with increased migraine prevalence across diverse racial and age groups. These results highlight thyroid dysfunction as an important comorbid condition in migraine and support further prospective and mechanistic investigation.

BACKGROUND AND OBJECTIVES: Pediatric large-volume brain arteriovenous malformations (AVMs) carry a substantial lifelong hemorrhage risk, neurological symptoms, and treatment morbidity. Single-session stereotactic radiosurgery (SRS) is often unsuitable due to constraints on dose-volume toxicity. Volume-staged SRS (VS-SRS) enables sequential dosing of large nidus volumes, potentially enhancing safety while maintaining efficacy. Evidence in children remains limited. We aimed to evaluate outcomes of VS-SRS for large AVMs in pediatric patients. METHODS: A multicenter retrospective cohort was assembled from 21 centers, including patients aged younger than 21 years treated with VS-SRS for AVMs >10 cm 3 . Clinical and radiological end points included obliteration, hemorrhage, and permanent symptomatic radiation-induced changes (RIC). RESULTS: A total of 103 patients were included (median age 14 years; IQR, 12-17). The median nidus volume at first stage was 18.2 cm 3 (IQR, 12.3-25.6). Median prescription dose per stage was 17 Gy (IQR, 16-18). The median clinical follow-up from the first stage was 57.5 months (IQR, 25-138). Obliteration occurred in 42 of 103 patients (40.8%), with actuarial rates of 6.9% (95% CI: 2.8-14) at 3 years and 29% (95% CI: 20-39) at 5 years. Hemorrhage occurred in 17 of 103 patients (16.5%) during follow-up, and permanent RIC was observed in 9 of 103 patients (8.7%). CONCLUSION: VS-SRS is a reasonably safe, selected option for pediatric large-volume AVMs when microsurgical or endovascular cure is not feasible or prudent. Delivering ≥17 Gy per stage while limiting each treatment volume to <15 cm 3 supports durable nidus control with acceptable toxicity. VS-SRS represents a key modality in multidisciplinary management of this historically difficult-to-treat population.

OBJECTIVE Ruptured, large pediatric arteriovenous malformations (AVMs) pose a significant management challenge due to high rerupture risk and the morbidity of conventional treatments. Volume-staged stereotactic radiosurgery (VS-SRS) has emerged as an alternative; however, evidence for its use in this specific population is limited. This study aimed to evaluate the long-term efficacy and safety of VS-SRS for ruptured, large AVMs in a dedicated pediatric cohort. METHODS This international, multicenter, retrospective cohort study from 21 centers analyzed outcomes for 42 pediatric patients (age < 18 years) with previously ruptured, large AVMs treated with VS-SRS. The primary outcome was complete AVM obliteration, and secondary outcomes included post-SRS hemorrhage, radiation-induced changes (RICs), and favorable outcome. Favorable outcome in this study was defined as obliteration without post-SRS hemorrhage or permanent RIC. RESULTS At the initial SRS, the median patient age was 14.5 years, and the median AVM volume was 15.0 cm 3 ; most AVMs were high grade (Spetzler-Martin grades IV and V). With a median follow-up of 41.5 months, complete AVM obliteration was achieved in 21 patients (50.0%). The cumulative obliteration rate was 37% at 5 years and 56% at 10 years. Patients with a nidus volume of ≤ 10 cm 3 had significantly higher cumulative obliteration rates than those with a nidus volume > 10 cm 3 (log-rank test, p = 0.021). Similarly, patients treated with a prescription dose > 17 Gy showed significantly higher cumulative obliteration rates compared to those treated with a dose ≤ 17 Gy (log-rank test, p = 0.012). The cumulative 5-year incidences of hemorrhage and RICs following VS-SRS were 19% and 7%, respectively. In multivariable analysis, only larger total AVM volume was an independent predictor of a lower likelihood of favorable outcome (hazard ratio 0.89, 95% CI 0.80–0.99; p = 0.036). CONCLUSIONS In this multicenter pediatric cohort, VS-SRS for ruptured, large AVMs provides a reasonable chance of long-term obliteration, but generally acceptable risks of post-SRS hemorrhage and RICs exist. VS-SRS should be considered as an option for pediatric patients with large, ruptured AVMs.

Abstract Neoadjuvant therapy (NAT) with HER2-targeted agents is the standard treatment for patients with HER2-positive early breast cancer (HER2 + EBC). Although high levels of tumor-infiltrating lymphocytes (TILs) are associated with higher pathologic complete response (pCR) rates and improved recurrence-free survival (RFS), the specific immune components responsible remain unclear. In this study, pretreatment tumor biopsies from 188 patients receiving HER2-targeted NAT were analyzed. Univariate analysis revealed that enrichment of TIL-B cells in tumors, high HER2 mRNA and low ESR1 mRNA expression were linked to pCR (both p < 0.01). Multivariate analysis confirmed TIL-B-cell enrichment as an independent predictor of pCR. Mature IgD/IgM-high B cells, but not immature RAG1 + B cells, independently predicted pCR. Transcriptomic profiling identified 265 upregulated genes in pCR tumors enriched in MHC class II antigen presentation pathways. Immunofluorescence demonstrated increased spatial interaction of mature B cells with CD4 + T cells in pCR tumors, consistent with active antigen presentation. The antigen presenting B-cell signature, integrated mature B-cell and MHC II profile, was the strongest independent predictor of pCR (OR = 3.008, 95% CI: 1.196–7.544, p = 0.019) and was also significantly associated with improved RFS (HR = 0.109, 95% CI: 0.014–0.872), highlighting B-cell–mediated antigen presentation as a clinically relevant biomarker in HER2 + EBC.

Abstract INTRODUCTION Anti—amyloid‐β (Aβ) therapies are reshaping Alzheimer's disease (AD) management. Understanding changes in real‐world patterns of diagnostic testing and infusion chair usage is essential for optimizing access to care. METHODS Retrospective analysis of Mayo Clinic enterprise electronic health records (Jan 2019–Mar 2025) assessed trends in AD‐relevant brain imaging, fluid biomarkers, apolipoprotein E (APOE) testing, and lecanemab infusions. Rates of amyloid‐beta (Aβ) positivity by sex and age, APOE genotype frequencies, and lecanemab treatment initiation and discontinuation were evaluated. RESULTS Following national insurance coverage changes, lecanemab infusions grew by 110 infusions per quarter to 605 in Q1 2025. Aβ positron emission tomography scans increased (+22/quarter), cerebrospinal fluid biomarker orders declined (−25/quarter), and plasma p‐tau 217 orders rapidly increased (+238/quarter). Females were more likely to be Aβ positive ( p < 0.006). APOE ‐ε4 homozygotes were less likely to initiate lecanemab (HR = 0.11, p < 0.001). DISCUSSION The adoption of anti‐Aβ therapies coincided with a rapid shift in diagnostic workflows.

The regulation of the cardiomyocyte cell cycle is central to understanding heart regeneration. In adult mammals, cardiomyocytes withdraw from the cell cycle, limiting their ability to proliferate and repair heart tissue after injury. This process is controlled by intrinsic genetic programs and extrinsic signals, which together restrict the regenerative response in mature hearts. Understanding the mechanisms that regulate cardiomyocyte cell cycle activity is therefore critical for advancing cardiac regenerative medicine. In this review, we provide a comparative and integrated overview of cardiomyocyte cell cycle regulation in lower vertebrates and mammals, and discuss the major intrinsic factors that govern this process, including cyclin/CDK pathways, transcription factors and co-activators, oxygen and metabolic regulation, and epigenetic mechanisms. We also review the influence of hormones and growth factors, as well as the supportive roles of nonmyocyte populations in heart regeneration. By integrating findings across species, developmental stages, and regulatory levels, these findings highlight the complex regulatory network controlling cardiomyocyte proliferation and provide insight into potential therapeutic strategies for stimulating cardiac repair in the adult mammalian heart.

ABSTRACT J‐wave syndromes (JWS)—comprising Brugada syndrome (BrS) and early repolarization syndrome (ERS)—are important causes of malignant ventricular arrhythmias and sudden cardiac death in patients whose hearts appear structurally normal. Since the 2016 consensus, advances in genetics, pathophysiology, and therapy have redefined both understanding and management. BrS, once viewed as a purely electrical disorder, is now recognized along a microstructural–electrical continuum, with sodium‐channel dysfunction and subtle epicardial fibrosis of the right ventricular outflow tract as key contributors. Likewise, ERS—historically considered benign—carries significant risk when inferolateral J‐waves coexist with arrhythmic events. Genetically, SCN5A remains the sole gene with definitive disease association, while polygenic susceptibility materially modulates risk, underscoring complex inheritance. Risk stratification remains challenging: patients with prior cardiac arrest or arrhythmic syncope are highest risk, whereas asymptomatic individuals warrant multiparametric assessment integrating clinical features, ECG markers, electrophysiologic studies, and genetics. For decades, treatment centered on implantable cardioverter‐defibrillators and quinidine, both limited by availability, tolerance, and device complications. More recently, epicardial substrate ablation has emerged as a transformative therapy, with large registries and randomized trials demonstrating durable suppression of ventricular fibrillation and acceptable safety. This APHRS‐organized international consensus updates and extends the 2016 Expert Consensus and the 2022 ESC Guidelines, providing contemporary diagnostic frameworks, pragmatic risk‐stratification tools, and treatment algorithms for BrS and ERS. It emphasizes JWS as a microstructural–electrical disease spectrum and elevates substrate ablation as a major therapeutic advance, while outlining priorities for genetics, risk‐stratification and treatment algorithms.

Migraine is one of the most disabling diseases worldwide, especially when it transforms into chronic migraine, which is often associated with medication overuse and can become resistant or even refractory to treatments. Molecular, neuroimaging and neurophysiological changes have been described in chronic migraine, some of which might not be fully reversible with preventive treatment. For these reasons, we should aim to prevent this transition, and initiate preventive treatment before disease becomes refractory and burden increases. Preventive migraine treatments are often delayed because of access to care, stigma leading to undertreatment and patients’ reluctance as a result of fear of side effects and, in some cases, fear of being labeled as chronically ill. With the availability of effective and well-tolerated preventive treatments, we must shift our mindset and take advantage of new opportunities to initiate preventive treatment earlier. In this International Headache Society position statement, we propose a migraine preventive strategy under the idea of shifting from reactive treatment once disability is established (prevention of attacks), to proactive, individualized prevention initiated early with safe, effective and tolerable therapies (prevention of disease progression). This approach is based on 1) promoting the early initiation of effective and tolerable preventive therapies, starting from two to four monthly migraine days in line with the majority of current guidelines and recommendations and 2) fostering longitudinal studies to gather more evidence on the potential benefit of early prevention, with the final goal of improving patient outcomes, promoting excellent migraine care, enhancing individual and social well-being, and, ultimately, preventing migraine progression and preserving brain health.