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Objectives To describe the incidence, presentation and long-term health outcomes of suicidal thoughts and behaviours (STBs) in children aged 12 years or under. Methods This population-based study included children identified through the Rochester Epidemiology Project who presented between 2005 and 2023 with STBs across primary, secondary and tertiary care centres in Olmsted County, Minnesota, USA. Information related to the patient and family characteristics, presentation, prior history and outcomes was manually extracted by two independent researchers. Patients were excluded if the index visit note could not be located, the patient had no suicidal ideation, attempts, intent or plan, was older than 12 years 11 months at the index date, less than 2 years old or was a duplicate entry. Results The average annual population was 28,035 children, of which 637 presented with STBs (mean (SD) age, 10.6 (1.7) years; 51.2% girls, 76.3% White, average follow-up 7 years). The majority of the cases presented to the emergency department (ED) 491 (77.1%). The annual incidence per 100,000 person-years tripled from 68.8 in 2005 to 208.6 in 2023. Overall, 105 patients (16.5%) presented with a suicidal attempt. There were no cases of death by suicide. A prior psychiatric diagnosis was present in 454 (71.3%). STB events were preceded by a precipitating event in 471 (73.9%), the most common of which was an argument with a parent, followed by a bullying event and family distress. A specific suicide plan was reported by 328 (51.5%) with laceration reported most frequently, followed by hanging and overdose. Significant predictors of a suicide attempt were previous use of mood stabilisers (OR 3.21; 95% CI 1.24 to 7.97) and having a specific plan (OR 2.73; 95% CI 1.72 to 4.41). Children who had suicidal attempts had more subsequent ED visits (3.50 vs 2.58; p=0.009) and hospitalisations for psychiatric reasons (1.90 vs 1.30; p=0.003) and psychiatric hospitalisation days (12.70 vs 9.04; p=0.048). Subsequent suicide attempts occurred in 31% of the cohort during follow-up. Conclusion STBs in preadolescent children are rare but are increasing in incidence. Such children have significant psychological diagnoses, use of mental health services, and subsequent suicide attempts. Novel age-appropriate interventions are needed.

Background: Losmapimod is an orally administered small molecule and selective p38α/β mitogen-activated protein kinase (MAPK) inhibitor able to reduce aberrant expression of DUX4 in vitro and thereby potentially slowing disease progression in patients with facioscapulohumeral muscular dystrophy (FSHD). Objective: This global, randomized, placebo-controlled, double-blind phase 3 study in patients with FSHD1 and FSHD2 examined the efficacy and safety of losmapimod over a 48-week treatment period compared to placebo (NCT05397470, EUDRACT 2022-000389-16). Methods: The primary endpoint was change in quantification of reachable workspace (RWS) expressed as relative surface area (RSA). Other endpoints included measures of muscle composition (fat content and lean muscle) using magnetic resonance imaging (MRI), muscle strength using quantitative dynamometry, and quality of life measures. Results: 130 participants received losmapimod and 130 participants received placebo, with 252 participants completing the 48-week treatment period. There were no statistically significant differences between groups in change in RSA and all secondary efficacy endpoints from baseline to Week 48. Losmapimod treatment was well-tolerated, and most adverse events were mild. Conclusions: Losmapimod was generally well tolerated with a favorable safety profile at a dose of 15 mg twice daily. Although none of the efficacy endpoints were met, study design and data from the study may inform future studies of FSHD therapies.

Abstract In a real-world analysis of brexucabtagene autoleucel recipients with relapsed/refractory B-cell acute lymphoblastic leukemia (N = 278), lack of response to prior blinatumomab correlates with significantly worse following chimeric antigen receptor T-cell therapy outcomes.

Abstract Background Recurrent pericarditis (RP) predominantly shows features consistent with IL-1-mediated chronic autoinflammatory disease (1-4). A recent analysis suggested that supplementing anakinra with colchicine incrementally reduced pericarditis recurrence vs. anakinra alone (5). Rilonacept (a weekly IL-1α and IL-1β cytokine trap with 6-week washout) prevents engagement with IL-1 receptor, inhibiting both IL-1α and IL-1β activity (6). The Phase 3 trial RHAPSODY demonstrated rilonacept efficacy in two independent analyses: Randomized Withdrawal (RW) and Long-Term Extension (LTE) periods (7,8). Purpose Assess long-term recurrence-free persistence with rilonacept as monotherapy in pts with RP during the combined RW and LTE periods of RHAPSODY. Methods Post-hoc analysis. Freedom from recurrence on rilonacept monotherapy was quantified using the Kaplan-Meier (KM) method from RW start (if randomized to rilonacept) or from initiation of bailout rilonacept (if randomized to placebo) until the end of treatment. Prespecified recurrence adjudication criteria were pericarditis pain (numerical rating scale [NRS]) ≥4 plus C-reactive protein (CRP) ≥1 mg/dL. Per RHAPSODY protocol, background therapies were discontinued during the Run-In Period before randomization. In pts treated with rilonacept, concomitant colchicine was not added during the RW period. In the LTE, 6.8% (5/74) of pts added colchicine: one for 2 days of chest pain without CRP elevation, 4 in the absence of chest pain, CRP elevation, or recurrence; these 5 pts were censored in the KM curve at 6 days after last rilonacept dose or at colchicine initiation (whichever was first). One additional pt added colchicine prophylactically before an intentional rilonacept treatment interruption for elective cardiac surgery and experienced a recurrence after this interruption; this pt was not censored from the recurrence-free persistence analysis at colchicine initiation in order to capture this event. Results 74 pts (mean [SD] age 43.9 [15.7] years, 83.8% idiopathic pericarditis, mean [SD] disease duration 2.5 [3.2] years) were analyzed over three years. Rilonacept was well tolerated. Recurrence-free persistence was 95.9% (n=71/74) while receiving rilonacept as monotherapy (Figure 1). The three observed adjudicated recurrences were each associated with temporary interruptions of 1-3 doses of rilonacept. Conclusions Rilonacept as monotherapy provided recurrence-free persistence over the three-year trial duration when used continuously without interruption; pericarditis recurrences occurred only after interruptions. These findings support evidence-based use of rilonacept as monotherapy, minimizing the need for adjunctive treatments and reducing polypharmacy in long-term RP management. Further investigations are warranted to address how to assess pts as candidates for long-term treatment with rilonacept and when to cease rilonacept treatment.

Abstract Background Loeys-Dietz Syndrome (LDS) is a rare connective tissue disorder characterized by mutations indifferent genes including TGFRB2, TGFBR1, TGFB2, TGFB3, and SMAD3, which significantly increase the risk of vascular abnormalities, including aneurysms and dissections. These vascular events can involve various arterial territories, although the thoracic aorta is of most concern. The current literature is limited on characterizing the aortic and extra-aortic vascular manifestation on larger cohorts of patients. Purpose This study aims at analyzing the rates of aneurysms and dissections across different vascular territories inpatients with LDS. Methods A retrospective analysis was conducted on a cohort of individuals diagnosed with LDS at our institution. Medical records were reviewed for imaging findings, including CT scans, MRIs, and ultrasounds, to identify the presence of aneurysms and dissections. Vascular territories involved included the aortic arch (ascending, and descending aorta), coronary, cerebral, carotid, vertebral, renal, splanchnic, and peripheral arteries. Results A total of 94 patients with LDS were included. 76 patients (81%) had an ascending aortic aneurysm, and 21 patients (22.5%) had an abdominal aortic aneurysm. 49 patients (52%) had aneurysms in other vascular territories, with some patients having multiple aneurysms in different regions. These included 9 patients (9.5%) with carotid, 3 patients (3.2%) with vertebral, 5 patients (5.3%) with splenic, 11 patients (11.7%) with mesenteric, 2 patients (2.1%) with renal, 15 patients (15.9%) with iliac/femoral, 6 patients (6.4%) with subclavian, 23 patients (24.5%) with cerebral, and 10 patients (10.6%) with coronary aneurysms. For aortic dissections, 13 patients (14%) had type A and 9 patients (9.5%) had type B dissections. Additionally, 20 patients had dissections in other vascular territories, with some patients experiencing dissections in multiple regions. These included 8 patients (8.5%) with carotid, 8 patients (8.5%) with vertebral, 1 patient (1.1%) with renal, 3 patients (3.2%) with iliac, 2 patients (2.1%) with coronary, and 3 patients (3.2%) with innominate artery dissections. Conclusion Aortic involvement is the most common in patients with LDS; however, these patients are also at an increased risk of developing aneurysms and dissections in various vascular territories. This highlights the importance of screening and close follow-up in these patients, potentially through whole-body imaging to identify such abnormalities. Further research is needed to identify patients at higher risk for aneurysms and dissections compared to others.

Abstract Background Loeys-Dietz Syndrome (LDS) is a connective tissue disorder caused by mutations in the TGFBR1 or TGFBR2 genes, leading to significant cardiovascular complications, particularly aortic aneurysms and dissections. Due to the progressive nature of these issues, patients often require multiple cardiac interventions throughout their lives, although this has not been comprehensively reviewed in the literature. Purpose This study aims to review trends in cardiac interventions in LDS patients to better understand the surgical course these patients go through in their lives. Methods A retrospective analysis was conducted on a cohort of individuals diagnosed with LDS at our institution. Medical records were reviewed for data on demographics and types of interventions (e.g., aortic surgeries, valve procedures) were collected. Descriptive statistics were used to analyze the frequency of interventions with comparisons made between intervention types. Results A total of 94 patients with LDS were included in the study. Among them, 69 patients (73.4%) had an ascending aortic aneurysm, and 13 patients (14%) had a type A aortic dissection. A total of 60 patients underwent aortic root replacement surgery due to aneurysm or dissection, with 10 patients (11%) having the procedure following the occurrence of a dissection. Mitral valve prolapse (MVP) was found in 34 patients (36%). Valvular interventions were performed as follows, with some patients undergoing repairs on multiple valves: 12 patients (13%) had mitral valve repair, 10 patients (11%) had tricuspid valve repair, and the aortic valve was the most intervened upon, with 37 patients (39.5%) undergoing either replacement or repair. In total, 45 patients (48%) underwent at least one valvular intervention. Additionally, 4 patients (4.5%) underwent ventricular septal defect (VSD) closure, 3 (3.5%) underwent atrial septal defect (ASD) closure, and 3 (3.5%) had both defects closed. 29 patients (31%) had a patent foramen ovale, with 17 of these patients (59%) undergoing PFO closure. Finally, 16 patients (17%) underwent coronary artery bypass grafting (CABG). Conclusion Patients with LDS often require multiple surgeries and interventions throughout their lives due to the progressive nature of the disease and its impact on the cardiovascular system. The high incidence of aortic aneurysms, dissections, and valvular abnormalities necessitates frequent surgical management, with many patients undergoing interventions such as aortic root replacement, valve repairs, and septal defect closures. Given the complex and multifaceted cardiovascular involvement in LDS, close monitoring and timely intervention are crucial for optimizing outcomes and improving quality of life for these patients.

Abstract Background Marfan syndrome (MFS) predisposes individuals to aortic dissections. Recent data suggest that atrial fibrillation and atrial flutter (AF/AFL) may increase complications and mortality in MFS patients; however, their independent role in aortic dissection remains unclear. Purpose This study aims to assess the risk of aortic dissection in MFS patients with and without AF/AFL. Methods Using the TriNetX database and ICD-10 codes, 2,447 MFS patients with AF/AFL and 20,520 without were identified. Demographics (age, sex, race, ethnicity) were evaluated, and aortic dissection outcomes were compared using risk ratios and Kaplan-Meier survival analysis. Results Patients in the AF/AFL cohort were older (mean age 60.9 ± 16.7 years vs. 38 ± 16.6 years) and had higher proportions of males (62.51% vs. 56.76%) and white patients (74.67% vs. 66.3%). Aortic dissections occurred in 13.9% of MFS patients with AF/AFL compared to 3.4% of those without, resulting in a risk difference of 10.5% (95% CI: 9.0%–11.9%) and a risk ratio of 4.04 (95% CI: 3.547–4.603). Kaplan-Meier analysis revealed significantly lower survival rates in the AF/AFL cohort (74.07% vs. 90.63%; log-rank test, p < 0.0001), with a hazard ratio of 4.232 (95% CI: 3.686–4.858). Conclusion In MFS patients, those with AF/AFL were over four times more likely to experience aortic dissection and had over four times the hazard of mortality. Screening and managing AF/AFL may be essential to preventing aortic dissections and improving outcomes in this population.Figure 1

Abstract Enhancer is a critical epigenetic feature in head and neck squamous cell carcinoma (HNSCC), yet the functional roles of individual enhancers remain poorly understood. Here, we conducted an integrative multi-omics analysis based on publicly available ATAC-seq, H3K27ac ChIP-seq, transcriptomic profiling, and genetic association datasets to systematically map HNSCC-associated enhancers and their target genes. Integrating ATAC-seq and H3K27ac ChIP-seq, we identified 20,362 enhancers and 18,040 enhancer-associated genes, highlighting widespread regulatory complexity. Functional characterization of the TERT -associated enhancer GH05J001312 (GRCh38/hg38: chr5:1312099-1317743) revealed strong transcriptional activity in HNSCC. CRISPR-mediated deletion of a core sequence significantly reduced TERT expression, impaired cellular proliferation in vitro , and suppressed tumor growth in vivo , confirming its role as a key cis-regulatory element. RNA-seq analysis of enhancer-edited cells uncovered 742 differentially expressed genes enriched in cancer-related pathways, including MAPK and IL-17 signaling, indicating a broad transcriptional impact. Collectively, our findings establish GH05J001312 as a functional enhancer driving oncogenic programs in HNSCC and suggest enhancer-targeted strategies as a potential therapeutic avenue.

Abstract Glioblastoma (GBM) remains the most aggressive primary adult brain cancer with limited therapeutic options. Our prior research demonstrated that androgen receptor antagonists (ARAs) enhance survival in GBM mouse models by preferentially suppressing glioma stem cells. This study investigates the potential of ARAs as radiosensitizers in combination with radiotherapy (RT). Combined effects of ARAs and RT were evaluated using an orthotopic GBM mouse model. RNA-Seq and TCGA analyses delineated AR-associated regulatory networks, while integrated cellular and molecular approaches utilizing human and mouse GBM cell lines, as well as in patient-derived primary high-grade glioma cultures, interrogated signaling and immune paradigms. ARA treatment induced G2/M cell cycle arrest, apoptosis, and downregulated DNA repair genes, with AR expression correlating with the DNA repair and TGF-β pathway. In both immortalized GBM cell lines and primary high-grade glioma cultured cells, ARAs in combination with RT showed only a modest enhancement of radiosensitivity. However, in an orthotopic GBM mouse model, ARA + RT demonstrated a strong synergy, achieving 100% long-term survival, compared to less than 50% with ARA alone and 0% with RT alone. Mechanistically, ARA modulated the TGF-β pathway, durably switching from Smad3 linker to c-terminal phosphorylation (pSmad3C) and inhibiting LIF/STAT3 axis. Distinct TGF-βs ligand expression patterns were observed in ARA-treated GBM cells. A protein–protein interaction noted between AR and Smad3, which was disrupted following ARA treatment, leading to elevated protein levels and nuclear localization of pSmad3C (S423/425), indicating normalization/activation of the TGF-β/pSmad3C-dependent anti-tumorigenic cascade. Comprehensive analyses in GBM cell lines and mouse model tissues demonstrated pathway reprogramming characterized by elevated TGF-β2 and increased pSmad3C. Tissue analysis revealed immune activation in the tumor microenvironment, while peripheral blood and spleen showed systemic immune responses following ARA + RT. Our study provides novel insights into how ARAs enhance RT efficacy through immunomodulation involving TGF-β/pSmad3C cascade, offering therapeutic implications in GBM.