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ABSTRACT Background Atherothrombosis, the main event leading to acute coronary syndrome (ACS), is strongly linked to disturbed blood flow (d-flow) regions. Although the involvement of the Hippo pathway and its kinases Large Tumor Suppressor Kinase 1and 2 (LATS 1 and 2) in mechanical stress responses is known, the mechanisms by which d-flow simultaneously induces senescence, proliferation, and atherothrombosis remain unclear. Methods The role of endothelial cells (EC)-specific LATS1/2 was examined using EC specific knock-out (EKO) mice in a partial left carotid ligation (PLCL) model. Plaque spatial multi-omics analysis was performed by integrating imaging mass cytometry, sequential immunofluorescence (COMET™), and spatial metabolomics at the single-cell level in human and mouse atherosclerotic plaques. Results In tamoxifen-inducible Lats1 homo( -/- ) / Lats2 homo( -/- ) EC-specific knockout (EKO) mice, deletion of LATS1/2 induced by tamoxifen led to fatal outcomes, characterized by severe systemic edema and markedly increased vascular permeability. In contrast, Lats1 het(+ /- ) / Lats2 homo( -/- ) -EKO mice survived and developed atherothrombotic plaques exhibiting neovascularization even without further additional dietary or genetic intervention. Spatial proteomics analysis revealed that LATS1/2 depletion in ECs triggered a senescence-associated stemness (SAS) phenotype, primarily driven by CD38 upregulation. Complementary spatial metabolomics profiling demonstrated a significant increase in sulfite and taurine within LATS1/2-deficient plaques, indicating lowered sulfite oxidase (SUOX) activity. Mechanistically, CD38 upregulation was found to suppress SUOX expression, induce the reverse mode of mitochondrial complex V, and increase succinate dehydrogenase (SDH) activity along with ATP consumption. Paradoxically, despite ATP depletion, this metabolic disturbance enhanced glutamate metabolism and the tricarboxylic acid (TCA) cycle, sustaining EC proliferation under energetically stressed conditions. The combined effect of LATS1/2 deletion and CD38 activation established a unique EC phenotype defined by increased SAS, leading to proliferation, senescence, and eventual cell death. These pathological processes culminated in the formation of atherothrombotic plaques, which were attenuated by inhibition of CD38. Notably, a similar phenotype—marked by metabolically active ECs—was observed in human atherothrombotic plaques, suggesting translational relevance. Conclusion Loss of LATS1/2 in ECs induces SAS state that promotes excessive EC proliferation, senescent cell accumulation, and the development of structurally fragile, leaky neo vessels—hallmarks of atherothrombotic lesions. CD38-mediated SUOX deficiency further amplifies this pathological process by inducing mitochondrial dysfunction, depleting ATP, and triggering compensatory upregulation of glutamate and TCA cycle metabolism. These findings identify a novel LATS1/2–CD38–SUOX axis in ECs that orchestrates SAS-driven atherothrombosis. Targeting CD38 may represent a promising therapeutic strategy to mitigate vascular dysfunction and plaque instability in high-risk ACS patients. Graphical abstract Under normal physiological conditions, LATS1/2 and Lamin A work together to suppress CD38 expression. Lamin A binds directly to the CD38 promoter to repress transcription, and LATS1/2 interact with Lamin A to reinforce this suppression. This collaboration helps maintain low CD38 activity and preserves cellular NAD⁺ levels. However, under disturbed flow (d-flow), both LATS1/2 and Lamin A are downregulated. The loss of this dual repression leads to increased CD38 NADase expression. Elevated CD38 accelerates NAD⁺ consumption, causing NAD⁺ depletion—a hallmark of cellular senescence. Reduced NAD⁺ disrupts key metabolic and stress-response pathways, contributing to the onset of the senescent state. At the same time, CD38 suppresses sulfite oxidase (SUOX), leading to sulfite accumulation and mitochondrial redox imbalance. This shift activates the reverse mode of mitochondrial Complex V, which decreases ATP production and increases mitochondrial ROS, intensifying metabolic and oxidative stress in endothelial cells (ECs). In response, ECs compensate by upregulating succinate dehydrogenase (SDH), enhancing TCA cycle activity and glutamate metabolism. This metabolic adaptation provides the biosynthetic building blocks needed for cell growth and proliferation. As a result, ECs adopt a paradoxical phenotype: they show classical features of stress-induced senescence (such as NAD⁺ depletion, oxidative stress, and cell cycle arrest signals), while simultaneously undergoing metabolic activation and proliferation, also mediated by YAP. This defines a non-canonical endothelial program known as senescence-associated stemness (SAS), characterized by the formation of abnormal, proliferative, yet fragile neovessels. These dysfunctional vessels contribute to atherothrombosis, setting this process apart from the more stable lesions typical of conventional atherosclerosis.

This international multicenter study seeks to determine the frequency and characteristics of meningitis in myelin oligodendrocyte glycoprotein antibody (MOGAD)–associated disease and highlight its pathology.

Objective To compare the efficacy of abatacept to placebo for the treatment of relapsing, nonsevere granulomatosis with polyangiitis (GPA). Methods In this multicenter trial, eligible patients with relapsing, nonsevere GPA were randomized to receive abatacept 125 mg subcutaneously once a week or placebo, both together with prednisone 30 mg/day (or equivalent), tapered and discontinued at week 12. Patients already taking methotrexate, azathioprine, mycophenolate, or leflunomide continued this medication at a stable dose. Patients achieving remission remained on their randomized assignment until relapse, early termination, or the common close date 12 months after enrollment of the last patient. Those who had a nonsevere relapse, had nonsevere worsening, or were not in remission by month 6 had the option to receive open‐label abatacept. The primary end point was the rate of treatment failure, defined as relapse, disease worsening, or failure to achieve a Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) of 0 or 1 by six months. Results Sixty‐five patients were randomized; 34 received abatacept and 31 received placebo. No statistical difference in the treatment failure rate was found between those who received abatacept and those who received placebo ( P = 0.853). Treatment with abatacept did not demonstrate any statistical difference from placebo in key secondary end points, including time to full remission (BVAS/WG = 0), duration of glucocorticoid‐free remission, relapse severity, prevention of damage, and patient‐reported quality‐of‐life outcomes. There was no difference in the frequency or severity of adverse events between treatment arms, including infection. Conclusion In patients with relapsing, nonsevere GPA, abatacept did not reduce the risk of relapse, severe worsening, or failure to achieve remission.

ABSTRACTBackgroundLate gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR) imaging is a well‐established indicator of myocardial fibrosis in hypertrophic cardiomyopathy (HCM). However, its association with electrocardiographic (ECG) abnormalities and the risk of atrial fibrillation (AF) remains uncertain.ObjectivesTo investigate the association between the presence and burden of LGE with ECG characteristics, including precordial voltage, depolarization and repolarization abnormalities, and the incidence of AF in adults with HCM.MethodsWe conducted a retrospective cohort study of 144 adults with HCM with CMR and 12‐lead ECG within 30 days of each other. LGE was quantified as a percentage of LV mass and categorized as absent, < 5%, or ≥ 5%. ECG parameters, including QRS voltage, repolarization abnormalities, and LVH criteria, were analyzed. Incident AF was assessed during a median follow‐up of 6.6 years.ResultsLGE was present in 96 (67%) patients, with 21 (22%) having ≥ 5% LGE. There were no significant differences in precordial voltage between patients with and without LGE across Sokolow‐Lyon, Cornell, and Romhilt‐Estes criteria. However, T‐wave inversion was more common in leads I (41% vs. 19%, p = 0.009), aVL (50% vs. 31%, p = 0.033), and V4 (41% vs. 23%, p = 0.035) in patients with LGE. Patients with ≥ 5% LGE had a significantly lower median LVEF (64% vs. 74%, p = 0.003). Additionally, LGE presence was not associated with an increased risk of incident AF (HR 1.8, 95% CI 0.6–5.3, p = 0.308).ConclusionIn contrast to pediatric HCM, LGE is associated with specific ECG repolarization abnormalities, particularly T‐wave inversion in lateral leads, but does not significantly affect precordial voltage in adults.

Thymomas and thymic carcinomas are rare mediastinal tumors that originate in the thymus. Patients with thymoma may experience symptoms associated with autoimmune paraneoplastic diseases (such as myasthenia gravis), which typically do not occur in patients with thymic carcinoma. The NCCN Guidelines for Thymomas and Thymic Carcinomas provide guidance for the diagnosis, treatment, and surveillance of patients with thymoma and thymic carcinoma. Involvement of a multidisciplinary team with experience treating thymomas and thymic carcinomas is highly recommended.

ABSTRACT Peritoneal fibrosis is one of the main causes of peritoneal dysfunction and withdrawal of patients from peritoneal dialysis (PD). Our previous study has shown that high‐glucose dialysis solution promotes glycolysis in peritoneal mesothelial cells, leading to mesothelial‐to‐mesenchymal transition (MMT) and peritoneal fibrosis. However, the molecular mechanisms remain unclear. Using single‐cell RNA sequencing (scRNA‐seq) analysis of cells from the effluent of patients undergoing PD from our previous study, we found that pyruvate kinase isozymes M2 (PKM2), a key rate‐limiting enzyme of glucose metabolism, was significantly upregulated in the mesothelial cells of patients with long‐term peritoneal dialysis (LPD). Using co‐immunoprecipitation, chromatin immunoprecipitation assay, and gene silencing techniques, we revealed that PKM2 promotes the expression of transcription factor SNAI2 by acetylating histone H3K9 (H3K9ac), thereby promoting the occurrence of MMT and hence peritoneal fibrosis. l ‐cysteine, a known PKM2 inhibitor, blocked these responses and prevented PD‐induced peritoneal fibrosis. These results could provide a novel therapeutic strategy for treating peritoneal fibrosis.