Management after an ischemic stroke occurring despite direct oral anticoagulant (DOAC) therapy for atrial fibrillation (AF) varies widely. Switching anticoagulation is common in clinical practice, although evidence supporting this strategy is limited.

To evaluate whether continuation of treatment with the same DOAC was noninferior to switching oral anticoagulant therapy with respect to 90-day clinical outcomes.

This multicenter registry-based cohort study with an emulated target trial design included consecutive adult patients with AF who experienced a breakthrough ischemic stroke while receiving uninterrupted DOAC therapy and resumed anticoagulation therapy thereafter. Patients were enrolled between February 2020 and February 2025, across 35 stroke centers in 9 countries in Europe and North Africa, with a standardized 90-day follow-up. The dataset was locked on September 1, 2025. A noninferiority comparison of switching vs continuation strategies was performed. Baseline confounding was addressed using inverse probability of treatment weighting (IPTW). The primary noninferiority margin was an absolute risk difference of 3.0 percentage points in 90-day net clinical benefit.

The intervention group switched to treatment with a different DOAC or vitamin K antagonist; the comparator group continued therapy with the prestroke DOAC.

The primary outcome was 90-day net clinical benefit, defined as recurrent ischemic stroke and moderate to severe bleeding. Secondary outcomes included recurrent ischemic events, symptomatic intracerebral hemorrhage, moderate to severe extracranial bleeding, all-cause mortality, and vascular death.

Among 1006 patients included in the analysis (median age, 80.4 [IQR, 73.4-85.4] years; 503 female [50.0%] and 503 [50.0%] male), 463 (46.0%) continued the same DOAC therapy and 543 (54.0%) switched therapy. After IPTW adjustment, the 90-day net clinical benefit was 4.9% with switching and 5.1% with continuation, corresponding to a risk difference of -0.3 percentage points (90% CI, -2.7 to 2.1 percentage points), meeting the prespecified noninferiority criterion. For recurrent ischemic events and bleeding outcomes, the absolute differences were within the predefined noninferiority margins. Noninferiority was not demonstrated for all-cause or vascular mortality.

In patients with breakthrough ischemic stroke during DOAC therapy, switching anticoagulation treatment was not associated with clinically meaningful short-term benefit compared with continuation. These findings suggest that switching does not provide additional benefit compared with continuing treatment with the same DOAC. Randomized clinical trials are needed to identify strategies to improve secondary prevention after a breakthrough ischemic stroke.

Subarachnoid hemorrhage (SAH) is associated with high mortality and poor outcomes, which are closely related to white matter injury (WMI). (-)-Epigallocatechin-3-gallate (EGCG) exerts neuroprotective effects by inhibiting oxidative stress-related ferroptosis in astrocytes and improving neurological function. However, the role and mechanism of EGCG in regulating reactive astrocytes (RAs) to alleviate WMI after SAH remain unclear.

A mouse model of SAH was used to evaluate the effects of EGCG-loaded nanoparticles (EGCG-NPs). Western blot, qPCR, and immunofluorescence were performed for biochemical analysis. Neurological function was assessed using neurological deficit scores and the Morris water maze test.

Following SAH, HO-1-mediated iron accumulation and ROS production promoted A1/A2 reactive astrocyte polarization, resulting in myelination damage and aggravated WMI. Knockdown of S100A10 inhibited iron-dependent oxidative stress in RAs and attenuated WMI. EGCG-NPs significantly suppressed HO-1/S100A10-mediated iron overload and oxidative stress in both A1 and A2 RAs, thereby alleviating WMI after SAH.

EGCG-NPs attenuate SAH-induced WMI by inhibiting the iron overload-activated HO-1/S100A10 axis in RAs, representing a promising therapeutic strategy.

Neutrophil-mediated neuroinflammation plays a crucial role in secondary brain injury following severe cerebral venous thrombosis (CVT). Although previous studies have reported that the combination of glucocorticoids (GCs) and anticoagulation is associated with improved clinical outcomes, its mechanism remains unknown. We hypothesized that the combination therapy may exert benefit by modulating neutrophil-driven inflammation.

This study included a cohort of 50 patients diagnosed with severe CVT who were undergoing treatment with the combination therapy. We investigated the dynamic alterations in the NLRP3/NETosis inflammatory process by analyzing paired serum and cerebrospinal fluid (CSF) samples collected at baseline and 1 week post-treatment. Neurological function was systematically evaluated using the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS).

The combined therapy was associated with reduced CSF levels of key NLRP3/NETosis mediators, including NOD-like receptor family pyrin domain containing 3 (NLRP3), polymorphonuclear neutrophil elastase (PMN Elastase), myeloperoxidase (MPO), and citrullinated histone H3 (CitH3), while the corresponding serum levels were unchanged. Baseline CSF levels of NLRP3, PMN Elastase, and MPO strongly correlated with admission NIHSS and mRS. Early reductions in these central markers were associated with neurological improvement at discharge (ΔNIHSS). Moreover, patients with unfavorable outcomes (discharge mRS > 1) had significantly higher baseline NIHSS and CSF NLRP3 levels.

The combined therapy may alleviate severe CVT by modulating the central NLRP3/NETosis inflammatory process.

Abdominal aortic aneurysm (AAA) is a progressive degenerative vascular disease characterized by structural weakening and pathological dilatation of the abdominal aortic wall. Currently, no effective pharmacological therapies are available, and treatment remains largely limited to surgical intervention. This underscores the urgent need to better understand the mechanisms driving disease development and progression. Among the cellular mediators implicated in AAA, neutrophils have emerged as key contributors to vascular inflammation and tissue destruction.

We performed a comprehensive literature review of original research articles and relevant reviews addressing the role of neutrophils in AAA pathogenesis. Studies were identified through systematic searches of major databases, including PubMed and Google Scholar, using the keywords "abdominal aortic aneurysm", "neutrophils", "vascular inflammation", "oxidative stress", "proteases", and "extracellular matrix degradation". Both experimental and clinical studies were included to provide an integrated overview of current knowledge in the field.

Accumulating evidence indicates that neutrophils actively infiltrate the aortic wall during AAA development, where they release a diverse array of effector molecules, including reactive oxygen species, proteolytic enzymes, pro-inflammatory cytokines, chemotactic mediators, and granule proteins. Collectively, these mediators sustain chronic vascular inflammation, promote extracellular matrix degradation, and contribute to progressive structural weakening of the arterial wall. This review summarizes both established and emerging roles of neutrophils in AAA pathogenesis, with a particular focus on their contribution to vascular inflammation, thereby providing a conceptual framework for future diagnostic and therapeutic development.

Neutrophils are central regulators of AAA pathogenesis through their multifaceted roles in vascular inflammation and extracellular matrix remodeling. Targeting neutrophil activation and downstream inflammatory pathways may represent a promising therapeutic strategy. A deeper mechanistic understanding of neutrophil-driven processes may facilitate the development of novel biomarkers and pharmacological approaches aimed at limiting AAA progression and preventing rupture.

Post-hemorrhagic hydrocephalus (PHH) represents a prevalent clinical form of hydrocephalus, where surgical interventions frequently fail or result in severe complications. While current research underscores the role of innate immunity and neuroinflammation in PHH pathogenesis, the precise mechanisms remain elusive. The cyclic guanylate adenylates synthase-stimulator of interferon genes (cGAS-STING) pathway, a pivotal component of innate immunity, has been implicated in various neuroinflammatory disorders. However, its mechanism of action in PHH has not yet been explored. Here, we propose that sustained activation of the cGAS-STING pathway in microglia following intraventricular hemorrhage (IVH) drives persistent neuroinflammation. Our results showed that dsDNA released from pyroptotic neurons and impaired mitochondrial autophagy in microglia can serve as substrates for cGAS detection, forming a cascade of interconnected pathways. Pharmacological inhibition or conditional knockout of cGAS attenuated global neuroinflammation, suppressed microglial activation, and reduced both pyroptosis-dependent (IL-1β and IL-18) and nonpyroptosis-dependent (TNF-α, IFN-β, and IL-6) cytokine release. Additionally, these interventions mitigated neuronal damage, apoptosis, and hydrocephalus-related neurological deficits after IVH Our results demonstrate that cGAS-STING pathway activation, mediated by neuronal pyroptosis and microglial mitophagy dysfunction, perpetuates post-IVH neuroinflammation. Our findings suggest that targeting cGAS may serve as a promising therapeutic approach for PHH.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with heart failure with preserved ejection fraction (HFpEF), independent of shared risk factors. The aim of this study was to discover metabolic pathways associated with HFpEF in individuals with MASLD to explore shared mechanisms and identify biomarkers of risk.

We examined HFpEF cases and non-HF controls in the Duke CATHeterization GENetics (CATHGEN) study. HFpEF was defined as left ventricular ejection fraction (LVEF) ≥ 45%, diastolic dysfunction grade ≥ 1 on transthoracic echocardiogram (TTE), and history of clinical heart failure. MASLD was phenotyped using ICD codes or hepatic steatosis index (HSI) > 36, in the presence of ≥ 1 metabolic risk factor. Metabolomic profiling was performed in fasting plasma using targeted tandem flow injection (absolute quantification, n = 60) and non-targeted (relative quantification, n = 210) mass spectrometry. Logistic regression models tested the association between metabolite factors and HFpEF. An interaction term analyzed the influence of MASLD on associations between metabolites and HFpEF.

A total of 430 participants were included; 247 (57.4%) had HFpEF. In participants with MASLD (N = 222, 51.6%), a factor composed of markers of kidney function, acylcarnitines, and modified amino acids was associated with HFpEF (OR: 2.2, 95% CI: 1.5-3.2, FDR-adjusted p-value = 0.002). The association of a PC composed primarily of ketoglutarate and phenyl sulfate with HFpEF was modified by MASLD (unadjusted p-value = 0.03).

Markers of kidney function and mitochondrial metabolism were associated with HFpEF in participants with MASLD. Mitochondrial energy pathways may link MASLD to HFpEF.

Inhaled corticosteroid (ICS) overuse is common in chronic obstructive pulmonary disease (COPD) and associated with substantial adverse effects. Deprescribing has emerged as a strategy to optimize therapy, yet large-scale evidence on the prevalence and associated factors of eligibility for ICS deprescribing is limited. This nationwide cross-sectional study analyzed data from the Cough and Wheeze Pharmaceutical Care Clinics database between January 2021 and September 2024. Patients aged ≥40 years with physician-diagnosed COPD receiving long-acting inhaled therapies were included. We examined treatment patterns, estimated ICS use, and assessed eligibility for deprescribing using European Respiratory Society (ERS), American Thoracic Society (ATS), and Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2026 criteria, applied respectively to any ICS-containing regimens, triple therapy, and ICS/long-acting beta-agonist (LABA) combinations. Factors associated with ICS deprescribing eligibility were identified using multivariable logistic regression, with sensitivity analyses on complete-case data. Of 33,243 patients, 24,886 (74.9%) received ICS-containing regimens, mainly triple therapy and ICS/LABA. Among them, 79.5% met ERS criteria for deprescribing. In the triple therapy subgroup (n = 12,388), 68.9% met ATS criteria, while 74.0% of patients on ICS/LABA combinations (n = 12,340) met GOLD criteria. Eligibility was positively associated with male sex, older age, higher regional economic level, lack of health insurance, and care in secondary hospitals, whereas higher comorbidity burden was negatively associated. Sensitivity analyses yielded consistent results. These findings highlight that ICS overuse is common among COPD patients in China, with most being eligible for deprescribing. Implementing targeted strategies that address the identified associated factors could support deprescribing and enhance treatment optimization.

Partial hydrogenation (PH) is a traditional modification technique used to tailor the physicochemical properties of vegetable oils for applications in bakery products, margarines, shortenings, and confectioneries. However, evidence from clinical studies has linked trans-fatty acids (TFAs) in partially hydrogenated oils (PHOs) to increased risks of cardiovascular diseases and other metabolic disorders. This has prompted regulatory bans and global phase-outs of tailored vegetable oils produced using the decades-old process of PH. In response, significant efforts have been directed toward developing alternative modification techniques (such as modified hydrogenation, genetic engineering, interesterification, oleogelation, sonocrystallization) aimed at reducing or eliminating TFAs. In this article, the recent advances in the use of these alternative techniques are reviewed. The progress in global regulatory frameworks targeting TFA elimination as well as current challenges and prospective directions in the development of TFA-free fats are discussed. The insights presented here offer a comprehensive understanding of the technological advancements and policy actions shaping the future of oil modification in the food industry.

Necrotising pyelonephritis is an uncommon but severe renal infection that may lead to septic shock and thrombotic complications. Cardiac arrhythmias are recognised in sepsis; however, presentation with supraventricular tachycardia (SVT) is unusual and may obscure the underlying diagnosis. A previously healthy woman in her late teens presented with fever, flank pain and hypotension associated with SVT unresponsive to vagal manoeuvres and adenosine. Sinus rhythm was restored following fluid resuscitation. Further evaluation revealed septic shock due to right-sided necrotising pyelonephritis complicated by right renal vein thrombosis, with blood and urine cultures growing Escherichia coli Echocardiography demonstrated transient left ventricular systolic dysfunction consistent with sepsis-induced myocardial dysfunction. She was managed with early haemodynamic optimisation, broad-spectrum antibiotics, ureteric stenting and anticoagulation, resulting in full recovery. This case highlights that SVT may rarely represent a presenting feature of septic shock and underscores the importance of prompt source control and multidisciplinary management.

ObjectiveThis study aimed to identify immune-related hub genes shared between acute myocardial infarction (AMI) and metabolic syndrome (MetS), and to construct and validate a blood-based gene diagnostic signature for AMI, with the hypothesis that this signature may be informative for AMI risk assessment in MetS patients.MethodsTwo AMI datasets (GSE66360, GSE61145) and one MetS dataset (GSE98895) were obtained from the Gene Expression Omnibus (GEO) database. Based on the GSE66360 dataset, 285 AMI-related common genes were identified as the intersection between 1409 differentially expressed genes (DEGs) and 304 module genes, identified via Limma and weighted gene co-expression network analysis (WGCNA), respectively. Subsequently, the intersection of these 285 AMI-related common genes and 1446 MetS-related DEGs yielded 40 genes that were primarily associated with immunoregulation, as revealed by functional enrichment analysis. After constructing a protein-protein interaction (PPI) network, 30 node genes were selected and ranked according to node degree. Six candidate hub genes (THBD, MMP9, IRAK3, CXCL16, NLRP3, and JDP2) identified via machine learning were used to establish a diagnostic model and evaluate its diagnostic value.ResultsWe revealed that the six candidate genes demonstrated strong diagnostic value for AMI (AUC ranging from 0.86 to 0.94, with 95% confidence intervals [CIs]). Moreover, a diagnostic nomogram constructed from these genes allows for visual quantification of AMI probability. Immune cell infiltration analysis revealed dysregulation across multiple immune cell subsets in AMI. These six immune-based hub genes have been identified as potential diagnostic biomarkers for AMI, with hypothesized relevance in MetS patients.ConclusionsThese findings provide a hypothesis-generating resource for understanding inflammatory links between MetS and AMI, though clinical utility for risk stratification in MetS patients requires further prospective validation.