Pulmonary arterial hypertension (PAH) is a progressive vascular disorder in which oxidative stress and ferroptosis are key pathogenic drivers. Although β-sitosterol (BS) shows therapeutic potential in PAH; however, its link to ferroptosis modulation remain poorly elucidated. This study evaluated the anti‑PAH efficacy of BS and its underlying mechanisms, focusing on the Nrf2-GPX4 axis, using a monocrotaline (MCT)‑induced rat model and hypoxia‑induced pulmonary arterial endothelial cells (PAECs) and smooth muscle cells (PASMCs). Inflammation responses, reactive oxygen species (ROS), and ferroptosis-related markers were assessed, along with molecular docking and pharmacological inhibition. In vivo, BS significantly ameliorated pulmonary vascular remodeling, improved right ventricular function, and mitigated oxidative stress by reducing ROS and MDA while restoring GSH levels, while up regulating the ferroptosis-protecive proteins xCT and GPX4. Molecular docking suggested direct interaction between BS and Nrf2. Notably, immunofluorescence revealed Nrf2 localization in both CD31⁺ endothelial and α‑SMA⁺ smooth muscle cells, with BS treatment substantially enhancing Nrf2 accumulation in both lineages. In vitro, BS promoted Nrf2 nuclear translocation in hypoxia-induced PAECs and PASMCs, correlating with suppressed oxidative and inflammatory responses and elevated xCT and GPX4 expression. Notably, the anti-oxidative and anti-ferroptotic effects of BS were abolished by the Nrf2 inhibitor ML385. These findings demonstrate that BS attenuates PAH via Nrf2‑GPX4‑driven ferroptosis inhibition in both in PAECs and PASMCs, uncovering a novel therapeutic target and new research directions regarding PAH pathogenesis and treatment.

Understanding how skeletal muscle responds to weight loss is crucial for developing targeted strategies to manage obesity and promote sustained improvement in metabolic health. Here, we investigated the molecular mechanisms underlying skeletal muscle reprogramming of gene expression and metabolic activity following Roux-en-Y gastric bypass (RYGB).

Forty-one women were studied before and one year after RYGB surgery. We leveraged multi-omics (DNA methylomics and transcriptomics) and machine learning approaches to complement muscle metabolic analyses and clinical data to identify mechanisms underlying RYGB-induced muscle metabolic reprogramming.

RYGB markedly decreased body weight and fat mass and improved metabolic health. Integrative analysis of vastus lateralis muscle identified 8233 genes with differentially methylated regions and 2173 differentially expressed genes post-RYGB surgery, of which 1197 genes were both differentially methylated and differentially expressed. Promoter hypomethylation was associated with the enhanced expression of transcription factors involved in skeletal muscle development and ribosomal subunits. In contrast, expression of genes encoding mitochondrial proteins decreased despite increases in mitochondrial content and enhanced mitochondrial function in skeletal muscle post-RYGB. Pre-operative muscle OXPHOS capacity, and expression of skeletal muscle hypertrophy and differentiation genes MYOC and EHMT2 were associated with weight loss success.

RYGB improves systemic metabolic health and induces sustained skeletal muscle bioenergetic reprogramming characterised by enhanced expression of genes involved in myogenesis and protein translation, but decreased expression of genes involved in mitochondrial metabolism, which may reflect improved mitochondrial quality and function. These findings advance our understanding of skeletal muscle metabolic responses to weight loss and of individual variability in metabolic phenotypes.

Canadian Institutes of Health Research (CIHR PJT183651-M-EH, 201709FDN-CEBA-116200-GRS), Diabetes Canada Investigator Award grant OG-3-22-5645-GS (GRS), J. Bruce Duncan Endowed Chair in Metabolic Diseases (GRS), Tier 1 Canada Research Chair in Mitochondrial Bioenergetics and Metabolic Health (M-EH), Tier 1 Canada Research Chair in Metabolic Diseases (GRS).

Genetic testing (GT) is established in ambulatory cardiomyopathy (CM), but its utility after heart transplantation (HTx) recipients remains poorly characterized.

This study aimed to evaluate the clinical utility of GT in adult HTx recipients with CM, focusing on etiologic reclassification, family cascade screening, and the genetic architecture of end-stage disease.

GenbaseHTx is a nationwide, multicenter retrospective study of adult HTx recipients transplanted for CM across 12 Spanish centers (2010-2023). GT results were centrally adjudicated using American College of Medical Genetics and Genomics criteria. Outcomes included prevalence of pathogenic/likely pathogenic variants, etiologic reclassification after GT, and cascade screening activation.

Among 657 HTx recipients, a pathogenic/likely pathogenic variant was identified in 53% (351/657). GT led to etiologic reclassification in 35% (231/657) (42% when performed post-HTx -106/253-). Family screening (performed in 69% of families -224/328-) identified affected relatives in 22% (19/90) of genotype-negative and 42% (49/107) of genotype-positive cases. Notably, a genetic etiology was identified in 36% (15/42) of CM initially attributed to acquired or "second-hit" causes. In dilated cardiomyopathy, the genetic architecture of transplanted patients differed from ambulatory cohorts, with lower TTN variant prevalence and enrichment of arrhythmogenic genes.

GT remains clinically actionable after HTx, enabling etiologic reclassification and driving cascade screening. These findings support systematic GT in HTx recipients with CM, including those with prior environmental triggers or second-hit etiologies, and regardless of time from transplantation.

Bioelectrical impedance analysis (BIA) has been widely applied for assessing body composition. The phase angle (PhA), a raw parameter derived from BIA, reflects body cell mass, cellular hydration, and cell membrane integrity. Although the PhA has been proposed as a potential marker for various aspects of diseases, its role in dysglycemia remains uncertain. We therefore aimed to investigate its associations with early and advanced stages of dysglycemia in a large population-based sample.

This cross-sectional study used data from participants (19-74 years) enrolled at the baseline assessment (2014-2019) from a large population-based cohort. The whole-body PhA at 50 kHz was obtained from multi-frequency BIA. Two samples were analyzed. In the main sample (N = 178,097), the types of known diabetes (type 1, type 2, and a history of gestational diabetes vs. no diabetes) were ascertained. Among individuals with known type 2 diabetes, data on disease duration, current treatment, glycemic control (hemoglobin A1c levels), and diabetes-related microvascular complications were further analyzed. Additionally, in a random subsample without known diabetes (N = 16,153), oral glucose tolerance tests (OGTT) were performed to ascertain early stages of glucose dysregulation (prediabetes and newly detected diabetes vs. normoglycemia). Logistic regression was applied to assess sex-specific associations of the PhA with glucose dysregulation at different stages.

In the main sample (mean age: 49.5 years; 50.1% men), 309 individuals (0.2%) reported having known type 1 diabetes, 8234 (4.6%) type 2 diabetes, and 1044 (1.2% of women) a history of gestational diabetes. In the OGTT subsample, 2662 participants (16.5%) had prediabetes and 534 (3.3%) had newly detected diabetes. A higher PhA (per 1°) was associated with a lower odds of known type 1 diabetes (relative risk ratio [RRR] and 95% confidence intervals [CIs], men: 0.33 [0.27, 0.40]; women: 0.39 [0.29, 0.52]) and known type 2 diabetes (RRR [95% CIs], men: 0.72 [0.69, 0.76]; women: 0.88 [0.81, 0.96]) after adjustment for age, lifestyle factors, obesity, and disease markers. Stronger inverse associations of the PhA with known type 2 diabetes were observed for those with longer disease duration (i.e., > 10 years), advanced-stage treatment (i.e., insulin only), poorer glycemic control (i.e., hemoglobin A1c ≥ 64 mmol/mol), or microvascular complications. Men showed stronger inverse associations with advanced dysglycemia than women (p_{sex-interaction} < 0.001). In contrast to the inverse associations observed for known type 1 and type 2 diabetes, the PhA showed positive associations with early dysglycemia. Specifically, a higher PhA (per 1°) was associated with a higher odds of a history of gestational diabetes (RRR [95% CIs]: women: 1.69 [1.51, 1.88]), prevalent prediabetes (RRR [95% CIs]: men: 1.45 [1.32, 1.59]; women: 1.34 [1.13, 1.58]) and newly detected diabetes (RRR [95% CIs]: men: 1.33 [1.11, 1.60]; women: 1.37 [1.05, 1.79]).

The bioimpedance-derived PhA showed positive cross-sectional associations with early dysglycemia and inverse cross-sectional associations with advanced dysglycemia. The observed associations may partly reflect reverse causation and disease-related changes in body composition accompanying advanced dysglycemia. Longitudinal studies are warranted to assess temporal relationships between the PhA and dysglycemia.

Perivascular spaces (PVS), when abnormally enlarged and visible in magnetic resonance imaging (MRI) structural sequences, are important imaging markers of cerebral small vessel disease and potential indicators of neurodegenerative conditions. Despite their clinical significance, automatic enlarged PVS (EPVS) segmentation remains challenging due to their small size, variable morphology, similarity with other pathological features, and limited annotated datasets. This paper presents the EPVS Challenge organized at MICCAI 2024, which aims to advance the development of automated algorithms for EPVS segmentation across multi-site data. We provided a diverse dataset comprising 100 training, 50 validation, and 50 testing scans collected from multiple international sites (UK, Singapore, and China) with varying MRI protocols and demographics. All annotations followed the STRIVE protocol to ensure standardized ground truth and covered the full brain parenchyma. Seven teams completed the full challenge, implementing various deep learning approaches primarily based on U-Net architectures with innovations in multi-modal processing, ensemble strategies, and transformer-based components. Performance was evaluated using dice similarity coefficient, absolute volume difference, recall, and precision metrics. The winning method employed MedNeXt architecture with a dual 2D/3D strategy for handling varying slice thicknesses. The top solutions showed relatively good performance on test data from seen datasets, but significant degradation of performance was observed on the previously unseen Shanghai cohort, highlighting cross-site generalization challenges due to domain shift. This challenge establishes an important benchmark for EPVS segmentation methods and underscores the need for the continued development of robust algorithms that can generalize in diverse clinical settings.

Kawasaki disease (KD) is a systemic inflammatory illness characterized by medium blood vessel vasculitis and is considered to be the leading cause of acquired heart disease in children less than 5 years old in developed countries. KD can present as either a classical or atypical/incomplete presentation based on distinct laboratory parameters seen in Table 1. The exact cause of KD remains unknown; however, specific purported infectious agents have been theorized to be linked to it. It classically presents with fever and four of the following: conjunctival injection, oral mucosal changes, cervical lymphadenopathy, changes in the extremities and polymorphous rash. Rarely, KD can present with hepatobiliary syndrome such as hepatic congestion, obstructive jaundice, acalculous cholecystitis and gallbladder hydrops. We present a case of a 12-year-old, otherwise healthy male who presented with an 8-day history of upper respiratory infection symptoms and fevers up to 102 F along with significant jaundice, dilated common bile duct and transaminitis initially thought to be ascending cholangitis. His clinical course evolved to also show rash, abdominal pain, vomiting, diarrhea, cervical lymphadenopathy and non-exudative, bilateral conjunctival injection with limbic sparing. Absence of improvement to antibiotic and distinct clinical evolution prompted the diagnosis of atypical KD. He received high dose IVIG and high dose aspirin with apparent clinical improvement. His surveillance echocardiography studies and subsequent physical exam findings have all been reassuring. This case underscores how KD can initially present as cholangitis and how it can manifest as a concomitant process during a viral infection.

Kawasaki disease (KD) is an acute, self-limited vasculitis that primarily affects young children, and early treatment is essential to prevent coronary artery complications. Diagnosis is clinical and can be challenging in children who present atypically or receive initial evaluation in resource-limited settings. We report a case of KD in a 6-year-old girl who presented to a rural clinic with six days of fever, a progressive polymorphous rash, bilateral conjunctivitis, and mucocutaneous changes. Her evaluation showed leukopenia, marked transaminitis, elevated inflammatory markers, and an extensive negative infectious workup. These findings, along with her older age and a pruritic rash, complicated initial recognition and broadened the differential to include viral exanthems and systemic infections. KD was suspected based on her clinical course, and she was promptly transferred to a tertiary pediatric center, where she met four of the five diagnostic criteria. She received intravenous immunoglobulin and high-dose aspirin, resulting in rapid improvement. Echocardiography showed no coronary involvement. This case reinforces the importance of maintaining suspicion for KD in children with prolonged fever and mucocutaneous findings, even when laboratory abnormalities are atypical. It also highlights the value of early consultation, efficient transfer pathways, and collaboration between rural and tertiary facilities to ensure timely treatment and reduce the risk of cardiac complications.

Matching brain stimulation to the brain's natural rhythms can drive plasticity, yet this principle has rarely been tested in humans. We targeted the cerebellum, a key hub for motor coordination and learning, using a rhythm-tuned protocol that pairs theta-frequency transcranial alternating current stimulation with intermittent theta-burst stimulation to engage plasticity of cerebello-cortical circuits. In young healthy adults, this pairing enhanced fine motor control and hand dexterity, with gains closely tracking physiological markers of cerebellar-driven plasticity. Applying the same approach in chronic stroke survivors yielded parallel behavioral and neural gains, demonstrating preserved rhythm-plasticity coupling despite injury. Control experiments confirmed both frequency specificity and site specificity, underscoring the mechanistic precision of the intervention. By linking theta-frequency cerebellar stimulation to circuit-level and functional outcomes, these findings establish a biologically grounded framework for targeted neurorehabilitation. Rhythm-specific cerebellar stimulation provides a scalable strategy for enhancing plasticity and improving motor function across movement disorders and motor impairments.

Venom-induced compartment syndrome (VICS) is a rare but severe complication of snakebite which poses unique challenges in diagnosis and treatment. Published literature largely focuses on VICS in the North American context, while information on clinical presentations, diagnostic and treatment approaches, clinical outcomes and associated challenges from the world's most snakebite endemic regions remain fragmented and scarce.

A scoping review using PRIMSA-ScR methodology of the global literature on VICS was performed by searching the PubMed, Embase, and Cochrane databases. Literature was divided into 1) Case reports on VICS and 2) General literature. Clinical data from eligible case reports was extracted to describe management of VICS and associated challenges. Available evidence on diagnostic and treatment strategies was extracted from the general literature.

Of 115 cases of VICS analyzed, most were from Europe (40%); Only 13% and 6% were reported from South-East Asia and Africa respectively. Viperids caused 73% of bites and upper extremities were most frequently affected (63%). Compartment pressure was measured in 38% of patients. Compartment pressure was more commonly measured in the 12% of non-surgically treated patients, none of whom developed ischaemic contracture or required amputation. Coagulopathy was the most common systemic toxicity, present in 40% of patients at admission. Results from eight animal studies support the use of antivenom for treating VICS. Analysis of 17 human observational studies suggests an overdiagnosis of VICS using clinical symptoms alone, highlighting the need to investigate diagnostic tools, such as ultrasound, for diagnosing compartment swelling.

Antivenom as first-line treatment for VICS is supported by animal and human observational studies. However, additional data is needed to inform decision-making on when fasciotomy is indicated as a rescue therapy. Improved evidence generation will depend on the collection of high-quality clinical and diagnostic observational data from patients treated with antivenom in snakebite-endemic regions.

Graves' disease (GD) may be associated with ischemic stroke through nonatherosclerotic intracranial arteriopathy during thyrotoxicosis. However, the optimal antithrombotic regimen and treatment duration for this condition remain uncertain.

A 38-year-old man presented approximately 6.5 hours after the last known well with sudden dysarthria, aphasia, and right-sided weakness. His National Institutes of Health Stroke Scale (NIHSS) score was 9 on admission.

Brain magnetic resonance imaging demonstrated acute ischemic infarcts, and magnetic resonance angiography revealed left middle cerebral artery M2 stenosis. In the setting of overt Graves' thyrotoxicosis and no identified alternative stroke source, the findings supported a diagnosis of Graves' disease-related reversible intracranial arteriopathy presenting with ischemic stroke.

The patient received dual antiplatelet therapy with aspirin 100 mg and clopidogrel 75 mg daily for 21 days, together with atorvastatin and antithyroid treatment with thiamazole. The thiamazole dosage was subsequently adjusted according to serial thyroid function tests.

The patient's neurological deficits improved rapidly, and his NIHSS score decreased to 1 at discharge. Biochemical euthyroidism was achieved approximately 5 months after treatment initiation. At 12 months, magnetic resonance angiography demonstrated marked reversal of the left M2 stenosis. At the latest follow-up at 24 months, the patient was neurologically intact and remained free of recurrent ischemic or hemorrhagic events.

Graves' disease-related reversible intracranial arteriopathy should be considered in young patients presenting with ischemic stroke, intracranial arterial stenosis, and thyrotoxicosis. This case suggests that short-term dual antiplatelet therapy may be considered as early bridging treatment in selected patients, whereas long-term management should prioritize sustained thyroid control and clinical and vascular imaging follow-up. Further evidence is required to establish the optimal antithrombotic regimen, treatment duration, and criteria for discontinuation.