Citations

Abstract Background Vagally mediated syncope and functional bradyarrhythmias can cause recurrent symptoms, injury and a need for permanent pacing, yet standard therapies do not address the underlying autonomic reflex. Cardioneuroablation (CNA) targets this mechanism, but adoption has been limited by uncertainty about patient selection, procedural endpoints and durable outcomes. Methods We studied 95 consecutive patients with vagally mediated syncope (n=78) or functional bradyarrhythmia (n=17) who underwent CNA at a single center by a single lead operator under a uniform, prospectively maintained protocol. Extracardiac vagal stimulation (ECVS) was performed before and after ablation to confirm vagally mediated sinus or atrioventricular (AV) nodal responses and to verify their attenuation. Outcomes through 1 year included clinical recurrence, quality of life, pacing burden and pacemaker extraction. Results Before ablation, ECVS provoked sinus pauses in 95.8% of patients and AV block in 91.6%; after ablation, sinus pauses were abolished in every patient and residual AV block was present in 4.2%. One-year freedom from recurrent syncope and from bradyarrhythmia-related events was 93.8% and 94.1%. Syncope burden fell from a median of 2.7 episodes per year to none, and disease-specific quality of life improved substantially (P<0.001). Among patients with pre-existing devices, atrial pacing burden fell from a median of 22% to 0%. There were no strokes, deaths or myocardial infarctions. Conclusions In this single-center cohort, physiology-guided CNA was associated with durable symptom control, improved quality of life and reduced pacing across vagally mediated bradyarrhythmia syndromes. Multicenter controlled studies are needed to confirm these findings.

ABSTRACT Consumer‐grade wearables, including smartwatches, fitness trackers, and smart rings, are accessible tools for studying pharmacologic responses in real‐time, monitoring participant health in decentralized clinical trials, optimizing outcome measures, and delivering digital interventions that promote behavior change. However, incorporating consumer wearables into clinical studies is not as straightforward as simply purchasing devices and providing them to participants. It requires engaging with a complex engineering ecosystem with multiple investigator decisions on device selection, associated data management practices, and patient/participant engagement and technical support. This tutorial, based on experience running large clinical trials using consumer wearables, outlines the wearables market landscape across varying form factors and manufacturers as well as the data management software products supporting wearable use. It delineates the major decision processes involved in designing studies that incorporate wearables and presents a structured framework to guide the selection of devices and supporting data tools according to study objectives.

Background: Corticosteroids are widely used in pericarditis despite guideline recommendations reserving them for select indications. Observational studies have reported inconsistent associations between corticosteroid use and pericarditis recurrence, and optimal dosing and tapering strategies remain unclear. We conducted a systematic review of oral corticosteroids for acute or recurrent pericarditis to characterize patterns of treatment and evaluate the association between corticosteroids and pericarditis recurrence across different disease contexts. Methods: MEDLINE, EMBASE, CENTRAL, and Scopus were searched from inception to November 26, 2025. Studies enrolling adults with acute or recurrent pericarditis treated with oral corticosteroids were included. Randomized trials, cohort studies, and case–control studies reporting clinical outcomes were eligible. Risk of bias was assessed using the Newcastle–Ottawa Scale (NOS). Data were synthesized descriptively due to anticipated clinical and methodological heterogeneity. Results: Ten studies (2 prospective, 8 retrospective) including 2632 patients (800 corticosteroid-treated) met inclusion criteria. Prednisone was most frequently studied, with heterogeneous dosing (0.25–1.0 mg/kg/day) and non-standardized tapering strategies. Follow-up ranged from 1 to 6.7 years, and overall risk of bias was moderate with limited adjustment for confounding. Findings on recurrence were inconsistent in acute idiopathic and post-procedure pericarditis, while most studies in recurrent pericarditis reported higher recurrence with corticosteroid exposure. Conclusions: Evidence evaluating oral corticosteroids in pericarditis is limited by heterogeneity, confounding, and inconsistent reporting of treatment strategies. Observational data show variable associations with recurrence across clinical contexts. High-quality randomized trials stratified by pericarditis etiology and acuity are needed to define the optimal use of corticosteroids in pericarditis.

Abstract Although sequencing costs have steadily decreased with advances in technology, they remain high for large scale studies. The design of traditional individual-disease sequencing studies is either case only or cases with relatively few controls, resulting in potential loss of statistical power for discovery of disease associated genes. Here we show that for a given number of sequenced cases, a large control sample size is critical to maximize power for rare variant burden analysis. Furthermore, we have developed an end-to-end workflow based tool (CoCoRV-nf) to facilitate the use of external biobank sequence resources as controls. The modules include consistent variant QC, variant annotation, ancestry population prediction, and gene based burden analysis using summary genotype information, and combined analysis from multiple independent results. The tool supports exomes and genomes from gnomAD and All of Us as controls with preprocessed datasets. We apply the tool in two rare neurological diseases: amyotrophic lateral sclerosis and neuroblastoma. For each disease, two case cohorts are paired with gnomAD and All of Us data, respectively, followed by a combined analysis. Not only did we recapture known genes, but also, we identified new candidate genes for both diseases. By leveraging multiple large external biobank sequence data, we demonstrate the feasibility of using our tool to maximize statistical power to identify new disease predisposition genes.

Deregulated inflammatory signaling via STAT family transcription factors, particularly STAT1, underlies a variety of immune-related diseases, including inflammatory bowel disease. Whereas activation of STATs by JAKs via canonical receptor-driven JAK–STAT signaling is well understood, little is known about JAK-independent mechanisms of STAT activation. Here, we identify the understudied nonreceptor tyrosine kinase TNK1 as a therapeutically targetable, JAK-independent activator of STAT signaling. Using a multiomics approach, we mapped a network of TNK1 substrates associated with protein condensates and proinflammatory signaling, including STAT1. We found that TNK1, but not its sister kinase ACK1, directly phosphorylates STATs at well described STAT-activating JAK sites. In cells, TNK1-mediated STAT1 phosphorylation and activation occurs independently of JAKs. Imaging and interactomics data suggest that TNK1 interacts with STAT1 in cytosolic condensates, which likely compartmentalize TNK1-substrate interactions. We show that an intrinsically disordered proline-rich region in TNK1, which includes a 14-3-3 docking phosphorylation site, is required for the formation of kinase-active TNK1 condensates and STAT1 phosphorylation. Mutations within the proline-rich region that eliminate 14-3-3 binding increase formation of TNK1 condensates, suggesting a model in which 14-3-3 acts as a clamp that constrains the flexible PRR to inhibit condensate formation and STAT1 activation. Finally, we show that TNK1 is a targetable driver of STAT1-mediated inflammation in the gut as inhibition of TNK1 reduces active STAT1 in the colon and ameliorates colitis symptoms in mice.

Introduction Ultra-marathon races present a prolonged cardiopulmonary physiological stress but the magnitude, persistence, and impact of race environment on respiratory function are incompletely understood. The aim of this study is to observe the effect of ultra-marathon trail races on both lung function and airway impedance. Methods Fifty-seven individuals (49/8, M/F) participated in either the Courmayeur-Champex-Chamonix (CCC ® , 101.5km), Ultra Trail du Mont-Blanc (UMTB ® , 171.5 km), or the Hong Kong 100 (HK, 100 km) races. Participant demographics were measured pre-race and included: age (40.7±10.3 yrs); height (175.5±7.1 cm), body mass (69.7±8.3 kg). Spirometry, airway impedance (via forced oscillation technique, FOT), maximal inspiratory (MIP) and expiratory pressure (MEP), and exhaled nitric oxide (ExNO) were assessed before, immediately (18–4 hours after), and 188–24 hours post-race. Mixed effects analysis with Dunnett’s post-hoc correction were conducted to evaluate the effects of race and time. Results Results demonstrated significant effects of time for: forced vital capacity (FVC), forced expiratory flow over one second (FEV 1 ), peak expiratory flow (PEF), forced expiratory flow between 25-75% (FEF25-75), forced expiratory flow at 25% and at 50% (FEF 25 and FEF 50 , respectively), MIP, MEP, airway reactance (X) at all frequencies from FOT (X 5 , X 11 , X 19 ), respiratory rate, and ExNO (all p &lt;0.05). A significant effect of race was also observed for ExNO ( p =0.002). Discussion Findings indicate declines in lung function and airway impedance immediately after ultra-marathon races, some of which, persisted up to 24 hours post-race. Further investigations are required to better understand the etiology of changes in lung function following ultra-endurance events.

Heart transplantation remains the definitive treatment for end-stage heart failure. Preservation of donor hearts is a critical determinant of graft function and post-transplant outcomes. Traditional static cold storage (SCS) has limitations in ischemia tolerance and functional assessment, particularly for marginal and donation after circulatory death (DCD) hearts. Emerging strategies, including normothermic ex vivo perfusion (NEHP) and hypothermic oxygenated perfusion (HOPE), enable extended preservation, functional evaluation, and improved utilization of high-risk donor organs. This review summarizes current preservation techniques, discusses mechanistic strategies to mitigate ischemia-reperfusion injury, highlights emerging trends and controversies, and identifies future research directions to optimize outcomes in heart transplantation.

Abstract Background: Glioma diagnosed during pregnancy and pregnancy following glioma treatment present complex management challenges. The safety of glioma treatment during pregnancy is not well established. The ability to counsel patients on timing of conception after treatment remains limited. The aim of this study was to review our institution’s experience with glioma during and before pregnancy. Methods: In this single-institution study, we retrospectively identified patients diagnosed with glioma during or prior to pregnancy and reviewed treatment course and maternal and neonatal outcomes. Results: Twenty-one female patients were included in our study. Glioma diagnoses included 12 high-grade tumors and 9 low-grade tumors. Cohort A consisted of 8 patients who presented with glioma during pregnancy, of which, 7 underwent glioma treatment during pregnancy. All pregnancies in cohort A were without significant maternal complications and resulted in delivery of a healthy neonate. Cohort B consisted of 13 patients who experienced pregnancy after a prior diagnosis of glioma, totaling 23 pregnancies. Antepartum course was complicated by seizure in three pregnancies. Functionally inconsequential anatomic abnormalities in childhood offspring of cohort B occurred in 5 (27.8%) of the pregnancies. Four of the offspring with anatomic abnormalities had exposure to TMZ prior to conception. Conclusions: In this retrospective series, diagnosis of glioma before or during pregnancy was associated with generally favorable maternal, fetal and childhood outcomes. We observed a higher-than-expected rate of anatomic abnormalities in the post-diagnosis cohort, though none carried meaningful functional consequences. These findings add to the limited literature exploring maternal and fetal outcomes in patients with glioma.

ABSTRACT This study assessed the level of agreement of perceived improvements among pediatric patients with chronic pain and their parents following an interdisciplinary pain management program. This is a retrospective chart review of a heterogeneous group of pediatric patients with chronic pain who completed an interdisciplinary pain management program (IPMP) and their parents ( N = 172 pairs). The IPMP took place in an outpatient pain management center affiliated with an academic rehabilitation hospital. The outcome measures included the Multidimensional Patient Impression of Change (MPIC) and the MPIC parent version were administered post‐treatment. The levels of agreement on the MPIC were analyzed between child and parent using the free‐marginal kappa statistic. The majority of both the parents and the children evaluated the patients to be much or very much improved in six of the eight domains assessed. The levels of agreement in the ratings were fair to moderate among the patient–parent dyads. Parents endorsed significantly higher levels of improved overall pain and mood than their child did, whereas the patients reported greater levels of improved ability to cope with pain than their parents did. Both the patients and their parents reported high levels of perceived improvement following the IPMP. However, there were some differences in their ratings of improvements in overall pain, mood, and ability to cope with pain. Given that some of the perceptions were discrepant, it is recommended that feedback be obtained from the patient and their parent.

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.