Citations

BACKGROUND: Accurate assessment of left ventricular outflow tract (LVOT) gradients is critical for hypertrophic cardiomyopathy management, yet Doppler-based measurements are technically demanding and require expertise. The objective of this work was to develop a multi-view deep learning model capable of classifying LVOT obstruction (>20 mm Hg) using routine 2-dimensional echocardiographic windows without reliance on Doppler imaging. METHODS: We trained and externally validated a cross-attention-based video-to-video fusion framework that integrated EchoPrime-derived video representations from 3 standard transthoracic echocardiographic views to classify LVOT gradients. RESULTS: Training was performed on a derivation cohort (N=1833) from a tertiary care system in the United States, with model performance evaluated on an internally held-out test set (N=275) and a Korean external validation cohort (N=46). Single-view baselines showed limited discrimination (external area under the receiver operating curves, 0.47–0.70). Conversely, the domain-specific foundational model (EchoPrime) achieved superior single-view performance (area under the receiver operating curves, 0.75–0.80 internal; 0.79–0.83 external), highlighting the importance of echo-specific pretraining and temporal modeling. The proposed multi-view fusion further enhanced predictive performance, with the late fusion model reaching an area under the receiver operating curve of 0.84 on the external cohort with significant population-shift. CONCLUSIONS: These results suggest LVOT physiology is encoded in routine 2-dimensional imaging and can be leveraged for clinically relevant gradient classification without Doppler input. The proposed artificial intelligence-guided strategy demonstrates substantial cost savings compared with the screen-all approach. By integrating complementary spatial-temporal information across multiple views, our approach generalizes robustly across populations and may enable real-time decision support, extend LVOT assessment to portable or resource-limited settings, and complement Doppler-based evaluation for longitudinal hypertrophic cardiomyopathy management.

We report an innovative interleaved voltammetric strategy to simultaneously quantify tonic levels of dopamine and serotonin in vivo using a single unmodified microelectrode, advancing our capability to monitor complex neurochemical interactions.

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.

Introduction: Atherosclerotic lesions preferentially form in arterial regions exposed to disturbed flow (DF), where ECs exhibit mitochondrial (mt) dysfunction, metabolic reprogramming, and senescence. Hippo pathway kinases LATS1/2 maintain EC homeostasis, but how DF–mediated LATS1/2 suppression drives EC metabolic remodeling remains unclear. Hypothesis: We propose that DF activates CD38, leading to mt dysfunction and metabolic reprogramming that promotes EC senescence and aberrant proliferation by LATS1/2 inhibition. Methods: EC-specific Lats1/2 knockout mice were generated using tamoxifen-inducible Cre systems, and DF was induced by partial carotid ligation. Murine and human plaques were analyzed using COMET™ immunofluorescence, and spatial metabolomics. Bioenergetic profiling included Seahorse XF analysis, 13 C-glucose/ 13 C-glutamine tracing, and pharmacologic modulation of CD38, mtROS, and ATP synthase. Results: Complete Lats1/2 deletion caused fatal edema and vascular leakage, while partial loss produced fragile, highly neovascularized plaques. Spatial proteomics revealed a CD38-driven senescence-associated stemness (SAS) phenotype under LATS1/2 deficiency. Metabolomics showed sulfite and taurine accumulation, consistent with SUOX deficiency. Mechanistically, CD38 suppressed SUOX, induced Complex V reverse-mode , increased succinate flux, and accelerated ATP consumption. Despite ATP depletion, glutamate metabolism and TCA cycle flux were enhanced, sustaining EC proliferation under energetic stress. LATS1/2 knockdown reduced mt respiratory capacity (lower OCR peak) without significantly increasing glycolysis, and DF suppressed both OCR and ECAR, indicating impaired energy metabolism under pathological shear stress. CD38 inhibition restored mt respiration and glycolytic capacity by preserving NAD, and rescuing LATS1/2 and DF-mediated defects. Blocking reverse-mode Complex V reduced DF- and LATS1/2-dependent EC senescence and proliferation. Conclusion: Complete LATS1/2 deletion causes fatal vascular leakage, while partial loss drives plaque formation with fragile neovessels through a CD38-dependent SAS phenotype. CD38 suppresses SUOX, induces Complex V reverse-mode , increases succinate flux, and accelerates ATP consumption, enabling EC proliferation despite energy stress. DF and LATS1/2 loss impair mt and glycolytic function, whereas CD38 inhibition restores mt respiration and reduces EC senescence and proliferation to prevent atherothrombosis in DF regions.

Abstract Background Ionizing radiation (IR) accelerates atherosclerosis through induction of cellular senescence, DNA damage, defective efferocytosis, and dysregulation of clonal hematopoiesis (CH) drivers. Although low-dose colchicine reduces ischemic cardiovascular events in coronary artery disease, the precise molecular mechanisms underlying its vasculoprotective effects remain incompletely defined, and whether it mitigates radiation-associated vascular injury is unknown. Methods Bone marrow–derived macrophages (BMDMs) were pretreated with low-dose colchicine and exposed to 2 Gy IR. Molecular effects were assessed by RNA-seq, immunoblotting, and molecular docking. In vivo effects were tested in a partial carotid ligation (PLCL) model using spatial proteomics. Human monocyte-derived macrophages (HMDMs) from thoracic malignancy patients were analyzed before and after radiation therapy (RT). Results Low-dose colchicine suppressed IR-induced macrophage senescence signaling while preserving NRF2 activity. In a cell-free assay, colchicine directly activated aldehyde dehydrogenase 2 (ALDH2) in a dose-dependent manner (EC 50 1–5 nM), identifying ALDH2 as a direct molecular target of colchicine. Following irradiation, colchicine restored ALDH2, reduced mitochondrial (mt)ROS - dependent p90 ribosomal S6 kinase ( p90RSK ) activation and lipid peroxidation, preserved TET2 and DNMT3A expression, and rescued impaired efferocytosis while preventing nicotinamide adenine dinucleotide (NAD⁺) and adenosine triphosphate (ATP) depletion. These protective effects were ALDH2-dependent, as they were lost with ALDH2 inhibition or depletion and were mimicked by pharmacologic ALDH2 activation. In vivo, colchicine attenuated radiation-induced atherosclerosis and macrophage senescence-associated stemness (SAS). Consistently, macrophages from patients after RT showed reduced ALDH2 with increased mtROS, lipid peroxidation, and senescence. Conclusion These findings identify ALDH2 as a previously unrecognized molecular target of colchicine that links mitochondrial redox control to suppression of radiation-induced macrophage senescence and atherosclerosis and may contribute to the efficacy of low-dose colchicine in cardiovascular disease.

BACKGROUND: Atherothrombosis, which underlies most acute coronary syndromes and is driven by intraplaque thrombosis, preferentially occurs in regions of disturbed blood flow (d-flow). Although LATS1/2 (large tumor suppressor kinases 1 and 2) are known regulators of endothelial mechanotransduction, the mechanisms by which d-flow connects endothelial senescence, proliferation, and intraplaque thrombosis remain poorly understood. METHODS: We investigated endothelial cell (EC)-specific roles of Lats1/2 using inducible EC-specific knockout mice in a partial carotid ligation model. Spatial multiomics of human and mouse plaques was performed using imaging mass cytometry, COMET sequential immunofluorescence, and spatial metabolomics. RESULTS: Tamoxifen-induced deletion of both Lats1 and Lats2 (homozygous) in ECs caused fatal edema and increased vascular permeability. In contrast, Lats1 het ( ± ) / Lats2 homo ( −/−) -EC-specific knockout mice survived and developed spontaneous atherothrombotic plaques with neovascularization. Spatial proteomics revealed that LATS1/2 loss induced a senescence-associated stemness phenotype driven by CD38 upregulation. Spatial metabolomics showed sulfite and taurine accumulation, indicating SUOX (sulfite oxidase) deficiency. CD38 suppressed SUOX, demonstrated a switch into the reverse mode of mitochondrial complex V, increased succinate dehydrogenase activity, and promoted ATP consumption. Despite ATP depletion, glutamate metabolism and the citric acid cycle flux increased, sustaining EC proliferation under energetic stress. This senescence-associated stemness state promoted both proliferation and senescence, leading to fragile, leaky neovessels and intraplaque thrombotic lesions. Pharmacological CD38 inhibition attenuated these phenotypes. Similar EC states were observed in human plaques. CONCLUSIONS: Loss of Lats1/2 in ECs induces a CD38-associated senescence-associated stemness-like phenotype that promotes intraplaque thrombosis through mitochondrial metabolic reprogramming, including changes consistent with reverse-mode operation of mitochondrial complex V. These findings define a mechanistic link between disturbed flow, endothelial metabolic reprogramming, and intraplaque thrombosis and hemorrhage.

Abstract Background Accurate assessment of left ventricular outflow tract (LVOT) gradients is critical for hypertrophic cardiomyopathy (HCM) management, yet Doppler-based measurements are technically demanding and require expertise. Objective To develop a multi-view deep learning model capable of classifying LVOT obstruction (> 20mmHg) using routine 2D echocardiographic windows without reliance on Doppler imaging. Methods We trained and externally validated a cross-attention-based video-to-video fusion framework that integrated EchoPrime-derived video representations from three standard transthoracic echocardiographic views to classify LVOT gradients. Results Training was performed on a derivation cohort (N = 1833) from a tertiary care system in the United States, with model performance evaluated on an internal held-out test set (N = 275) and a Korean external validation cohort (N = 46). Single-view baselines showed limited discrimination (external AUROCs 0.47–0.70). Conversely, domain-specific foundational model (EchoPrime) achieved superior single-view performance (AUROCs 0.75–0.80 internal; 0.79–0.83 external), highlighting the importance of echo-specific pretraining and temporal modeling. The proposed multi-view fusion further enhanced predictive performance, with the late fusion model reaching an AUROC of 0.84 on the external cohort with significant population-shift. Conclusions These results suggest LVOT physiology is encoded in routine 2D imaging and can be leveraged for clinically relevant gradient classification without Doppler input- proposed AI-guided strategy demonstrates substantial cost savings compared with the screen-all approach. By integrating complementary spatial-temporal information across multiple views, our approach generalizes robustly across populations and may enable real-time decision support, extend LVOT assessment to portable or resource-limited settings, and complement Doppler-based evaluation for longitudinal HCM management.

Importance Novel blood culture diagnostics provide rapid antimicrobial susceptibility testing (AST) results for bacteria causing bloodstream infections (BSIs) but have unclear clinical impact. Objective To evaluate clinical outcomes of blood culture testing using a rapid AST method compared with standard AST in patients with BSIs caused by gram-negative bacilli in regions with high prevalence of antimicrobial resistance. Design, Setting, and Participants Open-label randomized clinical trial that enrolled participants from December 2023 to May 2025 (final follow-up, June 18, 2025) at 7 medical centers in Greece (n = 2), India (n = 1), Israel (n = 3), and Spain (n = 1). Hospitalized patients (adults and children) with BSIs caused by gram-negative bacilli were eligible. Statistical analysis was conducted from August 2025 to January 2026. Intervention Patients were randomized to undergo blood culture evaluation using rapid, phenotypic AST directly from positive blood cultures plus standard susceptibility testing (n = 413) vs standard susceptibility testing alone (n = 437). Local antimicrobial stewardship teams reviewed all patients and provided treatment recommendations. Main Outcomes and Measures The primary outcome was a desirability of outcome ranking (DOOR) at day 30, with 3 categories (alive without deleterious events, alive with deleterious events, and death). The difference between rapid and standard testing was summarized as the probability that the DOOR outcomes were more desirable in the rapid testing group. Superiority was concluded if the lower limit of the 95% CI exceeded 50%. Secondary outcomes included 30-day mortality, length of hospitalization, intensive care unit admission, acquisition of hospital-acquired infections, time to effective antibiotic therapy within 3 days, and time to antibiotic escalation or deescalation within 3 days. Results Of the 899 patients randomized, 850 were included in the primary outcome analysis (median [IQR] age, 72 [21] years; 43% female). The probability that DOOR outcomes were more favorable in the rapid testing group was 48.8% (95% CI, 45.3%-52.4%). Median time to effective antibiotic therapy was not different between the groups in the as-randomized population. Median time to antibiotic escalation or deescalation was faster in the rapid testing group by 14 hours (95% CI, 6-22) in the as-randomized population. There were no differences between the groups in other secondary outcomes. In the prespecified subgroup with carbapenem-resistant infections, median time to effective therapy was 9.5 hours in the rapid testing group vs 28 hours in the standard testing group (difference, −18 hours [95% CI, −42 to 6]). Conclusions and Relevance Among patients with gram-negative bacilli BSIs, rapid blood culture AST was not superior to standard testing by DOOR. When considered with other efficacy and safety outcomes, these findings may help inform the use of rapid susceptibility testing in clinical practice. Trial Registration ClinicalTrials.gov Identifier: NCT06174649

Abstract Faciobrachial dystonic seizures (FBDS), paroxysmal dizziness spells, and thermal sensory attacks are highly frequent and stereotypic phenomena experienced in leucine‐rich glioma inactivated 1 (LGI1)‐antibody encephalitis. This study aims to describe the electrophysiologic mechanism underlying these pathognomonic symptoms. LGI1‐antibody encephalitis patients with active symptoms were enrolled from two separate centers in South Korea and the United States. Patients were evaluated with simultaneous magnetoencephalography (306 channels) and electroencephalography. Regional alterations in neuronal excitability represented by interictal epileptiform discharges were present in the faciobrachial area of the motor cortex, insula, and somatosensory cortex, somatotopically aligned with each of the ictal semiologies observed in patients. FBDS and other LGI1‐antibody encephalitis‐specific spells localized to cortical regions neuroanatomically corresponding to ictal semiologies: the faciobrachial homunculus (FBDS), insular cortex (paroxysmal dizziness spells), and somatosensory cortex (thermal sensory attacks). Our findings support the ictal hypothesis underlying these unique phenomena.