Citations

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.

Abstract Aims Pulsed field ablation for atrial fibrillation offers shorter procedural times and improved safety compared with thermal ablation, but the optimal anaesthesia strategy remains uncertain. Most centres in the USA use general anaesthesia with endotracheal intubation, whereas monitored anaesthesia care without endotracheal intubation may be a safe and efficient alternative. Objectives To compare procedural efficiency and safety between monitored anaesthesia care and general anaesthesia for pulsed field ablation. Methods and results Consecutive adults who underwent pulsed field ablation for atrial fibrillation between 2024 and 2025 at Marshfield Clinic Health System were included. The anaesthesia approach was determined by operator preference. Procedural times, medication use, complications, and patient tolerance were recorded prospectively. Among 200 patients, 100 received monitored anaesthesia care without endotracheal intubation, and 100 received general anaesthesia. The mean age was 67 years, 42% were female, and the mean body mass index was 33 kilograms per square metre. Monitored anaesthesia care shortened case duration (77 vs. 95 min; P < 0.001) and laboratory time (118 vs. 153 min; P = 0.002) and required fewer adjunct medications (P < 0.001). Twenty-five procedures (25%) were challenging due to cough or motion but were all completed safely. Complications occurred in one monitored anaesthesia care case and six general anaesthesia cases (P = 0.054). Pulmonary vein isolation was achieved in all patients. Conclusion Monitored anaesthesia care without endotracheal intubation was safe, efficient, and resource-sparing compared with general anaesthesia for pulsed field atrial fibrillation ablation.

Extracellular vesicles (EVs) are lipid-bound vesicles secreted by cells, including exosomes, microvesicles, and apoptotic bodies. Proteomic analyses of EVs, particularly in relation to cancer, reveal specific biomarkers crucial for diagnosis and therapy. However, isolation techniques such as ultracentrifugation, size-exclusion chromatography, and ultrafiltration face challenges regarding purity, contamination, and yield. Contamination from other proteins complicates downstream processing, leading to difficulties in identifying biomarkers and interpreting results. Future research will focus on refining EV characterization for diagnostic and therapeutic applications, improving proteomics tools for greater accuracy, and exploring the use of EVs in drug delivery and regenerative medicine. In this review, we provide a bird’s eye view of various challenges, starting with EV isolation methods, yield, purity, and limitations in the proteome analysis of EVs for identifying protein targets.

To evaluate deep learning-based calcium segmentation and quantification on ECG-gated cardiac CT scans compared with manual evaluation. Automated calcium quantification was performed using a neural network based on mask regions with convolutional neural networks (R-CNNs) for multi-organ segmentation. Manual evaluation of calcium was carried out using proprietary software. This is a retrospective study of archived data. This study used 40 patients to train the segmentation model and 110 patients were used for the validation of the algorithm. The Pearson correlation coefficient between the reference actual and the computed predictive scores shows high level of correlation (0.84; P < .001) and high limits of agreement (±1.96 SD; −2000, 2000) in Bland–Altman plot analysis. The proposed method correctly classifies the risk group in 75.2% and classifies the subjects in the same group. In total, 81% of the predictive scores lie in the same categories and only seven patients out of 110 were more than one category off. For the presence/absence of coronary artery calcifications, the deep learning model achieved a sensitivity of 90% and a specificity of 94%. Fully automated model shows good correlation compared with reference standards. Automating process reduces evaluation time and optimizes clinical calcium scoring without additional resources.

AbstractPurpose has often been proposed as a quantitative imaging biomarker for diagnosis, prognosis, and treatment response assessment for various tumors. None of the many software tools for quantification are standardized. The ISMRM Open Science Initiative for Perfusion Imaging–Dynamic Contrast‐Enhanced (OSIPI‐DCE) challenge was designed to benchmark methods to better help the efforts to standardize measurement.MethodsA framework was created to evaluate values produced by DCE‐MRI analysis pipelines to enable benchmarking. The perfusion MRI community was invited to apply their pipelines for quantification in glioblastoma from clinical and synthetic patients. Submissions were required to include the entrants' values, the applied software, and a standard operating procedure. These were evaluated using the proposed score defined with accuracy, repeatability, and reproducibility components.ResultsAcross the 10 received submissions, the score ranged from 28% to 78% with a 59% median. The accuracy, repeatability, and reproducibility scores ranged from 0.54 to 0.92, 0.64 to 0.86, and 0.65 to 1.00, respectively (0–1 = lowest–highest). Manual arterial input function selection markedly affected the reproducibility and showed greater variability in analysis than automated methods. Furthermore, provision of a detailed standard operating procedure was critical for higher reproducibility.ConclusionsThis study reports results from the OSIPI‐DCE challenge and highlights the high inter‐software variability within estimation, providing a framework for ongoing benchmarking against the scores presented. Through this challenge, the participating teams were ranked based on the performance of their software tools in the particular setting of this challenge. In a real‐world clinical setting, many of these tools may perform differently with different benchmarking methodology.

Background: Low urine pH and volume are established risk factors for uric acid (UA) stone disease (UASD). Renal tubular epithelial cells exposed to an acidic pH and/or UA crystals can shed extracellular vesicles (EVs) into the tubular fluid, and these EVs may be a pathogenic biomarker of UASD. Methods: Urinary EVs bearing UA transporters (SLC2A9, SLC17A3, SLC22A12, SLC5A8, ABCG2, and ZNF365) were quantified in urine from UA stone formers (UASFs), calcium stone formers (CSFs), and age-/sex-matched non-stone formers (NSFs) using a standardized and published method of digital flow cytometry. Results: Urinary pH was lower (p < 0.05) and serum and urinary UA were greater (p < 0.05) in UASFs compared with NSFs. Urinary EVs carrying SLC17A3 and SLC5A8 were lower (p < 0.05) in UASFs compared with NSFs. Urinary EVs bearing SLC2A9, SLC22A12, SLC5A8, ABCG2, and ZNF365 were lower (p < 0.05) in CSFs than UASFs, while excretion of SLC17A3-bearing EVs did not differ between groups. Conclusion: EVs bearing specific UA transporters might contribute to the pathogenesis of UASD and represent non-invasive pathogenic biomarkers for calcium and UA stone risk.

AbstractThe COVID‐19 pandemic caused by SARS‐CoV‐2 is a deadly disease afflicting millions. The pandemic continues affecting population due to nonavailability of drugs and vaccines. The pathogenesis and complications of infection mainly involve hyperimmune‐inflammatory responses. Thus, therapeutic strategies rely on repurposing of drugs aimed at reducing infectivity and inflammation and modulate immunity favourably. Among, numerous therapeutic targets, the endocannabinoid system, particularly activation of cannabinoid type‐2 receptors (CB2R) emerged as an important one to suppress the hyperimmune‐inflammatory responses. Recently, potent antiinflammatory, antiviral and immunomodulatory properties of CB2R selective ligands of endogenous, plant, and synthetic origin were showed mediating CB2R selective functional agonism. CB2R activation appears to regulate numerous signaling pathways to control immune‐inflammatory mediators including cytokines, chemokines, adhesion molecules, prostanoids, and eicosanoids. Many CB2R ligands also exhibit off‐target effects mediating activation of PPARs, opioids, and TRPV, suggestive of adjuvant use with existing drugs that may maximize efficacy synergistically and minimize therapeutic doses to limit adverse/ side effects. We hypothesize that CB2R agonists, due to immunomodulatory, antiinflammatory, and antiviral properties may show activity against COVID‐19. Based on the organoprotective potential, relative safety, lack of psychotropic effects, and druggable properties, CB2R selective ligands might make available promising candidates for further investigation.

Abstract Backgrounds: Previous studies have demonstrated that excretion of urinary extracellular vesicles (EVs) from different nephron segments differs between kidney stone formers and non-stone formers (NSFs), and could reflect pathogenic mechanisms of urinary stone disease. In this study we quantified selected populations of specific urinary EVs carrying protein markers of immune cells and calcium/phosphorus physiology in calcium stone formers (CSFs) compared to non-stone formers (NSFs). Methods Incident CSFs (n = 24) and age- and sex- matched NSFs (n = 21) were studied. Clinical data were abstracted and biobanked cell-free urine samples were used to quantify specific urinary EV populations. EVs carrying proteins related to renal calcium/phosphorus physiology (phosphorus transporters (PiT1 and PiT2), Klotho, and fibroblast growth factor 23 (FGF23)); markers associated with EV generation (anoctamin-4 (ANO4) and Huntington interacting protein 1 (HIP1)), and markers shed from activated immune cells were quantified by standardized and published method of digital flow cytometry. Results The urine pH of CSFs was lower than NSFs (P < 0.05), whereas urine excretion of calcium, phosphorus, and calcium oxalate and uric acid supersaturation (SS) were significantly higher in CSFs compared to NSFs (P < 0.05). Urinary excretion of EVs with markers of total leukocytes (CD45), neutrophils (CD15), macrophages (CD68), Klotho, FGF23, PiT1, PiT2, and ANO4 were each markedly lower in CSFs than NSFs (P < 0.05) whereas excretion of those with markers of monocytes (CD14), T-Lymphocytes (CD3), B-Lymphocytes (CD19), plasma cells (CD138 plus CD319 positive ) were not different between the groups. Urinary excretion of EVs expressing PiT1 and PiT2 negatively (P < 0.05) correlated with urinary phosphorus excretion whereas excretion of EVs expressing FGF23 correlated negatively (P < 0.05) with both urinary calcium and phosphorus excretion. Conclusions Urinary excretion of EVs derived from specific types of activated immune cells and EVs with proteins related to calcium/phosphorus regulation were different between CSFs and NSFs. Thus, further validation of these and other populations of urinary EVs could identify biomarkers that elucidate novel pathogenic mechanisms of calcium stone formation in specific subsets of patients.