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 Background Current risk assessment tools for guiding direct oral anticoagulant (DOAC) therapy for patients with atrial fibrillation (AF) based on clinical risk factors demonstrate modest predictive performance limiting clinical impact. Additionally, while guidelines recommend periodic reassessment of risk over time, there remains an absence of modelling solutions for capturing evolving risk in AF patients. Methods Using UK electronic health records, we developed and validated the Transformer-based Risk assessment survival model (TRisk), an artificial intelligence model that predicts 12-month thromboembolic and bleeding events in AF patients by leveraging temporal patient journeys up to baseline. A cohort of 411,850 prevalent non-valvular AF patients aged ≥18 years between 2010 and 2020 was identified from 1,442 English general practices. Practices were randomly allocated to derivation (n=1,079) and external validation (n=363) cohorts. TRisk was compared with CHA 2 DS 2 -VASc and CHA 2 DS 2 -VA for thromboembolic event prediction, and HAS-BLED and ORBIT for bleeding prediction, with subgroup analyses by sex, age, and baseline characteristics. A second validation of TRisk was also performed on 16,218 US AF patients between 2010 and 2023. A decision model compared outcomes and healthcare costs for TRisk versus standard care. Findings TRisk achieved higher discrimination for thromboembolic event prediction (C-index: 0.82; 95% confidence interval [CI]: [0.81, 0.83]) as compared to CHA 2 DS 2 -VASc (0.71 [0.70, 0.73]) in UK validation. Application of TRisk to US data yielded similar C-index: 0.82 (0.80, 0.84). For bleeding prediction, TRisk (C-index: 0.70 [0.69–0.71]) outperformed both HAS-BLED (0.63; [0.61, 0.64]) and ORBIT (0.64; [0.63, 0.65]), with comparable US results (0.71; [0.69, 0.74]). The model remained well-calibrated across both populations and performed equitably across subgroups, including by race and during the COVID-19 pandemic. Impact analyses showed TRisk could reduce DOAC prescriptions by 8% in the UK and 7% in the US relative to guideline-recommended approaches, while preventing at least as many thromboembolic events. This refined approach would generate annual healthcare savings of £5.5 million and $456.2 million in the UK and US respectively among patients initiating DOACs, rising to £48.6 million and $1.8 billion when extended to all AF patients on DOACs. Interpretation TRisk enabled more precise prediction for both thromboembolic and bleeding events across AF populations in UK and US compared to established clinical scoring systems. Incorporating TRisk into routine AF care would result in substantial cost savings without compromising the identification of true high-risk patients. Funding None

Abstract Background Proton pencil beam scanning (PBS) enables highly conformal dose distributions; however, its lateral dose fall‐off (penumbra) can be compromised by the use of range shifters (RSs) and increased air gaps. In PBS for head and neck regions, where critical organs at risk (OARs) are frequently adjacent to the target, penumbra degradation may lead to increased OAR doses or suboptimal target coverage. The integration of a dynamic multi‐leaf collimator (dMLC), which adjusts leaf positions at each energy layer, has been shown to improve dose conformity in single‐field uniform dose (SFUD) delivery. In parallel, intensity‐modulated proton therapy (IMPT) offers enhanced dose shaping over SFUD by modulating beam intensity across multiple fields and does not require a single beam to encompass the entire target volume, providing greater flexibility in utilizing dMLC capabilities. Purpose This study integrates dMLC into IMPT for head and neck cancer and proposes a novel leaf positioning strategy. We evaluate the dosimetric impact of this approach and assess its potential clinical benefits in terms of target coverage and OAR sparing. Methods Treatment plans were retrospectively created for five patients with head and neck cancer. For each patient, IMPT plans with three beam angles were generated using three techniques: (1) uncollimated PBS, (2) dMLC cover , in which the MLC encloses the target cross‐section at each energy layer, and (3) dMLC block , in which the MLC actively blocks OARs and their distal regions. Dose‐volume histogram (DVH) metrics for the clinical target volume (CTV) and OARs were evaluated, including a total of 21 perturbed scenarios that combined ± 2 mm setup uncertainties (7 scenarios) and ± 3.5% range uncertainties (3 scenarios). The accuracy of dose calculations was validated by comparing calculated and measured lateral dose distributions at the isocenter plane in water using two‐dimensional gamma analysis with a 2%/2 mm criterion. Results The integration of dMLC with IMPT significantly reduced the dose to surrounding OARs while maintaining comparable target coverage and robustness relative to uncollimated PBS. Notably, dMLC block demonstrated an enhanced dose‐sparing effect than dMLC cover , particularly for OARs surrounded by the target. While maintaining comparable CTV D98% across three techniques, dMLC cover achieved the greatest reduction in the mean doses to the eyeballs and optic nerves, as well as in the D2% to the optic chiasm, brain, and brainstem in most cases. The gamma passing rate between calculated and measured doses for dMLC block exceeded 95% for all beams, confirming the accuracy of dose calculations involving complex leaf positions. Conclusions The combination of IMPT and dMLC provides notable dosimetric advantages, supporting its potential for clinical applications. Further validation across a broader range of cases is necessary to comprehensively assess its efficacy and safety, particularly with respect to leaf positioning accuracy and potential variations in biological effectiveness.

Acute-on-chronic liver failure (ACLF) has been associated with excellent post-liver transplant (LT) outcomes at 1 year; however, the impact of alcohol as ACLF precipitant, specifically alcohol-associated hepatitis (AH), and as etiology of chronic liver disease remains uncertain. This study aimed to assess the effect of alcohol as ACLF precipitant and chronic liver disease etiology (alcohol-associated liver disease vs. non–alcohol-associated liver disease) on posttransplant outcomes. We performed a retrospective study using the Multi-Organ Dysfunction and Evaluation for LT Consortium database and included 640 patients with ACLF who underwent LT across 15 transplant centers in North America. The primary outcome was 1-year posttransplant survival. We used logistic regression and Cox proportional hazards to compare posttransplant survival, mortality risk, and health care utilization, adjusting for age, ACLF grade, comorbid diabetes mellitus, chronic kidney disease, and HCC. The median follow-up from LT was 2.8 years (P25–P75, 2.2–5.5 y) for patients with AH-ACLF (n=42) and 3.1 years (P25–P75, 1.6–4.9 y) for patients without AH (n=598). No significant difference was observed in 1-year survival after LT in patients with AH-ACLF versus those without AH ( p =0.36). Patients with AH had significantly higher health care utilization evidenced by greater length of stay (28.5 vs. 19.0 d, p =0.004; adjusted linear estimate 16.89, 95% CI: 7.66–26.11, p <0.001), higher rates of rehabilitation placement (71.4% vs. 41.8%, p =0.002; adjusted odds ratio: 4.13, 95% CI: 2.04–8.89, p <0.001), and non-ambulatory status (39.0% vs. 21.0%, p =0.005; adjusted odds ratio: 4.54, 95% CI: 1.90–10.79, p <0.001). Compared with other etiologies, alcohol-associated liver disease was not associated with differences in 1-year mortality, mortality risk over time, or health care utilization, after excluding patients with AH as ACLF precipitant. While there were no differences in 1-year survival, AH-ACLF was associated with higher health care resource utilization compared with other ACLF precipitants. LT centers should ensure adequate resources are allocated for the management of these patients.

Importance Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure. Objective To estimate the worldwide burden of SAH. Design, Setting, and Participants Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021. Exposures SAH and 14 modifiable risk factors. Main Outcomes and Measures Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor–specific population attributable fractions (PAFs). Results In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100 000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF] = 51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF = 14.4%; 95% UI, 12.4%-16.5%) had the highest attribution. Conclusions and Relevance Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.

ABSTRACT The rare human neuroendocrine tumors pheochromocytoma and paraganglioma (PPGL) can result from loss of mitochondrial succinate dehydrogenase. The resulting succinate accumulation is tumorigenic in certain neuroendocrine cells. Here, we explore two theoretical approaches to mitigate tumorigenic succinate accumulation in a cell culture model of PPGL. We first study a gene replacement strategy using transposition technology, and conclude that many of the changes in mitochondrial morphology, oxidative cell metabolism and succinate accumulation can be reversed by this process. We then investigate whether riboflavin supplementation has the potential to rescue succinate dehydrogenase activity in the intact SDHA catalytic subunit to suppress succinate accumulation even in the absence of SDHB. We show that this latter strategy is not successful.

Abstract Disclosure: L. Rahimi: None. F. Al-Khazal: None. N. Becker: None. L. Maher, III: None. Carriers of loss-of-function alleles in genes encoding the four succinate dehydrogenase (SDH) subunits exhibit a heightened risk for pheochromocytoma/paraganglioma (PPGL), a rare neuroendocrine tumor of chromaffin cells. Tumorigenesis begins with the somatic loss of the remaining functional gene copy, resulting in a cell devoid of functional SDH. Compared to wild-type immortalized chromaffin cells (WT imCCs), SDHB-KO immortalized chromaffin cells (SDHB-KO imCCs) are larger, grow more slowly, display deformed mitochondria, show strikingly heightened succinate accumulation, and altered metabolism. Among several mechanisms proposed to link SDH deficiency with PPGL tumorigenesis, the accumulation of succinate as an oncometabolite is a leading hypothesis. We describe two attempts to suppress succinate accumulation in SDHB-KO imCCs. First, riboflavin has previously been shown to enhance residual SDHA flavinylation and enzymatic function, possibly reducing succinate levels by supporting conversion of accumulated succinate to fumarate in the absence of SDHB. We tested this by treating WT and SDHB-KO imCCs with 5 µM riboflavin for 2 weeks. Metabolomic analysis did not show decreased succinate, suggesting that enzyme activity of any remaining SDHA subunit was not rescued by increased flavinylation. Second, we envisioned a gene therapy approach to replace defective SDHB with a rescuing transgene. SDHB-KO imCCs received DNA encoding SDHB or SDHC cDNAs via transposon technology, confirmed by PCR and analyzed by western blot analyses. These studies showed that whereas WT imCCs successfully expressed processed transgene products in mitochondria, SDHB-KO imCCs could not process or transport rescuing SDH subunits into mitochondria. This shows that transposed SDHB-KO imCCs cannot properly express a rescuing SDHB subunit and do not revert to a wild-type phenotype. It is likely that the severely damaged mitochondria of SDHB-KO imCCs are incompetent to process and import rescuing SDHB subunits, so unprocessed protein accumulates without effect. This defect may lie in the mitochondrial targeting peptide recognition system because the targeting peptide of rescuing SDHB protein is not removed in SDHB-KO imCCs as judged by western blotting. In summary, we show the failure of two conceptually simple tactics to suppress succinate accumulation in SDHB-KO imCCs with highly defective mitochondria: rescue of SDHA by supporting flavinylation, or rescue of SDHB with a replacement gene copy. Further research may allow screening for small molecules that suppress succinate accumulation by other mechanisms. It remains to be determined if blocking succinate accumulation would be therapeutic in SDH-loss PPGL tumors. Presentation: 6/1/2024