Citations

Age-associated mitochondrial decline reduces NAD+ availability, impairs oxidative phosphorylation (OXPHOS), and leads to accumulation of reactive oxygen species (ROS) thereby reshaping cellular metabolism. However, the regulatory logic coupling mitochondrial aging to metabolic dysregulation resulting in tumorigenic cell-fate transitions has not been modeled systematically. In this work, we propose a Boolean biomolecular network model of mitochondrial aging and integrate it with metabolic, cell-cycle, and apoptotic biomolecular networks comprising 94 nodes and 370 edges. We then examined how NAD+ decline, hypoxia and extracellular ROS shifts the balance between OXPHOS and glycolysis. To this end, the consolidated network model underwent dynamical analysis to elucidate the system-level outcomes as well as its molecular triggers. In particular, we investigated whether the metabolic phenotypes are reversible and how cancer-driver perturbations act in the absence of extracellular pyruvate. The model recapitulates a quiescent, OXPHOS-leaning baseline and predicts that progressive NAD+ decline lowers OXPHOS propensity (0.686 to 0.186) while raising glycolysis (0.256 to 0.426). Hypoxia and extracellular ROS synergize glycolytic and hybrid oxidative–glycolytic (W/O) states. Furthermore, these two triggers, together with elevated mitogenic signaling, give rise to a hyperproliferative, glycolytic, and apoptosis-resistant cellular state. Interesting, this state is conditionally reversible wherein receptor tyrosine kinase (RTK) inhibition redirects this cell fate toward apoptosis and collapses the W/O state. Cancer-driver analysis further indicates that, without extracellular pyruvate, VHL loss and RAS, PI3K, or AKT activation preferentially stabilizes glycolytic and hybrid states. Age-resolved TCGA-BRCA analysis provided expression-level support for the predicted remodeling, with declining OXPHOS-associated expression and concurrent OXPHOS/glycolysis activity in older Basal-like tumors. Together, our results show that mitochondrial aging is a priming condition whose tumor-permissive metabolic output is gated by microenvironmental and nutrient inputs. The model provides a novel framework for evaluating age-associated metabolic reprogramming and predicting early tumorigenic cell fates.

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.

e16023 Background: Stroke is an underrecognized cause of death among patients with gastric cancer. While overall cancer mortality has improved, less is known about long-term trends and disparities in stroke-related deaths. We examined national patterns in stroke mortality among gastric cancer patients from 1999 to 2023. Methods: U.S. national mortality data were used to calculate age-adjusted mortality rates (AAMR) per 100,000. Joinpoint regression identified temporal changes and estimated annual percent change (APC) and average annual percent change (AAPC). Analyses were stratified by age, sex, race and ethnicity, census region, and urbanization. Results: Between 1999 and 2023, an overall decline in stroke-related mortality was noted with AAMR falling from 167.29 to 111.35 per 100,000 people (AAPC −1.70%, 95% CI −1.9 to −1.5). The decline was greatest between 2002 and 2009 (−5.28% per year) after which it began to plateau until it rose significantly between 2018 and 2021 (APC 6.56%) followed by a decline after 2021 (−3.63%). Older adults had the highest level of stroke related mortality, and therefore the greatest reduction over time (from 756.36 to 479.63) with a total reduction of −36.6% yet they saw a significant increase in mortality between 2018 and 2021. Middle aged patients had little overall improvement and demonstrated the steepest recent increase (APC 8.46%). Younger patients concluded the study period at rates similar to those seen in 1999. Men demonstrated a greater incidence of stroke related mortality compared to women (118.67 vs 104.15 in 2023) with similar trends over time. Racial disparities were present with Black patients showing the highest stroke related mortality in all years (from 242.47 to 156.26) and the largest recent increase (APC 7.37%). Regionally, the South and rural areas carried the highest mortality burden; however, all geographic areas demonstrated an identical increase between 2018 and 2021. Conclusions: Although stroke-related mortality among gastric cancer patients has declined over two decades, recent nationwide increases highlight ongoing vulnerability and persistent disparities. Targeted integration of cardiovascular risk assessment and stroke prevention into gastric cancer care may help sustain progress and reduce inequities. Group (Category A / Category B) AAMR 1999 (A / B) AAMR 2023 (A / B) Recent Surge Trend 2018–2021 (APC) Overall 167.3 111.4 +6.6%* Sex (Male / Female) 181.5 / 156.2 118.7 / 104.2 +6.8%* / +6.2%* Race (NH White / NH Black) 160.4 / 242.5 108.2 / 158.4 +6.3%* / +7.4%* Race (Hispanic / Asian) 140.3 / 153.6 97.7 / 80.0 +6.9%* / +5.2%* Age (Young / Middle) 6.7 / 47.7 6.7 / 42.3 +7.8%* / +8.5%* Age (Old 65+) 756.4 479.6 +6.2%* Region (Northeast / Midwest) 141.5 / 172.0 82.7 / 115.3 +4.4%* / +6.7%* Region (South / West) 177.5 / 171.4 125.7 / 107.2 +6.9%* / +6.2%* An asterisk (*) indicates that the APC is statistically significant (p < 0.05).

Acute type A aortic dissection is a life-threatening condition requiring emergency surgery and complex postoperative management. Although survival rates have improved, many patients experience long-term functional impairments, reduced quality of life, and an elevated risk of complications. Despite strong evidence supporting cardiac rehabilitation in other cardiovascular populations, structured programs remain underutilized in patients with surgically resolved acute type A aortic dissection. Exercise-based cardiac rehabilitation appears feasible and can be delivered safely in carefully selected patients when appropriately adapted to individual needs and conducted under close supervision. Postoperative patients are often physically deconditioned, prone to hospital-acquired disability, and may misjudge exercise intensity. Therefore, individualized exercise prescription, guided by exercise testing when available, is important to support safe training thresholds. Early and gradual introduction of physical activity may help prevent complications associated with immobility, support blood pressure control, and contribute to improvements in functional capacity. However, training volume should be purposefully lower than in conventional program settings to reduce hemodynamic stress. Education on safe exercise parameters and self-monitoring plays a central role in enabling long-term adherence and promoting patient autonomy. Cardiac rehabilitation programs should incorporate dietary, nutritional, and psychological support. Although evidence specific to this patient population remains limited, available data suggest the feasibility and potential benefits of cardiac rehabilitation when delivered with appropriate precautions. Our review underscores the need for a tailored, multidisciplinary CR approach aimed at enhancing physical recovery, supporting cardiovascular stability, and improving overall quality of life in patients following surgery. Further research is required to define optimal program protocols.

ABSTRACT Objective Hypertension is a key risk factor for aortic dissection (AD). AD, if left untreated, carries significant mortality rates. Our aim is to analyse trends in mortality due to AD in adults with primary hypertension in the United States (US). Methods We used the CDC WONDER database to extract mortality data for patients with primary hypertension who died due to AD. Age‐adjusted mortality rates (AAMRs) and crude mortality rates (CMRs) were extracted per 100 000 persons. Annual percentage changes (APCs) and average APCs (AAPCs) in AAMRs and CMRs were calculated using Joinpoint regression. Results From 1999 to 2020, a total of 13 128 deaths due to AD were reported in patients with primary hypertension in the US. Males displayed a higher overall AAMR (0.3) than females (0.2) throughout the study period. Slight regional variations were observed, with the West showing the highest overall AAMR (0.4), followed by the Midwest (0.3), and the Northeast and South (0.2). In urban areas, AAMRs were higher than in rural areas until 2008. From 2009 to 2020, AAMRs remained stable in urban areas (0.3) but increased in rural areas from 2010 to 2020 (4.7). The highest state‐level AAMRs were observed in Hawaii, Oregon, and Oklahoma. Conclusion Significant differences were observed in AAPCs compared to AD‐related mortality trends in the general population. Mortality trends revealed an initial decline followed by a gradual rise. Clinicians should focus on high‐risk groups and raise awareness about the disease in these populations.

Background/Objective: Diabetic nephropathy (DN), a key microvascular complication of type 2 diabetes (T2DM), drives significant morbidity, mortality, and healthcare costs. Vitamin D deficiency has been linked to renal dysfunction, but its role in DN remains unclear. This study assessed the association between vitamin D status and DN versus T2DM without nephropathy. Methods: This cross-sectional hospital-based study included 399 participants (299 DN, 100 T2DM without nephropathy) at a tertiary endocrine clinic. Demographic, clinical, and biochemical data, including serum 25(OH)D, were collected. Chi-square and Mann–Whitney compared categorical and continuous variables, respectively, and multinomial logistic regression assessed the association between vitamin D status and DN (p < 0.05). Results: Patients with DN were older (58.2 ± 7.95 vs. 51.4 ± 9.94 years, p < 0.001), had more advanced CKD (stages 2–3b: 84.6% vs. 20.0%, p < 0.001), and higher albuminuria (moderate: 80.3% vs. 19.0%; severe: 18.4% vs. 0%, p < 0.001). They also showed poorer glycemic control, elevated urea and creatinine, lower serum albumin, dyslipidemia, elevated liver enzymes, and higher uric acid (all p < 0.05). Vitamin D deficiency was more prevalent in DN (37.7% vs. 8.0%, p < 0.001). Unadjusted multinomial regression indicated that T2DM patients without nephropathy had a 91% lower risk of vitamin D deficiency (RRR 0.09; 95% CI 0.04–0.19, p < 0.001) and an 87% lower risk of insufficiency (RRR 0.13; 95% CI 0.05–0.26, p < 0.001) compared with DN patients. After adjusting for age, HbA1c, creatinine, duration of diabetes and eGFR, the reduced risk of deficiency remained significant (RRR 0.04; 95% CI 0.01–0.16, p < 0.001), while the association with insufficiency was no longer significant (p = 0.310). Conclusions: This study shows a significant association between vitamin D deficiency and diabetic nephropathy, though its cross-sectional design precludes causal inference. Reverse causality and residual confounding cannot be excluded. Patients with DN had poorer glycemic control, dyslipidemia, and renal function, along with more frequent vitamin D deficiency. Routine vitamin D monitoring may support early detection and risk stratification in T2DM.

Coronary artery bypass grafting (CABG) remains a cornerstone of treatment for patients with advanced or complex coronary artery disease, yet long-term success is influenced by graft patency, progression of native disease, and ventricular remodeling. Optimizing the follow-up of these patients requires a structured approach in which multimodality cardiovascular imaging plays a central role. Echocardiography remains the first-line modality, providing readily available assessment of ventricular function, valvular competence, and wall motion, while advanced techniques, such as strain imaging and myocardial work, enhance sensitivity for subclinical dysfunction. Coronary computed tomography angiography (CCTA) offers excellent diagnostic accuracy for graft patency and native coronary anatomy, with emerging applications of CT perfusion and fractional flow reserve derived from CT (FFR-CT) expanding its ability to assess lesion-specific ischemia. Cardiovascular magnetic resonance (CMR) provides comprehensive tissue characterization, quantifying scar burden, viability, and inducible ischemia, and stress CMR protocols have demonstrated both safety and independent prognostic value in post-CABG cohorts. Nuclear imaging with single-photon emission computed tomography (SPECT) and positron emission tomography (PET) remains essential for quantifying perfusion, viability, and absolute myocardial blood flow, with hybrid PET/CT approaches offering further refinement in patients with recurrent symptoms. In patients after CABG, multimodality imaging is tailored to the patient’s characteristics, symptoms, and pre-test probability of disease progression. In asymptomatic patients, imaging focuses on surveillance, risk stratification, and the early detection of subclinical abnormalities, whereas in symptomatic individuals, it focuses on establishing the diagnosis, defining prognosis, and guiding therapeutic interventions. Therefore, the aim of our review is to propose updated and comprehensive guidance on the crucial role of multimodality cardiovascular imaging in the evaluation and management of post-CABG patients and to provide a practical, evidence-based framework for optimizing outcomes.

Abstract Disclosure: H. Ahmad: None. M. Kakakhel: None. A. Ullah: None. M. Saeed: None. J. Ikram: None. A. Qadeer: None. M. Khawar: None. H. Jawad: None. S. Haider: None. R. Haider: None. F. Ahmed: None. R.W. Kirchoff: None. Background: Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by the destruction of insulin-producing cells in the pancreas. It is a global health concern with regional variation in incidence and prevalence. This study aims to analyze the regional incidence and prevalence of T1DM among adolescents and young adults (15-39 years) from 1990 to 2021 in 26 regions. Methods: Global Burden of Disease (GBD) data for 2021 were analyzed to assess regional incidence and prevalence of T1DM among adolescents and young adults. The Annual Average Percentage Change (AAPC) was calculated to evaluate trends from 1990 to 2021, with statistical significance determined using p-values. Results: In 2021, middle socio-demographic index (SDI) has the highest incidence (54541) as well as prevalence (1.86 million), followed by Low-middle SDI (I: 48416, P: 1.80 million) and South Asia (I: 46310, P: 1.73 million). Oceania has the lowest incidence (356) as well as prevalence (12885), followed by Andean Latin America (I: 911, P: 31954) and Caribbean regions (I: 1214, P: 54610), respectively. The largest increase in AAPC of incidence was showed by Southern Latin America (2.23, CI: 2.11-2.30), High-income Asia Pacific (2.22, CI: 2.18-2.26), and Western Europe (1.80, CI: 1.73-1.84) regions, while Western Europe (1.72, CI: 1.66-1.75), Eastern Europe (1.64, CI: 1.63-1.66), and Australasia (1.38, CI: 1.36-1.40) showed largest increase in AAPC of prevalence. The Caribbean region had the greatest decline in AAPC of prevalence (-0.11, CI: -0.08 to -0.12) followed by Eastern Sub-Saharan Africa (-0.07, CI: -0.06 to -0.09) and Central Latin America (-0.04, CI: -0.02 to -0.07). There was no region with decline in incidence. All AAPC values were statistically significant (p &lt; 0.000001). Conclusion: Middle SDI region exhibited the highest incidence and prevalence, highlighting the vulnerability of these populations, while Oceania and Andean Latin America bore the least burden. Notably, several regions, particularly in Europe, experienced substantial increases in both incidence and prevalence, emphasizing the need for targeted interventions. Conversely, some regions, such as the Caribbean, showed encouraging declines in prevalence, suggesting that effective prevention and control strategies can be implemented. These findings underscore the importance of tailored approaches to address the evolving burden of T1DM. Presentation: Saturday, July 12, 2025

Abstract Disclosure: M. Kakakhel: None. S. Cheema: None. R. Haider: None. R. Noor: None. S. N.l: None. S.M. Irshad: None. A. Ullah: None. H. Jawad: None. A. Nawaz: None. M. Khawar: None. A. Qadeer: None. H. Ahmad: None. R. Alcaraz: None. F. Ahmed: None. Background: Bone density and structure-related disorders, such as osteoporosis and related fractures, significantly contribute to morbidity and mortality, particularly among aging populations. Monitoring temporal trends and geographic variations in mortality is essential to inform targeted public health interventions. In this study, we aimed to examine temporal and geographic variations in mortality associated with bone density and structure-related disorders in the United States from 1999 to 2022. Methods: Using ICD-10 codes M80-M85, this retrospective ecological study utilized mortality data extracted from the CDC WONDER database for the years 1999-2022. Age-adjusted mortality rates (AAMRs) were calculated and stratified by demographic variables (age, sex, and race/ethnicity) and geographic regions. Temporal trends were analyzed using Joinpoint regression to estimate annual percent changes (APCs). Geographic variations were visualized using choropleth maps, and subgroup analyses were performed to explore disparities. Statistical significance was set at p &lt; 0.05. Results: Age-adjusted mortality rates (AAMRs) for bone density and structure-related disorders decreased overall from 1999 to 2019, with a subsequent rise observed in 2020 and 2022. Joinpoint regression revealed a significant negative trend from 2007-2016 (APC = -7.46%, p &lt; 0.000001), followed by a positive reversal from 2019-2022 (APC = 3.78%, p = 0.013). Both males and females experienced declines in mortality, but females had a slightly higher APC of -3.10% compared to -2.82% for males. Asian/Pacific Islander groups exhibited the most pronounced decrease in mortality (APC = -11.92%, p &lt; 0.000001) from 2009-2015, with a positive rebound in recent years. Black or African American populations had the smallest decline (APC = -1.35%). The Southern U.S. experienced the steepest decline in mortality from 2010-2016 (APC = -10.92%, p &lt; 0.000001), followed by a strong positive trend from 2019-2022 (APC = 6.61%, p &lt; 0.000001). Conversely, the West and Northeast regions showed milder trends with less pronounced reversals. Older age groups (65-74, 75-84) showed significant decreases in mortality, particularly the 65-74 group, which reversed to a positive trend (APC = 6.97%) from 2019-2022. The highest number of deaths occurred at the decedent’s home (3,330 in 2022). Subgroup analyses indicated significant temporal shifts in the mortality patterns across different racial/ethnic groups and geographic regions. Hispanic/Latino and Asian/Pacific Islander populations exhibited an increase in mortality rates post-2019, particularly in 2020. Conclusion: From 1999 to 2022, mortality from bone density and structure-related disorders in the U.S. exhibited significant temporal and geographic variations. These findings highlight the need for targeted public health strategies. Presentation: Monday, July 14, 2025

Abstract Disclosure: A. Ullah: None. R. Haider: None. M. Khawar: None. M. Abid: None. M. Hadeed Khawar: None. M. Shaukat: None. M. Asad Cheema: None. A. Komel: None. M. Ahmed Khan: None. R. Noureen: None. A. Batool: None. M. Mubashir: None. A. Qadeer: None. R. W. Kirchoff: None. Background: The role of dissecting the right paraesophageal lymph node (RPELN) in managing papillary thyroid carcinoma (PTC) remains a subject of debate. This meta-analysis examines both established and novel risk factors associated with RPELN metastasis. Methods: Relevant studies published up to December 2024 were retrieved using PubMed, Embase, Ovid, and Scopus search engines. Data were extracted and evaluated using the Newcastle-Ottawa scale. Statistical analysis was performed using Review Manager 5.4, with heterogeneity assessed through the Q-test and I²-test. Sensitivity analysis was conducted using the leave-one-out method, and the Egger regression test was used to generate a funnel plot for publication bias assessment. Results: Out of 2,444 articles screened, 26 studies involving 16,427 patients were included in the meta-analysis. The overall RPELN metastasis rate was 12.98% (2,133/16,427). The pooled analysis revealed significant associations between RPELN metastasis and the following factors: age under 55 years (P &lt; 0.00001), male gender (P &lt; 0.00001), tumor size &gt;1 cm (P &lt; 0.00001), multifocality (P &lt; 0.00001), capsular invasion (P &lt; 0.00001), vascular invasion (P &lt; 0.00001), extra-thyroidal extension (P &lt; 0.0001), central lymph node metastasis (P &lt; 0.00001), lateral lymph node metastasis (P &lt; 0.00001), Hashimoto’s thyroiditis (P = 0.002), micro-calcifications (P = 0.01), and altered echogenicity (P = 0.03). Conversely, no significant associations were observed for tumor location in the right lobe (P = 0.07), superior pole (P = 0.08), middle pole (P = 1.00), inferior pole (P = 0.28), or tumor margins (P = 0.93) (all P &gt; 0.05). Conclusion: Factors such as age &lt;55, male sex, tumor size &gt;1 cm, multifocality, capsular invasion, vascular invasion, extra-thyroidal extension, central lymph node metastasis, lateral lymph node metastasis, and Hashimoto’s thyroiditis are significantly associated with RPELN metastasis. These should be carefully considered during RPELN dissection in PTC management. Presentation: Sunday, July 13, 2025