Elhadi, Muhammed

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 The expanding use of biologic and small-molecule therapies for ulcerative colitis (UC) has raised concerns regarding perioperative safety. We conducted a network meta-analysis to compare short-term postoperative complications associated with preoperative exposure to these agents in patients undergoing colorectal surgery. Methods We systematically searched PubMed, Web of Science, and the Cochrane Library through September 15, 2025, for cohort studies of adults with UC who were exposed to biologic or small-molecule therapy within 12 weeks prior to surgery. Interventions included biologic therapy, small-molecule therapy, and no biologic or small-molecule therapy (control). The primary outcome was overall postoperative complications at 30 and 90 days. Venous thromboembolism (VTE) was assessed as a key secondary outcome. Random-effects network meta-analysis was performed using risk ratios (RRs) with 95% confidence intervals (CIs). Results Sixteen retrospective cohort studies involving 3235 patients were included. At 30 days, ustekinumab and tofacitinib were associated with lower overall postoperative complication rates than control (RR: 0.29; 95% CI: 0.09-0.96; and RR: 0.66; 95% CI: 0.46-0.96, respectively). Anti-tumor necrosis factor (TNF) therapy was associated with higher complication rates compared with vedolizumab, ustekinumab, and tofacitinib at 30 days (RR: 1.27; 95% CI: 1.00-1.63; RR: 3.67; 95% CI: 1.12-12.03; and RR: 1.61; 95% CI: 1.14-2.27, respectively). At 90 days, anti-TNF therapy was associated with higher complication rates than control (RR 1.20, 95% CI 1.03-1.40), although the 90-day analysis was based on limited data. VTE rates were similar across treatments at both time points. Conclusion Preoperative ustekinumab and tofacitinib were associated with fewer 30-day postoperative complications than control or anti-TNF therapy, while vedolizumab was associated with fewer complications than anti-TNF therapy. At 90 days, anti-TNF therapy was associated with higher complication rates compared with control. These findings, particularly at 90 days based on limited data, should be interpreted with caution and require confirmation in well-designed prospective studies with rigorous adjustment for confounding factors.

Introduction: Carcinoid cancer is a rare neuroendocrine tumor (NET) secreting vasoactive substances. Case Presentation: A 66-year-old woman presented to cardiology clinic for evaluation of dyspnea with exertion and leg swelling. Comorbidities included chronic kidney disease and a history of jejunal neuroendocrine tumor (NET) with prior resection and recent recurrence complicated by peritoneal carcinomatosis. A transthoracic echocardiogram was obtained at time of recurrence (1 year prior to presentation) and showed mild mitral regurgitation (MR), mild bi-atrial enlargement, moderate tricuspid regurgitation (TR), and mild aortic regurgitation (AR) with preserved ejection fraction. In clinic, physical exam showed jugular venous distention with prominent V waves and a systolic and diastolic murmur. Transthoracic echocardiogram (TTE) demonstrated severe TR, moderate to severe AR, moderate MR, severe pulmonary valve regurgitation, and a right to left shunt with enlarged right ventricle and reduced function. Patient was diagnosed with left and right carcinoid heart disease involving all 4 cardiac valves in the setting of a patent foramen ovale (PFO). After multidisciplinary discussion, surgical intervention was recommended. She underwent successful cardiopulmonary bypass with mitral valve replacement, aortic valve, pulmonary valve replacement, and tricuspid valve replacement in addition to closure of PFO. She did well postoperatively and was stable for dismissal from the hospital after 12 days. Discussion: Rarely, carcinoid heart disease can involve the left side of the heart. Left sided involvement is typically seen in the presence of a right to left side cardiac shunt. In patients with severe valve dysfunction secondary to carcinoid heart syndrome, surgical intervention is the definitive treatment and has been found to improve quality of life and prolong survival

e13167 Background: Abemaciclib represents a significant therapeutic advancement in the treatment of advanced metastatic breast cancer. As a selective protein-dependant kinase 4 and 6 (CDK4/6) inhibitor, it acts as a growth blocker. This study aims to evaluate the efficacy and safety of abemaciclib in combination with endocrine therapy for patients with metastatic breast cancer. Methods: We conducted an electronic search on December 27, 2024 using PubMed, Scopus, and the Cochrane database. Our inclusion criteria involved only randomized clinical trials evaluating the efficacy and safety of abemaciclib in combination to endocrine therapy in advanced breast cancer. Our primary outcomes were progression-free survival, overall response rate, overall survival, and grade 3 or 4 adverse effects. The hazard, odds, and risk ratios with 95% confidence intervals were used to determine the effect size. A random-effects model was applied. Results: Out of the 1,648 articles screened, only seven papers from five clinical trials met our inclusion criteria, comprising a total of 2,362 patients. Progression-free survival was significantly improved with abemaciclib in combination with endocrine therapy compared to endocrine therapy alone (hazard ratio: 0.58; 95% CI: 0.51–0.65; p < 0.001). Moreover, abemaciclib improved overall survival (hazard ratio: 0.78; 95% CI: 0.66–0.91; p = 0.002). Additionally, the overall response rate was higher with abemaciclib plus endocrine therapy compared to endocrine therapy alone (odds ratio: 2.75; 95% CI: 1.98–3.80; p < 0.001). However, grade three or higher adverse events were significantly more common in the abemaciclib group (risk ratio: 2.62; 95% CI: 2.30–2.99; p < 0.001). Conclusions: Abemaciclib combined with endocrine therapy is an effective treatment option for patients with HR-positive, HER2- negative advanced breast cancer. This combination significantly improves progression-free survival, overall survival, and response rate, making it a valuable therapeutic option in breast cancer. However, higher adverse events were observed in the abemaciclib group.

e16052 Background: Patients with esophageal squamous cell carcinoma (ESCC) who fail definitive treatment are candidates for second-line therapy. They often present with more aggressive disease and suboptimal responses to definitive treatments. In this individual patient-level meta-analysis, we aim to evaluate the efficacy of PD-1/PD-L1 inhibitors as second-line treatment in advanced ESCC. Methods: A systematic search of PubMed, Scopus, and Cochrane databases (December 5, 2024) identified randomized controlled trials (RCTs) comparing PD-1/PD-L1 inhibitors to chemotherapy as second-line treatment for advanced ESCC. Kaplan-Meier (KM) curves were reconstructed, and individual patient data (IPD) were extracted using R scripts. A patient-level meta-analysis was performed using the reconstructed IPDs and the Cox proportional hazards regression model. The Schoenfeld residuals test and Restricted Mean Survival Time (RMST) were also applied. The following R packages were used: MASS, Splines, survival, survRM2, survminer, and dbplyr . Results: Out of 3,930 records, five RCTs met the criteria: four phase 3 trials and one phase 2 trial (ORIENT-2), all were open-label, comparing PD-1 inhibitors to chemotherapy. Overall survival (OS) improved significantly with PD-1/PD-L1 inhibitors compared to chemotherapy (HR: 0.718, 95% CI: 0.650–0.793, p < 0.001). For patients with CPS ≥ 10, OS further improved (HR: 0.626, 95% CI: 0.446–0.878, p = 0.007), ), indicating an additional beneft in those with high PD-1 expression. The proportional hazards assumption was met for both OS and CPS ≥ 10 (Schoenfeld residuals test: p > 0.05). Progression-free survival (PFS) showed no significant difference (HR: 0.913, CI: 0.828–1.007, p = 0.069). However, the proportional hazards assumption was violated (Schoenfeld residuals test p < 0.001); therefore, these results should be interpreted with caution. PFS was further evaluated using RMST at 6, 12, 18, and 24 months. At 6 months, no significant difference was observed (RMST difference: -0.047, p = 0.593). However, PD-1 inhibitors showed significant differences at 12 months (0.37 months, p = 0.022), 18 months (0.74 months, p = 0.001), and 24 months (0.97 months, p < 0.001). Despite these significant differences, the magnitude of the difference is relatively small and may not be clinically meaningful. Conclusions: PD-1/PD-L1 inhibitors as second-line therapy improve overall survival in patients with advanced esophageal squamous cell carcinoma, compared to chemotherapy. However, the improvements in progression-free survival (PFS) were modest, and the clinical significance of these PFS benefits may be limited.

e15581 Background: Sentinel lymph node (SLN) assessment is critical in colorectal cancer (CRC) for accurate staging and determining optimal treatment strategies. The one-step nucleic acid amplification (OSNA) assay, which measures cytokeratin 19 (CK19) mRNA expression, has shown potential as a molecular diagnostic tool for the intraoperative detection of SLN metastases. This study aims to evaluate the diagnostic accuracy of OSNA for SLN metastasis in CRC. Methods: A systematic search was conducted in PubMed, Cochrane Library, and Web of Science for studies published up to December 2024. Studies reporting diagnostic accuracy metrics for OSNA in detecting SLN metastases in CRC were included. R software (version 4.0.3) with the mada package was used to compute pooled sensitivity, specificity, false-positive rates, diagnostic odds ratios (DOR), and likelihood ratios (LR), all expressed within 95% confidence intervals (CI). Results: Six studies involving 3,016 patients, of whom 363 had SLNs, were included. The pooled sensitivity of OSNA was 91% (95% CI: 84.8–94.8%), while the specificity was 95.6% (95% CI: 91.7–97.8%). The diagnostic odds ratio (DOR) was 220.59 (95% CI: 74.02–657.43). The false-positive rate was 4.4% (95% CI: 2.2–8.3%). The positive likelihood ratio (LR+) was 20.8 (95% CI: 10.5–41.2), and the negative likelihood ratio (LR−) was 0.09 (95% CI: 0.05–0.16). These findings demonstrate that in diagnostic accuracy, OSNA outperforms traditional histopathological methods, such as hematoxylin and eosin (H&E) staining. Conclusions: OSNA demonstrates superior diagnostic accuracy for detecting SLN metastases in colorectal cancer, supporting its integration into clinical workflows. Its high diagnostic accuracy and rapid intraoperative turnaround time make it an invaluable resource for improving surgical decision-making. However, variability in CK19 expression across tissues and the lack of standardized assay thresholds remain challenges that require further investigation. However, its adoption has the potential to enhance staging accuracy and improve surgical and oncological outcomes, warranting broader implementation in CRC management.

Abstract Introduction Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder with a pathogenic mutation identified in approximately 50% of cases. The MYH7 and MYBPC3 genes account for over half of these cases, while dozens of other genes can be pathogenic(1). Genetic test results are not independently used to determine which people with HCM benefit from implanted cardiac defibrillators (ICDs)(2, 3). Little is known about the additive role of genetic testing results to existing indications for ICD insertion. Purpose This study aims to examine the interaction between genetic testing results and existing ICD indications and imaging results on defibrillator discharge rates in HCM. Methods Patients who underwent an ICD for HCM, who underwent a cardiac magnetic resonance (CMR) study and who underwent genetic testing were included across 3 sites. The outcome was the incidence rate of appropriate ICD discharges, calculated using cox regression controlling for current age and primary vs secondary prevention. Interaction analysis between genetic risk factors and existing ICD indications, and with CMR quantification of LGE and septal thickness, was performed, and stratum specific estimates calculated using linear computation. Results 177 patients were included in the study, of whom 70 (39.55%) had a pathogenic mutation, 5 (2.82%) had a variant likely pathogenic (VLP), 44 (24.86%) had a variant of undetermined significance (VUS) and 58 (39.55%) had no identifiable mutation. The event rate was 3.32 {2.28 to 4.84) per 100 person years. There was no association between genetic variables and ICD discharge rate. There was an 80% reduction in ICD discharge rate in people who underwent ICD insertion exclusively for family history of sudden cardiac death or for syncope who had no pathogenic or likely pathogenic mutation, however this change was not statistically significant (table 2). Conclusion There is no strong association between genetic characteristics and ICD discharge rates among people with hypertrophic cardiomyopathy with an existing ICD indication. There is a nonsignificant trend towards fewer ICD discharges among people who underwent ICD insertion for family history alone or for a history of syncope and did not have a pathologic variant.Table 1 Table 2

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 Background Delirium, an acute brain dysfunction, is proposed to be highly prevalent in clinical care and shown to significantly increase the risk of mortality and dementia. Objectives To report on the global prevalence of clinically documented delirium and delirium-related clinical practices in wards caring for paediatric and adult patients in healthcare facilities. Design A prospective, cross-sectional, 39-question survey completed on World Delirium Awareness Day, 15 March 2023. Participants Clinicians or researchers with access to clinical data. Main Outcome and Measure The primary outcome was the prevalence of clinically documented delirium at 8:00 a.m. (4 h) and 8:00 p.m. (±4 h). Secondary outcomes included delirium-related care practices and barriers to use. Descriptive statistics were calculated and multilevel modelling was completed. Results 1664 wards submitted surveys from 44 countries, reporting on delirium assessments at 8:00 a.m. (n = 36 048) and 8:00 p.m. (n = 32 867); 61% reported use of validated delirium assessment tools. At 8:00 a.m., 18% (n = 2788/15 458) and at 8:00 p.m., 17.7% (n = 2454/13 860) were delirium positive. Top prevention measures were pain management (86.7%), mobilisation (81.4%) and adequate fluids (80.4%). Frequently reported pharmacologic interventions were benzodiazepines (52.7%) and haloperidol (46.2%). Top barriers included the shortage of staff (54.3%), lack of time to educate staff (48.6%) and missing knowledge about delirium (38%). Conclusion and Relevance In this study, approximately one out of five patients were reported as delirious. The reported high use of benzodiazepines needs further evaluation as it is not aligned with best-practice recommendations. Findings provide a benchmark for future quality improvement projects and research.

Abstract Background Delirium is a common complication of older people in hospitals, rehabilitation and long-term facilities. Objective To assess the worldwide use of validated delirium assessment tools and the presence of delirium management protocols. Design Secondary analysis of a worldwide one-day point prevalence study on World Delirium Awareness Day, 15 March 2023. Setting Cross-sectional online survey including hospitals, rehabilitation and long-term facilities. Methods Participating clinicians reported data on delirium, the presence of protocols, delirium assessments, delirium-awareness interventions, non-pharmacological and pharmacological interventions, and ward/unit-specific barriers. Results Data from 44 countries, 1664 wards/units and 36 048 patients were analysed. Validated delirium assessments were used in 66.7% (n = 1110) of wards/units, 18.6% (n = 310) used personal judgement or no assessment, and 10% (n = 166) used other assessment methods. A delirium management protocol was reported in 66.8% (n = 1094) of wards/units. The presence of protocols for delirium management varied across continents, ranging from 21.6% (on 21/97 wards/units) in Africa to 90.4% (235/260) in Australia, similar to the use of validated delirium assessments with 29.6% (29/98) in Africa to 93.5% (116/124) in North America. Wards/units with a delirium management protocol [n = 1094/1664, 66.8%] were more likely to use a validated delirium test than those without a protocol [odds ratio 6.97 (95% confidence interval 5.289–9.185)]. The presence of a delirium protocol increased the chances for valid delirium assessment and, likely, evidence-based interventions. Conclusion Wards/units that reported the presence of delirium management protocols had a higher probability of using validated delirium assessments tools to assess for delirium.