Trinity Health

Left ventricular (LV) dysfunction is a potential cardioembolic source of ischemic stroke, but its role in recurrent stroke risk and treatment response remains unclear. We explore whether LV injury associates with the risk of recurrent stroke and modifies the association between anticoagulation and stroke recurrence using real-world data. We performed a multicenter, retrospective study of Cardiac Abnormalities in Stroke Prevention and Recurrence cohort across 27 US sites. Patients with LV ejection fraction ≥20% were included. LV injury, defined as LV ejection fraction 20% to 40% and wall motion abnormality, was the primary exposure and treatment effect modifier. The treatment of interest was anticoagulant versus antiplatelet therapy. The composite outcome included recurrent stroke, major bleeding, or death. Outcomes were evaluated using unadjusted and inverse probability weighting adjusted Cox proportional hazards models, with treatment effect modification tested by LV injury status. Among 2685 patients enrolled, 2328 with complete data were analyzed (median age, 65 years; 49.8% female; median follow-up, 1.6 years). LV injury was present in 310 patients (13.3%). Overall, 535 events occurred: 258 recurrent ischemic strokes, 28 hemorrhagic strokes, 67 major hemorrhages, and 256 deaths. LV injury was associated with a higher unadjusted risk of the primary outcome (hazard ratio [HR], 1.51 [95% CI, 1.21-1.87]), though nonsignificant after inverse probability weighting adjustment (adjusted HR, 1.29 [95% CI, 0.97-1.70]). In the LV injury subgroup, anticoagulation versus antiplatelet therapy was associated with a lower risk of the primary outcome (adjusted HR, 0.24 [95% CI, 0.10-0.59]), relative to the non-LV injury subgroup (adjusted HR, 1.28 [95% CI, 0.83-1.95]; p[LV-interaction], 0.001). Similar interactions were seen for EF 20% to 40% (versus >40%; adjusted HR, 0.19 [95% CI, 0.04-0.86]; p[LV-interaction], 0.001) and wall motion abnormality (versus no wall motion abnormality; adjusted HR, 0.33 [95% CI, 0.15-0.73]). After cryptogenic stroke, anticoagulation in those with LV injury was associated with lower rates of recurrent stroke, major bleeding, and death. These findings warrant confirmation in a dedicated randomized controlled trial. URL: https://www.clinicaltrials.gov; Unique identifier: NCT06398366.

The neutrophil-to-lymphocyte ratio (NLR) is a novel inflammatory marker predicting cardiovascular mortality (CVM) and all-cause mortality (ACM). To investigate the association between the NLR and CVM and ACM in patients with peritoneal dialysis (PD). We reviewed articles from PubMed, Google Scholar, and Scopus until May 2024 for the association of ACM and CVM in patients with NLR following PD. We used a fixed effects model and I 2 statistics to pool hazard ratio (HR) and measure heterogeneity. Leave-one-out sensitivity analysis assessed the robustness of our study. Multivariate meta-regression (MMR) was utilized to identify influencing confounding factors. Joanna Briggs Institute (JBI) tool was used for quality assessment. Out of 160 articles screened, seven studies from 2011 to 2024 with 4350 patients, a mean age of 49.9 years ± 15 years, and a median follow-up of 4 years were included. We found that higher NLR (> 3) was significantly associated with ACM [adjusted HR (aHR): 1.18, 95%CI: 1.03-1.36, P = 0.016]. However, there was no significant association of NLR (> 3) with CVM (aHR: 1.16, 95%CI: 0.68-1.98, P = 0.59) in patients following PD. Sensitivity analysis showed no variations. JBI tool revealed low bias among the studies. MMR revealed a significant relationship between age and ACM (coefficient: 0.14, P = 0.04). Our meta-analysis identifies a significant association between NLR (> 3) and ACM outcome, which can help prevent deaths in the elderly and optimize resource use. Caution is needed when predicting mortality in this group as age significantly confounds ACM in patients undergoing PD.

Invasive Aspergillosis (IA) is a rare but life-threatening fungal infection in immunocompromised hosts, including solid organ transplant (SOT) recipients. While extensively studied in other SOT populations, data on IA in pancreas transplant (PT) recipients are limited. Earlier studies reported mortality rates nearing 100%, whereas more recent data show that 12-week mortality still exceeds 20% despite improvements in antifungal therapy. Current prophylaxis strategies for PT recipients mainly focus on Candida species, and there are no clear, standardized recommendations for Aspergillus prevention. Given the paucity of focused data, the epidemiology, clinical characteristics, and outcomes of IA in PT recipients are not well defined. This study aimed to assess the incidence, clinical characteristics, and outcomes of IA among hospitalized PT patients using a nationally representative dataset. We conducted a descriptive analysis using the National Inpatient Sample (NIS) from 2016 to 2020. PT admissions were identified using International Classification of Diseases, Tenth Revision (ICD 10) codes for transplant status and procedures. IA was defined using validated ICD 10 codes. Baseline demographics, hospital characteristics, comorbidities, and outcomes, including sepsis, acute kidney injury (AKI), acute respiratory failure (ARF), invasive mechanical ventilation (IMV), all-cause in-hospital mortality, length of stay, and total hospitalization costs and charges were compared between PT admissions with and without IA. National estimates were calculated using discharge weights, and comparisons were performed using the chi-square test and adjusted Wald test. Multivariable analysis was performed to identify predictors of all-cause in-hospital mortality among PT admissions complicated by IA. Two-sided p values < 0.05 were considered statistically significant. Between 2016 and 2020, 65,980 PT-related hospitalizations were identified, of which 250 (0.4%) had IA. PT admissions complicated by IA were more commonly aged 41 to 60 years (59% vs. 46%, p = 0.012) and were less likely to have a Charlson Comorbidity Index greater than 3 (54% vs. 68.6%, p < 0.001) compared with PT hospitalizations without IA. The PT with the IA cohort had higher rates of sepsis (100% vs. 46.1%, p < 0.001), AKI (60% vs. 36.7%, p < 0.001), ARF (28% vs. 9.4%, p < 0.001), and IMV use (18% vs. 4%, p < 0.001) compared with the PT without the IA cohort. Among PT hospitalizations with IA, IMV use was independently associated with higher all-cause in-hospital mortality (adjusted odds ratio 48.777, p = 0.009). Overall, in-hospital mortality was significantly higher in PT hospitalizations with IA compared with those without IA (12% vs. 2%, p < 0.001). Mean length of stay was longer (24.86 vs. 6.13 days, p < 0.001), and total charges ($378,494 vs. $94,938, p < 0.001), and total costs ($93,019 vs. $24,463, p = 0.023) were significantly higher compared with PT hospitalizations without IA. Although rare, IA in PT recipients is associated with higher rates of sepsis, AKI, ARF, venous thromboembolism, prolonged hospitalization, increased mortality, and greater healthcare utilization. Despite the inherent limitations of administrative datasets, this nationally representative analysis highlights the substantial clinical and economic burden of IA in this high-risk population. These findings emphasize the need for targeted surveillance, early diagnosis, and evidence-based antifungal strategies in this vulnerable population.

Abstract The Incidence of renal cell carcinoma (RCC) continues to increase in the United States, ranking among the ten most frequently diagnosed cancers in men and women. Unfortunately, resistance to existing treatments remain a major obstacle, driving the need for identification of clinically relevant biomarkers and therapeutic targets. TNF-related apoptosis inducing ligand (TRAIL) is a promising cancer therapy that selectively induces apoptosis in malignant cells while sparing normal cells. TRAIL exerts its cytotoxic effects through binding death receptors DR4 and DR5, initiating caspase dependent programmed cell death. However, intrinsic and acquired resistance mechanisms have limited TRAIL’s efficacy as anti-cancer strategy. We have identified a link between the overexpression of oncogenic PIM kinases and regulation of DR5 expression and sensitivity to TRAIL apoptosis in RCC. PIM1 is emerging as a clinically relevant biomarker and therapeutic target in RCC. Nuvisertib (TP-3654) is a selective PIM1 kinase inhibitor currently being evaluated in Phase 1/2 clinical trials for patients with myelofibrosis and has received FDA fast track designation. We find that treatment of RCC cells with low dose (2.5 µM) of Nuvisertinib over 24 hours induces a 5.75-fold (p&amp;lt;0.01) increased mean membrane expression of DR5 compared to vehicle control assessed by flow cytometry. We also investigated synergism between Nuvisertib and Dordaviprone, a newly FDA approved imipridone and TRAIL inducer. We evaluated combinations of Nuvisertib and Dordaviprone via Cell Titer Glo in RCC cells and find that combination indices indicate synergism which significantly reduce RCC cell viability more potently than either agent alone. Our findings highlight actionable novel candidate targets and strategies for therapeutic intervention in RCC. Ongoing studies are aimed to uncover mechanistic insights of these treatments in RCC and guide the development of optimal treatment strategies. Citation Format: Kimberly S. Meza, Sheldon L. Holder, Wafik S. El-Deiry. Nuvisertib (TP-3654) and Dordaviprone (ONC201) synergize to reduce renal cell carcinoma cell viability [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr A038.

Older adults with acute myeloid leukemia (AML) have inferior outcomes, yet current genetic risk models do not explicitly account for how age modifies the prognostic impact of molecular features. We hypothesized that integrating apoptosis and p53-related gene expression with recurrent mutations would improve prediction of complete remission (CR) and 2-year overall survival (OS), particularly across age groups. Using the BeatAML2 dataset (805 patients; 942 specimens), we built two cohorts: a clinical cohort of 916 adults with full data and an expression-linked cohort of 852 with matched RNA-seq. Patients were divided into four age groups 18-30, 30-45, 45-60, and 60+ years. We tested whether adding expression of 12 apoptosis and p53-related genes to five well-known mutations, that is TP53, NPM1, FLT3, RUNX1, and ASXL1, could improve the prediction of CR and 2-year OS. Adding gene expression improved predictive performance across models. For 2-year OS, AUCs rose from 0.765 to 0.772 in XGBoost, 0.703 to 0.843 in Random Forest, and 0.697 to 0.721 in Logistic Regression. For CR, performance improved from 0.770 to 0.851 in XGBoost, 0.811 to 0.861 in Random Forest, and 0.731 to 0.696 in Logistic Regression. Calibration was strongest for tree-based models, and reclassification improved most with XGBoost. Multivariable regression confirmed TP53 as the most adverse marker for OS (HR: 3.07), with added risk from ASXL1 (HR: 1.53) and FLT3 (HR: 1.39). NPM1 increased the chance of remission (OR: 2.47) but did not extend survival. SHAP analysis showed that age remained the leading predictor of OS. Among genes, CHEK2 expression was most important for survival, especially in patients 60 years and older, while CCNG1 expression best predicted remission, along with BAX and MCL1. These results demonstrate that combining gene expression with recurrent mutations makes risk prediction more accurate, especially in older patients who formed the largest group and had the poorest outcomes. Although treatment variables were not included and analysis focused on selected genes, these findings support incorporation of expression-based features into genetic risk models and warrant prospective validation. The authors have confirmed clinical trial registration is not needed for this submission.

Background: Patients diagnosed with Acute Respiratory Distress Syndrome (ARDS) who require Intensive Care Unit (ICU) admission often require invasive vascular access including central venous catheters and arterial lines. Early reports of excessive thrombosis combined with the severity of illness in COVID-19 could lead to more line-related thrombosis and infections, requiring more line replacements. This retrospective cohort study explores differences in vascular access usage and line-related complications between patients with COVID-19 ARDS and non-COVID-19 ARDS. Methods: A cohort of patients with COVID-19 ARDS (n = 81) was compared to a cohort of patients with non-COVID-19 ARDS (n = 46). We compared baseline characteristics, total number and placement rate of lines (arterial lines, central venous catheters, and dialysis catheters), and incidence of line-related complications (bleeding, thrombosis, or infection). Statistical analysis was performed utilizing Excel software, with associations assessed using Chi-squared, Fisher’s exact, and t-tests. A p-value &lt; 0.05 was considered statistically significant. Results: The COVID-19 cohort had significantly greater total number of lines per patient (4.00 vs. 2.76, p &lt; 0.001). This was due to more arterial (2.17 vs. 1.41, p = 0.003) and dialysis lines (0.43 vs. 0.13, p = 0.002) per patient. There was no significant difference in the number of central venous catheters. When adjusted for length of stay in the ICU, the rate of line placement was not significantly different between groups. The COVID-19 cohort had a significantly greater number of line-related complications defined as thrombosis, bleeding, and infections (18 vs. 2, p = 0.008). Conclusions: The significantly greater total number of lines in the COVID-19 group was likely attributable to COVID-19 patients’ longer lengths of stay in the ICU. Patients with COVID-19 appear to have significantly more line-related complications, which may be due to the greater total number of lines, the longer lengths of stay, and inherent demographic and comorbid differences. Future studies are needed to assess methods for prevention of line-related complications in patients with COVID-19 ARDS.