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Abstract Background: Sickle cell crisis (SCC) remains a leading cause of emergency hospitalization and acute morbidity in patients with sickle cell disease (SCD). With improved survival in SCD, long-term complications such as cardiovascular disease are emerging as critical determinants of morbidity and mortality. While right-sided heart failure has been adequately explored in SCD, the specific contribution of the other cardiovascular conditions to in-hospital mortality during sickle cell crisis remains unclear. This study evaluates the independent impact of cardiovascular comorbidities on in-hospital mortality among adults hospitalized for SCC using a large, nationally representative database. Methods: This is a retrospective analysis involving adult hospitalizations (≥ 18 years old) for SCC in the United States (U.S) using 2016-2020 National Inpatient Sample (NIS). The study was exempt from institutional review board approval as the NIS database contains deidentified patient information. ICD-10 codes used for SCC were: D570, D5721, D5741, D5743, D5745, D5781. Regarding cardiovascular co-morbidities, the study considered age, race (African American, Hispanic and Caucasian), dyslipidemia, hypertension, diabetes mellitus (both type 1 and type 2), systolic and diastolic heart failure, rheumatic valvular heart disease, atrial fibrillation/flutter, pulmonary hypertension, chronic coronary artery disease and ischemic stroke. Univariable Cox regression was performed to identify independent predictors associated with in-hospital mortality among patients admitted for SCC. All factors from the univariable analysis with p<0.20 were included in a multivariable Cox regression model. All the outcomes were adjusted for age, sex, and Charlson Comorbidity Index. P-value of ≤0.05 was used to determine statistical significance. Results: The current study analyzed 424,540 SCD patients admitted for SCC (mean age 32.4 years, 55.4% females), from 2016 to 2020. Each additional year of age beyond 18 was associated with a linearly increasing in-hospital mortality among study patients hospitalized for SCC. This observation was confirmed in both univariate (HR: 1.06, 95% CI: 1.05–1.07, p<0.001) and multivariate (HR: 1.05, 95% CI: 1.04–1.06, p<0.001) analyses. On univariable analysis of cardiovascular co-morbidities in patients admitted for SCC, a higher in-hospital mortality was conferred by: hypertension (HR: 2.40; 1.95 – 2.94, p <0.01) dyslipidemia (HR: 2.38; 1.54 – 3.65, p <0.01), diabetes mellitus (HR: 2.15; 1.51 – 3.04, p <0.01, systolic (HR: 5.20; 3.70 – 7.31, p <0.01) and diastolic heart failure (HR: 2.11; 1.44 – 3.08, p <0.01), atrial fibrillation/flutter (HR: 5.43; 4.04 – 7.32, p <0.01), pulmonary hypertension (HR: 2.34; 1.75 – 3.13, p <0.01) and ischemic stroke (HR: 5.75; 3.30 – 10.03, <0.01); a lower in-hospital mortality was associated with the African American race (HR: 0.43; 0.20 – 0.91, p = 0.027). In multivariable analysis of cardiovascular comorbidities that demonstrated nominal significance (p < 0.20) in univariable analysis, only the following remained significantly associated with in-hospital mortality: systolic heart failure (HR: 2.65; 1.77 – 3.98, p <0.01), atrial fibrillation/flutter (HR: 2.01; 1.41 – 2.8), p <0.01) and ischemic stroke (HR: 3.25; 1.85 – 5.71, p <0.01). Although not statistically significant in univariable analysis (p = 0.065), chronic coronary artery disease (CAD) emerged as a significant predictor of reduced in-hospital mortality in the multivariable analysis (HR: 0.52; 0.29–0.91, p = 0.021). Conclusions: Among adults hospitalized for sickle cell crises, select cardiovascular comorbidities, including systolic heart failure, atrial fibrillation/flutter, and ischemic stroke, were independently associated with significantly increased in-hospital mortality. Interestingly, CAD was linked to reduced mortality in adjusted models. This may be attributed to closer medical surveillance and management in patients with established CAD, along with the potential protective mechanism(s) in SCD that limit atherosclerotic progression — warranting further investigation

Abstract Background Neurolymphomatosis (NL) is a rare and frequently underrecognized manifestation of lymphoma, characterized by infiltration of peripheral or cranial nerves by malignant lymphocytes. Limited data exist to guide optimal management. We present the largest single-enterprise (included the 3 Mayo Clinic sites) cohort to date, evaluating disease characteristics, treatment patterns, and outcomes in patients (pts) with NL. Methods We conducted a retrospective analysis of pts ≥18 years (yrs) diagnosed with clinical, radiographic, or biopsy-confirmed NL at Mayo Clinic between January 2002 and December 2024. Baseline characteristics were compared using independent t-tests for continuous variables and Fisher's exact or Pearson's chi-square tests for categorical variables. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Objective response rate (ORR) was a secondary endpoint. Kaplan–Meier methods, log-rank tests, and Cox proportional hazards regression were used to assess survival outcomes and associated factors. Results We included 149 pts. Median age at diagnosis was 64 yrs (range 22–83), and 23% were female. Most presented with stage IV disease (89%), and NL was part of the initial lymphoma presentation in 42% (primary NL). Diagnostic confirmation was based on histopathology and imaging in 55%, imaging alone in 26%, histopathology alone in 16%, and clinical features in 4%. Diffuse large B-cell lymphoma was the most common histology (61%), followed by marginal zone lymphoma (7%), and T-cell lymphoma (7%). Clinical presentation included painful neuropathy (65%), concurrent CNS involvement (37%), systemic disease (43%), elevated LDH (46.9%), and ECOG ≥2 (38%). Pattern of involvement included cranial nerves (29%), peripheral nerves (28%), and spinal nerve roots (27%). Median follow-up was 92 months (95% CI, 63–119). Among 137 treatment-evaluable pts, first-line regimens included methotrexate-based (MTX) (62%), bendamustine-based (B) (11%), cytarabine-based (Ara-C) (4%), and rituximab-based (R) (excluding MTX, B, or Ara-C) (15%) therapies. Radiation was used in 18%, and 21% underwent autologous stem cell transplant (ASCT). Among 103 response-evaluable pts, the ORR was 67% (52% complete response [CR], 16% partial response [PR]). ORRs by regimen were 78% (MTX), 92% (B), and 86% (R). On univariate analysis, primary NL (OR 4.3) and frontline ASCT (OR 8.47) were associated with higher odds of response (p<0.05), while ECOG ≥2 (OR 0.24) and localized disease (OR 0.33) were associated with lower odds. On multivariable analysis (MVA), primary NL (OR 5.0 [1.5–12.1], p=0.02) and ECOG >1 (OR 0.2 [0.06–0.79], p=0.018) remained significant predictors of response. Median PFS was 13 months (95% CI, 9–36), with a 2-yr PFS of 43% (95% CI, 35–53). On MVA, concurrent CNS involvement (HR 2.4, p=0.05), systemic disease (HR 2.7, p=0.02), and ECOG >1 (HR 2.4, p=0.02) were associated with inferior PFS, while primary NL was associated with improved PFS (HR 0.3, p=0.002). Patients undergoing frontline ASCT had a median PFS of 108 months (95% CI, 58–not reached) with a 7-yr PFS of 62% (95% CI, 46–84). Among those receiving second line and beyond (2+) therapy, 24 received MTX-based regimens, 10 received CAR-T, and 8 received tyrosine kinase inhibitors. Post-ASCT median PFS was 30 months (95% CI, 15–NR). Among CAR-T recipients, evaluable responses (n=8) included 4 CR, 1 PR, and 3 PD. Median OS was 56 months (95% CI, 29–133), with a 5-yr OS of 50% (95% CI, 41–60). On MVA, ECOG ≥2 (HR 2.5, p=0.02) predicted worse OS, while receipt of ASCT (HR 0.4, p=0.04) and primary NL (HR 0.5, p=0.04) were associated with improved OS. Conclusion This study represents the largest single-enterprise cohort of pts with NL, providing comprehensive insight into its clinical presentation, treatment patterns, and outcomes. Primary NL and preserved PS were independently associated with improved response rates and survival, while CNS and systemic involvement at diagnosis portended poorer PFS. MTX and bendamustine-based regimens achieved high ORR, and frontline ASCT was associated with significantly prolonged remission duration and OS. These findings highlight the prognostic importance of baseline disease burden and functional status, support the early incorporation of high-intensity regimens in eligible patients, and underscore the urgent need for prospective studies to guide evidence-based management in this rare and understudied population.

Abstract Background: Chemotherapy-induced cardiomyopathy (CIC) is a serious, and often irreversible complication in patients treated for hematologic malignancies. While therapies for hematologic malignancies continue to evolve, data on trends in in-hospital mortality among patients with concurrent hematologic malignancies and CIC are limited, and disparities by race and sex remain poorly characterized. This study examines national trends and demographic disparities in in-hospital mortality among patients with hematologic malignancies who developed CIC. Methods: The United States (U.S) National Inpatient Sample (NIS) from 2016 to 2020 was queried for patients diagnosed with malignant hematologic and lymphoid neoplasms who also developed CIC. Hematologic malignancies were identified using ICD-10 codes C81–C96, which include: C81 for Hodgkin lymphoma; C82–C86 for non-Hodgkin lymphomas; C88 for malignant immunoproliferative diseases (e.g., Waldenström macroglobulinemia, heavy chain disease); C90–C95 for leukemias of lymphoid, myeloid, monocytic, mixed, and unspecified cell types; and C96 for other or unspecified malignant neoplasms of lymphoid, hematopoietic, and related tissue. CIC was identified using ICD-10 code I42.7. The study was exempt from institutional review board approval as the NIS database contains deidentified patient information. Multivariable regression analysis was performed to determine the odds of in-hospital mortality among patients with hematologic malignancies who developed CIC. Multivariable logistic regression followed by marginal effects was used to plot yearly trends in in-hospital mortality. All the outcomes were adjusted for gender, race, Charlson comorbidity index and hospital characteristics. P < 0.05 was used to determine statistical significance. The analysis was performed on STATA 16 software. Results: The study identified a total of 3,021,434 hospitalizations with hematologic malignancies, of which 11,115 (0.004%) had secondary diagnosis of CIC (mean age = 56.5 years, 52.5% males). Among 11,115 patients with hematologic malignancies who developed CIC, 740 (6.6%) patients died during the hospitalization. Multivariable logistic regression followed by marginal effects estimated a decrease in adjusted in-hospital mortality trend from 6.5% in 2016 to 4.3% in 2020. However, this decreasing mortality trend was not statistically significant after adjusting for gender, race, Charlson comorbidity index, and hospital characteristics (OR: 0.93; 95% CI: 0.83 – 1.05; trend p = 0.260). In-hospital mortality did not differ significantly between male vs. female patients with hematologic malignancies who developed CIC (OR: 1.02; 95% CI: 0.72 – 1.43; p = 0.921). There was no difference in overall in-hospital mortality of patients of White (reference) vs. Black (OR: 1.12; 95% CI: 0.72 – 1.76, p = 0.61) or Hispanic (OR: 0.63; 95% CI: 0.32 – 1.25, p = 0.18) race. However, males of the Black race demonstrated a lower in-hospital mortality vs. males of the White race (OR: 0.26; 95% CI: 0.09 – 0.77, p = 0.01). In addition, females of the Black race showed a higher in-hospital mortality vs. females of the White race (OR: 2.43; 95% CI: 1.40 – 4.25, p <0.01). Conclusions: In patients with hematologic malignancies who developed CIC, overall in-hospital mortality did not differ significantly by race alone. However, on sex-based stratification, Black males had lower in-hospital mortality compared to White males, while Black females had higher mortality than White females. These differences highlight potential race–sex disparities in outcomes that warrant further investigation.

Abstract Background Red blood cell distribution width (RDW) is an easily accessible diagnostic test that is underutilized as a prognostic marker, despite substantial supporting evidence in cancer, cardiovascular diseases, and helathy individuals (Pilling et al. PLoS One 2028;13:e0203504). The association between increased RDW and incident acute myeloid leukemia (AML) has long been suggested in healthy volunteers (Abelson et al. Nature 2019;559:400). We looked into a similar phenomenon in patients with polycythemia vera (PV) or essential thrombocythemia (ET) in large discovery and validation cohorts. Methods A machine learning (ML) approach was used to identify baseline clinical and laboratory parameters that were predictive of leukemic transformation (LT) and develop a predictive model in a large discovery cohort of PV and ET, obtained from electronic medical records of the Maccabi Healthcare Services (MHS; Tel-Aviv, Israel). Receiver operating characteristic (ROC) curve analysis was utilized to determine the optimal cutoff points for RDW and other continuous variables. Mayo Clinic databases (Rochester, MN, USA) for patients with PV and ET were utilized as validation cohorts. Identification of study patients in the latter was according to the International Consensus Classification (Arber et al. Blood 2022; 140:1200) while in the discovery cohort was based on presence of ICD-9 codes associated with documentation of disease-specific driver mutations or treatment records that are consistent. Statistical analyses were performed using the R statistical software 4.4.2 (November, 2024) (Foundation for Statistical Computing, Vienna, Austria) or JMP Pro 18.0.0 software (SAS Institute, Cary, NC, USA). Results The discovery cohorts from Israel included 4,592 patients with PV (median age 63 yesrs; 53% males) and 5,968 with ET (median age 61 yesrs; males 40%). The validation cohorts from the Mayo Clinic included 633 PV (median 65 years; 51% males) and 634 ET (median 60 years; females 64%) patients that were informative for RDW. In the discovery cohorts, median follow-up (incident AML) was 6.1 years (N=186; 4.1%) in PV and 6.1 years (N=85; 1.4%) in ET. The corresponding values for the validation cohorts were 6.6 years (N=24; 3.8%) in PV and 7.0 years (N=22; 3.5%) in ET. Discovery cohort analyses Covariate-adjusted Cox regression analysis was utilized to estimate associations between LT and several clinical variables followed by machine learning pipeline to predict LT in a given timeframe. Conversion from continuous to binary variables was accompliched by ROC analysis. Shapley Additive exPlanations (SHAP) application enabled selection of top-ranked features that included RDW >15.5 (HR 3.2, 1.1-9.5; p=0.03), age >60 years (HR 2.9, 1.4-5.9; p<0.01), and LDH >1.5 x UNL (HR 4.0 (1.6-10.0; p<0.01). A similar analysis in ET also identified RDW >15.5 (p<0.01), age >60 years (p=0.01) as well as male sex (p=0.03) as independent risk factors for LT. Subseqent risk models based on these risk factors were externally validated and enabled robust risk stratification with 10-20 year AUCs rangening from 0.75 to 0.81. Validation cohorts analyses The indpendent predictive value of increased RDW observed in the discovery cohort was confirmed in the validation cohorts for both PV and ET and further gender-specified: female/male RDW ≥16.4/15.8 in PV (HR 7.9, 1.9-33.8) and ≥16.1/14.4 in ET (HR 5.1, 2.2-11.9). Also confirmed were the additional prognostic contributions of age ≥60 years (HR 3.8, 1.3-10.9) and LDH >1.5 x UNL (HR 3.9, 1.6-9.4), in PV, while no other clinical risk factor showed RDW-independent prognostic relevance in ET. The prognostic impact of RDW in ET was most apparent in females (p<0.01), as opposed to males (p=0.32) while the effect was equally significant in PV. In multivariable analysis that included previously recognized high risk mutations in PV (SRSF2) and ET (SF3B1), both RDW and mutations sustained significance (p<0.05). Conclusion The current study identifies higher RDW as a key risk factor for LT in both PV and ET, independent of other clinical or genetic risk factors. Possible underlying mechanisms include increased RDW as a marker of long-term pre-leukemic clones with sub-clinical ineffective erythropoiesis or an associated pro-leukemic inflammatory state.

Background: Despite obesity being a major cardiovascular risk factor, studies in heart failure populations have reported an inverse association between body mass index and mortality—a phenomenon termed the "obesity paradox." However, the consistency and shape of this relationship across different HF phenotypes and clinical subgroups remain unclear. This meta-analysis aimed to quantify the dose-response relationship between BMI and mortality in HF patients and assess potential variations across subgroups. Hypothesis: Higher BMI is associated with reduced mortality in patients with heart failure, and that this relationship varies across clinical subgroups and U-shaped relationship. Methods: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A search strategy was developed, and studies were extracted from Cochrane and PubMed databases through December 2023. The main outcomes were all-cause mortality, cardiovascular deaths, and heart failure hospitalizations. Data were summarized as hazard ratios with 95% confidence intervals, and a spline model was used to assess non-linear relationships, with 21.7 kg/m2 as the reference point in the dose-response curve. PROSPERO: CRD42023455124 Results: Thirty-three studies (457,124 person-years) showed that each 5 kg/m2 increase in BMI was significantly associated with a 6% reduction in all-cause mortality (HR 0.94; 95% CI 0.92–0.96). Significant reductions were observed in acute decompensated heart failure (7%), HFpEF (9%), HFrEF (8%), diabetes (9%), males (9%), and females (8%). Cardiovascular mortality declined by 5% per 5 kg/m2 increase. Non-linear analysis revealed a significant U-shaped relationship, with lowest all-cause mortality between BMI 21.7 and 39 kg/m2. Subgroup analysis showed significant non-linear all-cause mortality reductions in acute decompensated heart failure (23.5–26 kg/m2), HFpEF (21.7–31 kg/m2), HFrEF (21.7–43 kg/m2), females (24–25.5 kg/m2), diabetes (21.7–36 kg/m2), and non-diabetics (21.7–33 kg/m2). Conclusion: Higher BMI is significantly associated with lower all-cause and cardiovascular mortality in patients with heart failure, supporting the presence of an obesity paradox. This protective effect was consistent across clinical subgroups, including HFpEF, HFrEF, males, females, and individuals with diabetes. The BMI paradox was evident in patients with acute decompensated heart failure, HFpEF, HFrEF, females, and both with and without diabetes.

ABSTRACT Background Patients with hypertrophic obstructive cardiomyopathy (HOCM) were excluded from all major trials for transcatheter aortic valve replacement (TAVR). “Suicide left ventricle” occurring after TAVR is postulated to occur as a result of chronic pressure overload from fixed obstruction that is acutely relieved after the valve deployment resulting in worsening left ventricular outflow tract obstruction. Aims The aim of this study was to determine the clinical and readmission outcomes in HOCM patients undergoing TAVR. Methods Data was extracted from the National Inpatient and National Readmission 2016−2020 Databases. We performed multivariable Logistic regression analysis to determine the odds of in‐hospital mortality and other relevant clinical outcomes in patients undergoing TAVR with and without comorbid HOCM. Multivariable Cox regression analysis was used to assess 30‐day hospital readmission in HOCM patients undergoing TAVR. Results We identified 296,670 patients who underwent TAVR, of whom 534 (0.2%) had comorbid HOCM. The patients undergoing TAVR with comorbid HOCM had more than threefold higher risk of in‐hospital mortality (adjusted odds ratio: 3.47, 95% CI 1.37–8.81, p = 0.009) when compared to patients without HOCM. Additionally, patients undergoing TAVR with comorbid HOCM had a higher risk of atrioventricular blocks, cardiogenic shock, acute kidney injury, and the need for intubation. There was no difference in readmission outcomes post‐TAVR among patients with and without HOCM. Conclusion Our analysis of a large, real‐world cohort of patients undergoing TAVR showed that patients with HOCM have a significantly higher risk of in‐hospital mortality and procedural complications when compared to patients without HOCM.

ABSTRACTBackgroundTricuspid regurgitation (TR) is a common occurrence in patients with heart failure (HF), and its role in disease progression has gained attention in recent years. Although TR can worsen clinical outcomes in HF patients, the impact of gender, racial, and socioeconomic factors remains largely unexplored. With growing evidence supporting the role of percutaneous interventions for the treatment of significant TR, understanding these disparities is more crucial than ever.MethodsData were extracted from the National Inpatient and National Readmission 2016–2020 Databases. We used ICD‐10 code I50 to identify the patients primarily admitted for HF and subdivided the cohort into two groups based on the presence or absence of TR. We performed multivariable logistic regression analysis to determine odds of the in‐hospital mortality and multivariable Cox regression analysis to assess the 30‐ and 90‐day hospital readmission in HF patients with and without TR. All the analyses were adjusted for age, gender, insurance status, Charlson comorbidity index, and hospital characteristics. STATA 16 software was used for analysis.ResultsThere was no difference in the in‐hospital mortality among HF patients with and without TR (OR: 1.04, 95% CI 0.94–1.16, p = 0.442) except in certain subgroups of HF patients. HF patients with TR were 6% more likely to have HF‐specific readmission in 30 days (HR: 1.06, 95% CI 1.00–1.13, p = 0.044) and 9% more likely to have HF‐specific readmission in 90 days (HR: 1.09, 95% CI 1.03–1.15, p = 0.002). Subgroup analysis revealed significant gender, racial, and socioeconomic disparities in the in‐hospital mortality and the readmission outcomes of HF patients with TR compared to those without TR.ConclusionIn our population‐based survey analysis, we observed significant gender, racial, and socioeconomic disparities in the clinical outcomes of HF patients with TR compared to those without TR.