Citations

Abstract Background: Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by ineffective hematopoiesis, cytopenias, and an increased susceptibility to infections. Sepsis remains a common and serious cause of morbidity and mortality in this population. While racial disparities in sepsis-related outcomes have been described in the general population, their presence and magnitude among patients with MDS remain poorly understood. Methods: We performed a retrospective cohort study using the National Inpatient Sample (NIS) from 2016 to 2022 to identify adult hospitalizations with co-diagnoses of MDS and sepsis. Patients were stratified by race into White (reference), Black, Hispanic, Asian, Native American, and Other categories. Multivariable logistic regression models, adjusted for demographics, comorbidities, and hospital characteristics, were used to evaluate associations between race and seven key sepsis-related complications: septic shock, acute renal failure, respiratory failure, encephalopathy, disseminated intravascular coagulation (DIC), Clostridioides difficile infection (CDI), and fungal sepsis. Results: Among 78,549 hospitalizations for MDS with sepsis, significant racial disparities were observed. Asian patients had higher odds of developing septic shock (OR 1.26, 95% CI 1.05–1.50, p = 0.014), and both Black (OR 1.24, 95% CI 1.17–1.31, p < 0.001) and Asian (OR 1.14, 95% CI 1.04–1.24, p = 0.004) patients had increased odds of acute renal failure. Respiratory failure was less likely among Black (OR 0.84, 95% CI 0.79–0.90, p < 0.001) and Hispanic (OR 0.76, 95% CI 0.70–0.82, p < 0.001) patients. Encephalopathy was significantly more common in Black (OR 1.29, 95% CI 1.18–1.41, p < 0.001) and Other (OR 1.20, 95% CI 1.01–1.42, p = 0.042) patients. DIC was more frequent in Asian (OR 2.11, 95% CI 1.37–3.27, p = 0.001) and Hispanic (OR 1.53, 95% CI 1.09–2.14, p = 0.014) patients, with a borderline association in Black patients (OR 1.35, p = 0.082). No statistically significant racial differences were noted for CDI or fungal sepsis, although Asian patients trended toward lower odds of CDI (OR 0.64, p = 0.067), and Native American patients had high but non-significant odds for fungal sepsis (OR 3.03, p = 0.287). Conclusion: Our study highlights significant racial disparities in sepsis-related complications among hospitalized MDS patients. Black and Asian patients were more likely to experience acute renal failure and encephalopathy, while Asian and Hispanic patients had higher odds of developing DIC. Conversely, Black and Hispanic patients had lower risk of respiratory failure. These findings underscore the need for race-conscious approaches in sepsis management for patients with MDS and suggest that tailored interventions may be necessary to ensure equitable outcomes across racial groups. Keywords: Myelodysplastic syndromes, sepsis, racial disparities, acute kidney injury, encephalopathy, DIC, respiratory failure, fungal sepsis, National Inpatient Sample

Abstract Background Pirtobrutinib is a highly selective, non-covalent Bruton tyrosine kinase inhibitor (BTKi) approved for patients (pts) with relapsed/refractory (R/R) chronic lymphocytic lymphoma (CLL) who have previously received a covalent BTKi (cBTKi) and a BCL-2 inhibitor such as venetoclax. Pirtobrutinib monotherapy has demonstrated a median duration of response of 12.2 months in the BRUIN trial. Pirtobrutinib is increasingly being used as a second-line therapy after failure of a cBTK inhibitor without prior BCL-2 inhibitor exposure. We aim to characterize short-term survival outcomes and adverse events of pirtobrutinib in venetoclax-naïve versus venetoclax-exposed pts with R/R CLL. Methods We conducted a retrospective cohort study using TriNetX Global Collaborative Network, comprising data from 152 healthcare organizations. Adults (≥18 years) with R/R CLL who received pirtobrutinib after venetoclax were classified into the “V+P” cohort. Pts who received pirtobrutinib without prior venetoclax exposure were included in the “P” cohort. 1:1 propensity score matching (PSM) was performed, and the cohorts were balanced for gender and age. The primary outcome was all-cause mortality (ACM). Secondary outcomes assessed were anemia, neutropenia, sepsis, neutropenic fever, tumor lysis syndrome (TLS), and major adverse cardiovascular and cerebrovascular events (MACCE). Kaplan-Meier analysis and risk analysis were used to assess outcomes at 6 months and 1 year. Results We identified 200 pts in V+P and 172 pts in P, with 149 matched pts in each group after PSM. The mean age of pts in V+P and P was 72.4 +/- 8.6 years and 72.7 +/- 10.5 years, respectively. 6-month ACM was 15.5% in V+P, and 12.7% in P. However, the odds ratio of ACM at 6 months, in pts in V+P when compared to P was 1.259 (95% CI 0.654 to 2.425, p = 0.490) and was not statistically significant. At 6 months, the odds ratios of the secondary outcomes in the V+P pts were higher when compared to P pts, but were not statistically significant; anemia 1.614 (95% CI 0.617 to 4.225, p = 0.327), neutropenia 1.445 (95% CI 0.599 to 3.486, p = 0.411), sepsis 1.196 (95% CI 0.477 to 2.998, p = 0.703), neutropenic fever 1.353 (95% CI 0.573 to 3.195, p = 0.490), TLS 1.180 (95% CI 0.474 to 2.939, p = 0.722), and MACCE 1.046 (95% CI 0.541 to 2.024, p = 0.893). 1 year ACM was 18.75% in V+P vs. 10.55% in P (OR 1.96; 95% CI 1.03-3.71; p=0.038) and was statistically significant. However, the secondary outcomes were clinically significant but statistically insignificant in V+P pts when compared to P pts- anemia 1.614 (95% CI 0.617 to 4.225, p = 0.327), neutropenia 1.269 (95% CI 0.568 to 2.834, p = 0.561), sepsis 1.077 (95% CI 0.438 to 2.650, p = 0.872), neutropenic fever 1.24 (95% CI 0.589 to 2.607, p = 0.571), TLS 1.180 (95% CI 0.474 to 2.939, p = 0.722), and MACCE 1.338 (95% CI 0.724 to 2.472, p = 0.352). Conclusion Pirtobrutinib use in venetoclax-exposed pts was associated with a statistically significant higher odds of all-cause mortality at 1 year, which was not present at 6 months. Although adverse event rates of anemia, neutropenia, TLS, sepsis, and neutropenic fever were numerically higher in the venetoclax-exposed cohort, these differences did not reach statistical significance. These findings suggest early survival benefit of pirtobrutinib in venetoclax-naïve patients and aligns with existing evidence supporting its role as a second-line therapy following covalent BTK inhibitor failure, including results from the BRUIN trial. Prospective studies are needed to validate these preliminary observations.

Abstract Background: Patients with myelodysplastic syndromes (MDS) are highly susceptible to infections, with sepsis being a major cause of hospitalization and death. While gender differences in sepsis outcomes have been described in broader populations, their impact among patients with MDS remains poorly defined. Methods: We performed a retrospective cohort study using the National Inpatient Sample (NIS) from 2016 to 2022 to identify adult hospitalizations with co-diagnoses of MDS and sepsis. Patients were stratified by sex: male (n = 47,170) and female (n = 31,365). Multivariable logistic regression was used to evaluate the association between female sex and key outcomes: respiratory failure, encephalopathy, disseminated intravascular coagulation (DIC), Clostridioides difficile infection (CDI), fungal sepsis, and in-hospital mortality. Models were adjusted for demographics, comorbidities, and hospital characteristics. Results: Female sex was independently associated with increased odds of respiratory failure (OR 1.05, 95% CI 1.01–1.08, p = 0.011) and encephalopathy (OR 1.07, 95% CI 1.02–1.12, p = 0.010). There was a nonsignificant trend toward higher odds of CDI (OR 1.14, p = 0.086). No significant sex-based differences were observed for DIC (OR 0.84, p = 0.103), fungal sepsis (OR 0.89, p = 0.598), or in-hospital mortality (OR 0.98, p = 0.653). Conclusion: In this large national analysis of MDS patients hospitalized with sepsis, female patients were more likely to experience respiratory failure and encephalopathy, but sex was not significantly associated with mortality, DIC, or fungal infections. These findings suggest that while certain complications may differ by sex, overall in-hospital survival remains comparable between male and female patients with MDS and sepsis.Keywords: Myelodysplastic syndromes, sepsis, gender disparities, mortality, respiratory failure, encephalopathy, NIS

Abstract Description Fungal species, such as Candida albicans, are commonly found as part of the normal microbiota in both the skin and intestine. However, these fungal species, including C. albicans, can also become opportunistic pathogens and have been associated with intestinal and allergic disorders. We hypothesized C. albicans colonization could occur in early life when the neonatal microbiota is permissive to pathogens and lacks colonization resistance compared to later times in life. To investigate this question, we sequenced stool of premature and term infants and frequently found C. albicans colonization, suggesting fungal colonization within the human GI tract. To investigate the impact of long-term C. albicans colonization to the immune system, we established colonization by oral administration of C. albicans to neonatal mice. Colonization of C. albicans was associated with increased diversity of bacterial species in the intestinal microbiota at weaning. Additionally, we observed significant increases of inflammatory cytokines IL-17 and G-CSF in the serum. Future research will expand on the impact of C. albicans colonization on the intestinal microbiota and immune systems. Funding Sources Center for Individualized Medicine Microbiome Program Research Team Science Award, Mayo Clinic NIH, NIDDK R01 DK134366 Topic Categories Mucosal and Regional Immunology (MUC)

Abstract Background and Aims Upadacitinib (UPA)—an oral, reversible selective Janus kinase inhibitor—has a favorable benefit–risk profile for patients with Crohn’s disease (CD) and ulcerative colitis (UC). We evaluated the benefit–risk of UPA in select subgroups with CD or UC. Methods Patients were randomized to UPA 45 mg (UPA45) once daily (QD) or placebo (PBO) induction for 12 (CD: U-EXCEED, U-EXCEL) or 8 weeks (UC: U-ACHIEVE, U-ACCOMPLISH). Clinical responders were re-randomized to QD UPA 15 mg (UPA15), UPA 30 mg (UPA30), or PBO for 52-week maintenance (CD: U-ENDURE; UC: U-ACHIEVE). This exploratory post hoc analysis assessed efficacy and safety outcomes (adverse events of special interest [AESIs]: serious infections, major adverse cardiovascular [CV] events, malignancies, and venous thromboembolic events) by CV risk, prior treatment failure, and age. Results This analysis included 1021 patients with CD and 1097 with UC during induction, and 673 with CD and 746 with UC during maintenance. Improved efficacy outcomes comparable to the overall study populations were observed with UPA versus PBO across subgroups. Patients receiving UPA30 generally showed numerically higher rates of improvements versus UPA15. AESI rates were generally comparable between UPA and PBO across subgroups except for numerically higher rates of herpes zoster and serious infections in CD with UPA. Conclusions UPA resulted in consistent benefit versus placebo across CV risk, prior treatment failure, and age subgroups. No treatment differences were seen in AESIs across subgroups except herpes zoster and serious infections, reinforcing the favorable benefit–risk profile for UPA in CD and UC seen in the overall study populations. Clinical trial numbers NCT02819635, NCT03653026, NCT03345836, NCT03345849, NCT03345823

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, with a dismal 5-year survival rate of ~6.5%. Vasogenic cerebral edema is a severe complication that occurs in the majority of GBM patients, leading to a significant increase in intracranial pressure, neurological deficits, and increased mortality rates. GBM-associated edema is almost exclusively managed by the corticosteroid dexamethasone, the use of which is associated with immunosuppression and interference with radiation therapy. While there is considerable research on edema formation, little is known about how edema resolution occurs in GBM, particularly in response to dexamethasone or other anti-edema therapies. This gap in understanding highlights the need for new approaches to treat edema effectively. The water channel aquaporin-4 (AQP4), a key player in the brain’s water homeostasis, is upregulated in GBM compared to the normal brain. To investigate the role of AQP4 in GBM-associated edema, we used the RCAS/tv-a system to generate de novo GBM with different driver mutations in Aqp4 knockout (KO) and wild-type (WT) mice. Our results indicated that Aqp4 KO tumor-bearing mice had shortened survival and increased edema content. Additionally, Aqp4 loss decreased astrocyte coverage specifically in the tumor core but not the tumor periphery. Our single cell RNA-seq data suggested that Aqp4 loss led to an astrocytic shift towards a less reactive, progenitor-like state, while also decreasing the myeloid and CD8+ T cell population in the tumor microenvironment. Interestingly, tumor-bearing mice treated with anti-VEGFA antibody, which has anti-edema properties, showed increased expression of Aqp4 and reduced vessel leakage. This suggests that AQP4 plays a critical role in mediating the effects of anti-VEGFA therapy. Overall, this study highlights the important role of AQP4 in the resolution of edema, while also revealing its additional effects on astrocyte activation and the immune microenvironment in GBM.

Introduction: Seasonal, geographic, and socioeconomic factors all influence cardiovascular (CV) mortality. Long-term seasonal trends across United States regions remain insufficiently characterized. Research Question: We evaluated longitudinal trends in CV mortality across seasons in the U.S., stratified by geographic region and degree of urbanisation, from 1999 through 2020. Methods: Data on CV mortality (ICD-10: I00-I99) were extracted from the CDC WONDER database and stratified by season (Winter, Spring, Summer, Fall), U.S. Census region (Northeast, Midwest, South, West), and degree of urbanisation (6-level National Center for Health Statistics classification). Age-adjusted mortality rates (AAMRs) were calculated, and Joinpoint regression was used to estimate annual percent change (APC) and average annual percent change (AAPC) with 95% confidence intervals. Results: From 1999 to 2020, 18.8 million CV deaths were recorded (Table 1). Winter accounted for the highest mortality burden across all regions and urban settings but also showed the greatest improvement of the the 20-year study period, with AAPC reductions most pronounced in the Northeast (–2.83%) and Large Central Metro areas (–2.79%; p < 0.000001 for all trends; Figure 1). Summer and Fall, while associated with fewer deaths, showed slower progress, particularly in the Midwest (Fall AAPC: –1.81%; Summer: –1.77%) and rural areas (NonMetro Fall AAPC: –1.56%). Notably, Midwest Fall mortality demonstrated a statistically significant reversal, with an APC increase of +3.87% from 2018 to 2020 (p = 0.02)(Figure 1). Conclusion: CV mortality in the U.S. follows a distinct and evolving seasonal pattern. Although winter remains the deadliest season, it has seen the most substantial mortality reductions, likely tied to improved awareness, continuity of care, and cold-weather adaptations. However, slower progress during summer and fall, particularly in the Midwest and rural areas, reveals growing seasonal and geographic disparities. Most notably, the recent and statistically significant rise in Midwest fall mortality signals an urgent concern. This reversal may reflect emerging climate stressors such as prolonged heat, air pollution, and environmental volatility during transitional months compounded by reduced healthcare access or changing behavioral risk factors. These findings call for year-round, seasonally tailored public health strategies especially for underserved and climate-vulnerable populations.

Background: Acute heart failure affects ~9% of patients with hematological malignancies. This study aimed to evaluate the impact of acute heart failure on in-hospital mortality among patients with hematological malignancies and to identify independent predictors of mortality in this population. Methods: The National Inpatient Sample (2016–2021) was queried for adults (⩾18 years of age) with hematological malignancies and those who experienced in-hospital mortality. Among these, we identified patients who were hospitalized with a diagnosis of acute heart failure. Univariate analysis and multivariate regression were employed to analyze the mortality risk. A p ⩽ 0.05 was considered significant. Results: Among 40,246 patients with hematological malignancies who died in the hospital, the univariate analysis showed a higher in-hospital mortality in the acute heart failure cohort compared to the non-acute heart failure group (8.08% versus 4.52%, p < 0.001). However, after adjusting for sociodemographic factors and comorbidities, acute heart failure was associated with a lower risk of in-hospital mortality (OR 0.87, 95% CI 0.84–0.9, p < 0.001). Predictors of mortality in the acute heart failure cohort were age >60 years, hematopoietic stem cell transplant, severe sepsis, arrhythmias, infective endocarditis, bleeding from any source, acute respiratory failure, hepatic dysfunction, metabolic encephalopathy, and invasive ventilation (all p < 0.01). On subgroup analysis, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, and multiple myeloma had a higher in-hospital mortality in the acute heart failure cohort compared to the non-acute heart failure group ( p < 0.001). Conclusion: Acute heart failure in patients with hematological malignancies was associated with poor outcomes in the presence of severe sepsis, organ dysfunction, and the need for mechanical ventilation. Close monitoring and a multidisciplinary team approach are recommended to optimize the treatment plan for this population.