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Abstract Background Cardiac dysfunction is a common complication in septic population. Though traditionally considered an acute and reversible phenomenon, the true prevalence of reversible cardiac dysfunction and its long-term prognostic implications remain unclear. Purpose Using serial echocardiographic assessments, this study aimed to investigate the prevalence and reversibility of cardiac dysfunction in septic patients, and to determine whether the recovery of cardiac function is associated with improved 5-year mortality. Methods We retrospectively screened 16,041 septic patients who underwent transthoracic echocardiography during their ICU stay. After excluding patients with a history of heart failure, pre-existing cardiac dysfunction, or lacking follow-up echocardiographic assessments post-ICU discharge, 3,112 patients were enrolled for analysis. To assess the reversibility of cardiac dysfunction, paired-sample t-tests were used to evaluate changes in echocardiographic parameters between in-ICU and post-ICU measurements. Furthermore, 5-year mortality were compared among controls and patients with or without recovery of echocardiographic abnormalities. Results Totally 1,604 patients (51.5%) were found to have newly recognized cardiac dysfunction during ICU stay. The mean interval between ICU admission and follow-up echocardiography was 425 days. Most in-ICU echocardiographic abnormalities demonstrated partial recovery over time, with the exception of left atrial volume index (LAVi) and right ventricular fractional area change (RV FAC) (Figure 1). Recovery of left ventricular ejection fraction (LVEF), average E/e', and tricuspid regurgitation (TR) velocity was significantly associated with reduced 5-year mortality (Figure 2). Older age [adjusted hazard ratio (aHR) 0.99, p=0.034], male gender (aHR 0.54, p=0.003), and elevated troponins (aHR 0.87, p=0.006) were negative predictors for LVEF recovery; while older age (aHR 0.099, p=0.043), higher APACHE III scores (aHR 0.99, p=0.018), atrial fibrillation (aHR 0.59, p=0.046), and chronic pulmonary disease (aHR 0.68, p=0.042) were negative predictors for TR velocity recovery. Conclusions Both the presence and recovery of newly recognized echocardiographic abnormalities during ICU stay were significantly associated with long-term mortality. Certain abnormalities, such as increased LAVi, persisted despite resolution of sepsis.Figure 1 Figure 2

Objectives: Cerebral hemodynamic impairment in patients with asymptomatic high-grade internal carotid artery (ICA) stenosis confers a risk of stroke and cognitive decline, but correlations between degree of stenosis and hemodynamic impairment are derived from small case series only. Using baseline data from 282 participants in the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis – Hemodynamics (CREST-H) study, we hypothesized that degree of stenosis, measured by peak systolic velocity (PSV) and end diastolic velocity (EDV) in the ipsilateral ICA, would correlate with time-to-peak (TTP) delay using MR (n=275) or CT (n=7) perfusion scans, adjusting for demographic and cardiovascular risk variables. Methods: Using a 7-10MHz Doppler probe, ICA PSV and EDV were assessed. Doppler results were adjudicated centrally. Dynamic contrast perfusion imaging was standardized across 61 CREST-H sites, using sequential T2*-weighted time-sequence scanning (e.g. TR=1500, TE=25ms, flip angle=60deg, phase=128, slice thickness=5mm for GE 3T magnet). CTP was acquired with standard clinical protocols. TTP delay was calculated in the ipsilateral versus contralateral MCA/ACA territories using OLEA software. Linear regression used TTP delay as the outcome variable and PSV and EDV as predictor variables, adjusting for covariates.The 282 with complete data for all variables were included in the analysis. Results: Among 392 CREST-H participants, 63% were men, 7% Black, 3% Hispanic, 33% with less than college education. Tables 1a/b show the regression results for PSV and EDV as main predictor variables. PSV and EDV on the index side significantly correlated with TTP delay (p=0.004, p=0.002 respectively). Neither PSV nor EDV on the non-index side correlated with TTP delay (p=0.49, p=0.82). Compared with moderate exercise, vigorous exercise correlated with lower TTP delay in both models (p=0.05. p=0.04). Compared with college graduates, those with HS education had longer TTP delays in both models (p=0.03. p=0.02). Conclusions: In this large cohort of patients with high-grade asymptomatic carotid stenosis, higher flow velocities correlated with greater TTP delays, suggesting an increasing hemodynamic impairment with greater degree of stenosis above 70%. Our findings have implications for management of asymptomatic carotid stenosis which are being tested in the CREST-H and CREST-2 studies. Exercise and education may independently impact cerebral hemodynamics.

BACKGROUND: Cerebral hemodynamic impairment in patients with asymptomatic high-grade (>70%) internal carotid artery (ICA) stenosis is associated with risk of stroke and cognitive decline, but correlations between the degree of stenosis and hemodynamic impairment are derived from small case series. Using baseline data from 242 participants in the CREST-H study (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis–Hemodynamics), we hypothesized that the degree of stenosis in the ICA would correlate with time-to-peak (TTP) delay in ipsilateral cerebral blood flow using MR/CT perfusion scans, adjusting for demographic and cardiovascular risk variables. METHODS: From all participants, ICAs were insonated using a 7 to 10 MHz probe for peak systolic velocity (PSV) and end diastolic velocity. Dynamic contrast perfusion imaging was standardized across 61 CREST-H sites, using standard sequential T2*-weighted perfusion imaging. CT perfusion used standard clinical protocols. TTP delay was calculated in the ipsilateral versus contralateral hemispheres. In cross-sectional analysis, linear regression was used to model TTP delay as the outcome variable and PSV, end diastolic velocity, and PSV ICA/common carotid artery ratio on the index and nonindex side as primary predictor variables in 6 separate models, adjusting for covariates, followed by automated backward elimination model reduction. RESULTS: Among 392 CREST-H participants, the 242 with complete data for all variables were included in the regression analysis (age, 70±7.6; 62% M). End diastolic velocity on the index side correlated with TTP delay (β=0.003, P =0.005). PSV had a similar correlation but did not reach significance (β=0.001, P =0.099), nor did ICA/common carotid artery ratio (β=0.003, P =0.126). Nonindex side PSV, end diastolic velocity, and ICA/common carotid artery ratio showed no correlation with TTP delay ( P =0.268, P =0.495, P =0.380, respectively). Circle of Willis completeness did not correlate with TTP. CONCLUSIONS: In this large cohort of patients with high-grade asymptomatic carotid stenosis, higher end-diastolic flow velocities correlated with greater TTP delays, supporting a definition of hemodynamically significant stenosis. Our findings have implications for the management of asymptomatic carotid stenosis, which will be tested in the CREST-H study. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03121209.

Background: Sinonasal undifferentiated carcinoma (SNUC) is an extremely rare, high-grade, and aggressive tumor of the sinonasal tract. Due to the rarity of this malignancy, current treatment guidelines are based on small and often/mainly single-center retrospective datasets. In the absence of a universally accepted standard of care for SNUC, treatment approaches vary across countries and institutions, reflecting real-world clinical practice. The primary aim of this study was to describe real-world treatment and outcomes for patients with confirmed SNUC. Methods: This was an international, multi-center, retrospective, observational cohort study that pooled patients into the largest SNUC dataset to date. Fifteen centers were enrolled to contribute data, including seven from Europe, four from the United States, three from the United Kingdom, and one from Canada. In the absence of a universally accepted standard of care for SNUC, treatment approaches varied across countries and institutions, reflecting real-world clinical practice. Patients included were those with histologically confirmed SNUC who were treated between 1997 and 2021. Results: This study yielded 485 patients treated for SNUC. The median age at diagnosis was 55.6 years (IQR: 44.5–67.6), and 63.7% were male. Most cases presented at advanced stages, with 70.8% as T4a or T4b. Overall survival (OS) outcomes were available for 412 patients, with a median follow-up of 26.0 months. The 5- and 10-year OS were 47.2% (95% CI: 40.8–53.3%) and 39.6% (95% CI: 32.5–46.6%), respectively. Advanced age, dichotomized T-stage (T4a/b vs. T1–3), M-stage, and orbital involvement were significant poor prognostic factors on univariable analysis (p’s < 0.01). On multivariable analysis, orbital involvement (HR: 2.73, 95% CI: 1.42–5.27, p = 0.003) and distance metastasis stage (HR: 3.00, 95% CI: 1.25–7.21, p = 0.014) were both independently associated with worse OS. Conclusions: This observational study presents the largest multi-center cohort analysis of SNUC to date, providing new insights into prognostic factors for a rare cancer treated at global centers of excellence. Orbital involvement and the presence of metastases are candidate independent risk factors associated with poorer OS.

Abstract Motivation: Epilepsy is a diverse group of neurological disorders affecting over 50 million people worldwide. While common epilepsy types are well studied, rare epilepsies—often severe and genetically complex—pose significant challenges in diagnosis, research, and treatment. Accurate and interoperable etiology and disease classifications are critical for improving data sharing, supporting clinical decision-making, and advancing rare disease research. Results: To enhance the accuracy of epilepsy-related disease concept representation within the Mondo Disease Ontology (Mondo), we conducted a series of expert-driven workshops in collaboration with the team from the Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP). Specialists in epileptology, genetics, neurodevelopment, biomedical ontology, and patient community advocates systematically reviewed and revised the epilepsy hierarchy in Mondo, aligning it with the International League Against Epilepsy (ILAE) classification system. These updates include reclassification of epilepsy subtypes, including syndromes, age-related epilepsies, and developmental epileptic encephalopathies, resulting in a more granular, standardized, and clinically relevant structure. Mondo now offers an enhanced framework for integrating epilepsy data across resources, enabling improved interoperability and facilitating rare disease research and data curation, with continued efforts underway to further refine and expand this integration.

Abstract Aim To assess the long‐term efficacy of vagus nerve stimulation (VNS) in Dravet syndrome and identify key factors influencing treatment response. Method We conducted a two‐center, retrospective cohort study of 15 patients (six females, nine males; median age at seizure onset 4 months [range 2–12 months]) with Dravet syndrome who underwent VNS implantation. Seizure frequency was evaluated over 12 months and up to 10 years after implantation. Linear mixed‐effects regression was used to analyze the impact of antiseizure medications (ASMs) and VNS parameters on seizure outcomes. Results A 50% or greater reduction in seizure frequency was observed in 93.3% (14 of 15) of patients at 12 months and 86.7% (13 of 15) of patients across the 10‐year follow‐up. This seizure reduction was independent of ASM use; the VNS duty cycle was a significant predictor of seizure reduction. Two individuals (13.3%) experienced minor adverse events. Interpretation VNS provides durable seizure reduction in Dravet syndrome, independent of ASM adjustments. These findings highlight the importance of early VNS initiation and parameter optimization in managing genetically defined epilepsy syndromes.

Purpose of review Increasing evidence suggests that epigenetic regulation plays a central role in chronic rhinosinusitis pathogenesis, heterogeneity, and treatment response. This review summarizes current knowledge of epigenetics in CRS pathogenesis, their role in endotype differentiation, and potential as diagnostic and therapeutic targets. Recent findings Distinct epigenetic signatures have been identified across CRS subtypes. Hypermethylation of TSLP and differential regulation of FZD5, IL8, and EMT-related genes distinguish eosinophilic CRSwNP from other phenotypes. Specific microRNAs (miR-941, miR-21, miR-125b, miR-155) correlate with disease severity, tissue eosinophilia, and corticosteroid responsiveness, highlighting their utility as noninvasive biomarkers. Experimental data suggest that targeting DNMTs or HDACs may reverse pathogenic remodeling. Emerging therapeutic approaches – such as biologics modulating epigenetically controlled cytokines (e.g. tezepelumab) and engineered extracellular vesicle-based miRNA delivery – illustrate translational promise. Summary Epigenetic mechanisms critically influence CRS pathogenesis and clinical variability. Their modulation offers novel opportunities for biomarker discovery, disease stratification, and personalized therapy. Future research should focus on standardizing epigenetic profiling methodologies, validating candidate biomarkers in diverse populations, and integrating multiomics and single-cell approaches to uncover cell-specific regulatory networks. These advances may enable precision medicine in CRS, bridging the gap between molecular mechanisms and targeted clinical management.

Abstract Abstract Introduction: Leukemia, a heterogeneous group of hematologic malignancies, has established associations with modifiable risk factors such as tobacco use. Despite the widespread implementation of tobacco control measures over the past three decades, disparities persist in tobacco-attributable leukemia mortality across sex and socio- demographic strata. This study aimed to quantify and compare long-term global and regional trends in mortality due to tobacco-associated leukemia between 1990 and 2021, with a focus on sex-based and income-level disparities. Methods: We obtained age-standardized mortality rates (ASMRs) for leukemia attributable to tobacco use from the Global Burden of Disease (GBD) 2021 dataset for 204 countries and territories. ASMRs were analyzed for the years 1990 and 2021 and stratified by sex (male, female, both) and socio-demographic index (SDI) regions (high, high-middle, middle, low- middle, low). Temporal trends were assessed using Average Annual Percent Change (AAPC) with corresponding 95% confidence intervals (CI). Additionally, univariate linear regressions by location were conducted to quantify associations between time and mortality. Results: Globally, tobacco-related leukemia mortality decreased substantially between 1990 and 2021. The overall ASMR declined from 0.64 to 0.40 per 100,000 population (AAPC: –1.51%; 95% CI: –1.59 to –1.43). Sex-disaggregated data revealed a more favorable reduction in females (from 0.23 to 0.12; AAPC: –2.25%; 95% CI: –2.41 to –2.09) compared to males (from 1.20 to 0.77; AAPC: –1.45%; 95% CI: –1.51 to –1.39), suggesting persistent gender disparities in tobacco exposure and/or access to care. These trends were statistically significant (p &lt; 0.001), and global univariate regression confirmed a significant negative slope (–0.0088; p = 0.021). Marked regional differences emerged by SDI status. High-SDI countries experienced the steepest declines in mortality. In these regions, ASMRs dropped from 1.16 to 0.69 among both sexes combined (AAPC: –1.70%; 95% CI: –1.80 to –1.61), with females improving from 0.56 to 0.31 (AAPC: –1.90%; 95% CI: –2.03 to –1.76) and males from 2.07 to 1.17 (AAPC: –1.88%; 95% CI: –1.96 to –1.80). The associated regression slope (–0.0183) was statistically significant (p = 0.0014), with an R² of 0.10, indicating a strong temporal association. High-middle SDI regions showed moderate progress: ASMRs declined from 0.62 to 0.45 among both sexes (AAPC: –0.99%; 95% CI: –1.10 to –0.88). Reductions were steeper in females (0.12 to 0.07; AAPC: –1.32%; 95% CI: –1.55 to –1.09) than in males (1.40 to 0.96; AAPC –1.19%; 95% CI: –1.29 to –1.09). However, regression slopes were not statistically significant (p = 0.18), suggesting heterogeneous trends within this group. Low-SDI regions, in stark contrast, exhibited minimal improvements. Between 1990 and 2021, ASMRs decreased marginally from 0.098 to 0.074 (AAPC: –1.01%; 95% CI: –1.10 to –0.91), with male mortality decreasing from 0.17 to 0.12 (AAPC: –1.22%; 95% CI: –1.32 to –1.13) and female rates from 0.037 to 0.027 (AAPC: –0.88%; 95% CI: –1.04 to –0.72). However, the regression slope (–0.00084) was not statistically significant (p = 0.17), and the effect size (R² = 0.02) suggested only a weak temporal association. Middle and low-middle SDI countries also demonstrated underwhelming progress. In low- middle SDI settings, the combined-sex ASMR dropped from 0.21 to 0.16 per 100,000, with a weak negative slope (–0.0012; p = 0.43), and an AAPC of –0.83% (95% CI: –0.95 to –0.71). These results highlight stagnation and growing inequities in health burden mitigation. Conclusion: From 1990 to 2021, global mortality due to tobacco-attributable leukemia significantly declined, with the greatest improvements seen in high-SDI countries and among females. However, regions with lower income levels lagged, showing minimal or no significant decline in mortality despite decades of global tobacco control efforts. The pronounced disparities by sex and socioeconomic status underscore the need for context- specific, equity-focused tobacco cessation initiatives and leukemia screening programs, especially in underserved populations. Without urgent intervention, the global burden of leukemia attributable to tobacco may continue to disproportionately affect those with the fewest resources and weakest health infrastructure.

Abstract Background: Atypical Hemolytic Uremic Syndrome (aHUS) remains a diagnostic challenge as it shares overlapping features of Thrombotic Thrombocytopenic Purpura (TTP) and Shiga-toxin mediated HUS (STM-HUS). It is caused by complement activation in the alternative pathway and is mostly related to genetic defects in complement-related factors or acquired autoantibodies. Early recognition and treatment have excellent outcomes. Case Presentation: A 74-year-old female with Hypertension presented with a 3-week history of non-bloody diarrhea and was found to have acute kidney injury (AKI) with creatinine 5.27 mg/dL (baseline 0.5), anemia (7.5 g/dL), and thrombocytopenia (123×10⁹/L) and normal liver function. CT imaging of the abdomen revealed uncomplicated sigmoid diverticulitis and mesenteric lymphadenopathy. She was treated with intravenous fluids and started on antibiotics with ceftriaxone and metronidazole for diverticulitis. Despite fluid resuscitation, renal function deteriorated, necessitating initiation of intermittent hemodialysis. Due to anemia, thrombocytopenia and AKI further workup with peripheral smear pursued showed schistocytes, helmet cells, and keratocytes. Hemolysis labs showed LDH 1433 U/L, undetectable haptoglobin, and a negative direct Coombs test. Methylmalonic acid level was normal. Homecystine level was elevated. These findings were consistent with microangiopathic hemolytic anemia. Coagulation profile was normal. Given concern for TTP, ADAMTS13 was obtained but returned at 68%, ruling out TTP. Shiga toxin PCR was negative, ruling out STM-HUS. Complement level checked showed low C3 and C4, suggesting complement activation and consumption. Total complement, Factor 8, factor B, monoclonal protein were within normal. A renal biopsy was initially postponed due to uncontrolled hypertension. Eculizumab was started. Renal biopsy later done confirmed aHUS. Following initiation of eculizumab, the patient's renal function progressively improved, and she was able to discontinue hemodialysis. Laboratory markers of hemolysis stabilized, with normalization of LDH, haptoglobin, homocystine and complement. She completed the induction phase of eculizumab and entered a long-term monitoring phase, with labs every 2 weeks for 6 months, then monthly for 36 months. No relapses were noted to date and is off dialysis. Conclusion: Differentiating aHUS from TTP and STM-HUS is critical, as management strategies differ significantly. Prompt initiation of eculizumab can reverse renal injury and prevent further organ damage.