Citations

Abstract Background The mechanisms of left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy (HCM) with moderate septal hypertrophy (≤ 18 mm) remain uncertain with therapeutic implications. This study investigated the role of three-dimensional echocardiography (3DE)-derived myocardial mechanics in LVOTO. Methods We retrospectively analyzed 216 HCM patients with moderate septal hypertrophy, stratified into nonobstructive (n = 38), provokable LVOTO (n = 63), and resting LVOTO (n = 115). Transthoracic echocardiography assessed LV geometry, LVOT diameter, anterior mitral leaflet length, and papillary muscle abnormalities (via a composite SubMV score). 3DE-derived strain parameters, including global longitudinal (GLS), circumferential, radial, area (GAS) strain, twist, and torsion, were quantified. Determinants of LVOTO were evaluated using multivariate regression, restricted cubic splines (RCS), and receiver operating characteristic (ROC) analysis. Results Both LVOTO subgroups showed significantly augmented strain mechanics versus nonobstructive patients, greatest in resting LVOTO (p < 0.05); twist and torsion were the strongest discriminators (p < 0.001). Multivariate regression showed that, beyond LVOT diameter and SubMV score, torsion (B = 9.47), twist (B = 1.92), and GAS (B = 1.29) independently predicted provoked LVOT gradients (all p < 0.05); RCS demonstrated nonlinear twist/torsion–LVOTO relationships, with obstruction risk rising sharply above twist = 15° and torsion = 3°/cm, especially under provocation. Torsion discriminated provokable LVOTO achieving 81% specificity (cutoff 2.4°/cm, AUC = 0.72), outperforming all structural parameters. Integrating 3DE-derived mechanics with structural metrics improved diagnostic accuracy, especially in provokable LVOTO (AUC 0.84 vs. 0.76, DeLong p = 0.003). Conclusions In moderate-hypertrophy HCM, 3DE-derived strain mechanics, especially twist and torsion, independently determine LVOTO beyond structural narrowing, particularly under provocation, strengthening mechanistic insight and clinical applicability.

ABSTRACT Objective This study aims to identify both fluid and neuroimaging biomarkers for CSF1R‐RD that can inform the optimal timing of treatment administration to maximize therapeutic benefit, while also providing sensitive quantitative measurements to monitor disease progression. Methods Our study compared neuroimaging and fluid (plasma and cerebrospinal fluid (CSF)) biomarkers across three distinct populations: asymptomatic CSF1R pathogenic variant carriers ( N = 14), symptomatic CSF1R pathogenic variant carriers ( N = 17), and healthy controls ( N = 30). We evaluated biomarker correlations with both an established (Montreal Cognitive Assessment (MoCA)) and a novel (CSF1R Clinical Severity Score (CCSS)) clinical diagnostic scale to investigate potential clinical utility. Additionally, we tested the relationship between select biomarkers and cortical thickness using 3D T1‐weighted MPRAGE scans, providing a highly valuable physiological component to our analyses. Results Our results demonstrate that while plasma glial fibrillary acidic protein (GFAP) displays a high sensitivity for distinguishing early‐stage CSF1R‐RD patients from healthy controls, plasma neurofilament light chain (NfL) is more effective for tracking disease progression following the onset of symptoms. Interpretation Overall, our study provides evidence for plasma NfL and GFAP as valuable biomarkers of earliest symptom onset and disease progression for CSF1R‐RD.

BACKGROUND: Patients with cervical artery dissection (CeAD) may experience a recurrent dissection, but its frequency, risk factors, and clinical implications are not well defined. We aimed to determine the risk, associated factors, and clinical impact of recurrent CeAD. METHODS: The STOP-CAD study (Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection) was a multicenter international retrospective observational study of patients with CeAD treated between January 2015 and June 2022. Recurrent dissection was defined as a CeAD occurring at least 7 days after the diagnosis of the index event that affects a different artery or a different segment of the same artery. Patients were followed from day 7 up to 2 years. The absolute risk of recurrent CeAD over time was calculated using Kaplan-Meier survival estimates. Multivariable logistic and Cox regression models were used to assess predictors of CeAD recurrence. RESULTS: Of the 4023 patients included in STOP-CAD, 3836 (median age 46 years, 45% women) were eligible for this analysis. During a median (interquartile range) follow-up of 295 (97–720) days, 88 (2.29%) patients had a CeAD recurrence. Median time-to-recurrent CeAD was 53 (interquartile range, 18–157) days. The estimated risk of recurrent CeAD at 2 years was 3.22% (95% CI, 2.59%–4.00%). In multivariable analyses, younger age (adjusted odds ratios, 0.98 [95% CI, 0.96–0.99]), migraine (adjusted odds ratio, 1.88 [95% CI, 1.14–3.07]), and fibromuscular dysplasia (adjusted odds ratio, 2.90 [95% CI, 1.66–5.06]) were associated with CeAD recurrence, while presenting with an ischemic stroke was associated with a lower likelihood of recurrence (adjusted odds ratio, 0.47 [95% CI, 0.29–0.75]). These associations with CeAD recurrence over time were confirmed by Cox regression analyses. Among the 88 patients with recurrent CeAD, only 5 had accompanying ischemic events (3 strokes, 2 transient ischemic attacks). CONCLUSIONS: In this retrospective study, recurrent CeAD was uncommon, approximately half of the events were diagnosed within the first 2 months of the index event, and recurrent events rarely caused new ischemic events. Younger age, migraine, absence of ischemic stroke at presentation, and signs of fibromuscular dysplasia may help identify high-risk patients.

Key Points α Klotho as an antiaging protein can extend the lifespan of healthy animals; serum α Klotho was lower in patients with autosomal dominant polycystic kidney disease. Transgenic α Klotho and recombinant α Klotho delayed cyst growth in Pkd1 mutant mouse kidneys. α Klotho exerted its proapoptotic and anti-inflammatory function through interacting with and destabilizing cellular inhibitor of apoptosis protein 1. Background α -Klotho ( α Klotho) is expressed mainly in the kidney, which is encoded by the KL gene, existing in a membrane-bound form and a soluble circulating form. Soluble serum α Klotho was lower in patients with autosomal dominant polycystic kidney disease (ADPKD). However, the role of α Klotho in ADPKD remains unknown. Methods To investigate the roles of α Klotho in ADPKD, we generated transgenic α Klotho and Pkd1 mutant Pkd1-HOMO-KL Tg mice to evaluate cyst growth and investigated underlying mechanisms with single-cell RNA sequencing analysis. Results We showed that α Klotho was lower in diverse kidney cell types in Pkd1 mutant kidneys, which was restored by transgenic α Klotho. We identified differential expression genes and pathways mediated by transgenic α Klotho at single-cell resolution and determined the cytokines and their receptors mediated cell-to-cell communication networks in Pkd1 mutant and Pkd1-HOMO-KL Tg kidneys by CellChat analysis. We further showed that α Klotho exerted a proapoptotic and anti-inflammatory function through interacting with and destabilizing cellular inhibitor of apoptosis protein 1, which disturbed TNF and its receptor mediated prosurvival complex, leading to ( 1 ) the formation of predeath complex to increase cystic cell death and ( 2 ) the decrease of the activation of NF-κB, the expression of cytokines, and the recruitment of macrophages, resulting in a delay of cyst growth. Treatment with recombinant α Klotho also delayed cyst growth in Pkd1 mutant kidneys. Conclusions This study defined an unknown role and mechanism of α Klotho in the regulation of a TNF-dependent cystic cell apoptosis and inflammation in Pkd1 mutant kidneys.

Abstract Background Bipolar disorder (BD) is associated with impairments in facial emotion recognition (FER), affecting social functioning and quality of life. Understanding FER deficits in BD is crucial for tailoring interventions and improving treatment outcomes. This systematic review and meta-analysis aims to evaluate FER differences among individuals with BD, unaffected first-degree relatives (FDRs), and healthy controls (HCs), exploring predictors related to patient and study characteristics. Methods We systematically searched PubMed/MEDLINE, Scopus, EMBASE, and PsycINFO databases from inception to March 28, 2024. Random-effects meta-analyses were conducted to explore differences in accuracy and reaction time during FER identification and discrimination tasks. Results A total of 100 studies were included, comprising 4920 individuals with BD (females = 56%, mean age = 34.1 ± 9.1), 676 FDRs (females = 55%, mean age = 36.1 ± 12), and 4909 HCs (females = 53.2%, mean age = 32.5 ± 9.5). Compared to HCs, adults with BD exhibited significantly lower accuracy (SMD = −0.47; 95% CIs = −0.56, −0.38) and higher reaction time (SMD = 0.57; 95%CIs = 0.33, 0.81) during facial emotion identification tasks. During facial emotion discrimination tasks, adults with BD had significantly lower accuracy than HCs (SMD = −0.59; 95%CIs = −0.78, −0.4), but similar speed. No significant differences were observed between BD and FDRs. Meta-regressions identified several predictors of FER performance, including manic symptom severity, stimulus duration, and presence of practice before task. Conclusions FER deficits appear to be a core feature of BD and require specialized, systematic assessment. Identifying these deficits may help guide interventions aimed at improving affective cognition and social outcomes in individuals with BD.

Abstract Background Chimeric antigen receptor T-cell therapy (CAR-T) has transformed care for relapsed or refractory B-cell malignancies. Cytokine-release syndrome (CRS) complicates most infusions, yet the ensuing infection risk is ill-defined.Table 1Profile of 230 patients undergoing with CRS following CAR-T therapyTable 2Cytokine Release Syndrome Severity, Management, and Early Outcomes by 90-Day Infection Status Methods CAR-T recipients who developed CRS at our institution from 1 Jan 2018 to 3 June 2024 were retrospectively reviewed. Variables were abstracted into REDCap. CRS was graded with American Society for Transplantation and Cellular Therapy (ASTCT) criteria. All infections occuring after CRS onset to day 90 were adjudicated. Continuous data are reported as medians with interquartile ranges (IQR); categorical data as counts and percentages. Table 2 comparisons used Mann-Whitney U for continuous and χ² or Fisher exact tests for categorical variables (two sided, P &lt; 0.05). Multivariable logistic regression was used to identify independent predictors of infection.Table 3Infectious Syndromes, Pathogens, and Timing of First Infection Following CRS Onset Results Among 230 CRS cases, median age was 64 yr (IQR 57–70) and 59% were male. Non-Hodgkin lymphoma accounted for 62% and multiple myeloma for 38%. Median prior therapy lines were 3. CRS was grade 1–2 in 97%. CAR-HEMATOTOX was low in 156 (68%) (Table 1). Within 90 days, 51 patients (22%) developed infection; median onset was 15 days (IQR 5–26). Infected patients more often received anakinra (22% vs 8%, p = 0.02) and required ICU care (18% vs 7%, p = 0.05); grade ≥3 CRS trended higher (10% vs 3%, p = 0.06). In multivariable analysis adjusting for age, CAR-HEMATOTOX, ICU admission, and anakinra, both ICU admission (aOR 2.06; 95% CI 0.70–5.81; p = 0.18) and anakinra use (aOR 2.18; 95% CI 0.83–5.53; p = 0.10) were associated with higher infection odds, though not statistically significant. 90-day survival was 88% with infection versus 96% without (p = 0.09) (Table 2). 51 infectious episodes were documented: bacteremia 22; gastrointestinal 9; central line–associated bloodstream infection 7; other sites 22. Bacteria caused 59%, viruses 37% (15 CMV, 4 SARS-CoV-2), and fungi 4%. No infection-related deaths occurred (Table 3). Conclusion Infection was common after CRS, but did not alter early survival. Anakinra exposure and ICU admission were associated with a higher likelihood of infection, though not statistically significant. Targeted surveillance should focus on patients requiring intensified CRS management. Disclosures Yi Lin, M.D., BMS: Board Member|Caribou: Advisor/Consultant|Genentech: Board Member|Jassen: Board Member|Jassen: Steering Committee|Kite/Gilead: Steering Committee|Legend: Board Member|NexImmune: Advisor/Consultant|NexT Therapeutics: Board Member|Pfizer: Board Member|Regeneron: Board Member|Sanofi: Board Member|Tessera: Board Member Paschalis Vergidis, MD, MSc, Current Fungal Infection Reports: Honoraria|F2G: Grant/Research Support|Merck Manuals: Honoraria|Mundipharma: Grant/Research Support|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support

Abstract Background Adenovirus is a ubiquitous dsDNA virus with potential for end-organ disease. End-organ or disseminated adenoviral disease (EOD) occurs more frequently in hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients. We aim to characterize the clinical manifestations and outcome of adenovirus viremia in adults, including HSCT and SOT recipients. We describe severity of illness, organ-involvement, and graft and patient survival. Methods This retrospective, multi-site, study enrolled adults patients with positive adenovirus PCR in blood and other clinical specimens from January, 2010 through April, 2025. We excluded patients with insufficient medical records, follow up less than 30 days, and isolated conjunctivitis without viremia. EOD was defined by the presence of clinical signs or symptoms consistent with organ involvement, confirmed by a positive adenovirus PCR or by histopathology. Descriptive and comparative statistics were performed using R. Results Fifty patients with adenovirus viremia were included in this study. The most common immunocompromising conditions were corticosteroid use (84%, n = 42), HSCT (40%, n = 20) and SOT (34%, n = 17) (Table 1). Only 3 patients (6%) had no known immunocompromising condition. 20 patients (40%) had EOD while 30 patients (60%) had isolated viremia. Lungs were the most affected organ, followed by the gastrointestinal tract and liver (Figure 1). EOD was more prevalent in older patients (60 vs. 41 years, p =0.03) and in those with higher initial plasma viral load (673364 vs. 6593, p=0.005). The most common treatment was reduction in immunosuppression (Table 2). Cidofovir was more often used in patients with EOD. Adenovirus-related outcomes were worse in patients with EOD [higher rates of mortality (45% vs. 13.3%) and ICU admission (60% vs. 20%)] vs. without EOD (Table 3). Conclusion Adenovirus viremia is associated with high mortality in a cohort of mostly immunocompromised adults, particularly those with EOD. Older age and a higher initial plasma viral load are associated with EOD. Patients with EOD had worse clinical outcomes such as ICU admission and adenovirus-related mortality. Disclosures All Authors: No reported disclosures

Abstract Background Persistent candidemia (PC) occurs in a minority of Candida bloodstream infections (BSIs) but is associated with increased morbidity. Comparative data on patient profile, species distribution and outcomes are limited.Table 1Clinical profile and outcomes of patients with persistent candidemia in the primary study cohort. ANC = absolute neutrophil count. SD = standard deviation.Table 2Comparative analysis of persistent candidemia and non-persistent candidemia cases. Methods All candidemia episodes at three academic medical centers (2018-2025) were reviewed. Persistence was defined as ≥72 hours of positive blood cultures after appropriate antifungal initiation. Each PC case was matched 1:2 to non-PC controls who survived ≥72 hours. Demographics, Charlson Comorbidity Index (CCI), Candida species distribution, and outcomes were used for comparative analysis. Continuous variables were summarized as median (interquartile range [IQR]) and compared with Wilcoxon rank-sum, while categorical data (n%) were analyzed by Fisher’s exact test (species by χ²), yielding odds ratios (ORs) with 95% confidence intervals (CIs). Two-tailed p &lt; 0.05 denoted significance. Results Each PC case (n = 46) was matched 1:2 to non-PC controls (n = 92). Clinical profiles and outcomes of PC cases are presented in Table 1. Most PC patients (54.3%) had an immunocompromising condition, and non-urinary intra-abdominal sources were the most frequently suspected infection source (21/46; 45.7%). All but one of 46 PC cases had antibiotic exposure within the preceding 90 days. Comparative demographics and outcomes for PC cases and non-PC controls are displayed in Table 2. PC patients were younger (median 62 yr, IQR 45–69 vs 68 yr, 57–76; p = 0.01), more often female (59% vs 30%; OR 3.3, 95% CI 1.5–7.1; p = 0.002), and had higher comorbidity (CCI 5, IQR 3–8 vs 3, 1–4; p &lt; 0.001). Species distribution differed (χ² p = 0.04), driven by C. guilliermondii over-representation in PC cases (9% vs 0%) (Figures 1 and 2). Hospital stay was longer in PC cases (median 36 d, 24–54 vs 16 d, 8–28; p &lt; 0.001) and time from admission to first culture greater (12 d, 3–26 vs 3 d, 1–10; p = 0.003). 90-day mortality was 54.3% (25/46) in PC cases versus 31.5% (29/92) in controls (OR 2.57, 95% CI 1.17–5.71; p = 0.016). Conclusion In this 7-year multicenter study, there were significant differences in demographics, microbiology, and clinical outcomes between PC and non-PC cases, including higher short-term mortality rates with PC in univariate analysis. Disclosures Paschalis Vergidis, MD, MSc, Current Fungal Infection Reports: Honoraria|F2G: Grant/Research Support|Merck Manuals: Honoraria|Mundipharma: Grant/Research Support|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support

Abstract Background Candidemia can occur as a consequence of gastrointestinal (GI) injury. The mortality of candidemia is high, ranging 30-60%, even with treatment with antifungal agents. In this retrospective matched case-control study, we aimed to elucidate the medical and surgical risk factors of developing candidemia in patients who received emergency surgery for GI ischemia and/or perforation, and compare clinical outcomes in these patients with or without candidemia. Methods All patients ≥ 18 years of age who had emergency GI surgery at Mayo Clinic Rochester, MN, for the indication of GI ischemia and/or perforation between 01/01/2018 to 07/31/2024 were included. Cases were defined as patients who developed candidemia during index admission and had no alternative sources of candidemia. Controls and cases were matched 4:1 on age (± 5 years), Charlson Comorbidity Index (± 3), and year of surgery (± 2 years). The relationships between risk factors of interest and case/control were assessed using conditional logistic regression. Results Among medical risk factors, any shock requiring vasopressor (OR = 3.44, 95% CI 1.00, 11.97) or respiratory failure (OR = 8.20, 95% CI 1.04, 64.53) during hospitalization were associated with increased risk of candidemia. Among surgical risk factors, perforation in the upper GI tract was strongly associated with development of candidemia (OR = 16.99, 95% CI 2.11, 136.95) and perforation in the lower GI tract were less likely to lead to candidemia (OR = 0.06, 95% CI 0.01, 0.44). The patients who had diffuse intraabdominal contamination were more likely to develop candidemia compared to those who had no contamination or contained contamination (OR = 3.87, 95% CI 1.33, 11.25). The patients with candidemia showed signal towards higher in-hospital and 30-day mortality, and had significantly longer stay in the hospital. Conclusion Candidemia was more frequently identified in patients with shock, respiratory failure, upper GI perforation, and intra-abdominal contamination, and contributed to significant morbidity and mortality. Further analysis will include building a multivariate logistic regression model to implement prospective trial for early initiation of antifungal therapy for high-risk population. Disclosures All Authors: No reported disclosures