Citations

BACKGROUND: Small, randomized trials of patients with cervical artery dissection showed conflicting results regarding optimal stroke prevention strategies. We aimed to compare outcomes in patients with cervical artery dissection treated with antiplatelets versus anticoagulation. METHODS: This is a multicenter observational retrospective international study (16 countries, 63 sites) that included patients with cervical artery dissection without major trauma. The exposure was antithrombotic treatment type (anticoagulation versus antiplatelets), and outcomes were subsequent ischemic stroke and major hemorrhage (intracranial or extracranial hemorrhage). We used adjusted Cox regression with inverse probability of treatment weighting to determine associations between anticoagulation and study outcomes within 30 and 180 days. The main analysis used an as-treated crossover approach and only included outcomes occurring with the above treatments. RESULTS: The study included 3636 patients (402 [11.1%] received exclusively anticoagulation and 2453 [67.5%] received exclusively antiplatelets). By day 180, there were 162 new ischemic strokes (4.4%) and 28 major hemorrhages (0.8%); 87.0% of ischemic strokes occurred by day 30. In adjusted Cox regression with inverse probability of treatment weighting, compared with antiplatelet therapy, anticoagulation was associated with a nonsignificantly lower risk of subsequent ischemic stroke by day 30 (adjusted hazard ratio [HR], 0.71 [95% CI, 0.45–1.12]; P =0.145) and by day 180 (adjusted HR, 0.80 [95% CI, 0.28–2.24]; P =0.670). Anticoagulation therapy was not associated with a higher risk of major hemorrhage by day 30 (adjusted HR, 1.39 [95% CI, 0.35–5.45]; P =0.637) but was by day 180 (adjusted HR, 5.56 [95% CI, 1.53–20.13]; P =0.009). In interaction analyses, patients with occlusive dissection had significantly lower ischemic stroke risk with anticoagulation (adjusted HR, 0.40 [95% CI, 0.18–0.88]; P interaction =0.009). CONCLUSIONS: Our study does not rule out the benefit of anticoagulation in reducing ischemic stroke risk, particularly in patients with occlusive dissection. If anticoagulation is chosen, it seems reasonable to switch to antiplatelet therapy before 180 days to lower the risk of major bleeding. Large prospective studies are needed to validate our findings.

6073 Background: Laryngeal Squamous Cell Carcinoma (LaSCC) has varying outcomes based on the stage of cancer patients present with. Currently, a high proportion of patients are diagnosed with advanced-stage LaSCC complicating the treatment landscape and over-treating low risk patients. Risk stratification of LaSCC can help tailor treatment plans. Numerous studies have identified spatial architecture of tumor-infiltrating lymphocytes (TILs) as a prognostic biomarker in oral cavity and oropharyngeal SCC. In this work, we evaluate the prognostic value of an artificial intelligence (AI)-leveraged approach that characterizes the spatial architecture of TILs on digitized hematoxylin and eosin (H&E)-stained slides from patients with LaSCC. Methods: H&E slides from 192 patients with LaSCC were collected from Baylor Medical Center. This dataset was randomly divided into two equal cohorts, A and B. The slides were digitized as whole slide images at 40x magnification. The nuclei of all cells were automatically segmented using a deep-learning model (Hover-Net). Each nucleus was then classified as TIL or non-TIL based on morphological features. TILs and non-TILs were clustered based on proximity, and features related to the density and spatial distribution were extracted. The top features, determined by the least absolute shrinkage and selection operator, were used to train a Cox Proportional Hazards regression model that assigned a risk score for recurrence of cancer to each patient in cohort A. For validation, the model was applied to patients in cohort B. The 25 th percentile training risk score was used as a cutoff for classifying patients as high or low risk. The performance of the model in prognosticating loco-regional recurrence (LRR) was evaluated using survival analysis. Results: Patients in Cohort B identified as “high risk” by the model based on spatial organization of TILs had a significantly shorter survival time. Univariate survival analysis showed this model was prognostic for DFS with a hazard ratio of 2.57 (95% Confidence Interval: 1.12-5.89, p-value=0.048), meaning that patients classified as “high risk” are approximately 2.5 times more likely to develop LLR. Conclusions: We used computational pathology to characterize the architecture of TILs and develop a model to predict risk of LLR in LaSCC. With additional validation, this approach can be used to assist clinicians with making clinical decisions. Multivariate analysis. Variable Reference vs Comparison Pr(>|z|) HR (95% CI) Race Black vs Caucasian 0.93 0.92 (0.40 - 2.31) N N0 vs N+ 0.67 1.80 (0.12 - 26.06) T 1-2 vs 3-4 0.83 1.28 (0.13 - 12.38) Chemo Yes vs No 0.38 3.49 (0.21 - 56.90) Tobacco Yes vs No 0.26 2.08 (0.58 - 7.47) Alcohol Yes vs No 0.43 1.53 (0.54 - 4.35) TIL Architecture Risk High vs Low 0.03 * 0.26 (0.08 - 0.89)

Abstract The use of radiofrequency ablation (RFA) of benign, symptomatic thyroid nodules is growing in clinical practice. Objective outcomes of symptom relief are needed to support the use of this treatment. Thus, a previously established thyroid nodule symptom scoring system was prospectively administered to patients prior to RFA of symptomatic thyroid nodules and then at 1, 3, 6, and 12 months following ablation. A total of 38 patients of mean age 57 years were treated with RFA between August 2022 and January 2024 and completed at least 1 follow-up survey. Five of these patients underwent simultaneous ablation of 2 thyroid nodules; the remainder had a single nodule treated. Mean modified symptom score prior to RFA was 3.5 (SD 1.6) with higher scores correlating with increasing baseline nodule volume (R = 0.46, P = 0.0038). Patient symptom scores decreased at the first 1-month survey (mean 1.2; SD 1.3) and 3-month survey (mean 0.9; SD 1.3) with durable response in those patients with more extended follow-up. In those patients with imaging follow-up, decreasing nodule size was shown to correlate with decreasing symptoms. The early results of this study show that RFA of benign, symptomatic thyroid nodules results in quantifiable symptom relief within 3 months of treatment. Such objective measures of symptom relief may be used to measure long-term durability of treatment.

Abstract RATIONALE. Significant sex-differences exist in asthma across the lifespan. Asthma prevalence and severity are greater in pre-pubescent boys compared to girls but greater in women after puberty. In women, asthma may improve after menopause when sex hormones wane. To address potential mechanisms underlying these changes, we compared the airway transcriptomics signatures of post-menopausal vs. premenopausal women. METHODS. We used bulk RNA seq data from bronchial epithelial cells from three different cohorts (SARP III, GEO-GSE85567, GEO-GSE201955) to perform a comprehensive analysis of differential gene expression and regulation. Data were combined into a meta-analysis, to compare pre-menopausal (n=114 cases with asthma, 48 controls) to post-menopausal women (n=52 cases with asthma, 13 controls). Differential gene expression between pre- and postmenopausal women was analyzed separately for asthma (Figure 1A) and control groups (not shown). Significant differentially expressed genes (DEGs) were identified by contrasting effect sizes (log fold-changes) between asthma and control groups using a Z-score interaction test. Accordingly, a scatter plot (Figure 1B) was created to represent whether differential gene expression between pre- and post-menopausal conditions is modified by disease status (asthma vs. control). The scatter plot also highlights that these findings are related to asthma per. se. and not to normal aging and menopausal transition. Pathway enrichment analysis was conducted using the differential expression data, followed by differential regulation analysis of the identified pathways. Statistical significance was assessed using a false discovery rate (FDR) threshold of 5%. RESULTS. Out of 15,468 genes that passed quality control, 19 genes were differentially expressed in bronchial epithelial cells from pre- and post-menopausal women with asthma (as compared to controls) (Figure 1A). Of these, 5 genes were down-regulated (ITLN1, POSTN, FCRL3, CCL22, PCSK6), and 14 genes were up-regulated (SPP1, S100A9, A2ML1, TNFRSF10C, CSF3R, OLFM1, C1QL2, NLRP3, HAL, PI3, RNASE1, TMEM178B, TNNI3, RNF175) when comparing pre- and post-menopausal women with asthma (Figure 1A). Of these 19 DEGs, 14 were differentially expressed in pre- as compared to post-menopausal women with asthma, but not in controls (Figure 1B). Comparing pre- to post-menopausal women with asthma, biologic pathways related to the innate and adaptive immune system activation and mitochondrial function (Electron transport Chain oxidative phosphorylation and ATP production) were both differentially regulated and expressed. CONCLUSIONS. This analysis highlights several DEGs and pathways that characterize asthma pathogenesis when comparing pre- and post-menopausal women, and emphasize the role of female sex hormones on the immune system response and mitochondrial function in asthma pathogenesis.

Abstract Introduction: The airway inflammation of asthma is characterized by immune phenotypes, often classified as Type 2 inflammation high or low. Social determinants of health (SDoH) can influence asthma risk and severity, but whether or not SDoH influence immune phenotypes is unclear. The social deprivation index (SDI) is a composite measure of seven neighborhood level characteristics: poverty level, less than 12 years of education, single parent household, living in rented housing unit, living in overcrowded housing unit, households without a car, and non-employed adults under 65 years of age. The scale of SDI ranges from 1 to 100, correlating with increasing deprivation. We hypothesized that social deprivation influences immune phenotype of asthma, and that deprivation effects vary by sex and race. Methods: Using the American Community Survey summary file spanning 2015 to 2019, we linked SDI to participant zip codes for 680 Black and White participants in the Severe Asthma Research Program (SARP), a NHLBI-multicenter network phenotyping asthma across the US from 2001-2024 (table 1). We compared SDI among the cohort by sex, race and asthma severity, and correlated SDI to superoxide dismutase (SOD) and T2-high biomarkers, such as eosinophils, IgE and Fraction of Exhaled Nitric Oxide (FENO). Results: SDI is similar across healthy and asthmatic participants (SDI: median [interquartile range]: healthy: 40 [56]; asthmatics: 51 [53], P = 0.53). When evaluated by race, SDI is significantly higher in Black asthmatics, independent of sex (SDI: Black male: 76 [4], White male: 35 [45]; P<0.0001; Black females: 77 [35], White females: 40 [45]; P<0.00010). Within SARP asthmatics, SDI shows a positive association with the T2 inflammatory markers, log IgE (R=0.13 [90%CI: 0.1, 0.2)] and log FENO (R=0.15 [90%CI: 0.1, 0.2]), while it correlates negatively with log of absolute neutrophil count (R= -0.12 [90%CI: -0.19,-0.1]). The antioxidant enzyme SOD increases with SDI (R=0.11, [90% CI: 0.04, 0.17]). Notably, within Black asthmatic males only, SDI is associated with Type 2 biomarkers, showing a positive correlation with log FENO (R=0.24 [90%CI: 0.1,0.4]) and negative correlation with log IgE levels (R= -0.25, [90% CI: -0.4, -0.1]). No association was found between SDI and eosinophils or with SOD in Black males. Conclusions: Neighborhood level social deprivation is associated with a unique asthma phenotype in Black males. Black males living at high social deprivation have a lower IgE and higher FENO, with no change in SOD activity.

Abstract Rationale: The club cell secretory protein (CC16), encoded by the SCGB1A1 gene, has an anti-inflammatory role in airways diseases, including asthma (Li, AJRCCM 2023; Voraphani, AJRCCM 2023). We hypothesize that additional pathway genes regulated or co-expressed with CC16 have cumulative effects on asthma severity outcomes by modulating airway inflammation and maintaining lung homeostasis. Methods: As published previously, four genes were downregulated in CC16 knockout experiments and correlated with CC16 levels: BPIFA1, SFTPD, LTF, and LYZ (Iannuzo, Front. Immunol 2023). We developed a four-gene biomarker score in 94 patients with asthma from the NHLBI-sponsored Severe Asthma Research Program (SARP3) who underwent research bronchoscopy for lower airway epithelial brushings, RNA isolation, and bulk RNA sequencing. We log-transformed the raw values of each transcript; obtained standardized residuals from regression models that included sex, age, and batch effects; and summed the standardized residuals of all four proteins to estimate a standardized sum score (Zhai, JACI Allergy 2024). Logistic regression models tested the four-gene score, three-gene score without LTF, and individual transcripts for associations with exacerbations during 12-month follow-up and zero-inflated negative binomial regression for number of exacerbations. Results: 30.85% percent of 94 patients experienced at least one exacerbation at the end of follow-up. The CC16-associated four-gene biomarker score showed protective effects on asthma exacerbation risk with a 54% percent reduction in exacerbation risk for every one-fold higher score (OR=0.46, 95% CI: 0.27-0.78, p =0.0040, Figure 1). Transcript expression of BPIFA1 (OR=0.87, 95% CI:0.66-1.16, p=0.337), SFTPD (OR=0.33, 95% CI:0.04-2.52, p=0.283), LYZ (OR=0.62, 95%CI:0.28-1.39, p=0.248), and LTF (OR=0.36, 95% CI:0.18-0.74, p=0.0053) all indicated protective directionality with respect to exacerbation risk. However, only LTF demonstrated a statistically significant association. When we excluded LTF, the remaining three-gene score showed a trend toward association with risk (OR=0.64, 95% CI:0.40-1.03, p=0.068) and was significantly associated with number of exacerbations (RR=0.49, 95% CI:0.26-0.95, p=0.034). Compared to LTF alone (OR=0.48, PPV=0.50, NPV=0.71, Sensitivity=0.14, AUC=0.65), the combined four-gene score (OR=0.46, PPV=0.60, NPV= 0.73, Sensitivity=0.21, AUC=0.68) showed improved predictive performance. Conclusions: We identified a CC16-associated transcriptomic predictive score for asthma exacerbations, with LTF showing the strongest effect. Although the other three genes showed individually weak and non-significant associations with exacerbations, the three gene score was significant for number of exacerbations.We demonstrate the potential of this transcriptomic score as a predictive biomarker for asthma severity-related outcomes. Further research investigating these genes and their interaction with other CC16-associated immune pathways could provide insight into therapeutic targets.

AbstractINTRODUCTIONSelf‐reported sex influences brain resilience, but its role in genetic frontotemporal dementia (FTD) remains unclear.METHODSWe analyzed 394 genetic‐FTD patients and 279 controls from the ALLFTD consortium, assessing annual neuropsychological performance and MRI‐based cortical thickness. Clinical characteristics and cortical thickness were compared between sexes. We used the residuals of linear regression models, which predict each participant's cognitive and behavioral performance levels relative to cortical thickness, as a proxy for reserve. We then modeled sex differences in longitudinal trajectories with linear mixed‐effects models.RESULTSSymptomatic females with genetic FTD had lower frontal cortical thickness than males, and the C9orf72 subgroup showed lower‐than‐expected frontal cortical thickness for a given level of executive functioning. Differences in cognitive reserve between sexes peaked near symptom onset but diminished thereafter.DISCUSSIONFemales with genetic FTD showed higher cognitive reserve than males, suggesting that self‐reported sex modulates resilience to frontotemporal neurodegeneration.Highlights Females with genetic FTD showed higher cognitive reserve than males. Those differences were particularly pronounced in the C9orf72 and GRN subgroups. The higher cognitive reserve in females declined as the disease progressed.

Abstract INTRODUCTION Sex differences are apparent in neurodegenerative diseases but have not been comprehensively characterized in frontotemporal dementia (FTD). METHODS Participants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to 6 years. Linear mixed‐effects models investigated how sex and disease stage are associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL). RESULTS While sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. In asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that was not present in symptomatic participants. DISCUSSION In genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in the disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD‐causing mutations. Highlights Females with genetic FTD exhibit overall steeper increases in plasma neurofilament light chain (NfL) than males. Females with genetic FTD outperform NfL levels in asymptomatic stages compared to males. Once symptomatic, females with genetic FTD decline more rapidly than males. Plasma NfL is a stronger prognostic marker in asymptomatic males than females.

Abstract Background We aimed to evaluate the effectiveness and safety of risankizumab (RZB) for Crohn’s disease (CD) in routine clinical practice. Methods We performed a retrospective review of a multicenter consortium of CD patients treated with RZB. Co-primary outcomes were week 12 clinical remission (Harvey Bradshaw Index [HBI] score of ≤4 or physician global assessment in those without HBI or with ileostomy) and 6-month endoscopic remission (Simplified Endoscopic Mucosal Assessment for Crohn’s Disease of 0-1 or absence of ulcers). Secondary outcomes included steroid-free clinical remission, clinical response, radiographic response, cumulative clinical and endoscopic remission rates at 6 and 12 months, and adverse events. Results A total of 309 patients were included (median disease duration 14 years [IQR, 6-24]; median follow-up 7.1 months [IQR, 4.1-10.3]). Most patients (85.8%) were advanced therapy (AT)-exposed, and 169 (54.7%) had prior ustekinumab (UST) exposure. Week 12 clinical remission rates were 49.7% (98/197) overall, and 44.2% (50/113) vs 57.1% (48/84) in UST-exposed vs naïve patients (P = .073). Among those with active disease on baseline endoscopy (n = 122) who had an available follow-up at 6 months, 52.4% (22/42) achieved endoscopic remission. Cumulative rates of clinical and endoscopic remission at 12 months were 65.0% and 49.5%, respectively. Cumulative 12-month endoscopic remission was 33.9% (19/56) in UST-exposed and 68.1% (32/47) in UST-naïve patients (P < .001). Risankizumab was well-tolerated with no new safety signals identified. Conclusions In this large multicenter cohort of patients with CD, RZB was well-tolerated and effective in achieving favorable clinical and endoscopic outcomes in both AT-exposed and naïve populations, including those with exposure to UST.