Citations

Abstract Objective Myositis is a heterogeneous family of inflammatory myopathies. We sought to define the differential expression of cytokines, cytokine receptors and immune checkpoint genes in muscle biopsies from patients with different forms of myositis in order to characterize patterns of inflammation in each. Methods Bulk RNA-sequencing was performed on muscle biopsy samples from 669 patients, including 105 with DM, 80 with immune-mediated necrotizing myopathy (IMNM), 65 with anti-synthetase syndrome, 53 with IBM, 19 with anti-PM/Scl myositis, 310 with other inflammatory or genetic myopathies and 37 controls with normal tissue (NT). Myositis clinical groups and autoantibody subgroups were analysed separately. Expression data were analysed for 338 genes encoding cytokines, cytokine receptors and immune checkpoints. Myositis group-specific genes were identified from this list by finding genes that were specifically differentially expressed in one group compared with all samples and compared with NT (α < 0.001). Results IBM patients had the most differentially overexpressed genes (71) among all clinical groups, including 37 that were IBM-specific. Among the top genes were several involved in type 1 inflammation, including CCL5, CXCR3, CCR5, CXCL9 and IFNG. Anti-Jo1 and anti-PM/Scl patients exhibited differential overexpression of a similar set of genes, while DM patients exhibited differential overexpression of a different set of genes involved in type 1 inflammation. IMNM patients had the least number of differentially overexpressed genes with no predominant inflammatory pattern. Conclusion Each myositis clinical group and autoantibody subgroup had differentially overexpressed inflammatory mediators, including a strong type 1 inflammatory gene signature in IBM.

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.

PURPOSE Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m 2 and nab-paclitaxel 125 mg/m 2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.

Abstract We conducted a national survey of current pediatric infectious diseases (PID) fellows and PID fellowship graduates from the past 10 years to assess satisfaction with existing PID initial certifying exam preparatory materials. Satisfaction with existing resources was low. The most desired new resource was additional board-style questions.

Importance Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure. Objective To estimate the worldwide burden of SAH. Design, Setting, and Participants Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021. Exposures SAH and 14 modifiable risk factors. Main Outcomes and Measures Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor–specific population attributable fractions (PAFs). Results In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100 000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF] = 51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF = 14.4%; 95% UI, 12.4%-16.5%) had the highest attribution. Conclusions and Relevance Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.

Background: Young women with breast cancer (YWBC) typically undergo intensive treatment that negatively impacts their quality of life (QoL). However, limited information is available on how their QoL changes, as most research has focused on older patients. Objectives: To assess changes in QoL among YWBC, identify the most affected QoL domains, and identify the factors associated with these changes. Design: Joven & Fuerte is a multicenter cohort of women aged ⩽40 in Mexico with newly diagnosed BC from 2014 to 2020. Methods: Participants completed the European Organization for Research and Treatment of Cancer Breast Cancer module QLQ-BR23 questionnaire at five different time points from enrollment until year 5 postdiagnosis. Clinical and treatment data were also collected. Group-based multivariate trajectory modeling was used to analyze longitudinal changes across QoL domains and classify patients into appropriate groups. Logistic models were then employed to identify associations between variables and group classification. Results: A total of 477 women (median age: 36 years; interquartile range 32–38) were included. Most had public health insurance (87%) and were diagnosed with stage II (49%) or III (39%) BC. Two trajectory groups, namely, “good” and “poor,” were identified based on QLQ-BR23 scores. Most patients ( n = 294, 62%) were in the poor group. In the good group, sexual enjoyment scores remained stable from baseline to year 5 (51.4), whereas those in the poor group decreased (51.0–37.3). Distress related to hair loss over time declined, with scores decreasing from 36.3 to 27.0 in the good trajectory group and from 43.4 to 31.2 in the poor trajectory group. For future perspective, the good group improved from 56.4 to 79.0, while the poor group increased from 39.3 to 57.2. Patients with human epidermal growth factor receptor 2-positive BC (adjusted odds ratio (aOR) = 0.57, 95% confidence interval (CI) 0.35–0.94, p = 0.028) and those with public health insurance (aOR = 0.41, 95% CI 0.16–0.90, p = 0.035) were less likely to belong to the poor trajectory group. Conclusion: A high proportion of YWBC experience a poor QoL trajectory over time, particularly in areas related to sexual health, future perspective, and hair loss.

Abstract Rationale: Primary ciliary dyskinesia (PCD) is a heterogeneous, rare genetic disorder characterized by dysfunctional motile cilia. PCD pulmonary manifestations include impaired airway mucociliary clearance, mucus obstruction, recurrent infection, and bronchiectasis (BE). Notably, thoracic imaging studies indicate that alveolar atelectasis is more prevalent in children with PCD than in age-matched children with cystic fibrosis (CF). However, morphologic and molecular analyses of the site of initiation and progression of PCD airway disease and relationships to PCD alveolar disease have not been reported. In this study, we analyzed region-specific morphologic and molecular characterizations of airway epithelia and alveolar regions in PCD lungs excised at transplantation to address these questions. Methods: Nine PCD lungs and seven non-diseased control lungs were included in the morphometric studies. Bronchi and proximal and distal bronchioles were defined using unique morphologic structures, and distal airway secretory cell (DASC) markers were used to differentiate between proximal and distal bronchioles. Morphologic characteristics of airway epithelia and luminal mucus were quantitated by histology, immunohistochemistry, and RNA in situ hybridization. Spatial transcriptomic technologies (GeoMx) characterized region-specific transcript expression in three airway epithelial regions (bronchi, proximal bronchioles, and distal bronchioles), intraluminal mucus plugs, and alveolar regions of PCD compared to control lungs. Finally, pulmonary function data from a cohort of PCD subjects were analyzed to investigate correlations between alveolar morphologic findings and alveolar gas exchange function, i.e. diffusing capacity for carbon monoxide (DLCO). Results: PCD bronchi and proximal bronchioles exhibited ectasia, characterized by increased MUC5AC and MUC5B-producing cells, mucus plugs containing MUC5AC and MUC5B mucins infiltrated by neutrophils, and epithelial gene signatures associated with ectasia. In contrast, PCD distal bronchioles were not ectatic and exhibited MUC5B-dominant DASCs, mucus plugs containing selectively MUC5B mucin infiltrated by mixture of neutrophils and macrophages, and gene signatures suggestive of impaired ciliogenesis. Molecular analysis revealed upregulation of pathways associated with muco-inflammation, antimicrobial defense, and the innate immune system routinely in PCD airway epithelia. IL-1β gene signatures were observed in both PCD airway and alveolar epithelia, whereas interferon-stimulated gene signatures were restricted to airway epithelia. Transcriptomic and morphologic analyses suggested that PCD alveolar disease was initiated by distal bronchiolar obstruction, associated with chronic microatelectasis, progressive loss of alveolar epithelial type 2 (AT2) cells, and eventual non-resolving fibrosis. A significant percentage (28%) of people with PCD exhibited reduced DLCO. Conclusions: PCD airway disease is manifest by distinct profiles of proximal vs distal bronchiolar disease associated with microatelectatic and fibrotic alveolar disease.

Introduction: Hypertension (HTN) is highly prevalent among patients with chronic kidney disease (CKD) and end-stage kidney disease (ESKD), uncontrolled HTN as well as high blood pressure variability (BPV) can significantly impact cardiovascular health. This study aims to understand the impact of BPV in patients with ESKD following arteriovenous fistula (AVF) creation for hemodialysis, to better understand its association with age, sex, BMI, and cardiovascular risk. Methods: A retrospective analysis was conducted on 83 patients who underwent AVF creation between February 2019 and October 2020 at University of Miami Hospital. During 20 months, blood pressure measurements were collected from medical records at four different times during AVF access creation process, and BPV was quantified using machine learning clustering techniques. Results: The study identified three distinct clusters among the 83 patients with ESKD who underwent AVF creation. Cluster 1 ( n = 28) was characterized by high blood pressure variability, with a mean systolic blood pressure standard deviation of 16.2 mmHg. This cluster exhibited a significantly higher cardiovascular risk rate of 42.9% compared to Cluster 2 ( n = 30) and Cluster 3 ( n = 25), which had lower variability with mean systolic blood pressure standard deviations of 10.3 and 8.7 mmHg, respectively, and cardiovascular risk rates of 16.7% and 12.0%. Age, sex, and BMI did not differ significantly across the clusters. Conclusion: This study underscores the association between blood pressure variability and the increased risk of cardiovascular events, including myocardial infraction, stroke or heart failure in patients with ESKD undergoing AVF creation. Our findings highlight the critical need for vigilant monitoring of blood pressure fluctuations in this population and demonstrate how these variations are influenced by individual demographic factors. Further research is needed to develop targeted interventions to mitigate this risk.

Abstract Purpose: Black women are disproportionately affected by aggressive breast cancers compared to white women, suggesting underlying biological differences in normal breast tissue. This study aims to identify molecular disparities in normal breast tissue between premenopausal Black and white women that may contribute to increased breast cancer risk. Experimental Procedures: Visium spatial transcriptomic analysis was performed on a pilot cohort of normal breast tissue samples from premenopausal Black and white women. Tissue sections were spatially profiled, and capture spots were classified based on predominant cell types: epithelial, stromal, or endothelial. Differential gene expression analysis between racial groups was conducted for each cell type classification. Multiplex immunofluorescence (mIF) was used to validate selected markers in the pilot cohort. Meta-analysis compared differentially expressed genes with published gene sets associated with breast cancer subtypes. Results: Significant racial differences in gene expression profiles were identified in both epithelial and stromal spots. In epithelial spots, genes upregulated in Black women significantly overlapped with over 20 published gene sets associated with estrogen receptor-negative (ER−) breast cancer, including key genes involved in Wnt signaling inhibition (e.g., WIF1) and basal epithelial markers (e.g., KRT14, KRT15). This suggests alterations in pathways linked to more aggressive breast cancer phenotypes. In stromal spots, differentially expressed genes related to extracellular matrix remodeling and fibroblast activation (e.g., PI16, DPT, EFEMP1) were observed, indicating potential differences in stromal-epithelial interactions. Ongoing deconvolution and spatial analyses are being performed to further elucidate these findings. Preliminary mIF validation confirmed increased expression of PI16 in samples from Black women. Validation of additional markers is underway in a larger cohort of premenopausal Black and white women. Conclusions: Spatial transcriptomic profiling of normal breast tissue reveals distinct molecular differences between Black and white women, particularly in pathways associated with aggressive breast cancer subtypes and stromal interactions. These findings suggest that inherent variations in the normal breast microenvironment may contribute to the increased risk and aggressiveness of breast cancer in Black women. Further validation and analysis may identify potential biomarkers for risk assessment and inform targeted prevention strategies. Citation Format: Camila Pacheco Erak, Nicole Cruz-Reyes, Pria Westerman, Joshua Ogony, Jean R. Clemenceau, Tae Hyun Hwang, Sarah McLaughlin, Derek Radisky. Spatial transcriptomic profiling of normal breast tissue reveals potential mechanisms underlying increased breast cancer risk in Black women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 765.