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ImportanceIdentifying factors associated with resilience during the COVID-19 pandemic can inform targeted interventions and resource allocation for groups disproportionately affected by systemic inequities.ObjectiveTo examine factors associated with self-reported resilience during the COVID-19 pandemic in racially and ethnically diverse, community-dwelling US adults.Design, Setting, and ParticipantsThis cross-sectional study was conducted as part of the Collaborative Cohort of Cohorts for COVID-19 Research (C4R) study, which assessed the associations of the pandemic with self-reported resilience of participants from 14 established US prospective cohorts since January 2021. This report includes participants who responded to the self-reported resilience question on C4R questionnaires. Data was initially analyzed from October 2023 to May 2024, with updated analyses performed from August 2024 to April 2025.ExposureRace and ethnicity, behavior factors, health conditions, and social determinants of health measurements accessed before and during the COVID-19 pandemic through cohort visits and C4R questionnaires.Main Outcomes and MeasuresSelf-reported resilience was collected via 1 question (from the Brief Resilience Scale) in C4R questionnaires, “I tend to bounce back quickly after hard times.” Participants who answered agree or strongly agree were classified as resilient, and those who reported neutral, disagree, or strongly disagree were classified as not resilient. Modified Poisson regression was performed to estimate prevalence ratios (PRs) and access multivariable-adjusted associations with resilience.ResultsOf 31 045 participants (18 672 [60%] women; 10 746 [34.6%] aged <65 years), 1185 (3.8%) identified as American Indian, 6728 (21.7%) as Black, 293 (0.9%) as East Asian, 6311 (20.3%) as Hispanic, 565 (1.8%) as South Asian, and 15 961 (51.3%) as White; a total of 23 103 participants (74.4%) self-identified as resilient. Compared with White participants, Black and Hispanic participants had higher prevalence of self-reported resilience (adjusted PR [aPR], 1.04; 95% CI, 1.02-1.06; aPR, 1.08; 95% CI, 1.06-1.11; respectively) and American Indian and East Asian participants had lower prevalence (aPR, 0.90; 95% CI, 0.86-0.94; aPR, 0.76; 95% CI, 0.68-0.84; respectively). Higher education, being married or living as married, higher income, and overweight were also associated with higher prevalence of resilience. Being female, having diabetes, and being unemployed were associated with lower prevalence of self-reported resilience. Compared with participants with public insurance only, participants with private insurance had higher prevalence of resilience (aPR, 1.07; 95% CI, 1.03-1.10). COVID-19 vaccination and infection statuses were not significantly associated with resilience. Modification analyses showed important racial and ethnic differences in how factors such as hypertension, marital status, and insurance status were associated with resilience.Conclusions and RelevanceIn this cross-sectional study of 31 045 adults, self-reported resilience varied by race, ethnicity, and sociodemographic factors. These findings highlight the complex interplay of individual and social factors in shaping the perception of resilience.

Background/Objectives: Inflammatory bowel disease (IBD) is a chronic inflammatory condition encompassing ulcerative colitis (UC) and Crohn’s disease (CD). The role of environmental factors in the pathogenesis of IBD remains elusive. Nevertheless, evidence suggests a pivotal role of viruses, specifically Epstein–Barr virus (EBV), in the progression of IBD through mechanisms such as molecular mimicry and bystander activation. Our previous findings demonstrate EBV DNA’s significant role in exacerbating colitis symptoms and elevating the levels of the pro-autoimmune cytokine interleukin-17A (IL-17A) in an IBD mouse model via toll-like receptor 9 (TLR9). Therefore, we aimed to examine the role of EBV particles in the pathogenesis of IBD, and the potential role of TLR9 inhibition in ameliorating disease outcomes. Methods: Three days post colitis induction, EBV particles were intra-rectally injected into female C57BL/6J mice, followed by the intra-peritoneal administration of TLR9 inhibitor. Thereupon, mice were monitored daily and the disease activity index (DAI), colon lengths, and damage scores, as well as the number of cells, double-positive for IL-17A+ and IFN-γ+, and triple-positive for IL-17A+, IFN-γ+, and FOXP3+, were evaluated. Results: Our findings revealed a significant role of TLR9 inhibition in mitigating colitis features in an EBV-injected IBD mouse model compared to the control group. Conclusions: These results indicate an essential role of TLR9 in initiating immune responses against recurrent EBV reactivation events, which ultimately contributes to inflammation aggravation in IBD patients. Consequently, TLR9 could serve as a potential therapeutic target to alleviate the severe symptoms of IBD in EBV-infected individuals.

Abstract Accurate prediction of risk of progression from smoldering (SMM) to active multiple myeloma (MM) is paramount to individualized early therapeutic strategies with minimum risk of overtreatment. Current risk stratification models do not account for evolving biomarker trajectories. We assembled the largest cohort to date of 2,270 SMM patients from six international centers with longitudinal clinical and biological data to train and validate the PANGEA 2.0 risk models. Four evolving biomarkers were significantly associated with shorter time-to-progression: M-protein increase ≥0.2g/dL, involved:uninvolved serum free light chain ratio increase ≥20, creatinine increase >25%, and hemoglobin decrease ≥1.5g/dL. PANGEA 2.0 outperforms established models including the 20/2/20 and IMWG models by more accurately predicting progression (C-statistics=0.69–0.84), even without biomarker history (C-statistics=0.69–0.83) or recent bone marrow biopsy. PANGEA 2.0 is an easy-to-use, open-access tool (https://ghobrial.shinyapps.io/pangea_2_calculator) to improve and individualize SMM risk stratification. Validation tools are available to compare PANGEA 2.0 to established models (https://ghobrial.shinyapps.io/pangea_validation).

6037 Background: The incidence of HPV-associated head and neck squamous cell carcinoma (HNSCC) continues to rise with over 90% of cases being driven by HPV16. Median overall survival (OS) with pembrolizumab in first-line recurrent/metastatic (R/M) HNSCC is 12.3 months in subjects with CPS ≥1, 10.8 months for CPS ≥1-19, and 14.9 months for CPS ≥20. There is an urgent need to improve survival rates in the growing population of HPV16-positive R/M HNSCC. PDS0101 (Versamune HPV) is an investigational T cell stimulating immunotherapy that unleashes a potent, durable attack against HPV16-positive cancers and is being studied in combination with pembrolizumab. Preliminary results were presented at ASCO 2023. (Price KAR, et al. ASCO 2023. Abstract 6012). Methods: VERSATILE-002 is a single-arm phase 2 study evaluating PDS0101 and pembrolizumab for first-line HPV16-positive R/M HNSCC with CPS ≥1. Subjects received pembrolizumab 200 mg IV Q3W with PDS0101 1 mL SC administered concurrently during Cycles 1, 2, 3, 4, and 12 and pembrolizumab alone for all other Cycles up to Cycle 35 (approx. 2 years). The primary study endpoint is confirmed objective response rate (ORR) per RECIST 1.1. Secondary endpoints include progression-free survival (PFS), OS, and safety. Results: The median follow-up is 18.4 months (range 0.2-42.7 months). The efficacy population consists of 53 subjects: 32 (60%) with CPS ≥1-19 and 21 (40%) with CPS ≥20. The median OS for subjects with CPS ≥1 is 30 months (95% CI 23.9, NE). For the CPS ≥1-19 subgroup, the median OS is 29.5 months (95% CI 15.3, NE). For the CPS ≥20 subgroup, the median OS is 39.3 months (95% CI 18.4, NE). Confirmed response rates by investigator assessment are shown in the Table. Twenty-three subjects are still on study: 3 on treatment and 20 in long-term follow-up. No new safety signals have emerged. The most common TRAEs are injection site reactions, fatigue, headache, and pruritus. Only 19% of subjects experienced Grade ≥3 TRAEs. No subject had a Grade 5 TRAE. Conclusions: These data represent one of the most extended follow-up periods to date of subjects receiving an HPV16-targeted therapy for HPV16-positive R/M HNSCC. The PDS0101 and pembrolizumab combination is well tolerated and has demonstrated deep and durable clinical responses. Median OS is promising in light of historic expectations, both overall and relative to PD-L1 subgroup, and remains durable with continued follow up. The results support further evaluation in a randomized phase 3 study with OS as the primary endpoint. Clinical trial information: NCT04260126 . Summary of results. CPS ≥1-19 (N=32) CPS ≥20 (N=21) CPS ≥1 (N=53) ORR, % 28.1 47.6 35.8 DCR, % 75.0 81.0 77.4 Median DOR, months (95 % CI) 21.8 (4.2, NE) NE (5.6, NE) 21.8 (11.5, NE) Median PFS, months (95% CI) 5.1 (2.4, 8.1) 14.1 (2.1, NE) 6.3 (3.5, 9.0) Median OS, months (95% CI) 29.5 (15.3, NE) 39.3 (18.4, NE) 30.0 (23.9, NE)

TPS6111 Background: Human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) has surpassed cervical cancer as the most common HPV-related cancer in the US, with the majority being caused by HPV16. Persistent expression of HPV16 oncoproteins E6 and E7 by host genome may promote HNSCC. HPV16-positive HNSCC may be associated with poor clinical outcomes in the recurrent/metastatic (R/M) setting. PDS0101 (Versamune HPV) is an HPV16-immunotherapy that generates a potent, targeted T cell attack against HPV16 E6 & E7. In a Phase 2 study, PDS0101 plus pembrolizumab has shown encouraging safety and survival benefit in patients with HPV16-positive R/M HNSCC. (Weiss J et al. ESMO 2024. Poster 879P. NCT04260126). Methods: VERSATILE-003 is a global Phase 3, randomized, controlled, open-label study evaluating PDS0101 plus pembrolizumab vs. pembrolizumab in patients with HPV16-positive R/M HNSCC with PD-L1 positive disease (CPS ≥1). Key eligibility criteria include age ≥18-years-old, histologically- or cytologically-confirmed diagnosis of R/M HNSCC with primary tumor location of oropharynx, oral cavity, hypopharynx, or larynx and no prior systemic anticancer treatment in the R/M setting, HPV16 tumor positivity (centrally tested), PD-L1 positivity defined as CPS ≥ 1 using FDA-approved PD-L1 IHC 22C3 pharmDx kit, and measurable disease based on RECIST 1.1 confirmed by blinded independent central review (BICR). Patients will be randomized 2:1 to receive pembrolizumab 200 mg IV Q3W with PDS0101 1 mL SC administered concurrently during Cycles 1, 2, 3, 4, and 12 (investigational arm), or pembrolizumab 200 mg IV Q3W alone (control arm). The primary objective is to compare overall survival (OS) between the investigational and control arms. Secondary objectives include objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and progression-free survival (PFS) using RECIST 1.1 and assessed by BICR. Exploratory objectives include tumor response assessed by investigator and by irRECIST, PFS2, quality of life as assessed by EQ-5D, QLQ-C30, and QLQ H&N35, and assessment of ctHPVDNA. Updated enrollment data will be provided. Clinical trial information: NCT06790966 .

Abstract RATIONALE: Susceptibility to severe COVID-19 and long COVID may be influenced by pre-existing lung structure. ECG-gated, non-contrast cardiac CT scans, originally acquired for assessing coronary artery calcium, are available in multiple longitudinal cohort studies and have been previously validated against lung CT scans for densitometry; however, protocol variation across cohorts may hinder direct comparison. To address this, we developed a quality control (QC) rubric to grade cardiac CT scans for standardized quantitative lung measures across cohorts. METHODS: C4R assessed SARS-CoV-2 infection and outcomes in 14 NHLBI cohorts, of which 10 (six community-based and four longitudinal case-control studies) included CT scans (12,459 participants with lung and 13,752 with cardiac CTs). Logic rules were applied to categorize scans (Table): Grade “A-B” scans had 2-3.5mm slice thickness, at least 20 axial slices, no lung cropping in axial view and lung and airway volumes greater than the cohort-specific 1st percentile. “C-D” scans had one lung obscured by cropping around the heart, so quantitative measures were restricted to the lung in complete view. “F-H” scans were deemed unusable, suffering from low slice count (<20), severe image cropping, low lung or airway volumes (< 1st%ile). Visual inspection was performed on a sample from each category to ensure accuracy. Percent of lung voxels in low attenuation areas < -950 HU (LAA950), high attenuation areas (-600 to -250 HU, HAA) and 15th percentile HU value (perc15) were measured. Within-participant variability was quantified using the intraclass correlation coefficient (ICC). RESULTS: We performed QC on cardiac CT scans from an initial sample of 6,275 participants from three C4R cohorts (ARIC, CARDIA, MASALA), imaged with GE or Siemens scanners. Of these, 5,125 (81.7%) were graded “A-B”, 496 (7.9%) were “C-D” and 654 (10.4%) were “F-H”. The percentage of “F-H” scans varied widely across cohorts [<1% to 26%] due to image cropping. Among the 5,621 cardiac CT scans graded A-D, the mean±SD for LAA950, HAA and perc15 respectively were 1.1±2.1%, 7.2±4.7% and -887±33 HU. Repeated imaging was available for 107 participants (time interval 5.1±0.7y). For paired scans in grades A-B (n=101/107), the within-participant correlation for LAA950, HAA and perc15 were 0.91, 0.38 and 0.74 respectively. CONCLUSION: Initial application of QC to cardiac CT scans identified scans with high reproducibility, with the aim to provide valid quantitative lung metrics on over 20,000 highly characterized participants in C4R.

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.

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.