Citations

Abstract RATIONALE: Deferral and declination of the COVID-19 vaccine is correlated with many factors, including different health guidelines and difficulties accessing the vaccine. In the US, COVID-19 vaccines were made available in tranches of clinical risk starting in December 2020 and were available to all adults on April 19, 2021. In the post-pandemic period, repeating COVID-19 vaccination with updated formulations is broadly recommended. Given that the public health impact of vaccine allocation strategies depends on public acceptance of vaccination, we aimed to evaluate demographic, clinical and social correlates of (1) receiving at least one COVID-19 vaccine by May 1, 2021 (prompt vaccination) and (2) the total number of vaccine doses received (vaccine count) through 2023-2024. METHODS: The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a prospective observational meta-cohort study comprising 14 extant NIH-funded population-based cohorts. C4R assessed COVID-19 vaccination using three waves of standardized questionnaires (2020-2021, 2021-2023, 2023-2024). Prompt vaccination was defined by participant self-report of vaccination before May 1, 2021; participants vaccinated after May1, 2021 were classified as non-prompt; participants with missing vaccination information were excluded. Vaccine count was defined by self-report on the 2023-2024 wave Questionnaire. Demographic, clinical and social factors were classified by self-report and/or objective measures from the most recent pre-pandemic cohort exam. Poisson models regressed either prompt vaccination or vaccine count on pre-pandemic factors. RESULTS: Of 17,866 participants (mean age, 6713 years; 60.1% female; 42.1% non-Hispanic White, 22.0% Black, 28.9% Hispanic/Latino, 3.4% American Indian, 2.3% South Asian, 1.4% East Asian), 11,481 (64.3%) reported prompt vaccination. Of the subset of 14,529 participants completing the Wave 3 questionnaire, the median vaccine count in 2023-24 was 3 (Q1, 2; Q3 4). Likelihood of prompt vaccination was higher with greater age, income, and education and with history of diabetes and hypertension; prompt vaccination was less likely with male sex, current smoking, and non-White race and ethnicity (table). Similar associations were observed with respect to vaccine count (table). CONCLUSIONS: In a diverse C4R cohort community-based sample, earlier and greater COVID-19 vaccination was associated with older age and several clinical comorbidities; in contrast, later and lesser vaccine uptake was observed among historically marginalized groups. Whether disparities in COVID-19 vaccination could contribute to disparities in post-COVID-19 conditions merits further investigation.

Abstract Rationale: SARS-CoV-2 infection may be associated with new or worsening respiratory symptoms that, if persistent, may contribute to “Long COVID.” Research is needed on the prevalence and risk determinants of Long COVID and related respiratory symptoms in adults with and without pre-existing obstructive lung disease or smoking history. Methods: C4R is a prospective, observational study that collected information on SARS-CoV-2 infection using standardized methods across 14 NIH-funded cohorts. The third wave of C4R questionnaires, administered June 2023 to January 2025, assessed self-reported Long COVID via the question, “Do you think that you are experiencing, or have ever experienced, what has been called “long COVID,” or symptoms related to COVID at least a month after your infection?” Questionnaires also assessed the presence (vs absence) of 22 symptoms that have been linked to Long COVID, including cough, shortness of breath, and post-exertional malaise. Pre-pandemic obstructive lung disease (COPD or asthma) and smoking status (ever/never) were harmonized from self-reported data collected at the most recent pre-pandemic cohort exam. Poisson regression was used to assess prevalence ratios (PRs) adjusting for age, sex, BMI, education, and pre-pandemic hypertension, diabetes, cardiovascular disease, and depressive symptoms. PRs for respiratory symptoms were tested according to self-reported Long COVID and history of non-hospitalized or hospitalized infection; effect modification by pre-pandemic lung disease and smoking was assessed by multiplicative interaction terms and in fully stratified models. Results: Among 23,434 questionnaire respondents, 1,484 (6.3%) self-reported Long COVID, including 246/1,262 (19.5%) with pre-pandemic lung disease and 664/4,018 (16.5%) with smoking history. The adjusted PR for Long COVID was 1.17 (95%CI:0.99-1.39;P=0.06) comparing participants with/without lung disease and 1.17 (95%CI:1.04-1.32;P=0.01) comparing participants with/without smoking history. Respiratory symptoms were more prevalent in those with self-reported Long COVID, as well as in those with a history of hospitalized or non-hospitalized infection (Table). Associations were generally stronger in participants without pre-pandemic lung disease (p-interaction<0.05 for all comparisons). Respiratory symptoms were also more prevalent with a history of repeated, and pre-Omicron infections, and were less prevalent among participants vaccinated prior to their first infection; findings were similar even after excluding participants with self-reported Long COVID. Conclusions: Long COVID is common, particularly in adults with pre-existing COPD or asthma or smoking history. Long COVID and history of SARS-CoV-2 infection, including non-hospitalized infections, was associated with greater respiratory symptom burden. Whether SARS-CoV-2 infection or Long COVID are associated with development or progression of obstructive lung diseases warrants future studies.

Abstract RATIONALE: Chronic kidney disease (CKD) is common in the general population and is associated with inflammation and compromised immune function. Since these mechanisms are hypothesized to promote severe COVID-19, we tested associations of pre-pandemic CKD with incident COVID-19 hospitalization or death in a large, multi-ethnic, US general population-based meta-cohort of adults. METHODS: Data were harmonized and pooled from 9 NIH-funded longitudinal cohorts participating in the Collaborative Cohort of Cohorts for COVID-19 Research (C4R). CKD was classified by KDIGO 2024 CKD guideline (Low Risk, Moderately Increased Risk, High Risk, Very High Risk) using pre-pandemic urinary albumin-to-creatinine ratio (uACR) and estimated glomerular filtration rate using creatinine (eGFRcr). Incident COVID-19 hospitalization or death was ascertained over 2020−2023 via self-report and active surveillance, with medical record adjudication in a subset. In our primary analysis, we assessed associations between CKD stages and incident COVID-19 hospitalization or death. A secondary analysis examined joint association of CKD stages and the number of comorbidities (obesity, hypertension, diabetes, and cardiovascular disease) with the severe COVID-19. Multivariable hazard ratios (HRs) were estimated by cause-specific Cox regression, adjusting for socio-demographics and smoking. RESULTS: Among 26,039 multi-ethnic adult participants (mean age 66.1±14.8, 60.6 % female, 28.6% Whites, 3.2% Asians, 20.6% Blacks, 41.3% Hispanics, 6.3% American Indians) with a median follow-up of 550 days since the onset of the pandemic (baseline: March 1, 2020), there were 734 incident COVID-19 hospitalizations or deaths. The mean time since CKD markers were measured before the baseline was 6.5 years. The cumulative incidence of severe COVID-19 was 2.3, 3.5, 6.5, and 7.3% across CKD risk stages, and similar patterns were observed within variant types (Figure 1). Compared to participants with Low Risk of CKD, there was a graded increased hazards of severe COVID-19 across CKD stages, with HRs (95% CIs) of 1.27 (1.03−1.55) for Moderately Increased Risk, 2.33 (1.77−3.06) for High Risk, and 2.72 (1.89−3.92) for Very High Risk. In a joint analysis, both increased CKD risk and a higher number of comorbidities were associated with a higher risk of severe COVID-19, showing the highest HR of 12.29 (5.75−26.27) in Very High Risk individuals with four comorbidities compared to Low Risk individuals with none. CONCLUSIONS: Higher CKD stages were associated with a greater risk of COVID-19 hospitalization or death and the risk is substantially heightened with additional comorbidities. These results suggest that adults with CKD and related comorbidities may merit enhanced COVID-19 risk mitigation.

Objective We aimed to assess the occurrence of carpal tunnel syndrome (CTS) before and after rheumatoid arthritis (RA) incidence and by serologic status. Methods This population‐based study included residents of a geographically defined area meeting the 1987 American College of Rheumatology classification criteria for RA in 1980 to 2019 matched 1:1 with individuals without RA. At least two diagnosis codes ≥30 days apart were used to identify CTS. Cumulative incidence of CTS adjusting for competing risk of death was assessed. Logistic regression and Cox proportional hazard models were used, adjusting for age, sex, calendar year, smoking, obesity, diabetes mellitus, and hypothyroidism. Results We included 1,335 patients with RA and 1,331 individuals without RA. The overall prevalence of CTS before or on RA incidence or index was 179 patients with RA (13%) and 85 individuals without RA (6%), respectively (odds ratio [OR] 2.23; 95% confidence interval [CI] 1.69–2.94). Most previous incidences of CTS occurred ≥2 years before the index date (112 events in patients with RA and 75 events in individuals without RA, respectively). Following RA incidence or index, individuals with RA (vs those without RA) had ~80%‐higher risk of CTS (hazard ratio [HR] 1.78; 95% CI 1.38–2.30). The risk estimates of CTS in patients with seronegative (vs seropositive) RA were OR 1.33 (95% CI 0.96–1.84) before RA incidence and HR 1.37 (95% CI 0.99–1.88) after RA incidence. In RA, obesity (HR 1.42, 95% CI 1.02–1.99) and seronegative cyclic citrullinated peptide antibody status (HR 1.79, 95% CI 1.07–2.99), but not other risk factors, were associated with increased CTS risk. Conclusion We found a more than two‐fold increase in risk of CTS in the years preceding RA and a 1.8‐fold increased risk of incident CTS following RA onset. image

Background. The Fontan procedure has transformed the management of congenital heart defects characterized by single ventricle physiology, yet it predisposes individuals to Fontan-associated liver disease. Combined heart and liver transplantation (CHLT) emerges as a therapeutic option, but evidence of its efficacy and safety remains limited. This study aimed to comprehensively evaluate CHLT in Fontan patients, focusing on patient characteristics, perioperative outcomes, and posttransplant morbidity and mortality. Methods. Following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, a systematic search of PubMed, Embase, and the Cochrane Central Register of Controlled Trials was conducted. Studies meeting the intervention of CHLT in Fontan patients were included, and data were collected and synthesized using proportion meta-analysis techniques. Statistical analysis was carried out using R software. Results. Four studies met inclusion criteria, comprising 67 Fontan patients undergoing CHLT. All included studies were observational retrospective cohorts performed in the United States. The 1-y survival rate post-CHLT was 88% (95% confidence interval [CI], 70%-98%). Liver graft rejection rates were low, 4% (95% CI, 0%-22%), and no heart graft rejection greater than mild was reported. Postoperative complications included acute kidney injury 75% (95% CI, 50%-93%), temporary dialysis 27% (95% CI, 9%-51%), neurologic events 7% (95% CI, 0%-26%), infection 23% (95% CI, 3%-55%), and unplanned medical procedures 40% (95% CI, 23%-59%). Conclusions. CHLT in Fontan patients demonstrates promising survival rates, but graft rejection and postoperative complications pose challenges. The rate of renal complications is particularly notable and requires further evaluation. Future research should prioritize comparative different management strategies and long-term follow-up to refine protocols and optimize outcomes.

Abstract Objective Glucocorticoid withdrawal syndrome (GWS) may develop in patients following successful surgery for endogenous hypercortisolism. Effective strategies to minimize GWS and improve quality of life (QoL) are currently lacking. We aimed to determine the impact of hydrocortisone vs prednisone therapy on GWS and QoL during the first 12 weeks postsurgery. Methods Single-center prospective cohort study (2019-2024) of adults with endogenous hypercortisolism who developed postoperative adrenal insufficiency and treated with either prednisone or hydrocortisone. Quality of life was assessed with Short Form-36 (SF-36) and Cushing QoL questionnaires at baseline and at 12 weeks postsurgery. GWS was assessed using weekly AddiQoL questionnaires for the first 12 weeks postsurgery. Results Of 165 patients, 101 (61%) were treated with hydrocortisone and 64 (39%) with prednisone. At baseline, no group differences were found in the hypercortisolism subtype, comorbidities, or QoL assessments. At follow-up, no group differences in final total daily hydrocortisone equivalent dose were seen. When adjusting for the baseline QoL assessment, patients treated with prednisone demonstrated a higher degree of improvement in their QoL, particularly in the SF-36 mental component score (estimate 0.33, 95% CI, 0.04-0.63), SF-36 role-emotional limitation (estimate 0.52, 95% CI, 0.2-0.84), and SF-36 body pain (estimate 0.31, 95% CI, 0.07-0.56) subcomponents. In the multivariable analysis of age, sex, body mass index, glucocorticoid type, baseline clinical severity score, and baseline QoL assessment, prednisone therapy was an independent predictor of better SF-36 mental component at 12 weeks postsurgery. Conclusions Prednisone therapy was associated with better mental health QoL than hydrocortisone at 12 weeks postsurgery in patients with hypercortisolism.

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.

Immunosuppression within the tumor microenvironment (TME) poses a significant challenge to the efficacy of Chimeric Antigen Receptor (CAR) T-cell therapy in solid tumors, including glioblastoma (GBM), the most common and deadly primary brain tumor. Tumor and TME-residing immunosuppressive cells can hijack program death 1(PD1) pathway to evade antitumor T-cell immunity by upregulating its ligand, PD-L1. Thus, targeting PD-L1 emerges as a promising therapeutic strategy to simultaneously eliminate tumor cells and immunosuppressive components within the TME. We developed a novel PD-L1-targeting CAR T-cell therapy, MC9999, and investigated its therapeutic effects against GBM. The antigen-specific cytotoxicity of MC9999 CAR T-cells was firmly validated using a LN229 GBM cell line and its PD-L1-deficient variant, as well as patient-derived brain tumor-initiating cells (BTICs). Furthermore, in vivo therapeutic antitumor effects were confirmed in orthotopic GBM models through intracranial administration of MC9999 CAR T-cells. To pave the way to the translation of MC9999 CAR T-cell therapy to patient bedside, we established a unique experimental system using patient-specific CAR T-cells against their own tumor and immunosuppressive cells. High-quality, patient-specific MC9999 CAR T-cells were manufactured using T cells isolated from peripheral blood, while paired autologous BTICs were generated to serve as target cells. Autologous immunosuppressive cells include monocyte-derived M2 macrophages from patient’s peripheral blood and tumor-associated macrophages (TAMs) isolated from patient’s tumor. Data from multiple patients’ samples consistently demonstrated that these patient-specific MC9999 CAR T-cells elicited robust cytotoxicity against autologous GBM tumor and TME-residing immunosuppressive cells, supporting our hypothesis that targeting PD-L1 effectively address both tumor and its TME. Immunohistochemistry (IHC) staining of our GBM patients’ tissues showed that PD-L1 expression was restricted to tumor cells and macrophages /microglia within the tumor, with no expression detected in neurons, astrocytes, oligodendrocytes, or blood vessels. These findings suggest that MC9999 CAR T-cells can be safely delivered to the brain without compromising normal cell populations. Ongoing studies are underway to further validate the safety profile of MC9999 CAR T-cell therapy. Collectively, the data obtained from this preclinical study support the effectiveness, feasibility and safety of local administration of MC9999 CAR T-cells as a promising new approach for GBM treatment. These encouraging results have motivated us to prepare an Investigational New Drug application to initiate a phase I clinical trial. Citation Format: Yan Luo, Yaqing Qie, Maria J. Ulloa-Navas, Jesus E. Sanchez-Garavito, Vanessa K. Jones, Martha E. Gadd, Mieu M. Brooks, Tanya Hundal, Andrew D. Brim, Isas K. Vazquez-Rosario, Haidong Dong, Alfredo Quinones-Hinojosa, Hong Qin. Intracranial delivery of MC9999 CAR T-cell therapy: a novel strategy to simultaneously eliminate GBM tumors and immunosuppressive components in the tumor microenvironment [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 4812.

Background: Despite the availability of effective vaccines and a recent decrease in annual deaths, coronavirus disease-2019 (COVID-19) remains a leading cause of death. Serological studies of anti-nucleocapsid (N) antibody response to infection provide insights into host immunobiology of adaptive immune response, which holds promise for identifying high-risk individuals for adverse acute and chronic COVID-19 outcomes. Hypothesis: Among participants previously infected with SARS-CoV-2, traditional vascular disease risk factors are associated with higher anti-N antibodies while vaccination is associated with lower anti-N antibodies. Methods: Among previously infected participants, anti-N antibodies were measured from dried blood spots collected between February 2021-February 2023 among 1,419 Collaborative Cohort of Cohorts for COVID-19 Research (C4R) participants with prior SARS-CoV-2 infection. We measured anti-N IgG antibodies reported as median fluorescence intensity (MFI) units; reactivity (i.e., seropositivity) was defined based on MFI above a validated threshold. Vascular disease risk factors were assessed via pre-pandemic in-person examination, questionnaires, and medical record review. Multivariable generalized linear models regressed anti-N reactivity (modified Poisson) or LN transformed MFI (linear). Results: Among 1,419 participants with prior infection, mean age (standard deviation) was 65.8(12.1) years, 61% were women, and 42.8% were self-reported from a race/ethnicity minority group. Participant reactivity to nucleocapsid peaked at 69% by 4 months post-infection and waned to only 44% ≥12 months after infection. After multivariable adjustment, higher anti-N antibody response was associated with older age, Hispanic (vs. White) or American Indian (vs. White) race/ethnicity, lower income and education, former smoking, and higher anti-spike antibody levels. Asian race (vs. White) and vaccination ( even after infection ) were associated with lower nucleocapsid reactivity; common cardiometabolic co-morbidities were not associated with anti-N reactivity or levels (Figures 1 and 2). Conclusions: Among participants previously infected with SARS-CoV-2, select sociodemographic and behavioral risk factors were associated with higher anti-N antibody levels while vaccination was associated with lower anti-N antibody levels. The observation that vaccination, even after infection, is related to lower anti-N antibody levels merits further investigation.