Citations

Objective: To investigate the longitudinal effects of COVID-19 on major vascular structures and parameters and clinical outcomes. Design: Observational prospective trial. Setting: Post-COVID-19 research clinic established by University of Louisville Division of Infectious Diseases. Participants: The study population consisted of 72 post-COVID-19 individuals and 11 non-COVID-19 infected participants in the control group. The participants were recruited from adult hospitals and from the community. The enrollment started in October 2020 and follow-up periods were at 3, 6, and 12 months from their initial COVID-19 diagnosis. Interventions: The participants were interviewed for medical and COVID-19 infection history. Samples of white blood cell (WBC), C-reactive protein (CRP), and D-dimer were taken at each visit. Certified sonographers performed vascular ultrasound on the study participants. Measurements and Main Results: Median intima-media thickness (IMT) was increased in mild/asymptomatic (0.80 mm) and severe/critical (0.90 mm) groups when compared with controls (0.60 mm; P < .001 for both groups). In the asymptomatic/mild group, 6-month median IMT (0.88 mm) was increased, compared with the 3-month group (0.75 mm), with P = .026. Increased age was associated with decreased mean arterial blood velocities (cm/s): common carotid ( r = −0.236, P = .032), internal carotid ( r = −0.208, P = .048), and subclavian artery mean velocity ( r = −0.357, P = .003). We did not find any instance of deep vein thrombosis. Median D-dimer, CRP, and WBC in the control group differed from asymptomatic/mild COVID-19 group ( P = .026, .011, and .003, respectively). Moreover, WBC in the asymptomatic/mild group and moderate COVID-19 group differed from severe/critical group ( P = .025 and P = .027, respectively); CRP also differed between asymptomatic/mild group and severe/critical group ( P = .014). Conclusions: There were differences in intima-media lumen thickness (IMT), arterial velocities, and inflammatory markers in post-COVID-19 patients. There was no instance of deep vein thrombosis in this post-COVID-19 study cohort. The increased IMT might infer atherosclerosis, which has shown to increase cardiovascular risks. It is not yet known whether the increase in IMT due to COVID should be treated in the same way as non-COVID-19 atherosclerosis—through statins, for example—or whether regular cardiovascular risk reduction would be useful. Clinical trial and mechanistic studies should be performed to further our understanding of COVID-19-related vascular pathologies.

Abstract Atrial fibrillation (AF) is a globally prevalent cardiac arrhythmia with significant genetic underpinnings, as highlighted by recent large-scale genetic studies. A prominent clinical and genetic overlap exists between AF, heritable ventricular cardiomyopathies, and arrhythmia syndromes, underlining the potential of AF as an early indicator of severe ventricular disease in younger individuals. Indeed, several recent studies have demonstrated meaningful yields of rare pathogenic variants among early-onset AF patients (∼4%–11%), most notably for cardiomyopathy genes in which rare variants are considered clinically actionable. Genetic testing thus presents a promising opportunity to identify monogenetic defects linked to AF and inherited cardiac conditions, such as cardiomyopathy, and may contribute to prognosis and management in early-onset AF patients. A first step towards recognizing this monogenic contribution was taken with the Class IIb recommendation for genetic testing in AF patients aged 45 years or younger by the 2023 American College of Cardiology/American Heart Association guidelines for AF. By identifying pathogenic genetic variants known to underlie inherited cardiomyopathies and arrhythmia syndromes, a personalized care pathway can be developed, encompassing more tailored screening, cascade testing, and potentially genotype-informed prognosis and preventive measures. However, this can only be ensured by frameworks that are developed and supported by all stakeholders. Ambiguity in test results such as variants of uncertain significance remain a major challenge and as many as ∼60% of people with early-onset AF might carry such variants. Patient education (including pretest counselling), training of genetic teams, selection of high-confidence genes, and careful reporting are strategies to mitigate this. Further challenges to implementation include financial barriers, insurability issues, workforce limitations, and the need for standardized definitions in a fast-moving field. Moreover, the prevailing genetic evidence largely rests on European descent populations, underscoring the need for diverse research cohorts and international collaboration. Embracing these challenges and the potential of genetic testing may improve AF care. However, further research—mechanistic, translational, and clinical—is urgently needed.

Abstract Funding Acknowledgements None. Background Hyperoxemia (a high PaO2, i.e. &gt;200-300 mmHg) has been associated with adverse outcomes in general critical care settings as well as in acute cardiovascular care conditions. The association between hyperoxemia and mortality has not been characterized in the heterogeneous population admitted to the cardiac intensive care unit (CICU). We aimed to examine the association between hyperoxemia on CICU admission with in-hospital mortality. Methods We retrospectively analyzed Mayo Clinic CICU patients from January 2007 to April 2018. PaO2 closest on admission was analyzed as a continuous variable (per 100 mmHg) and categorized as: 60-100 mmHg (51.9%), 101-150 mmHg (28.6%), 151-200 mmHg (10.6%), 201-300 mmHg (6.4%), and &gt;300 mmHg (2.5%). Those without PaO2 on admission and those with hypoxemia were excluded. The primary outcome was all-cause in-hospital mortality evaluated using logistic regression, after adjusting for age, Charlson Comorbidity Index, M-CARS, and use of IMV and NIPPV. Results A total of 3,368 patients were included (median 70.3 years, 39.4% women). Admission diagnoses included ACS (37.0%, with 19.8% STEMI), HF (67.8%), shock (33.0%) and cardiac arrest (25.3%). Median admission PaO2 was 99 (IQR 78, 136) mmHg, with no difference in median PaO2 between hospital survivors and inpatient deaths (99 versus 98, p = 0.38). A J-shaped relationship was observed between admission PaO2 and in-hospital mortality (Figure A), with slightly higher mortality below 100 mmHg and incrementally higher mortality above this threshold (esp. at &gt;200 mmHg). The incremental association between higher PaO2 and mortality (adjusted OR 1.17 per 100 mmHg higher, 95% CI 1.01-1.34, P = 0.03) was focused in the highest PaO2 group (i.e., &gt;300 mmHg; Figure B). Conclusion Hyperoxia (esp. PaO2 &gt;300 mmHg) on CICU admission is associated with increased in-hospital mortality, demonstrating a J-shaped association with an inflection point of lowest mortality around 100 mmHg. Further studies are warranted to assess if specific oxygen targets influence outcomes in critically ill cardiac patients.

Abstract Background: Germline Pathogenic Variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are known to increase breast cancer (BCa) risk, but the effect of these PVs on tumor biology is not well-understood. Ki-67 is an established prognostic marker in hormone receptor (HR) positive breast cancer but the distribution of Ki-67 in breast cancer associated with germline PVs is not known. Methods: The study included patients with loco-regional (Stage I-III) HR-positive (ER+ or PR+), HER2-negative invasive ductal or lobular breast cancer evaluated at Mayo Clinic for curative intent treatment between 2012 and 2021. PV carrier status was ascertained in more than two-thirds of cases from germline whole exome sequencing (Regeneron) of patients who participated in a prospective registry at Mayo Clinic. Additional PV carriers were identified through a review of the results of clinical germline genetic testing in electronic medical records aided by natural language processing. Clinically performed Ki-67 values were abstracted from electronic medical records and analyzed as continuous and categorical variables (low: &lt; 20% vs. high: ≥20%). Throughout the timeline of the study, a consistent method for assessment of Ki-67 was utilized at Mayo Clinic, Rochester: Immunohistochemical staining of the Ki-67 antigen in formalin-fixed paraffin-embedded tissue was performed using MIB-1 clone, the scanned slides were reviewed by a technologist and traced areas further analyzed for Ki-67 using Aperio Software. Patients who received neoadjuvant therapy prior to the assessment of Ki-67, with metastatic disease at diagnosis, with PVs in two or more genes of interest, or unknown germline PV or Ki-67 status were excluded from the analysis. Multiple primary tumors in the same patient diagnosed within one year of each other were analyzed independently. The control (non-carrier) group included randomly selected patients from the prospective registry who tested negative for PVs in the five genes over the same time period. Ki-67 values were compared between germline PV carriers and non-carriers in a multivariable logistic regression analysis adjusting for sex, race, age at diagnosis, stage at presentation, and histology of the tumor. Results: A total of 113 HR+/HER2- tumors from 111 PV carriers (ATM: 27, BRCA1: 24, BRCA2: 28, CHEK2: 22, and PALB2:12) along with 431 HR+/HER2- tumors from 422 randomly selected non-carriers were evaluated. The majority (&gt;95%) of patients were non-Hispanic White. Germline PV carriers in each gene were diagnosed at a significantly younger age (P&lt; 0.05) compared to non-carriers. The median Ki-67 value was 12 (Range: 1 to 93) for non-carriers, 16 (Range: 0 to 79) for ATM, 31 (Range: 4 to 86) for BRCA1, 30 (Range: 6 to 80) for BRCA2, 13 (Range: 1 to 38) for CHEK2, and 20 (Range: 3 to 46) for PALB2 PV carriers. In multivariable analysis, compared to non-carriers, we observed significantly higher odds of a high Ki67 value (≥20%) for tumors arising from germline PV carriers in BRCA1 (Odds Ratio (OR): 7.3, 95%CI: 2.3 – 23.3, p&lt; 0.001), BRCA2 (OR: 3.0, 95%CI: 1.2 – 7.4, p=0.02) and PALB2 (OR: 3.9, 95%CI: 1.1 – 14.5, p=0.04). No such relationship was observed with either ATM (OR: 1.1, 95%CI: 0.4 – 2.9, p=0.81) or CHEK2 (OR: 0.8, 95%CI: 0.3 – 2.2, p=0.63). Conclusion: This study reveals that HR+/HER2- tumors in BRCA1, BRCA2, and PALB2 PV carriers have a significantly higher Ki-67 expression compared to non-carriers. These findings have implications for understanding prognosis and endocrine response PV with HR+ breast cancer. Further exploration of the relationships between Ki67 and germline PV status is necessary to personalize systemic therapy options in germline PV carriers. Acknowledgments: Thank you to Regeneron Genetics Center. The study was funded in part by the NIH Specialized Program of Research Excellence in Breast Cancer [P50CA116201] to Mayo Clinic, Mayo Clinic Department of Oncology Small Grants Program, and the Paul Calabresi Program at Mayo Clinic Citation Format: Robert Scheel, Grace Choong, Tara Rao, Nicholas Boddicker, Chunling Hu, Jie Na, Vinod Kaggal, Sean Murphy, Karthik Giridhar, Saba Yasir, Matthew Goetz, Fergus Couch, Siddhartha Yadav. Ki-67 Expression in Breast Cancer associated with ATM, BRCA1, BRCA2, CHEK2 and PALB2 Pathogenic Variants [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-08-07.

AbstractPurposeBy assessing longitudinal associations between COVID‐19 census burdens and hospital characteristics, such as bed size and critical access status, we can explore whether pandemic‐era hospital quality benchmarking requires risk‐adjustment or stratification for hospital‐level characteristics.MethodsWe used hospital‐level data from the US Department of Health and Human Services including weekly total hospital and COVID‐19 censuses from August 2020 to August 2023 and the 2021 American Hospital Association survey. We calculated weekly percentages of total adult hospital beds containing COVID‐19 patients. We then calculated the number of weeks each hospital spent at Extreme (≥20% of beds occupied by COVID‐19 patients), High (10%–19%), Moderate (5%–9%), and Low (<5%) COVID‐19 stress. We assessed longitudinal hospital‐level COVID‐19 stress, stratified by 15 hospital characteristics including joint commission accreditation, bed size, teaching status, critical access hospital status, and core‐based statistical area (CBSA) rurality.FindingsAmong n = 2582 US hospitals, the median(IQR) weekly percentage of hospital capacity occupied by COVID‐19 patients was 6.7%(3.6%–13.0%). 80,268/213,383 (38%) hospital‐weeks experienced Low COVID‐19 census stress, 28% Moderate stress, 22% High stress, and 12% Extreme stress. COVID‐19 census burdens were similar across most hospital characteristics, but were significantly greater for critical access hospitals.ConclusionsUS hospitals experienced similar COVID‐19 census burdens across multiple institutional characteristics. Evidence‐based inclusion of pandemic‐era outcomes in hospital quality reporting may not require significant hospital‐level risk‐adjustment or stratification, with the exception of rural or critical access hospitals, which experienced differentially greater COVID‐19 census burdens and may merit hospital‐level risk‐adjustment considerations.

ObjectivesTo report an autoimmune paraneoplastic encephalitis characterized by immunoglobulin G (IgG) antibody targeting synaptic protein calmodulin kinase‐like vesicle‐associated (CAMKV).MethodsSerum and cerebrospinal fluid (CSF) samples harboring unclassified antibodies on murine brain‐based indirect immunofluorescence assay (IFA) were screened by human protein microarray. In 5 patients with identical cerebral IFA staining, CAMKV was identified as top‐ranking candidate antigen. Western blots, confocal microscopy, immune‐absorption, and mass spectrometry were performed to substantiate CAMKV specificity. Recombinant CAMKV‐specific assays (cell‐based [fixed and live] and Western blot) provided additional confirmation.ResultsOf 5 CAMKV‐IgG positive patients, 3 were women (median symptom‐onset age was 59 years; range, 53–74). Encephalitis‐onset was subacute (4) or acute (1) and manifested with: altered mental status (all), seizures (4), hyperkinetic movements (4), psychiatric features (3), memory loss (2), and insomnia (2). Paraclinical testing revealed CSF lymphocytic pleocytosis (all 4 tested), electrographic seizures (3 of 4 tested), and striking MRI abnormalities in all (mesial temporal lobe T2 hyperintensities [all patients], caudate head T2 hyperintensities [3], and cortical diffusion weighted hyperintensities [2]). None had post‐gadolinium enhancement. Cancers were uterine adenocarcinoma (3 patients: poorly differentiated or neuroendocrine‐differentiated in 2, both demonstrated CAMKV immunoreactivity), bladder urothelial carcinoma (1), and non‐Hodgkin lymphoma (1). Two patients developed encephalitis following immune checkpoint inhibitor cancer therapy (atezolizumab [1], pembrolizumab [1]). All treated patients (4) demonstrated an initial response to immunotherapy (corticosteroids [4], IVIG [2]), though 3 died from cancer.InterpretationCAMKV‐IgG is a biomarker of immunotherapy‐responsive paraneoplastic encephalitis with temporal and extratemporal features and uterine cancer as a prominent oncologic association. ANN NEUROL 2024;96:21–33