tbuckley/cabot-search huggingface dataset:
Impact of the COVID-19 pandemic on health-care usage and mental health of clinically extremely vulnerable individuals in Wales: a population-scale data linkage study
Authors: Alisha Davies, Jiao Song, Ashley Akbari, Laura Bentley, Bethan Carter, Lynsey Cross, Joanna Dundon, David Florentin, Claire Newman, Tomos Smith, Lisa Trigg, Gareth John
Journal: The Lancet (2021)

BackgroundThe public health response to the COVID-19 pandemic in the UK included advising those identified as clinically extremely vulnerable (CEV) to self-isolate within their homes. We compared the health-care usage and mental health of the CEV population with that of the general population during the pandemic.MethodsIn this retrospective population-scale data linkage study in Wales, we used person-level linked, routinely collected, data sources available within the Secure Anonymous Information Linkage Databank. Age-standardised rates of monthly planned and emergency care attendances between Jan 1, 2020, and Dec 31, 2020, were examined. We used a Cox model to explore risk factors for depression or anxiety (identified from primary care diagnosis, symptoms, and prescription Read codes).FindingsThe CEV cohort included 127 787 patients and was older than the general population (52·4% (66 963) CEV were aged ≥65 years, vs 21·0% (662 376) of the general population, p<0·0001). Average monthly trends showed that the decline in planned care was greater among the CEV than the general population from March–August, 2020 (elective admissions: –7·2% for CEV vs –0·6 for general population; outpatient attendances: –3·8% vs –1·3%), with a slower recovery into December, 2020 for CEV (elective: CEV –1.4% vs general population 3·9%; outpatient: 1·7% vs 4·1%). There were increases in both ED attendances and emergency admissions from March–August, 2020, which were greater among the general population (7·0% vs 3·1%, respectively) compared with the CEV (4·3% vs 0·5%). Being CEV (hazard ratio 1·2 [95% CI 1·2–1·3]) and historical poor mental health (3·7 [3·5–3·9]) were associated with an increased risk of anxiety or depression.InterpretationDeclines in planned care were not unexpected given the impact of COVID-19 on the National Health Service, and suggest considerable unmet need. Declines in secondary care activity amongst the CEV could reflect reluctance to attend hospital, not reduced clinical need. Reliance on an algorithm to identify CEV might have led to overestimation of the heterogeneous CEV population.FundingThe Health Foundation as part of the Networked Data Labs.
Abstract 14321: A Validation Study of Myocardial Elastography Against Coronary Computed Tomography Angiography in Patients With Coronary Artery Disease
Authors: Jad El Harake, Vincent Sayseng, Julien Grondin, Rachel Weber, Changhee Lee, Andrew J Einstein, Elisa Konofagou
Journal: Circulation (2021)

Introduction: Myocardial Elastography (ME) is a new quantitative strain imaging method capable of detecting ischemia due to Coronary Artery Disease (CAD). ME has been compared to nuclear perfusion imaging with good agreement. Coronary Computed Tomography Angiography (CCTA) has been shown to have superior accuracy to nuclear perfusion imaging for CAD staging. In this study, ME is compared to CCTA in CAD patients. Methods: High framerate (300 fps) echocardiography in five patients presented with chest pain or shortness of breath symptoms, or having prior history of CAD. Standard short-axis views were acquired at the mid-, basal, and apical left-ventricular (LV) levels using a research ultrasound system (Vantage, Verasonics) with a phased array (P4-2, Philips). ME radial systolic strain (ε) was imaged to evaluate wall thickening using 2D cross-correlation and gradient-based methods on the raw (RF) signals. Average ε within each perfusion territory (LAD, RCA, LCX) was then computed N=45. CCTA was performed using an AcquilionOne Scanner (Canon) with Iohexol (Omnipaque, GE) for contrast. Echocardiograms were coregistered with CCTA using anatomical landmarks. Results: Good qualitative agreement between ε (ME) and stenosis level (CCTA) was obtained (Fig. 1A). ME was sensitive in detecting moderate to severe stenosis showing reduced ε. At mild stenosis, despite a trend of ε reduction, some territories maintained mechanical functionality, possibly due to collateral engagement, demonstrating that both structural (CCTA) and functional (ME) properties are complementary in informing on myocardial viability and functionality, especially at mild stenosis. Future work will entail incorporation of FFR CT measurements as an additional functional reference measurement to validate ME strain.
Abstract 403: FAM210A Maintains Cardiac Mitochondrial Homeostasis Through Regulating Letm1-dependent Ca <sup>2+</sup> Efflux
Authors: Jiangbin Wu, Chinna Venkata, Si Chen, Omar Hedaya, Chen Yan, Peng Yao
Journal: Circulation Research (2021)

Mitochondria play fundamental roles in supporting healthy myocardium function. Disturbed cardiac mitochondrial homeostasis causes mitochondrial dysfunction associated with cardiomyopathy in humans and mice. Recent genome-wide association studies (GWAS) discovered that the mutations of FAM210A (family with sequence similarity 210 member A) are associated with sarcopenia and osteoporosis. Interestingly, Fam210a is most highly expressed in the heart and multiple omics analyses in mouse hearts reveal Fam210a as a hub gene in cardiac hypertrophy. However, the molecular function of FAM210A in the heart remains elusive. Here, we discover that FAM210A is critical for maintaining cardiac mitochondrial function and homeostasis. Cardiomyocyte (CM) specific knockout (KO) of Fam210a in adult mice leads to progressive heart failure with enlarged left ventricle chamber and ultimately causes mortality at ~70 days after Fam210a KO. The FAM210A deficient CMs exhibit myofilament disarray at ~9 weeks post Fam210a KO. Moreover, Fam210a KO results in a remarkably elevated mitochondrial ROS production, dramatically compromised mitochondrial membrane potential, and reduced expression of mitochondrial electron transport chain (ETC) complex genes. As a result, the mitochondrial respiratory activity is significantly reduced and the mitochondrial cristae are disrupted in Fam210a KO CMs. In contrast, at the early stage of ~5 weeks post tamoxifen-induced Fam210a KO, we observe increased mitochondrial ROS production, disturbed mitochondrial membrane potential, and reduced respiratory activity in CMs prior to heart failure. Transcriptomic and proteomic analyses from Fam210a KO hearts indicate that FAM210A deficiency causes chronic integrated stress response (ISR) in the heart. Mechanistically, Interactome analyses show that FAM210A binds to mitochondrial Ca 2+ /H + exchanger LETM1 (leucine zipper and EF-hand containing transmembrane protein 1) and regulates LETM1-mediated mitochondrial Ca 2+ efflux. Altogether, we discover a novel function of FAM210A in maintaining the cardiac mitochondrial homeostasis by regulating mitochondrial Ca 2+ efflux, and deficiency of FAM210A causes mitochondrial dysfunction and leads to heart failure.
Abstract 11448: Time from Blood Draw to Multiple Electrode Aggregometry and Association with On-Clopidogrel Platelet Reactivity
Authors: David Hesselbarth, Diona Gjermeni, Sofia Szabo, Hannah Vetter, Viktoria Anfang, Philipp Diehl, Martin Moser, Christoph Bode, Christoph Olivier
Journal: Circulation (2021)

Background: Guidelines consider platelet function testing to guide dual antiplatelet therapy (DAPT) de-escalation in selected patients. On-clopidogrel platelet reactivity as measured by multiple electrode aggregometry (MEA) varies according to patients′ characteristics but may also depend on pre-analytic factors. Purpose: This study aimed to analyze the association of time from blood draw to MEA results in patients undergoing percutaneous coronary intervention (PCI). Methods: In this observational single center cohort study, in patients undergoing PCI, all patients received DAPT with ASA and clopidogrel. Platelet aggregation (aggregation units, U) was quantified by MEA (Multiplate Analyzer) after stimulation with adenosine diphosphate (ADP; 6.4 μM in patients treated with ASA and clopidogrel following PCI. High on-clopidogrel platelet aggregation (HPR) was defined as ≥46 U. The manufacturer recommends performing the analysis within 30-180 min after blood draw. Thus, patients were grouped according to the time from blood draw to MEA: 1) 30-180 min 2) &lt;30 min 3) &gt;180 min. Results: Platelet function of 273 patients with coronary artery disease undergoing PCI with DAPT were analyzed. The median age was 72 years (interquartile range, IQR 62-79) and 179 (66%) were male. Median ADP-induced aggregation was 25 (IQR 18-36) U. HPR was observed in 34 patients (12%). Median time to MEA was 65 (IQR 45-113) min and 245 measurements (90%) were performed within 30-180 min as recommend by the manufacturer of the aggregometer. Compared with measurements performed within the manufacturers′ recommendations (25 [IQR 18-36] U, median ADP-induced aggregation was not significantly different if performed outside these recommendations (&lt;30min: 24 [IQR 20-28] U, p=0.54; &gt;180min: 25 [IQR 21-40] U, p=0.31). For those analyzed within 30-180 min from blood draw, no relevant correlation of time from blood draw to MEA with ADP-induced platelet aggregation was observed (r= - 0.04; p=0.51). Conclusion: In patients undergoing percutaneous coronary intervention and treated with dual antiplatelet therapy, the time from blood draw to multiple electrode aggregometry does not correlate with ADP-induced aggregation.
Abstract 10583: A Novel Functional Variant, P.Gln419Pro, Residing Outside the <i>SCN5A</i> -Encoded Na <sub>V</sub> 1.5 Voltage-Sensing Domain Causes Multifocal Ectopic Purkinje-Related Premature Contractions
Authors: Xiaozhi Gao, Dan Ye, Wei Zhou, David J Tester, Michael J Ackerman, John Giudicessi
Journal: Circulation (2021)

Background: Multifocal ectopic Purkinje-related premature contractions (MEPPC), the most recent addition to the spectrum of SCN5A -mediated cardiac channelopathies, is characterized by frequent premature ventricular complexes (PVCs) originating from the Purkinje system, atrial arrhythmias, and a predilection for PVC-mediated dilated cardiomyopathy. MEPPC-causative variants tend to cluster within the voltage sensing domain (VSD) of Na v 1.5. Objective: To describe the clinical and cellular electrophysiological phenotype associated with a novel, putative MEPPC-causative SCN5A variant (p.Gln419Pro-SCN5A) that resides outside the VSD of Na v 1.5. Methods: p.Gln419Pro-SCN5A was identified in a 21-year-old male with a history of frequent, multifocal PVCs and atrial tachycardia. Subsequently, three p.Gln419Pro-SCN5A-positive relatives, each with early onset atrial arrhythmias and/or frequent, multifocal PVCs, were identified. All individuals had structurally normal hearts by echocardiography and/or cardiac magnetic resonance imaging. p.Gln419Pro-SCN5A was engineered by site directed mutagenesis and heterologously expressed in TSA201 cells. The standard whole-cell patch clamp technique was used to measure SCN5A wild-type (WT) and p.Gln419Pro-SCN5A sodium currents. Results: Analysis of the current-voltage relationship revealed that neither peak sodium current densities nor late inward sodium current were impacted by p.Gln419Pro-SCN5A. However, p.Gln419Pro-SCN5A significantly shifted V 1/2 in inactivation by -4.6 mV from -84.5±0.7 mV (WT, n=10) to -89.1±0.4 mV (Gln419Pro, n=12, p&lt;0.05 vs. WT) and V 1/2 in activation by -11.6 mV from -30.9±1.3 mV (WT, n=10) to -42.5±1.0 mV (Gln419Pro, n=12, p&lt;0.05 vs. WT) leading to a larger hyperpolarized window current. Flecainide dramatically reduced PVC burden in p.Gln419Pro-SCN5A-positive patients. Conclusions: p.Gln419Pro-SCN5A represents only the fifth MEPPC-causative variant described to date and the first associated with a classic MEPPC phenotype localizing outside Na v 1.5’s VSD. As class I antiarrhythmic drugs are highly efficacious in MEPPC, this clinical entity merits consideration in all young patients found to have a high burden of Purkinje-related PVCs.
Abstract 10805: Income and Antiplatelet Adherence Following Acute Coronary Syndrome: An Administrative Claims Analysis
Authors: Anna R Larosa, Gretchen Swabe, Jared W Magnani
Journal: Circulation (2021)

Introduction: Income and social resources are associated with cardiovascular health and outcomes. We examined income and medication adherence following acute coronary syndromes (ACS). We hypothesized that following percutaneous coronary intervention (PCI), individuals with lower income would have lower adherence to antiplatelet agents than higher income referents. Methods: We employed administrative claims of commercially insured and Medicare Advantage beneficiaries (Optum's de-identified Clinformatics® Data Mart Database) with incident ST- and non-ST elevation myocardial infarction from 2017-19. We collected data on age, sex, race, education, and covariates (medications, healthcare visits, insurance type, copay, antiplatelet type, and Elixhauser Comorbidity Index conditions). We compared antiplatelet adherence, measured with proportion of days covered (PDC) using up to 12 months of pharmacy claims, across income categories (&lt;$40K; $40-49K; $50-59K; $60-74K; $75-99K; and ≥$100K). Our multivariable-adjusted regression models determined odds of non-adherence (PDC&lt;80%) with the highest income category as referent. Results: Our dataset included 31,272 individuals (age 72.5 ±11.9, 34.3% women, 22.6% non-White) who presented with ACS and underwent PCI. We observed graded, decreased antiplatelet adherence across income categories (Figure): rates of PDC≥80% decreased with successively lower income, from 84.3% (≥$100K) to 73.1% (&lt;$40K). Individuals with income &lt;$40K had 1.6-fold higher odds of non-adherence (95% CI, 1.43-1.75) compared to those with income ≥$100K after multivariable adjustment. Conclusions: Lower income is associated with lower adherence to antiplatelet agents following PCI for ACS. These results support consideration of income and long-term barriers to medication access as part of strategies to address adherence.
Abstract 13025: The Inferior Vena Cava Plethora Is A Predictor Of Bleeding Events In Patients With Heart Failure With Reduced Ejection Fraction And Atrial Fibrillation
Authors: Kyuho Lee, Seung-young Roh, Soohyung Park, Seungmin Back, Jieun Lee, Dong O Kang, Ji Bak Kim, Jah Choi, Jin O Na, Cheol Ung Choi, Jin W Kim, Seung Woon W Rha, Chang Gyu Park, Hong-Seog Seo, Eung Ju Kim
Journal: Circulation (2021)

Introduction: In patients have heart failure with reduced ejection fraction (HFrEF) and atrial fibrillation (AF), anticoagulation therapy to prevent thromboembolic events was essential but occurs often bleeding complication. We explored echocardiographic markers to predict clinical outcome. Method: In-hospitalized 282 patients with HFrEF and AF between 2000 and 2021 were retrospectively analyzed. The presence of inferior vena cava plethora (IVCP) was confirmed by echocardiography at the time of admission. Eighty-five patients who had IVCP (IVCP group) was compared to 197 patients (70%) who did not have IVCP (control group) Result: IVCP group had more CKD (24% vs 13%, p=0.036), lower platelet (171k±63 vs 192k±64, p=0.007) and lower left ventricular ejection fraction (30±9 vs 34±11 p=0.001) than control group. Major bleeding event during 5 years follow up occurs significantly higher in IVCP group (Kaplan Meier Method, Log rank p=0.042) (figure). Gastrointestinal (GI) bleeding was 73% of major bleeding. In multivariable analysis, the IVCP was independent predictor of major bleeding (HR, 2.17; 95% CI 1.06-4.44). Conclusion: In patients with HFrEF and AF requiring antithrombotic treatment, IVCP was a predictor of major bleeding, especailly GI bleeding.
Abstract 14387: Impact of Bariatric Surgery on Mortality and Heart Failure Readmissions in Heart Failure With Reduced Ejection Fraction
Authors: Harsh P Patel, Samarthkumar J Thakkar, Aakash Sheth, Rezwan Munshi, Varun Victor, Smit Patel, Bhavin Patel, bipul baibhav, Alok Gandhi, Scott Feitell, Vishal Parikh
Journal: Circulation (2021)

Introduction: Real-world data on the impact of bariatric surgery in patients with acute heart failure with reduced ejection fraction (HFrEF) is limited. Hypothesis: Bariatric surgery in patients with HFrEF is associated with a reduction in mortality and HF readmissions at 1 year. Methods: We identified patients with HFrEF that underwent bariatric surgery by analyzing the nationwide readmission database from September 2015 to December 2018 and using the validated ICD-10 CM codes. Propensity score matching was performed to adjust for the confounders. Kaplan Meier curves were utilized for time to event analysis. Cox proportional hazard regression was used to generate hazard ratios. The primary outcome was all-cause mortality at 1 year. Secondary outcomes were readmission due to HF and any other cause at 1 year. Results: Out of 348668 patients with HFrEF, 1519 underwent bariatric surgery. After propensity match, we identified 1519 patients with bariatric surgery and 1544 patients without bariatric surgery. At 1 year, there was no significant difference in all-cause mortality between both the groups (4.01% vs. 3.14%, HR: 0.62, 95% CI: 0.31-1.26, p=0.19). Moreover, regarding the secondary outcomes, there was no significant difference in HF readmissions (20.92% vs. 22.16%, HR: 1.06, 95% CI: 0.89-1.25, p=0.48) as well as readmission due to any other cause (46.24% vs. 46.78%, HR: 0.97, CI: 0.87-1.09, p=0.97) among both the groups at 1 year. Conclusions: Bariatric surgery in patients with HFrEF did not reduce the mortality, HF readmissions, or readmissions due to any cause at 1 year. We need more data looking at larger sample size, long-term follow-up, and quality of life.
IMMU-11. SELECTIVE ENRICHMENT OF SUPPRESSED IMMUNE CELLS IN THE TUMOR MICROENVIRONMENT CORRELATES WITH ESTABLISHMENT OF DISTINCT IMMUNOLOGIC NICHES IN HUMAN GLIOBLASTOMAS CONTACTING THE LATERAL VENTRICLE
Authors: Todd Bartkowiak, Asa Brockman, Bret Mobley, Akshitkumar Mistry, Sierra Barone, Madeline Hayes, Caroline Roe, Justine Sinnaeve, Nalin Leelatian, Allison Greenplate, Lola Chambless, Reid Thompson, Kyle Weaver, Jonathan Irish, Rebecca Ihrie
Journal: Neuro-Oncology (2021)

Abstract Glioblastomas (GBM) account for 60% of adult primary brain tumors. With few advances in therapeutics, median overall survival remains 15-months post-diagnosis. Immunotherapies may provide therapeutic benefit in GBM patients; however, no predictive immune features currently inform therapeutic stratification in GBM. We have shown that, independently of known prognosticators, radiographic tumor contact with the lateral ventricle (C-GBM) correlates with 7-months worse prognosis compared to patients with ventricle non-contacting GBM (NC-GBM). This study sought to characterize the GBM immune microenvironment and identify targetable mechanisms of immunosuppression correlating with worse outcomes in C-GBM. Primary glioblastoma specimens were resected in accordance with the Declaration of Helsinki (IRB #131870). Twelve patients presented with C-GBM and thirteen with NC-GBM. Machine learning tools applied to mass cytometry data characterized tumor-infiltrating immune populations and identified biomarkers correlating with C-GBM and patient survival. C-GBM tumors were enriched in blood-derived macrophages compared to NC-GBM (19 ± 8% vs. 6 ± 2%; p&amp;lt; 0.001) and depleted in lymphocytes (2.9 ± 1% vs. 7.6 ± 2%; p&amp;lt; 0.001) and tissue-resident microglia (1.8 ± 0.3% vs. 7 ± 3%; p&amp;lt; 0.001). Further, T cells in C-GBM co-expressed the checkpoint receptors PD-1 and TIGIT, suggesting acute T cell exhaustion. Multiplex immunohistochemistry (mxIHC) on matched FFPE tissue provided spatial context to risk-stratifying immune populations, and defined structured immunological niches within the TME. Macrophage-tumor niches were most common (36%), followed by T cell-microglia-tumor niches (26%). Within niches, T cell-T cell interactions were more prevalent (log odds ratio = 0.90) whereas T cell-macrophage interactions were less prevalent (log odds ratio = -1.61). These findings suggest that factors within the periventricular space may influence antitumor immunity within tumors, and identify clinically targetable immune biomarkers in glioblastoma. Notably, radiologic assessment of lateral ventricle contact by standard-of-care MRI may guide clinical trial design for immunotherapies in neuro-oncology.
Delayed antiretroviral therapy in HIV-infected individuals leads to irreversible depletion of skin- and mucosa-resident memory T cells
Authors: Simona Saluzzo, Ram Vinay Pandey, Laura Marie Gail, Ruth Dingelmaier-Hovorka, Lisa Kleissl, Lisa Shaw, Bärbel Reininger, Denise Atzmüller, Johanna Strobl, Veronique Touzeau-Römer, Andrea Beer, Clement Staud, Armin Rieger, Matthias Farlik, Wolfgang Weninger, Georg Stingl, Georg Stary
Journal: Immunity (2021)
The Decrease of Anti-CD3 Antibody Concentration Improved the Cytotoxicity of Chimeric Antigen Receptor (CAR) T Cells in the Treatment of Chronic Lymphoblastic Leukemia (CLL)
Authors: Sanmei Wang, Yilian Yang, Yu Zhu, Lei Fan, Michael Schmitt, Maria Luisa Schubert, Jianyong Li
Journal: Blood (2021)
Abstract 12824: Culprit Plaque Morphology and Healing Capacity in Patients With and Without Pre-Infarction Angina: An Optical Coherence Tomography Imaging Study
Authors: Rocco Vergallo, Alfredo Ricchiuto, Ridolfi Francesco, Marco Lombardi, Alessandro Maino, Angela Buonpane, Emiliano Bianchini, Mattia Galli, D'Amario Domenico, Rocco Montone, Antonio Maria Leone, cristina aurigemma, Enrico Romagnoli, Antonino Buffon, Francesco Burzotta, Carlo Trani, Filippo crea
Journal: Circulation (2021)

Introduction: The relationship between culprit plaque morphology, healed culprit plaques prevalence and clinical presentation of acute myocardial infarction (AMI) remains largely unexplored. Hypothesis: We hypothesized that pre-infarction angina (PIA) may reflect a distinct morphologic phenotype of culprit plaques and a different healing capacity. Methods: We conducted a retrospective observational study in patients with AMI who underwent intracoronary optical coherence tomography (OCT) imaging of the culprit lesion before PCI at the Fondazione Policlinico Gemelli-Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome. Based on the clinical history, patients were classified into 2 groups: i) PIA group, defined as either intermittent chest pain within 6 hours preceding the final episode of chest pain, or unstable angina (or both) in the week preceding AMI; or ii) no-PIA group, defined as a single episode of chest pain without prodromal symptoms in the preceding week. Culprit plaques were classified as plaque rupture (PR) or intact fibrous cap (IFC), and presence of layered appearance (healed plaque, HP) was assessed. Thrombus burden (TB) was estimated, and prevalence of diffuse calcification, neovascularization, and OCT-defined macrophage accumulation were evaluated. Results: A total of 102 patients with AMI were included (50 PIA, 52 no-PIA). Patients with PIA showed a higher prevalence of IFC than PR (58% vs 42%, p=0.030). PR in patients with PIA were more frequently associated with macrophage accumulation (71.4% vs 28.6% p=0.001), and TB tended to be lower [22.0 (15.8-30.3) vs. 38.5 (12.8-67.5), p=0.145]. Diffuse calcifications were significantly less frequent in patients with PIA (22.0% vs. 40.4%, p=0.045), while neovascularization tended to be more frequent (58.0% vs. 42.3%, p=0.113). HPs prevalence was significantly higher in the PIA than in the no-PIA group (66.0% vs 25.0%, p&lt;0.001). Conclusions: Patients with PIA have a distinct culprit plaque phenotype, more frequently characterized by IFC and a relatively lower TB, with a significantly higher prevalence of plaque healing.