tbuckley/cabot-search huggingface dataset:
Abstract 12165: The Ratio of Right Ventricular Global Longitudinal Strain and Pulmonary Artery Systolic Pressure Determines Persistent Tricuspid Regurgitation After Closure of Atrial Septal Defect
Authors: seonhwa lee, Dae-Young Kim, Jiwon Seo, Iksung Cho, Geu-Ru Hong, Jong-Won Ha, Chi Y Shim
Journal: Circulation (2021)

Introduction: Functional tricuspid regurgitation (TR) will decrease after atrial septal defect (ASD) closure, but it may persist and require additional tricuspid valve (TV) surgery or intervention. Hypothesis: We aimed to find echocardiographic predictors for persistent TR after successful ASD closure. Methods: Among 348 adults who underwent isolated ASD closure between January 2010 and September 2020, 91 (26.1%) patients with significant TR (at least moderate degree) before ASD closure were included. Persistent TR was defined as a significant TR even after ASD correction on echocardiogram after 6 months to 1 year. To find echocardiographic predictors for persistent TR, conventional and speckle tracking echocardiography performed before ASD closure were analyzed. The right ventricular (RV)-pulmonary arterial coupling was assessed by the ratio of RV global longitudinal strain (RV GLS) and pulmonary arterial systolic pressure (PASP) (RV GLS/PASP). Results: Persistent TR was observed in 22 (24.2%) patients. Patients with persistent TR were significantly older, with larger TR jet area and lower RV GLS/PASP (0.46 ± 0.14 vs. 0.37 ± 0.13, p = 0.013) than those without persistent TR. However, there were no significant differences in RV volumes, RV systolic function, and TV annular diameter between the two groups. On multivariable logistic regression, persistent TR was independently associated with age (HR:2.031, 95% CI, 1.113-2.046; p=0.003) and RV GLS/PASP (HR:0.009, 95% CI, 0.000-0.790; p=0.039). RV GLS/PASP showed a good predictive value for persistent TR after ASD closure (cut off 0.39, the area under the curve 0.702, p=0.003). Conclusions: Persistent TR after successful ASD closure is not uncommon in patients with ASD and significant TR. RV GLS/PASP can predict persistent TR after ASD closure. It can be suggested that concomitant or subsequent TR intervention should be considered in elderly patients and patients with abnormal RV-pulmonary arterial coupling.
NIMG-10. OPTIMIZING IMAGE QUALITY FOR MAGNETIC RESONANCE SIMULATION IN SPINE STEREOTACTIC BODY RADIATION THERAPY
Authors: Lubna Hammoudeh, Ho Young Lee, Evangelia Kaza, Jeffrey Guenette, Tracy Balboni
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Currently, the standard MRI sequence for SC imaging in SBRT has been axial 2D T2-weighted Turbo Spin Echo (TSE). Even though 3D T2-weighted sequences such as SPACE (Sampling Perfection with Application optimized Contrasts using different flip angle Evolution) image a whole volume simultaneously and thus offer better reconstruction, they have not been clinically implemented due to their long acquisition times. However, the application of Compressed Sensing (CS) methods on SPACE sequences, achieving clinically acceptable time. METHODS A 3D T2 CS SPACE was obtained and evaluated against the standard 2D TSE for spine SBRT based on a MagPhan RT quality assurance phantom and patients data, analysis was done using the phantom manufacturer software ImageOwl that calculates image distortions by comparing the known position of phantom features to their detected position in the image. RESULTS Results of phantom comparison between 3D T2 and 2D T2 indicate that although the 3D sequence had lower signal-to-noise ratio (SNR) than the 2D sequence, it presented less geometric distortions caused by gradient non-linearities, particularly in the anterior-posterior (A/P) and head-feet (H/F) directions. Distortions caused by chemical shift are in theory smaller for the 3D T2 CS SPACE, amounting to 0.85mm compared to 1.62mm with 2D T2. Between 2D versus 3D MRI defined SC data among 4 patients, average deviation of the centroid point cord contours was 0.08cm. The volume of the cord showed 1cc larger 3D volumes compared to 2D T2. Finally, the mean voxel count overlap coefficient and DICE coefficient was 0.92 and 0.87 respectively. CONCLUSIONS Since 3D MRI is under consideration to replace 2D MRI, it is important to compare SC contours from 3D to 2D MRI and assess their impact on treatment plans. Positive results would pave the path for larger subject cohort evaluation.
Abstract 13640: Endothelial Dysfunction in Chronic Stress-Related Cardiovascular Disease May Be Driven by Epinephrine Exacerbating TNFα Effects in a JAK/Stat3-Dependent Manner
Authors: Yvonne Baumer, Brian Tirado, Veronica Gray, Valerie Mitchell, Billy Collins, Tiffany Powell-wiley
Journal: Circulation (2021)

Background: Chronic psychosocial and environmental stress (PSES) impairs endothelial function and accelerates cardiovascular disease (CVD); however, underlying signaling pathways are less understood. Studies have independently shown that chronic PSES increases catecholamine levels (e.g. epinephrine) and induces a low-grade chronic inflammation by cytokines (e.g. tumor necrosis factor α - TNFα). The potential impact of a combination of increased levels of epinephrine and TNFα on the endothelium has not been fully investigated. We sought to elucidate if epinephrine and TNFα synergistically impair endothelial function and which signaling pathways might underlie this phenomenon. Methods: Human aortic endothelial cells (HAoEC) were treated with 10μM epinephrine (E), 10ng/ml TNFα (T), or their combination (E+T). Endothelial monolayer integrity was measured in a transwell filter setup and visualized by immunofluorescence. Signaling pathway analysis was performed by western blotting and PCR. Various pathway inhibitors were deployed to identify key pathways for the observed effects. Results: The addition of epinephrine exacerbated the observed TNFα-induced loss of the adherens junction protein VE-cadherin accompanied with accelerated intercellular gap formation and loss of endothelial barrier integrity. Signaling pathway analysis revealed that E+T induced delayed and prolonged Stat3 activation lasting up to 24h of treatment, which could not be observed in the individual E or T treatments. Inhibition of the Stat3 pathway using Tofacetinib, an inhibitor of JAK/Stat signaling, prevented the E+T-induced activation of Stat3, loss in VE-cadherin, E+T-induced gap formation and loss in barrier integrity, indicating the crucial importance of JAK/Stat signaling in the E+T-induced effects on the endothelium. Conclusion: These data indicate long-term PSES-induced CVD might in part be mediated by a combined effect of epinephrine and TNFα that can induce endothelial dysfunction dependent on a JAK/Stat3 pathway. Understanding pathways involved in PSES-related CVD is crucial to elucidate the biology of adversity in CVD health disparities, or mechanisms by which populations most impacted by PSES are disproportionately susceptible to CVD.
TAMI-68. DECONVOLUTION OF IMMUNOTHERAPY-TREATED GLIOBLASTOMA IDENTIFIES CELLULAR HETEROGENEITY AND PLASTICITY AT THE SINGLE-CELL LEVEL
Authors: Josephine Hendriksen, Aidan Flynn, Simone Maarup, Hans Poulsen, Ulrik Lassen, Joachim Weischenfeldt
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma is the most aggressive cancer originating in the brain with an average survival of 15 months. One of the characteristics of glioblastoma is the high level of intra-tumor heterogeneity (ITH), but the composition and complexity at the single-cell level is poorly understood. Here, we aimed to assess the effects and consequences of immune checkpoint inhibitor (ICI) on the cellular and molecular heterogeneity of glioblastoma tumors at the single cell level. In collaboration with the phase I trials unit at Rigshospitalet, we performed paired molecular analysis of glioma cells from primary and relapse surgery after ICI treatment. Samples were analyzed using single-cell RNA sequencing (scRNA-seq) as well as bulk RNA sequencing and whole exome DNA sequencing. In an effort to trace cellular lineages we developed and refined methods to a identify copy number changes using scRNA-seq. To this end, we identified clonal and subclonal tumor cell populations in each sample. We found high levels of ITH prior to treatment, both with respect to the glioblastoma subtype enrichment and the cell type-specific gene expression. Using expression-based cell-type classification, we found defined recurrent cell-type populations present at both surgery time points. The immune checkpoint treatment had consequences on the cellular phenotypes and proportions of tumor cells, suggesting a level of plasticity in the neoplastic cells. Moreover, we identified examples of clonal dynamics and sweeps following ICI treatment, pointing to potential treatment response and resistance in these populations. We additionally found a recurrent pattern of a small population showing high levels of cell cycle activation and simultaneously expressing markers of stem cell potential. In summary, we pursued single cell-focused analysis of ICI treated glioblastoma patients to study the cellular and molecular heterogeneity within and between glioblastoma patients, which pointed to recurrent patterns of cellular responses following ICI treatment.
Abstract 14283: Metabolic Adaptations of the Maternal Heart During Pregnancy and Postpartum
Authors: Helen E Collins, Kyle Fulghum, Lindsey McNally, Mallory Z Foster, Kenneth Brittian, Julia Chariker, Shizuka Uchida, Pawel Lorkiewicz, Steven P Jones, Bradford G Hill
Journal: Circulation (2021)

During pregnancy, the maternal heart undergoes reversible, physiologic growth, which supports cardiac output and maintains the physiologic demands of the growing fetus and mother; however, the molecular processes underlying pregnancy-induced cardiac growth are unclear. It is well known that changes in metabolism influence cardiac remodeling, and reductions in pyruvate dehydrogenase activity and cardiac glucose oxidation have been associated with cardiac growth during pregnancy. Therefore, the goal of this study was to examine the underlying metabolic processes that contribute to the structural and functional adaptations of the heart to pregnancy. Timed pregnancy studies in 12-week-old female FVB/NJ mice showed that heart weight to tibia length (HW:TL) was increased throughout the duration of pregnancy with HW:TL being higher in mid-pregnancy (MP, 8 d pregnant), late-pregnancy (LP, 16 d pregnant), and in 1-week post birth (PB) mice versus non-pregnant, diestrus controls (NP). This hypertrophic phenotype was associated with increased myocyte cross sectional area and with significant increases in end systolic and diastolic LV volumes . Of note, we found that blood glucose levels (115 ± 4 v 151 ± 6 mg/dL; p &lt;0.0001) were reduced at LP versus NP. RNA-seq analyses and downstream immunoblot validation revealed changes consistent with reduced cardiac glucose catabolism at LP. Specifically, we found that Pdk4 transcript and protein expression (1.00 ± 0.22 v 1.68 ± 0.08; LP v NP; p &lt;0.03) were significantly increased at LP and phosphorylation of PFK2 was significantly reduced at LP (1.00 ± 0.12 v 0.48 ± 0.06; p &lt;0.01) versus NP. Because inhibition of cardiac glucose oxidation may spare glucose-derived carbon for synthesis of cellular building blocks to facilitate cardiac growth using stable isotope resolved metabolomics, we found that pregnancy increased 13 C-glucose-derived carbon allocation to glycerophospholipids and amino acids suggesting that demand for biosynthetic pathway end products during pregnancy is met in part by ancillary biosynthetic pathways of glucose metabolism. Together, these findings support the hypothesis that changes in metabolism contribute to structural and functional adaptation of the heart during and after pregnancy.
Abstract 13053: Cardiac Allograft Vasculopathy Following Donation After Circulatory-Determined Death Heart Transplantation
Authors: Caitlin Cheshire, Ismail Vokshi, Jason Ali, Simon Messer, Aravinda Page, Anna Kydd, Stephen Pettit, Clive Lewis, Katharine Tweed, Marius Berman, Pradeep Kaul, Steven Tsui, David Jenkins, Jayan Parameshwar, Sai Bhagra
Journal: Circulation (2021)

Introduction: Cardiac allograft vasculopathy (CAV) remains a major problem for heart transplant (HTx) recipients, limiting their long-term survival. Our centre has performed the world’s largest series of donation after circulatory-determined death (DCD) HTx. Five-year survival is equivalent to donation after brainstem-determined death (DBD) HTx. However, there is no information on CAV in DCD HTx recipients. We sought to evaluate the incidence of CAV in our cohort of DCD HTx recipients. Methods: All DCD HTx recipients at our centre between February 2015 and December 2019 who had undergone CAV screening were included. They were compared with all DBD recipients during the same period who had undergone CAV screening. Angiograms were retrospectively assigned an ISHLT CAV grade by two independent observers. Results: Thirty-six DCD and 70 DBD HTx recipients were included in the study. Median time to first imaging of coronary arteries was 621 days and 572 days for DCD and DBD cohorts respectively. There was a higher proportion of male donors in the DCD cohort (p= 0.03) but no other significant differences between donor baseline characteristics. DCD recipients had a lower median pre-transplant pulmonary vascular resistance (p=0.03) but there were no other significant differences in recipient baseline characteristics. The two cohorts had similar rates of pre-operative durable LVAD use, post-transplant mechanical circulatory support and post-transplant immunosuppression regimes. There was no significant difference in the rates of CAV between the DBD and DCD groups (p=0.41) (Figure 1). When adjusted for standard risk factors for development of CAV (including donor factors, CMV status and rejection) there remained no significant difference between rates of CAV between groups (OR 1.48, p=0.41, 95% CI 0.58-3.78). Conclusions: DCD HTx recipients have similar rates of CAV when compared to a contemporary population of DBD HTx recipients.
Abstract P117: Design, Deployment, And Usability Of A Mobile System For Cardiovascular Health Monitoring Within The Electronic Framingham Heart Study
Authors: Eric Y Ding, Chathurangi H Pathiravasan, Eric Schramm, Belinda Borrelli, Jelena Kornej, Emelia J Benjamin, Joanne M Murabito, David D McManus
Journal: Circulation (2021)

Introduction: The electronic Framingham Heart Study (eFHS) is an ongoing study nested within the Framingham Heart Study. eFHS examines associations between health data measured by mobile devices and cardiovascular risk and disease. We aim to describe the eFHS app design and deployment methodology, report the characteristics of the eFHS app users, and describe usability of the app. Hypothesis: We hypothesize that eFHS participants will find the app highly usable. Methods: Participants were eligible if they were part of FHS, had a mobile phone, and were willing to share data with the research center. After consent, they received a smartwatch, digital blood pressure (BP) cuff, and the eFHS smartphone app through which surveys were administered. Three years later, the app was enhanced to include an interactive health dashboard to promote participant engagement and facilitate survey completion. We assessed usability of the new app with the Mobile App Rating Scale (MARS) (specifically app functionality and aesthetics), and survey completion rates at baseline (measures include socio-demographics, self-reported health and health behaviors, and medical history) and 3 months (physical activity). Results: A total of 196 participants were recruited using the enhanced eFHS app. Of these, 97 (49.5%) completed the MARS. The average age of survey respondents was 53 years, 51.5% were women, 93.8% were white. At least one instrument of the baseline survey was completed by 86% of participants, and 50% completed the 3-month assessment. The mean score on the “overall impression” subscale of the MARS was 4.2 (SD 0.74) on a scale of 1 to 5, with all sub-domains scoring &gt; 4.0. Of those who shared their health data with others, 46% shared their BP data, and 7.7% shared their physical activity data with a healthcare provider. Conclusion: Participants rated the new, enhanced eFHS app positively overall. Mobile app survey completion rates were moderate, suggesting that mHealth-delivered cardiovascular research is feasible.
Abstract 11227: Ischemia Mediated Contractile Dysfunction Modulates Functional Mitral Regurgitation - Multiparametric Strain and Tissue Characterization Data from the Society of Cardiovascular Magnetic Resonance (scmr) Registry
Authors: Abigail Maciejewski, Jonathan Kochav, Jiwon Kim, Katherine Tak, Robert M Judd, Han Kim, John F Heitner, Dipan J Shah, Chetan Shenoy, Afshin FARZANEH-FAR, Venkateshwar R Polsani, Michele Parker, Omar Khalique, Martin B Leon, Mark B Ratcliffe, Robert Levine, William A Zoghbi, Richard B Devereux, Raymond J Kim, Jonathan W Weinsaft
Journal: Circulation (2021)

Introduction: LV ischemia has been linked to functional mitral regurgitation (FMR) but ischemia is present many pts without FMR. CMR concomitantly assesses MR, ischemia and LV function but has not been used to test factors modifying impact of ischemia on FMR. Methods: Vasodilator stress CMR was performed in CAD pts in a multicenter registry, in whom advanced (≥moderate) FMR was confirmed by core lab. LV ischemia was categorized by subpapillary involvement (subtending mitral apparatus). To test mechanism by which ischemia impacts FMR, LV strain was measured in pts with ischemia and &lt;5% LV infarct, with and without (1:2) FMR, matched for ischemia extent/distribution. Followup was done for mortality. Results: 2639 pts were studied; 7% had advanced FMR. While FMR pts had more ischemia in subpapillary (21.8 ± 28.3 vs 13.4 ± 21.9%) and nonpapillary (19.2 ± 25.5 vs 13.0 ± 22.2%) regions (p&lt;0.001), multivariate analysis showed only subpapillary ischemia (OR 1.13 per 5% LV [1.05, 1.21] p=0.001) to be associated with FMR (nonpapillary p=NS). Wall motion scores in ischemic subpapillary segments were higher in pts with FMR (1.7±0.9 vs 0.8±0.9, p&lt;0.001) paralleling strain subgroup data (n=114): FMR prevalence increased stepwise with impaired radial and circumferential strain ( Figure ). Adverse mitral remodeling associated with impaired strain; mitral tenting area (OR -0.01 per % [-0.02, -0.004] p&lt;0.01) and papillary fractional shortening (OR 0.36 per % [0.26, 0.47] p&lt;0.001) each associated with subpapillary radial strain controlling for nonpapillary strain (p=NS). On follow up (median 4.7 [2.2, 7.7] yr), FMR, age, subpapillary ischemia and infarction each independently predicted death (p&lt;0.001): When categorized as dysfunctional or non-dysfunctional, only ischemic/dysfunctional myocardium (HR 1.15 per 5% LV [1.05, 1.14] p&lt;0.001) associated with death. Conclusions: Ischemia mediated LV dysfunction on multiparametric CMR modulates likelihood of FMR and adverse prognosis.
Abstract 9845: Novel Oral Anticoagulants versus Vitamin K Antagonists in Patients with Atrial Fibrillation After Transcatheter Aortic Valve Replacement: A Systematic Review and Meta-Analysis
Authors: Muhammad Memon, Asad Ali Siddiqui, Emaan Amin, Fahd Niaz Shaikh, Mohammad Khan, Rami Doukky, Richard Krasuski
Journal: Circulation (2021)

Background: The efficacy and safety of novel oral anticoagulants (NOACs) compared to the current guideline-recommended vitamin K antagonists (VKAs) in atrial fibrillation (AF) patients undergoing transcatheter aortic valve replacement (TAVR) has not been well established. We pooled evidence from all available studies to assess the risks and benefits of this drug class. Methods: We queried electronic databases (MEDLINE, Scopus, and Cochrane central) up until 15 th May 2021 for studies comparing NOACs to VKAs in AF patients undergoing TAVR. Results from studies were presented as risk ratios (RR) with 95% confidence intervals (CI) and pooled using a random-effects model. Subgroup analysis by study design and meta-regression analysis were performed to explore heterogeneity. Results: A total of 12 studies (4 RCTs and 8 retrospective observational) containing 13,815 patients (mean age 81.1 years; 50.1% men) were identified and included in the analysis. Pooled analysis revealed no significant difference between NOACs and VKAs in terms of stroke or systemic embolism (RR 0.83; p=0.34), major bleeding (RR 0.84; p=0.30), intracranial hemorrhage (RR 0.72; p=0.60), all-cause mortality (RR 0.71; p=0.15), and myocardial infarction (RR 1.34; p=0.32) at a mean length of follow-up of 15.1 months. RCTs and observational studies did not significantly differ across outcomes on subgroup analysis. Meta-regression analysis found heterogeneity in all-cause mortality to be significantly explained by percentage of males (coefficient: 0.049, p=0.007), mean age (coefficient: 0.221, p&lt;0.001), and CHA2DS2-VASc score (coefficient: -1.657, p&lt;0.001). Conclusions: This meta-analysis suggests that outcomes with NOACs do not significantly differ compared to VKAs following TAVR in patients with AF. Future RCTs may help provide a clearer answer.
Covid-19: Government was “grossly negligent” in its handling of pandemic, says people’s inquiry
Authors: Clare Dyer
Journal: BMJ (2021)

The UK government's handling of the coronavirus pandemic was "grossly negligent" and amounted to misconduct in public office, an inquiry set up by the campaign group Keep our NHS Public has concluded. 11 People's Covid Inquiry.Misconduct in public office: why did so many thousands die unnecessarily?Dec 2021.https://www.peoplescovidinquiry.com.
BIOM-23. A PILOT STUDY OF WHOLE GENOME SEQUENCING (WGS) OF PLASMA CELL-FREE DNA (cfDNA) FOR ULTRASENSITIVE DETECTION OF TUMOR DNA IN PATIENTS WITH GLIOBLASTOMA (GBM)
Authors: Stephen J Bagley, Jacob Till, Aseel Abdalla, MacLean Nasrallah, Tomer Lauterman, Iman Tavassoly, Boris Oklander, Asaf Zviran, Erica Carpenter
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Plasma circulating tumor DNA (ctDNA) is rarely detectable by traditional methods in patients with GBM. As a result, unlike in lung and other cancers, serial next generation sequencing of ctDNA for monitoring GBM tumor burden has been challenging. In light of the low tumor fraction (TF) of DNA fragments in GBM patient plasma and the urgent need to improve upon MRI for tracking GBM tumor burden, we conducted a pilot study in patients with newly diagnosed GBM using the C2 intelligence platform (C2i Genomics), which leverages genome-wide mutational integration for highly sensitive ctDNA detection. METHODS Plasma was collected pre- and post-operatively in patients with newly diagnosed GBM undergoing surgical resection/biopsy. cfDNA was extracted, quantified, and analyzed for fragment size. Genomic DNA (gDNA) was extracted from matched tumor tissue. Whole genome sequencing (WGS) was performed on both gDNA and cfDNA. A specific copy number alteration (CNA) compendium was created for each patient to generate a readout of TF (Zviran, Nat Medicine 2020). We assessed the association between TF at post-operative day 1 (a surrogate for residual disease) and OS, adjusting for other prognostic factors using Cox regression. RESULTS 37 patients were enrolled. For samples with high tumor fraction (n=5), a statistically significant (p&amp;lt; 1e-4) correlation between CNA profiles of tumor tissue and plasma samples was observed. Post-operative TF above the median value was associated with inferior OS (median 7.7 vs. 19.3 months, p=0.019). This association persisted after adjusting for age, O6-methylguanine-DNA methyltransferase methylation status, extent of resection, and performance status (adjusted HR 2.5, 95% CI 1.1-5.6, p=0.03). CONCLUSION Genome-wide mutational integration enables ultra-sensitive detection of ctDNA in GBM patient plasma. Post-operative TF measured by the C2i test is independently associated with OS in newly diagnosed GBM, providing the foundation to evaluate this technology for personalized prognostication and disease monitoring.