tbuckley/cabot-search huggingface dataset:
CTNI-56. EVALUATING DRUG DISTRIBUTION IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) TREATED WITH CONVECTION ENHANCED DRUG DELIVERY
Authors: Elwira Szychot, Dolin Bhagawati, Steven Gill, David Walker, Harpreet Hyare
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND There is currently no method for evaluating drug distribution and tumour coverage using the convection-enhanced drug delivery (CED) technique in Diffuse Intrinsic Pontine Glioma (DIPG). AIMS To determine an imaging protocol that can be used to assess the distribution of infusate in children with DIPG treated with CED of carboplatin and sodium valproate. METHODS 12 children with DIPG received between 4–18ml of infusate, through 2 pairs of catheters to encompass tumour volume on 2 days. Volumetric T2W and Diffusion Weighted Imaging (DWI) MRI sequences were performed before and after the first cycle of CED therapy and Apparent Diffusion Coefficient (ADC) maps were calculated. The tumour volume pre and post CED was automatically segmented (ITKSnap) on T2W and ADC on the basis of signal intensity. The ADC maps pre and post infusion were registered and subtracted (FSL) to visualize the infusate distribution. RESULTS ADC and T2W demonstrated a significant (&amp;lt; 0.001) change in mean tumour volume post-infusion (mean ADC volume pre: 19.8ml, post 24.4ml; mean T2W volume pre 19.4ml, post 23.4ml). A significant correlation (p&amp;lt; 0.001) was observed for the difference in tumour volume and the actual infused volume (ADC, r=0.76, T2W, r=0.70). There was a significant increase (p&amp;lt; 0.001) in mean ADC and mean T2W signal intensity ratio post-infusion, no significant correlation with infusion volume. Finally, pixel-by-pixel subtraction of the ADC maps pre and post infusion visually demonstrated high signal intensity, presumed infusate coverage of the tumour. CONCLUSIONS ADC and T2W MR sequences could potentially be used to evaluate the volume of distribution of infusate delivered by CED, paramount to ensure tumour coverage and leading to more effective therapy evaluation. This will facilitate the use of CED in future clinical trials.
Constrained FL: A Genetically Distinct Subgroup of Follicular Lymphoma with Low Rates of Somatic Hypermutation and a Reduced Propensity for Histologic Transformation
Authors: Laura K Hilton, Kostiantyn Dreval, Shaghayegh Soudi, Susana Ben-Neriah, Manuela Cruz, Brett Collinge, Krysta M. Coyle, Bruno M. Grande, Gerben Duns, Christopher K Rushton, Merrill Boyle, Barbara Meissner, Pedro Farinha, Graham W Slack, Andrew J. Mungall, Marco A. Marra, Joseph M. Connors, Christian Steidl, David W. Scott, Ryan D Morin
Journal: Blood (2021)
Abstract 12466: Suppression of Inflammatory Activity in Vascular Endothelial Cells Reduces EndMT in Response to Oscillatory Shear Stress
Authors: Qingzhou Yao, Peng Zhao, Zichao Luo, Erlinda The, Yufeng Zhai, Lihua Ao, David Fullerton, Xianzhong Meng
Journal: Circulation (2021)

Background: The incidence of pro-atherogenic lesions is greater in the branching regions of artery compared to non-branching regions. Disturbed blood flow in the atheroprone regions exerts oscillatory shear stress (OSS) to the vascular wall, particularly endothelial cells (ECs), and OSS is a risk factor for the development of pro-atherogenic lesions. This study aims to assess the impact of OSS on phenotypic transition in artery ECs. Methods and Results: Immunofluorescence staining and image quantification revealed that inflammatory activity and endothelial-to-mesenchymal transition (EndMT) are greater in mouse aortic arch than in the descending thoracic aorta. Inflammatory biomarker ICAM-1 is colocalized with the EndMT biomarker, vimentin and α-smooth muscle actin, in ECs of the aorta arch. As cells in aortic arch sustain OSS, we tested the hypothesis that OSS induces EndMT in artery ECs by a pro-inflammatory mechanism, using a three-dimensional microengineered human artery-on-a-chip system. Human coronary artery ECs were cultured on the surface of a collagen I-coated membrane and subjected to OSS. Single-cell RNA sequencing analysis revealed that inflammatory and EndMT-related genes were enriched in ECs after being exposed to OSS for 24 h. OSS-induced inflammatory response and EndMT were confirmed by immunoblotting and immunofluorescence staining. These changes were abolished by inhibiting the p38 MAPK-NF-κB signaling pathway. Moreover, anti-inflammatory cytokine, IL-37, suppressed the inflammatory response and prevented EndMT in ECs exposed to OSS. Importantly, expression of IL-37 in mice markedly reduced the level of inflammatory biomarker and the density of cells displaying EndMT biomarkers in the endothelium of aortic arch. Conclusion: OSS induces EndMT in artery ECs through a pro-inflammatory mechanism involving the p38 MAPK-NF-κB signaling pathway and contributes to the pro-atherogenic microenvironment in regions sustaining disturbed blood flow. Anti-inflammatory cytokine IL-37 may have the therapeutic potential for suppressing endothelial phenotypic transition caused by disturbed blood flow.
Abstract 9922: Increased Susceptibility to Arrhythmias, Hypertension, and Hypertrophy in a Rat Model of Exposure to Electronic, Heat-Not-Burn, or Conventional Cigarettes, or Marijuana
Authors: Huiliang Qiu, Hao Zhang, Ronak Derakhshandeh, Xiaoyin Wang, Emily Wilson, Poonam Rao, Daniel D Han, Leila Mohammadi, Jeffrey E Olgin, Matthew L Springer
Journal: Circulation (2021)

Pathogenicity of cardiovascular disease (CVD) from smoking tobacco is well-known, but the CVD effects of vaping non-combustible tobacco products like e-cigarettes and heat-not-burn products (e.g., IQOS), and smoking marijuana (MJ), are less studied. We asked if 8 weeks of chronic use of e-cigs, IQOS, or MJ in rats would cause less adverse cardiac effects than tobacco cigarettes. We exposed SD rats to 1 session/day (10 puffs over 5 min) for 8 weeks with Marlboro Red cigarettes (Cig), JUUL, IQOS, 10% THC MJ (MJ), cannabinoid-depleted “placebo” MJ (pb-MJ), or air. We performed echocardiography and measured conscious systolic blood pressure (SBP) every 2 weeks. We then performed 24-hour conscious ECG telemetry and ex vivo optical mapping (OM) of arrhythmias and analyzed interstitial fibrosis. By 1 hour after exposure, SBP was acutely increased by all tobacco products and pb-MJ, while only marijuana reduced SBP. SBP of all non-air groups rose progressively over 8 weeks, exceeding 130 mmHg after 2 weeks, and 140 mmHg after 4 weeks. SBP increased by MJ was higher than those by JUUL, IQOS, or pb-MJ. Cardiac performance declined and ventricular mass increased. All non-air conditions led to reduced overall heart rate variability, including the total power, low and high frequency from the power spectrum, and SDNN, RMSSD, and NN9 from time-domain method. Poincaré plot suggested a similar distribution pattern of RR interval. Interestingly, when compared with air, reduced physical activity was found in all experimental groups. OM revealed that more arrhythmias were induced by electrical stimulation: Cig, JUUL, IQOS, pb-MJ, MJ had atrial fibrillation of 50%, 85.71%, 50%, 50%, 37.5% and left ventricular (LV) tachycardia of 62.5%, 71.43%, 37.5%, 37.5%, 75% respectively vs. 0% in air, P &lt; .05. Sirius red fibrotic staining showed significantly more interstitial fibrosis of atria and LV in all groups compared to air. Although no significant difference in interstitial fibrosis was found among tobacco products, MJ promoted more LV fibrosis than pb-MJ. Therefore, the use of different non-cigarette tobacco products and marijuana can increase CVD risks by causing hypertension, reduced cardiac performance, increased LV hypertrophy, and susceptibility to arrhythmias.
Abstract 12385: TBX5-Based Lineage Tracing Identifies a Propensity for Left Ventricular Cardiomyocyte Differentiation of Human Induced Pluripotent Stem Cells Using Biphasic Modulation of WNT Signaling
Authors: Francisco X Galdos, Soah Lee, William R Goodyer, Sharon Paige, Carissa Lee, Sidra Xu, Gabriela V Escobar, Rasmus O Bak, Matthew Porteus, Sean M Wu
Journal: Circulation (2021)

Introduction: Patient-derived induced pluripotent stem cells (iPSCs) present an exciting avenue for the modeling of adult and congenital heart diseases. While hiPSC cardiac differentiations generate various cell types, the presence of mixed cell populations can confound interpretation of study results. During cardiac development, progenitors from the first (FHF) and second heart fields (SHF) give rise to cells in the left (LV) and right ventricles (RV), respectively. The availability of a lineage tracing tool to identify these progenitors and their descendants during differentiation would enhance our understanding of the mechanisms that regulate heart development. Hypothesis: Heart field lineage tracing in human iPSCs will reveal the stepwise emergence of FHF and SHF progenitor cells and address whether 3D differentiation format provides greater capacity than 2D for generating cells in the SHF lineage. Methods/Results: Using CRISPR/Cas9, we introduced gene targeting constructs into two healthy human iPSCs lines to permanently label all TBX5 expressing FHF cells and their descendants with GFP. Standard small molecule biphasic WNT modulation protocols in both 2D and 3D differentiation formats were used to generate ventricular cardiomyocytes. At days 11-30 of differentiation, cells were analyzed by FACS for the percentage that express GFP and TNNT2. Analysis of GFP+ cells out of TNNT2+ CMs showed an increase in GFP expression on days 11 (55.8% ± 3.6%), 15 (67.0% ± 3.0%), 20 (89.2% ± 1.7%), and 30 (99.4% ± 0.4%) in 2D differentiations. Single-cell RNA-seq analysis of day 15 CMs confirmed the co-expression of GFP and HAND1 (a LV marker) in &gt;80% of total cells and showed absent expression of SHF-specific markers, TBX1 and FGF8. In 3D differentiations, we also observed GFP expression in greater than 95% of TNNT2+ CMs, confirming the FHF propensity of this differentiation protocol. Conclusions: We generated two FHF lineage tracing hiPSC lines and showed that the WNT modulation differentiation protocol gives rise to predominantly FHF (LV) but not SHF (RV) CMs in both 2D and 3D formats. Ongoing studies will clarify the mechanism for this increased propensity as well as the developmental signaling pathways that drive the differentiation of the FHF and SHF.
Abstract 12128: The Inflammatory Response to Percutaneous Coronary Intervention is Related to Myocardial Injury in Patients with Chronic Ischemic Heart Disease
Authors: Priscilla T Frisso, Fernando R Mattos, Henrique Trombini Pinesi, James A De Lemos, Antonio E Pesaro, Fabiana H Rached, Marcelo Franken, Adriano M Caixeta, Pedro A Lemos Neto, Antonio C Chagas, Carlos V Serrano Jr
Journal: Circulation (2021)

Introduction: In the setting of acute coronary syndromes, the association between a major release of both multiple inflammatory and myocardial injury markers after PCI is linked with a subsequent poor prognosis. However, little is known concerning the association between these markers in stable patients. Objective: We aimed to describe the association between systemic inflammatory response and myocardial injury after percutaneous coronary intervention (PCI) in patients with chronic ischemic heart disease (CIHD). C-reactive protein (CRP) and hematological indices were assessed to depict inflammation. Methods: In this retrospective, observational study, blood samples were taken before and 48 hours after successful PCI in 329 patients (65.3±11.7 y, 67% men) with CIHD. Inflammatory markers (IM) were determined: CRP, white blood cells (WBC) and subtypes, platelets, mean platelet volume (MPV), neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR). High-sensitivity cardiac troponin I (hs-cTnI) was measured post-PCI. Procedural myocardial injury was arbitrarily defined by increases of hs-cTnI values and no new electrocardiographic changes nor flow-limiting complications. Results: PCI produced a systemic inflammatory response with a rise in IM levels. 66.7% of the patients presented myocardial injury. To determine the strength and direction of the association between increased IM and hs-cTnI, Spearman's rank-order correlation was determined: CRP 0.570 (p&lt;0.001), NLR 0.190 (p&lt;0.001), MPV 0.182 (p&lt;0.001), PLR 0.180 (p&lt;0.001), WBC 0.166 (p&lt;0.001), neutrophils 0.145 (p&lt;0.001), eosinophils 0.142 (p&lt;0.001), lymphocytes -0.130 (p&lt;0.001), monocytes 0.031 (p=0.344), and platelets -0.009 (p=0.778). Conclusion: Thus, PCI in patients with CIHD induces a systemic inflammatory reaction, which is associated with burden of procedural myocardial injury.
Abstract 11650: Global, Regional and National Time Trends in Mortality for Congenital Heart Disease, 1990-2019 an Age-Period-Cohort Analysis for the Global Burden of Disease Study 2019
Authors: Zhanhao Su, Yiwei Liu, Shoujun Li, Huiwen Chen, Zhiyong Zou, Nicholas Kassebaum, George Patton, Hao Zhang
Journal: Circulation (2021)

Introduction: Congenital heart disease (CHD) is the leading birth defect worldwide. We report trends in CHD mortality in 204 countries and territories over the past 30 years, and associations with age, period, and birth cohort. Methods: Cause-specific CHD mortality estimates were derived from the Global Burden of Disease study 2019. We utilized an age-period-cohort model to estimate overall annual percentage change in mortality (net drifts), annual percentage change from 0-4 to 65-69 years (local drifts) and period (cohort) relative risks between 1990 and 2019. Results: Global CHD deaths in 2019 were 217,000 (95%UI: 177,000, 262,000). India, China, Pakistan and Nigeria were the top 4 countries accounting for 39.7% of deaths globally. The reduction in age-standardized mortality ranged from 66.3% in high-sociodemographic index (SDI) countries to 30.5% in low-SDI countries. Globally, there was an emerging transition in the age distribution of deaths from pediatric to adult population, except for an increasing trend of mortality in 10~34 years in Mexico and Pakistan. During 1990-2019, favorable mortality reductions were found in most high-SDI countries like South Korea (net drift = -4.0% per year) and United States (-2.3%), and also in many middle-SDI countries like Brazil (-2.7%) and a few low-SDI countries like Ethiopia (-2.3%). However, 52 out of 129 countries with at least 50 deaths had either increasing trends (net drifts≥0.0%) or stagnated reductions (≥-0.5%) in mortality. The relative risk of mortality generally showed improving trends over time and in successively younger birth cohorts among high- and high-middle SDI countries except Saudi Arabia and Kazakhstan. Fourteen middle-SDI countries such as Ecuador and Mexico, and sixteen low-middle-SDI countries like India and twenty low-SDI countries like Pakistan, had unfavorable or worsening risks for recent periods and birth cohorts. Conclusions: Improvements in the treatment of CHD should reduce the risk for successively younger cohorts and shift the risk for all age groups over time. Although there were gains in CHD mortality globally, unfavorable period and cohort effects were found in many countries, raising questions about adequacy of their health care for CHD patients across all age-groups.
Abstract 11222: A Combined, Fully Automated Electrocardiogram and Echocardiogram Strategy for Detection of Hypertrophic Cardiomyopathy
Authors: Shinichi Goto, Genki Ichihara, Hidehiko Ikura, Yoshinori Katsumata, Yuji Itabashi, Calum Macrae, Rahul C Deo
Journal: Circulation (2021)

Introduction: Hypertrophic cardiomyopathy (HCM) is a disorder characterized by abnormal thickening of the heart muscle and may affect up to 1 in 200 people in the general population. Detection of HCM, like other rare diseases, is challenging both because of its low prevalence and the fact that there are other more common diseases such as aortic valve stenosis (AS) and hypertension that also manifest as cardiac hypertrophy. Distinguishing among such conditions, though challenging for human interpretation, may be feasible with artificial intelligence (AI)-based approaches, but strategies to date have looked only at data from single centers using single modalities. Methods: Here we developed and validated a robust approach to accelerate detection of HCM using a combination of fully automated interpretation of electrocardiograms (ECG) and echocardiograms using convolutional neural networks and evaluated it on data from multiple institutions in multiple countries. The ECG model was trained on 4,935 ECGs from Brigham and Women’s Hospital (BWH) and was tested on an internal test set of 1,950 ECGs along with 842 and 1,103 ECGs from 2 different academic medical centers (AMC) in the United States (US). The echocardiogram model was trained on 4,483 studies from BWH and was tested on an internal test set of 1,945 studies, 1,025 and 554 studies from 2 AMCs in the US, and 239 studies from an AMC in Japan. Results: Both models had excellent accuracy for detecting HCM with C-statistics of 0.84-0.91 and 0.91-0.94 for the ECG and echocardiography models, respectively. The echocardiography model, which uses only a single commonly acquired view, discriminates HCM from AS and HTN with C-statistics of 0.92 and 0.86, respectively. Simulating deployment on 13,906 and 7,775 patients with ECG-echocardiography paired data for AMC2, and AMC3 indicated a positive predictive value (PPV) for the ECG model of 7% and 8% at 50% and 59% recall, respectively. Pre-screening with ECG enhanced the echocardiography model performance from PPV 43% and 36% to PPV 71% and 73% at 46% recall, respectively, for AMC2 and AMC3. Conclusions: We have developed a robust pipeline to augment detection of HCM, and that could enable patient identification in less specialized settings.
Abstract 11396: A Small but Significant Increased Incidence of Acute Pericarditis Identified After Vaccination for SARS-CoV-2
Authors: Kirk U Knowlton, Stacey Knight, Joseph B Muhlestein, Viet T Le, Benjamin D Horne, Heidi T May, Eddie Stenehjem, Jeffrey L Anderson
Journal: Circulation (2021)

Background: As SARS-CoV-2 vaccines are being administered on an unprecedented scale, it is critical to carefully assess risks to aid clinicians in the early detection and treatment of potential side effects. Here we examine increases in the risk of pericarditis following SARS-CoV-2 vaccination. Methods: We examined pericarditis cases from December 15, 2020, to April 15, 2021 seen within Intermountain Healthcare, an integrated healthcare system. Pericarditis was defined by at least two of the following criteria: chest pain, EKG changes, pericardial effusion, and pericardial rub; excluded cases secondary to non-infectious causes (e.g., AF ablation). We determined vaccination within 60 days prior to pericarditis diagnosis using Intermountain and Utah Department of Health vaccination information. Rates of pericarditis per 10 million patient days for vaccinated patients compared to unvaccinated patients were compared. We also examined a case-crossover design with 4 control dates for each pericarditis case. Results: Of the 29 identified pericarditis cases, 13 (44.8%) had a SARS-Cov-2 vaccination within 60 days before the onset of pericarditis. During the same period, 743,774 individuals in the Intermountain Healthcare system had received at least one dose of the SARS-CoV-2 vaccine. Thus, 1.7 per 100,000 vaccinated individuals were diagnosed with acute pericarditis. Within a 60-day post-vaccination window, the rate of acute pericarditis per 10-million patient-days was 3.90 in the vaccinated group and 0.84 in the unvaccinated group. Thus, there was a 4.49 times higher rate of acute pericarditis in vaccinated patients compared to the unvaccinated individuals (p=0.0002). Case-crossover analysis showed the odds of acute pericarditis was 3.33 higher (95% CI: 1.29, 10.14) in the vaccinated versus the unvaccinated group (p=0.01). Conclusions: We found acute pericarditis to be a rare post-SARS-CoV-2 vaccination event, but the risk was significantly higher than in comparable unvaccinated subjects. This risk of pericarditis post-SARS-CoV-2 vaccine is eclipsed by the risk of contracting COVID-19 and its associated, commonly seen severe outcomes. Nevertheless, clinicians should be informed of this risk to facilitate earlier recognition and treatment.
Clinical Predictors and Prediction Models for Frequency of Total and Joint Hemorrhage in Severe-Type Patients with Hemophilia a (PwHA) with/without Intermediate-Dose Prophylaxis Therapy with rFVIII
Authors: Chia-Yau Chang, Shiue-Wei Lai, Mei-Mei Cheng, Jung-Tzu Ku, Shu-Hsia Hu, Chen-Hua Tsai, Pei-Yi Lai, Yen-Lin Liu, Jia-Ruey Tsai, Chao-Neng Cheng, Yeu-Chin Chen
Journal: Blood (2021)
Abstract 14016: Sex-Related Differences in Type A Acute Aortic Syndromes
Authors: Candrika D Khairani, Briana Barns, Samantha Rizzo, Julia Snyder, Mariana Pfeferman, Gregory Piazza, Samuel Z Goldhaber, Umberto Campia
Journal: Circulation (2021)

Introduction: Acute aortic syndromes (AAS) involving the ascending aorta (Stanford type A) are medical emergencies that require multidisciplinary management. Limited data exist on sex differences in presentation, management, and outcomes of patients with type A AAS. We aimed to assess sex-related differences in patients with type A AAS. Methods: Retrospective analysis of all patients admitted with AAS to our tertiary academic medical center between July 2012 and October 2020. Type A AAS presentations included aortic dissection, intramural hematoma, and aortic rupture. Results: Of 159 patients presenting with type A AAS, 55 (34.6%) were women and 104 were men (65.4%). Women were older than men (74.3±13.4 vs. 60.4±14.9 years, p&lt;0.001). The most common cardiovascular risk factor both in men and women was diagnosed or self-reported hypertension (76.0% and 89.1%, respectively). Aortic rupture occurred at higher rates in women (16.4% vs. 5.0%, p=0.02), whereas aortic dissection occurred at higher rates in men (88.1% vs. 69.1%, p=0.004). Women were less likely to undergo surgical intervention than men (63.6% vs. 87.1% p=0.001). In-hospital complications and surgical mortality occurred at similar rates in both sexes. In-hospital mortality was higher in women than in men (30.9% vs. 15.8%, p=0.03). After adjusting for age, sex was not independently associated with mortality (unadjusted OR 2.35, 95% CI 1.07-5.14 vs. adjusted OR 1.08, 95% CI 0.44-2.67) (Table). Conclusions: While women with type A AAS had higher rates of aortic rupture and in-hospital mortality than men, sex was not independently associated with mortality. Further investigation is needed to better understand the impact of sex differences in type A AAS.
Chimeric Antigen Receptor T Cells for Refractory/Relapsed Diffuse Large B Cell Lymphoma and Acute Lymphoblastic Leukemia: The Hellenic Real-World Experience in Adult Patients
Authors: Ioannis Baltadakis, Despina Mallouri, Ioannis Tsonis, Eleni Gavriilaki, Maria Bouzani, Ioannis Batsis, Ifigeneia Tzannou, Tatiana Tzenou, Christos Varelas, Thomas Chatzikonstantinou, Damianos Sotiropoulos, Stavros Gigantes, Ioanna Sakellari, Dimitrios Karakasis, Achilles Anagnostopoulos
Journal: Blood (2021)
Randomised clinical trials in critical care: past, present and future
Authors: Anders Granholm, Waleed Alhazzani, Lennie P. G. Derde, Derek C. Angus, Fernando G. Zampieri, Naomi E. Hammond, Rob Mac Sweeney, Sheila N. Myatra, Elie Azoulay, Kathryn Rowan, Paul J. Young, Anders Perner, Morten Hylander Møller
Journal: Intensive Care Medicine (2021)