tbuckley/cabot-search huggingface dataset:
Abstract 13626: Aerobic Training Corrects Bbb Dysfunction Within Preautonomic Areas In Heart Failure Rats By Normalizing The Augmented Transcytosis
Authors: Hiviny de Ataides Raquel, Gustavo Masson, Sany Martins Pérego, Alison Colquhoun, Leonardo Jensen, Lisete C Michelini
Journal: Circulation (2021)

Introduction: Besides intense renin-angiotensin system activation and sympathoexcitation, heart failure (HF) is accompanied by marked autonomic dysfunction. We showed previously in hypertensive rats that blood-brain barrier (BBB) dysfunction in preautonomic areas aggravated the autonomic dysfunction but is corrected by aerobic training (T). There is no information in HF Hypothesis: We hypothesized that BBB dysfunction within the paraventricular hypothalamic nucleus (PVN) contributes to the autonomic imbalance, which may be ameliorated by T Methods: Wistar rats were submitted to anterior descending coronary artery occlusion or Sham surgery and echocardiography. Four weeks later, HF (ejection fraction≤40%) and Sham rats underwent a T (55% of maximal exercise capacity) or sedentary (S) protocol for 8 weeks and were chronically cannulated for hemodynamic/autonomic recordings and determination of BBB permeability (intra-arterial injection of fluorescent dyes with high and low molecular weight). To investigate the mechanisms underlying HF- and T-induced BBB changes, the PVN was harvested and processed for transmission electron microscopy Results: HF-S exhibited reduced arterial pressure (AP, -10%), increased sympathetic activity to vessels and heart (+45% on average), decreased spontaneous baroreflex sensitivity (BrS, -19%), large increase in systolic AP variability (+53%), and 4-fold increase in PVN BBB leakage (11.3±1.4 vs. 2.8±0.2 %area in Sham-S). HF-S also exhibited increased transcytotic vesicles (+80%) in PVN capillaries’ endothelium, without any change in tight junctions’ expression, capillary diameter, and pericytes’ coverage. These changes were completely normalized in HF-T rats. In Sham rats T only caused resting bradycardia, increased BrS, and a mild reduction of transcytotic vesicles and PVN leakage. There were significant correlations between the number of transcytotic vesicles x PVN BBB leakage (Y=0.82x -1.74, r 2 =0.843, P&lt;0.001) and BBB leakage x sympathetic activity (Y=0.66x +4.37, r 2 =0.415, P&lt;0.001) Conclusions: HF courses with PVN BBB dysfunction, which is due to increased transcytosis without changes in the paracellular pathway. Training ameliorates HF’s autonomic control by normalizing transcytosis
Abstract 13693: Tachyarrhythmias in COVID-19 Patients Admitted to the Intensive Care Unit
Authors: Mohsin Mughal, Ikwinder Kaur, Natale Mazzaferro, Ali Ghani, Haresh Gandhi, Patricia Greenberg, Vishaka Sirpal, Muhammad Khakwani, Ajay Shah, Howard Levitt, Mahboob Alam, Philip L Mar, Sergio Waxman
Journal: Circulation (2021)

Introduction: The SARS-CoV-2 infection has been associated with new-onset arrhythmias. New-onset tachyarrhythmias including atrial fibrillation, atrial flutter, and ventricular tachycardias (VT) have been reported from different retrospective studies. It is proposed that new-onset arrhythmias are likely associated with systemic illness, and not only triggered by SARS-CoV-2 infection. Hypothesis: We hypothesized that patients who were admitted to the ICU/CCU level of care were more likely to have new-onset tachyarrhythmias vs hospitalized patients who were not admitted to the ICU/CCU. Methods: This is a multi-center retrospective study. The RT-PCR confirmed adult COVID-19 patients consecutively admitted from March 1st to April 30, 2020, were included. Demographic characteristics, comorbidities, and the onset of new arrhythmias were manually extracted from EMR. Categorical variables are shown in percentages; continuous variables are shown in mean (SD). Data were extracted manually using the hospital’s electronic medical record. Categorical variables were compared using the chi-square test; continuous variables were compared using the t-test (with equal variance assumption). P-value &lt;0.05 was considered significant. Results: A total of 720 patients were admitted to the hospital. Of these, 11% had new-onset tachyarrhythmias. The onset of new tachyarrhythmias was significantly high in patients who were admitted to ICU/CCU vs non-ICU setting (p-value, &lt;0.001). 13% of patients admitted to ICU/CCU developed new-onset atrial fibrillation vs 7% in the non-ICU setting. 1.5% developed new-onset atrial flutter in ICU/CCU setting vs 1% in the non-ICU setting. Incidence of VT and VF were also higher in ICU/CCU settings. Table1 Conclusions: Patients who were hospitalized with COVID-19 and received ICU/CCU level care were more likely to develop new-onset tachyarrhythmias.
Abstract 11043: Clinical Safety Outcomes in Relation to Lipoprotein(a) Concentration: Insights from the FOURIER Trial
Authors: Baris Gencer, Robert P Giugliano, Minao Tang, Francois Mach, Erik S Stroes, Ioanna Gouni-berthold, Richard Ceska, Marat Ezhov, J Wouter W Jukema, Henrik Jensen, Lale S Tokgozoglu, Kurt Huber, Marc S Sabatine, Michelle L Odonoghue
Journal: Circulation (2021)

Background: Lipoprotein(a) is believed to play a causal role in atherogenesis. Drugs are in development that directly target Lp(a) and lower levels by &gt;75%. Thus, the safety of low Lp(a) levels is of importance. Methods: FOURIER randomized 27,564 patients w/ stable ASCVD to evolocumab (EVO) vs placebo on background statin (median f/up 2.2 y); EVO lowered Lp(a) levels by 27%. The relationships between Lp(a) levels, change in Lp(a) and 5 safety outcomes of interest based on prior reports (diabetes [DM], serious bleeding, hemorrhagic stroke, neurocognitive events, malignancy) were examined. Analyses were conducted in the overall population and by treatment arm. Multivariable models included age, sex, race, region, clinical predictors, high-intensity statin, ezetimibe, baseline hs-CRP, “Lp(a)-corrected” LDL-C, and treatment arm. Results: Lp(a) was assessed in 25,083 participants at baseline (median 37nM, range 5-1451) and 25,686 at week 12. There was no association between baseline or achieved Lp(a) levels and risk of serious bleeding, hemorrhagic stroke, neurocognitive events, or malignancy, even in the 3271 patients with Lp(a) levels ≤6nM. There was an inverse association between baseline Lp(a) levels and prevalent or incident DM [OR 1.09, 95%CI 1.07-1.12, for every 50nM lower Lp(a) below 250nM]. However, absolute change in Lp(a) with EVO was not associated with subsequent DM risk (HR 1.03, 0.91-1.16, per 50nM) and EVO did not increase the risk of DM irrespective of baseline Lp(a) (P int=0.97), even in participants in the top decile of baseline Lp(a) (HR 0.91, 0.51-1.62) in whom EVO reduced Lp(a) by 63nM. Conclusion: Lp(a) concentration and changes in Lp(a) were not associated with serious bleeding, hemorrhagic stroke, neurocognitive events, or malignancy. Levels were inversely correlated with having DM, but Lp(a) lowering over a median of 2.2 years with EVO did not further increase the risk. These findings provide new insights for ongoing trials of Lp(a)-lowering drugs.
Association of Genetic Variant at Chromosome 12q23.1 With Neuropathic Pain Susceptibility
Authors: Abirami Veluchamy, Harry L. Hébert, Natalie R. van Zuydam, Ewan R. Pearson, Archie Campbell, Caroline Hayward, Weihua Meng, Mark I. McCarthy, David L. H. Bennett, Colin N. A. Palmer, Blair H. Smith
Journal: JAMA Network Open (2021)

Neuropathic pain (NP) has important clinical and socioeconomic consequences for individuals and society. Increasing evidence indicates that genetic factors make a significant contribution to NP, but genome-wide association studies (GWASs) are scant in this field and could help to elucidate susceptibility to NP.To identify genetic variants associated with NP susceptibility.This genetic association study included a meta-analysis of GWASs of NP using 3 independent cohorts: ie, Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS); Generation Scotland: Scottish Family Health Study (GS:SFHS); and the United Kingdom Biobank (UKBB). Data analysis was conducted from April 2018 to December 2019.Individuals with NP (ie, case participants; those with pain of ≥3 months' duration and a Douleur Neuropathique en 4 Questions score ≥3) and individuals with no pain (ie, control participants) with or without diabetes from GoDARTS and GS:SFHS were identified using validated self-completed questionnaires. In the UKBB, self-reported prescribed medication and hospital records were used as a proxy to identify case participants (patients recorded as receiving specific anti-NP medicines) and control participants.GWAS was performed using linear mixed modeling. GWAS summary statistics were combined using fixed-effect meta-analysis. A total of 51 variants previously shown to be associated with NP were tested for replication.This study included a total of 4512 case participants (2662 [58.9%] women; mean [SD] age, 61.7 [10.8] years) and 428 489 control participants (227 817 [53.2%] women; mean [SD] age, 62.3 [11.5] years) in the meta-analysis of 3 cohorts with European descent. The study found a genome-wide significant locus at chromosome 12q23.1, which mapped to SLC25A3 (rs369920026; odds ratio [OR] for having NP, 1.68; 95% CI, 1.40-2.02; P = 1.30 × 10-8), and a suggestive variant at 13q14.2 near CAB39L (rs7992766; OR, 1.09; 95% CI, 1.05-1.14; P = 1.22 × 10-7). These mitochondrial phosphate carriers and calcium binding genes are expressed in brain and dorsal root ganglia. Colocalization analyses using expression quantitative loci data found that the suggestive variant was associated with expression of CAB39L in the brain cerebellum (P = 1.01 × 10-14). None of the previously reported variants were replicated.To our knowledge, this was the largest meta-analyses of GWAS to date. It found novel genetic variants associated with NP susceptibility. These findings provide new insights into the genetic architecture of NP and important information for further studies.
Prostate Cancer Risk Stratification via Nondestructive 3D Pathology with Deep Learning–Assisted Gland Analysis
Authors: Weisi Xie, Nicholas P. Reder, Can Koyuncu, Patrick Leo, Sarah Hawley, Hongyi Huang, Chenyi Mao, Nadia Postupna, Soyoung Kang, Robert Serafin, Gan Gao, Qinghua Han, Kevin W. Bishop, Lindsey A. Barner, Pingfu Fu, Jonathan L. Wright, C. Dirk Keene, Joshua C. Vaughan, Andrew Janowczyk, Adam K. Glaser, Anant Madabhushi, Lawrence D. True, Jonathan T.C. Liu
Journal: Cancer Research (2021)

Prostate cancer treatment planning is largely dependent upon examination of core-needle biopsies. The microscopic architecture of the prostate glands forms the basis for prognostic grading by pathologists. Interpretation of these convoluted three-dimensional (3D) glandular structures via visual inspection of a limited number of two-dimensional (2D) histology sections is often unreliable, which contributes to the under- and overtreatment of patients. To improve risk assessment and treatment decisions, we have developed a workflow for nondestructive 3D pathology and computational analysis of whole prostate biopsies labeled with a rapid and inexpensive fluorescent analogue of standard hematoxylin and eosin (H&E) staining. This analysis is based on interpretable glandular features and is facilitated by the development of image translation-assisted segmentation in 3D (ITAS3D). ITAS3D is a generalizable deep learning-based strategy that enables tissue microstructures to be volumetrically segmented in an annotation-free and objective (biomarker-based) manner without requiring immunolabeling. As a preliminary demonstration of the translational value of a computational 3D versus a computational 2D pathology approach, we imaged 300 ex vivo biopsies extracted from 50 archived radical prostatectomy specimens, of which, 118 biopsies contained cancer. The 3D glandular features in cancer biopsies were superior to corresponding 2D features for risk stratification of patients with low- to intermediate-risk prostate cancer based on their clinical biochemical recurrence outcomes. The results of this study support the use of computational 3D pathology for guiding the clinical management of prostate cancer. SIGNIFICANCE: An end-to-end pipeline for deep learning-assisted computational 3D histology analysis of whole prostate biopsies shows that nondestructive 3D pathology has the potential to enable superior prognostic stratification of patients with prostate cancer.
Recommendations for Managing Adults With Histiocytic Neoplasms: New NCCN Guidelines
Authors: Ronald S. Go
Journal: Journal of the National Comprehensive Cancer Network (2021)

The histiocytoses, a group of clonal and reactive conditions, arise from monocytic macrophage or dendritic cell lineages. The current NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Histiocytic Neoplasms reflect the most up-to-date, evidence-based data relating to the evaluation and management of this disease. Specifically, the guidelines focus on adult Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease. Because these disorders are rare, challenges have arisen regarding clinical suspicion, histologic diagnosis, treatment, and molecular subtyping. Future versions of the NCCN Guidelines will address the diagnosis and management of pediatric patients, as well as malignant histiocytosis.
Abstract 12914: Predicting Favorable Hemodynamic Response to Intravenous Morphine in ICU Patients With Congenital Heart Disease
Authors: Francesca Sperotto, Sivaram Emani, Lin Zhu, Marlon Delgado, Mauricio Santillana, John Kheir
Journal: Circulation (2021)

Introduction: Intravenous morphine is commonly used to treat pain in patients with congenital heart disease (CHD), though response is variable. For a variety of reasons (objective measure in small children, who cannot communicate verbally; intubation; neuromuscular blockade), heart rate (HR) is often used to assess medication response. As a groundwork for decision support, we created a model of predicting a favorable hemodynamic response to intravenous morphine. Methods: All doses of intravenous morphine administered to patients in the cardiac ICU between 2011 and 2020 were reviewed, excluding doses given on ECMO support, during pacing, or with missing hemodynamic data. The change in HR Z score from baseline (5 minutes prior to bolus) and putative peak effect (30 minutes post-bolus) was computed. Doses were dichotomized into ‘effective’ doses (HR decrease by ≥1 Z-score) and ‘ineffective’, denoting a particularly noticeable change at the bedside. Generalized mixed linear models (GMLM) and random forest (RF) classifiers were used to model the HR response over time. The dataset was divided (dose level) into training (80%) and validation (20%) cohorts. Results: Of 197,242 doses, 117,495 doses among 8,154 patients (median age 0.61 years, 44% post-surgical patients) were included. The median dose of morphine was 0.051 mg/kg (IQR 0.048, 0.099). Concomitant infusions included opioids (45%) and sedatives (53%); 23% of patients received NMB agents. The median HR Z score change was -0.8 (A). HR response category was well predicted by both GMLM (sensitivity = 0.69, PPV 0.90, AUC 0.74) and RF models (sensitivity = 0.73, PPV = 0.90, AUC = 0.76). Predictor variables for GMLM are shown in B. Conclusions: A favorable HR response to morphine can be accurately predicted prior to administration using logical patient factors. This tool represents a component of a decision-support tool for sedation and pain management in critically ill patients.
Whole Genome Sequencing of B-Cell Neoplasms with t(14;19)(q32;q13) Reveals Different Entities
Authors: Anna Carbó-Meix, Francesca Guijarro, Luojun Wang, Romina Royo, Isabel Granada, José Tomás Navarro, Blanca Espinet, Gustavo Tapia, Fina Climent, Mariana Fernández-Caballero, Esmeralda De la Banda, Janilson Do Nascimento, Alberto Pineda, Dolors Vela, María Rozman, Marta Aymerich, Estella Matutes, Sílvia Beà, Dolors Costa, Ferran Nadeu, Elías Campo
Journal: Blood (2021)
Abstract 12533: Progerin Causes a Disproportionate Senescence in Endothelial Cells
Authors: Qiu Xu, Anahita Mojiri, Elisa Morales, Brandon K Walther, Luay Boulahouache, John P Cooke
Journal: Circulation (2021)

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder caused by the mutation of LMNA gene leading to irreversibly farnesylated lamin A protein, i.e. progerin. The major causes of death in HGPS are coronary and arterial occlusive disease. In the murine model of HGPS, vascular smooth muscle cells (VSMCs) loss is the primary vascular manifestation, which is quite different from the human arterial occlusive disease. To identify the mechanisms of HGPS vascular disease in humans, we differentiated isogenomic endothelial cells (ECs) and VSMCs from the same lines of HGPS-iPSCs and control-iPSCs. Both HGPS-ECs and HGPS-VSMCs manifested cellular hallmarks of aging, including dysmorphic nuclei, impaired proliferation, increased β-galactosidase staining, shortened telomeres, upregulated secretion of inflammatory cytokines, increased DNA damage, loss of heterochromatin and altered shelterin complex expression. However, at similar passage number, HGPS-ECs are more severely affected compared to VSMCs, as indicated by a higher percentage of β-galactosidase positive cells, significantly shortened telomere length, and greater frequency of DNA damage signals. With increasing passage number, there is progressive senescence in HGPS-ECs that is greater than that observed in HGPS-VSMCs. Using immunoprecipitation and mass spectrometry, we compared the integrity of the Shelterin Protein Complex (SPC), which is composed of six different proteins and whose function is to protect the telomeres, on the ECs and VSMCs of HGPS and control cells. We observed increased γH2A.X binding to RAP1 (member of SPC) and to Lamin A (nuclear envelope) in HGPS cells. The expression of γH2A.X was greater in HGPS ECs than VSMCs, and is associated with loss of SPC integrity, telomere shortening and loss of heterochromatin formation. Whereas progerin expression has deleterious effect in both vascular ECs and VSMCs, the severity of dysfunction is more extensive in HGPS-ECs in comparison to HGPS-VSMCs. These studies indicate that an endothelial-targeted therapy may be useful in HGPS.
Abstract P311: Blocking Succinate Release Enhances Mitochondrial Reactive Oxygen Species Generation And Worsens Ischemia-reperfusion Injury
Authors: Alexander S Milliken, Sergiy M Nadtochiy, Paul S Brookes
Journal: Circulation Research (2021)

Succinate is a metabolite that plays a central role in ischemia-reperfusion (IR) injury,which is relevant to myocardial infarction (heart attack) and stroke. Succinateaccumulates during ischemia and is rapidly consumed at reperfusion driving reactiveoxygen species (ROS) generation at complex-I (Cx-I) and III of the mitochondrial electrontransport chain. This ROS production triggers cell-death, leading to tissue necrosis.Although succinate oxidation has been extensively studied and exploited as a noveltherapeutic target, only 1/3 of the succinate accumulated in ischemia is oxidized atreperfusion, with the remaining 2/3 being released from the cell via monocarboxylatetransporter 1 (MCT1). Extracellular succinate is thought to be pro-inflammatory, and ithas been proposed that preventing succinate release may be therapeutically beneficial.To determine the impact of preventing succinate release on IR injury, we comparedfunctional recovery (i.e. rate x pressure product, RPP) and infarction (i.e. tissue necrosis)of Langendorff perfused mouse hearts treated with an MCT1 inhibitor, AR-C155858,versus vehicle control. This revealed that succinate retention worsens IR injury (i.e.increased infarction and decreased functional recovery) likely due to increased ROS. Totest this hypothesis, we utilized a Langendorff apparatus positioned within aspectrofluorimeter, which permits real-time fluorescence measurements in beatingmouse hearts. Using the mitochondria targeted superoxide probe, MitoSOX red tomeasure ROS production at reperfusion + AR-C155858, demonstrated that succinateretention leads to enhanced mitochondrial ROS generation at the onset of reperfusion.Overall, these results suggest that inhibiting succinate release in the context of IR injurymay not be a viable therapeutic approach, regardless of any downstream anti-inflammatory effects.
Abstract 11318: Countering the Impact of Covid-19 on Fellow Transesophageal Echocardiogram Education in a Tertiary Academic Program
Authors: Adee Elhamdani, Mark Doyle, Kushani Gajjar, Daniel Pyle, Rachel A Hughes-Doichev, Robert W Biederman
Journal: Circulation (2021)

Introduction: TEE’s are an essential component of cardiology fellowship education. At our institution, COVID peaked twice in 2020. The first peak showed a drop in total fellow TEE’s. To counter this decline, the use of personal protective equipment (PPE) and COVID testing patients requiring TEE’s were implemented to maintain patient care and ensure the safety of health personnel. We analyzed the differences in fellow TEE’s during the second COVID wave compared to the first to determine if these interventions prevented a decline in fellow TEE’s. Methods: The monthly number of TEE’s performed by fellows on core TEE rotations was plotted for the year 2019, prior to the COVID pandemic. For the data set, a linear line was fit to account for the variation of studies read over the year. This linear variation was subtracted from the monthly totals to remove seasonal variation. The degree of variation was taken as the standard deviation (SD) for 2019. The 2020 data was processed using the predictions for 2019 and the upper and lower limits of variation were taken as three times the SD of the 2019 data. Results: Using the 2019 TEE data (Figure 1A), the linear seasonal variation line was created and used to account for variations in the 2020 TEE data (Figure 1B). After accounting for seasonal variation, a significant decline is noted, indicated by the red dot, in the number of fellow TEE’s during the month of April, the first peak (Figure 1C). Institutional guidelines for PPE and COVID testing were put in place in June 2020 and December 2020. After implementation, fellow TEE numbers improve back to baseline and remain consistent even through the December peak (Figure 1C). Conclusions: Our data demonstrates the value of PPE and COVID testing prior to TEE’s can help maintain fellow education during a pandemic while ensuring the safety of fellows, faculty, and technicians. COVID brings uncertainty to the healthcare field and these systems will allow for maintenance of both fellow education and patient care.