tbuckley/cabot-search huggingface dataset:
Abstract 9912: A Case of Left Ventricle Non-Compaction in an Asymptomatic Athlete
Authors: Tatiana Echeverry, Shivalika Mehan, Michael Weinrauch
Journal: Circulation (2021)

Introduction: Left ventricle non-compaction (LVNC) is defined as a primary genetic cardiomyopathy by the American Heart Association and as an unclassified cardiomyopathy by the European Society of Cardiology. Phenotypically, it is characterized by prominent trabeculations and intertrabecular recesses in the ventricular cavity. The clinical manifestations of LVNC range from an asymptomatic state to progressive heart failure and life-threatening arrhythmias. The following case highlights an athletic patient with LVNC. Case Presentation: A 22-year-old male presented to the cardiology clinic for evaluation prior to enrolling in the police academy. At age 15, an echo revealed prominent trabeculations. The patient has been a competitive soccer player since high school. Upon presentation, he was asymptomatic with non-specific T wave changes noted on ECG, stress echocardiography revealed preserved functional capacity, prominent trabeculations, and EF 55%. No arrhythmias were noted. CMR revealed a hyper-trabeculated LV predominantly at the mid-ventricular and apical segments, moderate left and right ventricular enlargement with EF 55%. No LGE enhancement was noted. Discussion: LVNC is estimated to affect 8-12 patients per 1 million annually, but the actual number is likely higher as many individuals are asymptomatic. Although the cause of LVNC is unclear, it has been associated with mutations in sarcomere encoding genes including MYH7 and MYBPC3. It remains controversial whether LVNC is a distinct disorder since it has been reported in other cardiomyopathies and since it has been reported in pregnancy and trained athletes. The current diagnostic criteria for LVNC include a ratio of non-compacted to compacted myocardium &gt;2.1:1 as demonstrated by echo or a ratio of &gt;2.3:1 by CMR. However, it has been proposed that trabeculation formation represents a physiological adaptation to increased loading conditions seen in pregnancy and vigorously trained athletes. Therefore, it remains unclear whether the current diagnostic criteria apply to an athletic population. Furthermore, the prognostic implications of prominent trabeculations meeting accepted diagnostic criteria for LVNC remain uncertain.
Abstract 9793: Walking Performance, Quality of Life, and Hemodynamic Characteristics in Patients with Peripheral Artery Disease and End-Stage Kidney Disease (PAD-ESKD)
Authors: Naomi Hamburg, Alik Farber, Marc P Bonaca, Manesh R Patel, William A Marston, Stephan Miller, Claire Padgett, Laurence H Keller, Joan Perelló, Alex Gold, Glenn M Chertow
Journal: Circulation (2021)

Background: Patients with peripheral artery disease and end-stage kidney disease (PAD-ESKD) have poor outcomes that may be related to the presence of medial arterial calcification. These patients have been excluded from prior studies of medical interventions; thus, there is a need to better understand baseline functional capacity to aid design of interventional studies. Methods: Patients receiving hemodialysis (HD) who met the following inclusion criteria: age ≥55 OR ≥45 with diabetes, PAD as defined by ankle-brachial index (ABI) &lt;0.90 and/or toe-brachial index (TBI) &lt;0.70, and described symptoms with walking were enrolled at 7 US sites in a cross-sectional study of functional status. Patients with chronic limb-threatening ischemia, recent revascularization, or a non-PAD condition limiting walking were excluded. We measured walking with the 6-minute walk distance (6MWD), repeated after a 1-week interval, and the Walking Impairment Questionnaire (WIQ). We assessed claudication symptoms with the San Diego Claudication Questionnaire (SDCQ). Results: Of 67 patients who were screened, 36 (54%) met eligibility criteria, and 30 have completed the ongoing study: 43% women, mean (SD) age 69 (8) years, and mean (range) time since initiation of HD 53 (1-219) months. All patients had abnormal TBI with mean 0.46 (0.15). Consistent with the presence of medial arterial calcification, 10 patients (33%) had ABI ≥1.2 in one or both legs. Ten patients (33%) had intermittent claudication (IC). Overall mean (SD) 6MWD was 357 (261) meters (range 60-975). Test-retest reliability of 6MWD was good with an intraclass correlation of 0.97. The 6MWD was &lt;350 meters in 19 patients (63%). Mean (SD) WIQ overall score was 32 (26), range 0-92, out of a possible 100 max. Patients who reported IC, as well as those who did not, had walking impairment as assessed by 6MWD and WIQ. Conclusion: We demonstrate the high prevalence of impaired walking ability in patients with PAD-ESKD, a previously poorly characterized population. The PAD-ESKD population has high clinical need, supporting a planned randomized, placebo-controlled trial to evaluate the effects of SNF472, a novel investigational inhibitor of vascular calcification.
Abstract 13777: Engineering of Bacterial Nano Cellulose-Based Small Diameter (CSD) Vascular Graft for Coronary Artery Bypass Grafting
Authors: Deborah Fusco, Florian G Meissner, Alessia Pisanu, Bruno Podesser, Bernhard Winkler, Anna Marsano, Friedrich Eckstein
Journal: Circulation (2021)

Coronary artery disease, mostly caused by atherosclerosis of coronary arteries, is one of the leading causes of death worldwide (Naghavi et al. , 2015). In the context of coronary artery bypass grafting (CABG), internal mammary arteries, radial arteries and saphenous veins cannot be always used as autologous arterial substitutes (Ishii et al. , 2016) e.g. in patients with multivessel disease (Wipperman et al ., 2009). Synthetic vascular grafts (e.g., Dacron (PET), Teflon (ePTFE)) are an alternative option only to autologous grafts for substitution of vessels with an inner diameter &gt;8 mm (Wippermann et al. , 2009; Weber et al ., 2017). The aim of the project is to develop a Cellulose-based Small Diameter (CSD, 3-4 mm) vascular grafts for coronary artery bypass made of Bacterial nano-Cellulose (BC) reinforced with a Cobalt Chrome mesh. The hypothesis of the study is that CSD vascular grafts are biomechanically suitable to substitute autologous small diameter vessels. In a proof-of-concept study predecessors of these CSD grafts were already used for CABG on pigs. After 4 weeks, angiography showed fully open grafts with no dissection and no narrowing at distal anastomoses. Histology of the explants showed endothelialization from autologous endothelial cells and formation of neointima.The CSD graft is generated in a customized bioreactor providing a temperature- and oxygen-controlled culture environment. BC is synthetized and deposited by Gluconacetobacter around a gas-permeable silicone tube delivering 100% of oxygen. Biological and morphological analyses will be performed and CSD patency will be tested in an in vivo large animal model. It was manufactured up to 20 cm long CSD vascular grafts with a 3-4 mm inner diameter (inner wall thickness 0.5 mm), a circumferential tensile strength of 0.34 ± 0.09 MPa (Force at the breaking point of 1.29 ± 0.28 N), and a burst pressure up to 515.5 ± 94.7 mmHg. Based on an in vitro cytotoxicity test CSD graft resulted not toxic (&gt;70%, n=3). These data indicate the engineered CSD graft as a promising alternative to autologous grafting for coronary artery bypass surgical procedure.
Flow-Cytometry Evaluation of Cellular Surface FVIII in Blood Cells and Its Correlation with FVIII Activity and Coagulation
Authors: Anjud Al-Mohannadi, Muhammad Elnaggar, Hani Bibawi, Che-Ann Lachica, Igor Pavlovski, Giusy Gentilcore, Dhanya Kizhakayil, Ayman Saleh, Elkhansa E Elgaali, Mohammed Elanbari, Chiara Cugno, Sara Deola
Journal: Blood (2021)
Abstract 11641: Targeted Intrathecal Nos1 Inhibition Rescues Pulmonary Hypertension and Right Ventricular Failure in Rats by Reducing Neuroinflammation, Apoptosis and Sympathoexcitation
Authors: Asif Razee, Somanshu Banerjee, JASON HONG, Soban Umar
Journal: Circulation (2021)

Introduction: Pulmonary hypertension (PH) is associated with aberrant sympathoexcitation leading to RV failure (RVF), arrhythmias and death. NOS1 is known to induce neuroinflammation, nitrosative stress and apoptosis in neural tissue. In spinal cord, NOS1 is activated by afferent signaling via Ca 2+ influx through activated NMDAR in dorsal horn by increased glutamate release via K + channels. Hypothesis: Cardiopulmonary afferent signaling in PH-RVF leads to NOS1-mediated neuroinflammation, nitrosative stress and apoptosis in thoracic spinal cord (TSC) resulting in aberrant sympathoexcitation. Targeted intrathecal NOS1-inhibition may rescue PH and RVF. Methods: Male rats received s.c. Monocrotaline (MCT, 60mg/kg, n=8, 4wk) or Sugen (SuHx, 20mg/kg, n=8, 3wk hypoxia+2wk normoxia). Controls received PBS (n=8). A group of MCT-rats received either daily intrathecal specific NOS1-inhibitor S-Methyl-L-thiocitrulline (SMTC; 0.5mg/kg, n=7) or PBS (n=7) from day 14-28. Echo and RV cath were performed. TSC and RV RNASeq, RT-qPCR, NOS1 activity, NOS1 immunolocalization, microglia+astrocyte quantification and TUNEL were performed. Plasma catecholamines were measured by ELISA. Values are mean±SD. Results: Rats developed severe PH-RVF (Increased RVSP, Fulton-index, decreased RVFAC; p&lt;0.01). TSC transcriptome showed common genes and pathways linked to neuroinflammation, nitrosative stress and apoptosis and identified NOS1 as one of the top-most upregulated genes (MCT / SuHx:8 fold; p&lt;0.05) in TSC but not lumbar. We found significantly increased microglia+astrocyte activation, NMDAR-1, Kv3.4, CX3CL1, nitrosative stress markers AP1B1, AP1M1 and pro-apoptotic p53, TGFβ1 expression in TSC. We observed increased NOS1 activity, its colocalization with microglia+astrocyte, apoptosis and norepi/epi in both models. SMTC decreased RVSP, Fulton-index, RVID d , pulmonary vascular wall thickness, increased RVFAC by reducing TSC NOS1 activity, CX3CL1/TGF β 1, microglia/astrocyte activation, apoptosis and plasma norepi/epi (p&lt;0.05). RV transcriptome demonstrated that SMTC decreased pro-fibrotic, pro-apoptotic, SNS &amp; RAAS related and pro-inflammatory RV gene expression profile. Conclusions: Intrathecal NOS1 inhibition rescues PH and RVF.
Abstract 12660: Novel Model of Oxalate Diet Induced Chronic Kidney Disease in Dahl-Salt-Sensitive Rats
Authors: Prabhatchandra Dube, Vaishnavi Aradhyula, Jacob Connolly, Fatimah Khalaf, Sophia Soehnlen, Armelle DeRiso, Ayla Cash, Andrew Kleinhenz, Oliver Domenig, Deepak Malhotra, Lance D Dworkin, Steven T Haller, David J Kennedy
Journal: Circulation (2021)

Background: Diet induced models of chronic kidney disease (CKD) may offer several advantages vs surgical models in terms of clinical relevance and animal welfare. Oxalate is a plant-based, terminal toxic metabolite that is eliminated by the kidneys through glomerular filtration and tubular secretion. Increased load of dietary oxalate leads to supersaturation, calcium oxalate crystal formation, renal tubular obstruction and eventually CKD. Dahl-salt-sensitive rats (Dahl-S) are a common strain used to study for hypertensive renal disease however characterization of other diet induced models on this background would allow for comparative studies of CKD within the same strain. We hypothesized that Dahl-S rats on a low-salt, oxalate rich diet would have increased renal injury and will serve as a novel rat model to study CKD. Methods/Results: Ten week-old male Dahl-S rats were fed either 0.2% salt normal chow (SS-NC) or a 0.2% salt diet containing 0.67% sodium oxalate (SS-OX) for five weeks (n=6-8/group). Real-time PCR demonstrated increased expression of inflammatory marker IL-6 (235% vs SS-NC, p&lt;0.0001) and fibrotic marker Timp-1 metalloproteinase (142% vs SS-NC, p&lt;0.0001) in the renal cortex of SS-OX rat kidneys compared to SS-NC. Immunohistochemistry of kidney tissue demonstrated increase in CD-68 levels, a marker of macrophage infiltration in SS-OX rats (275% vs SS-NC, p&lt;0.001). In addition, SS-OX rats displayed increased 24-hour urinary protein excretion (UPE) (97% vs SS-NC, p&lt;0.01) as well as significant elevations of plasma Cystatin C (135% vs SS-NC, p&lt;0.01). Furthermore, oxalate diet induced hypertension (23% increase in systolic blood pressure vs. SS-NC, p&lt;0.05) and renin-angiotensin-aldosterone system (RAAS) profiling (via LC-MS/MS) in the SS-OX plasma showed significant (p&lt;0.05) increases in angiotensin [1-5] (128% vs SS-NC) and angiotensin I (56% vs SS-NC) as well as suppression of the steroid aldosterone (-54% vs SS-NC). Conclusion: Oxalate diet induces significant renal inflammation, fibrosis, renal dysfunction, decreased aldosterone secretion as well as RAAS activation and hypertension in Dahl-S rats and provides a novel diet-induced model to study hypertension and CKD.
Abstract 14103: Loss of Bone Morphogenetic Protein (BMP) 9 Activity Reduces Survival and Increases Collagen Turnover via Enhanced Matrix Metalloproteinase Activity After Acute Myocardial Infarction
Authors: Shreyas Bhave, Michele Esposito, Lija Swain, Xiaoying QIAO, Gregory Martin, Kay Everett, Navin K Kapur
Journal: Circulation (2021)

Introduction: Acute myocardial infarction (AMI) is a major cause of heart failure and mortality. The extracellular matrix plays a central role in post-infarct remodeling. We recently reported that BMP9 negatively regulates cardiac fibrosis in heart failure. A functional role for BMP9 in post-infarct remodeling remains poorly defined. We hypothesize that BMP9 signaling via activin like kinase 1 (ALK1) promotes survival after AMI by negatively regulating fibrosis and limiting matrix metalloproteinase (MMP) activity. Methods: AMI was induced by left coronary artery ligation in wild type (WT), BMP9-/- and ALK-/+ mice. After 14 days, LV function was assessed using conductance catheter and myocardial BMP9 signaling pathways were studied. In vitro siRNA mediated protein knockdown in human atrial fibroblasts (AtFB) further tested this signaling pathway. Results: BMP9-/- and ALK-/+ mice had significantly reduced survival after AMI compared to WT (p=0.04 and 0.008 respectively) and was associated with an increased incidence of cardiac rupture. LV ejection fraction decreased significantly among BMP9-/- and ALK1+/- survivors compared to sham (p&lt;0.01 for both). pSMAD3 was increased and pSMAD1 decreased in both BMP9-/- and ALK1-/+ mice after AMI. Reduced pSMAD1 expression was directly associated with increased type 1 collagen levels in BMP9-/- (R 2 =0.48, p=0.02) and ALK1-/+ (R 2 =0.42, p=0.01) mice compared to WT. LV protein levels of endoglin increased significantly in both BMP9-/- and ALK+/- compared to WT sham (p&lt;0.01 for both) after AMI. LV levels and activity of MMP9 were increased in BMP9-/-, but not in ALK1+/-, compared to WT after AMI (p=0.02 and 0.8 respectively). Circulating biomarkers of collagen degradation:synthesis (ICTP:PINP ratio) increased significantly (p=0.02) in BMP9-/- compared to WT after AMI. BMP9 but not ALK1 knockdown in AtFBs increased expression and activity of MMP9 (p=0.01 and 0.3 respectively). Conclusions: These findings identify a novel functional role for BMP9 and ALK1 as determinants of post-infarct survival and cardiac remodeling and further suggest that loss of BMP9-ALK1 signaling increases collagen degradation and turnover. BMP9/ALK1 signaling may be a novel target of therapy for post-infarct remodeling and survival.
Unconvincing Evidence of SARS-CoV-2–Associated Myositis in Autopsied Muscles—Reply
Authors: Tom Aschman, Hans-Hilmar Goebel, Werner Peter Stenzel
Journal: JAMA Neurology (2021)

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Abstract 11857: Benchmarking a Functional Assay to Assist Clinical Classification of Variants of Uncertain Significance in <i>KCNH2</i> (Long QT Syndrome Type 2)
Authors: Connie Jiang, Jessica Farr, Adam Hill, Brett Kroncke, Jodie Ingles, Jamie Vandenberg, Chai A Ng
Journal: Circulation (2021)

Introduction: Our ability to determine the pathogenicity of variants is limited by the paucity of clinical data when variants are seen in very few individuals. In vitro functional assays could help overcome the deluge of variants of uncertain significance (VUS). To be clinically useful, such assays must satisfy stringent benchmarking criteria established by the ACMG/AMP. For variants in KCNH2 , the cause of Long QT Syndrome Type 2 (LQTS2), ~70% of missense variants are VUS. Here, we wish to formally evaluate the accuracy, replicability and robustness of a high-throughput automated patch-clamp (APC) assay for characterising KCNH2 variants. Aim: To evaluate an APC assay for KCNH2 variants against the criteria for the application of functional evidence within the ACMG/AMP framework. Methods: Twenty five variants classified as pathogenic/likely pathogenic and 18 variants classified as benign/likely benign from ClinVar were heterozygously expressed in stable Flp-In HEK293 cells and analysed for loss-of-function based on current density and changes in channel gating. Results: Twenty three of 25 pathogenic variants had &lt;50% wild-type (WT) peak current density, indicating loss-of-function. The two remaining pathogenic variants, G584S and N629S, had &lt;50% WT current levels (IKr) after incorporating additional gating measures. All 18 benign variants had &gt;50% WT current levels both before and after including gating measures. For 17 of the benign variants, current levels were not statistically different to WT. The current level for R148W was significantly different to WT (p&lt;0.005) but was still &gt;50%. Based on a 50% cut-off, the assay yields a sensitivity of 100% and specificity of 100%. Conclusions: High-throughput electrophysiological phenotyping correctly predicted loss of function for 25/25 pathogenic variants, and 18/18 benign variants. The assay should be able to assist with the clinical classification of KCNH2 variants.
Therapy-Related Acute Myeloid Leukemia (t-AML) and the Advantage of Intensive Chemotherapy: Real-Life Analysis from Two Regional French Centers
Authors: Amine Belhabri, Mael Heiblig, Stephane Morisset, Liliana Vila, Sandrine Hayette, Clemence Santana, Hélène Labussière, Isabelle Tigaud, Adriana Plesa, Anne-Sophie Michallet, Emmanuelle Nicolas-Virelizier, Franck E. Nicolini, Lila Gilis, Philippe Rey, Marie Balsat, Adrien Quintela, Sophie Ducastelle, Souad Assad, Marie Larcher, Gaelle Fossard, Xavier Thomas, Mohamad Sobh, Mauricette Michallet
Journal: Blood (2021)
Author Correction: A global effort to dissect the human genetic basis of resistance to SARS-CoV-2 infection
Authors: Evangelos Andreakos, Laurent Abel, Donald C. Vinh, Elżbieta Kaja, Beth A. Drolet, Qian Zhang, Cliona O’Farrelly, Giuseppe Novelli, Carlos Rodríguez-Gallego, Filomeen Haerynck, Carolina Prando, Aurora Pujol, Paul Bastard, Catherine M. Biggs, Benedetta Bigio, Bertrand Boisson, Alexandre Bolze, Anastasiia Bondarenko, Petter Brodin, Samya Chakravorty, John Christodoulou, Aurelié Cobat, Antonio Condino-Neto, Stefan N. Constantinescu, Hagit Baris Feldman, Jacques Fellay, Rabih Halwani, Emmanuelle Jouanguy, Yu-Lung Lau, Isabelle Meyts, Trine H. Mogensen, Satoshi Okada, Keisuke Okamoto, Tayfun Ozcelik, Qiang Pan-Hammarström, Anna M. Planas, Anne Puel, Lluis Quintana-Murci, Laurent Renia, Igor Resnick, Anna Sediva, Anna Shcherbina, Ondrej Slaby, Ivan Tancevski, Stuart E. Turvey, K. M. Furkan Uddin, Diederik van de Beek, Mayana Zatz, Pawel Zawadzki, Shen-Ying Zhang, Helen C. Su, Jean-Laurent Casanova, András N. Spaan
Journal: Nature Immunology (2021)
NCOG-18. RELATIONSHIP BETWEEN RANO-PRO WORKING GROUP STANDARDIZED PRIORITY CONSTRUCTS AND DISEASE PROGRESSION AMONG MALIGNANT GLIOMA PATIENTS AS MEASURED THROUGH CLINICAL OUTCOMES ASSESSMENTS
Authors: Elizabeth Vera, Tito Mendoza, Alvina Acquaye, Nicole Briceno, Anna Choi, Alexa Christ, Ewa Grajkowska, Varna Jammula, Heather Leeper, Jason Levine, Matthew Lindsley, Jennifer Reyes, Kayla Roche, James Rogers, Michael Timmer, Lisa Boris, Eric Burton, Nicole Lollo, Marissa Panzer, Lily Polskin, Marta Penas-Prado, Valentina Pillai, Brett Theeler, Jing Wu, Mark Gilbert, Terri Armstrong
Journal: Neuro-Oncology (2021)

Abstract Recognizing the importance of clinical outcomes assessments (COA), the RANO-PRO Working Group recommends inclusion of core symptoms/functions in clinical care/research for malignant glioma patients. This study evaluated the association between the recommended symptoms (pain, perceived cognition, seizures, aphasia, treatment-specific symptoms) and functions (physical: weakness, walking; and role/social: work, usual activities) and disease progression in these patients. MDASI-Brain Tumor and EQ-5D-3L scores, Karnofsky Performance Status (KPS), and Neurologic Function Score (NFS) were evaluated in relation to disease progression by chi-square tests, independent- and paired-samples t-tests, adjusted for multiple comparisons. Our sample included 336 patients with malignant glioma; 82% white, 64% male, median age=52 (21-79). Imaging study revealed disease progression for 46% of patients. All symptoms except seizures and difficulty concentrating were worse in the group whose imaging showed disease progression versus stable disease, as well as the functions of walking, work, activity, and self-care (0.8 &amp;lt; difference &amp;lt; 1.8). Patients with disease progression were 4 times more likely to have a poor KPS (≤ 80) and worse NFS. Among patients with disease progression (n=112), all symptoms, except seizures, worsened from first assessment to time of progression. Up to 22% of patients reported worsening mobility, self-care, and usual activity; 46% and 35% had worsened KPS and NFS, respectively. Seven symptoms and functions were each individually reported by at least 10% of patients as having worsened the most. Worsening of symptoms and functions was not observed among patients with stable disease, except in difficulty understanding. Identified core symptoms/functions worsen at the time of progression demonstrating the relationship between priority constructs and a traditional tumor response measure while highlighting the importance of longitudinal collection of COA. The pattern of worsening was observed via both patient- and clinician-reported outcomes, emphasizing the utility of COA in clinical care and clinical trials.