tbuckley/cabot-search huggingface dataset:
Abstract 16360: Clinical Progression of Aortic Disease Among Adults Enrolled in the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions Database
Authors: Erin R Lewis, Tracy Roberts Andrews, Federico M ASCH, Mary J Roman, Reed E Pyeritz, Scott A Lemaire, Sherene Shalhub, Kim Eagle, Gabriele Di Luozzo
Journal: Circulation (2020)

Objective: Evaluating progression of distal aortopathy among patients with GT-TAA. Methods: 1,160 patients (2007-2014) including 226 patients with &amp;gt=2 CT/MRI scans; mean surveillance=1.5±1.4 years. Rapid progression (RP) was within the fourth quartile growth rate. Multivariable logistic regressions analyzed RP, proximal surgery and downstream growth. Kaplan Meier analysis described the event-free survival. Results: Patients were white (85%), male (58%), with Marfan syndrome (35%) and median age 44.5 years; 65% underwent surgical intervention. 3 lost to follow-up and 12 died.142 patients were RP. Median inter-scan duration 24 months. RP was 2.5-times higher with initial distal diameters &amp;gt=3cm (p=0.032). Distal repairs more common with RP (41% vs. 20%, p=0.016); proximal interventions 55% less likely (p=0.009). Proximal interventions did not influence distal ROG but increased likelihood of distal intervention 5-fold (p=0.001). Calcium channel blockers were associated with 10.7-fold risk for RP (p=0.032). Overall, 5-year event-free survival was 37% with RP versus 34% for counterparts (p=0.706). Logistic regression found 22-fold higher likelihood of death in RP (p=0.055). Conclusions: Inter-scan intervals &amp;lt24 months is important due to vascular-related complications. Calcium channel blockers were associated with greater ROG. Despite the need for more distal interventions, RP median event-free survival similar to counterparts. Keywords: aorta, aneurysm, genetics, surveillance
Abstract 14802: Relation of Non-exercise Walking Activity With Exercise Performance in Patients With Peripheral Artery Disease
Authors: Ryan J Mays, Rachel Kahnke, Erica N Schorr, Diane J Treat-jacobson
Journal: Circulation (2020)

Introduction: Structured exercise programs in home settings are beneficial for patients with peripheral artery disease (PAD). However, the impact of lower levels of walking activity accumulated separately from formal home exercise in PAD is unclear. The aim of this study was to determine the relation of non-exercise walking (NEW) activity with exercise performance in PAD. Methods: This was a post-hoc analysis from twenty patients with PAD enrolled in a 12-week structured home-based walking exercise program using diaries and accelerometry. Formal exercise sessions (3 sessions·week -1 ) were detected using patient-reported diary entries that corresponded with accelerometer step data. NEW activity was characterized as steps completed over five days each week, excluding steps during formal exercise sessions. The primary outcome for the intent-to-treat analysis was peak walking time (PWT) assessed on a graded treadmill. Secondary outcomes were claudication onset time (COT) from the graded treadmill test and maximal distance achieved during the six-minute walk test (6MWT). Pearson correlations evaluated the relation between NEW activity (step·week -1 ) and exercise performance outcomes using intensity (step·week -1 ) and duration (min·week -1 ) from formal exercise sessions as covariates. Results: NEW activity demonstrated a strong, positive correlation with change in PWT (r=0.50, p=0.04) when controlling for exercise intensity and duration during the 12-week intervention. Other exercise performance outcomes were not significantly related to NEW activity (COT: r=0.14; 6MWT maximal distance: r=0.27). Conclusions: A positive association was demonstrated between NEW activity and the primary outcome of PWT following 12 weeks of structured home-based walking exercise. Interventions to improve physical activity outside of formal exercise sessions may be beneficial for patients with PAD.
How to Make a Rodent Giant: Genomic Basis and Tradeoffs of Gigantism in the Capybara, the World’s Largest Rodent
Authors: Santiago Herrera-Álvarez, Elinor Karlsson, Oliver A Ryder, Kerstin Lindblad-Toh, Andrew J Crawford
Journal: Molecular Biology and Evolution (2020)

Gigantism results when one lineage within a clade evolves extremely large body size relative to its small-bodied ancestors, a common phenomenon in animals. Theory predicts that the evolution of giants should be constrained by two tradeoffs. First, because body size is negatively correlated with population size, purifying selection is expected to be less efficient in species of large body size, leading to increased mutational load. Second, gigantism is achieved through generating a higher number of cells along with higher rates of cell proliferation, thus increasing the likelihood of cancer. To explore the genetic basis of gigantism in rodents and uncover genomic signatures of gigantism-related tradeoffs, we assembled a draft genome of the capybara (Hydrochoerus hydrochaeris), the world's largest living rodent. We found that the genome-wide ratio of nonsynonymous to synonymous mutations (ω) is elevated in the capybara relative to other rodents, likely caused by a generation-time effect and consistent with a nearly neutral model of molecular evolution. A genome-wide scan for adaptive protein evolution in the capybara highlighted several genes controlling postnatal bone growth regulation and musculoskeletal development, which are relevant to anatomical and developmental modifications for an increase in overall body size. Capybara-specific gene-family expansions included a putative novel anticancer adaptation that involves T-cell-mediated tumor suppression, offering a potential resolution to the increased cancer risk in this lineage. Our comparative genomic results uncovered the signature of an intragenomic conflict where the evolution of gigantism in the capybara involved selection on genes and pathways that are directly linked to cancer.
Abstract 13211: Atrial Fibrillation is an Independent Predictor for Cardiovascular Events in Hypertensive Patients Due to Primary Aldosteronism
Authors: Shintaro Sakaguchi, Ryuji Okamoto, Chisa Inoue, Kohei Kamemura, Isao Kurihara, Yoshiyuki Takeda, Youichi Ohno, Hiromi Rakugi, Takuyuki Katabami, Akiyo Tanabe, Kouichi Tamura, Yutaka Yano, Kaoru Dohi, Mitsuhide Naruse
Journal: Circulation (2020)

Introduction: A higher risk of cardiovascular events has been reported in patients with hypertension due to primary aldosteronism (PA) than essential hypertension. Hypothesis: This study sought to determine the independent predictors for the risk of cardiovascular events in hypertensive patients with PA. Methods: The nation-wide PA registration study (JPAS/JRAS) included patients aged 20 years and older. Data were collected between January 2006 and January 2019, with a mean follow-up duration of approximately 4 years. Characteristics of patients with or without atrial fibrillation (AF) on the diagnosis of PA were compared. Patients were treated by surgery or MR antagonists and incident cardiovascular events were followed up. Results: A total of 3,647 patients with PA were included at the time of analysis. Prevalence of AF was 2.4% (87/ 3,647). PA patients with AF were older, more male and had longer duration of hypertension than those without AF. Each prevalence of cerebral infarction, chronic kidney disease, coronary artery disease, heart failure and left ventricular hypertrophy evaluated by echocardiography was higher in PA patients with AF than those without AF. Patients with AF had more kinds of antihypertensive drugs. There was no significant difference of basal plasma aldosterone concentration, plasma renin activity, unilateral subtype and rate of surgery between the 2 groups. PA patients with AF had higher rates of cardiovascular events compared to those without AF (14.9% vs 6.7%, P=0.002). Multivariate cox regression analyses demonstrated AF in addition to older age, male gender, duration of hypertension and surgery performance as an independent prognostic factor for cardiovascular events (HR, 1.950 [95%CI, 1.021-3.726], P&lt;0.05; HR, 1.023 [95%CI, 1.008-1.039], P=0.003; HR, 1.385 [95%CI 1.025-1.870], P&lt;0.05; HR, 1.023 [95%CI, 1.008-1.038], P=0.002; HR, 1.580 [95%CI, 1.168-2.138], P=0.003;respectively). Conclusions: Among patients with PA, male gender, older age, and longer duration of hypertension are the predisposing factors of AF in PA patients. In addition, AF was an independent risk factor for cardiovascular events in PA patients. It is warranted to prevent and to treat appropriately AF in patients with PA.
Abstract 217: Glycation of Ryanodine Receptors in Peripheral Lymphocytes Predicts the Response to Cardiac Resynchronization Therapy
Authors: Marco Bruno Morelli, Jessica Gambardella, Alessandro Matarese, Xujun Wang, Salvatore D'Ascia, Celestino Sardu, Gaetano Santulli
Journal: Circulation (2020)

Introduction: Cardiac resynchronization therapy (CRT) is an effective treatment for patients with advanced heart failure (HF). The management of these patients depends on biomarkers for monitoring disease progression and therapeutic response. HF patients exhibit a pathologic remodeling of Ryanodine Receptors (RyRs) in heart, muscle, as well as circulating lymphocytes, leading to intracellular calcium leak, which has been shown to correlate with the clinical outcome. Hypotheses: 1) post-translational modifications of RyR in circulating lymphocytes in HF patients can predict CRT response; 2) CRT can improve the remodeling of RyRs and intracellular calcium leak. Methods: To test this hypothesis, we enrolled 34 patients who underwent CRT and examined RyR remodeling in peripheral lymphocytes before and 1 year after CRT using established biochemical and flow-cytometry assays. Non-responders to CRT were defined after 1 year of follow-up as patients with at least one of the following characteristics: deteriorating function (HF-related death, need for heart transplantation), increase in LVEF ≤ 4%, worsening in peak O 2 consumption, in Quality-of-Life score, or in the distance walked in 6 min. Results: We found that post-translational remodeling of RyR ( i.e. oxidation, phosphorylation, glycation) was significantly ( P&lt;0.01 ) reduced in circulating lymphocytes isolated from CRT responders compared to pre-CRT levels and to non-responders. Similarly, the binding to RyR of its stabilizing subunit (calstabin) was markedly increased by CRT, whereas intracellular Ca 2+ leak was attenuated ( P&lt;0.01 ). Importantly, these phenomena were not observed in CRT non-responders. Moreover, in a multivariate regression analysis, we observed that RyR glycation in peripheral lymphocytes at baseline was independently associated with CRT response at 1-year follow-up ( P&lt;0.05 ). Conclusions: This is the first study showing that CRT response can be predicted by the level of RyR glycation in peripheral blood lymphocytes. Moreover, we demonstrate that CRT responders exhibit a significantly reduced intracellular Ca 2+ leak through RyR in lymphocytes, mirrored by diminished post-translational modifications compared to baseline and to CRT non-responders.
Diagnosing and responding to serious child abuse
Authors: D. P H Jones, M. A Lynch
Journal: BMJ (1998)

Publishing recently in Pediatrics,Southall et al described their experience of using covert video recordings to diagnose life threatening abuse.1 Of 39 children (median age 9 months) referred to two UK hospitals for investigation of suspicion of induced illness, including 36 with apparent life threatening events, the authors filmed evidence of abuse in 33. This included suffocation in 30, poisoning in two, and the breaking of an arm. The transcripts of the recordings make distressing, yet essential, reading. Risk of abuse extended to other children within these families: 12 out of 41 siblings had died suddenly and unexpectedly (suffocation was subsequently admitted for 8, and reinvestigation of another revealed salt poisoning), and abuse was documented in a further 15.

Southall et al have revealed the grim world which has been intermittently explored over the past 100 or so years.2 4 Now, however, the filmed evidence concretely exposes what was previously available only to professional imagination. These children were not damaged during bouts of anger but harmed coolly and callously by parents who appeared concerned …
Virtual histological staining of unlabelled tissue-autofluorescence images via deep learning
Authors: Yair Rivenson, Hongda Wang, Zhensong Wei, Kevin de Haan, Yibo Zhang, Yichen Wu, Harun Günaydın, Jonathan E. Zuckerman, Thomas Chong, Anthony E. Sisk, Lindsey M. Westbrook, W. Dean Wallace, Aydogan Ozcan
Journal: Nature Biomedical Engineering (2019)
PTH-130 A retrospective study on the outcomes of patient with jackhammer oesophagus in a regional tertiary referral centre
Authors: Bpm Yeung, S Thomson
Journal: Gut (2017)

Introduction  Jackhammer oesophagus is a relatively new diagnosis based on high resolution manometry(HRM). It is rare and the management of this condition remains unclear. We aim to study the symptomology, diagnosis and management of patients with Jackhammer oesophagus in a tertiary teaching hospital, which is responsible for HRM assessment for a population of 1.2 million in the Scotland.  Method  Retrospective study from 01/10/2012 to 31/12/2016. Patients with at least one hypercontractile swallow (distal contractile integral[DCI]>8000 mmHg/s/cm) on HRM were analysed. Demographics, symptoms, HRM findings, and subsequent management plan were obtained from the local database and electronic record.  Results  16 (9F:7M) patients were identified. Median age at diagnosis was 61.2y(Max: 84.6y Min:43.9y). Three most common presenting complaints were dysphagia 15 (93.8%), regurgitation 9 (56.3%), and globus sensation 7 (43.8%). The median duration of symptoms reported by the patient prior to diagnosis was 4 years (Max: 20y Min: 0.1y). 12 (75%) patients were referred from general practice, 2 (12.5%) from respiratory medicine, 1 (6.3%) from ENT surgery and 1 (6.3%) from internal medicine. The median duration from referral to diagnosis was 126d (Max: 1320d Min: 85d). 11 (68.8%) had barium swallow. Of these, 8 (72.7%) were abnormal; findings included tertiary contraction, contrast stasis and oesophageal diverticulum. 15 (93.8%) had gastroscopy. Endoscopic findings can be classified into: 6 (40%) with hiatus hernia or reflux oesophagitis, 4 (26.7%) with gastritis or duodenitis, 3 (20%) with lower oesophageal hypertonicity and 2 (13.3%) were normal. Only 2 (12.5%) had 24 h pH study, which were normal. 1 (6.3%) had nuclear medicine study confirming delayed gastric emptying. Heterogenous treatment strategies were employed included: GTN 6 (43.8%), Sildenafil 2 (12.5%), BOTOX injection 1 (6.3%), and Nifedipine 2 (12.5%). Of these, only those who had Nifedipine had temporary symptom response. Median follow-up was 361.5d(Max: 1620d Min: 96d). At last follow-up, only 2 (12.5%) had symptom resolution with proton pump inhibition while 14 (87.5%) remained symptomatic.  Conclusion  Jackhammer oesophagus is a heterogenous motility disorder of the oesophagus. Most patients have prolonged symptoms prior to diagnosis. To date, no effective treatment has been identified and most patients remain symptomatic. Novel approach such as peroral endoscopic myotomy (POEM) may be a valuable option in selected subset of patients with Jackhammer oesophagus.  Reference  . Herregods TVK, et al. Jackhammer oesophagus: observations on a European cohort. Neurogastroenterology & Motility. 2016;1–8.  Disclosure of Interest  None Declared
Abstract PO-010: Elucidating intratumoral heterogeneity and predicting effective combination regimens in PDAC PDOs using scRNA-seq and snATAC-seq
Authors: Paola A. Guerrero, Anirban Maitra, Maria E. Monberg, Jaewon J Lee, Vincent Bernard-Pagan, Senthil Muthuswamy
Journal: Cancer Research (2020)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States. The overwhelming majority of patients (up to 85%) present with unresectable disease, and the 5-year survival rate stands at a dire 9%. Current chemotherapeutic regimens extend survival by only a few months, and the molecular underpinnings of treatment failure in advanced disease remain largely unknown. Recently, single-cell sequencing techniques have emerged as highly effective methods to uncover intratumoral heterogeneity across many cancer types, including PDAC. These studies, and our own unpublished data, have reiterated profound transcriptomic subclonal diversity in PDAC, which likely underlies the divergent therapeutic responses and eventual treatment failure. Using a patient-derived organoid (PDO) platform, we have characterized, on the single cell level, gene expression and regulation profiles to understand the heterogeneity and clinical utility of this model. We applied predictive RNA-seq-based algorithms (CMap) to our initial PDO profiling data to design “custom” PDO combinatorial regimens as a true precision medicine-based approach. We are in the process of validating these predictions in vitro; however, preliminary single-cell RNA (scRNA-seq) data shows treatment PDOs with CMap-predicted compounds induced dramatic transcriptomic shifts in subclones reflective of an efficacious treatment strategy. Additionally, we conducted single-nuclei ATAC sequencing (snATAC-seq) of PDOs pre- and post-treatment with CMap-predicted compounds. This data, coupled to our scRNA-seq, allowed for construction of chromatin regulatory maps, and determined alterations in chromatin accessibility and gene regulation induced by targeted combinatorial therapeutics. These findings provide meaningful insight to biological processes driven by treatment-induced chromatin accessibility, and its relationship to heterogeneous transcriptional architecture. Our data suggests that differential regulation across PDO subclones may drive responses to therapy and acquired resistance mechanisms observed in the clinic, which could be predicted and therapeutically targeted with scRNA sequencing. Thus, this work represents the importance of leveraging subclonal architecture in the preclinical space to ensure both treatment efficacy and the consideration of novel therapeutic combinations in PDAC patients. Citation Format: Paola A. Guerrero, Anirban Maitra, Maria E. Monberg, Jaewon J Lee, Vincent Bernard-Pagan, Senthil Muthuswamy. Elucidating intratumoral heterogeneity and predicting effective combination regimens in PDAC PDOs using scRNA-seq and snATAC-seq [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-010.
Abstract 13633: Predictors of Mental and Physical Health Outcomes of Patients Undergoing an Appointment-based Cardiac Rehabilitation Program
Authors: Catherine Xie, Sean Fournier, Susan Hiller, Joyce Oen Hsiao, Rachel P Dreyer
Journal: Circulation (2020)

Introduction: Cardiac rehabilitation (CR) is an evidence-based program to improve secondary prevention outcomes for patients with cardiovascular disease (CVD). Lower health-related quality of life is a known risk factor for worse CVD outcomes. We examined the effects of a patient-driven appointment-based CR program on health-related quality of life. Methods: We utilized data from the Yale New-Haven Health (YNHH) CR program over a 6-year period (2012-2017). Data was collected on patient demographics, clinical characteristics and socioeconomic status. The Medical Outcome Short-Form General Health Survey (SF-36) was used to measure general health status. We evaluated SF-36 score changes pre and post CR with paired T-tests and conducted logistic regression analysis to examine predictors of improvements in health-related quality of life. Results: Over the 6-year study period, a total of 2,135 patients (27.9% women, mean age 65±12 years) were enrolled in the CR program. Patients demonstrated significant improvements in both the SF-36 physical, mental and health transition components (P&lt;0.001) (Table) . In particular, patients had significant improvement in the social functioning domain (measures limitations patients see in their ability to participate in social activities due to physical/emotional issues), with an increase of 23.3 points out of 100. Physician-reported patient stress and/or depression on intake medical exam were significant negative predictors for improvement in the total SF-36 score (OR 0.23, 95% CI 0.08-0.80, P=0.021), with the effect driven largely by its impact on the physical component of SF-36 (OR 0.27, 95% CI 0.09-0.83, P=0.022). Conclusion: We demonstrated that a novel appointment-based CR program produced improvements in patient-reported health-related quality of life. Appointment-based CR could be a viable alternative for patients who prefer more scheduling flexibility, to optimize health status improvement and CVD outcomes.
Synthetic high-density lipoproteins delivering liver X receptor agonist prevent atherogenesis by enhancing reverse cholesterol transport
Authors: Wenmin Yuan, Bilian Yu, Minzhi Yu, Rui Kuai, Emily E. Morin, Huilun Wang, Die Hu, Jifeng Zhang, James J. Moon, Y. Eugene Chen, Yanhong Guo, Anna Schwendeman
Journal: Journal of Controlled Release (2020)
Abstract 16737: Inhibition of Tgf-β1 Signaling Protect Against Cell-Cell Decoupling and Asynchronous Automaticity of Tbx18-ipms
Authors: Jinqi Fan, Nam Kyun Kim, Natasha Fernandez, Minji Shin, Hee Cho
Journal: Circulation (2020)

Background: We have previously demonstrated that TBX18 suffices to reprogram postnatal ventricular cardiomyocytes to induced pacemaker cells (TBX18-iPMs). However, the nascent automaticity appeared to wane over time, characterized by loss of syncytial pacing but preservation of single cell automaticity. Hypothesis: Based on increase in Tgfβ ligands in TBX18-iPMs and the known role of Tgfβ signaling in electrical remodeling, we hypothesized that loss of syncytial automaticity is due to electrical decoupling of the iPMs mediated by Tgfβ signaling. Methods: Adenoviral vectors expressing either human TBX18 or GFP were used for gene transfer into neonatal rat ventricular myocytes (NRVMs) or adult rat ventricular myocardium in vivo. Results: NRVM monolayers transduced with GFP were mostly quiescent, interspersed by paroxysmal contractions. In contrast, TBX18 transduced NRVM monolayers showed spontaneous and rhythmic contractions, but the syncytial pacing wavered over the next 5-7 days although numerous iPMs continued to beat asynchronously. Treatment of TBX18-iPMs with an inhibitor of Tgfβ receptors, A83-01, preserved syncytial pacing, suggesting that electrical remodeling cues from Tgfβ signaling led to loss of iPM-iPM electrical coupling. We examined the molecules that are integral to the function of gap junction in the myocardium, namely Cx43, N-cadherin and β-catenin. Cx43 and N-cadherin were downregulated in TBX18-iPMs compared to control by 77±16% and 43±11% (p&lt;0.01, n=6), respectively. Total β-catenin protein level was unaltered, but its distribution decreased at the sarcolemmal and increased in the nuclei of TBX18-iPMs compared to control. Inhibition of Tgfβ with A83-01 restored Cx43 protein level in TBX18-iPMs (2.2-folds higher) compared to untreated TBX18-iPMs. Similarly, adult rats that received intramyocardial injection of TBX18 showed increased Cx43 expression at the boundary between the iPMs and the host myocardium when the animals were treated with systemic delivery of A83-01 for one week compared to TBX18 animals treated with DMSO. Conclusions: TBX18 activates Tgfβ signaling which suppresses cell-cell electrical coupling. Inhibition of Tgfβ signaling in TBX18-iPMs preserves gap junction components and syncytial pacing.