tbuckley/cabot-search huggingface dataset:
Abstract 12627: <i>I</i> <sub>Na</sub> Remodeling and Conduction Deficits in a Murine Model of Human <i>LMNA</i> -R545H Mutation
Authors: Adonis Z Wu, Cheng Wang, Katie Spoonamore, Thomas Everett, Zhenhui Chen, Loren J Field, Matteo Vatta, Tomohiko Ai, Michael RUBART, Peng-sheng Chen
Journal: Circulation (2020)

Introduction: We have identified a de novo mutation of LMNA ( LMNA -R545H) in a 34-year-old man with high-grade atrioventricular block. Studies in HEK-293 cells showed that LMNA -R545H reduced the amplitude and resulted in a shift in gating kinetics of the voltage-gated sodium current ( I Na ). These results have not been confirmed in cardiomyocytes. Hypothesis: (1) LMNA -R545H mutation replicates the electrocardiogram (ECG) phenotypes in vivo and (2) there is downregulation of I Na in cardiomyocytes. Methods: We used CRISPR/Cas9 to generate a knock-in mouse model with LMNA -R545H mutation. Isolated cardiomyocytes were used for whole-cell voltage-clamp studies of I Na . Results: Panel (A) shows P, PR, QTc intervals were significantly prolonged and the standard deviation (SD) of the RR intervals was increased during anesthesia in Lmna (R545H+/+) but not in Lmna (R545H+) mice compared with the wild-type control littermates (WT, N=5-8). In Langendorff perfused hearts, the sinus node recovery time (SNRT) and effective refractory period (ERP) were significantly prolonged in the Lmna (R545H+/+) compared with both WT and Lmna (R545H+) . Lmna (R545H+/+) cardiomyocytes showed decreased I Na current density (-20.1±2.3 pA/pF vs. -30.3±3.9 pA/pF, -40 mV, n=7-8, p&lt;.05, Panel B) and prolonged the recovery time constant from I Na inactivation (τ, 36.3±2.2 ms vs. 22.9±1.6 ms, each n=5, p&lt;.05, Panel C). There were no difference in Nav1.5 protein and mRNA levels between the Lmna (R545H+/+) and WT hearts. Conclusions: Homozygous LMNA -R545H mutation leads to reduced I Na , prolonged PR and QTc intervals, and increased sinus arrhythmias.
Abstract 16464: Coronary Artery Calcium Score and Incidence of Clinically Significant Carotid Stenosis
Authors: Aditya Singh, Tom Stys, Valerie Bares, Jeffrey Wilson, Adam Stys
Journal: Circulation (2020)

Introduction: Coronary artery calcium (CAC) has been found to be associated with coronary artery plaque burden and is a major predictor of coronary heart disease (CHD) events. The data on its role in predicting carotid artery stenosis (CAS) is limited. Methods: Participants age ≥ 18 years with heart screen done from Nov 2008- Feb 2019 were selected and were assessed for documented diagnosis of carotid artery stenosis after their heart screen. Only the most recent heart screen per person and earliest documented CAS was considered. The chi-squared test and Welch’s 2-sample t-test was used to test for significant association between CAS and the nominal variables and mean calcium score respectively. Results: A total of 35,084 patient were screened for CAC score and 1439 (4.1%), were recorded to have a diagnosis of carotid artery stenosis. 53.5% being females and mean age of 63.69±9.31 years. The mean time between heart screen and documented diagnosis of CAS was 1529.4 ± 1211.0 days. The presence of CAS was significantly higher in patients ≥ 60 years (8.5%) as compared to those age &lt;60 years (2%). There was a significant difference in mean CAC score between those with CAS as compared to non- carotid stenosis group (324.2, vs 107.27, p&lt;.0001). In patient with elevated CAC ≥ 100, 9.98% had diagnosis of CAS, as compared to 2.82% in patients with CAC &lt;100, however among patients with diagnosis of CAS 46.6% had elevated CAC ≥ 100. Conclusions: The presence of carotid artery stenosis (CAS) was significantly associated with elevated coronary artery calcium score (≥100) and was significantly higher in patients with age ≥ 60 years, which in correct clinical context is helpful in suspecting CAS.
Abstract 16466: Greater Body Mass Index Predicts Valve Function Following Transcatheter Pulmonary Valve Replacement in Adults With Tetralogy of Fallot
Authors: Zachary Daniels, Anudeep Dodeja, Victoria Shay, Yubo Tan, Shasha Bai, Darren Berman, Kan N Hor, Naomi J Kertesz, Curt J Daniels, Anna Kamp
Journal: Circulation (2020)

Introduction: After the initial surgical repair of tetralogy of Fallot (rTOF), right ventricular outflow tract dysfunction is common, with pulmonary stenosis (PS), regurgitation, or both. Obese adults with rTOF have worse biventricular systolic function, and greater post-operative pulmonary valve replacement morbidity than non-obese patients. Transcatheter PVR (TPVR) is used increasingly, though no studies have examined the impact of body mass index (BMI) on morbidity and hemodynamics in adults with rTOF and subsequent TPVR. Hypothesis: BMI affects outcomes of transcatheter PVR in adults with TOF. Methods: This was a 10 yr, single center, retrospective review of adults (&gt;18 yo) with rTOF who underwent TPVR. The cohort was split into 2 groups based on BMI at time of TPVR. Group A (Grp A): normal and overweight (BMI &lt;30), group B (Grp B): obese (BMI ≥30). Pre and post-TPVR echocardiogram, cardiac MRI, and catheterization data were reviewed. Results: There were 81 adults, 42 (52%) normal, 18 (22%) overweight (Grp A) and 21 (26%) obese (Grp B). Mean follow up was 6.4 + 3.1 yrs. With most recent post-TPVR echocardiogram, there was no significant difference in LV or RV size and function across groups. Compared to Grp A, Grp B patients were more likely to develop any degree of PS (mild, moderate, or severe) following TPVR (69% vs 94%, respectively, p = 0.032). An ROC curve analysis demonstrated BMI ≥ 26.3 had a low sensitivity (45%), but good specificity (89%) for predicting PS post TPVR. There was no difference between groups requiring re- intervention for PVR. Conclusion: This is the first study to show greater BMI affects valve function in adults with rTOF following TPVR. BMI &gt;26 was associated with a greater risk of PS in follow up echocardiograms after TPVR. Obesity is an epidemic in the US and patient prosthesis mismatch may be an issue when considering TPVR. Further studies are indicated to determine the long-term effects of BMI on TPVR and the need for re-intervention in adults with TOF.
Abstract 17381: Comparative Analysis of Mechanical Circulatory Support in Patients With Acute Coronary Artery Syndrome Induced Cardiogenic Shock
Authors: Waqas Ullah, Salman Zahid, yasar sattar, Houmam Moussa Pacha, Fahed Darmoch, Ali Banisad, Gaith Alhatemi, Roomi Sohaib, Ankur Panchal, David L Fischman, M Chadi Alraies
Journal: Circulation (2020)

Introduction: The relative safety of contemporary, real-world use of percutaneous ventricular assist device (pVAD) and intra aortic balloon pump (IABP) in patients with acute coronary artery syndrome (ACS) induced cardiogenic shock remains unknown. Hypothesis: Outcomes of pVAD and IABP in ACS Methods: Data were obtained from the Nationwide Inpatient Sample (NIS) database (2011-2014) using ICD-9 codes. Patients with the renal transplant or chronic kidney disease were excluded. Categorical and continuous data were compared using unadjusted odds ratio (uOR) and independent t-test analysis, respectively. Univariate and multivariate logistic regression analysis was performed to obtain adjusted odds ratio (aOR), controlled for patient comorbidities. Results: A total of 165,006 (pVAD 3104, IABP 161902) patients with cardiogenic shock following ACS were included. The proportion of demographics and baseline comorbidities for pVAD vs. IABP were significantly different between the two groups, including age (65 vs. 63 years, p=&lt;0.001, female (33.6% and 27.9%, p=&lt;0.001), caucasian (77.8% vs 72.8%, p=&lt;0.001), respectively. The undusted odds for In-hospital mortality (41.2% vs 29.6%%, uOR, 1.67; 95% CI, 1.55-1.78, P=&lt; 0.001), acute kidney injury (47.6% vs 28.7% uOR, 2.25; 95% CI, 2.09-2.41, P=&lt;0.001) and major bleeding (21% vs 14.8% uOR, 1.54; 95% CI, 1.40-1.68, P=&lt; 0.001) were significantly higher in patients undergoing pVAD compared to IABP. (Figure 1) However, there was no difference in the odds of vascular complications between the two groups (3% vs 2.6%, uOR 1.16; 95% CI, 0.94-1.42, P=0.18. The adjusted odds based on baseline characteristics including hypertension, diabetes, renal failure, anemia, bleeding disorders, age, race and hospital area did not deviate from unadjusted odds ratios. Conclusions: Compared to the IABP, pVAD might have higher odds of in-hospital all-cause mortality, acute kidney injury and major bleeding in ACS induced cardiogenic shock.
Effects of face masks on oxygen saturation and functional measures in patients with connective tissue disorder-associated interstitial lung disease
Authors: Anuroopa Vijayan, Sakir Ahmed, Sneha Joseph, Aswathy Sukumaran, Subin Ahmed, Padmanabha Shenoy
Journal: Annals of the Rheumatic Diseases (2021)

Face masks are a first-line defence against the COVID-19 pandemic.1 Concerns about face masks reducing oxygen saturation (SpO2) have been negated by controlled studies in healthy individuals.2 3 Universal masking must be followed without exceptions. However, persons with pre-existing cardiorespiratory diseases like interstitial lung diseases (ILD) have limited functional reserves. We explored the effects of face masks in patients with connective tissue disease (CTD)-associated ILD (CTD-ILD).

Patients between 18 and 75 years of age with high-resolution CT (HRCT)-proven CTD-ILD and with Medical Research Council scale grades 1–3 dyspnoea and forced vital capacity (FVC) of less than 70% were included in this crossover trial. If FVC was >70%, patients were included only if the extent of involvement on HRCT was more than 20% of the lung. Patients requiring oxygen supplementation and with myositis or lower limb pain were excluded. Initial SpO2 was recorded and a standard 6 min walk test (6MWT) was carried out with and then without a standard three-layer surgical face mask. Adequate precautions were taken to prevent the spread of COVID-19 during the tests. Distance covered during the 6MWT was the primary outcome measure. The secondary outcome measures …
Abstract 12955: A Novel Algorithm for Automated Titration of Autonomic Regulation Therapy for Heart Failure
Authors: Imad LIBBUS, Scott Stubbs, Lorenzo Dicarlo, Scott Mazar, Badri Amurthur, Bruce KenKnight
Journal: Circulation (2020)

Background: Autonomic Regulation Therapy (ART) using chronic vagus nerve stimulation (VNS) is a promising new therapy for patients with heart failure who remain symptomatic despite standard care. In the ANTHEM-HF Pilot Study, a therapeutic VNS intensity was successfully achieved in patients with HFrEF using manually programmed VNS up-titration. An algorithm has been developed for automatically intensifying VNS in small increments to a programmable target and capable of adjustments during up-titration process using a hand-held programmer or magnet. Methods: 6 healthy canines were implanted with an implantable pulse generator (IPG) and electrical lead for right cervical VNS. IPG programming at implant activated the TA algorithm with (1) a 1-week start delay; (2) initial stimulation intensity of 0.125 mA, 130 μsec pulse width, and 5 Hz frequency; (3) target stimulation intensity of 2.5 mA, 250 μsec pulse width, and 5 Hz frequency; and (4) trajectory to achieve the target intensity in approximately 10 weeks. Magnet placement over the IPG at scheduled intervals tested algorithm design intention to decrement VNS intensity, prolong the time to reach the target intensity, and/or temporarily inhibit VNS. Results: All animals underwent successful VNS system implantation and completed all scheduled activities. There was one transient implant-related adverse event (Horner’s Syndrome). The TA algorithm performed as designed. The targeted VNS intensity was achieved as scheduled, and automated titration was well tolerated in all animals. There were no stimulation-related adverse events. ECG monitoring demonstrated no clinically significant cardiac findings. Detailed gross necropsy and macroscopic examinations revealed vagus nerves and all major organs to be normal in all animals. Conclusion: An IPG for VNS having a programmable TA algorithm for automatically intensifying VNS to a target intensity and capable of adjustment in response to magnet applications to the IPG, was successfully tested in a preclinical study of healthy canines. The TA algorithm performed as designed, appears to be safe and could dramatically reduce burden of titration in a clinical setting.
UBQLN2-HSP70 axis reduces poly-Gly-Ala aggregates and alleviates behavioral defects in the C9ORF72 animal model
Authors: Kejing Zhang, Ailian Wang, Keke Zhong, Shuyuan Qi, Chen Wei, Xiaoqiu Shu, Wen-Yo Tu, Wentao Xu, Congcong Xia, Yatao Xiao, Aizhong Chen, Lei Bai, Jianmin Zhang, Benyan Luo, Wenyuan Wang, Chengyong Shen
Journal: Neuron (2021)
Abstract 15544: Implication of the Histone Methyltransferase “G9a” in Pulmonary Arterial Hypertension
Authors: Charifa awada, Karima Habbout, Valerie Nadeau, Sandra Breuils-Bonnet, Roxane Paulin, Steeve Provencher, Sebastien Bonnet, Olivier BOUCHERAT
Journal: Circulation (2020)

Rationale: Pulmonary arterial hypertension (PAH) is a cardiopulmonary disorder characterized by elevation of pulmonary arterial (PA) pressure and premature death. PA smooth muscle cells (PASMCs) from PAH patients present a cancer-like hyperproliferative and apoptosis-resistant phenotype contributing to remodeling of distal PAs. Although epigenetic alterations contribute to PAH development, one important challenge is defining which genes are the drivers . A growing body of literature points to the role of an epigenetic factor called G9a in cancer pathogenesis. Indeed, G9a is a histone methyltransferase overexpressed in many cancers promoting cell proliferation and survival. Given the similarities between PAH and cancer, it is of interest to determine whether G9a is implicated in PAH. We thus hypothesized that G9a inhibition reduces the pro-proliferative and apoptosis resistance phenotype of PAH-PASMCs. Methods and Results: Using Western blot (WB) and immunofluorescence (IF), we showed that G9a is overexpressed in distal PAs and isolated PASMCs from PAH patients (n= 6-14, p&lt;0.01). Similarly, G9a was increased (WB and IF, p&lt;0.05) in two models mimicking the disease; namely the monocrotaline rat and mice exposed to chronic hypoxia. In vitro, we found that pharmacological inhibition of G9a using BIX01294 and UNC0642 reduces PAH-PASMC proliferation (Ki67 and EdU assays, p&lt;0.001) and survival (Annexin V assay p&lt;0.001). Through RNA sequencing analysis conducted in PAH-PASMCs treated or not with BIX01294, we found that upregulated differentially expressed genes (DEGs) were enriched in cholesterol biosynthesis, autophagy-lysosome and ER stress-induced apoptotic pathways. However, downregulated DEGs were involved in cell cycle and fibrosis-related processes. Consistently, inhibition of G9a generates numerous cytoplasmic vacuoles positive for LC3-II and p62 (WB, IF), thus suggesting that the inhibition of G9a induces cell death by altering cholesterol metabolism-dependent autophagy. Conclusion: We showed for the first time that G9a is overexpressed in PAH contributing to the pro-proliferative and anti-apoptotic phenotype of PAH-PASMCs. Current experiments aim to determine whether G9a inhibition provides therapeutic benefits in PAH.
Abstract P043: <u>Distance And Clinical Outcomes Of Patients Admitted For Covid-19: Lessons Learned From The Neighbors Of An Inner-city Hospital.</u>
Authors: Shivani Patel, Aeliya Kazmi, Muhammed Sherif, Gouthami Chennu, Steve Lee, Umair Khan, Nana Safoah, Saadul Mallam, Srita Chakka, Jose Bustillo, Alexis K Okoh
Journal: Circulation (2021)

Background: In rural areas, the distance factor has been identified as key in the utilization of health services. We aim to determine whether distance to an inner-city hospital in Newark, was associated with mortality in patients admitted for COVID-19 during the peak of the pandemic. Methods: Patients who were admitted for COVID-19 at the Newark Beth Israel Medical Center (NBIMC) were stratified into two groups based on distance between the zip codes of their primary residence and the hospital. Baseline demographics, clinical characteristics and in-hospital outcomes were compared between subjects living within a 2-mile radius of the zip code of the hospital [Neighbors] and those living further than 2 miles [Distant]. The primary outcome was in-hospital mortality. Secondary outcomes were admission to the intensive care unit (ICU), length of hospitalization, and discharge disposition. Results: Between March 09 and May 04, 2020, a total of 769 patients were admitted for COVID-19 at NBIMC. 406 (53%) resided within a 2-mile radius of the hospital location. Of these 44% were obese. History of hypertension, diabetes mellitus and coronary artery disease was documented in 69%, 48% and 23% respectively. Compared with distant patients, neighbors were older (59 vs. 69 yrs. P=0.048), mostly of Black/African American race (64% vs. 82%; p&lt;0.001) and had a higher incidence of diabetes mellitus (40% vs. 48%; p=0.025) or coronary artery disease (17% vs. 23%; p=0.039). Visitors were more likely to report an exposure history to a COVID-19 patient than neighbors (31% vs. 21%, p=0.001). In-hospital death rate were significantly higher in neighbors than visitors (32% vs. 22%, p=0.007). Admission to the ICU was similar between both groups (p=0.438). Among those who survived to discharge, distant patients had longer length of hospitalization (12 vs. 10 days; p=0.006), than neighbors. Discharge disposition was comparable in both groups (p=0.249) Conclusions: In this cross-sectional study of patients admitted to an inner-city hospital for COVID-19, majority of patients living within a 2-mile radius were of Blacks/African Americans who had a higher incidence of DM and CAD. A paradoxical association between distance to the hospital and in-hospital mortality was observed. Based on these findings, targeted interventions aimed at Impacting social determinants of health seem prudent.
Single AAV-mediated CRISPR-Nme2Cas9 efficiently reduces mutant hTTR expression in a transgenic mouse model of transthyretin amyloidosis
Authors: Jinkun Wen, Tianqi Cao, Jinni Wu, Yuxi Chen, Shengyao Zhi, Yanming Huang, Peilin Zhen, Guanglan Wu, Lars Aagaard, Jianxin Zhong, Puping Liang, Junjiu Huang
Journal: Molecular Therapy (2021)

Transthyretin (TTR) amyloidosis is a hereditary life-threatening disease characterized by deposition of amyloid fibrils. The main causes of TTR amyloidosis are mutations in the TTR gene that lead to the production of misfolded TTR protein. Reducing the production of toxic protein in the liver is a validated strategy to treat TTR amyloidosis. In this study, we established a humanized mouse model that expresses mutant human TTR (hTTR; V30M) protein in the liver to model TTR amyloidosis. Then, we compared the efficiency of reducing the expression of mutant hTTR by dual adeno-associated virus 8 (AAV8)-mediated split SpCas9 with that by single AAV8-mediated Nme2Cas9 in this model. With two gRNAs targeting different exons, dual AAV-mediated split SpCas9 system achieved efficiencies of 37% and 34% reduction of hTTR mRNA and reporter GFP expression, respectively, in the liver. Surprisingly, single AAV-mediated Nme2Cas9 treatment resulted in 65% and 71% reduction of hTTR mRNA and reporter GFP, respectively. No significant editing was identified in predicted off-target sites in the mouse and human genomes after Nme2Cas9 targeting. Thus, we provide proof of principle for using single AAV-mediated CRISPR-Nme2Cas9 to effectively reduce mutant hTTR expression in vivo, which may translate into gene therapy for TTR amyloidosis. Transthyretin (TTR) amyloidosis is a hereditary life-threatening disease characterized by deposition of amyloid fibrils. The main causes of TTR amyloidosis are mutations in the TTR gene that lead to the production of misfolded TTR protein. Reducing the production of toxic protein in the liver is a validated strategy to treat TTR amyloidosis. In this study, we established a humanized mouse model that expresses mutant human TTR (hTTR; V30M) protein in the liver to model TTR amyloidosis. Then, we compared the efficiency of reducing the expression of mutant hTTR by dual adeno-associated virus 8 (AAV8)-mediated split SpCas9 with that by single AAV8-mediated Nme2Cas9 in this model. With two gRNAs targeting different exons, dual AAV-mediated split SpCas9 system achieved efficiencies of 37% and 34% reduction of hTTR mRNA and reporter GFP expression, respectively, in the liver. Surprisingly, single AAV-mediated Nme2Cas9 treatment resulted in 65% and 71% reduction of hTTR mRNA and reporter GFP, respectively. No significant editing was identified in predicted off-target sites in the mouse and human genomes after Nme2Cas9 targeting. Thus, we provide proof of principle for using single AAV-mediated CRISPR-Nme2Cas9 to effectively reduce mutant hTTR expression in vivo, which may translate into gene therapy for TTR amyloidosis.
Novel predictions arise from contradictions
Authors: Itai Yanai, Martin Lercher
Journal: Genome biology (2021)

In formal logic, a contradiction is the signal of defeat, but in the evolution of real knowledge, it marks the first step in progress toward a victory."Alfred North WhiteheadFrom the outside, science seems to be the epitome of order, with its careful logical process, white lab coats, the methodical analyses of data, and, at its core, the formal testing of hypotheses.While that image may capture the "day science" aspect of science, it ignores the creative "night science" part, which generates the hypotheses in the first place.When we are in night science mode, we recognize facts that do not sit quite right against our clear and precise mental representation of the state of knowledge.While such contradictions arise from the data generated by day science, it is night science that revels in them, as these are the first, faint glimpses of new concepts.Depending on our state of mind, contradictions might appear as nuisances; embracing them helps us to counteract our natural human tendency for confirmation bias, a well-documented phenomenon in psychology.To explore the interaction of confirmation bias with a contradiction present in a dataset, we devised a simple experiment: individuals with different expectations examined the same data plot, which showed a superposition of two conflicting trends.We found that participants who expected a positive correlation between the two variables in the plot were more than twice as likely to report detecting one than those expecting a negative correlation.We posit that night science's exploratory mode counteracts such cognitive biases, opening the door to new insights and predictions that can profoundly alter the course of a project.Thus, while science's practitioners may be biased, the cyclical process of day science and night science allows us to spiral ever closer to the truth. Data is not transparentScience prides itself on being above the "idols of the tribe and the cave" [1], unperturbed by assumptions and unproven theories.Data is objective, after all, and scientists commit to "letting the data do the talking."But data, of course, cannot speak for itself.It must be interpreted against an extensive conceptual, theoretical, and methodological background-and this background is unlikely to be bias-free.Thus, to venture that a dataset makes a particular statement hides the degree to which potential biases may have influenced our conclusions.
96MO A risk analysis of alpelisib (ALP)-induced hyperglycemia (HG) using baseline factors in patients (pts) with advanced solid tumours and breast cancer (BC): A pooled analysis of X2101 and SOLAR-1
Authors: J. Rodon, D. Demanse, H.S. Rugo, F. André, F. Janku, I. Mayer, H. Burris, R. Simo, A. Farooki, H. Hu, I. Lorenzo, C. Quadt, D. Juric
Journal: Annals of Oncology (2021)