tbuckley/cabot-search huggingface dataset:
Abstract 14698: Matrix Stiffening Induces a Pathogenic Qki-microrna-7-srsf1 Axis in Pulmonary Arterial Endothelial Cells
Authors: Chen-shan J Woodcock, Neha Hafeez, Adam Handen, Ying Tang, Leonard Estephan, Gil Speyer, Seungchan Kim, Thomas Bertero, Stephen Y Chan
Journal: Circulation (2020)

Introduction: Early increases in pulmonary artery stiffness drive pathogenic alterations of pulmonary arterial endothelial cells (PAECs), leading to vascular remodeling, a prominent feature of pulmonary hypertension (PH). However, the molecular mechanisms by which PAECs respond to altered extracellular matrix (ECM) mechanics remain unclear. Recent RNA sequencing study of PAECs exposed to stiff versus soft matrices has identified miRNA-7 (miR-7) as a mechanosensitive downregulated miRNA. The biogenesis of miR-7 is inhibited by the RNA binding protein quaking (QKI), which is shown to be correspondingly upregulated in ECM stiffness. Moreover, subsequent RNA sequencing and computational analyses have identified serine and arginine rich splicing factor 1 (SRSF1) as a miR-7 target in PAECs with ECM stiffening. Hypothesis: The QKI-miR-7-SRSF1 axis is a pivotal ECM stiffening-mediated pathogenic signal in PAECs. Methods: Human PAECs were cultured on soft (0.5 or 1 kPa) or stiff (50 kPa) matrices. Lungs from PH patients and rats (SU5416/Hypoxia- and MCT-exposed models) were used to evaluate genes and miRNA expression. Boyden chamber migration analysis examined PAEC mobility. Results: In human and rat PH lungs, miRNA-7 (miR-7) was down-regulated ( P &lt; 0.05). To validate RNA sequencing data by RT-qPCR, QKI level was increased (2.13 ± 0.19, P &lt;0.0001) in PAECs cultured on stiff versus soft matrices and correspondingly miR-7 level was decreased (0.71 ± 0.17, P &lt;0.0001). Furthermore, miR-7 targeted the 3’-untranslated region of SRSF1 mRNA as demonstrated by luciferase activity assay. In PAECs, forced miR-7 overexpression decreased SRSF1, and conversely miR-7 inhibition increased SRSF1. QKI overexpression increased SRSF1 by downregulating miR-7 level. Moreover, forced miR-7 overexpression significantly inhibited PAEC migration ( P &lt;0.0001), accompanied by downregulation of SRSF1 mRNA level (0.75 ± 0.07, P &lt;0.0001). Conclusions: Our data demonstrate that mechanoactivation of a QKI-miR-7-SRSF1 signal axis promotes PAEC pathophenotypes driven by ECM stiffness. These insights broaden our understanding of RNA pathobiology in vascular stiffening and carry important therapeutic implications in PH.
Abstract 13826: Lipoprotein (a) Levels Among Children Diagnosed With a Primary Hypercholesterolemia
Authors: Duygu Uzun, Premchand Anne, James Maciejko
Journal: Circulation (2020)

Introduction: The American Academy of Pediatrics (AAP) recommends universal lipid screening in all children beginning at nine years of age. Although not a component of the lipid profile, an elevated lipoprotein (a) (Lp(a)) (≥30 mg/dL) is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) in adults. Plasma Lp(a) levels are a product of the Lp (a) gene, which is fully expressed by 5 years of age, and remains relatively unchanged into adulthood. Limited number of studies have examined Lp(a) levels in children diagnosed with a primary hypercholesterolemia. Hypothesis: To determine the frequency of Lp(a) excess, defined as ≥30 mg/dL, among children diagnosed with a primary hypercholesterolemia (i.e., Familial Hypercholesterolemia (FH), Familial Combined Hyperlipidemia (FCH), Polygenic Hypercholesterolemia (PH). Methods: We reviewed the Ascension St. John Children’s Center Lipid Clinic database between 8/1/2012 and 12/31/2019. Only children diagnosed with a primary hypercholesterolemia and having a baseline Lp(a) assessment were included. FH was diagnosed using the Dutch Lipid Score. PH was diagnosed as an elevated LDL-C level not associated with a monogenic mutation or a secondary cause. FCH was diagnosed as an elevated LDL-C in combination with any triglyceride elevation in the absence of secondary causes. Results: One-hundred and twenty patients were evaluated (mean age: 12.1 ± 2.0 years). Seventy-eight percent (93) of the children were white and 52% (62) were male. The frequency of an Lp(a) excess was 44% (53) in this group. The frequencies of Lp(a) excess by diagnosis, and the median Lp(a) and mean LDL-C levels are displayed in Table 1. Conclusions: Lp(a) excess is relatively frequent among children diagnosed with a primary hypercholesterolemia. Since an Lp(a) excess is an ASCVD risk factor, it should be considered clinically relevant when determining the baseline LDL-C level at which a lipid-lowering agent is initiated in children.
Poly(anhydride-ester) gemcitabine: Synthesis and particle engineering of a high payload hydrolysable polymeric drug for cancer therapy
Authors: Rodrigo S. Heyder, Fatemah S. Sunbul, Rashed M. Almuqbil, Cory B. Fines, Sandro R.P. da Rocha
Journal: Journal of Controlled Release (2020)
Abstract 14944: Drug Utilization Study in Heart Failure (HF) Patients Concomitantly Prescribed Sodium-glucose Cotransporter-2 Inhibitors (SGLT2i) and Sacubitril/valsartan (sac/val), a Database Cohort Study Using Optum Electronic Health Record (EHR) US Data
Authors: Emil Loefroth, Maria Hughes, Yulin Shi, Yitong Wang, Clare Proudfoot, Maximiliano D Domenico, Vikas Modgill, Raymond Schlienger, Rachel Studer
Journal: Circulation (2020)

Background: Sac/val, an angiotensin receptor neprilysin inhibitor, reduces the risk for cardiovascular (CV) death and hospitalization for HF in HF with reduced ejection fraction (HFrEF). SGLT2i are glucose lowering medications that have shown reduction in CV risk in patients with very high CV risk and diabetes. Recently, the SGLT2i dapagliflozin has shown improvement in outcomes in patients with chronic HFrEF, with or without diabetes, when used in addition to standard of care including sac/val. As the use of SGLT2i in HF evolves, and given the large overlap of HF and type 2 diabetes (T2D) populations, it is of interest to understand the drug utilization of concomitant use of sac/val and SGLT2i. This study describes the time to discontinuation for patients treated concomitantly with sac/val and SGLT2i or with sac/val and dipeptidyl peptidase-4 inhibitors (DPP4i) or glucagon-like peptide-1 receptor agonists (GLP1). Methods: This retrospective non-interventional cohort study describes two mutually exclusive adult patient cohorts diagnosed with HF and T2D concomitantly prescribed sac/val and SGLT2i, or sac/val and DPP4i/GLP1. All patients had a minimum follow-up time of 3 months. All patients were identified any time between 1 st July 2015 and 30 th Sep 2019 in the Optum® de-identified EHR data from providers across the continuum of care. Results: 783 patients were prescribed sac/val and SGLT2i (cohort 1) and 1,855 sac/val and DPP4i-/GLP1 (cohort 2). Treatment continuation was higher for cohort 1 compared to cohort 2 (57.3% and 49.9%). 11.1% and 10.6% of patients discontinued sac/val in cohort 1 and 2, respectively, 20.3% discontinued SGLT2i in cohort 1 and 23.1% discontinued DPP4i/GLP1 in cohort 2. Conclusions: Of the patients with HF and T2D prescribed sac/val and SGLT2i or DPP4i/GLP1 concomitantly, discontinuation rates of at least one product within 3 months are relatively high. Fewer patients discontinued sac/val compared to SGLT2i or DPP4i/GLP1.
Antibody potency, effector function, and combinations in protection and therapy for SARS-CoV-2 infection in vivo
Authors: Alexandra Schäfer, Frauke Muecksch, Julio C.C. Lorenzi, Sarah R. Leist, Melissa Cipolla, Stylianos Bournazos, Fabian Schmidt, Rachel M. Maison, Anna Gazumyan, David R. Martinez, Ralph S. Baric, Davide F. Robbiani, Theodora Hatziioannou, Jeffrey V. Ravetch, Paul D. Bieniasz, Richard A. Bowen, Michel C. Nussenzweig, Timothy P. Sheahan
Journal: The Journal of Experimental Medicine (2020)

SARS-CoV-2, the causative agent of COVID-19, has been responsible for over 42 million infections and 1 million deaths since its emergence in December 2019. There are few therapeutic options and no approved vaccines. Here, we examine the properties of highly potent human monoclonal antibodies (hu-mAbs) in a Syrian hamster model of SARS-CoV-2 and in a mouse-adapted model of SARS-CoV-2 infection (SARS-CoV-2 MA). Antibody combinations were effective for prevention and in therapy when administered early. However, in vitro antibody neutralization potency did not uniformly correlate with in vivo protection, and some hu-mAbs were more protective in combination in vivo. Analysis of antibody Fc regions revealed that binding to activating Fc receptors contributes to optimal protection against SARS-CoV-2 MA. The data indicate that intact effector function can affect hu-mAb protective activity and that in vivo testing is required to establish optimal hu-mAb combinations for COVID-19 prevention.
Abstract 17176: Burden and Prognostic Importance of Heart Failure Signs and Symptoms - Differences in Heart Failure With Preserved versus Reduced Ejection Fraction
Authors: Karola Jering, Brian Claggett, Marc A Pfeffer, Akshay S Desai, Finnian R Mc Causland, Marty Lefkowitz, Milton Packer, Jean L Rouleau, Victor SHI, Karl B Swedberg, Michael R Zile, John J McMurray, Scott Solomon
Journal: Circulation (2020)

Introduction: In patients with heart failure (HF), worsening of HF signs and symptoms is associated with increased cardiovascular (CV) risk. Differences in burden of HF signs and symptoms and their prognostic value in HF with preserved (HFpEF) versus reduced ejection fraction (HFrEF) are poorly understood. Hypothesis: High burden of HF signs and symptoms is associated with adverse CV events, and is of greater prognostic value in patients with HFrEF. Methods: Using combined data from PARADIGM-HF (LVEF eligibility ≤40%) and PARAGON-HF (LVEF eligibility ≥45%), Cox models were fit to assess the relationship between burden of HF signs and symptoms (≤2 or ≥3) and first HHF or CV death in patients with HFrEF (n=8385) and HFpEF (n=4709) with available signs and symptoms at screening (rest dyspnea, exertional dyspnea, paroxysmal nocturnal dyspnea, orthopnea, fatigue, edema, jugular venous distension, rales, third heart sound). Results: High burden of HF signs and symptoms (≥3) was more common among patients with HFpEF (48%) than HFrEF (42%, p&lt;0.001). In both HF types, patients with high burden of signs and symptoms were more commonly female, had higher NYHA functional class and NT-proBNP and were more frequently prescribed diuretics (all p&lt;0.001). Patients with HFrEF and high burden of signs and symptoms more commonly had atrial fibrillation (AF) than those with low burden (32 vs 41%, p&lt;0.001) while prevalence of AF was similar regardless of sign and symptom burden in HFpEF (32 vs 32%, p = 0.98). High burden of signs and symptoms was associated with greater risk of HHF or CV death in patients with HFrEF (HR 1.47; 95% CI, 1.35-1.61) than in those with HFpEF (HR 1.28; 95% CI, 1.13-1.44; p interaction = 0.03) (Figure). Conclusion: Patients with HFpEF have slightly higher burden of HF signs and symptoms than those with HFrEF. High burden of HF signs and symptoms identifies patients at high risk foradverse CV events, and may have greater prognostic importance in patients with HFrEF than HFpEF.
Abstract 15431: Childhood Passive Smoke Exposure is Associated With Subclinical Left Ventricular Dysfunction in Adulthood - Childhood Determinants of Adult Health Study
Authors: Chigozie Ezegbe, Costan Magnussen, Marie-Jeanne BUSCOT, Thomas H Marwick, Terence Dwyer, Amanda Neil, Alison Venn, Seana L Gall
Journal: Circulation (2020)

Introduction: Prolonged childhood passive smoke exposure may affect adult cardiovascular health but there are few studies of cardiac function. Subclinical left ventricular dysfunction detected by global longitudinal strain (GLS) is predictive of the subsequent development of heart failure. We investigated the association of passive smoke exposure during childhood with GLS in adults. Methods: Data were from the Childhood Determinants of Adult Health (CDAH) study 34-year follow-up (2014-19). Three measures of passive smoking (severity of exposure index [SEI], cumulative years of exposure [CYE], total household smokers [THS]) were derived retrospectively from a validated questionnaire. GLS was measured in clinics using a Siemens Acuson SC2000 ultrasound machine and 4V1c transducer with speckle tracking analysis. Linear regression adjusted for confounding factors (age, gender, childhood socioeconomic position, childhood smoking, adult smoking status, parental education level) examined the association between childhood passive smoke exposure and GLS in adulthood. Results: Among 781 participants (mean age 45.2 ± 2.5 SD years, 52.6% females, 54.2% exposed to passive smoking), GLS showed a decrease (β adjusted -0.17% 95% CI -0.32%, -0.02%) per SD of SEI (range: 0-318, mean 24.2 ± 35.8 SD). CYE (range: 0-106, mean 10.4 ± 13.9 SD) was associated with a decrease in GLS (β adjusted -0.18% 95% CI -0.33%, -0.05%) per SD of exposure. For each THS in childhood (range: 0-5, mean 0.9 ± 1.0 SD), there was a decrease in GLS (β adjusted -0.20% 95% CI -0.36%, -0.05%). Conclusion: Childhood passive smoke exposure, independent of own smoking, was associated with a reduction in GLS, a measure of subclinical cardiac dysfunction. Each 1% decrease in GLS has been associated with 12% higher risk of cardiovascular morbidity and mortality in low-risk general population. There are potential long-term consequences to cardiac function from childhood passive smoke exposure.
Abstract 13771: Combining Clinical and Polygenic Risk Improves Stroke Prediction Among Individuals With Atrial Fibrillation
Authors: Jack W Osullivan, Anna Shcherbina, Johanne M Justesen, Mintu Turakhia, Marco V Perez, Hannah Wand, Catherine Tcheandjieu, Shoa L Clarke, Robert A Harrington, Manuel A Rivas, Euan A Ashley
Journal: Circulation (2020)

Introduction: Atrial fibrillation (AF) is associated with a five-fold increased risk of ischemic stroke. A portion of this risk is heritable, however current risk stratification tools (CHA 2 DS 2 -VASc) don’t include family history or genetic risk. Hypothesis: A polygenic risk scores (PRS) is both independently, and in integrated with clinical risk factors, predictive of ischemic stroke in patients with Atrial Fibrillation. Methods: Using data from the largest available GWAS in Europeans, we combined over half a million genetic variants to construct a PRS to predict ischemic stroke in patients with AF. We externally validated this PRS in independent data from the UK Biobank (UK Biobank), both independently and integrated with clinical risk factors. Results: The integrated PRS and clinical risk factors risk tool had the greatest predictive ability. Compared with the currently recommended risk tool (CHA 2 DS 2 -VASc), the integrated tool significantly improved net reclassification (NRI: 2.3% (95%CI: 1.3% to 3.0%)), and fit (χ2 P =0.002). Independently, PRS was a significant predictor of ischemic stroke in patients with AF prospectively (Hazard Ratio: 1.13 per 1 SD (95%CI: 1.04 to 1.21)). Lastly, polygenic risk scores were uncorrelated with clinical risk factors (Pearson’s correlation coefficient: -0.018). Conclusions: In patients with AF, there appears to be a significant association between PRS and risk of ischemic stroke. The greatest predictive ability was found with the integration of PRS and clinical risk factors, however the prediction of stroke remains challenging.
“We can conceive another history”: Trans activism around abortion rights in Argentina
Authors: Francisco Fernández Romero
Journal: International Journal of Transgender Health (2020)

Background: A growing body of work focuses on transgender reproductive justice. However, little research has been undertaken on trans activists' contributions to reproductive justice movements in general, or to abortion rights movements in particular. Countries where trans identities are depathologized, such as Argentina, provide a unique opportunity to study challenges, achievements, and demands around reproductive justice for trans individuals in contexts where reproductive trans bodies are enabled to exist and may obtain legal gender recognition. Aims: To explore critical interventions by trans and travesti activists and organizations in Argentina around the issue of abortion rights. Methods: This paper analyses public speeches, publications, artwork, and flyers by trans and travesti activists and organizations in Argentina. Results: Trans contributions to abortion rights struggles have established common ground between trans and feminist/women's movements around reproductive justice, have negotiated the inclusion of trans masculine persons within the abortion rights movement (both as activists and as potential users of abortion services), and have pointed to the country's depathologized Gender Identity Law as a potential model for abortion regulations. Discussion: This paper concludes by discussing trans and travesti activists' contributions to framing abortion rights within a wider social and political agenda at the intersection between health, gender, sexuality, and bodily autonomy, which furthers the work done by reproductive justice perspectives.
Low-dose ruxolitinib plus steroid in severe SARS-CoV-2 pneumonia
Authors: A. D’Alessio, P. Del Poggio, F. Bracchi, G. Cesana, N. Sertori, D. Di Mauro, A. Fargnoli, M. Motta, C. Giussani, P. Moro, G. Vitale, M. Giacomini, G. Borra
Journal: Leukemia (2020)

SARS-CoV-2 is a biphasic illness characterized by a first flu-like phase, followed by a pulmonary and systemic disease, in which a dysregulated cytokine storm may lead to acute respiratory distress (ARDS) and death [1].JAK-STAT inhibitors block the common pathway of cytokine activation, may reduce the over-exuberant inflammatory reaction and decrease mortality [2,3].Ruxolitinib is a JAK 1 and 2 (Janus Kinase) inhibitor used in the treatment of myelofibrosis, policytemia vera and hemophagocytic lymphohistiocytosis, which is characterized by a cytokine derangement similar to what observed in SARS-CO-V2 infection [4].We performed a non-randomized clinical study on the effect of ruxolitinib in patients with severe COVID-19 pneumonia not requiring mechanical ventilation at baseline (group A), comparing them to a control group of patients with the same clinical and radiological characteristics and hospitalized in the same time period (group B).All patients over age 18, admitted to our Hospital from March 13, 2020 to April 13, 2020 and eligible to ruxolitinib Managed Access Plan (MAP) were evaluated.The MAP program for ruxolitinib was registered by Novartis (https://clinicaltrials.
Abstract 14251: Creation and Validation of a Novel Sex-specific Mortality Risk Score in LVAD Patients
Authors: Aditi Nayak, Yingtian Hu, Yi-An Ko, Rebecca Steinberg, Subrat Das, Anurag Mehta, Chang Liu, John Pennington, Rongbing Xie, James K Kirklin, Robert L Kormos, Jennifer Cowger, Marc A Simon, Alanna A Morris
Journal: Circulation (2020)

Introduction: Prior studies have shown that females have worse 3-month survival post-LVAD. Currently used prognostic scores including the Heartmate II Risk Score (HMRS), were developed in &gt;75% male cohorts, and may not account for the increased residual risk in females. Hypothesis: A sex-specific risk score will predict post-LVAD mortality in females, and perform better than HMRS. Methods: Adult CF-LVAD patients from the ISHLT Mechanically Assisted Circulatory Support (IMACS) registry (Implant years: Jan 2013 - Sep 2017, age: 56 ± 13 yrs, 21% female, 36% centrifugal pumps) were randomly divided into derivation (DC, n=9113, 21% female) and validation cohorts (VC, n=6074, 21% female). Primary outcome of interest was 3-month mortality. IMACS risk score (IMACS-RS) was developed in the DC, from pre-operative candidate predictors selected using Akaike Information Criterion, or significant sex*variable interaction. Results: There were 1,466 deaths (9.7%) within 3 months after implant. In the DC, age, cardiogenic shock at implant, Body Mass Index, Blood Urea Nitrogen, bilirubin, hemoglobin, albumin, platelet count, LV End Diastolic Diameter, Tricuspid Regurgitation, dialysis and major infection pre-implant were retained as significant predictors of 3-month mortality. There was a significant ischemic HF*sex and platelet count*sex interaction. For each quartile increase in IMACS-RS, females had 93% increased odds (p&lt;0.0001), and males had 86% increased odds (p&lt;0.0001) of 3-month mortality. IMACS-RS represented a significant improvement over HMRS (p&lt;0.01 for improvement in AUC) and provided excellent risk calibration in both sexes (no significant difference between observed and predicted risk). Removal of sex-specific interaction terms resulted in significant loss of model fit. Conclusions: A sex-specific risk score provides excellent risk prediction in LVAD patients. Future prognostic studies in advanced HF should present sex-specific secondary outcomes.
Abstract 15636: Effect of COVID-19 Public Health Measures on Activity and Quality of Life in Patients With Pulmonary Arterial Hypertension
Authors: Jennifer T Middleton, Shiran Konganige, Payman Dahaghin, Hamza Zafar, Ashwin Reddy, Claire Martin, A.A.R Thompson, Andy J Swift, Paul Morris, Robin Condliffe, Nicholas W Morrell, David G Kiely, Mark Toshner, Alex M ROTHMAN
Journal: Circulation (2020)

Background: Limitation of physical activity has been widely enforced to reduce COVID-19 transmission, however it is a critical measure in the prevention of cardiovascular disease. In patients with pulmonary arterial hypertension (PAH), exercise capacity relates to clinical outcomes and exercise training improves cardiopulmonary function. Here, we describe the temporal effects of UK government restriction measures on daily activity and quality of life (QoL) in patients with PAH. Methods: Patients Enrolled in The United Kingdom National Cohort Study of Idiopathic and Heritable PAH Study were implanted with insertable cardiac monitors (LinQ, Medtronic) in the clinic setting. Data were transmitted and reviewed in accordance with established clinical protocols. Standard questionnaires were administered remotely to assess QoL (EmPHasis-10), anxiety (GAD-7) and depression (PHQ-9). Results: Median age of the 26 patients was 49 years, 23 (88%) were female and 5 (19%) had heritable PAH with mutations in BMPR2. At enrolment 10 (38.5%) patients were low risk (&lt;5% 1-year mortality), 10 (38.5%) were intermediate risk (5-10%) and 6 (23%) were high risk (&gt;10%). The mean duration from insertion to census date was 21.1 weeks (SD 5.7). No complications were reported. Completeness of remote monitoring data was 100%. Following lockdown, mean activity was reduced compared to pre-lockdown levels (3.16 vrs 2.68 hours/day, -0.48 hours, 95%CI -0.27- -0.69, 16%, p&lt;0.0001). This reduction was present each week following lockdown. Although not statistically significant the greatest reduction in activity was observed in patients in the low-risk group. Following lockdown QoL was reduced (26 (18-38) vrs 32 (17-47), p&lt;0.01) and anxiety (1 (0-9) vrs 10 (5-18), p&lt;0.001) and depression scores increased (3 (1-16) vrs 11 (3-17), p&lt;0.001) compared to pre-lockdown levels. No change in day or night heart rate, or heart rate variability was observed and no patients developed COVID-19. Conclusion: In this cohort of patients with PAH, protective health measures were effective in preventing COVID-19 in patients thought to be highly vulnerable. However, these measures resulted in reduced daily activity and QoL and were associated increased anxiety and depression indicators.