tbuckley/cabot-search huggingface dataset:
Give people choice of treatment options for depression, says NICE
Authors: Gareth Iacobucci
Journal: BMJ (2021)

People with depression should choose what treatment option is right for them, in discussion with their healthcare professional, the National Institute for Health and Care Excellence has recommended in draft guidance.1

In the first guideline for 12 years to focus on identifying, treating, and managing depression in adults, NICE advises that antidepressant drugs should not be offered as the first line treatment for less severe depression “unless that is the person’s preference.”

Patients with less severe depression should be able to choose from cognitive behavioural therapy (CBT), exercise, counselling, or psychotherapy as their first line treatment, it says.

The draft guidance puts much emphasis on shared decision making, with NICE creating a menu of treatment options to allow patients to pick the one that …
Intronic Architecture Links DNA Methylation to Gene Expression and Helps Drive Subtype-Specific Transcriptional Landscapes in <i>DNMT3A</i>- and <i>IDH1/2</i>-Mutant Acute Myeloid Leukemias (AML)
Authors: Aristeidis G. Telonis, Qin Yang, Hsuan-Ting Huang, Maria E. Figueroa
Journal: Blood (2021)
Abstract 12544: A miRNA Cassette for Reprogramming Vascular Smooth Muscle Cells Into Endothelial Cells
Authors: Michael G McCoy, Daniel Pérez Cremades, Nathan Belkin, Wenhui Peng, Bofang Zhang, Akm Wara, Henry Cheng, Rulin Zhuang, Mark W Feinberg
Journal: Circulation (2021)

Introduction: Vascular smooth muscle cells (SMCs) and endothelial cells (ECs) exhibit unique miRNA profiles, which regulate their overall function. However, whether differentially expressed miRNAs can be used for transcriptional reprogramming of SMCs into ECs is unknown. MiRNA profiling of SMCs and ECs revealed differential regulation of miR-143-3p, miR-145-3p, miR-146a-5p, and miR-181b-5p as a set of candidates for transdifferentiation. Methods: Human coronary SMCs were transfected with miR-143-3p and miR-145-3p inhibitors alongside miR-146a-5p and miR-181b-5p mimics and selectively expanded. Induced endothelial cells (iECs) were then assessed for their transcriptional, protein expression, and functional similarities to ECs (Fig. 1). Results: Principal component and gene set enrichment analyses determined that iECs are transcriptionally clustered closer to ECs than SMCs in whole transcriptome profiling and selected EC and SMC gene sets. Top pathways included ‘blood vessel morphogenesis’, ‘regulation of angiogenesis’ and ‘Notch, VEGF, integrin signaling’. Transcriptome data was validated via PCR and Western blot analyses as iECs exhibited robust upregulation in EC markers CD31, VE-Cadherin, and VEGFR2 and downregulation of SMC markers MHY11, Vimentin, and αSMA. The similarity of iECs to ECs was functional as iECs demonstrated oxLDL and Ac-LDL uptake, tube formation in Matrigel™ assays, eNOS phosphorylation in response to VEGF, and iEC migratory and cell growth properties were similar to human umbilical vein ECs in the presence of VEGF. A hindlimb ischemia model validated iEC similarity to ECs as injected iECs restored blood flow and significantly reduced limb necrosis similar to ECs. Conclusion: A miRNA cassette consisting of miR-143-3p and miR-145-3p inhibitors and miR-146a-5p and miR-181b-5p mimics transformed SMCs into endothelial-like cells and show promise as a potential novel regenerative strategy for endothelial cells.
Abstract MP259: The Role Of Sertad4 In Pathological Cardiac Remodeling
Authors: Matthew Stratton, Ashley Francois, Oscar Bermeo-Blanco, Alessandro Canella, Lynn Marcho, Erin McGrail, Shamama Nishat, Bryan Whitson, Paul M Janssen, Federica Accornero, Richard J Gumina
Journal: Circulation Research (2021)

Over 6 million Americans suffer from heart failure (HF) while the 5-year mortality rate following first admission for HF is over 40%. Cardiac fibrosis is a clinical hallmark of HF, regardless of the initiating pathology and is thought to contribute to disease progression. Using an epigenomics discovery approach, we uncovered a nuclear protein, Sertad4, as a potential anti-fibrotic target. Our data indicate that Sertad4 is a positive regulator of fibroblast activation. Specifically, cultured cardiac fibroblast experiments demonstrate that Sertad4 targeting with shRNAs blocks fibroblast proliferation and causes cells to arrest in the G2/M phase of the cell cycle. Also, shRNA targeting of Sertad4 dramatically blocked activation of myofibroblast differentiation genes (αSMA/POSTN/COL1A1). Mechanistically, these effects appear to be mediated by Sertad4 regulation of SMAD2 protein stability in the presence of TGF-β1 stimulation as demonstrated by proteasome inhibition experiments. RNA-seq analysis indicate that Sertad4 also regulates the expression of genes involved in ubiquitination and proteasome degradation. Next, we sought to determine the effect of global Sertad4 knockout on post-myocardial infarct (MI) remodeling and cardiac function in mice. After 4 weeks of permanent LAD ligation, echocardiography was performed to measure systolic function. Relative to wild-type (WT) controls, the Sertad4 KO mice showed preserved systolic function as evident by improved ejection fraction (WT 14.4 +/- 3.6 vs. KO 33.9+/-5.9, p=0.035) and fractional shortening (WT 6.5 +/- 1.7 vs. KO 16.4 +/- 3.4, p=0.046). β-gal staining in the Sertad4/LacZ reporter mouse subjected to MI showed robust Sertad4/LacZ expression in the ischemic scar and boarder-zone with almost no expression in control hearts. This data supports the notion that Sertad4 has a key role in cardiac remodeling in response to ischemic injury.
Abstract 10855: Cardiovascular Effectiveness of Empagliflozin Compared to Glucagon Like Peptide-1 Receptor Agonists and to Dipeptidyl Peptidase-4 Inhibitors in Older Patients: Results from the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) Study
Authors: Phyo Htoo, Julie Paik, Helen Tesfaye, Sebastian Schneeweiss, Dureshahwar Jawaid, Deborah Wexler, Robert Glynn, Lisette Koeneman, Anouk Deruaz Luyet, Mehdi Najafzadeh, Elisabetta Patorno
Journal: Circulation (2021)

The EMPA-REG OUTCOME trial showed cardioprotective effects of empagliflozin (EMPA) in patients with established cardiovascular diseases (CVD). Within the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) multi-database study of patients in routine care, we evaluated the relative cardiovascular benefits of EMPA versus therapeutic alternatives in older patients with type 2 diabetes (T2D) across the broad spectrum of cardiovascular risk. Using Medicare data (08/2014-09/2018), we identified 31,719 pairs of 1:1 propensity score-matched (PSM) T2D patients ≥65 years initiating EMPA or a GLP-1RA [Cohort 1], and 23,307 pairs initiating EMPA or a DPP-4i [Cohort 2]. We assessed (i) a modified major adverse cardiovascular event (MACE) outcome (MI, stroke, all-cause mortality) and (ii) hospitalization for heart failure (HHF) in primary discharge position. In each cohort, we estimated hazard ratios (HR) and rate differences (RD) per 1,000 person years of follow-up, adjusting for &gt;140 baseline covariates and accounting for death as a competing risk, overall and in subgroups (i) with and (ii) without baseline CVD (that includes atherosclerotic CVD and HF). After PSM, exposure groups had similar characteristics (Table 1). Compared to GLP-1RA, EMPA had a similar risk of the modified MACE outcome [HR (95% CI): 1.05 (0.93,1.18)] and a reduced risk of HHF [HR 0.70 (0.57,0.86)]. Absolute benefit for HHF was larger in patients with CVD [RD -6.24 (-9.92, -2.56)] than in patients without CVD [RD -0.81 (-2.15, 0.54)]. Compared to DPP-4i, EMPA reduced the risk of both modified MACE outcome [HR: 0.67(0.59,0.77)] and HHF [HR: 0.46 (0.37,0.57)]. For both outcomes, the absolute benefit with EMPA was larger among patients with CVD compared to those without CVD. EMPA reduced the risk of HHF vs. GLP-1RA and DPP-4i and the risk of a modified MACE outcome vs. DPP-4i. The absolute benefit associated with EMPA was larger among patients with CVD compared to those without CVD.
Abstract 13208: Deletion of the Type I Interleukin-1 Receptor Prevents the Development of Cardiomyopathy Associated With Aging in Mice
Authors: Pratyush Narayan, Elefterios Trikantzopoulos, Eleonora MEZZAROMA, Adolfo G Mauro, Habeebah Vohra, Antonio Abbate, Stefano A Toldo
Journal: Circulation (2021)

Background: Aging is associated with metabolic and structural changes causing heart failure with preserved ejection fraction (HFpEF). Interleukin-1 (IL-1) is a pro-inflammatory cytokine involved in aging-related inflammation. We sought to determine whether IL-1 mediates aging-related changes in the heart as seen in HFpEF. Hypothesis: We hypothesize that mice with genetic deletion of IL-1RI, not responsive to IL-1β, would be protected from age-associated cardiac dysfunction. Methods: We studied age-matched young (4-month-old), middle-aged (14-month-old) and old (23-month-old) wild-type (WT) C57BL/6J and IL-1 receptor type I deficient (IL1RI-KO) male mice. Echocardiography was used to left ventricular (LV) dimensions and systolic/diastolic function, and a pressure-transducer was used to measure the LV end-diastolic pressure. Picrosirius red stain was used to assess for myocardial interstitial fibrosis (MIF) at pathology. Results: WT and IL-1RIKO mice showed a normal cardiac phenotype at young age, without any differences in between the two groups. With aging, the WT mice developed LV concentric hypertrophy (as measured by a significant increase in LV mass [+42%, P&lt;0.01] and relative wall thickness [+34%, P&lt;0.01]), whereas the aging IL-1RI-KO mice did not (Figure 1a,b). With aging the WT mice also developed diastolic dysfunction (as measured by a significant increase in isovolumetric relaxation time [+148%, P&lt;0.01] and a significantly higher LV end diastolic pressure [+174%, P&lt;0.01]), whereas the aging IL1RI-KO did not (Figure 1c,d). With aging WT mice showed a significant increase in MIF (+124%, P&lt;0.01) at cardiac pathology, whereas the aging IL-1RI-KO did not (Figure 1e). Conclusions: Genetically-modified mice lacking the IL-1RI receptor, not responsive to IL-1, are protected from aging-related LV hypertrophy, fibrosis and diastolic dysfunction. These data support a central role of IL-1 in the pathophysiology of aging-related HFpEF.
Abstract 11588: Variation in Reader-Reported Severity of Paradoxical Low-Flow Low Gradient Aortic Stenosis: Observations from AaLarge Academic Health System
Authors: Nimish N Shah, Lissa Sugeng, Kangxin Wang, Robert L McNamara, Vratika Agarwal, David Hur, Bernardo Lombo, Lavanya Bellumkonda, John K Forrest, Harlan M Krumholz, Eric J Velazquez, Kamil Faridi
Journal: Circulation (2021)

Introduction: Paradoxical low-flow low-gradient (PLFLG) aortic stenosis (AS) is frequently reported as non-severe AS on transthoracic echocardiogram (TTE) in clinical practice. It is uncertain how reader characteristics are associated with reporting of AS severity in patients with PLFLG AS. Methods: We identified all adults ≥ 18 years old from 9/2015-11/2019 with PLFLG AS on TTE within a large academic health system, and included only readers with ≥10 TTEs in this cohort. We determined the proportion of TTEs reported as either severe or moderate-severe and non-severe, and evaluated differences in reporting based on years of experience, volume of PLFLG AS studies interpreted per year, and quaternary vs. non-quaternary care site. We performed unadjusted and adjusted analyses using multivariable logistic regression. Results: Among 1329 patients meeting TTE criteria for PLFLG AS, only 37.3% were reported as severe/moderate-severe AS. Among 53 readers, the median proportion of patients reported as having severe/moderate-severe AS was 31.6% (25 th -75 th percentile 20.0%-50.0%, range 0.0-91.7%). There were differences in reporting between quartiles based on reader years of experience (33.3-40.9% across Q1-Q4 for proportion of patients reported with severe/moderate-severe AS; p = 0.01) but not volume (34.3-43.1% across Q1-Q4; p = 0.10). Quaternary care readers reported severe/moderate-severe AS for a much higher proportion of patients than non-quaternary care readers (64.3% [reader median 55.2%] vs. 30.9% [reader median 27.3%]; p &lt; 0.001) (Figure), and this was the strongest reader-associated predictor of reporting severe-range AS (adjusted OR 7.6, 95% CI 5.1-11.5). Conclusions: Among patients with PLFLG AS, quaternary care TTE readers report severe AS much more commonly than non-quaternary care readers. Greater focus on TTE reporting of PLFLG AS at non-quaternary sites is likely needed to address underreporting of severe AS in this population.
EXTH-17. A FOCUSED ULTRASOUND BLOOD BRAIN BARRIER DISRUPTION MODEL TO TEST THE INFLUENCE OF TIGHT JUNCTION GENES TO TREAT BRAIN TUMORS
Authors: Jayashree Iyer, Adam Akkad, Nanyun Tang, Michael Berens, Frederic Zenhausern, Jian Gu
Journal: Neuro-Oncology (2021)

Abstract Treating primary or metastatic tumors in the brain (glioblastomas, melanoma, lung cancer, breast cancer) proves challenging by virtue of the protective function of the blood brain barrier (BBB). The tight junction proteins (TJPs) binding the specialized endothelial cells of the BBB largely contribute to the limited permeability of cancer-therapeutic drugs. In both preclinical and clinical models, low intensity focused ultrasound (LIFU) coupled with microbubbles has been proven to safely and transiently open the BBB. Despite this method being established, potential genetic influences on the durability and vulnerability of tight junctions to LIFU have not been elucidated, nor have the determinants of tight junction repair post LIFU been thoroughly investigated. We report the development of an ultrasound transparent organ-on-chip model populated by iPSC-derived endothelial cells (iPSC-EC) co-cultured with astrocytes. We aim to probe the contributions of various tight junction genes to barrier integrity along with the subsequent protein topology involved in reassembly post ultrasound. Thus, this model serves to determine parameters for ultrasound disruption for precision opening of the BBB. The BBB-On-Chip was successfully fabricated and assembled with an optimized technique that has an 80% yield of leak-free devices, with stable cavitation post nanobubble injection. Furthermore, Western blots show expression of claudin-5, a key TJP, in our iPSC-ECs. We have also demonstrated by confocal microscopy that another component of the TJP complex, ZO-1, can be visualized at iPSC-derived cell junctions. Further benchmarking of device-ultrasound interactions, successful iPSC differentiation, tight junction formation, and fabrication of nanobubbles and their assistance in ultrasound BBB disruption will be presented. Efforts are underway to characterize the contributions of tight junction genes and their variations to the integrity and disruption of the BBB.
Abstract 9839: Correlates of Exercise Self-Care Behavior in Type 2 Diabetes Adults with and without Comorbid Heart Failure at a Tertiary Healthcare Setting in Ethiopia
Authors: Fekadu Aga, Sandra B Dunbar, Melinda Higgins, tedla kebede, Senbeta Guteta, Rebecca Gary
Journal: Circulation (2021)

Introduction: Exercise self-care behavior (ESCB) is recognized to improve glycemic control, cardiorespiratory fitness, and reduce cardiometabolic risk factors in persons with type 2 diabetes (T2D) and heart failure (HF). Aim: This study compared the demographic, clinical, and psychosocial correlates of ESCB in T2D adults with and without HF. Methods: This cross-sectional study recruited 210 T2D adults (105 with HF and 105 without HF) from Tikur Anbessa Specialized Referral Hospital in Ethiopia. The exercise subscale of the Summary of Diabetes Self-Care Activities (SDSCA) was used to measure ESCB. Correlational bivariate and stepwise logistic regression analyses were used to examine and compare correlates of ESCB. Variables included in the logistic regression model were: demographic (age, sex, marital status, occupation, living arrangement), clinical (body mass index [BMI], years since diagnosis of T2D, diabetes medication type, Ney York Heart Association [NYHA] classification, Charlson comorbidity index) and psychosocial (diabetes self-efficacy, depressive symptoms, and social support). Results: The participants mean age was 58.7±10.9 years while those with HF (61.6±10.5) were significantly older ( p &lt; 0.001) than those without HF (55.7±10.6). The percentage who exercised 5 days per week was significantly lower ( p = 0.03) in comorbid HF participants (n = 41, 39.1%) compared to those without HF (n = 48, 45.7%). In T2D adults without HF, for each 1 kg/m 2 increase in BMI there was a 12% lower odds of ESCB ( p = 0.028). In T2D adults with HF, a 1-year increase in age ( p = 0.029) and a 1-unit increase in depressive symptom score ( p = 0.009) independently predicted a 5.5% and 12.4% lower odds of performing ESCB, respectively. A 1 unit increase in diabetes self-efficacy score predicted a 24% higher of odds of ESCB ( p = 0.01). Conclusions: Findings indicate that multimorbidity negatively influenced participation in ESCB in T2D. Studies that improve diabetes self-efficacy, address weight and depressive symptoms may be beneficial for enhancing ESCB in T2D patients with HF or other serious chronic conditions.
Abstract 13734: Biomechanical Comparison of Atrioventricular Valve Repair Strategies in Hypoplastic Left Heart Syndrome
Authors: Sumanth Kidambi, Stephen Moye, James Lee, Teaghan Cowles, Wilkerson Rob, Michael J Paulsen, Joseph Y Woo, Michael Ma
Journal: Circulation (2021)

Purpose: Atrioventricular valve (AV) regurgitation in hypoplastic left heart syndrome (HLHS) remains a challenging problem with no clear consensus on optimal repair strategies. We sought to evaluate the effect of AV repairs on leaflet biomechanics. Methods: Explanted fetal bovine tricuspid valves and right ventricles were sutured onto annular and ventricular mounts derived from imaging data of HLHS patients. The annulus underwent an average areal dilation of 21% with preferential dilation of the free wall (Fig 1A). The specimens were then placed in a previously validated univentricular heart simulator and subjected to the typical flows and pressures seen at Norwood, Glenn, early Fontan, and late Fontan stages. The valves underwent repair via De Vega suture annuloplasty (AP) or anteroseptal commissuroplasty (CP). Leaflet forces pre- and post-repair were measured using optical strain sensors (fiber Bragg grating) sutured to each leaflet edge. Statistical significance was determined using paired t-test. Results: A total of 8 AP and 7 CP specimens underwent testing. Regurgitation decreased from 2+ to &lt;1+ following both repairs. With AP, forces in the tricuspid valve anterior (TVAL), posterior (TVPL), and septal leaflets (TVSL) as a percentage change from pre-repair were [TVAL:-12.6%, p&lt;0.001 Conclusions: Force reduction was seen only in the anterior and posterior leaflets with CP in contrast to the global reduction seen in AP. This difference may compound with cardiac cycling and impact the longevity of the repair. Future studies with more complex pathologies and repair strategies can help develop more tailored techniques.
Abstract 9851: Mortality and Post-Discharge Acute Care Utilization for Cardiovascular Conditions at US Safety-Net and Non-Safety-Net Hospitals
Authors: Michael Liu, Jose F Figueroa, Yang Song, Rishi Wadhera
Journal: Circulation (2021)

Introduction: Safety-net hospitals disproportionately care for medically complex, socially vulnerable, and racial/ethnic minority populations. Prior to the Affordable Care Act, safety-net hospitals had higher mortality and readmission rates for common cardiovascular conditions than their non-safety-net counterparts, but it is unclear whether these disparities remain. Methods: We conducted a serial, cross-sectional study using data from 3265 acute-care hospitals in the US. Performance on 30-day mortality, readmission, and excess days in acute care (EDAC) measures for acute myocardial infarction (AMI), heart failure (HF), stroke, and coronary artery bypass graft surgery (CABG) was compared at safety-net hospitals versus non-safety-net hospitals in fiscal year (FY) 2020 (July 2016 to June 2019) using linear regression models that adjusted for hospital-level characteristics. Interaction terms for safety-net status and year were used to assess for differential changes between FY 2010 (July 2006 to June 2009) and FY 2020. Results: Thirty-day mortality rates at safety-net hospitals compared with non-safety-net hospitals were lower for HF (10.9% vs 11.5%; adjusted difference: -0.49%, 95% CI: -0.65% to -0.33%), higher for AMI (12.8% vs 12.6%; adjusted difference: 0.15%, 0.04% to 0.26%), and similar for CABG and stroke. Thirty-day readmission rates were modestly higher at safety-net sites for AMI (16.4% vs 16.0%; adjusted difference: 0.37%, 0.26% to 0.48%) and HF (22.4% vs 21.8%; 0.58%, 0.44% to 0.72%), and comparable for CABG. However, safety-net hospitals performed markedly worse on the 30-day EDAC measures for AMI (15.2 vs 3.4 excess days; adjusted difference: 10.8, 95% CI: 8.3 to 13.4) and HF (14.1 vs 3.9 excess days; adjusted difference: 10.2, 6.4 to 10.4). From FY 2010 to FY 2020, differences in 30-day mortality and readmission rates differentially improved at safety-net sites for HF, but not AMI. Conclusions: Thirty-day mortality rates for common cardiovascular conditions are now similar at safety-net and non-safety-net hospitals. However, large gaps in 30-day post-discharge acute care utilization indicate that policy initiatives are still needed to support under-resourced safety-net systems and the patients they serve.
A Phase II Study of Once Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Isatuximab in Newly Diagnosed, Transplant-Eligible Multiple Myeloma
Authors: Elizabeth K. O'Donnell, Clifton C. Mo, Andrew J. Yee, Omar Nadeem, Andrew R. Branagan, Jacob P. Laubach, Marilyn T. Gammon, Kathleen J. Lively, Lisette Packer, Cynthia C. Harrington, Emerentia Agyemang, Kerry Spillane, Brenton LaStofka, Jacalyn Rosenblatt, Noopur S. Raje, Paul G. Richardson
Journal: Blood (2021)