tbuckley/cabot-search huggingface dataset:
Abstract 17094: A New Grading of Tricuspid Regurgitation Beyond Severe and Its Clinical Importance
Authors: Omori Taku, Goki Uno, Shunsuke Shimada, Florian Rader, Robert J Siegel, Takahiro Shiota
Journal: Circulation (2020)

Introduction: Recently a new grading system for tricuspid regurgitation (TR) beyond severe has been proposed. However, few studies assessing the validity of the new grade of TR has been conducted. We evaluated the new grading system of TR by comparing it with patient hemodynamics and outcome. Methods: We retrospectively reviewed patients who underwent 2 dimensional echocardiography and had severe TR in 2014. According to the vena contracta width (VC) of TR jet, the patients were classified into 3 groups: VC&amp;lt;11mm, 11&amp;lt;=VC&amp;lt;14 and VC &amp;gt;=14mm (160,113 and 86 patients respectively). Stroke volume (SV), cardiac index (CI) and right atrial pressure (RAP) were estimated by echocardiography. Cardiac events were defined as cardiac death or admission for heart failure (HF). Results: 376 patients were diagnosed as severe TR. We excluded 15 patients on mechanical respiratory support and 2 with missing clinical data. Remaining 359 severe TR patients (75 ± 16 years, 204 (57%) female) were investigated. TR patients with VC &amp;gt;=14mm had significantly lower SV and CI compared to the other groups, though there was no difference in SV and CI between those with VC&amp;lt;11 and those with 11&amp;lt;=VC&amp;lt;14 (Figure). Compared to TR patients with VC&amp;lt;11, those with VC &amp;gt;=14 had a significantly higher frequency of RAP &amp;gt;=15mmHg (Odds ratio (OR) 1.30; 95% Confidence Interval (CI), 1.01 to 3.08; p=0.047 ), though those with 11&amp;lt;=VC&amp;lt;14 had no significant difference (OR 1.30; 95% CI 0.79 to 1.37; p=0.31 ) (Figure). During a follow-up period (median, 205 days; range, 36 to 1032 days), 124 (35%) patients experienced cardiac events (30 cardiac death and 94 HF admission). The Kaplan-Meier curves showed that TR patients with VC&amp;gt;=14 was at higher risk for cardiac events (Figure). Conclusion: TR patients with VC &amp;gt;=14mm showed significantly worse hemodynamics and outcome than those with VC&amp;lt;14mm. TR with VC &amp;gt;=14mm should be considered to clinical grade of TR that is beyond severe.
ALKBH1-demethylated DNA N6-methyladenine modification triggers vascular calcification via osteogenic reprogramming in chronic kidney disease
Authors: Liu Ouyang, Xiaoyan Su, Wenxin Li, Liangqiu Tang, Mengbi Zhang, Yongjun Zhu, Changming Xie, Puhua Zhang, Jie Chen, Hui Huang
Journal: Journal of Clinical Investigation (2021)

Vascular calcification (VC) predicts cardiovascular morbidity and mortality in chronic kidney disease (CKD). To date, the underlying mechanisms remain unclear. We detected leukocyte DNA N6-methyladenine (6mA) levels in patients with CKD with or without aortic arch calcification. We used arteries from CKD mice infected with vascular smooth muscle cell–targeted (VSMC-targeted) adeno-associated virus encoding alkB homolog 1 (Alkbh1) gene or Alkbh1 shRNA to evaluate features of calcification. We identified that leukocyte 6mA levels were significantly reduced as the severity of VC increased in patients with CKD. Decreased 6mA demethylation resulted from the upregulation of ALKBH1. Here, ALKBH1 overexpression aggravated whereas its depletion blunted VC progression and osteogenic reprogramming in vivo and in vitro. Mechanistically, ALKBH1-demethylated DNA 6mA modification could facilitate the binding of octamer-binding transcription factor 4 (Oct4) to bone morphogenetic protein 2 (BMP2) promoter and activate BMP2 transcription. This resulted in osteogenic reprogramming of VSMCs and subsequent VC progression. Either BMP2 or Oct4 depletion alleviated the procalcifying effects of ALKBH1. This suggests that targeting ALKBH1 might be a therapeutic method to reduce the burden of VC in CKD.
Cutaneous innate immune tolerance is mediated by epigenetic control of MAP2K3 by HDAC8/9
Authors: Yu Sawada, Teruaki Nakatsuji, Tatsuya Dokoshi, Nikhil Nitin Kulkarni, Marc C. Liggins, George Sen, Richard L. Gallo
Journal: Science Immunology (2021)

Inhibition of HDAC8 and HDAC9 impairs keratinocyte tolerance of TLR ligand stimulation, leading to cutaneous inflammation.
Abstract 030: The Association Of Hypnotics With Incident Cardiovascular Disease And Mortality Among Post-menopausal Women With Sleep Disturbances
Authors: Adam Haines, Aladdin Shadyab, Nazmus Saquib, Katie Stone, Sylvia W Wassertheil-smoller
Journal: Circulation (2021)

Background: Chronic insomnia is common in post-menopausal women and is associated with higher cardiovascular disease (CVD) risk. Hypnotics are a second-line therapy after cognitive behavioral therapy for management of chronic insomnia. Among the hypnotics, nonbenzodiazepine GABA agonists (Z-drugs) are commonly prescribed. However, it is unclear whether Z-drug use and other hypnotic use is associated with risk of incident CVD and mortality in older people with sleep disturbances. Objectives: Among post-menopausal women with sleep disturbances, to evaluate the association of Z-drug use compared with use of other prescription hypnotics, and with non-use of any prescription hypnotics with CVD and mortality. Methods: The population studied were post-menopausal women from the Women’s Health Initiative (WHI) Observational Study and Clinical Trials who, at baseline, scored &gt;=9 with the WHI Insomnia Rating Scale (N=40,728). Hypnotic use was ascertained from prescription medications scanned into the Medi-Span database at baseline and first follow-up clinic visit. Frequency of use was ascertained from self-report. Participants were categorized as users of Z-drugs, users of other prescription hypnotics or non-users. Outcomes were composite CVD (congestive heart failure, stroke, and fatal/non-fatal myocardial infarction) and mortality, centrally adjudicated with review of medical records and death certificates. Hazard ratios were estimated from Cox proportional hazards regression models adjusted for demographic, medical history, and sleep measures. To address potential confounding by indication, we also adjusted for propensity to be prescribed hypnotics. Results: At the first follow-up visit 1.1% (424 of 38,979) of participants were users of Z-drugs, 4.2% (1,653 of 38,979) were users of other prescription hypnotics, 3.1% (1,187 of 38,979) had discontinued prescription hypnotic use, and 91.6% (35,715 of 38,979) were non-users at both baseline and first follow-up visit. The mean age of our cohort was 63.6 years (SD = 7.2) and mean follow-up time after the initial follow-up visit was 14.0 years (SD = 6.3). Z-drug use was significantly associated with an increased risk of composite CVD (HR= 1.35, 95%CI: 1.02-1.79) and all-cause mortality (HR= 1.38, 95%CI: 1.13-1.69). Use of other prescription hypnotics and casual use (&lt;=2 times a week) of any hypnotic were not associated with either cardiovascular disease or mortality. Conclusion: Use of Z-drugs three or more times a week was associated with an increased risk of death and cardiovascular disease in post-menopausal women being treated for insomnia. Additional research is needed to evaluate association between frequency of hypnotic use and these outcomes and to investigate possible mechanisms.
Abstract 16425: Trends and Outcomes of 30-day Readmissions After Left Ventricular Assist Device Implantation
Authors: Hiroki Ueyama, Aaqib h Malik, Toshiki Kuno, Yujiro Yokoyama, Alexandros BRIASOULIS
Journal: Circulation (2020)

Introduction: Left ventricular assist devices (LVAD) improve morbidity and mortality in end-stage heart failure patients but high rates of readmissions remain a problem after implantation. We aimed to assess the incidence, trends, outcomes and predictors of 30-day readmissions after LVAD implantation. Methods: The National Readmission Database was used to identify patients who underwent LVAD implantation between 2012 and 2017 and those with 30-day readmissions. Results: The analysis included a total of 11,947 adults who survived the index hospitalization for LVAD implantation. Among those, 28.2% were readmitted at 30 days. The baseline characteristics were balanced between those with and without 30-day readmission except for the length of stay of index admission, which was significantly higher among those readmitted (39.0 days vs. 34.3 days, p&lt;0.001). As shown on Figure 1, most readmissions occurred in the first 15 days after discharge from the index admission. The most frequent cause of readmissions was gastrointestinal bleeding (21.8% of readmissions), followed by ventricular tachycardia, acute heart failure, abnormal coagulation profile, pump thrombosis and infection. The mean length of stay for readmission was 10.3 days (± 13.5 days). Although the readmission rates remained high during the study period, the rates of stroke and bleeding decreased significantly (Figure 2). Index admission length of stay, female gender, diabetes mellitus and chronic kidney disease were independent predictors of 30-day readmission after multivariate adjustment. Conclusions: Over one fourth of LVAD recipients have 30-day readmissions with gastrointestinal bleeding as the most frequent cause.
Abstract 15297: Discovery and Preclinical Optimization of Selective ABCA1 Inducers as Multifunctional Therapeutic Candidates
Authors: Cutler Lewandowski, Md. Wasim Khan, Manel Ben Aissa, Brian Layden, Gregory Thatcher
Journal: Circulation (2020)

Introduction: Reduced expression of cholesterol transporter ABCA1 is critical in pathogenesis of type 2 diabetes (T2D) and related conditions, such as cardiovascular disease (CVD) and Alzheimer’s disease (AD). Thus, increasing ABCA1 represents a novel therapeutic strategy for these conditions. However, prior drug development efforts have achieved limited success at increasing ABCA1 (controlled by liver X receptor [LXR] β) while avoiding unwanted liver triglyceride production (through LXRα via transcription factor SREBP1c). Hypothesis: We hypothesized that phenotypic screening for selective ABCA1 inducers followed by medicinal chemistry optimization would bypass the isoform selectivity issues encountered in traditional target-based drug discovery and enable development of lead therapeutic candidates with preclinical efficacy and safety. Methods/Results: We screened 20k compounds for ABCA1 and SREBP1c-linked luciferase activity, followed by qPCR to validate and prioritize selective ABCA1-inducing hits. We synthesized ~70 structural analogs of the best hit, achieving substantial EC 50 (4.5 μM to 270 nM) and E max (3.5-fold to 6.0-fold vs. vehicle) improvements in ABCA1 luciferase assay while maintaining selectivity against SREBP1c. Direct binding assays confirmed selectivity for LXRβ vs. LXRα, corroborating cell-based data. Lead compounds enhanced cellular cholesterol efflux, reduced inflammation in vitro , and attenuated high-fat diet (HFD) induced weight gain, insulin resistance, and inflammation in mice. Metabolomics analysis revealed that our lead compound corrected HFD-induced perturbations in liver glucose and fatty acid synthesis. Finally, side effects associated with published LXR agonists - liver steatosis and neutropenia - were not observed with our compound. Conclusions: We established a platform to develop selective ABCA1 inducers as drug candidates. Via this platform, we identified a safe and efficacious lead compound for T2D. Our study also represents the first report of an LXR agonist characterized by metabolomics - a powerful tool to complement biochemical readouts. Continued optimization to improve pharmacokinetic parameters, plus evaluation in CVD and AD models, is ongoing.
Estrogen‐Induced hsa‐miR‐10b‐5p Is Elevated in T Cells From Patients With Systemic Lupus Erythematosus and Down‐Regulates Serine/Arginine‐Rich Splicing Factor 1
Authors: Suruchi A. Ramanujan, Elena N. Cravens, Suzanne M. Krishfield, Vasileios C. Kyttaris, Vaishali R. Moulton
Journal: Arthritis & Rheumatology (2021)

Autoimmune diseases affect women disproportionately more than men. Estrogen is implicated in immune cell dysfunction, yet its precise molecular roles are not fully known. We recently identified new roles for serine/arginine-rich splicing factor 1 (SRSF1) in T cell function and autoimmunity. SRSF1 levels are decreased in T cells from patients with systemic lupus erythematosus (SLE) and are associated with active disease and comorbidity. However, the molecular mechanisms that control SRSF1 expression are unknown. Srsf1 messenger RNA (mRNA) has a long 3'-untranslated region (3'-UTR), suggesting posttranscriptional control. This study was undertaken to investigate the role of estrogen and posttranscriptional mechanisms of SRSF1 regulation in T cells and SLE.In silico bioinformatics analysis of Srsf1-3'-UTR revealed multiple microRNA (miRNA; miR)-binding sites. Additional screening and literature searches narrowed down hsa-miR-10b-5p for further study. Peripheral blood T cells from healthy individuals and SLE patients were evaluated for mRNA and miRNA expression by quantitative reverse transcription-polymerase chain reaction, and SRSF1 protein levels were assessed by immunoblotting. T cells were cultured with β-estradiol, and transient transfections were used to overexpress miRNAs. Luciferase assays were used to measure 3'-UTR activity.We demonstrated that estrogen increased hsa-miR-10b-5p expression in human T cells, and hsa-miR-10b-5p down-regulated SRSF1 protein expression. Mechanistically, hsa-mir-10b-5p regulated SRSF1 posttranscriptionally via control of its 3'-UTR activity. Importantly, hsa-miR-10b-5p expression levels were elevated in T cells from healthy women compared to healthy men and also elevated in T cells from SLE patients.We identified a previously unrecognized molecular link between estrogen and gene regulation in immune cells, with potential relevance to systemic autoimmune disease.
Abstract MP03: The Health And Economic Impact Of Using A Sugar Sweetened Beverage Tax To Subsidize Fruit And Vegetable Purchase In New York City: A Modeling Study
Authors: Zhouyang Lou, Heesun Eom, Junxiu Liu, Stella S Yi, Rienna Russo, Brandon K Bellows, Yiyi Zhang, Andrew E Moran, Yan Li, Nan Kong
Journal: Circulation (2021)

Background: Both high sugar intake and low fruit and vegetable (FV) consumption increase the risk of coronary heart disease (CHD). Sugar-sweetened beverage (SSB) taxes can reduce sugar intake, whereas FV subsidies increase FV consumption. Several cities in the US have proposed an innovative policy that used the SSB tax revenue towards FV subsidies. It is unclear what the long-term health and economic impact this innovative policy could have in large cities such as New York City (NYC). Objective: To project lifetime CHDs averted and costs if a penny-per-ounce SSB tax were used to subsidize FV incentives in NYC using a validated microsimulation model of cardiovascular disease. Methods: We used the SHINE CVD model to compare the cost and CHD outcomes of a combination of SSB tax and FV subsidy policy with only SSB tax, only FV subsidy, and no policy from a healthcare sector perspective, respectively. Population demographics and health profiles were estimated using data from the 2013-2014 NYC Health and Nutrition Examination Survey. We simulated 10,000 adults starting at age 40. CHD risk factor trajectories and risk of incident CHD events were derived from six pooled prospective U.S. cohorts. Policy effects and price elasticity were derived from recent meta-analyses. SSB tax (penny-per-ounce) and FV subsidy were modeled to directly affect incidence rates of CHD events. Medical costs were included and discounted at 3%. Results: Compared to the non-policy scenario over the simulated lifetime, the SHINE CVD model projected that the policy intervention with SSB taxes only would prevent 62 per 10,000 (95% CI: 57 - 67) CHD events at a penny-per-ounce rate, the intervention with FV subsidies only would prevent 28 per 10,000 (95% CI: 24-34), and the combined policy would prevent 91 CHD events (95% CI: 87 - 96). Total medical cost savings over the simulation period ranged from $22.5 million (95% CI: $21.5 - $23.6 million), $13.1 million (95% CI: $12.3 - $13.8million), and $37.9 million (95% CI: $36.5 - $39.4million), or $0.45 million/year, $0.27 million/year, $0.75 million/year for SSB taxes only, FV subsidies only, and the combined policy, respectively. Conclusion: Using a computer simulation model, we showed how converting SSB tax revenues into FV subsidies could result in substantial benefits within the NYC population in terms of CHD outcomes and overall healthcare cost savings. Results from the SHINE CVD model may inform the ongoing policy-making efforts.
Temporal Trends and Factors Associated With Cardiac Rehabilitation Participation Among Medicare Beneficiaries With Heart Failure
Authors: Ambarish Pandey, Neil Keshvani, Lin Zhong, Robert J Mentz, Ileana L Piña, Adam D DeVore, Clyde Yancy, Dalane W Kitzman, Gregg C Fonarow
Journal: JACC Heart Failure (2021)
Intradermal Drug Delivery: Miniaturized Needle Array‐Mediated Drug Delivery Accelerates Wound Healing (Adv. Healthcare Mater. 8/2021)
Authors: Mohamadmahdi Samandari, Fariba Aghabaglou, Kristo Nuutila, Hossein Derakhshandeh, Yuteng Zhang, Yori Endo, Seth Harris, Lindsay Barnum, Craig Kreikemeier‐Bower, Elmira Arab‐Tehrany, Nicholas A. Peppas, Indranil Sinha, Ali Tamayol
Journal: Advanced Healthcare Materials (2021)

In article number 2001800 by Nicholas A. Peppas, Indranil Sinha, Ali Tamayol, and co-workers, the effect of vascular endothelial growth factor (VEGF) delivered intradermally using liquid jet injectors and miniaturized needle arrays on wound healing is investigated in mouse and pig models. Miniaturized needle arrays facilitate proper drug distribution within the tissue and improve the rate and quality of wound healing.
Abstract 17474: End-Stage Renal Disease is Associated With Increased Complications From Watchman Implantation: A Propensity-Score Matched Analysis From National Readmission Database
Authors: Moghniuddin Mohammed, Amit Noheria, Seth Sheldon, Madhu Reddy
Journal: Circulation (2020)

Introduction: End-stage renal disease (ESRD) is associated with increased complications due to oral anticoagulation (OAC) use for stroke prevention in atrial fibrillation (AF). Left atrial appendage occlusion (LAAO) is indicated for patients who cannot tolerate or prefer not to use OAC but the outcomes of LAAO in ESRD has not been well studied. Methods: Using National Readmission Database January 2016-December 2017, we identified all adult AF patients who had LAAO performed in the months of January to November with no missing length of stay and/or mortality information. We excluded patients who had ablation, device implantation/revision, other form of LAAO and/or coronary artery bypass graft surgery performed during index hospitalization. 1:1 propensity score matching was performed for patients with and without ESRD based on variables shown in Table 1. The main outcome of interest was early mortality defined as mortality of index hospitalization or 30-day readmissions and index hospital complications. Results: A total of 13,790 procedures were included and of these 370 patients had history of ESRD. The baseline characteristics before and after matching are shown in table 1. After propensity score matching, ESRD group was associated with significantly higher early mortality, 30-day readmissions, systemic embolism and pericardial complications (Table 2). In the matched cohort, none of the patients had postprocedural cerebrovascular accident, transient ischemic attack, device thrombosis and device embolization. After propensity matching 2 (0.5%) developed acute kidney injury requiring hemodialysis. Conclusions: ESRD is associated with higher LOS, index hospital complications and early mortality from LAAO compared to patients without ESRD. Further studies comparing outcomes between OAC use and LAAO are warranted.
Epigenetic-age acceleration in the emerging burden of cardiometabolic diseases among migrant and non-migrant African populations: a population-based cross-sectional RODAM substudy
Authors: Felix P Chilunga, Peter Henneman, Hannah R Elliott, H Toinét Cronjé, Gagandeep K Walia, Karlijn A C Meeks, Ana Requena-Mendez, Andrea Venema, Silver Bahendeka, Ina Danquah, Adebowale Adeyemo, Kerstin Klipstein-Grobusch, Marlien Pieters, Marcels M A M Mannens, Charles Agyemang
Journal: The Lancet Healthy Longevity (2021)

African populations are experiencing health transitions due to rapid urbanization and international migration. However, the role of biological aging in this emerging burden of cardiometabolic diseases (CMD) among migrant and non-migrant Africans is unknown. We aimed to examine differences in epigenetic age acceleration (EAA) as measured by four clocks (Horvath, Hannum, PhenoAge and GrimAge) and their associations with cardiometabolic factors among migrant Ghanaians in Europe and non-migrant Ghanaians.Genome-wide DNA methylation (DNAm) data of 712 Ghanaians from cross-sectional RODAM study were used to quantify EAA. We assessed correlation of DNAmAge measures with chronological age, and then performed linear regressions to determine associations of body mass index (BMI), fasting blood glucose (FBG), blood pressure, alcohol consumption, smoking, physical activity, and one-carbon metabolism nutrients with EAA among migrant and non-migrants. We replicated our findings among 172 rural-urban sibling pairs from India migration study and among 120 native South Africans from PURE-SA-NW study.We found that Ghanaian migrants have lower EAA than non-migrants. Within migrants, higher FBG was positively associated with EAA measures. Within non-migrants, higher BMI, and Vitamin B9 (folate) intake were negatively associated with EAA measures. Our findings on FBG, BMI and folate were replicated in the independent cohorts.Our study shows that migration is negatively associated with EAA among Ghanaians. Moreover, cardiometabolic factors are differentially associated with EAA within migrant and non-migrant subgroups. Our results call for context-based interventions for CMD among transitioning populations that account for effects of biological aging.European Commission.
Functional Outcomes Among Patients With Acute Ischemic Stroke After Mechanical Thrombectomy With or Without Intravenous Thrombolysis
Authors: Hui Mai, Tao Chen, Bin Zhao
Journal: JAMA (2021)

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