tbuckley/cabot-search huggingface dataset:
Abstract 13759: Adherence to Healthy Lifestyle is Associated With Lower Total and Cause-Specific Mortality Risk Among Patients With Diabetes: The UK Biobank Study
Authors: Han Han, Yaying Cao, Chengwu Feng, yan zheng, Klodian Dhana, Shu Zhu, Cong Shang, Changzheng Yuan, Geng Zong
Journal: Circulation (2021)

Introduction: The association of an overall healthy lifestyle, involving 3 emerging factors (less sedentary time, adequate sleep duration, appropriate social connection) and 4 conventional factors (no current smoking, moderate alcohol consumption, regular physical activity, healthy diet) from the prevailing diabetes management guideline, with total and cause-specific mortality risk in patients with diabetes remains to be examined. Hypothesis: We hypothesized that an overall healthy lifestyle would be associated with a lower risk of total and cause-specific mortality in patients with diabetes. Methods: Analyses included 18,822 participants with diabetes at baseline in the UK Biobank. Lifestyle information was collected via a baseline questionnaire (2006-2010). Cox proportional hazard modeling was used to examine the association of a healthy lifestyle with mortality risk. Results: During a median follow-up of 11.2 years, 2,470 deaths occurred after 2 years of enrollment. The fully-adjusted hazard ratios (95% CIs) for patients with 6-7 low-risk lifestyle factors compared with those with 0-2 were 0.44 (0.38-0.51) for total mortality, 0.52 (0.40-0.67) for cancer mortality, 0.38 (0.26-0.56) for CVD mortality, 0.24 (0.13-0.45) for respiratory disease mortality, 0.96 (0.45-2.04) for neurodegenerative disease mortality, and 0.16 (0.04-0.62) for digestive system disease mortality. For each additional low-risk factor, the risk was 17% lower for total mortality and 13-26% lower for cause-specific mortality. The association for a summed score of the emerging factors was stronger in those with a lower score of conventional factors (P-interaction &lt;0.05). The inverse association between a healthy lifestyle and total mortality risk was consistently observed regardless of diabetes duration, vascular disease, glycemic control, and diabetes medication. Besides, the association was stronger in those with earlier diabetes onset or lower socioeconomic status (both P-interaction &lt;0.05). Conclusions: For patients with diabetes, a healthy lifestyle is associated with a lower risk of total and most cause-specific mortality. Our findings are consistent across sub-populations, especially for those differing in factors related to diabetes severity.
OCEAN (OP-103): Melflufen Plus Dexamethasone (Dex) Versus Pomalidomide (Pom) and Dex in Relapsed/Refractory Multiple Myeloma (RRMM) - Impact of Prior Treatments Analysis
Authors: Meletios-Athanasios Dimopoulos, Fredrik H. Schjesvold, María-Victoria Mateos, Pawel J. Robak, Roman Hájek, Paul G. Richardson, Jakob Lindberg, Marcus Thuresson, Kajsa Larsson, Pieter Sonneveld
Journal: Blood (2021)
Abstract 10370: Personalised Approach is the Key When it Comes to Pacing a Patient with an S-ICD
Authors: Mohamed ElRefai, Mohamed AbouelAsaad, John Morgan, Paul Roberts
Journal: Circulation (2021)

Introduction: Patients with an S-ICD may develop a pacing indication. When transvenous pacing is not feasible, the combination of an S-ICD and a leadless pacemaker (LP) might be a sound option. There are increased reports of concomitant use of LPs and S-ICDs. However, the effect of pacing on the S-ICD sensing is not well studied. Hypothesis: We hypothesize that pacing changes R and T waves morphology and amplitudes, causing changes in R:T ratios perceived by an S-ICD, increasing the risk for T wave oversensing (TWO) during paced rhythm with a subsequent risk of inappropriate shocks. Methods: We ran a prospective study in patients undergoing an electrophysiological study on clinical grounds. Participants were fitted with a Holter®, the leads of which placed to correspond to the three vectors of an S-ICD. We used a standard catheter to pace the right ventricle at four positions (figure 1) for 10 beats each at 8mA/2ms. We analysed the Holter® traces and used two-way ANOVA to assess the effect of pacing on the R:T ratio. Results: A total of 47 patients (mean age 56.02 ± 16.02,72% male) were enrolled (81% structurally normal heart, 15% DCM, 2% ICM, and 2% congenital heart disease). Age, sex, and aetiology had no effect on the R:T ratio. Pacing caused significant decrease in the R/T ratio, but there was no significant difference in the R/T ratio between different pacing sites. (P &lt;0.001). (figure 2) Conclusions: Pacing- regardless of position- causes the S-ICD perceived R:T ratio to fall below the eligibility screening threshold in most patients, increasing the risk of TWO and inappropriate shocks. Caution needs to be exercised and tailored programming of both devices is key for concomitant use of LPs and S-ICDs.
Sociodemographic Characteristics Associated With and Prevalence and Frequency of Cannabis Use Among Adults in the US
Authors: Abra M. Jeffers, Stanton Glantz, Amy Byers, Salomeh Keyhani
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Cannabis use has increased, but there are few studies on frequent and daily cannabis use among US adults. Individuals who engage in higher frequency use may suffer more health consequences. <h3>Objective</h3> To examine frequency of cannabis use and associated factors among US adults. <h3>Design, Setting, and Participants</h3> This survey study included data from 21 US states and 2 US territories reported in the Behavioral Risk Factor Surveillance System surveys from 2016 to 2019. Cross-sectional data on US adults ages 18 years and older were used to estimate demographic, socioeconomic, and behavioral risk factors for cannabis use, taking into account the survey strata and sampling weights for the 4 years of combined data. Using a multivariable ordinal logistic analysis, the association of demographic, socioeconomic status, and behavioral risk factors with past month cannabis frequency were examined. <h3>Exposures</h3> Sociodemographic characteristic, ie, age, gender, race and ethnicity, educational attainment, employment status, and annual household income. <h3>Main Outcomes and Measures</h3> Ordinal categorization of number of days of cannabis use in the past 30 days in terms of nonuse, infrequent use (1-5 days), frequent use (6-29 days), and daily use. <h3>Results</h3> Among the 387 179 respondents, 58 009 (27.9%) were ages 18 to 34 years, 186 923 (50.3%) were ages 35 to 64 years, and 142 225 (21.8%) were age 65 years or older (mean [SD] age, 48.3 [0.1] years). The sample included 28 345 (9.8%) Black, 36 697 (22.6%) Hispanic, and 292 210 (57.3%) White respondents. Smoking was the most common form of cannabis use. The frequency of cannabis use varied significantly by age, gender, race, marital status, education, and employment. Higher frequency cannabis use was associated with younger age (ages 18-34 years: adjusted odds ratio [aOR],4.12; 95% CI, 3.63-4.68; ages 35-64 years: aOR,2.22; 95% CI, 1.98-2.49), Black (aOR, 1.46; 95% CI, 1.33-1.71) and Native American (aOR, 1.25; 95% CI, 1.04-1.52) race, and less educational attainment (high school or less: aOR,1.09; 95% CI, 1.02-1.17; some college: aOR,1.27; 95% CI, 1.19-1.35). Being married (aOR, 0.54; 95% CI, 0.51-0.58) or identifying as Asian (aOR, 0.60; 95% CI, 0.51-0.71) or Hispanic (aOR, 0.71; 95% CI, 0.65-0.77) was associated with lower-frequency cannabis use after accounting for other baseline factors. <h3>Conclusions and Relevance</h3> This nationally based study found that higher-frequency cannabis use is more common among young and racial minority populations, as well as respondents with low socioeconomic status. Given the known and emerging negative health effects of cannabis use, more attention may need to be paid to high-frequency use among underserved populations in the form of screening, risk stratification, and treatment.
The Benefits Trial of PB-04 to Evaluate Safety, PK, and Preliminary Efficacy in Inducing Fetal Globin Expression in Beta Thalassemia Intermedia and Sickle Cell Disease
Authors: Kevin H.M. Kuo, Sylvia Singer, Sujit Sheth, Hanny Al-Samkari, Gershwin Blyden, Lanetta Bronte-Hall, Betty S. Pace, Abdullah Kutlar, Franciscus A. Kuypers, Aidan D Faller, Seyed Mehdi Nouraie, Pramod Terse, Haksong Jin, Xin Xu, Asaf Alimardanov, Arthur J. Sytkowski, Sharie Haugabook, Susan P Perrine
Journal: Blood (2021)
Abstract 14010: Tipifarnib Reduces Circulating Exosomes And Protects Against Pressure Overload-mediated Cardiac Hypertrophy
Authors: Vandana Mallaredy
Journal: Circulation (2021)

Clinically, Hypertrophic cardiomyopathy (HCM) in response to pathophysiological stress is one of the major initiating factors for the onset of cardiac remodeling leading to heart failure. Studies have revealed that HCM characterized by left ventricular hypertrophy, hypercontractility, and impaired relaxation is mainly driven by intricate crosstalk among the multiple cellular and molecular mechanisms, which leads to heart failure. In agreement with this observation, we investigated if the Tipifarnib-mediated reduction/alteration of circulating exosomes facilitates cardiac cell communication during HCM. Several studies have shown Tipifarnib as a potential Farnesyl transferase inhibitor. However, in recent pastTipifarnib has been shown to target exosomes biogenesis by several mechanisms such as inhibiting Raspathway, ESCRT complex etc. Tipifarnib treatment in mice significantly reduced the number of circulating plasma exosomes. We examined the response of Tipifarnib treatment (10 mg/kg body weight) in C57BL6Jmale mice subjected to transverse aortic constriction (TAC) surgery. Untreated TAC mice had worsening of systolic Left Ventricular function at 4 weeks that further deteriorated at 8 weeks, while the treatment with Tipifarnib substantially improved cardiac functions by reducing cardiac hypertrophy and fibrosis. Exosomes isolated from the serum of sham and TAC mice with or without tipifarnib were used for in vitro cell based analyses. We observed that the exosomes isolated from Tipifarnib treated TAC mice reduced isoproterenol (ISO)-induced cardiomyoblast hypertrophy and fibrosis-associated genes in adult cardiac fibroblasts. Taken together, our studies suggest Tipifarnib protects against pressure overload-induced cardiac remodeling and dysfunction by altering hypertrophic and fibrotic gene expression, by potentially reducing circulating exosomes or by altering exosome contents. Ongoing studies will clarify the molecularmechanisms of these observations.
EPCO-20. PEDIATRIC HIGH-GRADE GLIOMA EXHIBITS DISTINCT 3D GENOME STRUCTURE THAT IMPACTS TRANSCRIPTION REGULATION
Authors: Tina Huang, Juan Wang, Ye Hu, Andrea Piunti, Elizabeth Bartom, Ali Shilatifard, Feng Yue, Amanda Saratsis
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Pediatric high-grade gliomas (pHGGs), including glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG), are highly morbid brain tumors. Up to 80% of DIPGs harbor a somatic missense mutation in genes encoding Histone H3. To investigate whether the H3K27M mutant protein is associated with distinct chromatin structure affecting transcription regulation, we generated the first high-resolution Hi-C and ATAC-Seq maps of pHGG cell lines, and integrated these with tissue and cell genomic data. METHODS We generated sequencing data from patient-derived cell lines (DIPG n=6, GBM n=3, normal n=2) and frozen tissue specimens (DIPG n=1, normal brainstem n=1). Analyses included cell line RNA-Seq, ChIP-Seq (H3K27ac, H3K27me3, H3K27M) and genome-wide chromatin conformation capture (Hi-C), as well as tissue ATAC-Seq. Publicly available pediatric glioma tissue ChIP-Seq data was integrated with cell data. CRISPR knock-down of target enhancer regions was performed. RESULTS We identified tumor-specific enhancers and regulatory networks for known oncogenes in DIPG and GBM. In DIPG, FOX, SOX, STAT and SMAD families were among top H3K27Ac enriched motifs. Significant differences in Topologically Associating Domains (TADs) and DNA looping were observed at OLIG2 and MYCN in H3K27M mutant DIPG, relative to wild-type GBM and normal cells. Pharmacologic treatment targeting H3K27Ac (BET and Bromodomain inhibition) altered these 3D structures. Functional analysis of differentially enriched enhancers in DIPG implicated SOX2, SUZ12, and TRIM24 as top activated upstream regulators. Distinct genomic structural variations leading to enhancer hijacking and gene co-amplification were identified at A2M, JAG2, and FLRT1. CONCLUSION We show genome structural variations enhancer-promoter interactions that impact gene expression in pHGG in the presence and absence of the H3K27M mutation. Our results imply that tridimensional genome alterations may play a critical role in the pHGG epigenetic landscape and thereby contribute to pediatric gliomagenesis. Further studies examining the impact of the alterations is therefore underway.
Abstract 9974: Effect of Graves’ Disease on Female Probability Derived from Artificial Intelligence-Enabled Electrocardiograms in Women
Authors: Jwan A Naser, Zachi Attia, Sorin Pislaru, Marius Stan, Peter A Noseworthy, Paul Friedman, Grace Lin
Journal: Circulation (2021)

Introduction: Graves’ disease (GD) is known to cause menstrual changes and has been linked to infertility in women. This can be due to the increased production of androstenedione and testosterone induced by the excess thyroid hormone. However, screening for sex hormone levels in all women diagnosed with GD to identify patients more likely to have infertility is not cost-effective and not clinically indicated. AI-augmented ECG can identify the signature of female with an AUC of 0.97. In this model, AI- ECG gives a probability number between 0-100% of being female, with higher numbers indicating high probability of being female. Hypothesis: We hypothesized that this inexpensive AI ECG tool is reflective of hormonal levels and the resulting changes in menstrual cycle and fertility associated with GD in women. Methods: Patients diagnosed with GD (2009-2019) at our institution were included. Three intervals were identified: 1) Before GD: &gt;2 months before GD diagnosis 2) During GD: within 2 months before GD and before attaining euthyroidism 3) After GD: after attaining euthyroidism. The matched-pairs t-test was used to compare probability of being a female; patients acted as their own controls. A subset analysis was done on females &lt;45 years at GD diagnosis to study the association between female probability during GD and menstrual changes (defined as shorter, lighter, or newly irregular menstrual cycles). Results: 154 females with ECGs both before and during GD were identified. AI ECG female probability decreased with GD diagnosis (85% vs. 77%, P&lt;.001). On the other hand, 137 females with GD had ECGs during and after GD. Female probability increased after attaining euthyroidism (76% vs 83%, P=.005). Moreover, 72 females &lt;45 years were identified; 30 (42%) developed menstrual changes and had significantly lower AI-ECG female probability [77 (58-94)% vs 98 (92-100)%, P&lt;.001] Conclusions: AI-enabled ECG signature of female gender in women was altered by GD and was associated with menstrual changes, likely reflecting changes in sex hormone levels. Future studies to confirm its role in screening for infertility in women with GD are needed.
Abstract P411: Sex-based Differences In A Feline Model Of Hfpef
Authors: Deborah M Eaton, Remus Berretta, Jacqueline E Lynch, Joshua G Travers, Kathleen C Woulfe, Alexander R Hobby, Giana Schena, Jaslyn Johnson, Markus Wallner, Timothy A McKinsey, Marla R Wolfson, Steven R Houser
Journal: Circulation Research (2021)

Rationale: Heart Failure with preserved Ejection Fraction (HFpEF) accounts for approximately 50% of all HF diagnoses with no FDA approved therapies. HFpEF is more prevalent in females versus males, but the mechanisms driving the development of HFpEF as a sex-based disorder are not well understood. We have recently shown that slow progressive pressure overload (PO) in male felines induces a HFpEF phenotype but have not investigated the differences in response to the same physiological stress in females. Hypothesis: Females will develop a phenotype that is distinct from males in response to PO. Methods and Results: Male (m) and female (f) domestic short felines (age 2mo) underwent either a sham procedure (m: n=7; f: n=7) or aortic constriction (m: n=11; f: n=10) using a customized pre-shaped band. At baseline (prior to surgery), there was no difference in body weight between groups and echocardiography revealed no significant difference in the ratio of left atrium to aortic root (LA/Ao), LA ejection fraction (LA EF), left ventricle (LV) ejection fraction, LV wall-thickness, and E/A ratio. At 4mo post-surgery, both males and females developed cardiac dysfunction. Females gained significantly less weight than males throughout the study. Despite the size difference, both sexes developed comparable LV wall thickness and changes in E/A ratio vs. sham groups. There was no change in LV EF. Furthermore, there was a decrease in LA EF and increased LA/Ao, indicating LA dysfunction and enlargement. Invasive hemodynamics at 4mo post-surgery showed no differences between sexes for the systolic pressure gradient generated by the aortic banding. Banded males had a significantly higher LV end-diastolic pressure vs. banded females, but there was a trend towards prolongation of tau and lower dp/dt min in banded females, reflective of worse active relaxation. Both sexes had comparable dP/dt max . There were no differences between banded males and females in heart weight to body weight or cardiomyocyte cross-sectional area. Conclusion: Despite similar pressure gradients as a result of PO and the development of similar cardiac hypertrophy between sexes and a higher LVEDP in males, females had a trend towards worse relaxation. Other causes of HFpEF may have sex-based differences.
A sterile debate
Authors: Stephen Westaby, Keith Channon, Adrian Banning
Journal: BMJ (2007)

Did the recent BMJ articles improve the evidence for the superiority of coronary artery bypass grafting (CABG) over percutaneous coronary intervention (PCI) as claimed?1 2 3 In 2006 the featured minimally invasive direct coronary artery bypass graft (MIDCAB) operation for isolated left anterior descending disease accounted for less than 0.5% of 24 000 CABG procedures in the United Kingdom.1 2 Equally the economic arguments apply to practice and hospital costs 10 years ago,3 …
Abstract P389: Free Fatty Acid Receptor 4 Is Necessary For An Adaptive Response Following Heart Failure Induced By Metabolic Syndrome In Mice
Authors: Naixin Zhang, Katherine A Murphy, Dylan J Gyberg, Timothy D O'Connell
Journal: Circulation Research (2021)

Non-resolving inflammation is central to the pathogenesis of heart failure (HF). Heart failure preserved ejection fraction (HFpEF) is a type of HF that is particularly associated with inflammation provoked by metabolic syndrome (MetS). The G-protein coupled receptor, free fatty acid receptor 4 (Ffar4), is a receptor for medium and long chain fatty acids (FA) that regulates metabolism and attenuates inflammation. Ffar4 is expressed in the human heart, and downregulated in heart failure. Furthermore, polymorphisms in Ffar4 have been associated with eccentric remodeling in a patient cohort. Previously, Ffar4 was shown to protect the heart from pathologic stress by attenuating oxidative stress in a mouse model of pressure overload. Here, we tested the hypothesis that Ffar4 would attenuate the development of heart failure using a mouse model of MetS-induced HFpEF. Metabolic syndrome was induced in mice by feeding a high-fat, high-sucrose diet (42% fat, 30% sucrose) to produce obesity and delivering the nitric oxide synthase inhibitor, L-NAME, in the drinking water to induce hypertension. The combined intervention (referred to as HFpEF diet) resulted in mice developing excessive adiposity, glucose intolerance (in males only), and mild hypertension. After 20 weeks on the HFpEF diet, both male and female WT mice, developed diastolic dysfunction (increased E/A and E/e’) and preserved ejection fraction (EF), consistent with clinical HFpEF. In Ffar4KO male mice HFpEF diet induced a greater degree of diastolic dysfunction compared to WT mice, despite equivalent metabolic parameters. Female Ffar4KO mice fed the HFpEF diet had a greater increase in weight gain and adiposity compared to WT female mice. Surprisingly, diastolic function was equivalent between WT and FFAR4KO female mice, suggesting a sex-based difference in FFAR4 cardioprotection. Our data show that Ffar4 attenuates HFpEF secondary to MetS.
Abstract P492: Putative Protein Biomarkers For Reductive Stress Cardiomyopathy
Authors: Rajasekaran Namakkal-Soorappan, Cynthia L David, Krishna Parsawar
Journal: Circulation Research (2021)

Background: Nuclear factor erythroid 2-related factor 2 (NRF2) signaling is vital for redox homeostasis. We reported that transgenic mice expressing constitutively active Nrf2 (CaNrf2) exhibit reductive stress (RS). Here in, we identified novel protein signatures reacting to RS-induced cardiomyopathy. Methods: Tandem Mass Tag (TMT) proteomic analysis was performed in the heart tissues of Ca-Nrf2-transgenic (TG-low &amp; TG-high) and non-transgenic (NTg) mice at 6 months of age (N= 4/group). Differentially expressed proteins (DEPs) were then identified using Scaffold. Validated the key DEPs using immunoblotting. PANTHER and STRING analysis were used to identify potential targets and their interactions. Results: A total of 1105 proteins were extracted from 24369 spectra. Of note, 226 and 261 proteins were differentially expressed in TG-L and TG-H vs. NTg hearts indicating a unique proteome signature for RS. Heat map analysis revealed a clear distinction between the TG-L and TG-H due to the dose-dependent effects of transgene/RS. Majority of the DEPs that are significantly altered in RS mice found to involve in stress related pathways such as antioxidants, NADPH, protein quality control (PQC), etc. Interestingly, some of these proteins were redox modified at their cysteine residues under chronic RS setting. Conclusions: TMT based proteomic analyses revealed unique proteome signatures for RS. The cysteine modifications in multiple proteins likely to cause pathological alterations via impaired PQC mechanisms. Molecular studies related to RS-mediated redox modifications in structural and functional cardiac proteome are underway.