tbuckley/cabot-search huggingface dataset:
Abstract 207: Molecular Signatures of Sex Differences in Heart Failure with Preserved Ejection Fraction
Authors: Yang Cao
Journal: Circulation (2020)

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome involving diastolic dysfunction and metabolic disorders. Women are twice as likely to develop HFpEF as compared to men and present with a greater symptom burden. However, the sex-specific biology of HFpEF is unknown. This study aims to dissect sex-specific molecular signatures of diastolic dysfunction in HFpEF. Methods: We developed a ‘two-hit’ HFpEF model with HFD and l-NAME (Nω-nitrol-arginine methyl ester) in C57BL/6J male and female mice. RNA-seq for heart tissue from mice under HFpEF versus Chow condition was performed and results were integrated with multi-omics datasets including hybrid mouse diversity panel (HMDP, a panel of more than 100 inbred strains of mice) and human heart failure cohort to dissect novel gene-by-sex interactions in the heart. Results: HFD and l-NAME induced diastolic heart failure phenotypes in both male and female mice. We observed higher E/A (1.68 ± 0.09 vs. 1.40 ± 0.04, p &lt; 0.05 under chow diet), E/E’ (35.82 ± 2.05 vs. 26.13±1.11, p &lt; 0.05 under chow diet; 53.78 ± 3.94 vs. 43.92±2.08, p &lt; 0.05 after HFpEF) and lung weight (wet/dry ratio, 4.51 ± 0.09 vs. 4.15 ± 0.09, p &lt; 0.05 after HFpEF) in females compared to males. Pathway analysis revealed that compared with male mice, female mice exhibited a greater decrease in fatty acid metabolism, insulin signaling, heart development and an enhanced increase in cell cycle, inflammation, cholesterol efflux and serine synthesis upon HFpEF. Together with our high fat/high sucrose diet-induced metabolic disorder HMDP cohort and isoproterenol-induced heart failure HMDP cohort, HFpEF mice revealed that female hearts contained reduced mtDNA copy number relative to males (3102.56 ± 85.70 vs. 3770.43 ± 77.44, p = 4.51E-08). Cardiac mtDNA was inversely correlated with diastolic dysfunction (bicor = -0.307, p = 0.005) and was regulated by gonadal hormones. Conclusions: We utilize our systems genetics approach that integrates multi-omics datasets and dissect novel gene-by-sex interactions in the heart. Females exhibit more severe metabolic disorders and mitochondrial dysfunction relative to males, which are responsible for greater diastolic dysfunction of HFpEF.
Abstract 14073: Omega-3 Fatty Acid Levels and Risk for Incident Bleeding and Atrial Fibrillation: Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Karan Kapoor, Abdulhamied Alfaddagh, Mahmoud Al Rifai, Deepak L Bhatt, Matthew J Budoff, Khurram Nasir, Michael Miller, Francine K Welty, John W McEvoy, Zeina Dardari, Michael D Shapiro, Roger S Blumenthal, Michael Y Tsai, Michael J Blaha
Journal: Circulation (2020)

Introduction: The association between plasma OM3 FA levels and key safety endpoints identified in the REDUCE-IT trial such as bleeding and atrial fibrillation (AF) remains uncertain. Hypothesis: Consistent with REDUCE-IT, we hypothesized that higher baseline OM3 FA levels, particularly EPA, would be associated with incident bleeding and AF in a population free of clinical ASCVD or AF. Methods: We examined the association between baseline plasma OM3 FA levels (expressed as percent mass of total FA) with incident bleeding and AF in MESA. Bleeding events were identified from review of hospitalization ICD-9/10 codes, and AF from participant report, discharge diagnoses, Medicare claims data, and study ECGs performed at MESA visit 5. Multivariable Cox proportional hazard modeling was used to estimate HRs of the association of continuous OM3 FA (log EPA, log DHA, log (EPA+DHA)) and our outcomes. Results: Among the 6546 participants, mean age was 62.1(±10.2) and 3468(53%) were female. For incident bleeding, consistent statistically significant reductions were seen with increasing levels of EPA and EPA+DHA in unadjusted and adjusted models including medications that modulate bleeding risk, such as aspirin, NSAIDS, corticosteroids and proton pump inhibitors (Table). For incident AF, a significant reduction was seen with increasing levels of DHA in univariate analyses that did not persist following adjustment for AF risk factors. No significant associations were seen with either EPA or EPA+DHA. Conclusions: In MESA, a population free of clinical ASCVD or AF at baseline, higher plasma levels of OM3 FA (EPA and EPA+DHA, but not DHA) were associated with significantly lower risk of hospitalized bleeding events, but there was no significant association with AF. These findings from observational studies will need to be reconciled with clinical trial data of high-dose pharmacologic OM3 FA therapy.
Abstract 14681: Comparative Study Between International Guidelines in Detecting Pediatric Familial Hypercholesterolemia Through a Unique Community Health System in Kagawa, Japan
Authors: Keiji Matsunaga, Asako Mizobuchi, Hayato Tada, Tsuyoshi Sasaki, Yoshihiro Asano, Sigeru Ito, Ichiro Yokota, Jun Kunikata, Takashi Iwase, Masa-aki Kawashiri, Takashi Kusaka, Tetsuo Minamino
Journal: Circulation (2020)

Introduction: Familial hypercholesterolemia (FH) is an autosomal hereditary disease found in patients who have elevated low-density lipoprotein cholesterol (LDL-C) from birth. Early detection and treatment of FH during childhood potentially reduces the risk of premature cardiovascular events. In Kagawa prefecture, a unique community health system, involving three steps, has been conducted to prevent lifestyle-related diseases for 10-year-old children. This system includes universal lipid screening, selection by pediatricians, and next-generation sequencing (NGS) of FH-related genes in hospitals. The aim of this study is to compare 3 international guidelines to detect pediatric FH with this unique community health system in Kagawa. Methods: In Kagawa prefecture, the universal lipid screening of approximately 8,000 children at 10 years of age is performed annually, covering over 90% of the target group. After excluding secondary hypercholesterolemia, pediatric clinics introduced children with LDL-C &gt;140mg/dL to 4 designated hospitals to perform NGS. We applied the guidelines of the Dutch Lipid Clinic Network (DLCN), Simon Broome (SB), and the Japanese Atherosclerosis Society (JAS) to children who received NGS in the unique community health system in Kagawa. Results: We performed NGS for 46 children from January 2018 to February 2020 (LDL-C 186.0±50.3 mg/dL; Male/F 27/19) and 26 (57%) had FH genetic mutations (23 LDL-R and 3 PCSK9 mutations). Seventeen children met FH criteria for DLCN (35%), 10 for Simon Broome (22%), and 11 for JAS (24%), respectively. The combination of NGS and either of the 3 guidelines increased the number of children diagnosed as FH up to 31 (67%). Conclusion: International guidelines detected only half of pediatric FH who were diagnosed by the unique community health system in Kagawa. Further investigation will be required to build an effective universal screening system for pediatric FH.
Abstract 368: Does Filtered Rhythm Technology Lead to Increased Inappropriate Manual Defibrillation?
Authors: Jimmy To, Jenny Yang, David E Krummen, Gabriel Wardi, Rebecca E Sell
Journal: Circulation (2020)

Introduction: Defibrillation of ventricular fibrillation (VF) and pulseless ventricular tachycardia (VT) is an effective treatment for patients with cardiac arrest (CA). Identifying the rhythm during cardiopulmonary resuscitation (CPR) can be difficult with the rhythm obscured by chest compression artifact. “Rhythm” checks are usually recommended, but this interrupts the resuscitation attempt. Filtered rhythm technology such as See-Thru CPR aims to reduce these interruptions by filtering out chest compression artifact, leading to easier visualization of the underlying heart rhythm without stopping CPR. Hypothesis: While See-Thru CPR is effective at improving chest compression fraction, inappropriate shocks of non-VF/VT rhythms are still common. Methods: This is a retrospective review of an internal database of all cardiac arrests occurring within a two-hospital academic hospital system between July 2012 and September 2019. The local CPR algorithm trains responders to utilize See-Thru CPR to minimize interruptions and increase the chest compression fraction (the average chest compression fraction is &gt; 90%). The database includes all inpatient and emergency room CA and includes patient demographics, cardiac and resuscitation data including CPR parameter data when available, and outcomes. Cardiac arrests with CPR data were reviewed and all defibrillation attempts were identified and analyzed. Pre and post-shock rhythm were identified by reviewing the preceding rhythm strip, and the rhythm following the defibrillation delivery. Results: Three hundred thirty-six patients had CA with complete CPR data containing defibrillation attempts. These 336 patients had 1199 defibrillations delivered. Between 1 - 39 shocks were delivered during each event. The majority of defibrillations were delivered correctly for VF/VT (916/1199, 76%), however 23.6% of defibrillations were inappropriate - PEA in 232 attempts (19%) and asystole in 51 (4%). Of these inappropriate shocks, 23 converted to either VF/VT or ROSC, while the rest maintained a non-VF/VT rhythm. Conclusions: Defibrillation while using See-Thru CPR for inappropriate shocks is common. Further studies will be needed to show the clinical effects of shocking non-VF/VT rhythms.
Abstract 14049: Correlation of Cellular Indices and D-dimer/fibrinogen Ratio to Gender Differences in 6-minute Walk Test Distance in Patients Presenting With Acute Pulmonary Embolism
Authors: Nathalie Antonios, Dalila Masic, Katerina Porcaro, Sorcha Allen, Alexandru Marginean, Ahmad Manshad, Shannon Kuhrau, Ibrahim Chowdhury, Karim Merchant, Lucas Chan, Stephen Morris, Jeremiah Haines, Jawed Fareed, Yevgeniy Brailovsky, Amir Darki
Journal: Circulation (2020)

Introduction: The six-minute walk test (6MWT) is a simple and well-validated test to assess functional status and predict morbidity and mortality in several chronic cardiopulmonary disease states. Neutrophil to Lymphocyte ratio (NLR) reflects a pro inflammatory state. Increased platelet to lymphocyte ratio (PLR) has been associated with increase in thrombus burden. Elevated D-dimer to fibrinogen ratio (D/f) reflects fibrinolysis activation. No study has investigated the correlation of these indices with gender differences in 6MWT in patients presenting with pulmonary embolism (PE). Methods: We retrospectively evaluated all acute PE patients from our Pulmonary Embolism Response Team Registry who completed a 6MWT during their initial hospitalization. Differential complete blood count data along with d-dimer and fibrinogen were collected within 24 hours prior to PE diagnosis. Results: A total of 186 patients underwent baseline 6MWT and lab tests between March 2016 and January 2020. The mean walking distance for males (765 ft) was further than females (519 ft; figure 1). NLR, PLR, and D/f did not correlate with 6MWT in males. In females, NLR, PLR, and D/f had a negative correlation with walking distance (r = -0.20, p &lt;0.05; r = -3.0, p&lt;0.01; and r = -0.15, p&lt;0.05; figure 2) Conclusions: Female patients, in our study, had significantly shorter walking distance after acute presentation in PE. This may reflect higher inflammatory and prothrombotic state. Future studies will need to expand on these findings.
Bioinspired mineralized collagen scaffolds for bone tissue engineering
Authors: Zhengwei Li, Tianming Du, Changshun Ruan, Xufeng Niu
Journal: Bioactive Materials (2020)

Successful regeneration of large segmental bone defects remains a major challenge in clinical orthopedics, thus it is of important significance to fabricate a suitable alternative material to stimulate bone regeneration. Due to their excellent biocompatibility, sufficient mechanical strength, and similar structure and composition of natural bone, the mineralized collagen scaffolds (MCSs) have been increasingly used as bone substitutes via tissue engineering approaches. Herein, we thoroughly summarize the state of the art of MCSs as tissue-engineered scaffolds for acceleration of bone repair, including their fabrication methods, critical factors for osteogenesis regulation, current opportunities and challenges in the future. First, the current fabrication methods for MCSs, mainly including direct mineral composite, in-situ mineralization and 3D printing techniques, have been proposed to improve their biomimetic physical structures in this review. Meanwhile, three aspects of physical (mechanics and morphology), biological (cells and growth factors) and chemical (composition and cross-linking) cues are described as the critical factors for regulating the osteogenic feature of MCSs. Finally, the opportunities and challenges associated with MCSs as bone tissue-engineered scaffolds are also discussed to point out the future directions for building the next generation of MCSs that should be endowed with satisfactorily mimetic structures and appropriately biological characters for bone regeneration.
Abstract 14215: Cognitive Impairment in Adult Congenital Heart Disease Survivors: A Pilot Study
Authors: Carla P Rodriguez Monserrate, Rajeshwari Jakkam, Emily Clay, Kimberlee Gauvreau, Michelle Z GURVITZ
Journal: Circulation (2020)

Introduction: The most common comorbidities in children with congenital heart disease (CHD) are neurodevelopmental and psychosocial impairments, particularly in areas of executive function, memory, attention, and behavioral control. Limited studies in the adult CHD population suggest similar impairments exist and adults with CHD may be at increased risk for dementia. No studies have screened specifically for mild cognitive impairment and dementia in adult CHD patients. Methods: We performed a prospective cross-sectional study of adult CHD patients, ages 30-65 years, who were coming for routine clinic visits. We administered the Mini-Mental State Exam (MMSE) and scores were compared with population norms adjusted by age and education level. We also evaluated the association of MMSE scores with CHD complexity, demographic and clinical risk factors. Results: A total of 125 patients were recruited (55% male). The median age was 40 years (range 30-65). Almost all participants (97%) had a high school degree and 75% had some college education or advanced degrees. The majority of patients (94%) had moderate or complex CHD. Adjusting for age and education, CHD participants scored significantly lower than the general population (median 1 point lower, p=0.001). The greatest impairments occurred in recall and orientation. Factors associated with lower scores included decreased systemic ventricular function (p=0.028) and having ≥2 cardiac catheterizations (p=0.006). Five percent of the total cohort met the general threshold for mild cognitive impairment (MMSE&lt;24). Clinical factors associated with this degree of cognitive impairment were duration of cyanosis (p=0.005) and decreased systemic ventricular function (p=0.003). Conclusions: Our pilot study showed that, when adjusted for age and education level, adult CHD patients had significantly lower MMSE scores than the general population, with 5% meeting criteria for mild cognitive impairment. These findings suggest that subtle and early neurodevelopmental changes are present in the adult CHD population. Further studies are needed to investigate those changes and evaluate potential disease modifying therapies that might influence long-term outcomes in the adult CHD population.
Is Viral Vector Gene Delivery More Effective Using Biomaterials?
Authors: Yi Wang, Kiara F. Bruggeman, Stephanie Franks, Vini Gautam, Stuart I. Hodgetts, Alan R. Harvey, Richard J. Williams, David R. Nisbet
Journal: Advanced Healthcare Materials (2020)

Abstract Gene delivery has been extensively investigated for introducing foreign genetic material into cells to promote expression of therapeutic proteins or to silence relevant genes. This approach can regulate genetic or epigenetic disorders, offering an attractive alternative to pharmacological therapy or invasive protein delivery options. However, the exciting potential of viral gene therapy has yet to be fully realized, with a number of clinical trials failing to deliver optimal therapeutic outcomes. Reasons for this include difficulty in achieving localized delivery, and subsequently lower efficacy at the target site, as well as poor or inconsistent transduction efficiency. Thus, ongoing efforts are focused on improving local viral delivery and enhancing its efficiency. Recently, biomaterials have been exploited as an option for more controlled, targeted and programmable gene delivery. There is a growing body of literature demonstrating the efficacy of biomaterials and their potential advantages over other delivery strategies. This review explores current limitations of gene delivery and the progress of biomaterial‐mediated gene delivery. The combination of biomaterials and gene vectors holds the potential to surmount major challenges, including the uncontrolled release of viral vectors with random delivery duration, poorly localized viral delivery with associated off‐target effects, limited viral tropism, and immune safety concerns.
Bradykinin receptor antagonists
Authors: Ronald M. Burch, Stephen G. Farmer, Larry R. Steranka
Journal: Medicinal Research Reviews (1990)

Bradykinin and its active metabolites are produced at the sites of their actions by kallikreins. They potently elicit a variety of biological effects: hypotension, bronchoconstriction, gut and uterine contraction, epithelial secretion in airway, gut, and exocrine glands, vascular permeability, pain, connective tissue proliferation, and eicosanoid formation. These effects are mediated by at least two broad classes of receptors. The most common is the B2 subtype. The Stewart and Vavrek peptides characterized by a DPhe7 substitution have provided powerful tools for study of bradykinin's actions by competitively and specifically blocking bradykinin B2 receptors. The significance of kinins in certain human diseases is being explored using these new tools and potential therapeutic agents. At present, human clinical trials are underway to test the usefulness of bradykinin receptor antagonists in the symptoms of the common cold and in the pain associated with severe burns. Trials for use in asthma will be initiated in 1990.
Abstract 18078: Hdac4 Degradation Involves Hdac Inhibition-Induced Protective Effects in Hypoxia in Mouse Cardiomyocytes
Authors: Ting C Zhao, Jian Feng Du
Journal: Circulation (2013)

Background: Histone deacetylases (HDACs) have been recently demonstrated to play critical roles in modulating myocardial protection and cardiomyocyte survivals in response to stress. However, the molecular mechanism(s) of specific HDACs attributable for the regulation of myocyte survivals are poorly understood. Objective: Our goal was to investigate whether HDAC inhibition elicits a protective effect through specific HDAC4, and whether HDAC4 ubiquitination involves induction of cellular protective effect in mouse cardiomyocytes exposed to hypoxia/re-oxygenation. Methods: Neonatal mouse cardiomyocytes (1-3 day old) were isolated and then subjected to 48 hours of hypoxia (1% oxygen) followed 2 hours of reoxygenation. Prior to hypoxia cardiomyocytes were infected with adenoviral HDAC4 and adenoviral GFP. Cardiomyocytes were preconditioned with trichostatin A (TSA, 50nmol/L) to block HDAC activity, whereas MG132 (0.2 μmol/L), a selective proteasome inhibitor, was utilized to inhibit the proteasome pathway. The cytotoxicities were estimated by detection of lactate dehydrogenase (LDH) and myocyte viabilities were measured by MTT assays. Western blot was employed to assess HDAC4 degradation. RT-PCR was performed to analyze HDAC4 mRNA. Results: Inhibition of HDACs with TSA enhanced cardiomyocyte viabilities and reduced the LDH leakages of cardiomycytes during hypoxia/reoxygenation. Pretreatment of myocytes with MG132 abolished the protective effects of TSA. Infection of myocytes with adv-HDAC4 mitigated HDAC inhibition-induced protection. Co-immunoprecipitation assay and Western blot indicate the HDAC4 uniquitination following TSA treatments. TSA specifically resulted in the reduction of HDAC4 protein, but not mRNA, which was blocked by MG132. Conclusion: HDAC inhibition protects cardiomyocytes against hypoxic stress, which depends on HDAC4 and HDAC4 ubiquitination.
Prenatal screening for Down's syndrome.
Authors: M J Stone, S F Levy, W Tait, P J Allan, P J Riley
Journal: BMJ (1991)

Sir,?In the light of recent evidence that the  test is a good predictor of Down's syndrome we write to express our concern that this investiga? tion is not generally available on the NHS.1 All women in Stockport are offered an estimation of a fetoprotein concentration and an ultrasound scan at 16 weeks of pregnancy. On the advice of one of the local consultant obstetricians a patient of ours with a low a fetoprotein concentration (17 u.g/1) was offered a triple test at the cost of ?50. We consider that if this investigation is recom? mended for the detection of Down's syndrome and has become a part of accepted medical practice it is indefensible not to offer it to an at risk woman and it is wrong that, depending on the area of the country in which the woman lives, the investigation is either free or not. Is this further evidence of inequality of health care or just the result of market forces? MJSTONE S F LEVY W TAIT P J ALLAN P J RILEY Hazel Grove, Stockport SK7 4QR
Prevalence of Gestational Diabetes in India by Individual Socioeconomic, Demographic, and Clinical Factors
Authors: Goutham Swaminathan, Akshay Swaminathan, Daniel J. Corsi
Journal: JAMA Network Open (2020)

Gestational diabetes is common in pregnancy and is associated with adverse pregnancy and fetal outcomes. Currently, population-based data on the prevalence of gestational diabetes are limited in India.To provide a comprehensive national assessment of gestational diabetes in India and its socioeconomic, demographic, and geographic associations, using elevated random blood glucose data as a proxy for a gestational diabetes diagnosis.This cross-sectional study analyzed the fourth National Family Health Survey, conducted in India between January 2015 and December 2016. This nationally representative sample comprised 699 686 women 15 to 49 years of age, of whom 32 428 (4.6%) were pregnant. Data were analyzed between July and December 2019 and between July and August 2020.Age, body mass index, hypertension, wealth, and social caste were factors potentially associated with gestational diabetes.Gestational diabetes, defined as elevated random blood glucose according to predetermined thresholds (≥200 mg/dL for nonfasting, ≥92 mg/dL for fasting).Of the 31 746 pregnant women with complete data in the study, the mean (SD) age was 24.3 (4.7) years, and the mean (SD) gestational age was 5.1 (2.3) months. The weighted age-adjusted prevalence of gestational diabetes was 1.3% (95% CI, 1.1%-1.5%). The prevalence of gestational diabetes increased with age, from 1.0% (95% CI, 0.5%-1.5%) at age 15 to 19 years to 2.4% (95% CI, 1.0%-3.8%) at age 35 years or older. The age-adjusted prevalence of gestational diabetes was higher among women with a body mass index of 27.5 or greater (1.8%; 95% CI, 1.0%-2.5%) compared with women with a body mass index of less than 18.5 (0.8%; 95% CI, 0.5%-1.1%), among women in the highest wealth quartile (1.7%; 95% CI, 1.1%-2.5%) compared with those in the lowest (0.9%; 95% CI, 0.7%-1.2%), and women in the south (eg, Kerala: 4.5%; 95% CI, 2.4%-6.7%; Telangana: 5.4%; 95% CI, 0.0%-11.0%) compared with the northeast (eg, Assam: 0.23%; 95% CI, 0.0%-0.48%; Mizoram: 0.16%; 95% CI, 0.0%-0.49%).In this study, considerable variation was found in the prevalence of gestational diabetes by state, socioeconomic status, and demographic factors. This finding has implications for the method of gestational diabetes screening in low-resource settings in India, especially in areas or among demographic groups with lower prevalence.