tbuckley/cabot-search huggingface dataset:
Abstract 15438: Comprehensive Structural, Molecular, and Electrophysiological Maturation of Human Induced Pluripotent Stem Cell Derived Atrial Cardiomyocytes to Serve as a Platform to Model Atrial Fibrillation
Authors: Olivia T Ly, Grace Brown, Liang HONG, Arvind Sridhar, Meihong Zhang, Hanna Chen, Seock Won Youn, Yong Duk Han, Malek Massad, khaled Abdelhady, Zain Alzahrani, SALMAN KHETANI, Dawood Darbar
Journal: Circulation (2020)

Introduction: Increasingly, human induced pluripotent stem cells (hiPSC) faithfully recapitulate human models of arrhythmias. However, enhancing hiPSC-derived atrial cardiomyocyte (aCM) maturity is vital as modeling mature CMs will provide insights into cellular mechanisms of atrial fibrillation (AF) and signaling pathways critical to atrial development Hypothesis: Combinatorial conditioning of hiPSC-aCMs with biochemical cues (T3, IGF-1, dexamethasone; TID), fatty acids (FA; oleic/palmitic acid), and acute electrical stimulation (ES) at increasing intensity over 45 days comprehensively enhances structural, molecular, and electrophysiological (EP) maturity of hiPSC-aCMs Methods: HiPSCs generated from patient specific peripheral blood mononuclear cells were differentiated into aCMs using retinoic acid and glucose starvation. Maturity of atrial iPSC-CMs was enhanced using TID, FA, and acute ES for the final 4 weeks of culture. Structural (immunofluorescence; transmission EM), molecular (qPCR; RNAseq), and EP (patch clamping; multielectrode array; high throughput automated patch clamping) maturity is assessed and compared to untreated hiPSC-aCMs and adult human aCMs harvested from the same patient (optimal maturity) Results: We showed improved hiPSC-aCM structural maturity with TID, FA, and ES ( Fig. 1A ). EP maturity also displayed more hyperpolarized resting membrane potential (RMP; Fig. 1B ), and improved upstroke velocity, action potential duration (APD), and amplitude (not shown). Expression of ion channels, and calcium handling and structural proteins is significantly improved ( Fig. 1C ) Conclusions: Combinatorial conditioning with TID, FA, and ES markedly improved structural, molecular, and EP maturity of hiPSC-aCMs. Our findings will serve as a platform to model AF, elucidate underlying cellular mechanisms, and identify novel therapeutic targets for a personalized, mechanism based approach to treat this common condition
Abstract 15044: Impact of Chronic Kidney Disease on the Pharmacodynamic and Pharmacokinetic Effects of Ticagrelor in Patients With Diabetes Mellitus and Coronary Artery Disease
Authors: Francesco Franchi, Fabiana Rollini, Latonya Been, Naji Maaliki, Patrick Abou Jaoude, Andrea Rivas, Ricky Zhou, Sida Jia, Maryuri Briceno, Chang Hoon Lee, Andres Pineda, Siva Suryadevara, Daniel Soffer, Martin Zenni, Theodore Bass, Dominick J Angiolillo
Journal: Circulation (2020)

Background: Diabetes mellitus (DM) is a key risk factor for the development of chronic kidney disease (CKD) and patients having both risk factors have increased risk of atherothrombotic events, underscoring the importance of antiplatelet therapy. Ticagrelor reduces ischemic events compared with clopidogrel, with the greatest risk reduction in patients with both DM and CKD. However, how CKD status affects the pharmacodynamic (PD) and pharmacokinetic (PK) profiles of different ticagrelor dosing regimens in DM patients is unknown. Methods: This was a prospective, randomized, cross-over study testing the PD/PK profiles of ticagrelor 90mg bid and 60mg bid among DM patients with and without CKD. All patients had coronary artery disease and were on dual antiplatelet therapy with aspirin (81mg qd) and clopidogrel (75mg qd). PD and PK assessments were performed at 3 visits: baseline, after 7-10 days of ticagrelor therapy (pre-crossover; peak and trough), and after 7-10 days of alternative ticagrelor regimen (post-crossover; peak and trough). Results: A total of 92 patients were randomized (CKD-, n=48; CKD+, n=44). Platelet reactivity as assessed by multiple assays (VASP-PRI; VerifyNow P2Y12; LTA) was increased with 60mg compared with 90 mg, which was statistically significant in CKD- but not in CKD+ patients for most PD measures (Figure). Although trough levels of platelet reactivity were numerically lower in CKD+ patients compared with CKD-, there was no significant difference in the pre-defined primary endpoint (trough levels of VASP-PRI following ticagrelor 90 mg dosing) between DM subjects with and without CKD (31±20 vs 25±14; mean difference= 6.4; 95% CI: -1.1 to 14.3; p=0.105; primary endpoint; Figure). PK assessments tracked PD profiles. Conclusions: In patients with DM, platelet inhibition by ticagrelor is similar irrespective of CKD status. However, the PD effects of the 60mg ticagrelor regimen is reduced compared with the 90mg regimen in patients without CKD.
Abstract 14355: Mono- and Biallelic Structural Variants in Alpha-actinin 2 Cause Contractile Dysfunction and Cardiomyopathy in Humans
Authors: Malene E Lindholm, Han Zhu, Kinya Seo, David Jimenez-Morales, Chunli Zhao, Euan A Ashley, Matthew T Wheeler
Journal: Circulation (2020)

Background and Aim: Cardiomyopathy is a common cause of sudden cardiac death in children that often requires heart transplantation. Alpha-actinins are critical cytoskeletal proteins that anchor actin filaments within the cardiac sarcomere. Mutations in ACTN2 have been associated with cardiomyopathy, but the mechanisms behind how those lead to cardiac dysfunction remain poorly understood. The aim of the present study was to investigate the effects of two novel structural ACTN2 mutations in human cardiac tissue and patient-specific iPSC-derived cardiomyocytes. Methods and Results: We identified a patient homozygous for a stop-gain mutation (p.Q860X) and a family heterozygous for a large exon 8-10 deletion with a 41bp insertion (indel) in ACTN2 , using a custom mutation pipeline optimized for rare variant discovery. In the explanted cardiac tissue of the homozygous patient, we observed mild hypertrophy and interstitial fibrosis. Patient-specific hiPSC-CMs from both families were hypertrophic, displayed sarcomeric structural disarray on transmission electron microscopy, and had slower contractile velocity compared to control hiPSC-CMs. The ACTN2indel protein was expressed, with subsequent incorporation into cardiac sarcomeres. In the homozygous stop-gain cells and normal controls, we used Co-IP followed by mass-spectrometry to identify C-terminal interacting proteins that are disrupted with C terminal loss. We found an intricate ACTN2 interactome with many sarcolemma-associated proteins and showed lack of interaction of the truncated ACTN2 with ACTN1 and GJA1 (Fig. 1). ACTN1 association was verified using colocalization and Co-IP followed by Western blot. Conclusion: We provide evidence that two loss of function genetic variants in ACTN2 are associated with contractile dysfunction and lead to cardiac abnormalities through distinct mechanisms within cardiac sarcomeres and through lack of critical protein-protein interactions.
Abstract 15812: Oxidative Stress Promotes Susceptibility to Atrial Fibrillation in <i>Pitx2</i> Deficient Mice
Authors: Kyungsoo KIM, Tuerdi Subati, Matthew B Murphy, Joseph C Van Amburg, Isis L Christopher, Joyce E Johnson, Joey V Barnett, Dan M Roden, Katherine T MURRAY
Journal: Circulation (2020)

Introduction: The strongest genetic risk factor for atrial fibrillation (AF) is variants on chromosome 4q25, near the paired-like homeobox transcription factor 2 gene Pitx2 . Mice deficient in Pitx2 ( Pitx2 +/- ) have increased AF susceptibility, although the mechanism(s) remains controversial. Recent evidence indicates that with cardiac injury, Pitx2 encodes an antioxidant gene program that promotes repair. Isolevuglandins (IsoLGs) are highly reactive lipid peroxidation products that mediate a major component of oxidative stress-related injury. We used a small molecule scavenger of IsoLGs to test the hypothesis that oxidative stress is enhanced in the setting of Pitx2 deficiency to cause AF susceptibility. Methods: Pitx2 +/- and Pitx2 +/+ (wild type littermate control) mice were treated orally with either vehicle or the IsoLG scavenger 2-hydroxybenzylamine (2-HOBA) starting at weaning. At age 16-18 weeks, animals underwent transesophageal atrial pacing, echocardiography, and tissue harvest or flow cytometry to measure atrial inflammation. Results: Pitx2 +/- mice demonstrated a significant increase in inducible AF burden compared to control mice (242.9±105.3 vs 23.6±11 sec; n=7, 14; P &lt;0.05). There was also a trend for an increased incidence of sustained AF (71.4% vs 21.4; P=0.055). Flow cytometry revealed that there was no increase in the number of total leukocytes in the atria of Pitx2 +/- mice compared to control atria, nor were differences present in selected populations of immune cells (including CD3, CD19, NK1.1, F4/80, Ly6G, or CD11b/MHCII positive cells). For Pitx2 +/- mice treated with 2-HOBA, there was trend for a reduction in AF burden (39.6±14.4 sec; n=11; P =0.075) as well as sustained AF (27.2%), while the drug had no effect in control mice. Based on cardiac histology (n=5, 5) and echocardiography (n=11, 14), no major histologic, structural, or functional abnormalities were identified in Pitx2 +/- mice. Conclusions: The reduction in AF burden by the IsoLG scavenger 2-HOBA supports the hypothesis that enhanced oxidative stress is responsible for AF susceptibility in the setting of Pitx2 deficiency. These results suggest a potential role for genotype-specific AF therapy (in 4q25 variant carriers) using IsoLG scavengers.
Late dialysis referral of ESRD patients carries high hospital mortality: identification of risk factors
Authors: Regina Célia Rodrigues de Moraes Abdulkader, Dirce Maria Trevisan Zanetta, Luís Yu, Glaucia Maria Cavasin Oliveira, Maristela Carvalho da Costa, Américo Lourenço Cuvello Neto, José Luiz Monteiro, Emmanuel de Almeida Burdmann
Journal: Journal of the American Society of Nephrology (2000)
Intussusception after Rotavirus Vaccine Introduction in India
Authors: Samarasimha N. Reddy, Nayana P. Nair, Jacqueline E. Tate, Varunkumar Thiyagarajan, Sidhartha Giri, Ira Praharaj, Venkata R. Mohan, Sudhir Babji, Mohan D. Gupte, Rashmi Arora, Sunita Bidari, Sowmiya Senthamizh, Suhasini Mekala, Krishna B. Goru, Bhaskar Reddy, Padmalatha Pamu, Rajendra P. Gorthi, Manohar Badur, Vittal Mohan, Saroj Sathpathy, Hiranya Mohanty, Mrutunjay Dash, Nirmal K. Mohakud, Rajib K. Ray, Prasantajyoti Mohanty, Geeta Gathwala, Suraj Chawla, Madhu Gupta, Rajkumar Gupta, Suresh Goyal, Pramod Sharma, Mannancheril A. Mathew, Tarun J.K. Jacob, Balasubramanian Sundaram, Girish K.C. Purushothaman, Priyadarishini Dorairaj, Muthukumaran Jagannatham, Kulandaivel Murugiah, Hemanthkumar Boopathy, Raghul Maniam, Rajamani Gurusamy, Sambandan Kumaravel, Ashwitha Shenoy, Hemant Jain, Jayanta K. Goswami, Ashish Wakhlu, Vineeta Gupta, Gopinath Vinayagamurthy, Umesh D. Parashar, Gagandeep Kang
Journal: New England Journal of Medicine (2020)

A three-dose, oral rotavirus vaccine (Rotavac) was introduced in the universal immunization program in India in 2016. A prelicensure trial involving 6799 infants was not large enough to detect a small increased risk of intussusception. Postmarketing surveillance data would be useful in assessing whether the risk of intussusception would be similar to the risk seen with different rotavirus vaccines used in other countries.
Publishing in 2@84
Authors: Marco Lanzillotta, Chiara Crotti, Vital Manuel Da Silva Domingues, Kim Lauper, Gerd R Burmester
Journal: Annals of the Rheumatic Diseases (2020)

This article arose within the framework of the EMEUNET peer review mentoring program.1 This project allows mentees to independently review articles submitted to Annals of the Rheumatic Diseases and RMD Open, tutored by an expert reviewer, thus nurturing their critical skills in the interpretation of a paper. After reviewing several papers together, the authors of this manuscript concluded the program fantasising about the potential changes in the editorial processes in the near and not so near future, resulting in this brief story. In particular, the authors thought about the delicate role of reviewers and editors, whose intellectual independence and integrity represent the foundation of the peer-review process.

We take you into the year 2@84 and describe the last day of work of Professor Ned, the editor of Rheumacity, the global comprehensive rheumatology knowledge database. He now must now handover his tasks to Highly Automated Logic Editor (HAL-E), the recently developed artificial intelligence and future editor in chief of Rheumacity, who is of course no longer a human being. While in his home and performing the final tasks in this handover to the machine, he recapitulate show he started his career in this field, how publishing evolved, what can go wrong and what the future will bring. He is a human and his mind is rambling on his last day at work.

Professor Ned’s last day at Rheumacity

…Ned woke up at one of the hottest dawn of the summer, looking for his near-sightedness spectacles and a glass of water on the bedside table. The thirst quencher was waiting there, close to a new generation tablet and the touch free lamp. He took this habit from his old grandpa. ‘Always keep a glass of water on your nightstand, and a book. They both will make you sleep better.’ A book, …
Abstract 13852: Socioeconomic Status is Associated With Recurrent Cardiovascular Disease Events in People With Prevalent Cardiovascular Disease
Authors: Lena Mathews, Ning Ding, Yejin Mok, Matthew S Loop, Amira Collison, Deidra Crews, Wayne D Rosamond, Kamakshi Lakshminarayan, Silvia Koton, Anna Kucharska-newton, Patricia Chang, Josef Coresh, Kunihiro Matsushita, Chiadi E Ndumele
Journal: Circulation (2020)

Introduction: While low socioeconomic status (SES) is an established risk factor for incident cardiovascular disease (CVD), there is scarce data regarding the association between SES and recurrent CVD events. Hypothesis: SES measures are associated with recurrent CVD events and mortality among those with prevalent CVD. Methods: We examined 3,031 individuals in the ARIC Study who developed CVD (either myocardial infarction [MI], heart failure [HF] or stroke) from the baseline visit (1987-1989) through 2013 to allow 5 years follow-up for recurrent CVD. SES was defined using baseline measures of income, education and area deprivation index (ADI), modeled individually and combined in a cumulative SES score. We used adjusted Cox proportional hazard regression to evaluate the associations of SES with composite and individual outcomes of first recurrent CVD and mortality. Results: Median age was 69 years, 49% were female, 29% Black. Over a median follow up of 4.6 years, 2,033 participants (67%) had a recurrent CVD event, and 2,202 (73%) died. Relative to the highest income group, being in the lowest income group was associated with higher risk for recurrent CVD (HR 1.27; 95% CI: 1.07-1.51) and mortality (HR 1.32; 95% CI: 1.12-1.56) ( Table ). Similarly, less than high school education was associated with increased risk of recurrent CVD (HR 1.25; 95% CI: 1.04-1.51) and mortality (HR 1.21; 95% CI: 1.01-1.45). No significant outcome associations were seen for ADI. Low cumulative SES was associated with approximately 20% higher risk of recurrent CVD, total mortality and the composite of recurrent CVD and mortality. Similar patterns were seen for individual subtypes of CVD, with the strongest SES-mortality associations for MI and stroke. Conclusions: In the high-risk group of individuals with existing CVD, low SES was linked to greater likelihood of recurrent CVD events and death. SES should be a focus in the design of secondary prevention efforts to improve outcomes in CVD.
Evaluating the patient-perceived impact of non-alcoholic steatohepatitis with compensated cirrhosis
Authors: Matthew Breckons, Lynda Doward, Lorraine McSweeney, Maria Magdalena Balp, James Twiss, Yemi Oluboyede, Luke Vale, Laura Ternent, Clifford Brass, Arun Sanyal, Quentin Anstee
Journal: Journal of Hepatology (2020)
Abstract 12526: The Risk of Critical Congenital Heart Disease in Children Born After Assisted Reproductive Technology
Authors: Yoshihito Morimoto, Taichi Kato
Journal: Circulation (2020)

Introduction: Assisted reproductive technology (ART), which began 40 years ago, has spread all over the world. And 1 in 18 Japanese infants is conceived through ART. But it is known that infants conceived through ART have a high frequency of congenital anomalies and a high birth rate of congenital heart disease (CHD). Because of the high elderly birth rate and advanced medical system in Japan, Japan has the highest number of ART implementations in the world. However, there are no reports on the frequency of CHD in infants conceived through ART in Japan, so we performed this study. Methods: Four hundred eighteen infants diagnosed with critical CHD (lesions requiring catheter treatment or surgery within 28 days of life, or ductal-dependent lesions; CCHD) at the two pediatric heart centers from January 2014 to December 2019, were reviewed retrospectively. Results: In total, 229 males and 189 females were included in this study. The gestational age was 38± 2weeks. Maternal age was 32±5 years and paternal age was 34±6 years. Seventy-eight patients (19%) had chromosome abnormalities, gene abnormalities or syndrome. Sixty-one patients (15%) were conceived through fertility treatment and 46 patients (11%) were conceived through ART. One hundred eleven patients (27%) had univentricular heart defect (UVH). Compared with the proportion of ART (6%) in all births in Japan, the proportion of ART (11%) in CCHD was high. In addition, the proportion of ART in UVH was 20/111 (18%), while the proportion of ART in biventricular heart defect was 30/307 (10%) (p=0.0218). Among them, the highest proportion of ART in hypoplastic left heart syndrome and pulmonary atresia with intact ventricular septum was 7/23 (30%) and 5/19 (26%), respectively. Conclusions: The number of ART implementations in Japan is expected to increase in the future. At present, there are many cases in which infants conceived through ART cannot be diagnosed with CCHD before birth. Because infants conceived through ART might have a high incidence of complex CHD and UVH, they need more careful fetal follow-up than infants conceived naturally.
Abstract 16433: Quality Initiative Tied to Physician Reimbursement Significantly Improves Sacubitril/valsartan and Spironolactone Use Among Patients With Heart Failure With Reduced Ejection Fraction
Authors: Andrei Minciunescu, Laira Baez-Quintana, Rebecca Yantz, Therese del Castillo, Manuel Calcagno, Lynn T Soderstrom, Deanna Overbeck, Tiara Myhera, Warren S Levy, Christopher M O'Connor, Tariq M Haddad
Journal: Circulation (2020)

Introduction: Despite data showing reductions in risk of death and heart failure hospitalization in heart failure patients with reduced ejection fraction (HFrEF), sacubitril/valsartan (SV) and mineralocorticoid-receptor antagonist (MRA) adoption rates have remained low. We hypothesized that instituting a quality initiative (QI) that prospectively identified SV/MRA candidacy in HFrEF patients and tied successful use of MRA/SV in eligible patients to total health system compensation would improve utilization rates. Methods: A HFrEF QI was implemented whereby a portion of a large outpatient cardiology practice’s total compensation by the health system was tied to successful SV and MRA use in HFrEF patients (EF&lt;40%) with NYHA class II-IV symptoms. Quality metric goals that triggered maximum reimbursement were set at &gt;25% SV use and &gt;60% MRA use in eligible HFrEF patients, given the low rates of appropriate SV and MRA use nationally. Following QI introduction, patients with the above eligibility criteria were prospectively identified over one year. Providers were sent daily e-mails notifying them of eligible patients that day, and during the patient visit were prompted to complete a form, documenting use of SV, MRA, and/or any contraindications to their use including blood pressure, renal function, potassium level, ACE/ARB intolerance, or financial obstacles. To serve as a control arm, data was retrospectively collected on 6 months of consecutive HFrEF patients with the same eligibility criteria prior to QI initiation. Results: Of 1345 retrospectively identified HFrEF patients prior to initiating the QI, 855 (63.5%) and 964 (71.7%) met SV and MRA eligibility criteria. Of these, 324 (37.9%) were prescribed SV, 365 (37.9%) an MRA. Following QI implementation, 3792 patients with HFrEF were prospectively identified, and of these 2550 (67.2%) and 2589 (68.2%) met eligibility criteria for SV and MRA initiation. SV use in eligible patients increased from 37.9% pre-QI, to 72.1% post-QI (p &lt; 0.001). MRA use increased from 37.9% pre-QI to 66.2% post-QI (p &lt; 0.001). Conclusions: A quality initiative linking successful implementation of SV and MRA use in eligible HFrEF patients to physician compensation resulted in a significant increase in SV and MRA adoption rates.
Association Between Alzheimer Disease and Cancer With Evaluation of Study Biases
Authors: Monica Ospina-Romero, M. Maria Glymour, Eleanor Hayes-Larson, Elizabeth Rose Mayeda, Rebecca E. Graff, Willa D. Brenowitz, Sarah F. Ackley, John S. Witte, Lindsay C. Kobayashi
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Observational studies consistently report inverse associations between cancer and Alzheimer disease (AD). Shared inverse etiological mechanisms might explain this phenomenon, but a systematic evaluation of methodological biases in existing studies is needed. <h3>Objectives</h3> To systematically review and meta-analyze evidence on the association between cancer and subsequent AD, systematically identify potential methodological biases in studies, and estimate the influence of these biases on the estimated pooled association between cancer and AD. <h3>Data Sources</h3> All-language publications were identified from PubMed, Embase, and PsycINFO databases through September 2, 2020. <h3>Study Selection</h3> Longitudinal cohort studies and case-control studies on the risk of AD in older adults with a history of any cancer type, prostate cancer, breast cancer, colorectal cancer, or nonmelanoma skin cancer, relative to those with no cancer history. <h3>Data Extraction and Synthesis</h3> Two reviewers independently abstracted the data and evaluated study biases related to confounding, diagnostic bias, competing risks, or survival bias. Random-effects meta-analysis was used to provide pooled estimates of the association between cancer and AD. Metaregressions were used to evaluate whether the observed pooled estimate could be attributable to each bias. The study was designed and conducted according to the Preferring Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. <h3>Main Outcomes and Measures</h3> Incidence, hazard, or odds ratios for AD comparing older adults with vs without a previous cancer diagnosis. <h3>Results</h3> In total, 19 cohort studies and 3 case-control studies of the associations between any cancer type (n = 13), prostate cancer (n = 5), breast cancer (n = 1), and nonmelanoma skin cancer (n = 3) with AD were identified, representing 9 630 435 individuals. In all studies combined, cancer was associated with decreased AD incidence (cohort studies: random-effects hazard ratio, 0.89; 95% CI, 0.79-1.00; case-control studies: random-effects odds ratio, 0.75; 95% CI, 0.61-0.93). Studies with insufficient or inappropriate confounder control or greater likelihood of AD diagnostic bias had mean hazard ratios closer to the null value, indicating that these biases could not explain the observed inverse association. Competing risks bias was rare. Studies with greater likelihood of survival bias had mean hazard ratios farther from the null value. <h3>Conclusions and Relevance</h3> The weak inverse association between cancer and AD may reflect shared inverse etiological mechanisms or survival bias but is not likely attributable to diagnostic bias, competing risks bias, or insufficient or inappropriate control for potential confounding factors.