tbuckley/cabot-search huggingface dataset:
Abstract P178: The Association Between Multiparity And Endogenous Sex Hormone Levels In The Multi-ethnic Study Of Atherosclerosis (mesa)
Authors: Brigitte Kazzi, Oluseye Ogunmoroti, Di Zhao, Anum Minhas, Olatokunbo I Osibogun, Vinita Subramanya, Matthew A Allison, Pamela Ouyang, Erin Michos
Journal: Circulation (2021)

Introduction: Parity is a risk factor for adverse cardiovascular events in women compared to nulliparity. A more androgenic sex hormone profile, with increased testosterone to estrogen ratio, is associated with worse cardiovascular disease (CVD) outcomes in women and may be one mechanism that links a history of multiparity with future increased CVD risk. Given this, we investigated the relationship between parity and sex hormone levels. Methods: We studied 3,003 female MESA participants (ages 45-84 years and free of CVD) with complete data on parity and endogenous sex hormone levels at the baseline visit (2000 - 2002). Parity (number of live births) was categorized as 0 (reference), 1-2, 3-4, or ≥5. Progressively adjusted linear regression models were used to evaluate the association of parity categories with log-transformed levels of testosterone (T), estradiol (E2), sex-hormone binding globulin (SHBG), dehydroepiandrosterone (DHEA), and testosterone to estradiol (T/E2) ratio. Results: Mean (SD) age at the baseline MESA visit was 65 (9) years. Median sex hormone levels by parity group are shown in the Table . There were no significant associations of parity with E2, DHEA, and SHBG levels in multivariable-adjusted models. Compared to nulliparity, women with 1-2 and 3-4 live births had higher testosterone levels even after adjustment for CVD risk factors, but this was not significant for ≥5 live births. On the other hand, grand multiparity (≥5 live births) was associated with a higher T/E2 ratio compared to nulliparity, even after full covariate adjustment including demographics, lifestyle factors, CVD risk factors and medications. Conclusions: In a multiethnic US cohort of women, a history of grand multiparity is associated with a more androgenic sex hormone profile defined by higher T/E2 ratio at middle to older ages. The clinical significance of this is uncertain. Further longitudinal studies evaluating whether sex hormones influence the relationship between multiparity and CVD are warranted.
Abstract 16575: Synthetic TBX18 mRNA Induces Durable Reprogramming of Cardiac Myocytes to Pacemaker Cells
Authors: David W Wolfson, Nadine Zureick, Natasha Fernandez, Jared Beyersdorf, Christina Sheng, Sung Jin Park, Philip Santangelo, Hee Cho
Journal: Circulation (2020)

Introduction: Adenoviral gene delivery of transcription factor, TBX18, has been proven to reprogram ordinary cardiomyocytes to pacemaker cells, and provide ventricular pacing in the rodent and porcine heart. Yet host innate immune response to recombinant viral therapies remains a hurdle to overcome for successful translation. Somatic cell reprogramming does not require persistent expression of the reprogramming factors after arriving at the final cell fate. We hypothesized that brief expression of synthetic TBX18 mRNA suffices to convert chamber cardiomyocytes to induced pacemaker cells, thus obviating issues inherent to adenoviral gene therapy. Methods: Synthetic mRNAs were in vitro transcribed as previously described. Neonatal rat ventricular myocytes (NRVMs) were used as an in vitro platform to test pacemaker reprogramming by TBX18 mRNA. GFP or fLuc encoded mRNA was used as controls in all experiments. Results: Three days after synthetic TBX18 mRNA transfection, Hcn4 transcript level increased &gt;6-fold compared to control. After two weeks, genes enriched in the pacemaker tissue, e.g., Shox2, Hcn4, and Tbx3, continued to be expressed higher in TBX18-NRVMs compared to control by &gt;4.2-fold. The level of endogenously expressed, rat Tbx18 increased by 50% in NRVMs transfected with synthetic human TBX18 mRNA, which point to long-term reprogramming. To identify and lineage-trace reprogrammed pacemaker cells in real time, we cultured ventricular cardiomyoytes from transgenic mouse line Hcn4 ( GFP/+ ) , in which de novo pacemaker cells expressing Hcn4 contain eGFP fluorescence. Twelve days after synthetic mRNA or adenoviral gene transfer of TBX18 or GFP control, a significantly higher number of Hcn4 ( GFP/+ ) cells were observed in both mRNA and adenoviral TBX18-treated wells compared to their respective controls. TBX18 mRNA-transfected NRVM monolayers exhibited &gt;2-fold slower conduction velocities compared to fLuc-transfected myocytes. In line with slow conduction velocity in the induced pacemaker myocytes, expression of ventricular gap junction protein, Cx43, decreased significantly compared to control. Conclusions: Together, the data indicate durable nodal pacemaker cell reprogramming with transient expression of synthetic TBX18 mRNA.
喫煙誘発性の炎症におけるレクチン様酸化低密度リポ蛋白質受容体‐1(LOX‐1)の役割
Authors: Takanabe‐Mori Rieko, Ono Koh, Wada Hiromichi, Takaya Tomohide, Yamakage Hajime, Satoh‐Asahara Noriko, Shimatsu Akira, Takahashi Yuko, Fujita Masatoshi, Fujita Yoshiko, Sawamura Tatsuya, Hasegawa Koji
Journal: Circulation (2012)
Abstract 14835: Corona Virus Disease 2019 (covid-19) Myocarditis: Where and What is the Evidence?
Authors: Bibhuti B Das, Shriprasad R Deshpande
Journal: Circulation (2020)

Background and Objectives: Cardiac complications due to COVID-19 can occur either directly (myopericaridal involvement) or indirectly by the profound systemic inflammatory response and cytokine storm leading to cardiac dysfunction. No virus RNA has been detected in cardiac myocytes in patients with COVID-19 from China. Our objective is to analyze the COVID-19 myocarditis cases reported in literature to-date. Methods: We used terms COVID-19, myocarditis, and cardiac involvement in COVID-19 to perform a search for myocarditis cases due to COVID-19 in PUBMED. We found a total of 8 cases with a diagnosis of COVID-19 myocarditis and analyzed their clinical data as summarized in Table. Results: Age ranged from 21-69 years and 75% were male. Of eight COVID-19 myocarditis patients, 3/8(38%) had pre-existing cardiac issues, 5/7(71%) had abnormal electrocardiograms and decreased function by echocardiograms. Troponin and BNP levels were elevated in all cases. CMR was performed in 5 cases and showed myocardial edema in T2 mapping and late gadolinium enhancement suggesting scar/fibrosis in 100% cases. No endomyocardial biopsy or autopsy was performed except one case, who was dead on arrival and autopsy study showed eosinophilic myocarditis, not a typical finding of viral myocarditis. Overall outcomes were 2 deaths and 6 patients recovered. Conclusions: COVID-19 can cause direct myocardial injury but the evidence is extremely limited at this stage. Although serum markers and imaging suggest cardiac involvement, the pathogenesis and long term impact of COVID-19 on cardiovascular system is unknown. Evaluation for myocarditis by endomyocardial biopsies may be appropriate in selected cases when a treatable type of myocarditis is suspected (e.g. giant cell myocarditis) or unexplained severe bi-ventircular dysfunction or arhrhythmia with normal coronaries to confirm a definitive diagnosis of myocarditis and identify its cause to enable possible etiology-directed therapy.
Abstract 042: Do Disparities In Cardiovascular Comorbidities Account For Excess Covid-19 Morbidity And Mortality In African Americans?
Authors: Osama Dasa, Scott A Cohen, Yi Zheng, Ruba sajdeya, Mohamad B Taha, Hui Hu, Thomas A Pearson
Journal: Circulation (2021)

Introduction: COVID-19 incidence, severity, and death in African Americans (AA) has been reported to markedly exceed those of White Americans (WA), but the epidemiologic basis for this is unclear. Hypothesis: We hypothesize that AA have an excess of comorbid conditions compared to WA accounting for the disparity in COVID-19 infection and death. Methods: We examined 67,094 COVID-19 cases with laboratory-confirmed COVID-19 and compared them to 135,188 controls (2:1 match by age, sex, and zip code) representing a state-wide sample of healthcare recipients from the ‘OneFlorida’ research consortium through August 3, 2020. We assessed the prevalence of preexisting comorbid conditions (e.g. cardiovascular disease, cancer), behavioral risk factors, and health outcomes in the electronic health records of COVID-19 cases compared to controls. Results: Cases included 25,443 (37.9%) WA, 11,709 (17.5%) AA, and 16,119 (24%) Hispanic Americans (HA). Among cases, there was a significant increase in the prevalence of several cardiovascular comorbidities in AA vs. WA, such as hypertension, diabetes, heart failure, and stroke, but not for common cancers, liver disease, and COPD (Table 1). Likewise, smoking and BMI were higher in AA. Similar disparities were also appreciated in matched controls. Compared to WA, AA and HA had higher odds of becoming infected with COVID-19 (Unadjusted OR, 1.08; CI [1.05-1.11] and OR, 1.17; [1.15-1.2]) respectively. The prevalence of severe COVID-19 outcomes (intubation and death) was higher in AA (3.6 and 2.7%) than WA (2.5% and 2.3%) or HA (1.3 and 1.4%), respectively. Conclusions: Excess comorbidities for cardiometabolic diseases are present in this population-based sample of COVID-19 cases and controls. Careful mediation analyses will determine whether these differences in cardiovascular comorbidities alone account for disparities in COVID-19 in AA patients. Such data would be important to identify high-risk subgroups benefitting from enhanced preventive and early therapeutic interventions.
Abstract P035: Early Neurodevelopment Related Variables And Cardiovascular Health: Findings From The Multidimensional Assessment Of Preschoolers Study
Authors: Orna Reges, Xiaoyun Yang, Amy Krefman, Lauren Wakschlag, Rachel Flynn, Leigha MacNeill, Matthew Davis, Bradley S Marino, Darwin R Labarthe, Linda Van Horn, Lifang Hou, Donald M Lloyd-Jones, Norrina B Allen
Journal: Circulation (2021)

Background: Cardiovascular health (CVH) declines with age starting in early childhood. Neurodevelopmental health (NDH) measures, such as executive function, in early childhood have been associated with subsequent behavioral and lifestyle outcomes; however, little is known about the association of NDH measures in early life with CVH during childhood. Objective: To assess the association of preschool NDH with CVH in later childhood/early adolescence. Methods: Among participants from the Multidimensional Assessment of Preschoolers Study (MAPS), we defined 3 neurodevelopment domains at baseline (ages 3-7 years): executive functioning, developmental functioning, and emotion and behavior regulation (each as a z-score of its component surveys and direct assessment). At the tween follow-up wave (ages 9-14 years), MAPS participants completed a CVH examination including assessment of physical activity, diet, blood pressure, and BMI defined as favorable vs unfavorable CVH metrics according to AHA recommendations. Multivariate logistic regression models were used to assess the association of each NDH domain with favorable/unfavorable CVH metrics at follow up. Models were adjusted for age, race, gender, and poverty. Results: We included 229 SES-diverse children (46.2% boys; 52% living in poverty at baseline; mean baseline age 4.7 yr; mean follow-up age: 11.3 yr). At follow-up, there were 179 (78.2%) children with favorable CVH and 50 (21.8%) children with unfavorable CVH. Better performance on all 3 NDH domains at baseline was demonstrated among children with favorable CVH at follow-up compared to those with unfavorable CVH, with mean z-score of 0.04 among those with favorable CVH compared to -0.15 among those with unfavorable CVH for executive functioning (p&lt;0.001), 0.02 compared to -0.07 for developmental functioning (p=0.004), and 0.02 compared to -0.06 for emotion and behavior regulation (p=0.027). After adjustment, associations between executive functioning, developmental functioning, and emotion/behavior regulation and favorable CVH were attenuated to non-significance {OR (95% CI): 1.21 (0.80-1.81), 1.03 (0.64-1.67), 1.08 (0.73-1.59), respectively}. Conclusions: These findings suggest a possible association between neurodevelopmental domains and CVH, although findings were not significant after adjustment. The heterogeneity of the sample may have obscured effects and the moderating role of the environment may elucidate explanatory pathways. More research with larger sample sizes is needed to better understand the impact of early-life NDH with adolescent CVH.
Abstract 16828: Risk of Hematopoietic Cancer in Congenital Heart Diseased Children With or Without Genetic Syndromes
Authors: Mohammad Sazzad Hasan, Aihua Liu, Liming Guo, Elie Ganni, Jay S Kaufman, Ariane J Marelli
Journal: Circulation (2020)

Background: Individuals with genetic syndromes can manifest both congenital heart disease (CHD) and cancer due to possible common underlying pathways. However, reliable risk estimates of hematopoietic cancer (HC) among children with CHD based on large population-based data are scant. Method: We conducted a population-based analysis to estimate the cumulative incidence of HC in a cohort of children (0-18) born between 1999 and 2017 with at least one hospitalization records of CHD diagnosis or CHD-related procedural code. The data source was the Canadian Institute for Health Informatics-Discharge Abstract Database which regularly collects hospitalization and day surgery records in all Canadian provinces except Quebec, comprising over 30 million people. Hematopoietic cancer and syndromes were both identified by hospitalization diagnoses. We used modified Kaplan-Meier curve analysis to estimate the cumulative incidences [with 95% confidence intervals (CI)] up to 18 years of age, with death as a competing risk and stratified by the binary indicator of genetic syndrome status. Result: We followed 92815 CHD children from birth for 921,866 person-years. In this study population,10.5% had genetic syndromes and 461 cases of HC were observed, yielding incidence rates of HC 22.5 (95% CI: 19.4-25.4) and 3.0 (2.6-3.3) per 10,000 person-years for children with and without genetic syndrome, respectively. Cumulative incidence of HC up to age 18 was 2.6% (95% CI: 2.2-2.9%) among children with a genetic syndrome, and 0.40% (0.34-0.46%) without the syndrome. It was higher in the first 6 years of life (2.1%) than the subsequent 6-years intervals up to adulthood (0.4% in 6-12 years and 0.2% in 12-18 years of age). Conclusion: This is the first population-based analysis documenting that genetic syndromes in CHD children are a powerful predictor of hematopoietic cancers. The finding is important in informing risk-stratified policy recommendations to protect CHD children from cancer.
Caspases and therapeutic potential of caspase inhibitors in moderate–severe SARS‐CoV‐2 infection and long COVID
Authors: Matthew Plassmeyer, Oral Alpan, Michael J. Corley, Thomas A. Premeaux, Kimberleigh Lillard, Paige Coatney, Tina Vaziri, Suzan Michalsky, Alina P. S. Pang, Zaheer Bukhari, Stephen T. Yeung, Teresa H. Evering, Gail Naughton, Martin Latterich, Philip Mudd, Alfred Spada, Nicole Rindone, Denise Loizou, Søren Ulrik Sønder, Lishomwa C. Ndhlovu, Raavi Gupta
Journal: Allergy (2021)

COVID-19 can present with lymphopenia and extraordinary complex multiorgan pathologies that can trigger long-term sequela.Given that inflammasome products, like caspase-1, play a role in the pathophysiology of a number of co-morbid conditions, we investigated caspases across the spectrum of COVID-19 disease.We assessed transcriptional states of multiple caspases and using flow cytometry, the expression of active caspase-1 in blood cells from COVID-19 patients in acute and convalescent stages of disease. Non-COVID-19 subject presenting with various comorbid conditions served as controls.Single-cell RNA-seq data of immune cells from COVID-19 patients showed a distinct caspase expression pattern in T cells, neutrophils, dendritic cells, and eosinophils compared with controls. Caspase-1 was upregulated in CD4+ T-cells from hospitalized COVID-19 patients compared with unexposed controls. Post-COVID-19 patients with lingering symptoms (long-haulers) also showed upregulated caspase-1activity in CD4+ T-cells that ex vivo was attenuated with a select pan-caspase inhibitor. We observed elevated caspase-3/7levels in red blood cells from COVID-19 patients compared with controls that was reduced following caspase inhibition.Our preliminary results suggest an exuberant caspase response in COVID-19 that may facilitate immune-related pathological processes leading to severe outcomes. Further clinical correlations of caspase expression in different stages of COVID-19 will be needed.Pan-caspase inhibition could emerge as a therapeutic strategy to ameliorate or prevent severe COVID-19.
Umbilical Cord Blood Metal Mixtures and Birth Size in Bangladeshi Children
Authors: Mi-Sun Lee, Ki-Do Eum, Mostofa Golam, Quazi Quamruzzaman, Molly L. Kile, Maitreyi Mazumdar, David C. Christiani
Journal: Environmental Health Perspectives (2021)

Studies have evaluated environmental exposure to toxic metals such as arsenic (As), cadmium (Cd), manganese (Mn), or lead (Pb) on birth size; however, information on potential effects of exposures to metal mixtures is limited.We assessed the association between metal mixtures (As, Cd, Mn, Pb) in umbilical cord blood and neonate size in Bangladeshi children.In this birth cohort study, pregnant women who were ≥18 years of age with an ultrasound-confirmed singleton pregnancy of ≤16wk gestation were recruited from two Bangladesh clinics between 2008 and 2011. Neonate size metrics were measured at the time of delivery. Metals in cord blood were measured using inductively coupled plasma mass spectrometry. We employed multivariable linear regression and Bayesian kernel machine regression (BKMR) to estimate associations of individual metals and metal mixtures with birth size parameters.Data from 1,088 participants was assessed. We found a significant negative association between metal mixture and birth length and head circumference when all metal concentrations were above the 60th and 55th percentiles, respectively, compared with the median. An interquartile range (IQR) increase in log Cd concentration {log[Cd (in micrograms per deciliter)] IQR=2.51} was associated with a 0.13-standard deviation (SD) decrease in mean birth length (95% CI: -0.25, -0.02) and a 0.17-SD decrease in mean head circumference (95% CI: -0.28, -0.05), based on linear regression models adjusted for covariates and the other metals. An IQR increase in log Mn concentration {log[Mn (in micrograms per deciliter)] IQR=0.69} was associated with a 0.07-SD decrease in mean birth weight (95% CI: -0.15, 0.002).Metal mixtures in cord blood were associated with reduced birth size in Bangladeshi children. Results from linear regression models adjusted and the BKMR mixtures analyses suggest adverse effects of Cd and Mn, as individual metal exposures, on birth size outcomes. https://doi.org/10.1289/EHP7502.
Tenascin-C, a novel target to inhibit new bone formation in axial spondyloarthritis, linked with inflammation, mechanical strain and tissue damage
Authors: Margot Van Mechelen, Rik Lories
Journal: Annals of the Rheumatic Diseases (2021)

Axial spondyloarthritis is a chronic inflammatory musculoskeletal disease hallmarked by the paradoxical co-occurrence of inflammation, trabecular bone loss in the vertebrae and new bone formation with syndesmophyte growth potentially leading to spinal fusion or ankylosis. All these features can contribute to the burden of disease: pain, fatigue and loss of mobility and function.1 State of the art effective treatment strategies such as tumour necrosis factor (TNF) and interleukin (IL)-17 inhibitors focus on barring inflammation, but whether these approaches suffice to halt the bone remodelling aspects of the disease that determine the ultimate prognosis of patients is still debated.1 Long-term studies indicate that sustained suppression of inflammation impacts structural disease progression.2 Yet, the high individual variability in the ankylosis process suggests that there is an unmet need for early direct intervention in high risk or rapidly progressing patients.3 Anatomy and imaging studies demonstrate that spinal ankylosis originates from pathological changes in the enthesis, the insertion sites of ligaments and tendons onto the bone. Former studies highlighted how growth factor pathways that are essential in skeletal development and growth, are inappropriately reactivated in the ankylosis process.4 5 However, targeting signalling systems such as the bone morphogenetic protein and Wnt cascades comes with important considerations about impact on other tissues and organs.

More attractive therapeutic targets may be found in earlier and specific disease processes, an area that remains largely unexplored. In this journal, Li et al identify tenascin-C (TNC) as a key driver of new bone formation originating from the enthesis, and mechanistic experiments intriguingly position this extra-cellular matrix molecule as a converging node between inflammation, mechanical strain, tissue damage and new bone formation.6 TNC is a glycoprotein with a number of remarkable features as extensively discussed by Midwood et al . …
Treatment timing and the effects of rhythm control strategy in patients with atrial fibrillation: nationwide cohort study
Authors: Daehoon Kim, Pil-Sung Yang, Seng Chan You, Jung-Hoon Sung, Eunsun Jang, Hee Tae Yu, Tae-Hoon Kim, Hui-Nam Pak, Moon-Hyoung Lee, Gregory Y H Lip, Boyoung Joung
Journal: BMJ (2021)

Abstract Objective To investigate whether the results of a rhythm control strategy differ according to the duration between diagnosis of atrial fibrillation and treatment initiation. Design Longitudinal observational cohort study. Setting Population based cohort from the Korean National Health Insurance Service database. Participants 22 635 adults with atrial fibrillation and cardiovascular conditions, newly treated with rhythm control (antiarrhythmic drugs or ablation) or rate control strategies between 28 July 2011 and 31 December 2015. Main outcome measure A composite outcome of death from cardiovascular causes, ischaemic stroke, admission to hospital for heart failure, or acute myocardial infarction. Results Of the study population, 12 200 (53.9%) were male, the median age was 70, and the median follow-up duration was 2.1 years. Among patients with early treatment for atrial fibrillation (initiated within one year since diagnosis), compared with rate control, rhythm control was associated with a lower risk of the primary composite outcome (weighted incidence rate per 100 person years 7.42 in rhythm control v 9.25 in rate control; hazard ratio 0.81, 95% confidence interval 0.71 to 0.93; P=0.002). No difference in the risk of the primary composite outcome was found between rhythm and rate control (weighted incidence rate per 100 person years 8.67 in rhythm control v 8.99 in rate control; 0.97, 0.78 to 1.20; P=0.76) in patients with late treatment for atrial fibrillation (initiated after one year since diagnosis). No significant differences in safety outcomes were found between the rhythm and rate control strategies across different treatment timings. Earlier initiation of treatment was linearly associated with more favourable cardiovascular outcomes for rhythm control compared with rate control. Conclusions Early initiation of rhythm control treatment was associated with a lower risk of adverse cardiovascular outcomes than rate control treatment in patients with recently diagnosed atrial fibrillation. This association was not found in patients who had had atrial fibrillation for more than one year.
A deep learning-based framework for segmenting invisible clinical target volumes with estimated uncertainties for post-operative prostate cancer radiotherapy
Authors: Anjali Balagopal, Dan Nguyen, Howard Morgan, Yaochung Weng, Michael Dohopolski, Mu-Han Lin, Azar Sadeghnejad Barkousaraie, Yesenia Gonzalez, Aurelie Garant, Neil Desai, Raquibul Hannan, Steve Jiang
Journal: Medical Image Analysis (2021)