tbuckley/cabot-search huggingface dataset:
Preterm Delivery and Long-Term Risk of Stroke in Women: A National Cohort and Cosibling Study
Authors: Casey Crump, Jan Sundquist, Kristina Sundquist
Journal: Circulation (2021)

Stroke has a high burden of disease in women, and adverse pregnancy outcomes have been identified as important risk factors for stroke later in life. However, long-term risks of stroke associated with preterm delivery and whether such risks are attributable to familial confounding are unclear. Such knowledge is needed to improve long-term risk assessment and stroke prevention in women.A national cohort study was conducted of all 2 188 043 women with a singleton delivery in Sweden in 1973 through 2015 who were followed up for stroke identified from nationwide diagnoses through 2015. Cox regression was used to compute adjusted hazard ratios (aHRs) for stroke associated with pregnancy duration, and cosibling analyses assessed for confounding by shared familial (genetic or environmental) factors.In 48.0 million person-years of follow-up, 36 372 (1.7%) women were diagnosed with stroke. In the 10 years after delivery, the aHR for stroke associated with preterm delivery (gestational age <37 weeks) was 1.61 (95% CI, 1.45-1.79) and further stratified was 2.81 (95% CI, 2.02-3.91) for extremely preterm (22-27 weeks), 2.07 (95% CI, 1.74-2.46) for very preterm (28-33 weeks), 1.38 (95% CI, 1.21-1.57) for late preterm (34-36 weeks), and 1.15 (95% CI, 1.06-1.24) for early term (37-38 weeks), compared with full-term (39-41 weeks) delivery. These risks remained similarly elevated at 10 to 19 years after delivery (preterm versus full-term: aHR, 1.61 [95% CI, 1.50-1.74]) and then declined but remained significantly elevated at 20 to 29 years (aHR, 1.35 [95% CI, 1.28-1.44]) and 30 to 43 years (aHR, 1.35 [95% CI, 1.27-1.42]). Preterm delivery was associated with both hemorrhagic (aHR, 1.31 [95% CI, 1.25-1.38]) and ischemic (aHR, 1.54 [95% CI, 1.47-1.61]) stroke across the entire follow-up period (up to 43 years). These findings were not explained by shared determinants of preterm delivery and stroke within families. Stroke risks were higher after either spontaneous or medically indicated preterm delivery, and recurrent preterm delivery was associated with further increases in risk.In this large national cohort, preterm delivery was associated with higher future risks of both hemorrhagic and ischemic stroke. These associations remained substantially elevated at least 40 years later, and were largely independent of covariates and shared familial factors. Preterm delivery should be recognized as a risk factor for stroke in women across the life course.
Abstract 13792: Associations Between Urinary Isoprostane Levels and Cardiovascular Risk Factors in the Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Amir S Heravi, Dhananjay Vaidya, Erin D Michos, Di Zhao, Bharath Ambale-Venkatesh, Henrique Doria De Vasconcellos, Donald M Lloyd-jones, Pamela Schreiner, Jared P Reis, Cora E Lewis, Stephen Sidney, Colin Wu, Chiadi E Ndumele, Eliseo Guallar, Pamela Ouyang, Ron C Hoogeveen, Joao A Lima, Wendy S Post
Journal: Circulation (2019)

Introduction: Oxidative stress has been linked to many cardiovascular diseases (CVD) and suggested to be higher in women than in men. However, few community cohorts have explored these associations...
Abstract 15621: Checkpoint Kinases Important Players in Lung Fibrogenesis and Pulmonary Vascular Remodeling: A Translational Study
Authors: Wenhui Wu, Geraldine Vitry, Valerie Nadeau, Junichi Omura, Mark Orcholski, David Marsolais, Eve Tremblay, Sandra Martineau, Sandra Breuils Bonnet, Roxane Paulin, Steeve Provencher, Olivier BOUCHERAT, Sebastien Bonnet
Journal: Circulation (2020)

Introduction: Pulmonary fibrosis (PF) is an important commonality in pathogenesis of interstitial lung diseases, and pulmonary hypertension (PH) is a well-recognized severe complication of PF. Both significantly impact patients’ survival and functional status, but without validated treatments. In the lung, parenchymal and vascular remodeling share pathomechanisms, mainly including excessive proliferation and resistance to apoptosis of fibroblasts (LFs) and pulmonary arterial smooth muscle cells (PASMCs). In cancer, sustained cell proliferation is ensured, in part, by a fine tuning of cell cycle and DNA repair machinery, of which checkpoint kinases (CHK1 and CHK2) are critical regulators. They are upregulated in cancer and their inhibition are currently tested in clinical trials. However, these pathways have never been explored in PF-PH. We thus hypothesized that CHK1/2 are upregulated in PF and contribute to both fibrotic and vascular lesions in PF-PH patients. Methods and Results: Increased DNA damage (γH2Ax and p(S4/S8)-RPA32) as well as augmented expression and activity of CHK1/2 was observed by WB in lung and isolated LFs from PF patients compared to controls (p&lt;0.05, n=8~15 per group) with marked expression in fibroblastic foci. Similarly, increased levels of CHK1/2 and DNA damage were detected by WB and IF in remodeled pulmonary arteries (PA) of PF patients with or without PH. Similar findings were noted in mice exposed to bleomycin. In isolated PF-LFs and PASMCs, dual inhibition of CHK1/2 using MK-8776 and LY2606368 significantly reduced expression of TCTP and RAD51 (two factors required for efficient DNA repair), leading to exacerbation of DNA damage and resulted in reduced cell proliferation (Ki67 labeling, WB PCNA) and resistance to apoptosis (Annexin V assay, WB Survivin). Furthermore, inhibition of CHK1/2 mitigated the hyper-activated state of PF-LFs, as illustrated by reduced expression of FN, CTGF, and pSTAT3 (WB). Similar results were observed in control LFs exposed to TGF-β1; all p&lt;0.05. Conclusions: Our data provide compelling evidence that CHK1/2 are involved in lung fibrogenesis and PA remodeling in PF. Current experiments aim to determine whether CHK1/2 inhibitors elicit beneficial effects in animal models of PF-PH.
How can I refocus on my career after the pandemic?
Authors: Abi Rimmer
Journal: BMJ (2021)

How can I refocus on my career after the pandemic?Working through an extremely difficult period has left some doctors with an opportunity to assess their career options.Abi Rimmer hears what next steps might be useful at this stage Abi Rimmer Think back to why you went into medicine Adam Harrison, doctor and career and leadership coach for doctors, says, "Reflect on what you want for your post-pandemic life.Really think about what your life as a whole is currently like and consider the impact your work is having on your non-working life.If anything was possible, how would your career ideally look in five years?
Abstract 15323: Patients With Heart Failure With Preserved Ejection Fraction Contend With Deficits Across Multiple Domains of Health
Authors: Pedram Navid, Kate Zarzuela, Mahad Musse, Marcos Wang, Birgit Siceloff, Ruth M Masterson Creber, Hooman Yaghoobzadeh, Mark Lachs, Monika M Safford, Parag Goyal
Journal: Circulation (2020)

Introduction: The domain management approach to caring for heart failure patients outlines the importance of considering deficits from multiple health domains including: medical, mental and emotional, physical, and social. The extent to which these deficits exist in patients with HFpEF is unknown. We sought to characterize deficits across multiple domains among patients seen in an outpatient HFpEF program. Hypothesis: We hypothesized that HFpEF patients would have a high prevalence of deficits across multiple domains. Methods: We conducted a retrospective study of 134 patients with HFpEF seen between July 2018 and December 2019 in the Weill Cornell HFpEF Program, which incorporates the domain management approach through several assessments. The medical domain includes an assessment of multimorbidity (≥ 2 comorbid conditions), polypharmacy (≥ 5 medications), malnutrition (Mini Nutritional Assessment &lt; 12), and hearing and vision impairment (self-report). The mental and emotional domain includes cognitive impairment (Mini-Cog &lt; 3), depression (PHQ-9 ≥ 10), and anxiety (GAD-7 ≥ 10). The physical function domain includes frailty (Short Physical Performance Battery &lt; 10), functional impairment (Katz Index &lt; 6), and fall within the past year (self-report). The social domain includes loneliness (UCLA 3-Item Loneliness Scale ≥ 6) and living situation (self-report). Results: The median age was 75 years (IQR 69-82), 60% were women, and 64% were White. The Figure shows the prevalence for each deficit across the four domains. The most common deficits were multimorbidity (100%), polypharmacy (98%), frailty (79%), and loneliness (62%). Notably, 13% of patients had deficits in all four domains, 31% in three domains, 47% in two domains, and 9% in one domain. Conclusions: HFpEF patients have deficits spanning multiple domains. This supports the importance of considering issues such as multimorbidity, polypharmacy, frailty, and loneliness when caring for these patients.
Avasopasem manganese synergizes with hypofractionated radiation to ablate tumors through the generation of hydrogen peroxide
Authors: Brock J. Sishc, Lianghao Ding, Taek-Keun Nam, Collin D. Heer, Samuel N. Rodman, Joshua D. Schoenfeld, Melissa A. Fath, Debabrata Saha, Casey F. Pulliam, Britta Langen, Robert A. Beardsley, Dennis P. Riley, Jeffery L. Keene, Douglas R. Spitz, Michael D. Story
Journal: Science Translational Medicine (2021)

Avasopasem manganese enhances tumor cell killing after ablative hypofractionated radiation through the generation of hydrogen peroxide.
ACE2 downregulation in olfactory mucosa: Eosinophilic rhinosinusitis as COVID‐19 protective factor?
Authors: Concepció Marin, Valeria Tubita, Cristóbal Langdon, Mireya Fuentes, María Jesús Rojas‐Lechuga, Antonio Valero, Isam Alobid, Joaquim Mullol
Journal: Allergy (2021)

Dr. Alobid has consulted for Sanofi, Novartis, GlaxoSmithKline, Menarini, and Mylan. Dr. Mullol has participated in advisory boards for, has received research grants from, or participated in speakers' bureaus for AstraZeneca, Genentech, GlaxoSmithKline, Glenmark, Menarini, Mitsubishi-TanabePharma, MSD, Viatris (Mylan-Meda Pharmaceuticals), Novartis, Procter & Gamble, Regeneron Pharmaceuticals, Inc., Sanofi-Genzyme, UCB Pharma, and UriachGroup. Dr. Marin, Dr. Tubita, Dr. Langdon, M. Fuentes, M.J. Rojas-Lechuga, and Dr. Valero declare that they have no relevant conflict of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Abstract 16230: Pulmonary Autograft Wall Stresses One Year After Ross Operation
Authors: Edgardo Alonso, Yue XUAN, Alexander Emmott, Zhongjie Wang, Shalni Kumar, Francois-Pierre Mongeon, Richard L Leask, Ismail El-Hamamsy, Liang Ge, Elaine E Tseng
Journal: Circulation (2020)

Introduction: The Ross procedure is an excellent option for children and young adults who need aortic valve replacement as this surgery can restore patient survival to that of a normal sex and aged-matched population. However, some patients experience aneurysmal formation during autograft remodeling and require reoperation. As the underlying biomechanics of autograft remodeling are unknown, we investigated patient-specific wall stresses in pulmonary autografts one year post-operatively to better understand systemic pressure-driven early autograft wall stresses. Methods: Ross patients (n=16) who underwent intraoperative collection of pulmonary root/aortic specimen, and subsequent one-year MRI follow-up were recruited. Patient-specific material properties from their tissue were experimentally determined and incorporated into autograft ± Dacron and ascending aorta finite element models. A multiplicative approach was used to account for pre-stress geometry from in-vivo MRI. Physiologic pressure loading was simulated with LS-DYNA software. Results: At systemic systole, first principal stresses were 567kPa (25-75% IQR, 485-675kPa), 809kPa (691-1219kPa), and 382kPa (334-413kPa) at autograft sinuses, sinotubular junction (STJ), and ascending aorta, respectively. Second principal stresses were 355kPa (320-394kPa), 360kPa (310-426kPa), and 184kPa (147-222kPa) at autograft sinuses, STJ, and ascending aorta, respectively. Mean autograft diameters were 38.3±5.3mm, 29.9±2.7mm, and 26.6±4.0mm at sinuses, STJ, and annulus, respectively. Conclusions: First principal stresses were mainly located at STJ, particularly when Dacron reinforcement was applied to constrain STJ dilatation. However, at one-year after the Ross operation, autograft dilatation was not seen despite elevated autograft wall stresses compared to their internal controls, the lower wall stresses in corresponding native distal ascending aorta. In this group of patients, higher risk of dilatation is expected in the sinuses and STJ if not constrained by Dacron than the corresponding ascending aorta. Future follow-up will elucidate the biomechanics of long-term autograft remodeling to develop predictive models for autograft dilatation.
Abstract MP13: Lipid Peroxidation And Inflammatory Response Differentiate With Changes In Liver Fat Among Obese Latino Youth Following Lifestyle Intervention
Authors: Armando Pena, Kiley B Vander Wyst, Erica Soltero, Micah Olson, Janiel Pimentel, Stephanie Ayers, William Knowler, Yolanda Konopken, Donald Patrick, Houchun Hu, Felipe Castro, Colleen Keller, Allison N Williams, Arlene D Fernandez, Gabriel Q Shaibi
Journal: Circulation (2021)

Introduction: Lipid peroxidation and inflammation are pivotal pathological processes involved in the progression of NAFLD, a prelude to cardiovascular disease. Lifestyle intervention is the cornerstone approach for preventing cardiometabolic disease among high-risk populations, yet studies have not examined the mechanisms by which lifestyle intervention may mediate changes in liver fat in youth. Hypothesis: Lifestyle intervention will decrease hepatic fat fraction (HFF), tumor necrosis alpha (TNF)-α, and malondialdehyde (MDA)-protein adducts. Methods: Latino youth with obesity (n=26, age 13.9±1.3, BMI% 98.1±1.1) and prediabetes completed a 6-month lifestyle intervention that included nutrition education (1 d/wk) and physical activity (3 d/wk). HFF was measured by MRI before and after intervention. Fasting serum samples were collected for measurement of lipid peroxidation, measured by MDA-protein adducts, and inflammation, measured by TNF-α. Repeated measures ANOVA models were used to examine the effect of lifestyle intervention on HFF, MDA-protein adducts, and TNF-α. Data are presented as Mean±SE. Results: The intervention led to significant decreases in HFF (from 7.0±1.1% to 5.4±0.7%, p=0.027) and TNF-α (from 1.7±1.0 to 1.5±0.1 pg/mL, p=0.050), but not MDA-protein adducts (from 266.4±28.4 to 253.8±29.3 pmol/mL, p=0.105). However, there was significant heterogeneity in changes in HFF whereby those with the greatest response (n=14) decreased HFF by -44.0% while non-responders (n=12) increased HFF by 67.5%. HFF responders exhibited significantly greater reductions in MDA-protein adducts (from 256.2±39.4 to 228.1±40.0 pmol/mL, Δ-10.1%) compared to HFF non-responders (from 278.4±42.5 to 283.7±43.2 pmol/mL, Δ2.0%; p=0.023). TNF-α was reduced in HFF responders (from 1.8±0.2 to 1.5±0.1 pg/mL, Δ-17.8%) compared to HFF non-responders (from 1.5±0.2 to 1.5±0.1 pg/mL, Δ-4.4%) but was not significant (p=0.231). Conclusions: Reductions in HFF through lifestyle changes were associated with greater reductions in markers of lipid peroxidation, but not inflammation. The effect of lifestyle intervention on HFF may be mediated by markers that extend beyond traditional clinical risk factors among high-risk youth.
Abstract 12638: Autophagy-mitophagy Induction Improves Cardiovascular Inflammation in a Murine Model of Kawasaki Disease Vasculitis
Authors: Stefanie Marek-iannucci, Angela Gomez, Debbie Moreira, Malcolm Lane, Rebecca Porritt, Youngho Lee, Kenichi Shimada, Timothy R Crother, Magali Noval Rivas, Moshe Arditi
Journal: Circulation (2020)

Kawasaki Disease (KD), an acute febrile illness and systemic vasculitis of unknown etiology, is the leading cause of acquired heart disease among children. Recent experimental data from mouse models, as well as clinical, genetic and transcriptome evidence from KD patients suggest a key role of the NLRP3-IL-1β pathway in the pathogenesis of KD. NLRP3 can be activated by mitochondrial (mt) DNA released in the setting of defective autophagy/mitophagy, but a potential role for autophagy/mitophagy in KD cardiovascular inflammation has not been determined. In the Lactobacillus casei cell wall extract (LCWE) mouse model of KD vasculitis, LCWE injection in WT mice results in coronary arteritis, aortitis and myocarditis, mimicking human KD. We found that expression of the autophagy/mitophagy markers Parkin and p62 was significantly higher in whole lysate and mitochondrial fractions of heart tissue of LCWE-injected mice than controls, indicating impaired autophagic flux and mitophagy. Parkin -/- mice developed significantly more LCWE-induced cardiovascular lesions than control mice, and treatment of WT mice with a GLP-1 receptor agonist, known to activate Parkin, significantly reduced LCWE-induced inflammation. LCWE-induced cardiovascular lesions were amplified in mice deficient in OGG1, a base excision repair protein sensitive to mtDNA damage. Finally, inhibiting autophagy with chloroquine exacerbated LCWE-induced KD vasculitis, whereas inducing autophagy by intermittent fasting decreased cardiovascular inflammation in the model. Altogether, our data suggest that impaired autophagy/mitophagy exacerbates KD and supports a role for mtDNA damage in the disease. These findings enhance our understanding of KD pathogenesis and may provide novel therapeutic targets.
Abstract 12613: Patient-reported Outcomes in a Multidisciplinary Electrophysiology-psychology Ventricular Arrhythmia Clinic
Authors: Andrew Nguyen, John Dornblaser, Andrew Gray, Karen Paladino, Adrienne Kovacs, Babak Nazer
Journal: Circulation (2020)

Background: Ventricular arrhythmias (VAs) and their treatment have been associated with psychological distress and poorer quality of life (QOL) in research studies. Patient-reported outcome (PRO) measures are beginning to be introduced in clinical settings and early experiences with their clinical utility warrant attention. We wanted to describe PROs of patients attending a multidisciplinary VA clinic in order to elucidate roles that PRO measures might have in clinical settings. Methods: In this retrospective study, we enrolled patients with history of sustained VA and/or ICD shock at their initial visit to a clinic staffed by an electrophysiologist and a psychologist. Patients completed several PRO measures including the following: anxiety and depression symptoms, visual analog scales for health status and QOL, cardiac device acceptance, ICD shock anxiety, and general cardiac anxiety. Here we report total scores for general PROs and item-level analysis of the three cardiac-specific measures. Results: A total of 57 patients (56 ±15 years; 84% male) were included; 39% had a history of sudden cardiac arrest, 70% had prior ICD shock and 44% had previously undergone VA ablation. Symptoms that exceeded clinical thresholds were common for anxiety (49%) and depression (20%). On 0-100 visual analogue scales, the mean rating for health status was 57 ± 16 and for QOL was 66 ± 18. Item-level analysis of cardiac-specific PROs revealed that between 40% and 50% of patients endorsed specific concerns regarding return to work, resumption of physical activities, and sexual relations (Table 1). Conclusion: Among patients attending a VA clinic, elevated symptoms of anxiety and depression were common and self-reported health status and QOL were low. Although PRO total scores provided general information, review at the individual item level provided critical information about potential sources of anxiety that can guide cardiologists during discussions with patients.
MAP3K7 Is Recurrently Deleted in Pediatric T-Lymphoblastic Leukemia and Affects Cell Proliferation Independently of NF-κB
Authors: David M. Cordas dos Santos, Juliane Eilers, Alfonso Vizcaino, Elena Orlova, Martin Zimmermann, Martin Stanulla, Martin Schrappe, Kathleen Börner, Dirk Grimm, Martina Muckenthaler, Andreas E. Kulozik, Joachim B. Kunz
Journal: Blood (2017)
FDG-PET Utilizing Deauville Scoring Is Superior to Conventional Imaging for Staging and Response Assessment in Pediatric and Adult Patients with Nodular Lymphocyte Predominant Hodgkin's Lymphoma
Authors: M S Rauf, Z A Khan, M N Zahir, Suleimman Al-Sweedan, Amani Al-Kofide, Hannan Alharthy, Fahad A Almugbel, Asif Osmani, Irfan Maghfoor, Saad Akhtar
Journal: Blood (2017)
Abstract 15355: Interleukin-1beta Inhibition Attenuates Accelerated Atherosclerosis in Mice With <i>Tet2</i> Loss of Function in a Sex-dependent Fashion
Authors: Amelie Vromman, Shamsudheen Vellarikkal, Mariana Janini Gomes, Victoria Ruvkun, Eugenia Shvartz, Eva Kritikou, Paul Carter, Samuel Moscavitch, Tetsushi Nakao, Rob Sellar, Marie McConkey, Grasiele Sausen, Waihay Wong, Yevgenia Tesmenitsky, Shah Kavi, Andrew H Lichtman, Benjamin Ebert, Galina K Sukhova, Rajat Gupta, Peter Libby
Journal: Circulation (2020)

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) describes somatic mutations of bone marrow derived blood cells in the absence of overt hematological disease. CHIP correlates with aging and atherosclerotic cardiovascular diseases in humans. Tet2 mutations, common in CHIP, augment atherosclerosis. Tet2 -deficient macrophages over-express Interleukin-(IL)1β mRNA in response to LDL. IL-1β neutralization reduces recurrent events in patients post myocardial infarction with residual inflammatory risk.We previously showed that IL-1β neutralization reduces evolution of established mouse atherosclerosis. Hypothesis: This study tested the hypothesis that IL-1β neutralization will reduce early accelerated atherosclerosis caused by Tet2 deficiency in hematopoietic cells. Methods: We transplanted lethally irradiated LDL-R -/- atherosclerotic prone mice with either Tet2 +/+ or Tet2 - /- bone marrow cells. Chimeric mice consumed a western diet and received a selective anti-mouse IL-1β monoclonal antibody or isotype-matched control. After nine weeks of treatment, we analyzed atherosclerotic lesions morphologically and by single cell mRNA analysis. Results: IL-1β neutralization reduced accelerated atherosclerosis associated with Tet2 deficiency in female but not in male mice (Table). Single cell RNA-sequencing analysis of the dissociated aortic arch revealed differences in macrophage expression of genes involved in innate immune response interleukin signaling pathways between male and female mice. Conclusions: This unexpected sex-dependence of accelerated atherogenesis in Tet2 - /- bone-marrow mice on IL-1β signaling lays the ground for further mechanistic exploration.