tbuckley/cabot-search huggingface dataset:
Association of Early-Life Trauma and Risk of Adverse Cardiovascular Outcomes in Young and Middle-aged Individuals With a History of Myocardial Infarction
Authors: Zakaria Almuwaqqat, Matthew Wittbrodt, An Young, Bruno B. Lima, Muhammad Hammadah, Mariana Garcia, Lisa Elon, Bradley Pearce, Yingtian Hu, Samaah Sullivan, Puja K. Mehta, Emily Driggers, Ye Ji Kim, Tene` T. Lewis, Shakira F. Suglia, Amit J. Shah, J. Douglas Bremner, Arshed A. Quyyumi, Viola Vaccarino
Journal: JAMA Cardiology (2020)

<h3>Importance</h3> Compared with older patients, young adults with a history of myocardial infarction (MI) tend to have a higher burden of psychosocial adversity. Exposure to early-life stressors may contribute to the risk of adverse outcomes in this patient population, potentially through inflammatory pathways. <h3>Objective</h3> To investigate the association of early-life trauma with adverse events and examine whether inflammation plays a role. <h3>Design, Setting, and Participants</h3> This cohort study included patients aged 18 to 60 years with a verified history of MI in the past 8 months from a university-affiliated hospital network. Baseline data were collected from June 2011 to March 2016, and follow-up data were obtained through July 2019. Analysis began September 2019. <h3>Exposures</h3> Early-life trauma was assessed using the Early Trauma Inventory–Self Report short form (ETI-SR-SF), both as a continuous and as a binary variable at the threshold of a score of 7 or higher. Inflammatory biomarkers, interleukin 6, and C-reactive protein were obtained at baseline. <h3>Main Outcomes and Measures</h3> A composite end point of recurrent MI, stroke, heart failure hospitalization, and cardiovascular death over a median 3-year follow-up. <h3>Results</h3> Of 300 patients, the mean (SD) age was 51 (7) years, 198 (66%) were African American, and 150 (50%) were women. Compared with participants with MI with an ETI-SR-SF score less than 7, those with a score of 7 or higher had higher levels of interleukin 6 and C-reactive protein at baseline. Compared with participants with an ETI-SR-SF score less than 7, those with a score of 7 or higher were at a greater risk for adverse outcomes, with a hazards ratio of 2.3 (95% CI, 1.3-3.9). Results remained consistent in multivariable analysis. Further adjustment for C-reactive protein rendered the results no longer statistically significant. Early-life trauma displayed a dose-dependent response when analyzed as a continuous variable and by quartiles. <h3>Conclusions and Relevance</h3> Early-life trauma is an independent risk factor for adverse outcomes in young and middle-aged individuals with a history of MI. Neurobiological mechanisms leading to lifetime activation of systemic inflammatory cascades may be implicated.
Abstract 16744: MR Lymphatic Burden in Fontan Correlates With Outcomes
Authors: Aswathy Vaikom House, Dawn R David, Julien Aguet, Anne I Dipchand, Osami Honjo, Emilie M Jean-st-michel, Mike Seed, Shi-Joon Yoo, David Barron, Christopher Z Lam
Journal: Circulation (2020)

Introduction: The importance of the lymphatic circulation in Fontan physiology is incompletely understood and may have implications in Fontan ‘failure’. Non-invasive imaging of the lymphatic system with heavily T2-weighted MRI sequences could be a useful tool for patient surveillance and prognostication. We sought to quantify lymphatic burden in Fontan patients and correlate with clinical status. Methods: Consecutive pediatric Fontan patients, &lt;18 years-old with clinical cardiac MRI that had routine acquisition of lymphatic 3D T2 FSE imaging performed from May 2017 to Oct 2019 were included. ‘Lymphatic burden’ was quantified by thresholding-based segmentation of the 3D T2 FSE maximum intensity projection image (fig), generating a surrogate measurement of lymphatic volume, and was performed by 2 independent readers blinded to patient status. Spearman correlation and Mann-Whitney tests were used. Results: There were 48 patients (27 males) with median age at MRI of 12.9 (9.4-14.7) years, age at Fontan of 3.3 (2.9-3.8) years, and time from Fontan at MRI of 9.2 (5.9-10.4) years. Inter-rater agreement for lymphatic burden was excellent (ICC 0.96 [0.94-0.98]). Greater lymphatic burden correlated with hospital length of stay and duration of chest tube drainage post-Fontan (r =0.423, p=0.003 and r=0.419, p=0.003). Median lymphatic burden was greater in patients that had chylous effusions post-Fontan (286 (157-492) ml vs 123 (60-271) ml, p=0.011) and in patients with composite adverse outcome (n=12) defined by heart failure (n=3), transplant assessment (n=2), recurrent effusions (n=8), Fontan thrombus (n=2), and/or PLE (n=6) post-Fontan; (458 (266-2016) ml vs 130 (272-256) ml, p=0.005). Pre-Fontan mean PA pressure and time from Fontan did not correlate with lymphatic burden (r=0.062, p=0.676 and r=0.139, p= 0.343). Conclusion: Quantification of MR lymphatic burden is a reliable tool to assess lymphatic status post-Fontan and is associated with clinical outcomes.
Serum glucose excretion after Roux-en-Y gastric bypass: a potential target for diabetes treatment
Authors: In Gyu Kwon, Chan Woo Kang, Jong-Pil Park, Ju Hun Oh, Eun Kyung Wang, Tae Young Kim, Jin Sol Sung, Namhee Park, Yang Jong Lee, Hak-Joon Sung, Eun Jig Lee, Woo Jin Hyung, Su-Jin Shin, Sung Hoon Noh, Mijin Yun, Won Jun Kang, Arthur Cho, Cheol Ryong Ku
Journal: Gut (2020)

The mechanisms underlying type 2 diabetes resolution after Roux-en-Y gastric bypass (RYGB) are unclear. We suspected that glucose excretion may occur in the small bowel based on observations in humans. The aim of this study was to evaluate the mechanisms underlying serum glucose excretion in the small intestine and its contribution to glucose homeostasis after bariatric surgery.2-Deoxy-2-[18F]-fluoro-D-glucose (FDG) was measured in RYGB-operated or sham-operated obese diabetic rats. Altered glucose metabolism was targeted and RNA sequencing was performed in areas of high or low FDG uptake in the ileum or common limb. Intestinal glucose metabolism and excretion were confirmed using 14C-glucose and FDG. Increased glucose metabolism was evaluated in IEC-18 cells and mouse intestinal organoids. Obese or ob/ob mice were treated with amphiregulin (AREG) to correlate intestinal glycolysis changes with changes in serum glucose homeostasis.The AREG/EGFR/mTOR/AKT/GLUT1 signal transduction pathway was activated in areas of increased glycolysis and intestinal glucose excretion in RYGB-operated rats. Intraluminal GLUT1 inhibitor administration offset improved glucose homeostasis in RYGB-operated rats. AREG-induced signal transduction pathway was confirmed using IEC-18 cells and mouse organoids, resulting in a greater capacity for glucose uptake via GLUT1 overexpression and sequestration in apical and basolateral membranes. Systemic and local AREG administration increased GLUT1 expression and small intestinal membrane translocation and prevented hyperglycaemic exacerbation.Bariatric surgery or AREG administration induces apical and basolateral membrane GLUT1 expression in the small intestinal enterocytes, resulting in increased serum glucose excretion in the gut lumen. Our findings suggest a novel, potentially targetable glucose homeostatic mechanism in the small intestine.
Abstract 12715: Administration of Activated Protein C Stabilizes Membrane EPCR and Increases Resistance of Heart to Ischemic Insult in Aging
Authors: Di Ren, Julia Fedorova, Jingwen Zhang, Zhibin He, Ji Li
Journal: Circulation (2020)

Introduction: Activated protein C (APC) is a circulating protease with anti-coagulant property. Endothelial protein C receptor (EPCR) mediates APC's downstream events. We have revealed that APC exerts cardioprotective effects during ischemia and reperfusion (I/R). Hypothesis: There is an impaired APC signaling in aging and administration of APC restores APC signaling of aged heart to improve cardiac tolerance to ischemic insult caused by I/R stress. Methods: Young C57BL/6J (3-4 months), aged C57BL/6J (24-26 months), and EPCR R84A/R84A (3-4 months, C57BL6/J background) transgenic mice without APC binding affinity were subjected to ischemia (45 min) and reperfusion (24 hrs) by ligation/release of left anterior descending coronary artery. APC, signaling selective APC-2Cys, or anticoagulant selective APC-E170A was injected through jugular vein five-minutes before reperfusion. Results: I/R stress triggers APC signaling in both young and aged hearts, but APC activity was significantly impaired in the aged versus young hearts. Serum EPCR measurement demonstrated that membrane EPCR's shedding into circulation was dramatically promoted during I/R stress. Intriguingly, administration of APC significantly reduced EPCR shedding caused by I/R stress in both young and aged hearts but not EPCR R84A/R84A heart. The echocardiography data showed that APC and APC-2Cys but not APC-E170A ameliorated cardiac dysfunction by I/R insult in both young and aged mice. Interestingly, APC and APC-2Cys restored aged heart's resistance to a comparable level as young heart to ischemic damage. The cardioprotective effects of APC and ACP-2Cys are diminished in EPCR R84A/R84A mice. Furthermore, metabolomics analysis and working perfusion heart results demonstrated that AMP-activated protein kinase (AMPK) signaling mediates acute adaptive metabolic response while protein kinase B (Akt) signaling pathway is involved in chronic metabolic programming in the heart with APCs treatments. Conclusions: I/R stress causes membrane EPCR shedding in the heart and APC's cardioprotection against I/R injury is not related with its anti-coagulant activity. Administration of APC prevents I/R-induced cardiac EPCR shedding that is critical for limiting cardiac damage in aging.
Abstract 14576: Durability of Valve-sparing Tetralogy of Fallot Repair
Authors: Elizabeth H Stephens, Bryan L Wolfe, Abhinav A Talwar, Angira Patel, Joseph Camarda, Osama Eltayeb, Michael Monge, Joseph M Forbess
Journal: Circulation (2020)

Introduction: While valve-sparing repair is ideal for Tetralogy of Fallot (TOF), it’s durability and which patients may benefit from a transannular patch remains unclear. To this end, we reviewed our experience with valve-sparing TOF repair. Methods: Retrospective review was performed of all primary TOF operations at our institution from 1/2008 to 12/2018. Standard demographic, operative, and echo data were collected, along with clinical outcomes. Transannular patch and valve-sparing repair groups were then compared. Results: Sixty-eight patients underwent TOF repair with a mean age of 4.1±2.2 months and weight of 5.7±1.8 kg. There was no difference in age or weight between patients who underwent a transannular patch repair and valve-sparing repair (Table). There was also no difference in the frequency of hypercyanotic spells or beta-blocker use. As expected the pre-operative pulmonary valve size and z-score were significantly different between groups. Bypass times were longer in the transannular patch group (176±40 vs. 144±40 minutes, p=0.005). There were no differences in post-operative complications. At last follow-up (median 41.5 months) there was a trend of a higher peak pulmonary valve gradient (p=0.07) in the valve-sparing group, but no difference in pulmonary valve annulus z-scores. Additionally, the pulmonary valve z-scores in the valve-sparing group decreased from -2.3±1.0 on pre-discharge echocardiogram to -1.2±1.6 on last follow-up, with the peak gradient on pre-discharge 20 (33) mmHg stable on last follow-up at 18 (29) mmHg and degree of pulmonary regurgitation stable. There was one reoperation in the cohort: a pulmonary valve replacement in a patient who had undergone a transannular patch repair 6 years prior. Conclusions: Valve-sparing TOF patients demonstrated stable repairs with pulmonary valve growth, acceptable gradients, minimal regurgitation, and high freedom from re-intervention during follow-up.
PREVALENCE OF ELEVATED LIVER ENZYMES IN PATIENTS WITH NOVEL CORONAVIRUS DISEASE (COVID-19) INFECTION AND THEIR CLINICAL CHARACTERISTICS AND OUTCOMES
Authors: A. Krishnan, L. Prichett, X. Tao, A. T. Strauss, A. Kim, J. P. Hamilton, J. J. Potter, S. Alqahtani, P. H. Chen, T. A. Woreta
Journal: Hepatology (2020)

Background: Coronavirus disease 2019 (COVID-19) is an unprecedented global pandemic caused by the novel betacoronavirus SARS-CoV-2 Extrapulmonary clinical features such as abnormal liver enzymes are often present, and almost 50% of patients experienced different degrees of liver injury in studies from China However, the prevalence of elevated liver enzymes and the association with clinical outcomes in U S based cohorts have not been well studied Aims: 1 ) To assess the prevalence of elevated liver enzymes in patients with COVID-19 in a U S based cohort 2 ) To compare differences in clinical characteristics and outcomes in patients with and without elevated alanine aminotransferase (ALT) Methods: In this retrospective cohort study, we analyzed data from patients hospitalized at the Johns Hopkins Health System (JHHS) between February 1, 2020, and July 1, 2020, who tested positive for SARSCoV- 2  Identified COVID-19 patients were then stratified into two groups, those with elevated ALT (>35 U/L for men and > 25 U/L for women) at admission or subsequently and thosewith normal ALT Pearson's chi-squared test and analysis of variance and were used to compare variables between the two groups Clinical outcomes assessed included the need for mechanical ventilation or vasopressor support, hospital length of stay (LOS), and mortality Results: During the study period, 2293 patients with COVID-19 were hospitalized at JHHS The mean age was 60 (SD 17 7) years;52 5% were men 35 6% were black, 31 2% white, and 26 3% Hispanic 33 7% were obese;1479 (64 5%) had abnormal liver ALT values Compared to those with normal ALT, patients with elevated ALT were more likely to be non-white (72 3% vs 61 9%, p < 0 001), Hispanic (30 4% vs 18 5%, p < 0 001), obese (43 7% vs 34 2%, p < 0 001), and have underlying liver disease (7 1% vs 3 0%, p < 0 001) Those with elevated ALT more often required mechanical ventilation (23 7% vs 6 0%, p < 0 001) and vasopressor support (23 0% vs 7 2%, p < 0 001) The group with elevated ALT had a longer hospital LOS (11 0 vs 5 9 days, p < 0 001) However, there were no differences in mortality found between the two groups (13 8% vs 15 6%, p = 0 3) Conclusion: There was a high prevalence of elevated ALT among inpatients with COVID-19 (64 5%) The presence of elevated ALT was associated with adverse clinical outcomes, including the need for mechanical ventilation and vasopressor support and prolonged hospital LOS
Uptake and trafficking of different sized PLGA nanoparticles by dendritic cells in imiquimod-induced psoriasis-like mice model
Authors: Zibei Lin, Long Xi, Shaokui Chen, Jinsong Tao, Yan Wang, Xin Chen, Ping Li, Zhenping Wang, Ying Zheng
Journal: Acta Pharmaceutica Sinica B (2020)

Psoriasis is an autoimmune inflammatory disease, where dendritic cells (DCs) play an important role in its pathogenesis. In our previous work, we have demonstrated that topical delivery of curcumin-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) could treat Imiquimod (IMQ)-induced psoriasis-like mice. The objective of this study is to further elucidate biofate of PLGA NPs after intradermal delivery including DCs uptake, and their further trafficking in psoriasis-like mice model by using fluorescence probes. Two-sized DiO/DiI-loaded PLGA NPs of 50 ± 4.9 nm (S-NPs) and 226 ± 7.8 nm (L-NPs) were fabricated, respectively. In vitro cellular uptake results showed that NPs could be internalized into DCs with intact form, and DCs preferred to uptake larger NPs. Consistently, in vivo study showed that L-NPs were more captured by DCs and NPs were firstly transported to skin-draining lymph nodes (SDLN), then to spleens after 8 h injection, whereas more S-NPs were transported into SDLN and spleens. Moreover, FRET imaging showed more structurally intact L-NPs distributed in skins and lymph nodes. In conclusion, particle size can affect the uptake and trafficking of NPs by DCs in skin and lymphoid system, which needs to be considered in NPs tailing to treat inflammatory skin disease like psoriasis.
Abstract 14087: Psychosocial Determinants of Health Predict Depressive Symptoms and Anxiety in Rural Caregivers
Authors: Jennifer L Smith, Misook L Chung, Jennifer Miller, Martha J Biddle, Donna Schuman, Mary Kay Rayens, Terry A Lennie, Muna H Hammash, Gia Mudd-martin, Debra K Moser
Journal: Circulation (2020)

Introduction: Caregivers have an 82% increased risk of cardiovascular disease (CVD) compared to non-caregivers. Depressive symptoms (DS) and anxiety increase CVD risk, and these are worse in rural dwellers. Knowing predictors of DS and anxiety in rural caregivers of patients with chronic illness is important to reduce CVD risk. Purpose: To identify predictors of DS and anxiety in rural caregivers at risk for CVD using a social determinants of health (SDH) model. Method: In this cross-sectional study we measured multiple SDH. These variables included sociodemographic (i.e., age, gender, race, marital status, health insurance, education, financial status), behavioral (i.e., smoking and body mass index [BMI]), and psychosocial (i.e., caregiver burden measured by the Zarit Burden Interview, perceived stress by the Cohen Perceived Stress Scale, and social support by the Medical Outcomes Study Social Support Survey) factors. The outcomes of DS were measured by the Patient Health Questionnaire-9 and anxiety by the Brief Symptom Inventory – Anxiety subscale. Data were analyzed using two separate multiple regression models, one for DS and one for anxiety. As depression and anxiety are often comorbid, they were considered predictors in the appropriate models. Results: In the 262 participants (mean age 53±13, 78% female, 96% Caucasian, 70% were married), mean years of education were 14±2, 56.1% had enough money to make ends meet, and 55% had no insurance or Medicaid only. Significant predictors of worse DS were higher caregiver burden (β=0.05, p=0.004), higher perceived stress (β=2.04, p=0.001), and higher anxiety (β=3.79, p= &lt;0.001). Predictors of worse anxiety, were younger age (β=-0.006, p=0.03), higher caregiver burden (β=0.006, p=0.009), lower social support (β=-0.004, p=0.05), and higher DS (β=0.08, p=&lt;0.001). Conclusion: Predictors of DS and anxiety in these rural caregivers were psychosocial variables. Caregiver CVD Interventions could be optimized by including stress management, education about the psychological effects of caregiving, and social support components. Future research is needed on the role of DS and anxiety in CVD to better support rural caregivers at highest risk.
Abstract 14248: Efficacy and Safety of Bempedoic Acid in Patients Who Cannot Tolerate Statins: Pooled Analysis of 4 Phase 3 Clinical Trials
Authors: Ulrich Laufs, Maciej Banach, Harold E Bays, Alberico L Catapano, P Barton Duell, Anne C Goldberg, Antonio M Gotto, Lawrence A Leiter, Kausik K Ray, LeAnne T Bloedon, Zhan Ye, G Mancini
Journal: Circulation (2020)

Introduction: Some patients cannot tolerate statins mainly because of statin-associated muscle symptoms (SAMS). Bempedoic acid (BA) is a prodrug activated in the liver and not in skeletal muscle. BA has been shown to significantly lower LDL-C by a mean of ~18% in patients receiving background maximally tolerated statins and a mean of ~25% in patients with statin intolerance. Objective: Determine efficacy and safety of BA in statin-intolerant patients receiving no background statin therapy across 4 phase 3 clinical trials. Methods: Data were pooled from 4 randomized (2:1), placebo-controlled studies evaluating oral BA 180 mg once daily vs placebo for 12 to 52 weeks. Primary efficacy endpoint was LDL-C % change from baseline to week 12. Safety assessments included treatment-emergent adverse events (TEAEs), adverse events of special interest (AESI), and laboratory values. For patients who reported SAMs, additional information around etiology and location were collected. Results: Of 3621 patients, 586 (394 BA; 192 placebo) reported intolerance to multiple statins because of SAMS or other AEs and received no statins during the studies. Mean baseline LDL-C was 148.7 mg/dL. After 12 weeks, BA significantly lowered LDL-C vs placebo (placebo-corrected, -26.5%; P &lt; 0.001). Myalgia was the top reason for drug discontinuation, but was less common in the BA arm (17.7%) vs placebo (43.5%). CK &gt; 5 х ULN was uncommon in both groups. Among AESIs (Table) , muscle disorders were reported by 12.7% (BA) vs 14.1% (placebo). Myalgia was less common with BA (4.6%) vs placebo (7.3%). Muscle spasms (4.1% vs 3.6%) and pain in extremity (3.3% vs 2.1%) were comparable between treatment groups. Muscular weakness was rare (0.5% BA, 1% placebo). Conclusion: Among the population of patients unable to use statins, BA significantly lowered LDL-C vs placebo without increasing muscle-related TEAEs. BA may be an appropriate lipid-lowering therapy for patients with hyperlipidemia who are statin intolerant.
Interleukin-33 Promotes Serotonin Release from Enterochromaffin Cells for Intestinal Homeostasis
Authors: Zuojia Chen, Jialie Luo, Jian Li, Girak Kim, Andy Stewart, Joseph F. Urban, Yuefeng Huang, Shan Chen, Ling-Gang Wu, Alexander Chesler, Giorgio Trinchieri, Wei Li, Chuan Wu
Journal: Immunity (2020)
Efficacy and Safety Results from ASCEMBL, a Multicenter, Open-Label, Phase 3 Study of Asciminib, a First-in-Class STAMP Inhibitor, vs Bosutinib (BOS) in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Previously Treated with ≥2 Tyrosine Kinase Inhibitors (TKIs
Authors: Andreas Hochhaus, Carla Boquimpani, Delphine Rea, Yosuke Minami, Elza Lomaia, Sergey Voloshin, Anna G. Turkina, Dong-Wook Kim, Jane Apperley, Jorge E. Cortes, Andre Abdo, Laura Maria Fogliatto, Dennis Dong Hwan Kim, Philipp D le Coutre, Susanne Saussele, Mario Annunziata, Timothy P. Hughes, Naeem A. Chaudhri, Lynette C.Y. Chee, Valentín García Gutiérrez, Koji Sasaki, Paola Aimone, Alex Allepuz, Sarah Quenet, Véronique Bédoucha, Michael J. Mauro
Journal: Blood (2020)