tbuckley/cabot-search huggingface dataset:
AUTOIMMUNE HEPATITIS TRIGGERED BY COVID-19
Authors: J. Hong, S. Chopra, J. A. Kahn, B. Kim
Journal: Hepatology (2020)

Background: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease that is caused by environmental triggers in genetically predisposed patients Development of acute AIH has been described in patients recently infected with hepatotrophic viruses such as hepatitis A, B, and C viruses, as well as non-hepatotropic viruses such as Epstein Barr Virus  We describe the first known case of acute autoimmune hepatitis in a patient recently infected with the novel coronavirus disease 2019 (COVID-19) Methods: N/A Results: A 54 year-old man with a history of rheumatoid arthritis (RA) and scleritis on treatment with infliximab presented to the hospital with abdominal pain and jaundice His past medical history was significant for RA and scleritis for which he had been treated with infliximab for the past 10 years  He had no known history of chronic liver disease and denied consumption of alcohol, drugs, or herbal supplements One month prior, the patient had developed symptoms of anosmia and fevers and subsequently tested positive for COVID-19 Liver tests previously had been normal One month after his COVID-19 diagnosis, he began having symptoms of abdominal pain and pruritus He was found to have elevated serum total bilirubin to 25 mg/dL, alanine aminotransferase to 1,238 IU/L, aspartate aminotransferase to 1,084 IU/L, and alkaline phosphatase to 251 IU/L His international normalized ratio (INR) was 1 0 Serologies for acute and chronic hepatitis A, B, C, and E were negative HCV RNA was not detected COVID-19 PCR was tested twice, and both returned negative Immunological testing was significant for presence of antismooth muscle antibody titer 45 Immunoglobulin G subclass level was elevated to 3,151 mg/dL which were previously in normal range A liver biopsy obtained one day after admission showed moderate portal inflammation, mild interface hepatitis and moderate lobular and perivenular inflammation  There was a predominance of plasma cells (Figure 1) and mild steatosis  No fibrosis on trichrome stain  Given presentation and findings consistent with AIH, the patient was started on oral prednisone (40 mg/day) and switched from infliximab to rituximab for his RA and scleritis treatment His INR remained normal and he never developed encephalopathy Labs one month after admission showed significant improvement in his liver labs He continues on a prednisone taper, and last visit, he remained on 10 mg daily Conclusion: Since the onset of the COVID-19 pandemic, much has been learned about the virus and its clinical presentation Although COVID-19 has been associated with liver injury, this is the first case to demonstrate AIH triggered by COVID-19 Clinicians should be vigilant and aware that COVID-19 can be a trigger of severe AIH even after resolution of infection, especially, as case rates continue to rise around the world Figure: Perivenular and lobular inflammation with predominance of plasma cells (arrows) HE x 400x(Figure Presented)
Single and Dual Vector Gene Therapy with AAV9-PHP.B Rescues Hearing in Tmc1 Mutant Mice
Authors: Jason Wu, Paola Solanes, Carl Nist-Lund, Sofia Spataro, Olga Shubina-Oleinik, Irina Marcovich, Hannah Goldberg, Bernard L. Schneider, Jeffrey R. Holt
Journal: Molecular Therapy (2020)

AAV-mediated gene therapy is a promising approach for treating genetic hearing loss. Replacement or editing of the Tmc1 gene, encoding hair cell mechanosensory ion channels, is effective for hearing restoration in mice with some limitations. Efficient rescue of outer hair cell function and lack of hearing recovery with later-stage treatment remain issues to be solved. Exogenous genes delivered with the adeno-associated virus (AAV)9-PHP.B capsid via the utricle transduce both inner and outer hair cells of the mouse cochlea with high efficacy. Here, we demonstrate that AAV9-PHP.B gene therapy can promote hair cell survival and successfully rescues hearing in three distinct mouse models of hearing loss. Tmc1 replacement with AAV9-PHP.B in a Tmc1 knockout mouse rescues hearing and promotes hair cell survival with equal efficacy in inner and outer hair cells. The same treatment in a recessive Tmc1 hearing-loss model, Baringo, partially recovers hearing even with later-stage treatment. Finally, dual delivery of Streptococcus pyogenes Cas9 (SpCas9) and guide RNA (gRNA) in separate AAV9-PHP.B vectors selectively disrupts a dominant Tmc1 allele and preserves hearing in Beethoven mice, a model of dominant, progressive hearing loss. Tmc1-targeted gene therapies using single or dual AAV9-PHP.B vectors offer potent and versatile approaches for treating dominant and recessive deafness. AAV-mediated gene therapy is a promising approach for treating genetic hearing loss. Replacement or editing of the Tmc1 gene, encoding hair cell mechanosensory ion channels, is effective for hearing restoration in mice with some limitations. Efficient rescue of outer hair cell function and lack of hearing recovery with later-stage treatment remain issues to be solved. Exogenous genes delivered with the adeno-associated virus (AAV)9-PHP.B capsid via the utricle transduce both inner and outer hair cells of the mouse cochlea with high efficacy. Here, we demonstrate that AAV9-PHP.B gene therapy can promote hair cell survival and successfully rescues hearing in three distinct mouse models of hearing loss. Tmc1 replacement with AAV9-PHP.B in a Tmc1 knockout mouse rescues hearing and promotes hair cell survival with equal efficacy in inner and outer hair cells. The same treatment in a recessive Tmc1 hearing-loss model, Baringo, partially recovers hearing even with later-stage treatment. Finally, dual delivery of Streptococcus pyogenes Cas9 (SpCas9) and guide RNA (gRNA) in separate AAV9-PHP.B vectors selectively disrupts a dominant Tmc1 allele and preserves hearing in Beethoven mice, a model of dominant, progressive hearing loss. Tmc1-targeted gene therapies using single or dual AAV9-PHP.B vectors offer potent and versatile approaches for treating dominant and recessive deafness.
Abstract 13274: Predictors of Mortality in Critically Ill Covid-19 Patients - A Multicenter Prospective Analysis of 159 Patients
Authors: Randy Ip, Zulfiqar Qutrio Baloch, manel boumegouas, Abdullah Al abcha, Steven Do, Jelena Arnautovic, Krishna Meka, Chris Jacob, Matthew Wilcox, John Ip
Journal: Circulation (2020)

Introduction: Certain patient demographics and biomarkers have been shown to predict survival in patients infected with COVID-19. However, predictors of outcome in patients who are critically ill and require advanced respiratory support are unclear. Methods: We performed a multicenter analysis of 159 consecutive patients with confirmed COVID-19 who were admitted to Intensive Care Unit (ICU) between March 01, 2020 and April 30, 2020. Patients were then followed until May 23, 2020. Demographic data (age, sex, race, BMI) and past medical history (hypertension, diabetes, COPD, CKD, history of cardiac ischemic disease, atrial fibrillation and heart failure) were recorded. Laboratory values (troponin, CPK, pro-BNP, ferritin, LDH and d-dimer) were analyzed. Patient status was classified as either alive or deceased at hospital discharge or the end of follow up period. Results: Mean patient age was 66+/-15 and 53% were male. Mean BMI was 31+/- 9. Mean hospital ICU stay was 11+/-8 days. Mortality rate of this ICU cohort at the end of follow-up was 63%. Fifty-five (34%) patients were discharged from the hospital. A multivariable logistic regression analysis identified four factors (age, prior history of diabetes, prior history of atrial fibrillation and elevated troponin) that had significant and independent contributions to the likelihood of survival. Each increase in decade of age above 40 (p = 0.010) was predicted to reduce survival by 30%, the presence of diabetes (p = 0.041) by 57%, a prior history of atrial fibrillation (p= 0.011) by 75%, and each increase of 0.1 ng/mL of troponin above 0.05 ng/ml (p = 0.001) by 55%. Conclusion: Mortality of critically ill COVID-19 patients is high. Early aggressive treatment of high-risk patients identified in this study (advanced age, history of diabetes and atrial fibrillation and elevated troponin) could improve clinical outcome. The highly predictive value of elevated troponin levels on survival may indicate cardiac involvement of COVID-19 infection as a determinant of mortality. Additionally, of available published literature at this time, this is the first study that suggests a relationship between atrial fibrillation and increased mortality from COVID-19. Larger studies are needed to confirm these findings.
Abstract 14652: Systolic Blood Pressure Trajectories and Cardiovascular Outcomes in SPRINT
Authors: Charles A German, Tali Elfassy, Matthew J Singleton, Carlos J Rodriguez, Walter T Ambrosius, Joseph Yeboah
Journal: Circulation (2020)

Introduction: Blood pressure trajectories have been associated with cardiovascular disease (CVD) in observational studies. It is unclear whether these associations are independent of average blood pressure over time. Methods: We used data from SPRINT to identify systolic blood pressure (SBP) trajectories among a cohort of 8901 participants by incorporating SBP measures during the first 12 months of the trial post randomization. Trajectories were identified using latent class based modeling. Study outcomes included incident CVD, defined as myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure, or death attributable to CVD, and all-cause mortality. Cox proportional hazards models were used to evaluate associations between SBP trajectories and our outcomes of interest. Results: Four distinct SBP trajectories were identified: ‘low decline’ (40%), ‘high decline’ (6%), ‘low stable’ (48%), and ‘high stable’ (5%) (Figure 1). Relative to the low decline group, the low stable group was associated with a 29% increased risk of CVD (HR: 1.29, 95%CI: 1.06-1.57) and the high stable group was associated with a 76% increased risk of all-cause mortality (HR: 1.76, 95%CI: 1.15-2.68) after baseline multivariable adjustment. Relative to the low stable group, the high stable group was associated with a 54% increased risk of all-cause mortality (HR: 1.54, 95%CI: 1.05-2.28). When adjusting for average blood pressure across the 12 month time period, there were no significant differences in outcomes. Conclusion: We identified 4 SBP trajectories using data from SPRINT and found differences in the risk of CVD and all-cause mortality after baseline adjustment. However, there were no differences in the risk of these outcomes after adjusting for average blood pressure over time. These results suggest that the pattern of blood pressure control may not be relevant as long as the target blood pressure is achieved.
Abstract 314: Cardiac Arrest Related Cognitive Activity
Authors: Tara Keshavarz Shirazi, Anelly M. Gonzales, Analise Dickinson, Sam Parnia
Journal: Circulation (2020)

Background: Few studies have examined the psychological outcomes of cardiac arrest (CA) survivors. While some negative outcomes including post-traumatic disorder, anxiety and depression have been reported in ~50%, interestingly, ~10-20% of CA survivors have reported lucid, well-structured thought processes during CA associated with positive psychological outcomes and transformation post CA. We aimed to characterize the themes describing the cognitive experiences recalled by survivors. Method: In a qualitative study 118 self-reported cases were extracted from a CA survivor registry, coded the data using thematic analysis to identify emerging themes followed by descriptive statistics to identify frequencies of identified themes. Results: Analysis of 69 in-hospital and 45 out-of-hospital CA events led to identification of 10 major and 64 sub-themes describing the breadth of CA survivors’ cognitive experiences. Most predominate features included having no sense of pain during on-going CPR (18%), perception of being separate from the body (46%), observing the body from a point outside (40%), travelling through a tunnel towards a destination (16%) and having a life review (19%). Interestingly, in the life-review category 87% perceived the life-review to be an educational experience focused on their actions and intentions towards others, 38% described reliving of certain actions with a sense of shame, and 18% perceived to examine life events from others’ perspective. In addition, another category of cognitive experiences were also described that appeared to relate to events during recovery of consciousness around the time of return of spontaneous circulation (ROSC) where 14% of survivors sensed the pressure of CPR and 18% woke up with pain. Conclusion: CA survivor’s memories appear to reflect two categories: 1) a life review and perception of observing themselves during CPR without pain, which is felt to be educational, positive and peaceful and 2) memories related to the recovery phase around the time of ROSC. These include sensing CPR related events such as pain, chest pressure and distress. While the former category may explain the long-term positive transformation, the latter may explain the long-term occurrence of PTSD and anxiety in CA survivors.
Abstract 13648: Sex Differences in Modifiable Risk Factors and Severity of Coronary Artery Disease
Authors: Edina Cenko, Olivia MANFRINI, Jinsung Yoon, Mihaela van der Schaar, Sasko Kedev, Marija vavlukis, Goran Stankovic, Davor Milicic, Zorana Vasiljevic, Lina Badimon, Raffaele Bugiardini
Journal: Circulation (2020)

Introduction: It is still unknown whether traditional risk factors may have a sex specific impact on coronary artery disease (CAD) burden. Hypothesis: We sought to investigate at individual level whether there are sex differences in the four modifiable traditional cardiovascular risk factors and how these differences may impact the CAD and outcomes in ACS. Methods: We identified 14,793 patients who underwent coronary angiography for acute coronary syndromes in the ISACS-TC registry (NCT01218776) from 2010 to 2019. Main outcome measure was the association between traditional risk factors and severity of CAD and its relationship with 30-day mortality. The relative risk (RR) ratios and 95% CI were calculated from the ratio of the absolute risks of women versus men using inverse probability of weighting. Estimates were compared by test of interaction on the log scale. Severity of CAD was categorized as obstructive (≥50% stenosis) versus nonobstructive CAD. Results: The RR ratios for obstructive CAD in women versus men among nondiabetic people was 0.49 (95%CI 0.41-0.60) and diabetic people was 0.89 (95%CI 0.62-1.29); interaction by diabetes status: p=0.018. Exposure to smoking shifted the RR ratios from 0.50 (95%CI 0.4 -0.61) in nonsmokers to 0.75 (95%CI 0.54-1.03) in current smokers; interaction by smoking status: p=0.018. There were no significant sex-related interactions with hypercholesterolemia and hypertension. Women with obstructive CAD had higher 30-day mortality rates than men (RR 1.75, 95%CI 1.48-2.07). No sex differences in mortality were observed in patients with nonobstructive CAD. Conclusions: Obstructive CAD in women signifies a higher risk for mortality compared with men. Current smoking and diabetes disproportionally increase the risk of obstructive CAD in women. Achieving the goal of improving cardiovascular health in women still require intensive efforts toward further implementation of lifestyle and treatment interventions.
Abstract IA-16: Metabolic adaptations in pancreatic cancer
Authors: Kathryn E. Wellen
Journal: Cancer Research (2020)

Abstract Effective targeting of metabolism for cancer therapy is challenging in part because of extensive flexibility within metabolic pathways. For example, the enzyme ATP-citrate lyase (ACLY) has been of interest as a cancer therapeutic target because of its central role in generating nucleo-cytosolic acetyl-CoA for lipid synthesis and acetylation reactions. However, ACLY deficiency or inhibition triggers upregulation of the cytosolic acetyl-CoA synthetase ACSS2, enabling production of acetyl-CoA from acetate for the synthesis of fatty acids. In pancreatic cancer, tumor formation is suppressed in the absence of ACLY, but once tumors are established, ACSS2 is highly expressed and ACLY deficiency is tolerated. Despite this flexibility in acetyl-CoA generation, targeting of downstream processes that rely on acetyl-CoA, via combined BET inhibition and mevalonate pathway inhibition, suppresses tumor growth in mice. Analogously, it is possible that other metabolites whose abundance is tightly defended in cancer cells may point to targetable compensatory mechanisms or downstream processes on which tumor cells are reliant. Recent evidence suggests that the hexosamine biosynthesis pathway, which generates the glycosyl donor UDP-GlcNAc, holds promise for therapeutic targeting in pancreatic cancer, although its regulation in cancer cells remains poorly understood. In this presentation, I will discuss new data uncovering a key role for metabolic adaptation to nutrient deprivation in sustaining UDP-GlcNAc production and tumor growth. Citation Format: Kathryn E. Wellen. Metabolic adaptations in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr IA-16.
Thrombosis and Anticoagulation in Malignant Superior Vena Cava Syndrome
Authors: Avi Leader, Shlomit Tamir, Tal Friehmann, Nir Livneh, Roy Ratzon, Elizabeth Dudnik, Alon Rozental, Orly Hamburger-Avnery, Baruch Brenner, Pia Raanani, Hugo ten Cate, Galia Spectre
Journal: Blood (2017)
Abstract IA-04: Pancreatic cancer cells assemble a CXCL12-keratin 19 coating to resist immunotherapy
Authors: Douglas Fearon, Zhikai Wang
Journal: Cancer Research (2020)

Abstract How pancreatic ductal adenocarcinoma (PDA) cells stimulate CXCR4 to exclude T cells and resist T cell checkpoint inhibitors is not known. We find that CXCL12, the ligand forCXCR4 that is produced by the cancer-associated fibroblast, “coats” human PDA and colorectal cancer cells as covalent heterodimers with keratin 19 (KRT19). Modeling the formation of the heterodimer with three proteins shows that KRT19 binds CXCL12 and transglutaminase-2 (TGM2), and that TGM2 converts the reversible KRT19-CXCL12 complex into the covalent heterodimer. This model is validated by showing that cancer cells in mouse PDA tumors must express KRT19 and TGM2 to become coated with CXCL12, exclude T cells, and resist immunotherapy with anti-PD-1 antibody. Thus, PDA cells have a cell-autonomous means by which they capture CXCL12 to mediate immune suppression, which is potentially amenable to therapy. Citation Format: Douglas Fearon, Zhikai Wang. Pancreatic cancer cells assemble a CXCL12-keratin 19 coating to resist immunotherapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr IA-04.
Abstract 16788: Cardiopulmonary Exercise Testing in Pulmonary Atresia With Intact Ventricular Septum
Authors: Krishan Patel, Andrew L Cheng, Andrew Souza, Arash Sabati, Jon A Detterich
Journal: Circulation (2020)

Introduction: Pulmonary atresia with intact ventricular septum (PAIVS) is surgically managed with biventricular repair (2V), 1.5 ventricle palliation (1.5V), or single ventricle palliation (1V). Cardiopulmonary exercise testing (CPET) has been increasingly utilized in these patients. However, prognostic ability of CPET is limited by achievement of maximal exercise effort [respiratory exchange ratio (RER) &gt; 1.1]. Even during submaximal exercise, the VE/VCO2 can impact peak VO2. This study aims to identify CPET differences in 1V, 1.5V, and 2V PAIVS patients. Methods: A retrospective, cross-sectional study was performed, identifying PAIVS patients undergoing CPET. Contemporaneous echocardiography and CMR data was collected. CPET measures were compared by treatment group using ANOVA, Kruskal-Wallis, and chi-squared test, as appropriate. Comparisons of VE/VCO2 between individual groups were performed using Wilcoxon test. Univariate associations with VE/VCO2 were determined using Pearson correlation. Results: Nineteen PAIVS patients were identified (age 12.4 ± 0.68; seven 1V, five 1.5V, seven 2V). Only 7/19 (36.8%) patients achieved RER &gt; 1.1. Sex, age, RER, peak VO2, ventilatory anaerobic threshold, O2 pulse, BSA-adjusted O2 pulse, peak HR, and HR reserve did not differ between treatment groups. The VE/VCO2 ratio was different (p=0.037), with lower VE/VCO2 in 1.5V vs. 1V (p=0.021). Across all PAIVS patients, univariate associations with lower VE/VCO2 were male sex, higher BSA, hematocrit, and O2 pulse, and lower mitral inflow A wave velocity. In the 1.5V and 2V patients, higher RVEF and RV stroke volume by CMR were associated with lower VE/VCO2. Conclusions: The 1.5V palliation of PAIVS may be associated with better gas exchange efficiency compared to 1V palliation, while 2V patients were not different from either 1V or 1.5V. BSA-adjusted O2 pulse did not vary between treatment pathways, suggesting similar stroke volume response across all patients.
Abstract 16206: An Atypical Presentation of Spontaneous Coronary Artery Dissection in a Young Male Patient
Authors: Farhad Sami, Enrique Campos, Prakash Acharya, Tarun Dalia, Eric Hocsktad
Journal: Circulation (2020)

Background: Spontaneous coronary artery dissection (SCAD) is an important cause of myocardial infarction (MI) in women but rare in young healthy males. We report a case of a young male who presented with left hand tingling/numbness and was ultimately diagnosed with SCAD. Case Presentation: A 24-year-old male with history of asthma developed left hand tingling/numbness while playing basketball. This progressed to cold left upper extremity, prompting him to go to emergency room. Doppler ultrasound showed acute left brachial thrombus and emergent embolectomy of left brachial artery was done. Transesophageal echocardiogram, performed to investigate possible cardiac source of thrombus, showed normal ejection fraction, dyskinetic apex and biventricular thrombus (Figure 1A). Cardiac MRI revealed a large transmural MI in distribution of a wraparound left anterior descending artery (LAD) with associated regional akinesis of the left ventricular apex and an infarct in the right ventricular apex. Subsequent angiography revealed normal coronary arteries (Figure 1B) except a heterogenous linear filling defect in the apical LAD consistent with Type 1 SCAD (Figure 1C). No intervention was performed and the patient was treated conservatively. It was postulated that patient sustained an apical MI after SCAD of LAD, leading to formation of ventricular thrombi which then embolized to cause acute brachial artery thrombosis. Discussion: SCAD in young males is rare and can be a diagnostic challenge. Type 1 “pathognomic” angiographic finding in SCAD, is the classic appearance of multiple radiolucent lumens or arterial wall contrast staining. In case of inconclusive angiography, intravascular ultrasound or optical computed tomography can confirm diagnosis. Interventionalists should be familiar with angiographic appearance of SCAD as advanced imaging might not be available and in many cases, conservative management is preferred to percutaneous coronary intervention.
NC-015. CHANGES IN FDG-PET UPTAKE DURING A DELAYED MATCH TO SAMPLE MEMORY TASK
Authors: Constance Linville, Akiva Mintz, Robert Hampson, Sam Deadwyler, Ann Peiffer
Journal: Neuro-Oncology (2013)

BACKGROUND: This project seeks to reverse translate our Wake Forest School of Medicine (WFSM) non-human primate (NHP) model of radiation-induced cognitive decline. For NHP studies, performance on and uptake of fluorodeoxyglucose (FDG) during an internally developed delayed match to sample (DMS) task