tbuckley/cabot-search huggingface dataset:
Abstract 13914: Ischemic Preconditioning Induces MG53 Secretion From the Heart Through H <sub>2</sub> O <sub>2</sub> /PKC-delta Signaling
Authors: Dan Shan, Yan Zhang, Rui-ping Xiao
Journal: Circulation (2020)

Introduction: Ischemic heart disease is the leading cause of morbidity and mortality worldwide. Ischemic preconditioning (IPC) is the most powerful intrinsic protection against cardiac ischemia/reperfusion (I/R) injury. Previous studies have shown that a multifunctional TRIM family protein, MG53 (or TRIM72), not only plays an essential role in IPC-mediated cardioprotection, but also as a myokine/cardiokine, can be secreted from the heart and skeletal muscle in response to metabolic stress in addition to its intracellular actions. Hypothesis: We hypothesized that IPC-mediated cardioprotection is causally related to MG53 secretion and figured out the underlying mechanism. Methods and Results: Using proteomic analysis in conjunction with genetic and pharmacological approaches, we examined MG53 secretion in response to IPC and explored the underlying mechanism using rodents in in vivo , isolated perfused hearts, and cultured neonatal rat ventricular cardiomyocytes. IPC profoundly increased perfusate MG53 levels in mouse hearts by 5.50 ± 0.32 and 4.26 ± 0.40 folds from baseline over 0-60 and 60-120 min of reperfusion, respectively. Mechanistically, IPC-induced MG53 secretion is dependent on H 2 O 2 -evoked, Src-mediated phosphorylation of PKC-δ-Y311. Functionally, systemic delivery of recombinant human MG53 proteins (rhMG53) to mimic elevated circulating MG53 not only restored IPC function in MG53-deficient mice, but also protected rodent hearts from I/R injury even in the absence of IPC. Treatment of rhMG53 overtly decreased the infarct size (IF/AAR) induced by I/R compared to the BSA-treated control group (11.9 ± 1.8% vs 27.3 ± 2.0%, P &lt;0.01), and reduced the mortality from 44.7% to 5.3% in rats. Moreover, H 2 O 2 augmented MG53 secretion, and MG53 knockdown exacerbated H 2 O 2 -induced cell injury in human embryonic stem cell-derived cardiomyocytes. Conclusions: In conclusion, IPC and oxidative stress can trigger MG53 secretion from the heart via an H 2 O 2 -PKC-δ-dependent mechanism, and secreted MG53 acts as an essential factor conveying IPC-induced cardioprotection against ischemia/reperfusion injury. Recombinant MG53 proteins can be developed into a novel treatment for various diseases of human heart in which the endogenous MG53 is low.
Abstract 13837: Evaluating Predictors of Pulmonary Valve Replacement Failure in Congenital Heart Disease Patients
Authors: William A McEachern, Sudeep Sunthankar, M. O Ghani, George T Nicholson, Thomas P Doyle, David Bichell, David A Parra
Journal: Circulation (2020)

Introduction: We aimed to determine predictors of reintervention after pulmonary valve replacement (PVR) at our center with the novel consideration of valve angulation within the outflow tract. Methods: Patients with a history of PVR between 06/2007 and 06/2019 and subsequent cardiac catheterization, cardiac MRI, or chest CTA since PVR were eligible for inclusion, as stored images allowed for valve angle measurement. The angle relative to the patient’s anterior-posterior (horizontal) plane was measured using lateral angiography and sagittal cross-sectional images. Valve orientation was analyzed as follows: 1.) the measured angle, 2.) the difference in that angle from the mean of 40 control patients, and 3.) whether that angle was outside of 2 standard deviations from the mean. Other variables included: original cardiac anatomy, valve type, true internal valve diameter indexed for weight at PVR, and immediate post-operative peak systolic gradient and valve insufficiency. Freedom from reintervention was evaluated using the log-rank test and Cox proportional-hazards with multiple imputation of modest missing echocardiographic data. Results: Of 168 patients who underwent PVR during that period, 52 patients met inclusion criteria. Over a median follow-up time of 6.0 years (bootstrapped 95% CI [4.6, 7.4]), 14 of those 52 (26.9%) underwent reintervention (valvuloplasty or valve replacement). In both univariate analysis as well as bivariate analysis controlling for indexed valve diameter, no measure of valve orientation was associated with freedom from reintervention. Potential associations of valve type with the outcome disappeared in bivariate analysis. Higher internal valve diameter indexed for weight at PVR was consistently associated with earlier reintervention. Results for freedom from valve revision were similar to those for any reintervention, while acknowledging that we may be underpowered to detect certain associations. Conclusions: Valve orientation does not appear to impact freedom from reintervention following PVR; however, higher indexed internal valve diameter is associated with decreased time to reintervention. An augmented sample size through multicenter collaboration may allow for a more robust multivariate analysis.
Abstract 14886: Outcome of Early Surgery in Active Infective Endocarditis in Terms of Intraoperative Valve Culture
Authors: Kota Suzuki, Daisuke Yoshioka, Koichi Toda, Shigeru Miyagawa, Satoshi Kainuma, Takuji Kawamura, Ai Kawamura, Noriyuki Kashiyama, Takayoshi Ueno, Toru Kuratani, Yoshiki Sawa
Journal: Circulation (2020)

Introduction: In recent years, the benefit of early surgery in active infective endocarditis (IE) has been reported. The drawback of early surgery is the risk that residual bacteria in the operative field may cause IE recurrence. Little is known regarding the relationship between intraoperative valve culture and recurrence. In the present study, we investigated the value of early surgery for IE based on the results of valve cultures. Hypothesis: Positive intraoperative valve cultures in early surgery are associated with recurrence. Methods: Between 2009 and 2017, 585 patients underwent valve surgery for definitive left-sided active IE at 14 affiliated hospitals. Early surgery was defined as surgery within 14 days from diagnosis, and patients with unknown valve culture results were excluded. We analyzed the short and mid-term outcome in patients with early surgery (n=228). These 228 patients were compared in two groups: positive (Group P, n=106) and negative (Group N, n=122) valve cultures. The primary outcome was all-cause mortality. Secondary outcomes were recurrence of IE. Mean follow-up time was 2.5±2.8 years. Results: Patients in group P had a significantly higher inflammatory response on preoperative blood tests (White blood cell count: 10.4 (8.3-14.5) vs. 8.2 (6.0-12.7) х10 3 /μl, p=0.005, C-reactive protein: 7.3 (3.8-11.0) vs. 3.8 (2.1-6.8) mg/dl, p&lt;0.001). Patients in group P also had a significantly shorter duration from diagnosis to surgery (2 (1-4) vs. 4 (1-9) days, p&lt;0.001). There was no significant difference in in-hospital mortality between the two groups (13/106 (12%) vs. 11/122 (9%), p=0.43). The overall survival rate at 1 and 5 years was 83% and 69% in group P, 82% and 75% in group N, respectively (p=0.85). The rate of freedom from the recurrence of endocarditis at 1 and 5 years postoperatively was 97% and 82% in group P, and 98% and 92% in group N, respectively (p=0.02). In Cox's hazard analysis, positive valve culture was a risk factor for IE recurrence in multivariate analysis (hazard ratio, 3.39; 95% confidence interval, 1.07 to 10.67; p=0.037). Conclusions: Positive valve culture cases in early surgery for active IE have a significantly increased risk of recurrence compared with valve culture-negative cases and require careful management.
Integrative Tumor and Immune Cell Multi-omic Analyses Predict Response to Immune Checkpoint Blockade in Melanoma
Authors: Valsamo Anagnostou, Daniel C. Bruhm, Noushin Niknafs, James R. White, Xiaoshan M. Shao, John William Sidhom, Julie Stein, Hua-Ling Tsai, Hao Wang, Zineb Belcaid, Joseph Murray, Archana Balan, Leonardo Ferreira, Petra Ross-Macdonald, Megan Wind-Rotolo, Alexander S. Baras, Janis Taube, Rachel Karchin, Robert B. Scharpf, Catherine Grasso, Antoni Ribas, Drew M. Pardoll, Suzanne L. Topalian, Victor E. Velculescu
Journal: Cell Reports Medicine (2020)

In this study, we incorporate analyses of genome-wide sequence and structural alterations with pre- and on-therapy transcriptomic and T cell repertoire features in immunotherapy-naive melanoma patients treated with immune checkpoint blockade. Although tumor mutation burden is associated with improved treatment response, the mutation frequency in expressed genes is superior in predicting outcome. Increased T cell density in baseline tumors and dynamic changes in regression or expansion of the T cell repertoire during therapy distinguish responders from non-responders. Transcriptome analyses reveal an increased abundance of B cell subsets in tumors from responders and patterns of molecular response related to expressed mutation elimination or retention that reflect clinical outcome. High-dimensional genomic, transcriptomic, and immune repertoire data were integrated into a multi-modal predictor of response. These findings identify genomic and transcriptomic characteristics of tumors and immune cells that predict response to immune checkpoint blockade and highlight the importance of pre-existing T and B cell immunity in therapeutic outcomes.
Abstract 13670: Single versus Serial Measurements of Cardiac Troponin in the Evaluation of Emergency Department Patients With Suspected Acute Myocardial Infarction
Authors: Maereg A Wassie, Mingsum Lee, Benjamin C Sun, Yi-Lin Wu, Aileen S Baeker, Rita F Redberg, Maros Ferencik, Ernest Shen, Visanee Musigdilok, Adam Sharp
Journal: Circulation (2020)

Introduction: Chest pain is among the most common reasons for emergency department (ED) presentations. However, most patients are low risk for acute coronary syndrome (ACS) with low cardiac adverse outcomes. Biomarker testing with troponins is the mainstay of initial assessment for ACS. Although serial troponin testing can improve diagnosis of ACS, in clinical practice, some patients deemed to be low risk are discharged after a single negative troponin measurement. Our study evaluated the safety of single-troponin rule-out strategy using a conventional troponin assay. Hypothesis: We assessed the hypothesis that there is no significant difference in the clinical outcomes of patients deemed low-risk and discharged after a single negative troponin compared to patients discharged after serial troponin measurements. Methods: This is a retrospective study of ED encounters from January 2015 to December 2017 across 13 community emergency departments within an integrated healthcare system in Southern California. The study cohort includes adult ED encounters evaluated for suspected ACS with a HEART score and an initial conventional troponin-I below the level of detection (&lt;0.02). Multivariate logistic regression model was performed to evaluate the association between testing strategies and clinical outcomes. Results: Among 27,918 patients with an initial troponin measurement below the level of detection, 14,459 (51.8%) were discharged after a single measurement, and 13,459 patients (48.2%) had serial troponin orders. After adjusting for cardiac risk factors and comorbidities, there was no statistically significant difference in the primary outcome of AMI or cardiac mortality within 30 days between the two groups (single troponin 0.4% vs. serial troponin 0.4%, OR 1.41, 95% CI (0.96-2.07)). Single troponin was associated with a lower rate of CABG (OR 0.24, 95% CI: 0.11-0.48) and invasive coronary angiogram (OR 0.46, 95% CI: 0.38-0.56). Conclusions: When compared to serial troponin testing, discharge after a single negative troponin is routinely done among ED patients, and appears safe based on current physician decision making with no difference in rates of 30-day cardiac mortality and AMI.
Abstract 14912: Sotalol-induced Wide Complex Rhythm: What is the Mechanism?
Authors: Albert J Rogers, Paul J Wang, Nitish Badhwar
Journal: Circulation (2020)

Introduction: Delta waves associated with atrioventricular accessory pathways (APs) may manifest with autonomic tone, heart rate, and rhythm changes. Rarely, drugs like sotalol can block AV nodal conduction, revealing latent WPW, one treatable cause of sudden death. Case report: A 38-year-old man was admitted for sotalol loading due to frequent typical atrial flutter and SVT and a desire to avoid catheter ablation. He had a history of cardiac arrest with adenosine and tachycardia-induced cardiomyopathy. After recovery, cardiac MRI showed a normal heart without scar. Admission 12-lead ECG ( Figure A ) revealed normal sinus rhythm without other abnormality. With administration of sotalol, the patient developed a wide complex rhythm ( Figure B ). Interpretation of the rhythm indicated presence of a latent AP and a repeat ECG ( Figure C ) confirmed manifest preexcitation. After consenting to electrophysiology study, the patient developed a short RP tachycardia ( Figure D ) which terminated with Valsalva. The patient underwent successful catheter ablation of the pathway located at the anterior floor of the coronary sinus body and the cavotricuspid isthmus. Discussion: The differential diagnosis for a wide complex rhythm in this setting includes rate-related aberrancy, idioventricular rhythm, phase 4 aberrancy, and preexcitation from an AP. Shortened and consistent PR intervals in the tracing lead to preexcitation as the only possible mechanism. APs that are capable of anterograde conduction but are not manifest in sinus rhythm are termed latent APs. Conditions that may cause this phenomenon include opposite autonomic effects on the AP and the AV node, increased atrial conduction time, or concealed retrograde conduction into the AP. Sotalol typically increases the retrograde effective refractory period of the AP but has variable anterograde effect. Sotalol has not previously been reported to reveal a latent AP but may have acted through one of the stated mechanisms.
NAD+ Metabolism Maintains Inducible PD-L1 Expression to Drive Tumor Immune Evasion
Authors: Hongwei Lv, Guishuai Lv, Cian Chen, Qianni Zong, Guoqing Jiang, Dan Ye, Xiuliang Cui, Yufei He, Wei Xiang, Qin Han, Liang Tang, Wen Yang, Hongyang Wang
Journal: Cell Metabolism (2020)
Abstract 14116: Favorable Outcomes for Heart Transplantation in Barth Syndrome as Demonstrated by Multicenter/multiregistry Analysis
Authors: Yu Li, Justin Godown, carolyn taylor, Anne I Dipchand, Brian Feingold
Journal: Circulation (2020)

Introduction: Barth Syndrome (BTHS) is a rare (~1/350,000), X-linked mitochondrial disease characterized by cardioskeletal myopathy and neutropenia. Reported outcomes after heart transplant (HT) are limited to case reports. We sought to identify a large cohort of BTHS HT recipients to describe clinical outcomes. Hypothesis: HT in BTHS is associated with non-inferior survival, acute rejection (AR), infection, and vasculopathy (CAV) relative to non-BTHS dilated cardiomyopathy (DCM). Methods: We analyzed data from the Barth Syndrome Registry and Repository (BRR), Pediatric Heart Transplant Society (PHTS), and Scientific Registry of Transplant Recipients (SRTR). To avoid recounting patients occurring in &gt;1 source, we used years of birth, listing, and HT and listing/HT city to link records across registries. BTHS HT recipients were matched 1:4 on age, era, urgency status, and use of ECMO/VAD to male, non-BHTS, DCM HT recipients in PHTS. Survival was analyzed for all BTHS HT recipients. Because BRR and SRTR morbidity data are limited, AR, infection, malignancy, and CAV were analyzed only for those with PHTS data. Results: Forty-seven BTHS patients with 51 listings and 43 HTs (including 2 re-transplants) were identified; 29 BTHS HTs (1 re-transplant) had data in PHTS. Median age at HT was 1.9 yrs (IQR: 0.6-5.8) with 35% &lt;1 years-old at HT. Median follow up was 4.2 yrs (2.1-9.1). Mechanical circulatory support at HT was common (VAD 29%, ECMO 5%). We found no difference in survival between BTHS and non-BTHS HT recipients (HR 0.93, 95% CI 0.40-2.14). Freedom from infection (HR 0.63, 0.33-1.20), bacterial infection (HR 0.76, 0.29-1.99), malignancy (HR 0.22, 0.02-2.02), and CAV (HR 0.55, 0.15-1.97) were also similar between the groups. BTHS HT recipients had greater freedom from AR (HR 0.39, 0.17-0.87). Use of induction therapy (62 vs 74%, p=0.21), steroids at 30 days (76 vs 62%, p=0.17), and dual or triple immunosuppression at 1 year (80 vs 84%, p=0.58) were similar for BTHS and non-BTHS recipients. Conclusions: In this largest cohort yet reported, BTHS HT recipients show equivalent survival and freedom from infection, malignancy, and CAV, with a lower risk of acute rejection. Thus, individuals with BTHS should not be excluded from HT solely based on the diagnosis of BTHS.
Single B-Cell Genomic Analyses Differentiate Vitreoretinal Lymphoma from Chronic Inflammation
Authors: Wei Jian Tan, Mona Meng Wang, Paola Ricciardi Castagnoli, Tiffany Tang, Anita Sook Yee Chan, Tong Seng Lim
Journal: Ophthalmology (2020)

To test whether analyzing DEPArray (Menarini Silicon Biosystems) isolated single B cells from the vitreous fluid can reveal crucial genomic and clinicopathological features to distinguish patients with vitreoretinal lymphoma (VRL) from those with chronic inflammation using immunoglobulin heavy chain (IGH), disease biomarker myeloid differentiation primary response 88 (MYD88)L265P mutation, and copy number profiling.A single-center, retrospective study.Remnant vitreous biopsies from 7 patients with VRL and 4 patients with chronic inflammation were acquired for molecular analysis.Vitreous fluid samples were prefixed in PreservCyt (Hologic) and underwent cytologic analysis and immunohistochemistry examination. Single cells were isolated using the DEPArray NxT system, followed by downstream genomic analysis.The frequencies of the dominant IGH and MYD88L265P mutation and the genome-wide copy number aberration (CNA) profiles of individual vitreous-isolated B cells were characterized.An average of 10 to 13 vitreous B cells were used in the single-cell IGH and MYD88 analyses. Higher frequencies of dominant IGH (88.8% ± 13.2%) and MYD88L265P mutations (35.0% ± 31.3%) were detected in patients with VRL than in patients with chronic inflammation (65.9% ± 13.4% and 1.5% ± 2.6% for IGH and MYD88L265P, respectively). In a cytology-proven VRL case, all 15 vitreous isolated B cells were derived from the same clone with 100% paired IGH: immunoglobulin light chain (IGK) sequences. Genome-wide copy number profiling revealed a high degree of similarity between B cells from the same patient with VRL, with extensive gains and losses at the same areas across the whole genome. In addition, 14 of 15 B cells showed a BCL2/JH t(14;18) translocation, confirming cellular malignancy with a clonal origin. Clustering analysis of the copy number profiles revealed that malignant B cells derived from different patients with VRL had no common genome-wide signatures.Single B-cell genomic characterization of the IGH, MYD88L265P mutation, and copy number profile enables VRL diagnosis. Because our study involved only a small cohort, these meaningful proof-of-concept data now warrant further investigation in a larger patient cohort.
Harming Children to Benefit Others: A Reply
Authors: Heidi Malm, Mark Christopher Navin
Journal: The American Journal of Bioethics (2020)

This article refers to:Pox Parties for Grannies? Chickenpox, Exogenous Boosting, and Harmful InjusticesNot Society’s Sacrificial Lambs: It is Wrong to Withhold Vaccination from Children to Benefit OthersVaccine-Associated Shingles: What Do We Owe Varicella Vaccine Recipients in Adulthood?Are Generational Welfare Trades Always Unjust?Aggregate Wellbeing as Foundation to Discourage Childhood Chickenpox VaccinationThe Strawman at the Pox PartyVaricella Vaccination, Counting Harms and Benefits, and Obligations to OthersUnintended Effects, Iatrogenic Harms, and the Challenge of Population-Wide Vaccination ComplianceUsing Individuals as (Mere) Means in Management of Infectious Diseases without Vaccines. Should We Purposely Infect Young People with Coronavirus?Introducing Routine Varicella Vaccination? Not so Fast!Encouraging Vaccination Ethically: How Can Pox Parties for Grannies and Vaccine-Preventable Diseases Be Avoided?
Abstract 14153: Actigraphy-Derived Rest-Activity Patterns Are Associated With Blood Pressure Level and Hypertension: A Prospective Analysis of the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Nour Makarem, Marie-Pierre St-Onge, Daichi Shimbo, Brooke A Aggarwal, Andrea Baccarelli, Dorothy D Sears, Steven Shea, Sara Mariani, Catherine Marinac, Phyllis Zee, Pamela Ouyang, Susan Redline
Journal: Circulation (2020)

Introduction: Misalignment of lifestyle behaviors with circadian rhythms is related to hypertension (HTN) risk in experimental studies. Estimation of the circadian rhythm of 24 h rest-activity patterns, which serves as a measure of circadian rhythmicity in a free-living population setting, has been linked to health outcomes but its association with HTN is unknown. Hypothesis: Less robust and irregular 24 h rest-activity patterns will be associated with higher blood pressure (BP) and HTN. Methods: Participants were n=1667 diverse adults (mean age: 67 ± 9 y) in the MESA Sleep Study (2010-13) who completed 7 days of wrist actigraphy. Interdaily stability (IS), intradaily variability (IV), most active 10 h period (M10) and least active 5 h period (L5) timing and counts, and relative amplitude (RA) (defined in Table) were derived from actigraphy data using nonparametric rhythm analysis. Multivariable linear and logistic regression was used to examine associations with BP level and prevalent and incident HTN after 6 y of follow-up at Exam 6 (2016-18). Results: Greater RA (more robust rest-activity pattern i.e. higher wake-time activity and lower activity at night), IS (more day-to-day stability in rest-activity patterns), and M10 counts (more active wake period) were associated with lower BP (Table). Higher L5 midpoint and count (later timing and less restful sleep) was associated with higher BP. In sensitivity analyses excluding those taking HTN medication, associations persisted. Those in the highest vs. lowest category of RA and M10 counts had lower prevalent and incident HTN risk, while those in the highest vs. lowest category of L5 midpoint and counts and IV (more fragmented rhythm, lower sleep efficiency) had higher HTN risk. Conclusions: A less robust and stable rest-activity pattern, lower wake-time activity, and a less restful and later sleep period are associated with HTN. The timing and regularity of rest-activity patterns may be a novel target for HTN prevention.