tbuckley/cabot-search huggingface dataset:
Abstract 10714: The Role of Interleukin-6 in Heart Failure and Its Subtypes: Results from Mendelian Randomization and Mediation Analysis
Authors: Chang Liu, Qin Hui, Brian Charest, Krishna Aragam, Zeyuan Wang, Kelly Cho, Peter W Wilson, Juan P Casas, Michael M Gaziano, Lawrence S Phillips, Jacob Joseph, Yan V Sun
Journal: Circulation (2021)

Introduction: Heart failure (HF) increases morbidity, mortality, and costs, with complex pathogenic mechanisms. Interleukin-6 (IL-6) is a key cytokine and immune regulator with broad impact on inflammation – a critical component of HF pathophysiology. Circulating levels of IL-6 receptor (IL-6R) determines the activity of the IL-6 signaling pathway. We aim to estimate the causal effect of the IL-6R on HF and two clinical subtypes: HF with reduced (HFrEF) and preserved ejection fraction (HFpEF) in a Mendelian Randomization (MR) framework including mediators. Hypothesis: Plausible causal associations between IL-6R and HF, HFrEF and HFpEF are mediated by body mass index (BMI) or coronary artery disease (CAD). Methods: Two-sample MR analyses were conducted using genetic association results for composite HF, HFrEF and HFpEF among &gt;300,000 MVP participants of European ancestry. Thirty-four independent genetic variants within 250 kb from the IL6R gene associated with plasma IL-6R levels were used as genetic instrumental variables. We estimated the direct effect of IL-6R levels on HF and subtypes, and the indirect effect mediated through BMI and CAD. Results: Causal effects of IL-6R on composite HF, HFrEF and HFpEF were estimated as odds ratios (OR): 0.97 (CI 0.96-0.99, p=0.02), 0.96 (CI 0.93-0.98, p=0.003) and 1.00 (CI 0.97-1.03, p=0.89), respectively. Mediation analyses for composite HF and HFrEF showed significant mediation effects by CAD, with ORs 0.98 (CI 0.97-0.99) and 0.98 (CI 0.96-1.00), respectively. No mediation effect of BMI was identified. Conclusions: These findings support a causal role of IL-6 signaling in composite HF and HFrEF, but not HFpEF. Although the IL-6 signaling pathway plays a role in both BMI and CAD, the effect of IL-6 signaling on composite HF and HFrEF may be mediated through by CAD. Our findings demonstrate the role of IL-6 signaling in HF and its difference between HF subtypes, which may lead to more specific therapeutic targets for HF.
Abstract 11056: Thoracoscopic Left Atrial Appendage Occlusion with Atriclip <sup>TM</sup> : An Initial Experience
Authors: Edward Wang, Pragnesh Joshi, Paul Sadleir, Rukshen Weerasooriya, David Playford
Journal: Circulation (2021)

Introduction: Left atrial appendage (LAA) closure is an important tool in stroke prevention. Totally thoracoscopic LAA closure using the AtriClip™ device avoids intracardiac components, although early outcomes have not been systematically documented. Methods and Results: 105 consecutive fully thoracoscopic AtriClip TM procedures were examined, involving 84(80%) males, 21(20%) females and mean (+/- SD) age 70.1+/-9.2 years. The most common indication was as part of an AF ablation procedure (n=38, 36.2%), or anticoagulation-related hemorrhage (n=27, 25.7%). Median (interquartile range, IQR) CHADS 2 VaSc = 3 (2-4) and HAS-BLED = 3 (1-3). Half the patients (n=51, 48.6%) underwent isolated AtriClip insertion, 90% had a size 40 or 45mm AtriClip device, and none experienced circumflex coronary artery or phrenic nerve compromise. Intraprocedural transesophageal echocardiography demonstrated complete occlusion in all patients. Follow-up at 6 weeks with CT or transesophageal echocardiography confirmed occlusion in all patients (79% follow-up). The length of stay for isolated thoracoscopic AtriClip TM was 3 days (IQR 2-4) with longer admissions due to unrelated conditions (e.g. heart failure, AF or chest infection). No cases of LAA perforation were recorded and no patients with isolated AtriClip required transfusion. Transient pericarditis occurred in 10 patients (9.5%, 5 requiring readmission within 30 days) with a pericardial effusion in 3 patients (2.9%, requiring pericardiocentesis in one patient). No strokes occurred and 93% of isolated Atriclip patients had ceased anticoagulation at 30 days. Conclusions: Total thoracoscopic LAA closure using the AtriClip device is safe and effective. The most common complication is transient pericarditis (9.5%) and major complications were not seen.
A randomised phase II study of osimertinib and bevacizumab versus osimertinib alone as second-line targeted treatment in advanced NSCLC with confirmed EGFR and acquired T790M mutations: the European Thoracic Oncology Platform (ETOP 10-16) BOOSTER trial
Authors: R.A. Soo, J.-Y. Han, U. Dafni, B.C. Cho, C.M. Yeo, E. Nadal, E. Carcereny, J. de Castro, M.A. Sala, R. Bernabé, L. Coate, M. Provencio Pulla, R. Garcia Campelo, S. Cuffe, S.M.S. Hashemi, M. Früh, B. Massuti, J. Garcia-Sanchez, M. Dómine, M. Majem, J.-M. Sanchez-Torres, C. Britschgi, M. Pless, G. Dimopoulou, H. Roschitzki-Voser, B. Ruepp, R. Rosell, R.A. Stahel, S. Peters, Rolf Stahel, Solange Peters, Ross Soo, Ji-Youn Han, Martin Früh, Mariano Provencio, Linda Coate, Urania Dafni, Anita Hiltbrunner, Barbara Ruepp, Heidi Roschitzki-Voser, Anita Hiltbrunner, Adriana Gasca-Ruchti, Nino Giacomelli, Rosita Kammler, Nesa Marti, Lionel Nobs, Mariana Pardo-Contreras, Rita Pfister, Anne-Christine Piguet, Sabrina Ribeli-Hofmann, Virginia Rodriguez Martinez, Heidi Roschitzki-Voser, Susanne Roux, Barbara Ruepp, Magdalena Sanchez-Hohl, Mirjam Schneider, Robin Schweri, Sandra Troesch, Isabel Zigomo, Urania Dafni, Zoi Tsourti, Panagiota Zygoura, Marie Kassapian, Katerina Vervita, Georgia Dimopoulou, Charitini Andriakopoulou, Maria Fernandez, Eva Pereira, Carolina Simona, Lisa Tucker, Jillian Burnes, Aisling Barrett, Meghan McGrillen, Catherine Berset, Christine Biaggi, Martin Reist, Priska Rentsch, Linda Coate, Sinead Cuffe, Sayed Hashemi, Ernest Nadal, Enric Carcereny, Javier de Castro, Maria Angeles Sala, Bernabé Reyes, Mariano Provencio Pulla, Rosario Garcia Campelo, Bartomeu Massutí, Jose Garcia, Manuel Dómine, Margarita Majem, Jose Miguel Sanchez, Martin Früh, Christian Britschgi, Miklos Pless, Solange Peters, Ross Soo, Chong Ming Yeo, Ji-Youn Han, Byoung Chul Cho
Journal: Annals of Oncology (2021)
Abstract 9963: Early Guided Palliative Communication Intervention to Optimize Family Support and Manage Expectations for Patients Receiving Extracorporeal Membrane Oxygenation (ECMO)
Authors: Safanah Siddiqui, Ali Tabatabai, Rachel Nathan, Megan Anders, Miranda Gibbons, Marguerite Russo, Sarah Whitehead, Raya E Kheirbek
Journal: Circulation (2021)

Introduction: Extracorporeal membrane oxygenation (ECMO) is increasingly instituted for patients with severe circulatory or respiratory failure and as bridge to recovery or destination therapies (device implantation or organ transplantation). Morbidity and mortality for those patients is high. Hypothesis: ECMO combined with COVID isolation presents an additional set of challenges for patients, families. Objective: To test feasibility of an early, concurrent, and semi-structured palliative care intervention in improving communication, clarifying goals of care, and highlighting the experience of patients’ families. Methods: IRB Approved Qualitative study using content analysis of guided, in-depth discussions with families of COVID-19 patients within 48-72 hours of being cannulated for ECMO between March- October 2020. Scripted template was developed to guide and facilitate goals of care conversations and to ensure consistent communication with family members throughout patients’ disease trajectory. Patient demographics, comorbidities, clinical course, length of stay, and discharge disposition was obtained from the institution’s COVID-19 Data Warehouse and analyzed using descriptive statistics Setting: Large urban academic medical center. Results: Patients were 44 ± 10 years, Hispanic or Latino 27/43 (63%), white 3 (7%), Black 8 (19%). Palliative care documentation for ECMO acknowledgement meeting was 36/43 (84%). Timely and guided communication demonstrated themes expressed by families including 1) social isolation and related grief of not being at patient’s bedside; 2) helping children of patients adjust to a new normal; 3) coping with multiple family members suffering from COVID-19; 4) importance of faith and spirituality; 5) need for hope and gratitude 6) futility of prolonged ECMO stay. Survival to discharge 24/43 (56%). There was no statistical difference in hospital survival or length of stay between patients with and without documented palliative care. Conclusions: Early and ongoing palliative care intervention is feasible to support families’ acknowledgment of complexity, benefits and limitations of ECMO, and it is useful in highlighting families’ experiences, managing expectations and alleviating suffering.
Abstract 13865: Impact of Prior Aortic Aneurysm Diagnosis on Presentation and Outcomes in Stanford Type B Acute Aortic Syndromes
Authors: Briana M Barns, Candrika D Khairani, Samantha Rizzo, Mariana Pfeferman, Julia Snyder, Anthony Tristani, Gregory Piazza, Samuel Z Goldhaber, Umberto Campia
Journal: Circulation (2021)

Introduction: Acute aortic syndromes (AAS) involving the descending, but not the ascending, aorta (Stanford type B) are medical emergencies that require multidisciplinary management. Aortic aneurysms are a known risk factor for AAS. We investigated the impact of a history of aortic aneurysm on presentation and outcomes in patients with type B AAS. Hypothesis: We hypothesize that patients with a history of aortic aneurysm have higher in-hospital mortality rate and adverse outcomes compared to those without. Methods: We performed a retrospective analysis of all patients admitted with AAS to our tertiary medical center between July 2012 and October 2020. Type B AAS presentations included aortic dissection, aortic rupture, intramural hematoma (IMH), penetrating atherosclerotic ulcer, and symptomatic aneurysm. Prior history included presence of a thoracic and/or abdominal aortic aneurysm. Results: A total of 169 patients with type B AAS were included in our analyses. Of these, 54 (32%) had a history of prior aortic aneurysm and 115 (68%) patients did not (Table). Patients with prior aortic aneurysm were significantly older (74.3±14.6 vs. 68.7±14.1 years, p &lt;0.0001), had a lower proportion of aortic dissection (33.3% vs. 50.4%, p &lt;0.05) and a higher proportion of symptomatic aneurysm (27.8% vs. 8.7%, p &lt;0.001) as their presentation. Similar rates of mortality (8.9% vs. 7.4%), AAS related complications, and 30-day hospital readmission were observed between patients with a prior aortic aneurysm and those without. Conclusions: Among patients with type B AAS, those with a history of aortic aneurysm have a lower proportion of dissection and a higher proportion of symptomatic aneurysm at presentation. However, their rates of in-hospital mortality and 30-day readmission do not differ compared to those observed in patients without a history of aortic aneurysm.
Abstract 11473: Renal and Cardiac Effects of Remote Ischemic Preconditioning in Children Undergoing Cardiopulmonary Bypass Surgery
Authors: Yuk M Law, Christine Hsu, Ronit Katz, sangeeta hingorani, David MCMULLAN, Michael Richards, Howard Jeffries, Rong Tian, Jonathan Himmelfarb
Journal: Circulation (2021)

Introduction: Children undergoing cardiac surgery are at risk for AKI and cardiac dysfunction affecting outcome. Improved surgical techniques and post-operative care allow better outcomes in complex repairs and at-risk patients. Opportunity exists in further protecting multiple end organ function with remote ischemic preconditioning (RIPC) given promising but mixed data in adults and children. Hypothesis: A non-invasive technique of inducing reversible lower extremity ischemia with inflation of pressure cuff lessens renal and myocardial injury. Methods: A single center randomized, placebo controlled, double blinded trial of RIPC in children undergoing cardiac surgery of RACHS-1 category 2 or greater. RIPC was performed in the operating room after anesthesia and before sternotomy. Pre-specified end points are change in creatinine, eGFR, development of AKI, B-type natriuretic peptide and Troponin I at 6, 12, 24, 48, 72 hours post separation from bypass. Secondary end points included select clinical outcomes. Results: There were 45 in the RIPC and 39 patients in the control group: age was 3.5 and 3.8 years, respectively; 57 patients below 1 year of age; 35 patients below 1 month of age. There was no difference between groups in creatinine, cystatin C, eGFR at each time points. There was a trend for a larger rate of decrease, especially for cystatin C (p=0.042) in the RIPC group but the magnitude was small. AKI was observed in 21 (54%) of control and 16 (36%) of RIPC group (p=0.094). Adjusting for baseline creatinine, the odds ratio for AKI in in RIPC compared to control group was 0.31 (p=0.037). Adjusted for clinical characteristics, the odds ratio was 0.34 (p=0.056). Peak troponin occurred at 6 hrs. Compared to control, the RIPC group had a lower troponin at 6 hrs (p=0.140). However, no difference in other analyses of troponin and B-type natriuretic peptides between the groups. Length of stay, all-cause mortality, systolic function by echocardiography and composite clinical end points of advanced renal and heart failure were not different between groups. Conclusions: There is suggestion of RIPC delivering renal protection in an at-risk pediatric population. Additional larger, higher risk population studies will be required to fully determine its efficacy.
Abstract 9713: Ketosis Decreases Murine Plaque and Aortic Aneurysm Formation
Authors: Sergio E Sastriques Dunlop, Santiago Elizondo Benedetto, Batool Arif, Sean J English
Journal: Circulation (2021)

Introduction: Atherosclerosis and aortic aneurysm (AA) are associated with leading causes of mortality worldwide. There is no medical therapy for the treatment of AA, and though diet modification is essential for the management of cardiovascular disease. A ketogenic diet has been accepted as an effective complementary treatment for hypertension and dyslipidemia. Hypothesis: We sought to evaluate if a high fat, low carbohydrate diet could attenuate plaque and AA formation in a mouse model. Methods: Apo E -/- mice (N=30) 12 weeks old, underwent Angiotensin II pump administration, with daily provision of β-aminopropionitrile (BAPN) over 28 days. Control mice (StD, N=15) received a standard diet (fat 42%, carbohydrates 42.7%, proteins 15.2%); while mice undergoing ketosis induction (KD, N=15) received a high fat, low carbohydrate diet (fat 90.5%, carbohydrates 0.3%, proteins 9.2%). Ketosis was achieved by a β-hydroxybutyrate (BHB) whole blood level &gt;0.5 mmol/L. After 28 days, aortic diameters were measured by surgical microscopy. Isolated whole aortas were en-faced and stained with oil red O (ORO) to assess the grade of lesion area (plaque area + aneurysm degeneration area / whole aorta’s area) and plaque content (plaque area / whole aorta’s area). Results: KD mice remained in a ketotic state throughout the experiment. Thoracic and infrarenal AAs were identified in 60% and 74% of StD mice, respectively; however, only 13% and 33% of KD mice developed thoracic and infrarenal AAs, respectively. ORO staining (Fig. 1C and G) demonstrated a significantly smaller lesion area in KD mice (p = 0.04), (Fig. 1D). Furthermore, KD plaque content was attenuated in each segment of the aorta yet only significant in the thoracic aorta (p = 0.04), (Fig. 1H). Conclusions: Our results demonstrate that a ketogenic diet can attenuate the development of atherosclerotic plaque and AA degeneration in mice.
Immune checkpoint blocking impact and nomogram prediction of COVID-19 inactivated vaccine seroconversion in patients with cancer: a propensity-score matched analysis
Authors: Yifei Ma, Nianqi Liu, Youlong Wang, Jiling Zeng, Ying-Ying Hu, Wu Hao, Huazheng Shi, Pengfei Zhu, Jun Lv, Wei Fan, Xinjia Wang
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Patients with cancer on active immune checkpoint inhibitors therapy were recommended to seek prophylaxis from COVID-19 by vaccination. There have been few reports to date to discuss the impact of progression cell death-1 blockers (PD-1B) on immune or vaccine-related outcomes, and what risk factors that contribute to the serological status remains to be elucidated. The study aims to find the impact of PD-1B on vaccination outcome and investigate other potential risk factors associated with the risk of seroconversion failure. Methods Patients with active cancer treatment were retrospectively enrolled to investigate the interaction effects between PD-1B and vaccination. Through propensity score matching of demographic and clinical features, the seroconversion rates and immune/vaccination-related adverse events (irAE and vrAE) were compared in a head-to-head manner. Then, a nomogram predicting the failure risk was developed with variables significant in multivariate regression analysis and validated in an independent cohort. Results Patients (n=454) receiving either PD-1B or COVID-19 vaccination, or both, were matched into three cohorts (vac+/PD-1B+, vac+/PD-1B-, and vac-/PD-1B+, respectively), with a non-concer control group of 206 participants. 68.1% (94/138), 71.3% (117/164), and 80.5% (166/206) were seropositive in vac+/PD-1B+cohort, vac+/PD-1B- cohort, and non-cancer control group, respectively. None of irAE or vrAE was observed to be escalated in PD-1B treatment except for low-grade rash.The vaccinated patients with cancer had a significantly lower rate of seroconversion rates than healthy control. A nomogram was thus built that encompassed age, pathology, and chemotherapy status to predict the seroconversion failure risk, which was validated in an independent cancer cohort of 196 patients. Conclusion Although patients with cancer had a generally decreased rate of seroconversion as compared with the healthy population, the COVID-19 vaccine was generally well tolerated, and seroconversion was not affected in patients receiving PD-1B. A nomogram predicting failure risk was developed, including age, chemotherapy status, pathology types, and rheumatic comorbidity.
Dynamic changes in chromatin accessibility are associated with the atherogenic transitioning of vascular smooth muscle cells
Authors: Ying Wang, Hua Gao, Fudi Wang, Zhongde Ye, Michal Mokry, Adam W Turner, Jianqin Ye, Simon Koplev, Lingfeng Luo, Tom Alsaigh, Shaunak S Adkar, Maria Elishaev, Xiangyu Gao, Lars Maegdefessel, Johan L M Björkegren, Gerard Pasterkamp, Clint L Miller, Elsie G Ross, Nicholas J Leeper
Journal: Cardiovascular Research (2021)

De-differentiation and activation of pro-inflammatory pathways are key transitions vascular smooth muscle cells (SMCs) make during atherogenesis. Here, we explored the upstream regulators of this 'atherogenic transition'.
CSIG-26. NF2/MERLIN DRIVES MENINGIOMA APOPTOSIS AND SUCEPTIBILITY TO CYTOTOXIC THERAPY
Authors: Charlotte Eaton, Abrar Choudhury, Timothy Casey-Clyde, Danielle Swaney, Nevan Krogan, David Raleigh
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Alterations in NF2 underlie meningioma tumorigenesis, but tumor suppressor functions of the NF2 gene product, Merlin, are incompletely understood in meningiomas. Here we integrate proteomic proximity-labelling mass spectrometry with CRISPR interference (CRISPRi), RNA sequencing, and biochemical approaches to discover Merlin drives meningioma apoptosis and susceptibility to cytotoxic therapy. METHODS RNA sequencing was performed on triplicate M10G meningioma cells stably expressing CRISPRi machinery and either non-targeting control sgRNAs, sgRNAs suppressing NF2, or sgRNAs suppressing NF2 with Merlin rescue. QPCR in IOMM-Lee and MSC1 meningioma cells expressing non-targeting control shRNAs or shRNAs suppressing NF2 was used for orthogonal validation in vitro. RNA sequencing of euploid meningiomas (n=52) or meningiomas with loss of NF2 as the only copy number variant (n=28) was used for orthogonal validation in vivo. Merlin interactors in meningioma cells were identified using APEX proteomic proximity-labelling mass spectrometry. Mechanistic and functional studies were performed using biochemical, molecular, and cell biology approaches in meningioma cells and CH-157MN meningioma xenografts treated with cytotoxic chemotherapy or ionizing radiation. RESULTS Merlin suppression in meningioma cells and xenografts inhibited pro-apoptotic interferon regulatory factor (IRF) target genes and attenuated meningioma apoptosis. Merlin suppression did not alter IRF stability or subcellular localization in meningioma cells, and proteomic proximity-labelling mass spectrometry revealed a novel interaction between wildtype Merlin and ARHGAP35, a DNA binding factor that inhibits glucocorticoid receptor expression (NR3C1). NR3C1 inhibits IRF activity to prevent apoptosis, and Merlin suppression in meningioma cells induced NR3C1expression, which was inhibited by Merlin rescue. Further, NR3C1 suppression rescued meningioma cell apoptosis in the absence of Merlin, and NR3C1 expression was increased in human meningiomas with loss of NF2 compared to euploid meningiomas. CONCLUSIONS These data shed light on a novel pro-apoptotic tumor suppressor function of Merlin regulating glucocorticoid signalling and susceptibility to cytotoxic therapy in meningiomas.
Abstract 12906: Atypical Atrial Flutter Ablation Utilizing Ultra-High-Density Activation Mapping
Authors: Katherine C Romanowicz, Muhammad W Athar, ALEXANDRU I COSTEA
Journal: Circulation (2021)

Background: The incidence of atypical atrial flutters has increased in recent years, especially in the presence of atrial scar following valvular surgery involving atriotomy, surgical Maze procedures, or prior extensive radiofrequency ablation for persistent atrial fibrillation. Most are poorly tolerated and ablation is indicated. Ablation of these arrhythmias has historically presented a challenge with lower success rates and high recurrence rates. The concurrent advancement of mapping technology and the development of high-density mapping has allowed for more precise representation of the substrate of these complex arrhythmias. Objective: In this series, we report our experience utilizing CARTO3 Coherent mapping and the Confidense module (Biosense Webster, Inc.) in ablating complex left atrial flutters. Methods: Twelve patients with atypical atrial flutters and past history of valve surgery, Maze procedure, or persistent atrial fibrillation ablation were identified. We created ultra-high-density 3D maps using 3,000-6,000 points collected with a multipolar PENTARAY catheter and CARTO3 Coherent mapping. Radiofrequency ablation was performed at the narrowest isthmus using a Thermocool Smarttouch SF ablation catheter. Ambulatory ECG monitoring or CIED interrogation following the 3-month blanking period was utilized to evaluate the effectiveness of therapy. Results: In all cases, we had success in identifying and ablating small conduction gaps resulting in immediate termination of the arrhythmia. These gaps were not perceptible with voltage mapping and would have led to more extensive ablation and longer procedure time utilizing previous processing systems. Rhythm monitoring at least 3-months post-procedure demonstrated 8 of the 12 patients have not had recurrence of the arrhythmia. Conclusion: In our experience, the creation of ultra-high-density 3D mapping utilizing CARTO3 Coherent mapping has allowed for more precise mapping and simplifies the interpretation of arrhythmia mechanisms. Small gaps often responsible for these flutters are now more easily identifiable in comparison to previous mapping systems, facilitating efficient ablation, reducing procedure time, and reducing recurrence rates.