tbuckley/cabot-search huggingface dataset:
Abstract 12690: Outcomes of Tricuspid Valve Surgery in Patients With Septic Pulmonary Embolism From Drug-Associated Tricuspid Valve Endocarditis
Authors: Emaad Siddiqui, Carlos Alviar, Abhinay Ramachandran, Erin Flattery, Norma M Keller, Sripal Bangalore
Journal: Circulation (2021)

Introduction: Septic pulmonary emboli (PE) are a common sequela of drug-use associated infective endocarditis (DU-IE) of the tricuspid valve and is considered an indication for surgery. Methods: The Healthcare Cost and Utilization Project’s National Inpatient Sample was queried from 2008-2017 for adult patients hospitalized for septic PE with the diagnosis of DU-IE of the tricuspid valve. In-hospital outcomes of patients who underwent tricuspid valve operation (TVO) were compared with patients who did not. The primary outcome was perioperative major adverse cardiovascular events (MACE) defined as a composite of death, myocardial infarction (MI), stroke, cardiogenic shock, and cardiac arrest. Results: A total of 6,758 cases of DU-IE with septic PE were identified (mean age 32.2), of which 2,262 (33.6%) had a TVO during hospital admission. Patients who underwent a TVO had longer length of stay (32.3 vs 17.7, p&lt;0.05), higher hospital costs ($97,486 vs $34,728, p&lt;0.05), and more discharges to a long-term facility (33.7% vs 27.9%, p&lt;0.05). MACE was significantly higher in patients undergoing TVO (12.5% vs 7.1%, p&lt;0.05), which was driven by higher rates of stroke (5.0% vs 2.7%, p&lt;0.05) and cardiogenic shock (4.8% vs 0.8%, p&lt;0.05) but notably, a lower rate of mortality (2.0% vs 4.0%, p&lt;0.05). In addition, patients who underwent TVO had more pulmonary complication (49.0% vs 29.5%, p&lt;0.05), acute kidney injury (44.3% vs 34.0%, p&lt;0.05), permanent pacemaker placement (15.0% vs 0.2%, p&lt;0.05), and tracheostomy (3.7% vs 1.8%, p&lt;0.05). After multivariable adjustment, TVO was associated with an increased risk for MACE (aOR=1.55, 95% CI 1.25 - 1.86). Conclusion: The utility of surgical intervention remains controversial given the lower rate of mortality, but higher rate of adverse outcomes in this young patient population. Alternative management strategies including percutaneous intervention should be considered given the morbidity associated with this disease presentation.
BIOM-10. PRECLINICAL PLATFORM FOR THE IDENTIFICATION OF DEUTERIUM MAGNETIC RESONANCE SPECTROSCOPY-BASED BIOMARKERS OF BRAIN TUMOR METABOLISM
Authors: Georgios Batsios, Meryssa Tran, Céline Taglang, Anne Marie Gillespie, Sabrina Ronen, Joseph Costello, Pavithra Viswanath
Journal: Neuro-Oncology (2021)

Abstract Metabolic reprogramming is a fundamental hallmark of cancer, which can be exploited for non-invasive tumor imaging. Deuterium magnetic resonance spectroscopy (2H-MRS) recently emerged as a novel, translational method of interrogating flux from 2H-labeled substrates to metabolic products. However, to date, preclinical studies have been performed in vivo, an endeavor which suffers from low-throughput and potential wastage of animal life, especially when considering studies of treatment response. Developing in vitro assays for monitoring metabolism of 2H-labeled substrates will enhance throughput, lead to the rapid evaluation of new 2H-based probes and enable identification of treatment response biomarkers, thereby allowing the best 2H-based probes to be translated for further in vivo assessment. The goal of this study was to develop a preclinical cell-based platform for quantifying metabolism of 2H-labeled probes in brain tumor models. Since the Warburg effect, which is characterized by elevated glycolytic production of lactate, is a metabolic phenotype of cancer, including brain tumors, we examined metabolism of 2H-glucose or 2H-pyruvate in patient-derived glioblastoma (GBM6) and oligodendroglioma (BT88) cells and compared to normal human astrocytes (NHACONTROL). Following incubation in media containing [6,6’-2H]glucose or [U-2H]pyruvate, 2H-MR spectra obtained from live cell suspensions showed elevated 2H-lactate production in GBM6 and BT88 cells relative to NHACONTROL. Importantly, 2H-lactate production from [6,6’-2H]glucose or from [U-2H]pyruvate was reduced in GBM6 or BT88 cells subjected to irradiation and temozolomide, which is standard of care for glioma patients, pointing to the utility of this method for detecting response to therapy. Collectively, we have, for the first time, demonstrated the ability to quantify metabolism of 2H-MRS probes in live cell suspensions and validated the utility of our assay for differentiating tumor from normal cells and assessing response to therapy. Our studies will expedite the identification of novel 2H-MRS probes for imaging brain tumors and potentially other types of cancer.
Abstract 12066: The Long-Term Safety and Efficacy of Evinacumab in Patients With Homozygous Familial Hypercholesterolemia
Authors: Frederick J Raal, Robert S Rosenson, Rens Reeskamp, John J Kastelein, Paolo Rubba, Bart Duell, Masahiro Koseki, Erik S Stroes, Shazia Ali, Poulabi Banerjee, KuoChen Chan, Nagwa Khilla, Jennifer McGinniss, Robert Pordy, Yi Zhang, Daniel Gaudet
Journal: Circulation (2021)

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic lipid disorder characterized by marked elevations in LDL-C and premature atherosclerotic cardiovascular disease (ASCVD). EU guidelines recommend LDL-C treatment goals of &lt;55 mg/dL and &lt;70 mg/dL for pts with HoFH with and without ASCVD, respectively. Evinacumab (EVIN; an angiopoietin-like 3 inhibitor) significantly reduced LDL-C and was generally well tolerated in pts with HoFH during the 24-week double-blind treatment period (DBTP) of a pivotal Phase 3 study (NCT03399786). Methods: This post-hoc analysis assessed the long-term effect of EVIN on LDL-C goal attainment in pts with HoFH who participated in the subsequent 24-week open-label treatment period (OLTP) of the pivotal Phase 3 study. All pts received intravenous EVIN 15 mg/kg every 4 weeks. Efficacy by background lipid lowering medication (LLM) subgroups and the effect of EVIN on eligibility for apheresis were also assessed. Results: In total, 65 pts entered the OLTP and 64 pts (98.5%) received OL EVIN. Overall, 50.0% achieved LDL-C &lt;100mg/dL, 31.7% achieved LDL-C &lt;70 mg/dL and 23.3% achieved LDL-C &lt;55 mg/dL at Week 48 (end of OLTP) (Figure 1). For the subgroup with ASCVD (n=36), 50.0%, 37.5% and 31.3% achieved LDL-C &lt;100 mg/dL, &lt;70 mg/dL and &lt;55 mg/dL, respectively. Overall, 43.1%, 24.6% and 38.5% of pts qualified for apheresis at baseline and did not qualify for apheresis at Week 48 (using new US, US and EU criteria); no patient discontinued apheresis. EVIN markedly reduced LDL-C, irrespective of background LLM. Overall, treatment-emergent adverse events (TEAEs) occurred in 47 pts (73.4%) during the OLTP. Serious AEs (all unrelated to EVIN) were reported by 7 pts (10.9%), none led to death or EVIN discontinuation. Conclusions: EVIN enabled 31.7% of all pts to achieve LDL-C &lt;70 mg/dL and 31.3% of those with ASCVD to achieve LDL-C &lt;55 mg/dL. EVIN markedly reduced the proportion of pts qualifying for apheresis.
Abstract 12517: CardioSignal Smartphone Application Detects Atrial Fibrillation in Heart Failure Population
Authors: Juuso Blomster, Olli Lahdenoja, Kamal Jafarian Dehkordi, Matti Kaisti, Tero Tapiovaara, Kristiina Santalahti, Mikko Pankaala
Journal: Circulation (2021)

Introduction: The micro-electromechanical sensors of a common smartphone can be used to detect vibrations caused by cardiac motion when the smartphone is placed on chest. With commonly available CardioSignal application (App) the concept has been shown to detect atrial fibrillation (AFib) in clinical setting from a 60 second recording. The CardioSignal smartphone app is a certified CE IIa-class medical device and intended to detect AFib in adult population. AFib and heart failure (HF) frequently coexist and together can lead to increased morbidity. To address this subgroup of individuals with increased risk of Afib, we examined how CardioSignal solution performs in Afib detection in a population of recent HF decompensation. Methods: From a total of 83 HF patients (mean age 64, 70 % men) motion sensor signals were collected and analyzed with the CardioSignal solution. The signals were collected by placing a smartphone on the chest of the patients in supine position. From the recordings two 60 second strips were analyzed. A simultaneous 1-lead ECG data was collected with an ECG patch from the V4 position. The signals were analyzed for quality and rhythm diagnostics from the ECG recording was by a cardiologist blinded for the CardioSignal solution result. Finally a head-to-head comparison was conducted for CardioSignal result and the ECG data. A positive finding for Afib was concluded if both 60 second recordings detected Afib for each person. Results: From the 83 HF patients 166 measurements were recorded. Out of the 166 measurements, 163 passed the quality check for the sensor signals. The preliminary analyses showed sensitivity of the AFib detection algorithm of 80.7% (95% CI 62.5% to 92.6%) and the specificity of 100.0% (93.1% to 100.0%). The positive predictive value was 100.0% and the negative predictive value 89.7% (80.9% to 94.7%). The accuracy was 92.8% (84.9% to 97.3%). Conclusions: A smartphone-based recording and analysis with CardioSignal solution in HF patients appear to be an effective and reliable method to detect possible Afib.
Abstract 10875: Long-Term Mortality Associated with Use of Carvedilol vs Metoprolol in Heart Failure Patients with and Without Type 2 Diabetes
Authors: Brian Schwartz, Colin Pierce, Christian Madelaire, Morten Schou, Soren L Kristensen, Gunnar Gislason, Lars Kober, Christian Torp-Pedersen, Charlotte Andersson
Journal: Circulation (2021)

Background: Carvedilol may have favorable glycemic properties compared with metoprolol, but it is unknown if carvedilol has mortality benefit over metoprolol in patients with type 2 diabetes (T2DM) and heart failure with reduced ejection fraction (HFrEF). Methods and Results: Using Danish nationwide databases between 2010-2018, we followed patients with new-onset HFrEF treated with either carvedilol or metoprolol for all-cause mortality until the end of 2018. Follow-up started 120 days after initial HFrEF diagnosis to allow initiation of guideline-directed medical therapy. There were 39,260 patients on carvedilol or metoprolol at baseline (mean age 70.8 years, 35% women), of which 9,355 (24%) had T2DM. Carvedilol was used in 2,989 (32%) patients with TD2M and 10,411 (35%) of patients without T2DM. Users of carvedilol had a lower prevalence of atrial fibrillation (20% vs. 35%), but other characteristics appeared well-balanced between the groups. Totally 11,306 (29%) were deceased by the end of follow-up. We observed no mortality differences between carvedilol and metoprolol, multivariable-adjusted hazards ratio 0.97 (0.90-1.05) in patients with T2DM versus 1.00 (0.95-1.05) for those without T2DM, p for difference =0.99. Rates of new-onset T2DM were lower in users of carvedilol vs. metoprolol; age, sex, and calendar year adjusted hazards ratio 0.83 (0.75-0.91), p&lt;0.0001. Conclusion: In a contemporary clinical cohort of HFrEF patients with and without T2DM, carvedilol was not superior to metoprolol for long-term mortality reduction. However, carvedilol was associated with lowered risk of new-onset T2DM supporting the assertion that carvedilol have a more favorable metabolic profile than metoprolol overall.
Abstract 9811: Bone Marrow-Derived Mir-181a/b Controls Hematopoiesis, Monocytosis, and Angiogenic Responses in Diabetic Critical Limb Ischemia
Authors: Henry S Cheng, Rulin Zhuang, Daniel Perez-Cremades, Jingshu Chen, Anurag Jamaiyar, Jorge Henao-Mejia, Philip P Goodney, Marc S Sabatine, Mark A Creager, Marc P Bonaca, Mark W Feinberg
Journal: Circulation (2021)

Introduction: Humans with peripheral artery disease (PAD) that develop critical limb ischemia (CLI) have a high risk of amputation and cardiovascular complications. Diabetes mellitus (DM) is a prominent risk factor in development of CLI, yet the molecular mechanisms remain incompletely understood. Objective: To investigate microRNA biomarkers and their involvement in the pathogenesis of CLI in human subjects and mice with and without diabetes. Methods: miRNA-seq of diabetic patients with or without CLI was compared to diabetic mice with acute or subacute limb ischemia to identify conserved miRNAs. miRNA knockout (KO) mice on chow or high fat diet were generated to explore impact on CLI. Results: miR-181 family members were among the top conserved miRNAs from mice to human subjects. Compared to wild type (WT) controls, systemic Mir181a2b2 KO mice on chow-fed diet had increased blood flow recovery following FAL and higher M1-macrophage polarization in ischemic skeletal muscles. KO macrophages increased CCL4 and VEGFA to promote angiogenesis. Conversely, diabetic KO mice had impaired revascularization in limbs compared to WT, due to abrogation of circulating Ly6C hi monocytes with reduced accumulation of macrophages in ischemic skeletal muscles. Furthermore, M2-like macrophages deficient of miR-181a/b under diabetic conditions failed to produce pro-angiogenic cytokines. Reduced monocytosis in KO mice was a result of impaired hematopoiesis with increased CXCR4 signaling in Lin - Sca1 + Kit + (LSK) cells in the bone marrow. Importantly, supplying diabetic KO mice with exogenous delivery of Ly6C hi monocytes from non-diabetic KO mice rescued the impaired revascularization after limb ischemia. Conclusions: MiR-181a/b is a putative biomarker of diabetic CLI and contributes to alterations in hematopoiesis, monocytosis, and macrophage polarization. Pathways regulated by miR-181a/b may provide therapeutic targets for PAD patients at risk of developing CLI.
CNTM-03. Functional connectivity networks in patients with brain tumors and vascular lesions in the occipital cortex
Authors: Katharina Rosengarth, Katharina Hense, Tina Plank, Mark Greenlee, Christina Wendl, Martin Proescholdt, Nils-Ole Schmidt
Journal: Neuro-Oncology (2021)

Abstract OBJECTIVE Space-occupying brain lesions as brain tumors in the occipital lobe have only been sparsely investigated so far, as this localization is extremely rare with only 1% of cases. It is still unclear how this affects the overall organization of the visual system. We investigated functional connectivity of functional networks associated with higher visual processing between patients with occipital space-occupying lesion in the occipital cortex and healthy controls. METHODS 12 patients with brain tumors, 7 patients with vascular lesions in the occipital cortex and 19 healthy subjects matched for age and sex were included. During functional MRI patients and subjects performed a visual excentricity mapping task. Data analysis was done using CONN toolbox based on Matlab. See-to-ROI connectivities of 23 Regions of Interest (ROIs) implemented in the CONN toolbox which were assigned to the Default Mode, Visual, Salience, Dorsal Attention, and Frontoparietal network were assessed. For each subject, connectivity was calculated using Fischer transformed pairwise correlations. These correlations were first considered separately for each group in one-sample analyses and then compared between the groups. RESULTS Main results show, that compared to control subjects and vascular patients, tumor patients showed weaker intra-network connectivity of components of all networks except the default-network. Tumor patients showed even stronger between-network connectivity in the default-mode network compared to the other groups. Weaker connectivity was observed within the salience network in both patient groups compared to controls. CONCLUSION The results indicate that in the course of the disease, compensatory countermeasures take place in the brain against a brain tumor or a space-occupying brain lesion with the aim of maintaining the performance level and cognitive processes for as long as possible. However, more research is needed in this area to understand the mechanisms and effects of brain tumors and space-consuming brain lesions on surrounding tissue.
Abstract 12577: Pulmonary Endothelial Sulfatase-1 is Regulated by NEDD9 and Increased in Pulmonary Arterial Hypertension
Authors: Andriy Samokhin, Wang Yefang, Bradley M Wertheim, George A Alba, Elena Arons, Bradley Maron
Journal: Circulation (2021)

Introduction: Oxidation of the scaffolding protein NEDD9 by aldosterone (ALDO) increases NEDD9 bioactivity in human pulmonary artery endothelial cells (HPAECs), leading to pulmonary arterial hypertension (PAH). In tumor cells, oxidizing conditions alter Sulfatase-1 (SULF-1) activity. In turn, SULF-1 catalyzes 6-O-sulfate removal from heparan sulfate proteoglycans that releases cytokines implicated in the pathogenesis of PAH. Hypothesis: NEDD9 regulates SULF-1 expression in HPAECs, which is associated with pulmonary arterial remodeling in PAH. Methods: HPAECs were treated with ALDO (10 -7 mol/L) for 24 hr and then untransfected (Un-Tx) or transfected with siRNA against NEDD9, and cell lysates were used to isolate mRNA for RNA-Seq. Separately, SULF1 expression was measured by immunoblot in HPAECs transfected with si-NEDD9 or scrambled control siRNA. Paraffin-embedded lung specimens from donor controls (N=5), patients with PAH (N=5), or the monocrotaline (MCT) (inflammatory) and SU-5416/hypoxia (angioproliferative) experimental rat models of PAH were analyzed by immunofluorescence to quantify SULF1, NEDD9, and endothelial PECAM-1. Results: In ALDO-treated HPAECs, si-NEDD9 decreased SULF1 mRNA quantity vs. Un-Tx (logFC -6.39, N=3, P&lt;0.001, FDR&lt;0.001). Transfection with si-NEDD9 also decreased SULF1 protein compared to si-Scr (14 ± 2.0 vs. 2.7 ± 1.0 arb. units, N=3, P&lt;0.01) in vitro . In remodeled pulmonary arterioles from MCT-PAH and SU-5416/hypoxia-PAH, SULF1 was increased by 5.6-fold (P&lt;0.01) and 6.6-fold (P&lt;0.01), respectively, and correlated strongly with NEDD9 protein (r=0.91, N=9, P&lt;0.001). The translational relevance of these data was assessed next: compared to donor controls, pulmonary endothelial SULF1 was increased in remodeled pulmonary arterioles from PAH patients in situ (0.03 ± 0.01 vs. 0.14 ± 0.03 arb. units, P&lt;0.05). Conclusions: SULF1 is regulated by the scaffolding protein NEDD9 in HPAECs in vitro , and remodeled pulmonary arterioles from two experimental PAH models and PAH patients express increased NEDD9-SULF1. Identifying the molecular mechanism(s) regulating NEDD9-dependent regulation of SULF1 may have important implications for therapeutic target discovery to prevent vascular remodeling in PAH.
Clinical Significance of <i>FLT3</i> Mutations in a Comprehensive NGS Multicenter Study of AML: HM-Screen-Japan 01
Authors: Kentaro Fukushima, Hirohiko Shibayama, SungGi Chi, Naoko Hosono, Takahiro Yamauchi, Seiichiro Katagiri, Akihiko Gotoh, Motoki Eguchi, Takanobu Morishita, Reiki Ogasawara, Takeshi Kondo, Masamitsu Yanada, Kazuhito Yamamoto, Tsutomu Kobayashi, Junya Kuroda, Yoshimasa Kamoda, Kensuke Usuki, Yoshikazu Utsu, Nobuyuki Aotsuka, Makoto Yoshimitsu, Kenji Ishitsuka, Takaaki Ono, Naoto Takahashi, Satoshi Iyama, Makoto Nakamura, Yukinori Nakamura, Suguru Fukuhara, Koji Izutsu, Nobuhiko Yamauchi, Junichiro Yuda, Yosuke Minami
Journal: Blood (2021)
Effect of Intravenous or Intraosseous Calcium vs Saline on Return of Spontaneous Circulation in Adults With Out-of-Hospital Cardiac Arrest
Authors: Mikael Fink Vallentin, Asger Granfeldt, Carsten Meilandt, Amalie Ling Povlsen, Birthe Sindberg, Mathias J. Holmberg, Bo Nees Iversen, Rikke Mærkedahl, Lone Riis Mortensen, Rasmus Nyboe, Mads Partridge Vandborg, Maren Tarpgaard, Charlotte Runge, Christian Fynbo Christiansen, Thomas H. Dissing, Christian Juhl Terkelsen, Steffen Christensen, Hans Kirkegaard, Lars W. Andersen
Journal: JAMA (2021)

It is unclear whether administration of calcium has a beneficial effect in patients with cardiac arrest.To determine whether administration of calcium during out-of-hospital cardiac arrest improves return of spontaneous circulation in adults.This double-blind, placebo-controlled randomized clinical trial included 397 adult patients with out-of-hospital cardiac arrest and was conducted in the Central Denmark Region between January 20, 2020, and April 15, 2021. The last 90-day follow-up was on July 15, 2021.The intervention consisted of up to 2 intravenous or intraosseous doses with 5 mmol of calcium chloride (n = 197) or saline (n = 200). The first dose was administered immediately after the first dose of epinephrine.The primary outcome was sustained return of spontaneous circulation. The secondary outcomes included survival and a favorable neurological outcome (modified Rankin Scale score of 0-3) at 30 days and 90 days.Based on a planned interim analysis of 383 patients, the steering committee stopped the trial early due to concerns about harm in the calcium group. Of 397 adult patients randomized, 391 were included in the analyses (193 in the calcium group and 198 in the saline group; mean age, 68 [SD, 14] years; 114 [29%] were female). There was no loss to follow-up. There were 37 patients (19%) in the calcium group who had sustained return of spontaneous circulation compared with 53 patients (27%) in the saline group (risk ratio, 0.72 [95% CI, 0.49 to 1.03]; risk difference, -7.6% [95% CI, -16% to 0.8%]; P = .09). At 30 days, 10 patients (5.2%) in the calcium group and 18 patients (9.1%) in the saline group were alive (risk ratio, 0.57 [95% CI, 0.27 to 1.18]; risk difference, -3.9% [95% CI, -9.4% to 1.3%]; P = .17). A favorable neurological outcome at 30 days was observed in 7 patients (3.6%) in the calcium group and in 15 patients (7.6%) in the saline group (risk ratio, 0.48 [95% CI, 0.20 to 1.12]; risk difference, -4.0% [95% CI, -8.9% to 0.7%]; P = .12). Among the patients with calcium values measured who had return of spontaneous circulation, 26 (74%) in the calcium group and 1 (2%) in the saline group had hypercalcemia.Among adults with out-of-hospital cardiac arrest, treatment with intravenous or intraosseous calcium compared with saline did not significantly improve sustained return of spontaneous circulation. These results do not support the administration of calcium during out-of-hospital cardiac arrest in adults.ClinicalTrials.gov Identifier: NCT04153435.