tbuckley/cabot-search huggingface dataset:
Abstract 13667: Earlier Onset in Homozygous Val122Ile Hereditary Transthyretin Cardiac Amyloidosis Allows for Advanced Therapies
Authors: Austin Rim, Sreeram Yalamanchili, Thomas Bigham, Matthew Brown, Kunal Bhatt
Journal: Circulation (2021)

Introduction: Transthyretin cardiac amyloidosis (TTR-CM) is a progressive disease characterized by the misfolding and deposition of amyloid fibrils extracellularly in the myocardium. The most common mutation in the U.S. is Val122Ile, which is estimated to occur in 3.4% of all African Americans. While this mutation is believed to have a more malignant phenotype, the differences in homozygous vs. heterozygous carriers of this autosomal dominant disease are not known. Methods: We conducted a retrospective chart review of patients enrolled in Emory University's Cardiac Amyloidosis Clinic between January 2014 and April 2021. Patients who carried one or more alleles for the Val122Ile mutation were included in this study. Means testing was performed and all data reported as mean ± standard deviation or count (percentage). Kaplan-Meier analysis was performed with Breslow test. Results: Among 74 patients who had the Val122Ile mutation, 6 were homozygotes and 68 were heterozygotes. Homozygotes were significantly younger than heterozygotes at diagnosis (61±6.5 vs. 74±7.1 years, p &lt; 0.01) and were more likely to present with stage 4 heart failure (p = 0.02). Compared to patients with heterozygous mutation, patients with homozygous mutation were more likely to receive heart transplantation (p = 0.04). Kaplan-Meier analysis revealed lower rate of survival for homozygotes when compared to heterozygotes (p = 0.04). Extracardiac manifestations of amyloidosis including carpal tunnel syndrome, lumbar stenosis, polyneuropathy, and autonomic dysfunction did not differ significantly between the two groups. Conclusion: Val122Ile homozygotes were diagnosed at a younger age than Val122Ile heterozygotes, presented more frequently with advanced stage heart failure, and had worse survival time. There was no difference in extracardiac manifestations of amyloidosis between the two groups.
RADT-26. PROTON VERSUS PHOTON CRANIOSPINAL IRRADIATION FOR ADULT MEDULLOBLASTOMA: A DOSIMETRIC AND TOXICITY ANALYSIS
Authors: William Breen, Connie Geno, William Harmsen, Paul Brown, Mark Waddle, Jing Qian, Terence Burns, Michael Ruff, Bryan Neth, Elizabeth Yan, Nadia Laack, Anita Mahajan
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma is a posterior fossa tumor rarely diagnosed in adults. Treatment includes craniospinal irradiation (CSI). Proton CSI is increasingly utilized to decrease radiation dose to normal tissues, despite the lack of randomized data demonstrating decreased toxicity compared to photon CSI. This single institution retrospective study of 39 adult medulloblastoma patients includes nineteen patients treated with photon CSI prior to 2015, and twenty treated with proton CSI thereafter. Median age was 28 years (range 18-66). Molecular subtype was most commonly sonic hedgehog (68%). The most common fractionation schedule was 36 Gy CSI in 20 fractions (85% of photon and 58% of proton patients) with a boost to 54-55.8 Gy (92%). Proton CSI delivered significantly lower mean doses to the cochleae (median 32 Gy vs. 44 Gy), lacrimal glands (8 vs. 36 Gy), lens (2 vs. 28 Gy), parotid glands (3 vs. 26 Gy), pharyngeal constrictors (6 vs. 15 Gy), esophagus (2 vs. 29 Gy), heart (0 vs. 14 Gy), lungs (1 vs. 7 Gy), liver (0.1 vs. 7 Gy), and skin (38 vs. 51 Gy) (all p&amp;lt; 0.001). Patients receiving proton CSI had significantly lower rates of acute dysphagia of any grade (5% vs. 35%, p= 0.044) and decreased median weight loss during radiation (+1.0 vs. -2.8 kg, p= 0.011). Acute hospitalization was associated with increased weight loss (p= 0.009). Median follow-up was 2.9 and 12.9 years for proton and photon patients, respectively, limiting late toxicity and outcome comparisons. At last follow-up five photon patients had died (two of progressive disease, three without recurrence ages 41-63) and 21% had experienced major cardiovascular events. At 10 years, 89% were alive and 82% were recurrence free. In conclusion, this study demonstrates dosimetric improvements with proton CSI, potentially leading to decreased acute toxicity including dysphagia and weight loss during treatment.
ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death—Executive Summary
Authors: Douglas P. Zipes, A. John Camm, Martin Borggrefe, Alfred E. Buxton, Bernard Chaitman, Martin Fromer, Gabriel Gregoratos, George Klein, Robert J. Myerburg, Miguel A. Quinones, Dan M. Roden, Michael J. Silka, Cynthia Tracy, Sidney C. Smith, Alice K. Jacobs, Cynthia D. Adams, Jeffrey L. Anderson, Sharon A. Hunt, Jonathan L. Halperin, Rick Nishimura, Joseph P. Ornato, Richard L. Page, Barbara Riegel, Silvia G. Priori, Arthur J. Moss, Silvia G. Priori, Elliott M. Antman, Jean-Jacques Blanc, Andrzej Budaj, A. John Camm, Veronica Dean, Jaap W. Deckers, Catherine Despres, Kenneth Dickstein, John Lekakis, Keith McGregor, Marco Metra, Joao Morais, Ady Osterspey, Juan Luis Tamargo, José Luis Zamorano
Journal: Journal of the American College of Cardiology (2006)
CBIO-10. TARGETING HISTONE H4 Lys 20 MONOMETHYLATION IN THE TREATMENT OF GLIOBLASTOMA
Authors: Mingzhi Han, Xingang Li
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Glioblastoma (GBM) is the most malignant primary tumor of the central nervous system, while the pathogenesis remains unclear. Protein lysine methyltransferase SETD8, which is responsible for the modification of histone H4K20me1, has been shown to play an important role in cellular transcriptional regulation and the development of a variety of tumors, yet its role in the malignant progression of GBM has not been elucidated. MATERIAL AND METHODS In the present study, we used primary GBM cell lines, intracranial xenograft model, transcriptome sequencing together with ChIP-sequencing, aiming to elucidate the molecular mechanism of SETD8-mediated H4K20me1 transcriptional regulation in promoting GBM progression. Furthermore, we evaluated the potential therapeutic significance in GBM using SETD8 small molecule inhibitor, UNC0379. RESULTS We found that SETD8 is aberrantly expressed in GBM tissues, accompanied by the dysregulation of H4K20me1 modification, which is associated with tumor pathology and prognosis. Using SETD8 inhibitor UNC0379 or knockdown of SETD8 significantly inhibited GBM cell proliferation in vitro and in vivo, and downregulated H4K20me1 modification level as well as transcriptome expression. CONCLUSION In summary, our work provide a novel insight into the role of SETD8/H4K20me1 axis. SETD8 overexpression mediated aberrant H4K20me1 modification act as a novel "transcriptional switch" in the malignant progression of glioma.
Lockdown impact on age-specific contact patterns and behaviours, France, April 2020
Authors: Paolo Bosetti, Bich-Tram Huynh, Armiya Youssouf Abdou, Marie Sanchez, Catherine Eisenhauer, Noémie Courtejoie, Jérôme Accardo, Henrik Salje, Didier Guillemot, Mathieu Moslonka-Lefebvre, Pierre-Yves Boëlle, Guillaume Béraud, Simon Cauchemez, Lulla Opatowski
Journal: Eurosurveillance (2021)

BackgroundMany countries implemented national lockdowns to contain the rapid spread of SARS-CoV-2 and avoid overburdening healthcare capacity.AimWe aimed to quantify how the French lockdown impacted population mixing, contact patterns and behaviours.MethodsWe conducted an online survey using convenience sampling and collected information from participants aged 18 years and older between 10 April and 28 April 2020.ResultAmong the 42,036 survey participants, 72% normally worked outside their home, and of these, 68% changed to telework during lockdown and 17% reported being unemployed during lockdown. A decrease in public transport use was reported from 37% to 2%. Participants reported increased frequency of hand washing and changes in greeting behaviour. Wearing masks in public was generally limited. A total of 138,934 contacts were reported, with an average of 3.3 contacts per individual per day; 1.7 in the participants aged 65 years and older compared with 3.6 for younger age groups. This represented a 70% reduction compared with previous surveys, consistent with SARS-CoV2 transmission reduction measured during the lockdown. For those who maintained a professional activity outside home, the frequency of contacts at work dropped by 79%.ConclusionThe lockdown affected the population's behaviour, work, risk perception and contact patterns. The frequency and heterogeneity of contacts, both of which are critical factors in determining how viruses spread, were affected. Such surveys are essential to evaluate the impact of lockdowns more accurately and anticipate epidemic dynamics in these conditions.
Abstract 10854: Acute Venous Thromboembolism in Patients with Elevated Body Mass Index, Can We Prescribe Direct Oral Anticoagulants
Authors: Justin Armstrong, Adam Foglesong, Alexandra Halalau, Ramy Mando
Journal: Circulation (2021)

Background: Due to the efficacy and lower bleeding risk of direct oral anticoagulants (DOACs) compared to coumadin, they are becoming the treatment of choice for acute venous thromboembolism (VTE). There is limited data in using DOAC’s for treatment of VTE (deep vein thrombosis (DVT) or pulmonary embolism (PE)) in patients with morbid obesity (body mass index &gt;40 kg/mm 2 ). We conducted a retrospective study to examine the rates of recurrence (failure of treatment) in patients diagnosed with an acute VTE. Methods: Electronic health record (EHR) from 8 hospitals in the Beaumont Health system were queried. A retrospective review of patients &gt; 18 years old with morbid obesity who were diagnosed with a DVT or PE and treated with a DOAC (rivaroxaban, apixaban or dabigatran) from 2010 to 2020 was performed. Individual charts were reviewed for ultrasound as well as computed tomography angiography results confirming the presence of an acute or chronic DVT or pulmonary embolism. To assess for recurrence, imaging studies performed 3 months after original diagnosis were studied. Results: 461 patients were included. The mean age was 58.9 years old with a range of 18-88 years old. Majority of patients were female (65.9%). The mean BMI was 46.5 with standard deviation of 7.4. 337 (73.1%) had an acute diagnosis of DVT or PE. When reassessing imaging 3 months after original diagnosis, only 2 (0.6%) patients had findings of recurrence (formation of new DVT or PE). Conclusion: In patient with morbid obesity, DOACs appear to be an effective therapy for treatment of DVT and PE. Further prospective studies are needed to confirm the findings of this analysis.
Abstract 12082: Disparities in Medical Care and Impact on Secondary Cardiovascular Complications Among Patients With Peripheral Artery Disease: A Report From the PAD Go Pro Quality Program
Authors: Matthew C Bunte, Kensey Gosch, Sravanthi Vupputuri
Journal: Circulation (2021)

Introduction: Guideline-directed optimal medical treatment (OMT) is known to reduce secondary cardiovascular risk among those with peripheral artery disease (PAD). Rates of OMT have been reported lowest among minority subgroups. Hypothesis: Race and ethnic identity are associated with differences in rates of OMT and secondary cardiovascular (CV) complications among a large, metropolitan population with PAD. Methods: From a single-system quality improvement registry, we evaluated rates of OMT and major adverse CV events (MACE), including all-cause death, myocardial infarction, and stroke. OMT was defined as use of an antiplatelet agent, statin, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker if hypertensive, and tobacco abstention if smoking. Patients were stratified based on baseline OMT status, then censored for MACE events. Results: From January 1, 2016-May 31, 2021, 15,107 outpatients with PAD had a mean age of 72.5 +/- 10.9 years, 46.5 % were female, and 89.6% identified as non-Hispanic White (NHW), 8.4% as non-Hispanic Black (NHB), and 2.0% as Hispanic/Latino (H/L). OMT was provided to 28.2% of patients overall. Rates of OMT provided to NHW, AA, and H/L cohorts were 28.2%, 26.9%, 32.6%, respectively (p=0.14). Among all patients with OMT at baseline (n=4263), 5-year rates of MACE were higher among NHB compared to NHW and H/L groups (31.9% vs 23.8% vs 24.6%, p=0.004). Among NHB, those receiving OMT had a lower risk of MACE at 5 years (31.9% vs 41.2%; log-rank p=0.014). OMT was similarly associated with reductions in MACE at 5 years within the H/L cohort (24.6% vs 47.7%; log-rank p=0.032). Conclusions: Rates of OMT to reduce secondary CV risk among those with ambulatory PAD are poor overall, and lowest among NHB subgroups. Non-OMT was associated with worse outcomes among all subgroups. Additional analysis to evaluate baseline differences, particularly regarding those affecting the provision of OMT, are warranted.
Abstract 12087: Device-Related Infection Associated With Increased Mortality Risk in <i>de novo</i> Transvenous Implantable Cardioverter-Defibrillator Medicare Patients
Authors: Mikhael F El-Chami, Yiyan Liu, Robert Griffiths, Bradley P Knight, Raul Weiss, George Mark, Mauro Biffi, vincent probst, Pier Lambiase, Marc Miller, Caroline Jacobsen, Larry M Baddour
Journal: Circulation (2021)

Introduction: Device-related infection is estimated to occur in 1.9% of the Medicare patients with de novo transvenous (TV) implantable cardioverter-defibrillators (ICD) within 2 years post-implant. TV-ICD infection is a serious complication that frequently requires complete device removal for attempted cure, which can be associated with patient morbidity and mortality. The objective of this study is to expand on limited published data and assess mortality risk associated with TV-ICD infection in a large Medicare population with de novo TV-ICD implants. Methods: A survival analysis was conducted using 100% fee-for-service Medicare facility-level claims data to identify patients who underwent de novo TV-ICD implantation between 7/2016 and 1/2018. TV-ICD infection within 2 years of implantation was identified using ICD-10 and CPT codes. Baseline patient risk factors associated with mortality were identified using the Charlson Comorbidity Index categories. Infection was treated as a time-dependent variable in a multivariate Cox proportional hazards model to account for immortal time bias. Results: Among 26,742 Medicare patients with de novo TV-ICD, 518 (1.9%) had a device-related infection. The overall number of decedents was 4,721 (17.7%) over 2 years, with 4,555 (17%) in the non-infection group and 166 (32%) in the infection group. After adjusting for baseline patient demographic characteristics and various comorbidities, the presence of TV-ICD infection was associated with an increase of 2.4 [95% CI: 2.08-2.85] times in the mortality hazard ratio (see attached Figure). Most of the baseline patient risk factors were also associated with higher risk of mortality in the Cox model. Conclusion: The rate of de novo TV-ICD infection and associated mortality in a large, real-world Medicare population is noteworthy. The positive association between device-related infection and risk of mortality further highlights the need to reduce infections.
Abstract P432: Alpha-actinin 2 Missense Variant And Its Role In Cardiac Muscle Force Production And Diastolic Dysfunction
Authors: Michelle C Rodriguez Garcia, Maicon Landim-Vieira, Jeffrey Schmeckpeper, Lili Wang, Ben B Shoemaker, Prescott B Chase, Bjorn C Knollmann, Jose R Pinto
Journal: Circulation Research (2021)

ACTN2 gene encodes for the alpha-actinin 2 protein, which has an actin-binding role. In cardiac muscle, alpha-actinin 2 is located in the Z-disc of the sarcomere, where it anchors myofibrillar actin filaments. A 48-years old female patient presented with ventricular fibrillation arrest was successfully resuscitated. Coronary angiography exhibited normal coronary arteries. Cardiac MRI did not show myocardial scar tissue or arrhythmogenic right ventricular dysplasia (ARVD). Echocardiogram showed normal left ventricular ejection fraction, stage II diastolic dysfunction and elevated right ventricular systolic pressure. Genetic testing identified a missense variant of unknown significance in ACTN2 (a gene previously associated with dilated cardiomyopathy/ARVD), and in SCNB2 (encodes sodium voltage-gated channel beta subunit 2, a gene previously associated with long QT syndrome). We investigated the effects of the ACTN2 variant on cardiac muscle contraction, providing an inside view of the importance of ACTN2 in sarcomere function. Left ventricular free wall samples were obtained from the patient’s explanted heart at the time of cardiac transplantation. Mechanics of contraction were measured in permeabilized cardiac muscle preparations (CMPs) in the presence of 3% dextran T-500 (to restore the myofilament lattice to physiological dimensions) at 30°C. The experiments were performed at sarcomere lengths 2.1 μm and 2.3 μm achieved by HeNe laser diffraction. CMPs containing ACTN2 mutant protein displayed increased myofilament Ca 2+ sensitivity of isometric force and lower maximal isometric force compared to human donor samples (control). Sinusoidal stiffness was decreased at all levels of Ca 2+ activation and isometric force in ACTN2 variant CMPs. The rate of tension redevelopment was faster at all levels of Ca 2+ activation and isometric force. Alpha-actinin 2 is an important sarcomeric protein that regulates the kinetics of cardiac muscle contraction. This work establishes the importance of alpha-actinin 2 in the Z-disc mechanotransduction to thin and thick filament interactions.
Abstract 12614: Impact of Hospital Invasive Procedure Capability on Pulmonary Embolism Mortality
Authors: Kevin Chan, Daniel Lu, Luke K Kim
Journal: Circulation (2021)

Objective: This study aimed to evaluate the impact of hospital invasive procedure capability and inpatient mortality of patients with pulmonary embolism (PE). Background: PE is associated with significant mortality. Catheter-directed thrombolysis and surgical embolectomy are the interventional methods accessible to hospitals with specialized procedural resources. Limited data exist comparing outcomes of patients who are admitted to hospitals with these capabilities versus those that do not. Methods: PE hospitalizations were obtained from the National Inpatient Sample for the years 2012-2014. Hospitals equipped to perform either catheter-directed thrombolysis or surgical embolectomy were classified as specialized hospitals (SH). Those without such capabilities were classified as non-specialized hospitals (NSH). In-hospital mortality of patients with PE was compared among these two cohorts. Results: Among hospitals treating patients with PE, 333 (9.1%)were classified as SH and 3337 (91.0%) were classified as NSH. There were 43,461(21.9%) admissions with PE to SH and 154,731 (78.1%) to NSH. Mortality was 6.1% at SH and 7.6% at NSH (p&lt;0.01). Of patients admitted to SH, 3.6% underwent invasive procedures. Hospitalizations at SH were associated with higher hospitalization cost and longer lengths of stays. On multivariable analysis, there was no difference in mortality among patients admitted to SH versus NSH (OR 0.99, CI 0.93-1.04, p=0.61) Conclusions: Patients with pulmonary embolism being treated at specialized hospitals have a similar mortality rate to those being treated at non-specialized hospitals. Further investigation into the factors contributing to this similar rate is warranted.
Abstract 13569: A Composite Score Summarizing Use And Dosing Of Evidence-based Medical Therapies In Heart Failure: Application To The DAPA-HF Trial
Authors: Pooja Dewan, Olof Bengtsson, Kieran Docherty, Silvio E Inzucchi, Pardeep S Jhund, Lars Kober, Mikhail N Kosiborod, Anna Maria Langkilde, Felipe Martinez, Piotr Ponikowski, Marc S Sabatine, Mikaela Sjostrand, Scott Solomon, Tor Biering-srensen, Muthiah Vaduganathan, Ersilia M Defilippis, Mona Fiuzat, John J McMurray
Journal: Circulation (2021)

Introduction: The Heart Failure Collaboratory consortium (HFC) has developed a score to quantify background guideline-directed medical therapy (GDMT) in patients with heart failure and reduced ejection fraction (HFrEF). One potential use of this score is to test the incremental value of new therapies. We evaluated the effect of dapagliflozin according to a modified HFC score in the DAPA-HF trial. Methods: The key inclusion criteria in DAPA-HF were: 1) NYHA class II-IV, 2) LVEF ≤40%, and 3) elevated plasma NT-proBNP and 4) eGFR ≥30 ml/min/1.73m2. The primary outcome was a composite of a first episode of worsening HF (hospitalization for HF or an urgent HF visit requiring iv therapy) or cardiovascular death. The HFC score is calculated based on the use of GDMT and dose of GDMT. The modified HFC score used here also accounted for race (Black/non-Black) and ECG rhythm/rate with a maximum possible score of 100 (percent) for any patient (Panel A). Results: Among the 4744 patients (mean age 66 years; 23% women) randomized, an ACEi/ARB was used in 84%, beta-blocker 96%, MRA 71%, ARNI 11%, ivabradine 4.8%, and hydralazine 4.3%. During a median follow-up of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and 502 of 2371 patients (21.2%) in the placebo group (HR, 0.74; 95%CI 0.65 to 0.85; P&lt;0.001). The benefit of dapagliflozin on the primary outcome was consistent across the range of baseline treatment score (Panel B). Examination of the effect of dapagliflozin on the primary outcome by score tertile (T1 ≤40, T2 41-60 and T3 &gt;60) gave HRs for the effect of dapagliflozin, compared with placebo, of 0.75 (0.61-0.93), 0.77 (0.61-0.98), and 0.71 (0.55-0.90), respectively (P-interaction 0.87). Conclusions: A composite score for GDMT of the type developed by the HFC can be easily calculated in clinical trials and used to evaluate the incremental effect of new therapies.
PATH-02. TWO CASES WITH MULTIPLE HYBRID NERVE SHEATH TUMORS WITH ERBB2 MUTATIONS
Authors: Yoon Jae Choi, Mari Perez-Rosendahl
Journal: Neuro-Oncology (2021)

Abstract Hybrid nerve sheath tumors are new disease entity incorporated in WHO classification of tumors of the central nervous system 2016 version that includes benign peripheral nerve sheath tumors with combined features of more than one conventional type. Ronellenfitsch et al recently reported one case with ERBB2 D769Y mutation with good clinical response to lapatinib in 2020. We report two cases with imaging findings of multiple peripheral nerve sheath tumors with pathology proven hybrid nerve sheath tumors with ERBB2 mutations. Patient 1 has neurofibroma/schwannoma hybrid nerve sheath tumor with ERBB2 D769Y mutation and patient 2 has plexiform neurofibroma/schwannoma hybrid nerve sheath tumor with ERBB2 V777L mutation. Both of our patients have similar clinical features with adult-onset multiple peripheral nerve sheath tumors without other systemic features of neurofibromatosis type1 or vestibular schwannomas or family history. Hybrid nerve sheath tumors are newly recognized disease and more than half of the cases have multiple peripheral nerve sheath tumors, suggestive of tumor syndrome. Patients with multiple peripheral nerve sheath tumors without systemic features of neurofibromatosis type1 or vestibular schwannomas should be screened for genetic/molecular tests including ERBB2 mutation that might provide treatment options for these patients.