tbuckley/cabot-search huggingface dataset:
Abstract 115: Cell-type-specific Gene Expression And Transcriptional Networks Reveal <i>Adamts2</i> As A Powerful Regulator Of Cardiac Homeostasis During Heart Failure
Authors: Caitlin Lahue, Douglas Chapski, Manuel Rosa Garrido, Shuxun Ren, Thomas M Vondriska, Yibin Wang, Christoph Rau
Journal: Circulation Research (2021)

Background: Heart failure (HF) is a highly heterogeneous disorder characterized by the interactions of multiple genetic and environmental factors as well as the interaction of different cell types in the heart. Although reductionistic approaches have successfully identified many genes involved in HF, heritability studies suggest that many genes have resisted discovery through these approaches. By utilizing cell-type-specific gene expression paired with transcriptomic data from a large cohort of mice, we sought to identify important drivers of HF using a systems genetics approach. Methods and Results: Mice from 93 unique inbred lines of the Hybrid Mouse Diversity Panel were given 30 ug/g/day of isoproterenol for three weeks via osmotic minipump to induce heart failure. Transcriptomes were generated from these mice and the weighted Maximal Information Component Analysis (wMICA) algorithm was applied to generate transcriptomic gene networks. Cardiomyocytes and Fibroblasts were isolated from both control and isoproterenol-treated adult C57BL/6J hearts using a Langendorff apparatus (n=3 per sex/treatment) and transcriptomes were generated. Significantly differentially expressed genes were identified using DESEQ2 and used to query the wMICA-derived network, identifying the gene Adamts2 as a potential regulator of cardiac hypertrophy. Follow-up in vitro and in vivo work has demonstrated that Adamts2 knockdown significantly blunts the hypertrophic effect of isoproterenol on cardiomyocytes while simultaneously reducing fibroblast proliferation and increasing apoptosis as measured by TUNEL staining. Careful examination of the gene network reveals evidence of paracrine signaling between cardiomyocytes and fibroblasts and suggests a key trans-cell-type role of Adamts2 in the regulation of HF after catecholamine stimulation. Conclusion: Co-expression network algorithms combined with cell-type-specific transcriptomics identified Adamts2 as a driver of HF. Adamts2 plays an important role via paracrine signaling in the proliferative response of fibroblasts and the hypertrophic response of cardiomyocytes to catecholamines. Further mechanistic analysis of Adamts2 will further reveal its role in the progression of heart failure.
Response to: Correspondence on ‘Anticardiolipin and other antiphospholipid antibodies in critically ill COVID-19 positive and negative patients’ by Liu
Authors: Marvin J Fritzler, Uriel Trahtemberg
Journal: Annals of the Rheumatic Diseases (2021)

Response to: Correspondence on 'Anticardiolipin and other antiphospholipid antibodies in critically ill COVID-19 positive and negative patients' by LiuWe thank
Abstract 9747: Safety, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Doses of AZD8233, Targeting PCSK9, in Patients with Dyslipidemia
Authors: Alexis Hofherr, Catarina A Nilsson, Dinko Rekic, Jane Knoechel, Ronald Goldwater, David Han, Jorge Kusnir, J. Scott Overcash, Michael Waters, Alexander White, Eva Hurt-Camejo, Linda Wernevik, Rikard Isaksson, Yanfeng Wang, Sanjay Bhanot, Kristina Ryden-Bergsten, Michael Koren, Bjorn C Carlsson
Journal: Circulation (2021)

Introduction: Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces cardiovascular risk by lowering low-density lipoprotein-cholesterol (LDL-C) levels. AZD8233 is an antisense oligonucleotide in development for the treatment of dyslipidemia. In a single ascending dose study (NCT03593785), AZD8233 was well tolerated and effectively reduced PCSK9 and LDL-C levels in patients with elevated LDL-C. Here, we report results from a multiple ascending dose study of AZD8233. Methods: This was a phase 1, randomized, single-blind, placebo-controlled study (NCT04155645) in patients with dyslipidemia. Participants were receiving statins for ≥ 3 months, had an LDL-C in the range 70-190 mg/dL, and were 18-65 years old. Three cohorts of 11 participants received four subcutaneous injections over an 8-week period (days 1, 8, 29, and 57) of either AZD8233 (15 mg, 30 mg, or 90 mg; n = 8) or placebo (n = 3), and were followed up for 16 weeks post dose. The primary objective was to assess safety and tolerability; secondary objectives included assessment of pharmacokinetics and pharmacodynamics of AZD8233; circulating LDL-C was estimated using the Friedewald formula. Results: Overall, 34 patients were randomized and data are available from 33 patients; 15 were male, the mean age was 58 years, and baseline PCSK9 and LDL-C levels were comparable across treatment groups. Treatment with AZD8233 did not result in any clinically relevant safety or tolerability findings. Peak plasma concentrations of AZD8233 were reached within 0.5 to 5 hours post dosing, followed by a biphasic decline. A decrease from baseline in PCSK9 (69.7%, 79.9%, and 95.3%) and LDL-C levels (63.8%, 65.7%, and 83.3%) was observed at 12 weeks for the AZD8233 15 mg, 30 mg, and 90 mg groups, respectively vs placebo ( Figure ). Conclusions: Multiple doses of AZD8233 were generally safe, well tolerated, and reduced PCSK9 and LDL-C levels in a dose-dependent manner in statin-treated patients with dyslipidemia.
KarMMa-7, a Phase 1/2, Dose-Finding and Dose-Expansion Study of Combination Therapies with Idecabtagene Vicleucel (ide-cel, bb2121), a BCMA-Directed CAR T Cell Therapy for Relapsed/Refractory Multiple Myeloma (RRMM)
Authors: Noopur S. Raje, Jesús G. Berdeja, Paula Rodriguez-Otero, Damian J. Green, Sundar Jagannath, Sagar Lonial, Adrianna Gipson, Andrea Caia, Nathan Martin, Zhihong Yang, Gianfranco Pittari, Maria-Victoria Mateos
Journal: Blood (2021)
Covid-19: Poorly controlled asthma increases risk of hospital admission among children sixfold, finds study
Authors: Elisabeth Mahase
Journal: BMJ (2021)

Covid-19: Poorly controlled asthma increases risk of hospital admission among children sixfold, finds study Elisabeth MahaseChildren with poorly controlled asthma are at a higher risk of being admitted to hospital with covid-19 and should therefore be prioritised for vaccination, according to researchers who analysed data on 750 000 children.
Haploidentical Peripheral Blood Stem Cell Transplantation (Haplo-PBSCT) with Cyclophosphamide Pos Transplant (CyPost) in High-Risk Hematologic Malignancies. Results of 5 Years in Transplant Center in Northeast of Mexico
Authors: Severiano Baltazar, Myrna Patricia Pequeño Luevano, Guadalupe González Villarreal, Guillermo Sotomayor Duque, Raul Ramos Vazquez, Diego Cruz Contreras, Martha Lilia Guajardo Leal, Helga Patricia Sorkee Davila, Jose Alfredo Carrizalez Villarreal, Jose Luis Cedillo, Alba Nydia Ramirez López, Isabel Borjon Cabada, Christian Quirino Marquez, Arantxa Mecott Estudillo, Gerardo Avila Contreras, Willy Nava Gutiérrez, Dora Aldama Gutiérrez, Juan Daniel Garza Escobar, Yarezi Garcia Cerda, Victor Valerio Bugarin, Karen Machuca Adame, Luis Omar Gudiño Cobos, Rosa Elva De Leon Cantu, Roberto Hernadez Valdez
Journal: Blood (2021)
Abstract 11276: Safety and Tolerability of ALN-AGT, an RNA Interference Therapeutic Targeting Hepatic Angiotensinogen Synthesis, in Hypertensive Patients During Sodium Depletion or Irbesartan Coadministration
Authors: Stephen Huang, Jorg Taubel, Akshay S Desai, Yansong Cheng, Bahru Habtemariam
Journal: Circulation (2021)

Introduction: We have recently reported that ALN-AGT, a subcutaneous (SC) investigational RNA interference therapeutic targeting hepatic angiotensinogen (AGT) synthesis, reduced BP and was generally well tolerated in a single ascending dose study of hypertensive patients. To further assess its safety profile, additional studies have been initiated to test the effects of peak ALN-AGT pharmacology during salt depletion or irbesartan add-on treatment. Methods: As part of a Phase 1 program, hypertensive patients (mean seated SBP of &gt;130 and ≤165 mm Hg after washout of antihypertensive medication) were given a single dose of ALN-AGT 800 mg SC that has been shown to reduce serum AGT by ≥95%. At Day 43 (corresponding to expected peak serum AGT reduction), these ALN-AGT-treated patients were admitted to receive interventions of a 7-day sodium restricted diet (10 mmol sodium day) or a 14-day add-on treatment regimen with the angiotensin receptor blocker irbesartan 300 mg by oral administration daily. Results: In the salt depletion cohort, 12 patients (mean age 56 years, 75% male, 25% black, mean baseline 24-h SBP 141+/- 8 mm Hg) have been dosed 2:1 with ALN-AGT or placebo SC in advance of the sodium restricted diet. In the irbesartan add-on cohort, 10 patients (mean age 55 years, 30% male, 30% black, mean baseline 24-h SBP 147 +/- 8 mm Hg) have received ALN-AGT in advance of irbesartan add-on. The study has completed patient enrollment and interventions with no patient discontinuations due to AEs. The data analysis is ongoing at the time of abstract submission. Conclusions: This ongoing study will provide insight into ALN-AGT tolerability during potential augmented pharmacology, using salt restriction to test ALN-AGT’s effects during reduced extracellular fluid volume and irbesartan coadministration to assess the effects of ALN-AGT’s liver-specific AGT silencing during angiotensin II receptor blockade. Data on tolerability, laboratory safety monitoring, serum AGT reduction, RAAS-related biomarkers, and blood pressure will be presented.
EXTH-82. T CELL HITCHHIKING AS A MECHANISM OF DRUG DELIVERY TO THE BRAIN
Authors: Kirit Singh, Patrick Gedeon, Teilo Schaller, David Snyder, Mustafa Khasraw, John Sampson
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION The blood-brain barrier (BBB) restricts access to the central nervous system (CNS). Our brain bispecific T cell engager (hEGFRvIII:CD3 BRiTE) treats subcutaneous syngeneic tumor (CT2AvIII) but not intracranial CT2AvIII. CD3 engaging molecules such as nanoparticles can be carried into the brain by binding to activated T cells. We therefore sought to determine if co-administration of larger molecules (BRiTE, approx. 55kDa) with activated T cells could cross the BBB, enhancing survival. METHODS We implanted 8–10-week-old transgenic hCD3 mice (n=7-8 per group) with 30,000 CT2AvIII cells. Tumors were established for 6 days. Mice were administered either (1) autologous lymphocyte transfer (ALT) alone (single intravenous (IV) injection, 1 x 107 activated T cells), (2) serial IV BRiTE doses (50ug, 10 days) (3) BRiTE and ALT or (4) no treatment. Mice were followed for survival using Kaplan-Meier curves and compared via log rank test. Targeted mass spectroscopy analysis as well as PET/CT imaging of mice administered Iodine-124 radiolabelled BRiTE was performed to assess for intracranial accumulation. RESULTS Mice who received BRiTE and ALT demonstrated significantly enhanced survival compared to controls (median survival 29 vs 21 days, p=0.0135). Mice who received only BRiTE or ALT exhibited median survival comparable to controls (p=0.192, p=0.944 respectively). Mass spectroscopy analysis revealed that mice had a 7-fold increased peak area ratio of BRiTE in the CNS when co-treated with activated T cells compared to BRiTE alone (0.14, 0.02 respectively) while PET/CT imaging demonstrated increased radioactive signal over background localized to coordinates within the brain where tumors were injected. CONCLUSIONS Giving activated T cells alongside BRiTE allows better access to the intracranial compartment and is required to achieve efficacy in mice with syngeneic orthotopic glioma. Future work will determine the optimal dose and schedule for this approach, as well as defining the precise mechanism by which this occurs.
Nationwide effectiveness of five SARS-CoV-2 vaccines in Hungary—the HUN-VE study
Authors: Zoltán Vokó, Zoltán Kiss, György Surján, Orsolya Surján, Zsófia Barcza, Bernadett Pályi, Eszter Formanek-Balku, Gergő Attila Molnár, Róbert Herczeg, Attila Gyenesei, Attila Miseta, Lajos Kollár, István Wittmann, Cecília Müller, Miklós Kásler
Journal: Clinical Microbiology and Infection (2021)

ObjectivesThe Hungarian vaccination campaign was conducted with five different vaccines during the third wave of the coronavirus disease 2019 (COVID-19) pandemic in 2021. This observational study (HUN-VE: Hungarian Vaccine Effectiveness) estimated vaccine effectiveness against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19-related mortality in 3.7 million vaccinated individuals.MethodsIncidence rates of SARS-CoV-2 infection and COVID-19-related mortality were calculated using data from the National Public Health Centre surveillance database. Estimated vaccine effectiveness was calculated as 1 – incidence rate ratio ≥7 days after the second dose for each available vaccine versus an unvaccinated control group using mixed-effect negative binomial regression controlling for age, sex and calendar day.ResultsBetween 22 January 2021 and 10 June 2021, 3 740 066 Hungarian individuals received two doses of the BNT162b2 (Pfizer-BioNTech), HB02 (Sinopharm), Gam-COVID-Vac (Sputnik-V), AZD1222 (AstraZeneca), or mRNA-1273 (Moderna) vaccines. Incidence rates of SARS-CoV-2 infection and COVID-19-related death were 1.73–9.3/100 000 person-days and 0.04–0.65/100 000 person-days in the fully vaccinated population, respectively. Estimated adjusted effectiveness varied between 68.7% (95% CI 67.2%–70.1%) and 88.7% (95% CI 86.6%–90.4%) against SARS-CoV-2 infection, and between 87.8% (95% CI 86.1%–89.4%) and 97.5% (95% CI 95.6%–98.6%) against COVID-19-related death, with 100% effectiveness in individuals aged 16–44 years for all vaccines.ConclusionsOur observational study demonstrated the high or very high effectiveness of five different vaccines in the prevention SARS-CoV-2 infection and COVID-19-related death.
Abstract 11449: Classifying Multiple Cardiac Signals Simultaneously Using Radial Basis Function Neural Networks
Authors: Jonathan A Araujo Queiroz, Priscila L Rocha, Luis Fillype d Silva, Marta d Barreiros, Gean Sousa, Christian D Carvalho, Allan Kardec Barros
Journal: Circulation (2021)

Introduction: Classifying multiple cardiac signals simultaneously is still a challenge for computational methods. We propose a computational algorithm that performs a multi-class classification. We use a combination of global features of the electrocardiogram (ECG) signal, where we statistically analyze the complete signal, as well as include the local features of the cardiac cycles. Methodology: 286 ECG signals obtained from the MIT-BIH Database were evaluated:18 healthy, 48 with arrhythmia, 23 with Atrial Fibrillation, 70 with apnea, 78 with supraventricular arrhythmias, 15 with congestive heart failure, 11 with epilepsy, 5 with fetal electrocardiogram, 18 with ventricular tachyarrhythmia. For each of the 286 signals, 1200 cardiac cycles from a total of one second measurement were used, characterized by 400 milliseconds before and 600 milliseconds after the R wave. We calculated variance, skewness and kurtosis from the 286 signals, extracting 1200 features from the cardiac cycles for each of the ECG signals. These hyperparameters were used as input for the Radial Basis Function Neural Networks (RBF), where 80% were for training and 20% for testing, with cross-validation of K-fold = 10. The RBF had one hidden layer with error correction by mean squared error, number of iterations equal to 1000, number of neurons equal to 25 and learning rate 0.01. Results: Each group of cardiac signals evaluated in this study had its own features and, therefore, had unique parameters for each of the different pathologies in a three dimensional plot, as illustrated in the figure. The average accuracy of the proposed method for multi-class classification of cardiac signals was 99.98 %. Conclusion: The high success rate in the multi-class classification for eleven classes of cardiac signals makes the proposed methodology an promising alternative to aid in the diagnosis of cardiac pathologies.
Abstract 11619: Cost of Treatment is a Barrier to Hypertension Control in Puerto Rican Adults in Massachusetts
Authors: Lawreta Kankam
Journal: Circulation (2021)

Introduction: Little is known about hypertension (HTN) control among Puerto Ricans living on the U.S mainland. We examined awareness, treatment and control of HTN among Puerto Rican adults living in the Boston area to determine whether cost of treatment is a barrier to control. Methods: We used baseline data (2004-2009) from the Boston Puerto Rican Health Study, a longitudinal study of approximately 1500 Puerto Rican adults. Blood pressure was based on the mean of up to 4 determinations. Awareness, treatment and control among all participants, and those being treated, were defined as in the National Health and Nutrition Examination Survey (NHANES). Perceived cost as a barrier to treatment was based on response to a single item. The association of cost with HTN control was tested in multivariable logistic models, adjusting for covariates suggested in the literature, including BMI, serum, creatinine, diabetes, age, alcohol use, and nonsteroidal anti-inflammatory drugs (NSAIDs) use. Results: Participants with HTN (n= 941) had mean age 58.6 + 7.6 years, and 70% were female. Among these, 83.6%, were aware of their HTN, 77.8% were treated, and 37.0% were controlled. Among those being treated, 47.5% were controlled. Seventeen percent of those with HTN reported cost as barrier to treatment. Among those reporting cost as barrier, 27.6% were controlled compared to 38.9% of those with no cost barrier (p&lt;0.01). Among treated HTN patients, 36.4% of those reporting cost as a barrier to treatment were controlled compared to 49.5% of those with no cost barrier (p&lt;0.01). The odds ratio (95%Cl) for control was 0.63 (0.43, 0.93) for cost as a barrier among all participants with HTN, and 0.60 (0.39, 0.91) among those treated. Conclusion: HTN control in Boston-area Puerto Ricans is lower than reported in NHANES for the general US population. Cost of treatment appears to be an important barrier to achieving control.
Early Identification of Autism Spectrum Disorder Among Children Aged 4 Years — Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2018
Authors: Kelly A. Shaw, Matthew J. Maenner, Amanda V. Bakian, Deborah A. Bilder, Maureen S. Durkin, Sarah M. Furnier, Michelle M. Hughes, Mary Patrick, Karen Pierce, Angelica Salinas, Josephine Shenouda, Alison Vehorn, Zachary Warren, Walter Zahorodny, John N. Constantino, Monica DiRienzo, Amy Esler, Robert T. Fitzgerald, Andrea Grzybowski, Allison Hudson, Margaret H. Spivey, Akilah Ali, Jennifer G. Andrews, Thaer Baroud, Johanna Gutierrez, Libby Hallas, Jennifer Hall-Lande, Amy Hewitt, Li-Ching Lee, Maya Lopez, Kristen Clancy Mancilla, Dedria McArthur, Sydney Pettygrove, Jenny N. Poynter, Yvette D. Schwenk, Anita Washington, Susan Williams, Mary E. Cogswell
Journal: MMWR Surveillance Summaries (2021)

Autism spectrum disorder (ASD).
Abstract 13797: Does Alcohol Consumption Have a Cumulative Effect on the Risk of Stroke in Young Adults?
Authors: Jaewook Chung, So-Ryoung Lee, Eue-keun Choi, Sang-Hyeon Park, HuiJijn Lee, JungMin Choi, Minju Han, Seung-woo Lee, Kyung-Do Han, Sunhwa Kim, Seil Oh, Gregory Y Lip
Journal: Circulation (2021)

Backgrounds: Alcohol consumption is one of the major and modifiable risk factors for stroke in young people. There is a paucity of information regarding the risk of drinking on stroke development, especially in young adults. We investigated the effect of alcohol consumption on the risk of stroke and its subtypes in young adults. Methods: Using the Korean National Health Insurance Service database, a total of 1,523,299 subjects aged between 20 and 39 were identified, who underwent 4 consecutive annual health examinations between 2009 and 2012, with no history of stroke, myocardial infarction, and congestive heart failure. At each annual health examination, the alcohol consumption of the subjects was divided into non, mild (&gt;0 and &lt;105g/week), moderate (≥105g and &lt;210g/week), and heavy (≥210g/week) drinking. Cumulative alcohol burdens were evaluated in the following ways: (1) cumulative number of moderate to heavy drinking at each health examination (0 to 4 times); (2) drinking patterns in each cumulative alcohol burden (total 16 patterns). The incidence of total stroke, ischemic stroke (IS) or hemorrhagic stroke, was evaluated using Cox proportional-hazards models. Results: During a median follow-up of 5.6±1.2 years, 3093 (0.20%) subjects were diagnosed with stroke (1732 with ischemic and 1513 with hemorrhagic). Heavy drinkers were associated with an increased risk of total stroke compared to non-drinker (HR 1.256, 95% CI 1.112-1.419). The hazard ratio was proportional to the cumulative alcohol burdens (Fig. panel A). This positive linear relationship was mainly driven by hemorrhagic stroke rather than IS (Fig. panel B). While most drinking patterns were not associated with an increased risk of IS, alcohol burden 3 had a significant association with an increased risk of a hemorrhagic stroke (Fig. panel C). Conclusions: Moderate to heavy alcohol consumption has a cumulative association with a higher risk of stroke, especially for hemorrhagic stroke in young adults.
Abstract 9813: A Randomized, Double Blind, Clinical Trial to Evaluate Safety and Efficacy of Allogeneic Mesenchymal Human Stem Cells Infusion Therapy for Endothelial Dysfunction in Diabetic Subjects (ACESO)
Authors: Russell G Saltzman, Ivonne H Schulman, Barry E Hurwitz, Hua Li, lina V caceres, Mayra Vidro-Casiano, Jairo A Tovar, Yvenie Desire, Valeria Porras, Jeanette Soto, Aisha Khan, Dushyantha Jayaweera, Joshua M Hare
Journal: Circulation (2021)

Introduction: Endothelial dysfunction underlies the pathophysiology of cardiovascular disease (CVD) in patients with diabetes mellitus (DM), but no known effective therapies exist. The randomized, double-blind ACESO clinical trial evaluated the safety and efficacy of allogeneic human mesenchymal stem cells (allo-MSCs) infusion to target endothelial dysfunction in Type 2 DM subjects. Methods: An open label pilot phase (n=6) was followed by a blinded, randomized phase (n=10) study. DM subjects with endothelial dysfunction received a single peripheral intravenous infusion of either 20 or 100 million allo-MSCs (obtained from 3 healthy bone marrow donors) and followed for 1 yr. The primary endpoint was incidence of treatment-emergent serious adverse events (TE-SAE) within 1-month post-infusion. Secondary endpoints assessed endothelial function via endothelial progenitor cell-colony forming units (EPC-CFUs) and flow-mediated dilation (FMD%). Results: Participants had well-controlled DM, blood pressure, and kidney function (GFR ≥50 ml/min), and most were taking statins. The 6 pilot-phase participants were men (1 Asian, 5 non-Hispanic white) with mean (±SD) age of 69.3 (9.6) years. The 10 randomized participants were 5 men and 5 women (5 Hispanic, 3 non-Hispanic Black), with mean age of 60.9 (10.6) years. No TE-SAEs were reported. None of the patients in the pilot phase developed Panel Reactive Antibodies (PRAs). One randomized subject had a moderate increase in PRAs after infusion. Both treatment groups (20 and 100M allo-MSCs) in the pilot and randomized phases showed increased EPC-CFUs over time, particularly at 14 and 28 days post-infusion, that was sustained at 6-12 months. FMD data followed a trend rising above baseline and peaking at days 7 to 14, and then subsided to pre-infusion levels by 1 yr. Conclusion: Peripheral infusion of allo-MSCs for patients with DM and endothelial dysfunction is safe. Allo-MSCs improve EPCs and FMD within 14 to 28 days post-infusion, and the effect is sustained for 6 to 12 months. Larger clinical trials are warranted to assess the efficacy of allo-MSC therapy for cardiovascular outcomes in diabetic patients. Clinical Trial Registration: URL: https://www.clinicaltrials.gov.; Unique ID: NCT02886884