tbuckley/cabot-search huggingface dataset:
Automated Echocardiographic Detection of Severe Coronary Artery Disease Using Artificial Intelligence
Authors: Ross Upton, Angela Mumith, Arian Beqiri, Andrew Parker, William Hawkes, Shan Gao, Mihaela Porumb, Rizwan Sarwar, Patricia Marques, Deborah Markham, Jake Kenworthy, Jamie M. O’Driscoll, Neelam Hassanali, Kate Groves, Cameron Dockerill, William Woodward, Maryam Alsharqi, Annabelle McCourt, Edmund H. Wilkes, Stephen B. Heitner, Mrinal Yadava, David Stojanovski, Pablo Lamata, Gary Woodward, Paul Leeson
Journal: JACC. Cardiovascular imaging (2021)

The purpose of this study was to establish whether an artificially intelligent (AI) system can be developed to automate stress echocardiography analysis and support clinician interpretation.Coronary artery disease is the leading global cause of mortality and morbidity and stress echocardiography remains one of the most commonly used diagnostic imaging tests.An automated image processing pipeline was developed to extract novel geometric and kinematic features from stress echocardiograms collected as part of a large, United Kingdom-based prospective, multicenter, multivendor study. An ensemble machine learning classifier was trained, using the extracted features, to identify patients with severe coronary artery disease on invasive coronary angiography. The model was tested in an independent U.S.How availability of an AI classification might impact clinical interpretation of stress echocardiograms was evaluated in a randomized crossover reader study.Acceptable classification accuracy for identification of patients with severe coronary artery disease in the training data set was achieved on cross-fold validation based on 31 unique geometric and kinematic features, with a specificity of 92.7% and a sensitivity of 84.4%. This accuracy was maintained in the independent validation data set. The use of the AI classification tool by clinicians increased inter-reader agreement and confidence as well as sensitivity for detection of disease by 10% to achieve an area under the receiver-operating characteristic curve of 0.93.Automated analysis of stress echocardiograms is possible using AI and provision of automated classifications to clinicians when reading stress echocardiograms could improve accuracy, inter-reader agreement, and reader confidence.
Extranodal Presentation in Limited Stage DLBCL As a Prognostic Marker in Three Sequential SWOG Trials S0014, S0313 and S1001 (NCT00005089, NCT00070018, NCT01359592)
Authors: Deborah M. Stephens, Hongli Li, Louis S. Constine, John P. Leonard, Brad S. Kahl, Joo Y Song, Michael L. Leblanc, Thomas J. Fitzgerald, Sonali M. Smith, Jonathan W. Friedberg, Dan O. Persky
Journal: Blood (2021)
Targeting BTN2A1 By a Unique Activating Mab Improves Vγ9Vδ2 T Cell Cytotoxicity Against Primary Acute Lymphoblastic Blasts
Authors: Anne-Charlotte Le Floch, Caroline Imbert, Aude De Gassart, Florence Orlanducci, Aude Le Roy, Laurent Gorvel, Norbert Vey, Antoine Briantais, Nicolas Boucherit, Carla E Cano, Daniel Olive
Journal: Blood (2021)
Evaluating the Efficacy of PRMT5 Inhibitor C220 in Patient-Derived Xenograft Models of Pediatric Acute Myeloid Leukemia
Authors: Anilkumar Gopalakrishnapillai, Anne Kisielewski, Yang Zhang, Bruce Ruggeri, Peggy Scherle, E. Anders Kolb, Sonali P. Barwe
Journal: Blood (2021)
Hundreds of Out-of-Frame Remodeled Gene Families in the<i>Escherichia coli</i>Pangenome
Authors: Andrew K Watson, Philippe Lopez, Eric Bapteste
Journal: Molecular Biology and Evolution (2021)

Abstract All genomes include gene families with very limited taxonomic distributions that potentially represent new genes and innovations in protein-coding sequence, raising questions on the origins of such genes. Some of these genes are hypothesized to have formed de novo, from noncoding sequences, and recent work has begun to elucidate the processes by which de novo gene formation can occur. A special case of de novo gene formation, overprinting, describes the origin of new genes from noncoding alternative reading frames of existing open reading frames (ORFs). We argue that additionally, out-of-frame gene fission/fusion events of alternative reading frames of ORFs and out-of-frame lateral gene transfers could contribute to the origin of new gene families. To demonstrate this, we developed an original pattern-search in sequence similarity networks, enhancing the use of these graphs, commonly used to detect in-frame remodeled genes. We applied this approach to gene families in 524 complete genomes of Escherichia coli. We identified 767 gene families whose evolutionary history likely included at least one out-of-frame remodeling event. These genes with out-of-frame components represent ∼2.5% of all genes in the E. coli pangenome, suggesting that alternative reading frames of existing ORFs can contribute to a significant proportion of de novo genes in bacteria.
Covid-19: Antimicrobial misuse in Americas sees drug resistant infections surge, says WHO
Authors: Luke Taylor
Journal: BMJ (2021)

The use of antimicrobials against covid-19 is driving a surge in drug resistant infections in the Americas, WHO's Americas' branch, the Pan American Health Organization (PAHO), has said.Drugs such as azithromycin, chloroquine, and ivermectin have been shown to be ineffective against covid-19 in clinical trials but were widely prescribed by doctors and self administered by the public as the region was devastated by the coronavirus pandemic, PAHO said. 1 Latin American nations such as Argentina, Ecuador, Guatemala, Paraguay, and Uruguay have reported increases in drug resistant infections, and a recent PAHO Epidemiological Alert showed a spike in the emergence of bacteria resistant to antimicrobials across the region."We've seen the use of antimicrobials rise at unprecedented levels, with potentially serious consequences for years to come," PAHO director Carissa Etienne told journalists at a press briefing on 17 November.3 World Health Organization.WHO coronavirus (covid-19) dashboard.https://covid19.who.int.4 World Health Organization.Antimicrobial resistance.https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance. 5 UK Health Security Agency.Antibiotic-resistant infections fell in 2020 for first time since 2016, but UKHSA warns drop likely temporary.https://www.gov.
211 SQZ™ eAPCs generated from PBMCs by delivery of multiple mRNAs encoding for antigens, costimulatory proteins, and engineered cytokines
Authors: Michael Maloney, Emrah Ilker Ozay, Amy Merino, Andrea Silva, Amber Martin, Sanjana Manja, Madhav Upadhyay, Christine Trumpfheller, Pablo Umana, Armon Sharei, Howard Bernstein, Scott Loughhead
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Antigen-specific CD8+ T cells are critical components of mounting an effective immune response against tumors. Generation of antigen-specific T cells require interactions with multiple signals produced by antigen presenting cells (APCs). These signals are comprised of three components: (signal 1) the peptide-MHC complex binding to the T cell receptor, (signal 2) costimulatory molecules on the surface of APCs, and (signal 3) inflammatory cytokines binding to cognate receptors on T cells. Methods To engineer all major cell subsets of human peripheral blood mononuclear cells (PBMCs) to become enhanced APCs (eAPCs), we used Cell Squeeze® technology to deliver multiple mRNA encoding for non-self-antigens (signal 1), CD86 (signal 2), and/or membrane-bound cytokines (signal 3). The signal 3 molecules, membrane-bound IL-12 (mbIL-12) and membrane-bound IL-2 (mbIL-2), are chimeric proteins designed to increase the localized concentration of the cytokines and limit off-target effects. Flow cytometry and western blots were used to confirm the translation of each of the delivered mRNA. The increased capabilities of these enhanced APCs were assessed in vitro by culturing the APCs with antigen-specific T cells for multiple days before measuring the functionality of antigen-specific T cells via intracellular cytokine staining or ELISA. Results We demonstrate that Cell Squeeze® processing of PBMCs with mRNA encoding for signals 1, 2, and 3 results in highly effective enhanced APCs in vitro. In a single squeeze process, efficient delivery and translation of up to five mRNA is observed in all major PBMC cell subsets including T cells, B cells, NK cells, and monocytes. Once translated, the chimeric mbIL-2 and mbIL-12 can bind to their cognate receptors and exhibit minimal shedding from the surface. We show that enhanced APCs can present antigenic peptides derived from mRNA encoding for a foreign antigen on MHC complexes in an HLA agnostic manner, which drives antigen-specific T cell responses. The addition of CD86, mbIL-2, and mbIL-12 further enhance the activation and potency of antigen-specific T cells, as measured by an increase in the secretion of inflammatory cytokines upon restimulation (i.e. IFNγ). Conclusions Cell squeezing of human PBMCs with mRNA encoding for signals 1, 2, and 3 has the potential to generate enhanced APCs that drive robust CD8+ T cell response against multiple targets across several disease areas. The versatility of the Cell Squeeze® technology potentially enables rapid exchange of mRNA to other antigens or T cell activation signals.
Abstract 9129: Effect of Cardiovascular Risk Factors on Hypertensive Disorders of Pregnancy: A Mendelian Randomization Study
Authors: Maddalena Ardissino, Ophelia Millar, Rohin Reddy, Laura Lazzari, Kiran Patel, David Ryan, Dipender Gill, Mark Johnson, Fu Siong Ng
Journal: Circulation (2021)

Introduction: Cardiovascular risk factors have been associated with adverse maternal and fetal outcomes, including risk of hypertensive disorders of pregnancy such as pre-eclampsia (PE) and low fetal birth weight. However, it is difficult to establish causal relationships from retrospective evidence due to risk of confounding. We applied Mendelian randomization to explore the role of traditional cardiovascular risk factors in determining maternal and fetal outcomes of pregnancy. Methods: Summary statistics were used to perform a 2-sample Mendelian randomization study to investigate the association of genetically-predicted systolic blood pressure (SBP), body mass index (BMI), glycated haemoglobin A1C (HbA1C), low-density lipoprotein cholesterol (LDL-C), and smoking with the primary outcome of pre-eclampsia or eclampsia in 1,689 cases and 52,576 controls of Finnish ancestry, and secondary outcome of birth weight of the first child of 145,558 European women from the UK Biobank. Results: There was a significant association between PE and both genetically-predicted SBP (OR per mmHg increase: 1.05,95%CI 1.01-1.10, p=0.030) and genetically-predicted BMI (OR per kg/m 2 increase: 0.24 95%CI 1.07-1.90 p=0.017). Genetically-predicted SBP was associated with lower birth weight (OR per mmHg increase: 0.98, 95%CI 0.97-0.98 p&lt;0.001), whereas genetically-predicted HbA1C was associated with higher birth weight (OR per mmol/mol increase: 1.31 95%CI 1.11-1.56 p=0.002). Conclusion: Our results suggest a causal association between some cardiovascular risk factors, specifically hypertension, obesity and HbA1C, with adverse maternal and fetal outcomes, such as pre-eclampsia and low fetal birth weight. No causal association was found for LDL-C and smoking.The results provide insight into the genetic and pathophysiological basis of pre-eclampsia and identify important targets for pre-pregnancy counselling and optimization to improve maternal and fetal outcomes.
A regeneration process-matching scaffold with appropriate dynamic mechanical properties and spatial adaptability for ligament reconstruction
Authors: Xiaojing Xie, Junjie Xu, Jing Lin, Jia Jiang, Yunfan Huang, Jun Lu, Yuhao Kang, Yage Hu, Jiangyu Cai, Fujun Wang, Tonghe Zhu, Jinzhong Zhao, Lu Wang
Journal: Bioactive Materials (2021)

Ligament regeneration is a complicated process that requires dynamic mechanical properties and allowable space to regulate collagen remodeling. Poor strength and limited space of currently available grafts hinder tissue regeneration, yielding a disappointing success rate in ligament reconstruction. Matching the scaffold retreat rate with the mechanical and spatial properties of the regeneration process remains challenging. Herein, a scaffold matching the regeneration process was designed via regulating the trajectories of fibers with different degradation rates to provide dynamic mechanical properties and spatial adaptability for collagen infiltration. This core-shell structured scaffold exhibited biomimetic fiber orientation, having tri-phasic mechanical behavior and excellent strength. Besides, by the sequential material degradation, the available space of the scaffold increased from day 6 and remained stable on day 24, consistent with the proliferation and deposition phase of the native ligament regeneration process. Furthermore, mature collagen infiltration and increased bone integration in vivo confirmed the promotion of tissue regeneration by the adaptive space, maintaining an excellent failure load of 67.65% of the native ligament at 16 weeks. This study proved the synergistic effects of dynamic strength and adaptive space. The scaffold matching the regeneration process is expected to open new approaches in ligament reconstruction.
Reduced Dosing Frequency Following a Switch to Rix-FP for the Treatment of Hemophilia B: Results from the Athn 2 Study
Authors: Janna Journeycake, Dunlei Cheng, Tammuella Chrisentery-Singleton, Vidhi Desai, Annette von Drygalski, Carol Fedor, Nikki Hirsh, Birju Patel, Leslie J. Raffini, Michael Recht, Robert F. Sidinio, Michael Wang, Xiang Zhang, Ellis J. Neufeld
Journal: Blood (2021)
Suicide rates by ethnic group among patients in contact with mental health services: an observational cohort study in England and Wales
Authors: Isabelle M Hunt, Nicola Richards, Kamaldeep Bhui, Saied Ibrahim, Pauline Turnbull, Kristoffer Halvorsrud, Pooja Saini, Sadie Kitson, Jenny Shaw, Louis Appleby, Nav Kapur
Journal: The Lancet Psychiatry (2021)
Clinical and Immunological Assessment of Patients with Sars-Cov-2 Infections
Authors: Aditi Singh, Natali Salaytah, Daniel Lebovic, Zeyad Sako, Zachary Pounders, Laura Kohler, Zyad Kafri, Louis Saravolatz, Meredith Coyle, Hemang Patel
Journal: Blood (2021)
Abstract 9990: In-Hospital Outcomes of Left Atrial Appendage Closure with the Watchman Device in the Us: A Nationwide Study (2015-2018)
Authors: Pegah Khaloo, Uwajachukwumma Uzomah, Ayman Shaqdan, Pablo A Ledesma, Jennifer Galvin, Leon Ptaszek, Jeremy N Ruskin
Journal: Circulation (2021)

Introduction: Left atrial appendage closure with the Watchman device is the only FDA approved alternative to oral anticoagulation (OAC) therapy in patients with atrial fibrillation. The device is indicated for the reduction of thromboembolic events in patients in whom OAC is contraindicated. Methods: The Nationwide Inpatient Sample database was used to assess adverse events related to Watchman implants from 2015 to 2018. These were assessed using the appropriate ICD-10 codes. Results: Over the 39-month study period, 35,080 patients with the Watchman device were identified. Mean age was 75.9 and 58.2% of patients were male. In-hospital patient outcomes are shown in the table below. Independent predictors of in-hospital mortality were: age (adjusted odds ratio [aOR]:1.1; 95%CI:1.01-1.22), pericardial effusion without tamponade (aOR: 16.7; CI:2.34-119.44), tamponade (aOR: 34.3; 95%CI: 7.32-161.30), pneumothorax (aOR: 19.6; 95%CI: 1.79-214.49), ATRIA bleeding score (2.47; 95%CI: 1.61-3.81) and Elixhauser comorbidity score (1.12; 95%CI: 1.07-1.19). Conclusion: Left atrial appendage closure with the Watchman device is associated with a low rate of major adverse events. The most prevalent in-hospital complication is pericardial effusion, which is associated with a 16-fold increase in the risk of in-hospital mortality.
A Novel Antibody Drug Conjugate (ADC) Targeting Cell Surface Heat Shock Protein 70 (csHSP70) Is Active Against Pre-Clinical Models of Peripheral T-Cell Lymphoma (PTCL)
Authors: Rajan Kumar Choudhary, Richard J. Jones, Isere Kuiatse, Hua Wang, Francisco Vega, Alyssa C. Bouska, Waseem G. Lone, Javeed Iqbal, Robert Z. Orlowski
Journal: Blood (2021)
Lenalidomide Consolidation Added to Rituximab Maintenance Therapy in Patients Remaining PET Positive after Treatment for Relapsed Follicular Lymphoma: Phase 2 Australasian Leukaemia &amp; Lymphoma Group NHL26 Study
Authors: Judith Trotman, Peter Presgrave, Duncan P. Carradice, Douglas Stuart Lenton, Maher Gandhi, Tara Cochrane, Xavier Badoux, Gloria Nkhoma, Belinda Butcher, Michael Fulham, Anna Johnston
Journal: Blood (2021)
Understanding the Implications of Medicaid Expansion for Cancer Care in the US
Authors: Theresa Ermer, Samantha L. Walters, Maureen E. Canavan, Michelle C. Salazar, Andrew X. Li, Michael Doonan, Daniel J. Boffa
Journal: JAMA Oncology (2021)

<h3>Importance</h3> Insurance status has been linked to important differences in cancer treatment and outcomes in the US. With more than 15 million individuals gaining health insurance through Medicaid expansion, there is an increasing need to understand the implications of this policy within the US cancer population. This review provides an overview of the fundamental principles and nuances of Medicaid expansion, as well as the implications for cancer care. <h3>Observations</h3> The Patient Protection and Affordable Care Act presented states with an option to expand Medicaid coverage by broadening the eligibility criteria (eg, raising the eligible income level). During the past 10 years, Medicaid expansion has been credited with a 30% reduction in the population of uninsured individuals in the US. Such a significant change in the insurance profile could have important implications for the 1.7 million patients diagnosed with cancer each year, the oncology teams that care for them, and policy makers. However, several factors may complicate efforts to characterize the effect of Medicaid expansion on the US cancer population. Most notably, there is considerable variation among states in terms of whether Medicaid expansion took place, when expansion occurred, eligibility criteria for Medicaid, and coverage types that Medicaid provides. In addition, economic and health policy factors may be intertwined with factors associated with Medicaid expansion. Finally, variability in the manner in which cancer care has been captured and depicted in large databases could affect the interpretation of findings associated with expansion. <h3>Conclusions and Relevance</h3> The expansion of Medicaid was a historic public policy initiative. To fully leverage this policy to improve oncological care and to maximize learning for subsequent policies, it is critical to understand the effect of Medicaid expansion. This review aims to better prepare investigators and their audiences to fully understand the implications of this important health policy initiative.
Emicizumab Outcomes in Hemophilia A Using Real-World Data from the Canadian Hemophilia Bleeding Disorder Registry
Authors: Man-Chiu Poon, Adrienne Lee, Federico Germini, Arun Keepanasseril, Quazi Ibrahim, Francis Nissen, Fabian Sanabria, Michelle Santos, Emma Iserman, Davide Matino, Alfonso Iorio
Journal: Blood (2021)
Development and Evaluation of a Library of TikToks to Support Recruitment of Committed Hematopoietic Stem Cell Donors from Needed Demographic Groups
Authors: Brady Park, Lauren Sano, Becky Shields, Sylvia Okonofua, Mikyla Tak, Reihaneh Jamalifar, Aaron Wen, Farnaz Farahbakhsh, Kyla Pires, Kenyon Nisbett, Karen Barboza, Anastasia Pavlenkova, Shirin Pedram, Richard Fattouh, Alexa Gélinas, Bilguissou Bah, Christiane Rochon, Mai Duong, Warren Fingrut
Journal: Blood (2021)
Abstract 257: Endogenous Activating Transcription Factor 6 Preserves Heart Structure and Function in a Mouse Model of Myocardial Infarction-induced Heart Failure
Authors: Winston T Stauffer, Khalid Azizi, Erik A Blackwood, Randal J Kaufman, Christopher C Glembotski
Journal: Circulation Research (2017)

Rationale: The ER stress response is activated by the accumulation of misfolded, toxic proteins in the endoplasmic reticulum (ER), and upregulates proteins that restore ER protein-folding capacity. The ER-transmembrane protein, activating transcription factor 6 (ATF6) senses ER stress and responds by transcriptionally inducing many of these genes and is thus a key component of the adaptive ER stress response. We previously showed that in the heart, ischemia activates ATF6. Furthermore, transgenic mouse hearts expressing a conditionally activated form of ATF6, and subjected to ex vivo ischemia/reperfusion, exhibited preserved heart function and smaller infarcts. Our lab also showed that by serving as a novel inducer of a global anti-oxidant gene program, endogenous ATF6 limits cardiac damage caused by reactive oxygen species during reperfusion. However, the effect of endogenous ATF6 in the failing heart is not known. Given that acute ischemia caused by occlusion of the coronary arteries is the cause of myocardial infarction (MI), we hypothesized that endogenous ATF6 limits infarct size and preserves heart function during MI. Additionally, since deleterious cardiac remodeling and heart failure can be long-term consequences of MI, we hypothesized that ATF6 can mitigate these effects. Objective/Methods: To examine the role of endogenous ATF6 in heart failure, in vivo, we used a mouse model of MI-induced heart failure in mice with a global deletion of the ATF6 gene (ATF6 KO). Infarct size was measured by TTC staining and heart function was observed via longitudinal echocardiogram. Results: We found that following infarction, ATF6 KO mouse hearts had larger infarcts compared to control. Thus, ischemic cardiac tissue in the peri-infarct region requires ATF6 to limit cardiac myocyte death. Interestingly, ejection fraction following MI decreased more over 13 weeks in ATF6 KO mice relative to control. While control and ATF6 KO mouse hearts hypertrophied to a similar degree, KO mice showed greater cardiac dilation. Conclusions: Together these findings show for the first time that endogenous ATF6 acts to preserve heart structure and function in an MI model of heart failure, suggesting that ATF6 may be a viable therapeutic target for treatment of this disease.
On-Target Activity of Imetelstat Correlates with Clinical Benefits, Including Overall Survival (OS), in Heavily Transfused Non-Del(5q) Lower Risk MDS (LR-MDS) Relapsed/Refractory (R/R) to Erythropoiesis Stimulating Agents (ESAs)
Authors: Valeria Santini, Pierre Fenaux, Koen Van Eygen, Azra Raza, Ulrich Germing, Patricia Font, Maria Diez-Campelo, Sylvain Thepot, Edo Vellenga, Mrinal M. Patnaik, Jun Ho Jang, Laurie Sherman, Tymara Berry, Faye Feller, Souria Dougherty, Libo Sun, Ying Wan, Aleksandra Rizo, Fei Huang, Uwe Platzbecker
Journal: Blood (2021)
Preliminary Results of a Phase 1 Study in Healthy Subjects Administered Inclacumab, a Fully Human IgG4 Anti-P-Selectin Monoclonal Antibody in Development for Treatment of Sickle Cell Disease
Authors: Christina Mayer, Daniel Scott Cooper, Andrew Redfern, Xin Geng, Jianxia Shi, Mariëlle van Zutphen-van Geffen, Isabelle Kuan, Kathleen Koeck, Helen Kastrissios, Kashyap Patel, Mark Davis, Patrick Yue
Journal: Blood (2021)
A Phase I Trial of Nedd8-Activating Enzyme (NAE) Inhibitor, Pevonedistat (PEVO) in Combination with Ibrutinib in Patients with Relapsed/Refractory (R/R) Non-Hodgkin Lymphoma (NHL)
Authors: Pallawi Torka, Swetha Kambhampati, Alexandra Muir, Kirsten Orand, Lynne Smith, Alex F. Herrera, Lionel Lewis, Francisco J. Hernandez-Ilizaliturri, Lu Chen, Alexey V. Danilov
Journal: Blood (2021)
Pirtobrutinib (LOXO-305) Is Active and Overcomes ERK Related Pro-Survival Signaling in Ibrutinib Resistant, BTK Cys481 Mutant Expressing WM and ABC DLBCL Lymphoma Cells Driven By Activating MYD88 Mutations
Authors: Manit Munshi, Xia Liu, Amanda Kofides, Nickolas Tsakmaklis, Joshua Gustine, Shayna Sarosiek, Catherine A Flynn, Kirsten Meid, Timothy P White, Carly Leventoff, Christopher J Patterson, Andrew R. Branagan, Prafulla Gokhale, Michael J Poitras, Zachary R Hunter, Maria Luisa Guerrera, Jorge J. Castillo, Guang Yang, Steven P Treon
Journal: Blood (2021)