tbuckley/cabot-search huggingface dataset:
THU0113 Expression of galectin-3 in rheumatoid arthritis synovium
Authors: S Kuchen, CA Seemayer, P Kuenzler, RE Gay, ME Billingham, BA Michel, S Gay, M Neidhart
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Galectin-3 is a beta-galactoside-binding protein and belongs to the large family of lectins, which play important roles in a variety of physiological and pathophysiological processes via their recognition of glycoconjugates. Galectin-3 is involved in the regulation of cell growth and apoptosis, cell aggregation/adhesion and differentiation and is associated with cell transformation and metastasis in several tumours. Since it activates inflammatory cells by promoting cell-cell and cell-matrix interactions and acts as a chemoattractant on monocytes and macrophages, galectin-3 is suggested to play a role in inflammatory diseases. So far, galectin-3 has been shown to be expressed by monocytes and macrophages but not by T- and B-lymphocytes. <h3>Objectives</h3> Here we investigated the expression of galectin-3 in rheumatoid arthritis (RA) and osteoarthritis (OA) synovial tissues. Furthermore, we examined the expression of galectin-3 in cultured RA synovial fibroblasts (RA-SF) and OA synovial fibroblasts (OA-SF). <h3>Methods</h3> Paraffin-embedded synovial tissue samples from RA (n = 7) and OA (n = 3) patients were analysed for expression of galectin-3 by immunohistochemistry (IHC) and/or non-radioactive <i>in situ</i> hybridization (ISH) using monoclonal mouse anti-galectin-3 antibodies (Affinity bioreagents, clone A3A12) and galectin-3 specific digoxigenin-labelled RNA antisense probes, respectively. Immunohistochemical staining of CD68 with monoclonal mouse anti-human macrophage CD68 antibodies (DAKO, clone PG-M1) was performed on parallel sections. Isotype specific mouse IgG and sense RNA probes were used as negative controls. Expression of galectin-3 in cultured RA-SF (n = 10) and OA-SF (n = 1) from passage 2–7 was examined by RT-PCR. <h3>Results</h3> Galectin-3 was found to be expressed in all RA synovial tissue samples. Positive cells were detected throughout the lining and sublining layer with a predominant expression in the sublining. In contrast, CD68 was mainly expressed in the lining layer. Endothelial cells of small vessels in the sublining were mostly positive for galectin-3, whereas endothelial cells of larger vessels were negative. Clusters of galectin-3/CD68 positive cells were located around vessels. Interestingly, galectin-3 was rarely expressed at sites of bone invasion, in contrast to CD68. In OA synovial tissues, galectin-3 and CD68 were expressed by some cells in the lining layer. All cultured RA- and OA-SF were tested positive for galectin-3 mRNA by RT-PCR. <h3>Conclusion</h3> We conclude from our data that the expression of galectin-3 in RA synovium is not restricted to monocytes and macrophages. Moreover, we suggest that galectin-3 contributes to the inflammation rather than to the destructive processes at sites of invasion. S. Kuchen supported by the EMDO Stiftung. C. A. Seemayer supported by DAAD and by the Theodor und Ida Herzog-Egli Stiftung.
Prevalence of Transfusion Transmissible Infections in Beta-Thalassemia Major Patients of Pakistan: A Systematic Review
Authors: Hamid Ehsan, Ahsan Wahab, Muhammad Ammar Shafqat, Muhammad Salman Faisal, Ahmad Muneeb, Sundas Ali, Muhammad Khawar Sana, Farhan Khalid, Iqraa Ansar, Ali Jaan, Raheel Iftikhar, Faiz Anwer
Journal: Blood (2020)
Immunocluster: A Computational Tool to Explore the Immune Profile and Cellular Heterogeneity of Hematological Diseases Using Liquid and Imaging Mass, and Flow Cytometry Data
Authors: Jessica A. Timms, James W Opzoomer, Kevin Blighe, Benedetta Apollonio, Thanos Mourikis, Nicolas Chapuis, Richard Bekoe, Alan G. Ramsay, Donal P. McLornan, Claire Harrison, Paul R. Barber, Peter Parker, Michaela Fontenay, James N. Arnold, Shahram Kordasti
Journal: Blood (2020)
Outcomes of Chronic Automated RBC Exchange Program in Omaha, Nebraska 2015-2020
Authors: Aleh Bobr, Scott A Koepsell, Julie Eclov, Omar Abughanimeh, Steven Ebers, Mahammed Khan Suheb, Robin High, Alex Nester, Krishna Gundabolu, James Harper, Laxmi Narayana Buddharaju
Journal: Blood (2020)
<i>In vivo</i> multimodal imaging of adenosine A<sub>1</sub> receptors in neuroinflammation after experimental stroke
Authors: Ana Joya, María Ardaya, Alejandro Montilla, Maider Garbizu, Sandra Plaza-García, Vanessa Gómez-Vallejo, Daniel Padro, Juan José Gutiérrez, Xabier Rios, Pedro Ramos-Cabrer, Unai Cossío, Krishna R Pulagam, Makoto Higuchi, María Domercq, Fabio Cavaliere, Carlos Matute, Jordi Llop, Abraham Martín
Journal: Theranostics (2020)

Adenosine A1 receptors (A1ARs) are promising imaging biomarkers and targets for the treatment of stroke. Nevertheless, the role of A1ARs on ischemic damage and its subsequent neuroinflammatory response has been scarcely explored so far. Methods: In this study, the expression of A1ARs after transient middle cerebral artery occlusion (MCAO) was evaluated by positron emission tomography (PET) with [18F]CPFPX and immunohistochemistry (IHC). In addition, the role of A1ARs on stroke inflammation using pharmacological modulation was assessed with magnetic resonance imaging (MRI), PET imaging with [18F]DPA-714 (TSPO) and [18F]FLT (cellular proliferation), as well as IHC and neurofunctional studies. Results: In the ischemic territory, [18F]CPFPX signal and IHC showed the overexpression of A1ARs in microglia and infiltrated leukocytes after cerebral ischemia. Ischemic rats treated with the A1AR agonist ENBA showed a significant decrease in both [18F]DPA-714 and [18F]FLT signal intensities at day 7 after cerebral ischemia, a feature that was confirmed by IHC results. Besides, the activation of A1ARs promoted the reduction of the brain lesion, as measured with T2W-MRI, and the improvement of neurological outcome including motor, sensory and reflex responses. These results show for the first time the in vivo PET imaging of A1ARs expression after cerebral ischemia in rats and the application of [18F]FLT to evaluate glial proliferation in response to treatment. Conclusion: Notably, these data provide evidence for A1ARs playing a key role in the control of both the activation of resident glia and the de novo proliferation of microglia and macrophages after experimental stroke in rats.
Comparison of Haploidentical Donor Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide to Matched-Sibling, Matched-Unrelated, Mismatched-Unrelated, and Umbilical Cord Blood Donor Transplantation in Adults with Acute Lymphoblastic Leukemia: A CIBMTR Study
Authors: Matthew J. Wieduwilt, Leland Metheny, Mei-Jie Zhang, Hai-Lin Wang, Noel Estrada-Merly, Marcos de Lima, Mark Litzow, Partow Kebriaei, Chris S. Hourigan, Daniel J. Weisdorf, Wael Saber
Journal: Blood (2020)
Co-Targeting of CD38 and CD47 in T Cell Acute Lymphoblastic Leukemia
Authors: Fotini Vogiatzi, Kristina Müller, Dorothee Winterberg, Thies Rösner, Lennart Lenk, Gunnar Cario, Martin Schrappe, Andreas E. Kulozik, Beat Bornhauser, Jean-Pierre Bourquin, Thomas Valerius, Matthias Peipp, Christian Kellner, Denis Martin Schewe
Journal: Blood (2020)
Maintaining the balance of TDP-43, mitochondria, and autophagy: a promising therapeutic strategy for neurodegenerative diseases
Authors: Chunhui Huang, Sen Yan, Zaijun Zhang
Journal: Translational Neurodegeneration (2020)

Abstract Mitochondria are the energy center of cell operations and are involved in physiological functions and maintenance of metabolic balance and homeostasis in the body. Alterations of mitochondrial function are associated with a variety of degenerative and acute diseases. As mitochondria age in cells, they gradually become inefficient and potentially toxic. Acute injury can trigger the permeability of mitochondrial membranes, which can lead to apoptosis or necrosis. Transactive response DNA-binding protein 43 kDa (TDP-43) is a protein widely present in cells. It can bind to RNA, regulate a variety of RNA processes, and play a role in the formation of multi-protein/RNA complexes. Thus, the normal physiological functions of TDP-43 are particularly important for cell survival. Normal TDP-43 is located in various subcellular structures including mitochondria, mitochondrial-associated membrane, RNA particles and stress granules to regulate the endoplasmic reticulum–mitochondrial binding, mitochondrial protein translation, and mRNA transport and translation. Importantly, TDP-43 is associated with a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia and Alzheimer's disease, which are characterized by abnormal phosphorylation, ubiquitination, lysis or nuclear depletion of TDP-43 in neurons and glial cells. Although the pathogenesis of TDP-43 proteinopathy remains unknown, the presence of pathological TDP-43 inside or outside of mitochondria and the functional involvement of TDP-43 in the regulation of mitochondrial morphology, transport, and function suggest that mitochondria are associated with TDP-43-related diseases. Autophagy is a basic physiological process that maintains the homeostasis of cells, including targeted clearance of abnormally aggregated proteins and damaged organelles in the cytoplasm; therefore, it is considered protective against neurodegenerative diseases. However, the combination of abnormal TDP-43 aggregation, mitochondrial dysfunction, and insufficient autophagy can lead to a variety of aging-related pathologies. In this review, we describe the current knowledge on the associations of mitochondria with TDP-43 and the role of autophagy in the clearance of abnormally aggregated TDP-43 and dysfunctional mitochondria. Finally, we discuss a novel approach for neurodegenerative treatment based on the knowledge.
Single Cell Immune Profiling Reveals Distinct T Cell Clones and Functional States in <i>in-Vitro</i> Expanded Cord Blood Derived Gamma Delta T Cells
Authors: Kar Wai Tan, Zhihui Li, Joey Lai, Dianyan Guo, Yeh Ching Linn, William YK Hwang, Shang Li, Connie J. Eaves, Yeow Tee Goh, Alice Cheung
Journal: Blood (2020)
Sars-Cov-2 Infection and Systemic Light Chain Amyloidosis: The International Society of Amyloidosis' Survey
Authors: Paolo Milani, Vaishali Sanchorawala, Ramon Lecumberri, Sunil Saith, Mathew S. Maurer, M. Teresa Cibeira, Giampaolo Merlini, Stefan Schönland, Giovanni Palladini
Journal: Blood (2020)
SAT0005 Factors influencing fatigue and impact of fatigue on quality of life in ankylosing spondylitis (as) patients
Authors: A Van Tubergen, J Coenen, R Landewé, A Spoorenberg, A Chorus, A Boonen, S Van der Linden, D Van der Heijde
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> 1. To identify factors that influence fatigue in AS. 2. To assess whether fatigue is associated with quality of life in AS. <h3>Methods</h3> A total number of 812 AS patients were included. Fatigue was measured with a single-item question elicited from the Bath AS Disease Activity Index (BASDAI) and with the Multidimensional Fatigue Inventory (MFI). The patients also completed questionnaires on functional ability (BASFI), global well-being (BAS-G), and quality of life (SF-36). In addition, patients were asked to identify factors that influence fatigue. Patients were dichotomously divided into a F+ group if the BASDAI fatigue score was &gt;5.0, labelled as experiencing fatigue as a major symptom, and a F- group in case the fatigue score was &lt;5.0 (fatigue a minor symptom). Logistic regression analysis (dependent variable F+/F-) was used to determine which factors were associated with fatigue. Multiple regression analysis was used to investigate whether fatigue contributes in explaining quality of life (dependent variable dimensions from the SF-36; independent variable BASDAI fatigue question). In both analyses adjustments were made for age, sex, disease duration, and the presence of co-morbidity. <h3>Results</h3> 53% of the patients were categorised to the F+ group. They scored significantly worse compared to the F- group with respect to each dimension of the MFI and to all other questionnaires studied (all p &lt; 0.001). Fatigue was, in the opinion of the patients, highly influenced by pain (70% of the patients) and stiffness (54%). The hierarchical order of factors perceived to be associated with fatigue was grossly similar in the F+ and F- groups, but pain, poor sleep and work were significantly more often considered important by patients from the F+ group. Logistic regression analysis showed that scores on BASDAI (without fatigue question), BASFI and BAS-G were independently associated with fatigue (R2: 0.52). Multiple regression analysis showed that fatigue was significantly associated with all separate dimensions of the SF-36 studied (p &lt; 0.001). <h3>Conclusion</h3> Fatigue is a major symptom in AS and is associated with disease activity, functional ability, and global well-being. Fatigue independently contributes negatively to different dimensions of quality of life.
A Prospective Haploidentical Peripheral Blood Stem Cell Transplant Study Using a Pre-Defined Conditioning Regimen Intensity Based on Age and the Hematopoietic Cell Transplantation Comorbidity Index- Anzhit 1: Encouraging Preliminary Survival Outcomes at One Year Follow up
Authors: John Moore, John Kwan, David Gottlieb, Ashish Bajel, David Ritchie, David T Yeung, Matthew Greenwood, Duncan Purtill, Steven Tran, Donna Aarons, Nada Hamad
Journal: Blood (2020)
A Phase 1, Open Label Dose Escalation Trial Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Orally Administered CA-4948 in Patients with Acute Myelogenous Leukemia or Myelodysplastic Syndrome
Authors: Guillermo Garcia-Manero, Uwe Platzbecker, Stefano R. Tarantolo, Stefanie Gropper, Chetasi Talati, Katharina S. Götze, James Dugan, Eric S. Winer, Elizabeth Martinez, Christopher Lieberman, Reinhard von Roemeling
Journal: Blood (2020)
Polygenic Risk Score and Risk of Chronic Lymphocytic Leukemia, Monoclonal B-Cell Lymphocytosis (MBL), and MBL Subtypes
Authors: Geffen Kleinstern, J. Brice Weinberg, Sameer A. Parikh, Esteban Braggio, Dennis P. Robinson, Aaron D. Norman, Kari G Rabe, Celine M. Vachon, Connie E. Lesnick, Timothy G. Call, Danielle M. Brander, Janet E. Olson, James R. Cerhan, Neil E. Kay, Curtis A. Hanson, Richard R. Furman, Tait Shanafelt, Susan L. Slager
Journal: Blood (2020)
Is Hydroxyurea Deleterious in Patients with ELN Favorable AML and WBC Inferior to 50.109/L?
Authors: Sarah Bertoli, Suzanne Tavitian, Francoise Huguet, Muriel Picard, Francois Vergez, Eric Delabesse, Audrey Sarry, Emilie Berard, Christian Recher
Journal: Blood (2017)
Frequency and Prognostic Significance of Recurrent Gene Mutations in Pediatric B-ALL: Report from the DFCI ALL Consortium
Authors: Giacomo Gotti, Maneka Puligandla, Kristen E. Stevenson, Brenton G. Mar, Barbara L Asselin, Uma Athale, Luis A. Clavell, Peter D. Cole, Lisa M. Gennarini, Justine M. Kahn, Kara M. Kelly, Caroline Laverdiere, Jean-Marie Leclerc, Bruno Michon, Marshall A. Schorin, Maria L. Sulis, Thai Hoa Tran, Jennifer J.G. Welch, Kimberly Stegmaier, Marian H. Harris, Lewis B. Silverman, Yana Pikman
Journal: Blood (2020)
Association of ambient PM2·5 exposure with maternal bone strength in pregnant women from Mexico City: a longitudinal cohort study
Authors: Haotian Wu, Marianthi-Anna Kioumourtzoglou, Allan C Just, Itai Kloog, Alison Sanders, Katherine Svensson, Nia McRae, Marcela Tamayo-Ortiz, Maritsa Solano-González, Robert O Wright, Martha M Téllez-Rojo, Andrea A Baccarelli
Journal: The Lancet Planetary Health (2020)

Pregnancy is associated with deteriorations in maternal bone strength and heightened susceptibility to bone fractures. We aimed to investigate whether ambient particulate matter (PM)2·5 concentrations were associated with bone strength during pregnancy.In this longitudinal cohort study, we analysed longitudinal data from women participating in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) cohort in Mexico City, Mexico. Eligible women were aged 18 years or older, at less than 20 weeks' gestation at the time of recruitment, planning to stay in Mexico City for the next 3 years, without heart or kidney disease, did not use steroids or anti-epileptic drugs, were not daily consumers of alcohol, and had access to a telephone. Daily ambient PM2·5 concentrations were estimated from a spatio-temporal model that was based on the individual's address. Trabecular bone strength was measured using quantitative ultrasound from the radius of the middle finger and cortical bone strength from the proximal phalanx of the middle finger, during the second trimester, third trimester, and 1 and 6 months post partum. Bone strength T scores were modelled with PM2·5 concentrations using linear mixed models and distributed lag models.Adjusting for multiple exposure windows, each 10 ug/m3 increase in PM2·5 exposure concentrations in the first trimester was associated with a 0·18 SD decrease (95% CI -0·35 to -0·01; p=0·033) in ultrasound speed-of-sound (SOS) T score of trabecular bone strength from the second trimester until 6 months post partum. Similarly, each 10 μg/m3 increase in third trimester PM2·5 exposure was associated with a 0·18 SD decrease (-0·36 to -0·01; p=0·044) in the SOS T score of trabecular bone strength from the third trimester until 6 months post partum. PM2·5 exposure in the first month post partum was associated with a 0·20 SD decline (-0·39 to -0·01; p=0·043) in cortical bone strength until 6 months post partum.Ambient PM2·5 exposure during and after pregnancy was associated with diminished trabecular and cortical bone strength. Early pregnancy PM2·5 exposure was associated with a greater decline in bone strength later during pregnancy. Late pregnancy and early post-partum exposures adversely affected the post-partum bone strength recovery. Technological and policy solutions to reduce PM2·5 pollution could improve public health by reducing bone fracture risk.US National Institute of Environmental Health Sciences.
Validation of 4D Flow based relative pressure maps in aortic flows
Authors: David Nolte, Jesús Urbina, Julio Sotelo, Leo Sok, Cristian Montalba, Israel Valverde, Axel Osses, Sergio Uribe, Cristóbal Bertoglio
Journal: Medical Image Analysis (2021)

While the clinical gold standard for pressure difference measurements is invasive catheterization, 4D Flow MRI is a promising tool for enabling a non-invasive quantification, by linking highly spatially resolved velocity measurements with pressure differences via the incompressible Navier-Stokes equations. In this work we provide a validation and comparison with phantom and clinical patient data of pressure difference maps estimators. We compare the classical Pressure Poisson Estimator (PPE) and the new Stokes Estimator (STE) against catheter pressure measurements under a variety of stenosis severities and flow intensities. Specifically, we use several 4D Flow data sets of realistic aortic phantoms with different anatomic and hemodynamic severities and two patients with aortic coarctation. The phantom data sets are enriched by subsampling to lower resolutions, modification of the segmentation and addition of synthetic noise, in order to study the sensitivity of the pressure difference estimators to these factors. Overall, the STE method yields more accurate results than the PPE method compared to catheterization data. The superiority of the STE becomes more evident at increasing Reynolds numbers with a better capacity of capturing pressure gradients in strongly convective flow regimes. The results indicate an improved robustness of the STE method with respect to variation in lumen segmentation. However, with heuristic removal of the wall-voxels, the PPE can reach a comparable accuracy for lower Reynolds' numbers.
Interplay between Chromosomal Alterations and Gene Mutations Shapes the Evolutionary Trajectory of Clonal Hematopoiesis
Authors: Teng Gao, Ryan Ptashkin, Kelly L. Bolton, Christopher Fong, Barbara Spitzer, Kamal Menghrajani, Juan E. Arango Ossa, Yangyu Zhou, Elsa Bernard, Max Levine, Juan Medina, Yanming Zhang, Sebastià Franch-Expósito, Minal A Patel, Lior Braunstein, Daniel Kelly, Mariko Yabe, Ryma Benayed, Nicole M Caltabellotta, John Philip, Ederlinda Paraiso, Simon Mantha, David B. Solit, Luis Alberto Diaz, Michael F. Berger, Virginia M. Klimek, Ross L. Levine, Ahmet Zehir, Sean Devlin, Elli Papaemmanuil
Journal: Blood (2020)
Very Long Term Follow up a Phase II Study of Post-Remission Subcutaneous (SC) Azacitidine (AZA) in Patients with AML Post-MDS or Higher-Risk (HR) MDS
Authors: Amina Cherait, Thorsten Braun, Krimo Bouabdallah, Denis Caillot, Agnès Guerci, Emmanuel Raffoux, Jean Pierre Marolleau, Cecile Pautas, Anne Banos, Chantal Himberlin, Anne Laure Taksin, Arnaud Pigneux, Xavier Thomas, Norbert Vey, Sylvie Chevret, Herve Dombret, Fatiha Chermat, Lionel Ades, Claude Gardin, Pierre Fenaux
Journal: Blood (2020)
Abstract 12019: Augmented Reality Guidance for Cerebral Embolic Protection (CEP) With the Sentinel Device During Transcatheter Aortic Valve Replacement (TAVR): First-In-Human Study
Authors: Shirin Sadri, Gabrielle Loeb, Alon Grinshpoon, Carmine Elvezio, Poonam Velagapudi, Vivian G Ng, Omar Khalique, Jeffrey W Moses, Robert J Sommer, Amisha J Patel, Isaac George, Rebecca T Hahn, Martin B Leon, Ajay J Kirtane, Tamim M Nazif, Susheel K Kodali, Steven K Feiner, Torsten P Vahl
Journal: Circulation (2018)

Introduction: Augmented reality (AR) can improve transcatheter interventions by providing 3D visualization of patient anatomy, with potential to reduce contrast and procedure time. We present a nov...
Covid-19: Sidelining GPs in pandemic response was “a disaster,” says global health leader
Authors: Gareth Iacobucci
Journal: BMJ (2020)

The sidelining of general practices in the UK's response to the covid-19 is a "disaster" and "a national shame," a leading global health expert has said.Anthony Costello, professor of global health and sustainable development at University College London, said GPs and local public health teams should have been given additional funding to oversee covid-19 testing, rather than this being centralised and outsourced under the government's struggling national test and trace scheme, run by private companies Serco and Sitel.
An Age Analysis of the International Sickle Cell World Assessment Survey (SWAY), Focusing on Symptoms, Treatment Goals and the Impact of SCD on Patients' Daily Lives
Authors: Raffaella Colombatti, John James, Biree Andemariam, Baba PD Inusa, Fuad A El Rassi, Beverley Francis-Gibson, Alecia C Nero, Caterina P Minniti, Cassandra Trimnell, Miguel R Abboud, Jean-Benoît Arlet, Mariane de Montalembert, Suman Jain, Wasil Jastaniah, Erfan Nur, Marimilia Pita, Nicholas Ramscar, Tom Bailey, Olivera Rajkovic-Hooley, Ifeyinwa Osunkwo
Journal: Blood (2020)
DISC-0974, a Novel, First-in-Class, Anti-Hemojuvelin Monoclonal Antibody Decreases Hepcidin and Increases Transferrin Saturation in a Non-Human Primate Model of Cytokine (IL-6) Induced Hypoferremia
Authors: Brian MacDonald, Cecile Blaustein, Sophia Nguyen, Christopher King, Vu Hong, Will Savage, Srikanth Venkatraman, Maria G. Beconi
Journal: Blood (2020)
Activation of the ERK Pathway Drives Acquired Resistance to Venetoclax in MM Cell Models
Authors: Chandraditya Chakraborty, Yan Xu, Yao Yao, Eugenio Morelli, Anil Aktas-Samur, Mehmet Kemal Samur, Mariateresa Fulciniti, Nikhil C. Munshi, Kenneth Anderson, Chandraditya Chakraborty
Journal: Blood (2020)
Healthcare Utilization and Health Related Quality of Life in Persons with Von Willebrand Disease
Authors: Jonathan C. Roberts, Roshni Kulkarni, Peter A. Kouides, Robert F. Sidonio, Shannon L Carpenter, Barbara A. Konkle, Joanne Wu, Judith Baker, Megan M. Ullman, Randall Curtis, Steven Carrasco, Duc Quang Tran, Michael B. Nichol
Journal: Blood (2020)