tbuckley/cabot-search huggingface dataset:
Abstract 17081: Outcomes of Percutaneous Coronary Intervention in Cirrhosis: Does the Stent Type Matter?
Authors: Juan Daniel Del Cid Fratti, Miguel Salazar, Pedro Palacios, Tauseef Akhtar, Ezequiel Muñoz
Journal: Circulation (2020)

Methods: National Inpatient Sample was queried from 2016-2017 for discharges of adult patients with cirrhosis who underwent percutaneous coronary intervention (PCI) with placement of drug-eluding-stents (DES) and bare-metal-stents (BMS) using ICD-10CM/PCS-codes. Patients were subsequently divided between compensated/decompensated cirrhosis as per the BAVENO Score. The primary outcome was in-hospital mortality. Secondary outcomes were post-procedural complications, length of stay (LOS), total hospital charges/costs. Multivariate logistic regression analysis was performed to adjust for confounders. Results: 899,899 PCIs were identified out of which 0.6% (n=5,983) had concomitant cirrhosis. Patients with compensated and decompensated cirrhosis had higher odds of BMS placement when undergoing PCI when compared with patients without cirrhosis [aOR 1.57; (P&lt;0.01)], [aOR 1.54; (P=0.05) respectively]. There was no significant difference in mortality between BMS and DES in patients with compensated-cirrhosis, and similar results were obtained in patients with decompensated-cirrhosis. DES was associated to higher LOS when compared to BMS in patients with decompensated-cirrhosis [4.93; (P:&lt;0.01)], and higher total hospital costs [16, 031.94; (P:&lt;0.01)]. Patients with decompensated-cirrhosis and DES had higher risk of post-procedure bleeding when compared with BMS [aOR 4.22; (P:&lt;0.01)]. Conclusions: Patients admitted for PCI with decompensated-cirrhosis have higher LOS and total hospitalization costs when DES is placed. Likely driven by higher post-procedural bleeding in this set of patients, requiring further intervention. BMS seemed to be safe when used in patients with cirrhosis and is not associated with higher in-hospital mortality even in patients with decompensated-cirrhosis.
Abstract P106: Stabilization Muscles Drive Associations Between Lipoproteins And Total Abdominal Muscle And Intermuscular Adipose Tissue In The Multi-ethnic Study Of Atherosclerosis
Authors: Megan M Marron, Matthew Allison, Britta A Larsen, Joachim H Ix, Alexis C Wood, David M Herrington, Philip Greenland, Iva Miljkovic
Journal: Circulation (2021)

Introduction: Quality and quantity of skeletal muscle decrease with age, largely due to adipose tissue infiltration, and are important determinants of metabolic health. To inform efforts to slow aging-related decline in muscle mass and prevent myosteatosis, a better understanding of the biological determinants of muscle atrophy and quality is needed. We used targeted lipidomics to identify, with a greater specificity, lipoproteins associated with muscle and intermuscular adipose tissue (IMAT) area (quantity) and density (quality) of the total abdominal, locomotion, and stabilization muscles in the Multi-Ethnic Study of Atherosclerosis. Hypothesis: Lower density lipoproteins will be positively associated with muscle and IMAT quantity, but negatively associated with quality. Methods: At visit one, 105 serum lipoproteins were measured by Bruker lipoprotein subclass analysis with 1 H-Nuclear Magnetic Resonance spectroscopy. Muscle and IMAT area (cm 2 ) and density (Hounsfield units) were estimated 2.6 years, on average, after visit 1 for the total abdominal, locomotion (psoas), and stabilization (paraspinal, oblique, and rectus abdominis) muscles from computed-tomography scans at the L4/L5 spinal junction. We identified lipoproteins associated with body composition using linear regression adjusting for age, gender, race, diet, physical activity, lipid-lowering medication, and multiple comparisons using a 1% false discovery rate. Results: Participants (N=947) were 44-84 years old (mean: 63), 51% men, 40% White, 16% Black, 16% Chinese American, and 27% Hispanic American. Among 105 lipoproteins, 24 were associated with total muscle area, whereas none were associated with muscle density. When examining specific muscle groups, 25 lipoproteins were associated with stabilization muscle area, driven by the oblique muscles. As for total IMAT area, there were 27 associations with lipoproteins. Specifically, 27 lipoproteins were associated with stabilization muscle IMAT area, driven by oblique and rectus abdominis muscles. Last, 39 lipoproteins were associated with total IMAT density, with 28 and 33 associated with locomotion and stabilization (driven by obliques) IMAT density, respectively. Higher VLDL: cholesterols, free cholesterols, phospholipids, and triglycerides and lower HDL: cholesterols and free cholesterols were associated with higher muscle area and IMAT area, but lower IMAT density (
Case 14-2021: A 64-Year-Old Woman with Fever and Pancytopenia
Authors: Michael D. Gibbons, Dexter P. Mendoza, Anem Waheed, Miriam B. Barshak, Julian A. Villalba
Journal: New England Journal of Medicine (2021)

A 64-year-old woman with multiple sclerosis was admitted with fever and pancytopenia after a 7-month illness that began with nausea and fatigue. CT revealed splenomegaly; FDG-PET revealed uptake in the spleen and bone marrow throughout the axial and appendicular skeleton. A diagnostic test result was received.
ABCB10 exports mitochondrial biliverdin, driving metabolic maladaptation in obesity
Authors: Michael Shum, Chitra A. Shintre, Thorsten Althoff, Vincent Gutierrez, Mayuko Segawa, Alexandra D. Saxberg, Melissa Martinez, Roslin Adamson, Margaret R. Young, Belinda Faust, Raffi Gharakhanian, Shi Su, Karthickeyan Chella Krishnan, Kiana Mahdaviani, Michaela Veliova, Dane M. Wolf, Jennifer Ngo, Laura Nocito, Linsey Stiles, Jeff Abramson, Aldons J. Lusis, Andrea L. Hevener, Maria E. Zoghbi, Elisabeth P. Carpenter, Marc Liesa
Journal: Science Translational Medicine (2021)

Although the role of hydrophilic antioxidants in the development of hepatic insulin resistance and nonalcoholic fatty liver disease has been well studied, the role of lipophilic antioxidants remains poorly characterized. A known lipophilic hydrogen peroxide scavenger is bilirubin, which can be oxidized to biliverdin and then reduced back to bilirubin by cytosolic biliverdin reductase. Oxidation of bilirubin to biliverdin inside mitochondria must be followed by the export of biliverdin to the cytosol, where biliverdin is reduced back to bilirubin. Thus, the putative mitochondrial exporter of biliverdin is expected to be a major determinant of bilirubin regeneration and intracellular hydrogen peroxide scavenging. Here, we identified ABCB10 as a mitochondrial biliverdin exporter. ABCB10 reconstituted into liposomes transported biliverdin, and ABCB10 deletion caused accumulation of biliverdin inside mitochondria. Obesity with insulin resistance up-regulated hepatic ABCB10 expression in mice and elevated cytosolic and mitochondrial bilirubin content in an ABCB10-dependent manner. Revealing a maladaptive role of ABCB10-driven bilirubin synthesis, hepatic ABCB10 deletion protected diet-induced obese mice from steatosis and hyperglycemia, improving insulin-mediated suppression of glucose production and decreasing lipogenic SREBP-1c expression. Protection was concurrent with enhanced mitochondrial function and increased inactivation of PTP1B, a phosphatase disrupting insulin signaling and elevating SREBP-1c expression. Restoration of cellular bilirubin content in ABCB10 KO hepatocytes reversed the improvements in mitochondrial function and PTP1B inactivation, demonstrating that bilirubin was the maladaptive effector linked to ABCB10 function. Thus, we identified a fundamental transport process that amplifies intracellular bilirubin redox actions, which can exacerbate insulin resistance and steatosis in obesity.
Vaccination reshapes the virus-specific T cell repertoire in unexposed adults
Authors: Yi-Gen Pan, Benjamas Aiamkitsumrit, Laurent Bartolo, Yifeng Wang, Criswell Lavery, Adam Marc, Patrick V. Holec, C. Garrett Rappazzo, Theresa Eilola, Phyllis A. Gimotty, Scott E. Hensley, Rustom Antia, Veronika I. Zarnitsyna, Michael E. Birnbaum, Laura F. Su
Journal: Immunity (2021)
Abstract P007: Ankle-brachial Index And Cardiovascular Outcomes In Older Adults: The Atherosclerosis Risk In Communities Study
Authors: Frances M Wang, Chao Yang, Shoshana Ballew, Corey A Kalbaugh, Michelle L Meyer, Hirofumi Tanaka, Gerardo M Heiss, Matthew A Allison, Maya Salameh, Josef Coresh, Kunihiro Matsushita
Journal: Circulation (2021)

Introduction: The ankle-brachial index (ABI) is a representative diagnostic indicator of peripheral artery disease (PAD) and recognized as a risk enhancer in the ACC/AHA guidelines for primary prevention of atherosclerotic cardiovascular disease (ASCVD). However, our understanding of the association between ABI and cardiovascular (CVD) risk in older adults is limited. Additionally, the prognostic value of ABI among individuals with prior ASCVD is not well understood. Hypothesis: In a contemporary cohort of older adults, low ABI is independently associated with higher risk of CVD events, regardless of prevalent ASCVD at baseline (coronary heart disease [CHD], stroke, and/or symptomatic PAD). Methods: At ARIC Visit 5 (2011-2013), we studied 5,005 participants (4,160 without prior ASCVD [median age 74 years, 38% male], and 843 with ASCVD [median age 76 years, 65% male]). We quantified the association between ABI categories and subsequent risk of heart failure (HF) and composite CHD/stroke using multivariable Cox proportional hazards models. Results: Over a median follow-up of 5.5 years, we observed 400 CHD/stroke and 338 HF cases (242 CHD/stroke and 199 HF cases in those without prior ASCVD). After adjustment for CVD risk factors, in those without ASCVD history, ABI ≤0.9 was associated with a higher risk of both CHD/stroke and HF ( Table ). In those with a history of ASCVD, low ABI was not significantly associated with CHD/stroke, but was associated with HF (hazard ratio 7.1, 95% CI: 2.5-20.5); ABI categories of 0.9-1.1 and &gt;1.3 were also significantly associated with HF. Addition of ABI to traditional risk factors improved prediction of CHD/stroke risk in those without prior ASCVD and prediction of HF, regardless of baseline ASCVD ( Table ). Conclusions: Low ABI (≤0.9) was associated with incident CHD/stroke in those without prior ASCVD and HF regardless of baseline ASCVD status. These results support ABI as a risk enhancer for guiding primary prevention of ASCVD and suggest its potential value in HF risk assessment for older adults.
Resolving the Spatial and Cellular Architecture of Lung Adenocarcinoma by Multiregion Single-Cell Sequencing
Authors: Ansam Sinjab, Guangchun Han, Warapen Treekitkarnmongkol, Kieko Hara, Patrick M. Brennan, Minghao Dang, Dapeng Hao, Ruiping Wang, Enyu Dai, Hitoshi Dejima, Jiexin Zhang, Elena Bogatenkova, Beatriz Sanchez-Espiridion, Kyle Chang, Danielle R. Little, Samer Bazzi, Linh M. Tran, Kostyantyn Krysan, Carmen Behrens, Dzifa Y. Duose, Edwin R. Parra, Maria Gabriela Raso, Luisa M. Solis, Junya Fukuoka, Jianjun Zhang, Boris Sepesi, Tina Cascone, Lauren Averett Byers, Don L. Gibbons, Jichao Chen, Seyed Javad Moghaddam, Edwin J. Ostrin, Daniel Rosen, John V. Heymach, Paul Scheet, Steven M. Dubinett, Junya Fujimoto, Ignacio I. Wistuba, Christopher S. Stevenson, Avrum Spira, Linghua Wang, Humam Kadara
Journal: Cancer Discovery (2021)

Abstract Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from five early-stage LUADs and 14 multiregion normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and transcriptomic features geospatially evolve across normal regions to LUADs. LUADs also exhibit pronounced intratumor cell heterogeneity within single sites and transcriptional lineage-plasticity programs. T regulatory cell phenotypes are increased in normal tissues with proximity to LUAD, in contrast to diminished signatures and fractions of cytotoxic CD8+ T cells, antigen-presenting macrophages, and inflammatory dendritic cells. We further find that the LUAD ligand–receptor interactome harbors increased expression of epithelial CD24, which mediates protumor phenotypes. These data provide a spatial atlas of LUAD evolution, and a resource for identification of targets for its treatment. Significance: The geospatial ecosystem of the peripheral lung and early-stage LUAD is not known. Our multiregion single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecologic evolution of LUAD from the lung that comprise high-potential targets for early interception. This article is highlighted in the In This Issue feature, p. 2355
Abstract P064: Reducing Diabetes Disparities: Diabetes Screening In Asian Americans Should Begin At A Lower Body Mass Index Threshold
Authors: Rahul Aggarwal, Kirsten Bibbins-domingo, Nicholas Chiu, Rishi Wadhera, Robert W Yeh, Dhruv Kazi
Journal: Circulation (2021)

Introduction: Current guidelines recommend diabetes screening in all US adults 40 to 70 years of age who have a body mass index (BMI) ≥25kg/m 2 . Asian Americans are at increased risk of developing diabetes at lower BMIs compared with non-Hispanic Whites, yet the optimal BMI threshold for diabetes screening in Asian Americans is undetermined. Hypothesis: Asian Americans aged 40 to 70 years should be screened for diabetes starting at a BMI threshold of lower than 25 kg/m 2 . Methods: Using 2013-2018 cycles of NHANES data, we determine the prevalence of diabetes in normal-weight individuals, stratified by race/ethnicity (n = 8,496). Diabetes was diagnosed based on A1c or a health-care diagnosis. We then evaluate the proportion of individuals with diabetes that would be identified by universal screening at different BMI thresholds (sensitivity) and proportion of individuals without diabetes who would be tested based on universal screening at or above a BMI threshold. Analyses were done accounting for complex survey weights to determine national projections. Results: Compared with non-Hispanic Whites, normal-weight Asian Americans were more likely to have diabetes (15.3% vs 3.4%, prevalence ratio (PR): 4.5 [95% CI: 2.8-7.4], p&lt;0.001) and undiagnosed diabetes (24.1% vs 11.9%, PR: 2.02 [1.34-3.05], p = 0.002). Universal screening for diabetes in U.S. adults with BMI ≥25 kg/m 2 has a sensitivity of 94.2% [95% CI: 92.8%-95.5%] in non-Hispanic Whites but lower sensitivity of 62.3% (59.0%-65.7%) among Asian Americans (p&lt;0.001). Diabetes screening in Asian Americans with a BMI ≥22 kg/m 2 would have a sensitivity of 91.2% (89.3%-93.1%) and would subject 70.4% (68.2%-72.5%) of adults without diabetes to screening, which is comparable to the performance of the BMI ≥25kg/m 2 threshold in non-Hispanic Whites. Conclusions: Lowering the diabetes screening threshold in Asian Americans aged 40 to 70 years from BMI ≥25 kg/m 2 to BMI ≥22 kg/m 2 would provide screening parity between Asian Americans and non-Hispanic Whites.
An artificial intelligence system for predicting the deterioration of COVID-19 patients in the emergency department
Authors: Farah E. Shamout, Yiqiu Shen, Nan Wu, Aakash Kaku, Jungkyu Park, Taro Makino, Stanisław Jastrzębski, Jan Witowski, Duo Wang, Ben Zhang, Siddhant Dogra, Meng Cao, Narges Razavian, David Kudlowitz, Lea Azour, William Moore, Yvonne W. Lui, Yindalon Aphinyanaphongs, Carlos Fernandez-Granda, Krzysztof J. Geras
Journal: npj Digital Medicine (2021)

Abstract During the coronavirus disease 2019 (COVID-19) pandemic, rapid and accurate triage of patients at the emergency department is critical to inform decision-making. We propose a data-driven approach for automatic prediction of deterioration risk using a deep neural network that learns from chest X-ray images and a gradient boosting model that learns from routine clinical variables. Our AI prognosis system, trained using data from 3661 patients, achieves an area under the receiver operating characteristic curve (AUC) of 0.786 (95% CI: 0.745–0.830) when predicting deterioration within 96 hours. The deep neural network extracts informative areas of chest X-ray images to assist clinicians in interpreting the predictions and performs comparably to two radiologists in a reader study. In order to verify performance in a real clinical setting, we silently deployed a preliminary version of the deep neural network at New York University Langone Health during the first wave of the pandemic, which produced accurate predictions in real-time. In summary, our findings demonstrate the potential of the proposed system for assisting front-line physicians in the triage of COVID-19 patients.
The inhibitory receptor TIM-3 limits activation of the cGAS-STING pathway in intra-tumoral dendritic cells by suppressing extracellular DNA uptake
Authors: Álvaro de Mingo Pulido, Kay Hänggi, Daiana P. Celias, Alycia Gardner, Jie Li, Bruna Batista-Bittencourt, Eslam Mohamed, Jimena Trillo-Tinoco, Olabisi Osunmakinde, Reymi Peña, Alexis Onimus, Tsuneyasu Kaisho, Johanna Kaufmann, Kristen McEachern, Hatem Soliman, Vincent C. Luca, Paulo C. Rodriguez, Xiaoqing Yu, Brian Ruffell
Journal: Immunity (2021)
当院におけるtPA-Facilitated PCIの検討
Authors: Okawa Keisuke, Ishizawa Makoto, Sato Shinji, Hirose Hideki, Hirohata Atsushi, Kawamura Hiroshi, Yamaji Hirosuke, Murakami Masaaki, Murakami Mitsuru, Yamamoto Keizo, Hina Issei, Kita Toshimasa
Journal: Circulation (2008)
CTCF mediates dosage- and sequence-context-dependent transcriptional insulation by forming local chromatin domains
Authors: Hui Huang, Quan Zhu, Adam Jussila, Yuanyuan Han, Bogdan Bintu, Colin Kern, Mattia Conte, Yanxiao Zhang, Simona Bianco, Andrea M. Chiariello, Miao Yu, Rong Hu, Melodi Tastemel, Ivan Juric, Ming Hu, Mario Nicodemi, Xiaowei Zhuang, Bing Ren
Journal: Nature Genetics (2021)
Abstract 015: Geographic Variation In Pre-pregnancy Cardiometabolic Health In The United States, 2016-2018
Authors: Natalie A Cameron, Priya M Freaney, Michael C Wang, Amanda M Perak, Brigid M Dolan, Matthew J O'Brien, William A Grobman, Norrina B Allen, Philip Greenland, Donald M Lloyd-Jones, Sadiya S Khan
Journal: Circulation (2021)

Introduction: Poor cardiometabolic health is a major contributor to growing rates of maternal morbidity and mortality. Given known state-level variation in maternal outcomes, we sought to describe the geographic distribution of pre-pregnancy cardiometabolic health as it could inform policy changes to optimize maternal and offspring outcomes. Hypothesis: We hypothesized that pre-pregnancy cardiometabolic health has declined over time and varies by state. Methods: We conducted a nationwide, serial cross-sectional analysis using maternal birth record data from the CDC Natality Files 2016-2018, which include all live births in the US. We included all live births to women aged 20-44 years (N= 10,693,708). Pre-pregnancy cardiometabolic health was quantified by number of pre-pregnancy risk factors: overweight or obesity (body mass index &gt; 25 kg/m 2 ), diabetes, and/or hypertension. We calculated annual age-standardized prevalence of favorable (no risk factors), suboptimal (any single risk factor), or poor ( &gt; 2 risk factors) pre-pregnancy cardiometabolic health and quantified percentage change between 2016-2018 by state. Results: From 2016-2018, the percentage of live births to women with favorable cardiometabolic health decreased from 43.5% (43.4, 43.6) to 41.3% (41.2, 41.3), suboptimal health increased from 51.1% (51.1, 51.2) to 53.3% (53.3, 53.4), and poor health increased from 2.1% (2.1, 2.1) to 2.4% (2.4, 2.4). All states experienced declines in favorable cardiometabolic health. There was significant geographic variation with prevalence of favorable pre-pregnancy cardiometabolic health ranging from 32.7% (32.2, 33.3) in Mississippi to 48.2% (47.7, 48.6) in Utah in 2018 (FIGURE) ; poor health ranged from 1.3% (1.3, 1.4) in California to 4.6% (4.4, 4.8) in Louisiana in 2018. Conclusions: Less than half of women had favorable pre-pregnancy cardiometabolic health between 2016-2018, with significant geographic heterogeneity. Public health efforts to improve pre-conception cardiometabolic health are needed.
Cardiac MIBG Imaging is an Useful Tool for the Evaluation of Diastolic Heart Failure as well as Systolic Heart Failure.
Authors: Maejima Yasuhiro, Suzuki Jun-ichi, Kosuge Hisanori, Inagaki Hiroshi, Kawabata Mihoko, Hachiya Hitoshi, Hata Akihiro, Hirao Kenzo, Isobe Mitsuaki
Journal: Circulation (2006)
Clinical response to the MAGE-A3 immunotherapeutic in metastatic melanoma patients is associated with a specific gene profile present prior to treatment
Authors: Jamila Louahed, B. Dréno, Swann Gaulis, Thibault Helleputte, Pierre Dupont, Olivier Gruselle, A. Spatz, W. Kruit, F. Lehmann, Vincent Brichard
Journal: Annals of Oncology (2008)
Plant-derived exosomal microRNAs inhibit lung inflammation induced by exosomes SARS-CoV-2 Nsp12
Authors: Yun Teng, Fangyi Xu, Xiangcheng Zhang, Jingyao Mu, Mohammed Sayed, Xin Hu, Chao Lei, Mukesh Sriwastva, Anil Kumar, Kumaran Sundaram, Lifeng Zhang, Juw Won Park, Shao-yu Chen, Shuangqin Zhang, Jun Yan, Michael L. Merchant, Xiang Zhang, Craig J. McClain, Jennifer K. Wolfe, Robert S. Adcock, Donghoon Chung, Kenneth E. Palmer, Huang-Ge Zhang
Journal: Molecular Therapy (2021)

Lung inflammation is a hallmark of coronavirus disease 2019 (COVID-19). In this study, we show that mice develop inflamed lung tissue after being administered exosomes released from the lung epithelial cells exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Nsp12 and Nsp13 (exosomesNsp12Nsp13). Mechanistically, we show that exosomesNsp12Nsp13 are taken up by lung macrophages, leading to activation of nuclear factor κB (NF-κB) and the subsequent induction of an array of inflammatory cytokines. Induction of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β from exosomesNsp12Nsp13-activated lung macrophages contributes to inducing apoptosis in lung epithelial cells. Induction of exosomesNsp12Nsp13-mediated lung inflammation was abolished with ginger exosome-like nanoparticle (GELN) microRNA (miRNA aly-miR396a-5p. The role of GELNs in inhibition of the SARS-CoV-2-induced cytopathic effect (CPE) was further demonstrated via GELN aly-miR396a-5p- and rlcv-miR-rL1-28-3p-mediated inhibition of expression of Nsp12 and spike genes, respectively. Taken together, our results reveal exosomesNsp12Nsp13 as potentially important contributors to the development of lung inflammation, and GELNs are a potential therapeutic agent to treat COVID-19. Lung inflammation is a hallmark of coronavirus disease 2019 (COVID-19). In this study, we show that mice develop inflamed lung tissue after being administered exosomes released from the lung epithelial cells exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Nsp12 and Nsp13 (exosomesNsp12Nsp13). Mechanistically, we show that exosomesNsp12Nsp13 are taken up by lung macrophages, leading to activation of nuclear factor κB (NF-κB) and the subsequent induction of an array of inflammatory cytokines. Induction of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β from exosomesNsp12Nsp13-activated lung macrophages contributes to inducing apoptosis in lung epithelial cells. Induction of exosomesNsp12Nsp13-mediated lung inflammation was abolished with ginger exosome-like nanoparticle (GELN) microRNA (miRNA aly-miR396a-5p. The role of GELNs in inhibition of the SARS-CoV-2-induced cytopathic effect (CPE) was further demonstrated via GELN aly-miR396a-5p- and rlcv-miR-rL1-28-3p-mediated inhibition of expression of Nsp12 and spike genes, respectively. Taken together, our results reveal exosomesNsp12Nsp13 as potentially important contributors to the development of lung inflammation, and GELNs are a potential therapeutic agent to treat COVID-19.