Optimized synthesis of anti-COVID-19 drugs aided by retrosynthesis software

Considering the millions of COVID-19 patients worldwide, a global critical challenge of low-cost and efficient anti-COVID-19 drug production has emerged. Favipiravir is one of the potential anti-COVID-19 drugs, but its original synthetic route with 7 harsh steps gives a low product yield (0.8%) and has a high cost ($68 per g). Herein, we demonstrated a low-cost and efficient synthesis route for favipiravir designed using improved retrosynthesis software, which involves only 3 steps under safe and near-ambient air conditions. A yield of 32% and cost of $1.54 per g were achieved by this synthetic route. We also used the same strategy to optimize the synthesis of sabizabulin. We anticipate that these synthetic routes will contribute to the prevention and treatment of COVID-19.

Mechanism and Experimental Verification of the Use of Rhodiola crenulata to Cytokine Storm Based on Network Pharmacology and Molecular Docking

Objective: To identify the potential biological mechanisms by which Rhodiola crenulata (RC) treats cytokine storm (CS) using network pharmacology, molecular docking, and experimental verification. Method(s): The ingredients and targets of RC were collected from the Organchem database. CS-related genes were collected using the GeneCards and OMIM databases. Cytoscape 3.7.2 software was used to construct the RC-CS network diagram. These data were inputted into the STRING database to construct a protein-protein interaction network. we performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes enrichment analysis using DAVID and R software. Molecular docking of the active ingredient and pathway-related targets was carried out using AutoDock Vina and PyMOL, and then a CS model was established in rats induced by lipopolysaccharide for in vivo experimental verification. Result(s): The network pharmacology results showed that kaempferol was the most important active component of RC in the treatment of CS, and IL6 and STAT3 were identified as key targets. Molecular docking results showed that RC active components kaempferol had a good binding ability to IL6/STAT3. At the same time, compared with the model group, different doses of kaempferol could down-regulate the expression of inflammatory factors (P <.05), and protect against systemic inflammatory response multiple organ damage. Conclusion(s): This study preliminarily revealed that RC can prevent and treat CS by regulating the expression of inflammatory factors, inhibiting the systemic inflammatory response induced by lipopolysaccharide, and providing a theoretical basis for the study of its pharmacodynamic material basis and mechanism of action. Copyright © The Author(s) 2022.

Present therapeutic and diagnostic approaches for SARS-CoV-2 infection

The novel Coronavirus (nCoV), severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2), has shaken the whole world and posed significant challenges to the global healthcare system for more than a year. The scientific community across the globe is trying to combat this virus by developing a safe vaccine that can provide long-term immunity against the virus. The other means of overcoming its pathogenicity is to treat the infected people with available drugs and/or novel therapeutic strategies. The available drugs were previously designed to combat viral infections and come with tested safety. This appears to be the most practical approach as a quick response to the highly infectious pandemic with high morbidity and mortality. Although many repurposed drugs like favipiravir and hydroxychloroquine have been tried, they have been proven toxic and/or less efficacious. This has led the world to find urgent therapeutic interventions (traditional and novel), to help decrease the severity of COVID-19 infection and aim towards recovery. This chapter of the book will discuss the most up-to-date published data with respect to prevention and treatment of COVID-19 infection. Diagnosis also plays an important part in controlling the pandemic caused by the virus. A cheap, accurate and fast identification test for the virus is the need of the hour. This chapter will also throw light on the various diagnostic procedures available for the identification of SARS-CoV-2, till date, along with their advantages and disadvantages. © 2022 Elsevier Inc. All rights reserved.

POST-COVID-19 ORGANIZING PNEUMONIA: A RARER ENTITY THAN PREVIOUSLY IMAGINED

SESSION TITLE: Post-COVID-19 Outcomes SESSION TYPE: Rapid Fire Original Inv PRESENTED ON: 10/19/2022 11:15 am - 12:15 pm PURPOSE: Organizing pneumonia (OP) is well known complication of severe viral infections. Recent reviews of postmortem biopsies and CT imaging suggest that a subset of patients develop secondary organizing pneumonia following infection with SAR-COV2. High dose steroids have previously been proven efficacious in post viral OP following infections such as H1N1, severe acute respiratory syndrome and MERS. This study aims to discover the incidence and impact of high dose steroids in treatment of Covid 19 patients who have characteristics of OP following initial infection. METHODS: We reviewed records of adult patients over age 18 hospitalized with respiratory failure due to COVID-19 pneumonia between 3/1/20 and 6/30/21 in our institution. We isolated patients who survived initial presentation but developed persistent hypoxia and CT evidence of progression to OP. Of these, we reviewed those treated with high dose prednisone, the usual dexamethasone, or no steroid treatment. We documented age, gender, timing of initiation of steroids, timing of steroid tapering, oxygen requirements at initiation, at day 30, and day 90, and overall outcomes. RESULTS: We identified 881 patients with COVID of which 46 patients met the criteria of having OP. Age ranged from 18-73, median age of 60.5. 52% were male. 3 patients had lung biopsy to confirm OP. All other patients were diagnosed based on CT and clinical presentation. 23 patients were treated with Prednisone after the initial 10-day course of dexamethasone. 24 patients were treated with just 10 days of dexamethasone. 5 patients were not treated with steroids. CONCLUSIONS: The incidence of post-covid OP appears to be lower than anticipated, with an incidence rate of roughly 0.05% in our study population. A significant proportion of patients had at least 2 underlying medical conditions. Patients on lower supplemental oxygen requirement (<2 L NC) were not continued on steroids and did well with only 2 of the 23 requiring oxygen at 30 days with mortality. Patients on higher supplemental oxygen at 10 days (>2L NC) were continued on steroids and the mortality rate was high, ~40%. We would conclude the incidence of post-Covid associated OP seems to be low in this small cohort of patients, and the decision to continue steroids should be based on individual patient characteristics such as supplemental oxygen requirements at 10 days, rather than CT findings of OP and that they seem to have higher mortality. In the future, larger multicenter cohort studies would help to understand further treatment. CLINICAL IMPLICATIONS: Although our incidence of post-covid OP is low, the mortality and morbidity in select patients appears to be high. Anticipating specific populations who may be at higher risk and starting treatment earlier could help reduce mortality. Larger cohort studies are needed to help develop better treatment strategies. DISCLOSURES: No relevant relationships by Hajra Channa No relevant relationships by Cesar Davila-Chapa No relevant relationships by Prathik Krishnan No relevant relationships by uzoamaka ogbonnah No relevant relationships by arunima sharma no disclosure on file for Diana Song;No relevant relationships by Fereshteh Yazdi

Advances in small molecular inhibitors of IL-6/STAT3 signaling pathway

As a pleiotropic cytokine, interleukin-6 (IL-6) participates in many physiological activities in vivo. IL-6 plays an important role in the physiology and pathology of chronic inflammation, autoimmune diseases, tumors and other diseases through diverse mechanisms. At present, inhibitors targeting IL-6/IL-6R have been shown to improve treatments for some inflammatory diseases such as rheumatoid arthritis and systemic juvenile idiopathic arthritis. IL-6 binds to a specific receptor to activate the downstream JAK/STAT3 signaling pathway. However abnormally activated STAT3 often appears in various types of malignant tumors and participates in the occurrence and development of tumors. In addition, studies have shown that IL-6 is a key factor in the cytokine storm associated with COVID-19 patients. The physiological participation of IL-6/STAT3 pathway in complex diseases makes this pathway become a research hotspot for drug discovery. Therefore, we summarize the latest research progress of small molecular inhibitors on IL-6/STAT3 signaling pathway, in order to provide a reference for the development of IL-6/STAT3 related drug in the future. © 2021, Chinese Pharmaceutical Association. All rights reserved.

Impact and Enlightenment of EU’s “Industry 5.0” to High-quality Development of China’s Manufacturing —Research on Application of Think Tank Double Helix Methodology

The world is experiencing a great change with the combined impact of the COVID-19 pandemic. In the post-epidemic era, the world’s major economies have begun to plan their strategic adjustments, economic revival and transformation. Industry 5.0, as the EU’s new strategy to plan the “New Industrial Revolution” and promote industrial transformation in Europe, has raised wide attentions in the world and has become a hotspot of think tank research. Guided by the think tank double helix methodology, this study constructed a cognitive framework to study industrial strategy and its related complex system issues such as international relations, science and technology strategy, and economic and social development from systematic, subjective, scientific, global and practical perspectives, researched the feature, purpose and significance of Industry 5.0, as well as its impact, enlightenment and reference on the high-quality development of China’s manufacturing, and put forward the coping strategies. This study fully revealed the value and significance of think tank double helix methodology in expanding the research horizon of such issues. © 2022, Science Press. All rights reserved.

Echocardiographic findings with troponemia and its correlation in covid-19 patients

Introduction: Echocardiogram findings with Troponemia and its correlation in COVID 19 patients are not well studied Methods: Mean and standard deviation (SD) for continuous variables with normal distribution were reported. Pearson chi-square was performed to see the clinical correlation of dependent variables including regional wall motion abnormalities (RWMA), diastolic dysfunction (DF), paradoxical septal wall motion (PSWM) and pericardial effusion in COVID-19. The primary outcome was to observe the effect on in-hospital mortality and 1 year mortality of echocardiographic findings. Our secondary outcome was to retrospectively see the association of gender with echocardiographic findings. Results: In this small, retrospective, single-center study from an epicenter city of COVID-19 at the Detroit Medical Center. We included a total of 122 patients with confirmed COVID-19. The mean age of the cohort was 67.3 years SD= 14. The mean troponin (Tn) at baseline admission was 173 ng/l SD±762 (normal=3-17 ng/l), while the peak Tn were 693 SD±2941. The baseline RSVP was 16 SD±20, while the peaked RSVP was 4 SD±13. Statistically significant associations of RWMA are shown in figure 1. We also found statistically significant differences in DF with presence of MVR (21/35;p<0.05), and RWMA (event/total;14/35;p<0.05). We also found significance for RV dilation on initial echo for RVH (11/31;p<0.05), and peaked MVR (6/31;p<0.05). We also found statistically significant differences of PSWM for inpatient mortality (3/3;p<0.05), RVH ( 2/ 3;p <0.05), and LTVMV (3/3 ;p <0.05). We found statistical significance of pericardial effusion and LTVMV (3/14;p <0.05). We found statistical significant correlation of gender and RVH on admission echocardiogram: (Male 15/79;Female 2/43;p<0.05), and RWMA (Male 7/79;Female 0/43;p<0.05). Conclusion: COVID-19 patients have high mortality in the presence of RWMA and PSWM.

Synthesis and evaluation of N-cycloberberine derivatives as a novel class of anti-SARS-CoV-2 pseudovirus agents

There is no specific drug against COVID-19, but berberine (BBR) has moderate anti-SARS-CoV-2 pseudovirus activity. Taking BBR as the lead, 18 novel N-cycloberberine derivatives were synthesized and evaluated for their anti-SARS-CoV-2 pseudovirus activities in vitro. Structure-activity relationship analysis revealed that introducing an appropriate heterocyclic group at position 9 might be beneficial for potency. Among the tested compounds, compound 3m showed the most potent activity against SARS-CoV-2, with EC50 value of 1.61 μmol·L-1 and SI value of 22.2, much better than that of BBR. Additional experiment indicated that 3m had inhibitory activity on multiple processes in viral invasion, including adsorption and membrane fusion, suggesting a multi-target synergistic mechanism of action. These results provide a novel family of lead compounds for the discovery of anti-SARS-CoV-2 candidates. © 2021, Chinese Pharmaceutical Association. All rights reserved.

BASELINE CHARACTERISTICS AND PREDICTORS FOR ALL-CAUSE MORTALITY IN PATIENTS HOSPITALIZED WITH COVID-19 PNEUMONIA

TOPIC: Chest Infections TYPE: Original Investigations PURPOSE: COVID Pneumonia is associated with high morbidity and mortality accounting for 3 million deaths worldwide. This aim of this study is to identify risk factors related to mortality in patients admitted to the hospital with COVID Pneumonia and to compare baseline characteristics and outcomes of different racial groups. METHODS: This is a retrospective observational study of patients 18 years and older who were admitted to an academic medical center between March to May of 2020. Categorical variables were reported as counts and percentages, using Chi Square or Exact Fischer test. Continuous variables were reported in means and standard deviation using Student T test. Logistic regression was performed to identify factors associated with mortality. RESULTS: 190 patients were included in the study, 157 (82.63%) were African American (AA). AA patients had significantly higher weight, BMI and creatinine on admission. Prevalence of chronic kidney disease (CKD) was significantly higher in AA patients while the prevalence of atrial fibrillation was higher in non-AA patients. There was no difference in all-cause mortality between non-AA and AA groups (27.27% VS 20.38%, p=0.38). Factors that were associated with all-cause mortality included underlying CVA (OR=2.84, p<0.01, CI (1.3, 6.22)), thrombocytopenia (OR=0.99, p<0.01, CI (0.98, 0.99)), acute kidney injury (OR=2.95, p<0.01, CI (1.45, 6)), elevated alkaline phosphatase (OR=1.006, p=0.035, CI (1.0004, 1.01)), elevated D dimer (OR=1.0003, p<0.01, CI (1.00008, 1.0006)), elevated CRP (OR=1.1, p<0.01, CI (1.04, 1.16)), acute respiratory distress syndrome (ARDS) (OR=11.17, p<0.01, CI (4.9, 25.46)), intubation (OR=22.56, p<0.01, CI (9.49, 53.66)), vasopressor requirement (OR=14.77, p<0.01, CI (6.36, 34.3)) and use of hydroxychloroquine (OR=25.37, p<0.01, CI (2.96, 217.55)). Multi-variable logistic regression was used to control for confounding and race was not associated with mortality (OR=0.25, p=0.21, CI (0.03,2.19)). CONCLUSIONS: In patients with COVID pneumonia, organ dysfunction and the use of Hydroxychloroquine were factors associated with increased mortality. Despite significant differences in baseline weight, BMI, prevalence of AF and CKD among AA and non-AA patients, there was no significant difference in mortality between the 2 groups. CLINICAL IMPLICATIONS: Clinicians should consider early close monitoring of patients with COVID19 pneumonia and evidence of end organ dysfunction since there seems to be an association with increased mortality. Based on our retrospective study the use of hydroxychloroquine should be avoided in this patient population. DISCLOSURES: No relevant relationships by Adekola Adedeji, source=Web Response No relevant relationships by Prangthip Charoenpong, source=Web Response No relevant relationships by Nour Daoud, source=Web Response No relevant relationships by Deon Ford, source=Web Response No relevant relationships by Nasim Motayar, source=Web Response No relevant relationships by Diana Song, source=Web Response

Real-Time Low-Cost Personal Monitoring for Exposure to PM2.5 among Asthmatic Children: Opportunities and Challenges

This study aims to evaluate the accuracy and effectiveness of real-time personal monitoring of exposure to PM concentrations using low-cost sensors, in comparison to conventional data collection method based on fixed stations. PM2.5 data were measured every 5 min using a low-cost sensor attached to a bag carried by 47 asthmatic children living in the Seoul Metropolitan area between November 2019 and March 2020, along with the real-time GPS location, temperature, and humidity. The mobile sensor data were then matched with station-based hourly PM2.5 data using the time and location. Despite some uncertainty and inaccuracy of the sensor data, similar temporal patterns were found between the two sources of PM2.5 data on an aggregate level. However, average PM2.5 concentrations via personal monitoring tended to be lower than those from the fixed stations, particularly when the subjects were indoors, during nighttime, and located farther from the fixed station. On an individual level, a substantial discrepancy is observed between the two PM2.5 data sources while staying indoors. This study provides guidance to policymakers and researchers on improving the feasibility of personal monitoring via low-cost mobile sensors as an alternative or supplement to the conventional station-based monitoring.

An overlap of two pathologies: Anti-synthetase and IGG4-related disease

Introduction. Anti-Synthetase Syndromes and IgG4-related diseases have rarely been seen together. We present a 38-year-old female with connective tissue disease-associated interstitial lung disease from Anti-Synthetase syndrome who eventually develops autoimmune pancreatitis from IgG4-related disease. Case Presentation. A 38-year-old African American female with facial rash, joint swelling, and morning stiffness was seen to have pulmonary fibrosis on CXR and CT chest. Subsequent bronchoscopy was inconclusive. She was treated for presumed mixed Connected Tissue Disease (CTD) and associated pulmonary fibrosis with Mycophenolate, Hydroxychloroquine, and Prednisone. Several months later, she had shortness of breath and was diagnosed with COVID-19. Her mycophenolate was held while she recovered with supplemental oxygen, but has required 2 to 3 liters of supplemental oxygen chronically since her COVID diagnosis. A repeat bronchoscopy with transbronchial and cryobiopsies was suggestive of Cryptogenic Organizing Pneumonia (COP) and negative for malignancy. At that time, blood work revealed positive melanoma differentiation-associated (MDA) protein 5 antibodies, high antinuclear antibodies (ANA) titers, positive anti-Sjögren's-syndrome antigen A (SSA) autoantibodies, weakly positive PL-12, and negative Jo-1. Additionally, the patient had elevated concentrations of IgG4. A repeat CT revealed fatty infiltration of the pancreas. Her MDA positivity qualified the patient to begin Rituximab infusions weekly for four weeks. Her shortness of breath continued to improve on her previously stated treatments. However, she presented to a local emergency department for acute abdominal pain. She was diagnosed with acute pancreatitis and improved after receiving intravenous fluids. Discussion. This patient has connective tissue disease associated with interstitial lung disease from Anti-Synthetase syndrome. She has positive anti-MDA-5 antibodies and cryobiopsy diagnosed COP, a known finding in Anti-Synthetase syndrome. It is also possible that this patient has overlapping IgG4-related disease, correlated by elevated concentrations of IgG4 and autoimmune pancreatitis. This overlap is not well studied, considering that the pathophysiology of Anti-Synthetase syndrome involves autoimmunity towards aminoacyl-tRNA synthetase while IgG4-related disease pathophysiology is not well known and could involve abnormal activation of CD4-positive T cells. Interestingly, this patient had fatty infiltration of her pancreas found on imaging before she was symptomatic for autoimmune pancreatitis. It is possible that both disease processes were not only active simultaneously but also complicated the progression of one another. Clinicians should consider IgG4-related diseases in patients with Anti-Synthetase Syndrome as it might explain a patient's clinical picture and even change management.

Standardized out-patient diagnosis and treatment process for osteoporosis clinics during the COVID-19 pandemic.

Since the end of 2019, China and other regions around the world have been facing a pandemic of novel coronavirus pneumonia (COVID-19). The virus is highly transmissible, and the human population is generally susceptible. Most patients with osteoporosis are postmenopausal women or elderly people with hypoimmunity, so the osteoporosis clinic has become a new hotspot for corona virus infection. During the COVID-19 pandemic, it is necessary to establish standardized out-patient protocols to provide safe and effective treatment for osteoporosis patients and medical staff. In an osteoporosis clinic, we advocate the following suggestions to prevent and control osteoporosis during the pandemic period: (1) specialized diagnosis and treatment techniques for osteoporosis patients in the outpatient care, including enhancing the prevention for outpatient medical staff, strengthening awareness of COVID-19 prevention, strictly screening outpatients with COVID-19 infection, and insistent administration of anti-osteoporosis drugs during outbreaks; (2) home prevention for osteoporosis patients including keeping windows open, exposing them to sunlight, supplementing them with enough protein, exercising regularly, and administrating calcium supplements; and (3) simplifying the follow-up and evaluation of osteoporosis using online platforms.