Perspective for Discovery of Small Molecule IL-6 Inhibitors through Study of Structure-Activity Relationships and Molecular Docking.

Interleukin-6 (IL-6) is a proinflammatory cytokine that plays a key role in the pathogenesis and physiology of inflammatory and autoimmune diseases, such as coronary heart disease, cancer, Alzheimer's disease, asthma, rheumatoid arthritis, and most recently COVID-19. IL-6 and its signaling pathway are promising targets in the treatment of inflammatory and autoimmune diseases. Although, anti-IL-6 monoclonal antibodies are currently being used in clinics, huge unmet medical needs remain because of the high cost, administration-related toxicity, lack of opportunity for oral dosing, and potential immunogenicity of monoclonal antibody therapy. Furthermore, nonresponse or loss of response to monoclonal antibody therapy has been reported, which increases the importance of optimizing drug therapy with small molecule drugs. This work aims to provide a perspective for the discovery of novel small molecule IL-6 inhibitors by the analysis of the structure-activity relationships and computational studies for protein-protein inhibitors targeting the IL-6/IL-6 receptor/gp130 complex.

Identification of 1H-purine-2,6-dione derivative as a potential SARS-CoV-2 main protease inhibitor: molecular docking, dynamic simulations, and energy calculations.

The rapid spread of the coronavirus since its first appearance in 2019 has taken the world by surprise, challenging the global economy, and putting pressure on healthcare systems across the world. The introduction of preventive vaccines only managed to slow the rising death rates worldwide, illuminating the pressing need for developing effective antiviral therapeutics. The traditional route of drug discovery has been known to require years which the world does not currently have. In silico approaches in drug design have shown promising results over the last decade, helping to decrease the required time for drug development. One of the vital non-structural proteins that are essential to viral replication and transcription is the SARS-CoV-2 main protease (Mpro). Herein, using a test set of recently identified COVID-19 inhibitors, a pharmacophore was developed to screen 20 million drug-like compounds obtained from a freely accessible Zinc database. The generated hits were ranked using a structure based virtual screening technique (SBVS), and the top hits were subjected to in-depth molecular docking studies and MM-GBSA calculations over SARS-COV-2 Mpro. Finally, the most promising hit, compound (1), and the potent standard (III) were subjected to 100 ns molecular dynamics (MD) simulations and in silico ADME study. The result of the MD analysis as well as the in silico pharmacokinetic study reveal compound 1 to be a promising SARS-Cov-2 MPro inhibitor suitable for further development.

Identification of 1H-purine-2,6-dione derivative as a potential SARS-CoV-2 main protease inhibitor: molecular docking, dynamic simulations, and energy calculations

The rapid spread of the coronavirus since its first appearance in 2019 has taken the world by surprise, challenging the global economy, and putting pressure on healthcare systems across the world. The introduction of preventive vaccines only managed to slow the rising death rates worldwide, illuminating the pressing need for developing effective antiviral therapeutics. The traditional route of drug discovery has been known to require years which the world does not currently have. In silico approaches in drug design have shown promising results over the last decade, helping to decrease the required time for drug development. One of the vital non-structural proteins that are essential to viral replication and transcription is the SARS-CoV-2 main protease (Mpro). Herein, using a test set of recently identified COVID-19 inhibitors, a pharmacophore was developed to screen 20 million drug-like compounds obtained from a freely accessible Zinc database. The generated hits were ranked using a structure based virtual screening technique (SBVS), and the top hits were subjected to in-depth molecular docking studies and MM-GBSA calculations over SARS-COV-2 Mpro. Finally, the most promising hit, compound (1), and the potent standard (III) were subjected to 100 ns molecular dynamics (MD) simulations and in silico ADME study. The result of the MD analysis as well as the in silico pharmacokinetic study reveal compound 1 to be a promising SARS-Cov-2 MPro inhibitor suitable for further development.

Vulnerable individuals and changes in suicidal behaviour during the COVID-19 pandemic in Korea.

BACKGROUND: The COVID-19 pandemic poses a major threat to mental health and is associated with an increased risk of suicide. An understanding of suicidal behaviours during the pandemic is necessary for establishing policies to prevent suicides in such social conditions. AIMS: We aimed to investigate vulnerable individuals and the characteristics of changes in suicidal behaviour during the COVID-19 pandemic. METHOD: We retrospectively reviewed the medical records of patients with suicide attempts who visited the emergency department from February 2019 to January 2021. We analysed the demographic and clinical characteristics, risk factors and rescue factors of patients, and compared the findings between the pre-pandemic and pandemic periods. RESULTS: In total, 519 patients were included. During the pre-pandemic and pandemic periods, 303 and 270 patients visited the emergency department after a suicide attempt, respectively. The proportion of suicide attempts by women (60.1% v. 69.3%, P = 0.035) and patients with a previous psychiatric illness (63.4% v. 72.9%, P = 0.006) increased during the COVID-19 pandemic. In addition, patients' rescue scores during the pandemic were lower than those during the pre-pandemic period (12 (interquartile range: 11-13) v. 13 (interquartile range: 12-14), P < 0.001). CONCLUSIONS: Women and people with previous psychiatric illnesses were more vulnerable to suicide attempts during the COVID-19 pandemic. Suicide prevention policies, such as continuous monitoring and staying in touch with vulnerable individuals, are necessary to cope with suicide risk.

Evaluation of the Public Health Emergency Response to the COVID-19 Pandemic in Daegu, Korea During the First Half of 2020.

OBJECTIVES: This study evaluated the response in Daegu, Korea to the first wave of the coronavirus disease 2019 (COVID-19) pandemic according to a public health emergency response model. METHODS: After an examination of the official data reported by the city of Daegu and the Korea Centers for Disease Control and Prevention, as well as a literature review and advisory meetings, we chose a response model. Daegu's responses were organized into 4 phases and evaluated by applying the response model. RESULTS: In phase 1, efforts were made to block further transmission of the virus through preemptive testing of a religious group. In phase 2, efforts were concentrated on responding to mass infections in high-risk facilities. Phase 3 involved a transition from a high-intensity social distancing campaign to a citizen participation-based quarantine system. The evaluation using the response model revealed insufficient systematic preparation for a medical surge. In addition, an incorporated health-related management system and protection measures for responders were absent. Nevertheless, the city encouraged the participation of private hospitals and developed a severity classification system. Citizens also played active roles in the pandemic response by practicing social distancing. CONCLUSIONS: This study employed the response model to evaluate the early response in Daegu to the COVID-19 pandemic and revealed areas in need of improvement or maintenance. Based on the study results, creation of a systematic model is necessary to prepare for and respond to future public health emergencies like the COVID-19 pandemic.

Predictive Values of Procalcitonin and Presepsin for Acute Kidney Injury and 30-Day Hospital Mortality in Patients with COVID-19.

Background and Objectives: Acute kidney injury (AKI) is a common complication in patients with coronavirus disease 2019 (COVID-19). We investigated the values of procalcitonin (PCT) and presepsin (PSS) for predicting AKI and 30-day hospital mortality in patients with COVID-19. Materials and Methods: We retrospectively evaluated 151 patients with COVID-19 who were admitted to the hospital via the emergency department. The diagnosis of AKI was based on the Kidney Disease: Improving Global Outcomes clinical practice guidelines. Results: The median patient age was 77 years, and 86 patients (57%) were male. Fifty-six patients (37.1%) developed AKI, and 19 patients (12.6%) died within 30 days of hospital admission. PCT and PSS levels were significantly higher in patients with AKI and non-survivors. The cutoff values of PCT levels for predicting AKI and mortality were 2.26 ng/mL (sensitivity, 64.3%; specificity, 89.5%) and 2.67 ng/mL (sensitivity, 68.4%; specificity, 77.3%), respectively. The cutoff values of PSS levels for predicting AKI and mortality were 572 pg/mL (sensitivity, 66.0%; specificity, 69.1%) and 865 pg/mL (sensitivity, 84.6%; specificity, 76.0%), respectively. Conclusion: PCT and PSS are valuable biomarkers for predicting AKI and 30-day hospital mortality in patients with COVID-19.

Three-Terminal Ovonic Threshold Switch (3T-OTS) with Tunable Threshold Voltage for Versatile Artificial Sensory Neurons.

Inspired by information processing in biological systems, sensor-combined edge-computing systems attract attention requesting artificial sensory neurons as essential ingredients. Here, we introduce a simple and versatile structure of artificial sensory neurons based on a novel three-terminal Ovonic threshold switch (3T-OTS), which features an electrically controllable threshold voltage (Vth). Combined with a sensor driving an output voltage, this 3T-OTS generates spikes with a frequency depending on an external stimulus. As a proof of concept, we have built an artificial retinal ganglion cell (RGC) by combining a 3T-OTS and a photodiode. Furthermore, this artificial RGC is combined with the reservoir-computing technique to perform a classification of chest X-ray images for normal, viral pneumonia, and COVID-19 infections, releasing the recognition accuracy of about 86.5%. These results indicate that the 3T-OTS is highly promising for applications in neuromorphic sensory systems, providing a building block for energy-efficient in-sensor computing devices.

Staffing Levels and COVID-19 Infections and Deaths in Korean Nursing Homes.

The novel coronavirus disease 2019 (COVID-19) spread rapidly worldwide. Nursing home (NH) residents are the most vulnerable high-risk population to infection. Professional registered nurses' (RNs') infection control is irreplaceable. We used a secondary data analysis method using the government's senior citizen welfare department large data set about all NHs (N = 3,389) across Korea between January 20 and October 20, 2020. Bed size positively associated with the mortality rate (No. of COVID-19 resident deaths / No. of total residents) (p = .048). When the proportion of RNs to total nursing staff was higher, the infection rate was 0.626% lower (p = .049), the mortality rate was 0.088% lower (p = .076), the proportion of confirmed COVID-19 cases per resident out of the total number of NHs was 44.472% lower (p = .041), and the proportion of confirmed COVID-19 deaths per resident out of the total number of NHs was 6.456% lower (p = .055). This study highlighted nurse staffing criteria and suggests that increasing RNs in NHs will reduce infection and mortality rates during the COVID-19 pandemic. We strongly suggest NHs hire at least one RN per day to properly function, and a minimum of four RNs to provide a fully competent RN workforce in long-term care settings in Korean NHs.

Bioanalysis of niclosamide in plasma using liquid chromatography-tandem mass and application to pharmacokinetics in rats and dogs.

Niclosamide, which is an anti-tapeworm drug, was developed in 1958. However, recent studies have demonstrated the antiviral effects of niclosamide against the SARS-CoV-2 virus, which causes COVID-19. In this study, we developed and validated a quantitative analysis method for the determination of niclosamide in rat and dog plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS), and used this method for pharmacokinetic studies. Biological samples were prepared using the protein precipitation method with acetonitrile. Ibuprofen was used as an internal standard. The mobile phase used to quantify niclosamide in rat or dog plasma consisted of 10 mM ammonium formate in distilled water-acetonitrile (30:70, v/v) or 5 mM ammonium acetate-methanol (30:70, v/v). An XDB-phenyl column (5 µm, 2.1 × 50 mm) and a Kinetex® C18 column (5 µm, 2.1 × 500 mm) were used as reverse-phase liquid chromatography columns for rat and dog plasma analyses, respectively. Niclosamide and ibuprofen were detected under multiple reaction monitoring conditions using the electrospray ionization interface running in the negative ionization mode. Niclosamide presented linearity in the concentration ranges of 1-3000 ng/mL (r = 0.9967) and 1-1000 ng/mL (r = 0.9941) in rat and dog plasma, respectively. The intra- and inter-day precision values were < 7.40% and < 6.35%, respectively, for rat plasma, and < 3.95% and < 4.01%, respectively, for dog plasma. The intra- and inter-day accuracy values were < 4.59% and < 6.63%, respectively, for rat plasma, and < 12.1% and < 10.9%, respectively, for dog plasma. In addition, the recoveries of niclosamide ranged between 87.8 and 99.6% and 102-104% for rat and dog plasma, respectively. Niclosamide was stable during storage under various conditions (three freeze-thaw cycles, 6 h at room temperature, long-term, and processed samples). A reliable LC-MS/MS method for niclosamide detection was successfully used to perform pharmacokinetic studies in rats and dogs. Niclosamide presented dose-independent pharmacokinetics in the dose range of 0.3-3 mg/kg after intravenous administration, and drug exposure in rats and dogs after oral administration was very low. Additionally, niclosamide presented high plasma protein binding (>99.8%) and low metabolic stability. These results can be helpful for further developing and understanding the pharmacokinetic characteristics of niclosamide to expand its clinical use.

Infection control of operating room and anesthesia for cesarean section during the COVID-19 outbreak in Daegu, the Republic of Korea -a case series.

BACKGROUND: The coronavirus disease-19 (COVID-19) was first reported in Wuhan, China, with Korea being subsequently exposed. In Korea, COVID-19 screening guidelines have been established in every hospital as an attempt to prevent its spread. There has been a previous report of a successful cesarean section of a confirmed mother; however, there remain no guidelines for suspected mothers. Cesarean section is often urgently operated without sufficient infection evaluations. We would like to suggest anesthetic management guidelines for cesarean section patients suspected of COVID-19. CASE: Our hospital, which is located in Daegu, Korea, was designated as a quarantine and delivery facility for suspected mothers. We performed the cesarean section on seven suspected mothers and one confirmed mother. CONCLUSIONS: This case report presents guidelines for infection control during surgery and anesthesia for cesarean section of mothers with suspected COVID-19 involving operating room preparation and protection strategy.

A Brief Telephone Severity Scoring System and Therapeutic Living Centers Solved Acute Hospital-Bed Shortage during the COVID-19 Outbreak in Daegu, Korea.

With the epidemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2, the number of infected patients was rapidly increasing in Daegu, Korea. With a maximum of 741 new patients per day in the city as of February 29, 2020, hospital-bed shortage was a great challenge to the local healthcare system. We developed and applied a remote brief severity scoring system, administered by telephone for assigning priority for hospitalization and arranging for facility isolation ("therapeutic living centers") for the patients starting on February 29, 2020. Fifteen centers were operated for the 3,033 admissions to the COVID-19 therapeutic living centers. Only 81 cases (2.67%) were transferred to hospitals after facility isolation. We think that this brief severity scoring system for COVID-19 worked safely to solve the hospital-bed shortage. Telephone scoring of the severity of disease and therapeutic living centers could be very useful in overcoming the shortage of hospital-beds that occurs during outbreaks of infectious diseases.