Investigation of Treatment-Emergent Amino Acid Substitutions in Nonstructural Protein 5 from Ph2a Study of Ensitrelvir, a Novel Oral SARS-CoV-2 3C-Like Protease Inhibitor

Background. Ensitrelvir is a novel oral SARS-CoV-2 3C-like protease inhibitor, and under late clinical development stage for COVID-19 disease. In Ph2a and Ph2b studies, ensitrelvir demonstrated rapid decline of viral titer and viral RNA compared with placebo, and tolerability. To investigate treatment-emergent amino acid substitutions (TEAASs), we analyzed viral RNA sequences of nonstructural protein 5 (NSP5), target of ensitrelvir from Ph2a study in Japan. Methods. In Ph2a study, 69 patients with confirmed SARS-CoV-2 infection were randomized 1:1:1 to ensitrelvir with the loading dose on Day 1/maintenance dose on Day 2-5 (375/125 mg or 750/250 mg), or placebo. Intent-to-treat (ITT) population was defined as participants confirmed with positivity by qualitative RT-PCR at baseline. TEAASs were defined as novel amino acid substitutions identified after treatment with ensitrelvir. NSP5 sequence analysis was performed with sanger sequencing using nasopharyngeal swab samples at Day 1, 6, 9, 14, and 21 with allowances from ITT population with ensitrelvir. Infectious viral titer was measured by virus-induced cytopathic effects in VeroE6/TMPRSS2 cells. Viral RNA was quantified by RT-PCR. Results. By NSP5 sequence analysis, TEAASs were observed in 1 patient from 375/125 mg group and 2 patients from 750/250 mg group. H246Y in 375/125 mg was detected from specimen on Day 8, and A234S and T198I in 750/250 mg were detected from specimens on Day 8 and Day 14, respectively. Structural analysis revealed that these mutations are located outside of the active center of 3C-like protease which is the binding site of ensitrelvir. Viral titer and viral RNA in each specimen, in which TEAASs were observed, were below lower limit of detection and lower limit of quantification, respectively. Furthermore, H246Y, A234S and T198I are rare substitution (< 0.05%) among SARS-CoV-2 variants according to Global Initiative on Sharing Avian Influenza Data. Conclusion. In Ph2a study, H246Y, A234S, and T198I in NSP5 were detected as TEAASs. However, results of viral titer and viral RNA, and structural information suggest that these mutations do not have the impact on antiviral efficacy of ensitrelvir.

Indian Power System Operations during NCOVID-19 Pandemic

The NCOVID-19 pandemic has been an unforeseen calamity which affected almost all the countries in the world. On March 11, 2020, World Health Organization (WHO) declared NCOVID-19 as a pandemic. The Government of India (GOI) took several actions to control the spread of the pandemic in the country and issued several guidelines for public and organizations. The adversity caused by pandemic required continuity of electric supply to consumers. The latter was achieved through proper planning and execution. The Indian Power System Operator, POSOCO through its National and Regional Load Dispatch Centers (NLDC and RLDCs) assessed the situation early and took all planned efforts for the Indian power system operation which is essential for keeping 'lights ON' during these hours of crisis. Strategic team at the top management level and tactical teams at the individual control center level were formed to handle any unforeseen circumstances. This paper has discussed the various actions taken by POSOCO during NCOVID-19 scenario and impact of it on Indian power system. Impact of exceptional events as faced during pandemic period, like, Janata Curfew, Lights-Off event, Super Cyclonic Storms 'Amphan', 'Nisarga', and Solar eclipse is also discussed in the paper. The insights gained during these events may enhance the capability to envisage and handle such multiple high impact low probability events in the future. © 2021 IEEE.

Impact of daily high dose oral vitamin D therapy on the inflammatory markers in patients with COVID 19 disease.

COVID 19 is known to cause immune dysregulation and vitamin D is a known immunomodulator. This study aims to objectively investigate the impact of Pulse D therapy in reducing the inflammatory markers of COVID-19. Consented COVID-19 patients with hypovitaminosis D were evaluated for inflammatory markers (N/L ratio, CRP, LDH, IL6, Ferritin) along with vitamin D on 0th day and 9th/11th day as per their respective BMI category. Subjects were randomised into VD and NVD groups. VD group received Pulse D therapy (targeted daily supplementation of 60,000 IUs of vitamin D for 8 or 10 days depending upon their BMI) in addition to the standard treatment. NVD group received standard treatment alone. Differences in the variables between the two groups were analysed for statistical significance. Eighty seven out of one hundred and thirty subjects have completed the study (VD:44, NVD:43). Vitamin D level has increased from 16 ± 6 ng/ml to 89 ± 32 ng/ml after Pulse D therapy in VD group and highly significant (p < 0.01) reduction of all the measured inflammatory markers was noted. Reduction of markers in NVD group was insignificant (p > 0.05). The difference in the reduction of markers between the groups (NVD vs VD) was highly significant (p < 0.01). Therapeutic improvement in vitamin D to 80-100 ng/ml has significantly reduced the inflammatory markers associated with COVID-19 without any side effects. Hence, adjunctive Pulse D therapy can be added safely to the existing treatment protocols of COVID-19 for improved outcomes.

Experience of indian electricity market operation and other events during COVID-19 pandemic

World over, COVID-19 pandemic has affected the behavior and livelihoods of the people. The impact is reflected in the power system operations and electricity markets. This paper examines the impact of COVID-19 on different Indian electricity market segments. The utilities on both demand side and supply side responded to situation with depressed volumes and prices. The paper also describes the measures taken by the system operator to cope up with the situation. The paper traces the resilience exhibited by Indian power system stakeholders in handling exceptional events during lockdown such as cyclones, eclipse and lights switch-off event. The implementation of initiatives such as Real Time Market and expansion of Security Constrained Economic Despatch pilot in this challenging environment is discussed briefly. The paper concludes with possible course of action contemplated for the future of Indian electricity market post COVID-19. © 2020 IEEE