Recent advances in small-molecular therapeutics for COVID-19.

The COVID-19 pandemic poses a fundamental challenge to global health. Since the outbreak of SARS-CoV-2, great efforts have been made to identify antiviral strategies and develop therapeutic drugs to combat the disease. There are different strategies for developing small molecular anti-SARS-CoV-2 drugs, including targeting coronavirus structural proteins (e.g. spike protein), non-structural proteins (nsp) (e.g. RdRp, Mpro, PLpro, helicase, nsp14, and nsp16), host proteases (e.g. TMPRSS2, cathepsin, and furin) and the pivotal proteins mediating endocytosis (e.g. PIKfyve), as well as developing endosome acidification agents and immune response modulators. Favipiravir and chloroquine are the anti-SARS-CoV-2 agents that were identified earlier in this epidemic and repurposed for COVID-19 clinical therapy based on these strategies. However, their efficacies are controversial. Currently, three small molecular anti-SARS-CoV-2 agents, remdesivir, molnupiravir, and Paxlovid (PF-07321332 plus ritonavir), have been granted emergency use authorization or approved for COVID-19 therapy in many countries due to their significant curative effects in phase III trials. Meanwhile, a large number of promising anti-SARS-CoV-2 drug candidates have entered clinical evaluation. The development of these drugs brings hope for us to finally conquer COVID-19. In this account, we conducted a comprehensive review of the recent advances in small molecule anti-SARS-CoV-2 agents according to the target classification. Here we present all the approved drugs and most of the important drug candidates for each target, and discuss the challenges and perspectives for the future research and development of anti-SARS-CoV-2 drugs.

Histones released by NETosis enhance the infectivity of SARS-CoV-2 by bridging the spike protein subunit 2 and sialic acid on host cells.

Neutrophil extracellular traps (NETs) can capture and kill viruses, such as influenza viruses, human immunodeficiency virus (HIV), and respiratory syncytial virus (RSV), thus contributing to host defense. Contrary to our expectation, we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2, as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model. The histone H3 or H4 selectively binds to subunit 2 of the spike (S) protein, as shown by a biochemical binding assay, surface plasmon resonance and binding energy calculation as well as the construction of a mutant S protein by replacing four acidic amino acids. Sialic acid on the host cell surface is the key molecule to which histones bridge subunit 2 of the S protein. Moreover, histones enhance cell-cell fusion. Finally, treatment with an inhibitor of NETosis, histone H3 or H4, or sialic acid notably affected the levels of sgRNA copies and the number of apoptotic cells in a mouse model. These findings suggest that SARS-CoV-2 could hijack histones from neutrophil NETosis to promote its host cell attachment and entry process and may be important in exploring pathogenesis and possible strategies to develop new effective therapies for COVID-19.

Exploration and Thinking in Mixed Flipping-Classroom Teaching Approach on Clinical Endocrinolgy during the Coronavirus Disease 2019 Period

Background and Objectives: To explore the superiority of flipping-classroom lended learning in which the stay-home e-learning and traditional internship complements each other in resident training of endcorinology during coronavirus disease 2019 restriction period. Materials and Methods: A total of 44 residents were randomized as the study population. In the endocrine-rotation training, we reformed the clinical learning by unified online-teaching led by teachers' combination with individual guidance by residents. Moreover, the final implementation assessment was conducted by standard double-blind examinations. Results: After 4–8 weeks training, the 44 residents were assessed for clinical skills from six dimensions, including medical history collection, physical examination, history report and inpatient record writing, case analysis, and overviewing capability. Compared with the mean scores of 68 residents rotated in internal medicine in 2019, the mean scores on physical examination, inpatient record writing, and overviewing capability in 2020 group were higher with significance ([85.72 ± 8.33] vs.[79.22 ± 10.12], P = 0.0006), ([90.28 ± 10.70] vs. [81.82 ± 8.03], P < 0.0001), ([80.31 ± 8.70] vs. [73.04 ± 12.74], P = 0.0012), whereas scores on skills of medical history collection and history report were slightly lower ([82.11 ± 9.02] vs. [85.06 ± 7.23], P = 0.0586), ([79.30 ± 8.17] vs. [83.21 ± 5.01], P = 0.0022), while scores on case analysis did not show huge gap but with polarized performance in 2020 group ([74.38 ± 10.29] vs. [78.13 ± 8.53], P = 0.0386). Conclusions: Providing the novel pattern of unified online-teaching combined with individual-guidance at the bedside to the front-line residents can reduce the risk of cluster epidemics and effectively ensure the training effect on them but still with shortcomings. The future online teaching reform is better for focus more on how to make up for or reduce the actual problem of disconnection between theory and practice in the process of online clinical skills training for residents and teachers.

SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continually poses serious threats to global public health. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either boceprevir or telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 Mpro activity in vitro, with 50% inhibitory concentration values ranging from 7.6 to 748.5 nM. The cocrystal structure of Mpro in complex with MI-23, one of the most potent compounds, revealed its interaction mode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a transgenic mouse model of SARS-CoV-2 infection, oral or intraperitoneal treatment with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.

Health-related quality of life of hospitalized COVID-19 survivors: An initial exploration in Nanning city, China.

Understanding the health-related quality of life (HrQoL) of hospitalized COVID-19 survivors is an emerging global challenge arising from the current pandemic. A qualitative study of the experiences of sixteen hospitalized COVID-19 survivors from Nanning City, China, was conducted using semi-structured telephone interviews in May 2020. These first-hand accounts were critically and empirically analysed to identify emerging health and social issues, and provide potential solutions to improve survivors' quality of life. This in-depth, qualitative study of HrQoL for hospitalized COVID-19 survivors provides the first empirical evidence and conceptual framework with eight dimensions (physical symptoms, anxiety, trauma, economic loss, place-based identity, self-stigma, health self-interventions, and changing lifestyle) for understanding the physiological, psychological, socio-economic and health behavioral aspects of their daily lives. We argue that local and global governments should provide integrated healthcare, social and digital infrastructure to support this vulnerable group. More comparative and multi-disciplinary studies in this area are needed to generate academic standards of assessing health-related quality of life and produce good practice guidelines for promoting urban resilience in response to public health disasters.

Advice on Standardized Diagnosis and Treatment for Spinal Diseases during the Coronavirus Disease 2019 Pandemic.

Coronavirus disease 2019 (COVID-19) outbreak started in December 2019 that caused difficulties for clinical work. Practical work experience in our spinal outpatient and emergency department during the COVID-19 pandemic is summarized in this article, with combined evidence-based medical evidence to explore a standardized process of diagnosis and treatment for spinal diseases. Outpatient reservation, continuous screening, triage, and isolation, first consultation accountability system, pandemic reporting system, and online revisit were strictly followed. We hope that our experience in prevention and control of COVID-19 can help spine surgeons globally in stopping the spread of COVID-19. Spine surgeons should collaborate with infection control specialists to avoid cross-infection in hospitals and optimize treatment.

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19.

BACKGROUND: No therapeutics have yet been proven effective for the treatment of severe illness caused by SARS-CoV-2. METHODS: We conducted a randomized, controlled, open-label trial involving hospitalized adult patients with confirmed SARS-CoV-2 infection, which causes the respiratory illness Covid-19, and an oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen (Pao2) to the fraction of inspired oxygen (Fio2) of less than 300 mm Hg. Patients were randomly assigned in a 1:1 ratio to receive either lopinavir-ritonavir (400 mg and 100 mg, respectively) twice a day for 14 days, in addition to standard care, or standard care alone. The primary end point was the time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first. RESULTS: A total of 199 patients with laboratory-confirmed SARS-CoV-2 infection underwent randomization; 99 were assigned to the lopinavir-ritonavir group, and 100 to the standard-care group. Treatment with lopinavir-ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement, 1.31; 95% confidence interval [CI], 0.95 to 1.80). Mortality at 28 days was similar in the lopinavir-ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, -5.8 percentage points; 95% CI, -17.3 to 5.7). The percentages of patients with detectable viral RNA at various time points were similar. In a modified intention-to-treat analysis, lopinavir-ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care (hazard ratio, 1.39; 95% CI, 1.00 to 1.91). Gastrointestinal adverse events were more common in the lopinavir-ritonavir group, but serious adverse events were more common in the standard-care group. Lopinavir-ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events. CONCLUSIONS: In hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir-ritonavir treatment beyond standard care. Future trials in patients with severe illness may help to confirm or exclude the possibility of a treatment benefit. (Funded by Major Projects of National Science and Technology on New Drug Creation and Development and others; Chinese Clinical Trial Register number, ChiCTR2000029308.).