Review of preclinical data of PF-07304814 and its active metabolite derivatives against SARS-CoV-2 infection

Main protease (Mpro) is a superior target for anti-SARS-COV-2 drugs. PF-07304814 is a phosphate ester prodrug of PF-00835231 that is rapidly metabolized into the active metabolite PF-00835231 by alkaline phosphatase (ALP) and then suppresses SARS-CoV-2 replication by inhibiting Mpro. PF-07304814 increased the bioavailability of PF-00835231 by enhancing plasma protein binding (PPB). P-glycoprotein (P-gp) inhibitors and cytochrome P450 3A (CYP3A) inhibitors increased the efficacy of PF-00835231 by suppressing its efflux from target cells and metabolism, respectively. The life cycle of SARS-CoV-2 is approximately 4 h. The mechanisms and efficacy outcomes of PF-00835231 occur simultaneously. PF-00835231 can inhibit not only cell infection (such as Vero E6, 293T, Huh-7.5, HeLa+angiotensin-converting enzyme 2 (ACE2), A549+ACE2, and MRC-5) but also the human respiratory epithelial organ model and animal model infection. PF-07304814 exhibits a short terminal elimination half-life and is cleared primarily through renal elimination. There were no significant adverse effects of PF-07304814 administration in rats. Therefore, PF-07304814 exhibits good tolerability, pharmacology, pharmacodynamics, pharmacokinetics, and safety in preclinical trials. However, the Phase 1 data of PF-07304814 were not released. The Phase 2/3 trial of PF-07304814 was also suspended. Interestingly, the antiviral activities of PF-00835231 derivatives (compounds 5–22) are higher than, similar to, or slightly weaker than those of PF-00835231. In particular, compound 22 exhibited the highest potency and had good safety and stability. However, the low solubility of compound 22 limits its clinical application. Prodrugs, nanotechnology and salt form drugs may solve this problem. In this review, we focus on the preclinical data of PF-07304814 and its active metabolite derivatives to hopefully provide knowledge for researchers to study SARS-CoV-2 infection.

Telehealth readiness and its influencing factors among Chinese clinical nurses: A cross-sectional study.

AIM/OBJECTIVE: This study aimed to assess telehealth readiness among clinical nurses in China and explore the factors that affect their telehealth readiness and the relationships of telehealth readiness and telehealth practice-related variables. BACKGROUND: Telehealth is a new service model that uses information and communication technology to provide professional health care services for resource-poor areas. With the global spread of COVID-19, nurses urgently need to adapt and apply telehealth technology to replace conventional face-to-face treatment. However, nurse-led telehealth services in China are currently only in the pilot phase and the readiness of clinical nurses needs to be assessed to facilitate successful telehealth implementation. DESIGN: A cross-sectional, multicentre study was undertaken with the questionnaire survey method. METHODS: Data were collected in October-December 2020 used online questionnaires. A convenience sample of 3386 nurses from 19 hospitals in China completed the Chinese version of Telehealth Readiness Assessment Tools. RESULTS: The mean score of the telehealth readiness was in the category between 61 and 80 points (mean 61.23, SD 11.61). The percentages of nurses meeting the following levels of telehealth readiness were as follows: low (49.9%), moderate (42.0%) and high (8.1%). Significantly higher domain scores were recorded for nurses in the unmarried, head of responsible nursing group. Moreover, there were positive correlations between telehealth readiness level and service experience, service willingness, mode cognition, manpower allocation and policy guidance. CONCLUSIONS: There are still many factors hindering the successful implementation of telehealth. Nursing educators should formulate telehealth education curriculum and service standards to improve the telehealth readiness of nurses.

Uncertainty Spillover with Social Network Knowledge (preprint)

With the deepening of economic integration, it is important to study the spillover effect of macroeconomic uncertainty among regions along with social network knowledge. Based on microblog users' network connection, this paper analyzes the network factors that affect the uncertain spillover effect between regions by using ERGM. It is found that there are three peaks of uncertainty spillover effect in China, corresponding to the financial crisis in 2008, the post financial crisis in 2010 and COVID-19 in early 2020. As an effective transmission mode and a reflection of inter provincial relations, close social relationships are crucial in the study of uncertainty spillover effects. Relatively developed provinces have higher spillover effect, while relatively underdeveloped provinces are usually the recipients of uncertainty in the network. In particular, the impact of inter provincial social network on uncertainty spillover is statistically more significant than that of GDP, population, transportation and other node attributes.

Selectively expressing SARS-CoV-2 Spike protein S1 subunit in cardiomyocytes induces cardiac hypertrophy in mice. (preprint)

Cardiac injury is common in hospitalized COVID-19 patients and portends poorer prognosis and higher mortality. To better understand how SARS-CoV-2 (CoV-2) damages the heart, it is critical to elucidate the biology of CoV-2 encoded proteins, each of which may play multiple pathological roles. For example, CoV-2 Spike glycoprotein (CoV-2-S) not only engages ACE2 to mediate virus infection, but also directly impairs endothelial function and can trigger innate immune responses in cultured murine macrophages. Here we tested the hypothesis that CoV-2-S damages the heart by activating cardiomyocyte (CM) innate immune responses. HCoV-NL63 is another human coronavirus with a Spike protein (NL63-S) that also engages ACE2 for virus entry but is known to only cause moderate respiratory symptoms. We found that CoV-2-S and not NL63-S interacted with Toll-like receptor 4 (TLR4), a crucial pattern recognition receptor that responsible for detecting pathogen and initiating innate immune responses. Our data show that the S1 subunit of CoV-2-S (CoV-2-S1) interacts with the extracellular leucine rich repeats-containing domain of TLR4 and activates NF-kB. To investigate the possible pathological role of CoV-2-S1 in the heart, we generated a construct that expresses membrane-localized CoV-2-S1 (S1-TM). AAV9-mediated, selective expression of the S1-TM in CMs caused heart dysfunction, induced hypertrophic remodeling, and elicited cardiac inflammation. Since CoV-2-S does not interact with murine ACE2, our study presents a novel ACE2-independent pathological role of CoV-2-S, and suggests that the circulating CoV-2-S1 is a TLR4-recognizable alarmin that may harm the CMs by triggering their innate immune responses.

Seasonal association between viral causes of hospitalised acute lower respiratory infections and meteorological factors in China: a retrospective study (preprint)

Acute lower respiratory infections caused by respiratory viruses are common and persistent infectious diseases worldwide and in China, which have pronounced seasonal patterns. Meteorological factors have important roles in the seasonality of some major viruses. Our aim was to identify the dominant meteorological factors and to model their effects on common respiratory viruses in different regions of China. We analysed monthly virus data on patients from 81 sentinel hospitals in 22 provinces in mainland China from 2009 to 2013. The geographical detector method was used to quantify the explanatory power of each meteorological factor, individually and interacting in pairs. 28369 hospitalised patients with ALRI were tested, 10387 were positive for at least one virus, including RSV, influenza virus, PIV, ADV, hBoV, hCoV and hMPV. RSV and influenza virus had annual peaks in the north and biannual peaks in the south. PIV and hBoV had higher positive rates in the spring summer months. hMPV had an annual peak in winter spring, especially in the north. ADV and hCoV exhibited no clear annual seasonality. Temperature, atmospheric pressure, vapour pressure, and rainfall had most explanatory power on most respiratory viruses in each region. Relative humidity was only dominant in the north, but had no significant explanatory power for most viruses in the south. Hours of sunlight had significant explanatory power for RSV and influenza virus in the north, and for most viruses in the south. Wind speed was the only factor with significant explanatory power for human coronavirus in the south. For all viruses, interactions between any two of the paired factors resulted in enhanced explanatory power, either bivariately or non-linearly.

A repurposed, blood gene signature is associated with poor outcomes in SARS-CoV-2 (preprint)

Poor outcomes after SARS-CoV-2 infection are difficult to predict. Survivors may develop pulmonary fibrosis. We previously identified a 52-gene signature in peripheral blood, predictive of mortality in Idiopathic Pulmonary Fibrosis. In this study, we analyzed this signature in SARS-CoV-2 infected individuals and identified genomic risk profiles with significant differences in outcomes. Analysis of single cell expression data shows that monocytes, red blood cells, neutrophils and dendritic cells are the cellular source of the high risk gene signature.

Global economic footprint of the COVID-19 pandemic (preprint)

Countries around the world have sought to stop the spread of the 2019 novel coronavirus (COVID-19) by severely restricting travel and in-person commercial activities. Here, we analyse the economic footprint of such “lockdowns” using detailed datasets of global supply chains and a set of pandemic scenarios. We find that COVID-related economic losses are largely dependent on the number of countries imposing lockdowns, and that losses are more sensitive to the duration of a lockdown that its strictness—suggesting that more severe restrictions can reduce economic damages if they successfully shorten the duration of a lockdown. Our results also highlight several key vulnerabilities in global supply chains: Even countries that are not directly affected by COVID-19 can experience large losses (e.g., >20% of their GDP)—with such cascading impacts often occurring in low- and middle-income countries. Open and highly-specialized economies suffer particularly large losses (e.g., energy-exporting Central Asian countries or tourism-focused Caribbean countries). Supply bottlenecks and declines in consumer demand lead to especially large losses in globalized sectors such as electronics (production decreases of 13-53% across our scenarios) and automobiles (2-49%). Although retrospective analyses will undoubtedly provide further policy-relevant insights, our findings already imply that earlier, stricter, and thus shorter lockdowns are likely to minimize overall economic damages, and that global supply chains will magnify economic losses in some countries and industry sectors regardless of direct effects of the coronavirus.

Analysis on the Clinical Characteristics of 36 Cases of Novel Coronavirus Pneumonia in Kunming (preprint)

Objective: To analyze the clinical characteristics of patients with novel coronavirus pneumonia in Kunming City, and to study the correlation between nutritional status and immune function. Methods: Clinical data of 36 patients with novel coronavirus pneumonia in isolation area of Kunming Third People's Hospital from January 31 to February 15, 2020 were collected, and the basic situation, clinical characteristics, laboratory examination and CT imaging characteristics were analyzed. Serum albumin (ALB), prealbumin (PAB), hypersensitive c-reactive protein (hs-crp), CD3T cells, CD4T cells, CD8T cells and normal control group were analyzed. A simple linear regression analysis of the relationship between proalbumin and T cell subpopulation counts in the blood of patients. Results: (1) The patients with new coronavirus pneumonia in Kunming were mainly of common type. (2) 50% of the patients' first symptoms were fever and cough; (3) The total number of white blood cells in peripheral blood was normal or decreased in 23 cases (79%), and the lymphocyte count decreased in 5 cases (13.89%), without anemia. Hypersensitive c-reactive protein increased in 19 (52.78%) cases, and procalcitonin increased in 1 case. Albumin decreased in 5 cases (13.89%), proalbumin decreased in 15 cases (41.67%), alanine transaminase increased slightly in 4 cases (11.11%), alanine transaminase increased slightly in 4 cases (11.11%), total bilirubin increased slightly in 11 cases (30.56%), and renal function and blood coagulation were normal. Absolute value of CD3+T cells is with a decrease in 21 cases (58.3%), CD4+T in 28 cases (77.8%), CD8+T in 17 cases (47.2%), and CD4+/ CD8+ inverse in 6 cases (16.7%). (4) The prealbumin, CD3 T cells, CD4 T cells and CD8 T cells in the new coronavirus pneumonia group were significantly lower than those in the normal control group, and the hypersensitive c-reactive protein was higher than that in the normal control group. (5) The levels of PAB in the serum of the patients were linearly correlated with hs-crp, CD3 T cells, CD4 T cells and CD8 T cells, and the correlation coefficients were -0.474, 0.558, 0.467 and 0.613, respectively, showing statistical differences. Conclusion: The clinical characteristics of the novel coronavirus pneumonia in Kunming are different from those in Wuhan. The changes of serum proalbumin and T cell subsets are relatively obvious. Changes in serum proalbumin may contribute to the early warning of novel coronavirus pneumonia. The nutritional status of patients with common and mild pneumonia should be considered.