Electrostatic Interactions Are the Primary Determinant of the Binding Affinity of SARS-CoV-2 Spike RBD to ACE2: A Computational Case Study of Omicron Variants.

To explore the mechanistic origin that determines the binding affinity of SARS-CoV-2 spike receptor binding domain (RBD) to human angiotensin converting enzyme 2 (ACE2), we constructed the homology models of RBD-ACE2 complexes of four Omicron subvariants (BA.1, BA.2, BA.3 and BA.4/5), and compared them with wild type complex (RBDWT-ACE2) in terms of various structural dynamic properties by molecular dynamics (MD) simulations and binding free energy (BFE) calculations. The results of MD simulations suggest that the RBDs of all the Omicron subvariants (RBDOMIs) feature increased global structural fluctuations when compared with RBDWT. Detailed comparison of BFE components reveals that the enhanced electrostatic attractive interactions are the main determinant of the higher ACE2-binding affinity of RBDOMIs than RBDWT, while the weakened electrostatic attractive interactions determine RBD of BA.4/5 subvariant (RBDBA.4/5) lowest ACE2-binding affinity among all Omicron subvariants. The per-residue BFE decompositions and the hydrogen bond (HB) networks analyses indicate that the enhanced electrostatic attractive interactions are mainly through gain/loss of the positively/negatively charged residues, and the formation or destruction of the interfacial HBs and salt bridges can also largely affect the ACE2-binding affinity of RBD. It is worth pointing out that since Q493R plays the most important positive contribution in enhancing binding affinity, the absence of this mutation in RBDBA.4/5 results in a significantly weaker binding affinity to ACE2 than other Omicron subvariants. Our results provide insight into the role of electrostatic interactions in determining of the binding affinity of SARS-CoV-2 RBD to human ACE2.

Effects of Wearing Face Masks on Exercise Capacity and Ventilatory Anaerobic Threshold in Healthy Subjects During the COVID-19 Epidemic.

BACKGROUND Face masks have become an important part of the COVID-19 prevention approach. This study aimed to explore the effect of wearing masks on exercise ability and ventilatory anaerobic threshold (VAT). MATERIAL AND METHODS Thirty-four young, healthy volunteers were included in this study, consisting of 18 men and 16 women. The subjects were randomized to perform 2 cardiopulmonary exercise tests (CPET) on a cycle ergometer with gas exchange analysis, one with and another without wearing a face mask (cross-over design). The general data for all subjects and indicators from the 2 exercise tests performed with and without wearing a face mask were collected. RESULTS In cardiopulmonary exercise tests, wearing a mask significantly (P<0.05) decreased peak indexes (eg, work rate (WR), oxygen consumption per kg body weight (VO2/kg), heart rate (HR), ventilation per minute (VE) and carbon dioxide ventilation equivalent (VE/VCO2)) and anaerobic threshold indexes (eg, WR, HR, VE, breath frequency (BF), dead space ratio (VD/VT), and VE/VCO2). However, the PETCO2 at peak was significantly higher. There was a positive linear correlation between WR difference and VO2 difference at VAT (abbreviated as deltaWR@VAT and deltaVO2@VAT, respectively) (r=0.495, P=0.003). Subgroup analysis of the VAT indexes showed that WR, VO2/kg, and VE were significantly decreased in the advanced VAT group with mask compared with the stable VAT group with mask (P<0.05). Logistic regression showed that deltaVE, deltaBF, and deltaVE/VCO2 had independent influences on VAT. CONCLUSIONS Wearing masks advances VAT in healthy young subjects during CPET. The advanced VAT was associated with changes in VE, BF, and VE/VCO2 while wearing masks.

Association of 5-item Brief Symptom Rating Scale scores and health status ratings with burnout among healthcare workers.

This cross-sectional study evaluated and quantified the possible association of psychological symptoms and health status ratings on the burnout of healthcare workers from a tertiary medical center. Demographic data were obtained through a questionnaire survey. We evaluated their psychological symptoms using a 5-item Brief Symptom Rating Scale (BSRS-5) and burnout was measured using the Chinese version of the Maslach Burnout Inventory-Health Services Survey. The study began in Nov. 2018 and ended in Nov. 2020. A total of 2813 participants (men = 296, 10.5%; women = 2517, 89.5%) completed the questionnaires between December 2018 and March 2019. The response rate and complete rate were 71.7% and 93.2%. The multivariate analysis showed that, as the BSRS-5 level added, the odds ratio (OR) of burnout increased (BSRS-5 scores 6-9, 10-14, and 15-20; OR = 1.83, 3.23, and 9.15, separately; p value < 0.05). Overall, men (≥ 30 years of age) and women staffs with BSRS-5 scores ≥ 6; women with longer working hours (more than 46 h/week), men and women (≥ 30 years of age) working night shifts, and poor health status ratings were highly associated with burnout. The findings highlight the importance of screening for the BSRS-5 scores and health status ratings level for healthcare professionals at high risk of burnout, especially men ≥ 30 years of age and women with stressful working conditions.

Clinical Characteristics of Coronavirus Disease 2019 (COVID-19): A Comparison Between Laboratory-Confirmed and Clinically Suspected Patients.

To investigate the characteristic findings between laboratory-confirmed and clinically suspected patients with COVID-19. In this retrospective study, we included patients admitted to the Xiangya Hospital from Jan 24 to Feb 10, 2020. Two researchers separately collected and sorted out the patients' epidemiological, demographic, clinical, laboratory, and radiologic findings. SPSS was performed to analyze the collected data. 241 patients were admitted, including 28 (45.5; IQR, 34.0-52.5) confirmed and 213 (42.0; IQR, 30.0-57.0) suspected patients. The prevalence of COVID-19 disease in males was significantly higher than in females (64.3% vs. 35.7%, P = 0.033). Before admission of the confirmed and suspected undiagnosed cases, the onset of symptoms is often manifested as respiratory symptoms such as fever (35.7% vs. 27.7%) and cough (30.7% vs. 32.1%). Twenty patients (71.4%) had an exposure history to high-risk areas, and 14 patients (50.0%) traveled or lived in a high-risk area in the confirmed group, which was significantly different from the suspected group. The pulmonary imaging of the patients in the confirmed group was primarily manifested as ground-glass opacity (89.3%). A total of 499 nucleic acid testing (NAT) was performed to determine the 28 COVID-19 positive throat swabs among the 241 patients. Whether there is a history of high-risk area exposure in the epidemiological investigation is essential in distinguishing the suspected patients from the confirmed patients. Multiple nucleic acid tests were used as the basis for the diagnosis of COVID-19, and during CT examination, ground-glass opacity was used as a COVID-19 indicator. Trail registration Trail registration number. 202012195, Date of registration: 2020.12.22 "retrospectively registered".

[Proposal of Living Evidence-based Guideline for Combination of Traditional Chinese and Western Medicine for Treatment of COVID-19].

In order to standardize the clinical diagnosis and treatment decision-making with traditional Chinese medicine for pa-tients of coronavirus disease 2019(COVID-19) and put the latest clinical study evidence into clinical practice, the international trust-worthy traditional Chinese medicine recommendations( TCM Recs) working group started the compilation of Living Evidence-based Guideline for Combination of Traditional Chinese and Western Medicine for Treatment of COVID-19 on the basis of the standards and re-quirements of WHO handbook, GRADE and RIGHT. This proposal mainly introduces the formulation methods and processes of the living guidelines in details, such as the composition of the working group, the collection and identification of clinical issues and out-comes, the production of the living systematic review and the consensus of recommendations. The guidelines will continue to monitor the clinical study evidences of TCM in the prevention and treatment of COVID-19, and conduct regular evidence updating, retrieval and screening. When there is new study evidence, the steering committee will evaluate the possibility of the evidence to change clinical practice or previous recommendations, so as to decide whether the recommendations for the guidelines shall be implemented or upda-ted. The main criteria considered in the guideline updating are as follows:(1) There are new high-quality randomized controlled trial(RCT) evidences for TCM uninvolved in the previous edition of the guidelines;(2) as for the TCM involved in the guidelines, living sys-tematic review shows that new evidence may change the direction or strength of the existing recommendations. The specific implementation of the living evidence-based guidelines will take this proposal as the study basis and framework, in order to ensure the standardization of the formulation process and methods. This will be the first exploration of the methodology for living guidelines in the field of TCM.

How to Prevent and Cope with Coincidence of Risks to the Global Food System

The global food system faces major risks and threats that can cause massive economic loss;dislocation of food supply chains;and welfare loss of producers, consumers, and other food system actors. The interrelated nature of the system has highlighted the complexity of risks. Climate change, extreme weather events, and degradation and depletion of natural resources, including water, arable, forestry, and pastural lands, loss of biodiversity, emerging diseases, trade chokepoints and disruptions, macroeconomic shocks, and conflicts, can each seriously disrupt the system. Coincidence of these risks can compound the effects on global food security and nutrition. Smallholder farmers, rural migrants, women, youth, children, low-income populations, and other disadvantaged groups are particularly vulnerable. The coronavirus disease 2019 (COVID-19) pandemic exemplifies a perfect storm of coincidental risks. This article reviews major risks that most significantly impact food systems and highlights the importance of prospects for coincidence of risks. We present pathways to de-risk food systems and a way forward to ensure healthy, sustainable, inclusive, and resilient food systems. [ABSTRACT FROM AUTHOR] Copyright of Annual Review of Environment & Resources is the property of Annual Reviews Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Single-cell analysis of angiotensin-converting enzyme II expression in human kidneys and bladders reveals a potential route of 2019 novel coronavirus infection.

BACKGROUND: Since 2019, a novel coronavirus named 2019 novel coronavirus (2019-nCoV) has emerged worldwide. Apart from fever and respiratory complications, acute kidney injury has been observed in a few patients with coronavirus disease 2019. Furthermore, according to recent findings, the virus has been detected in urine. Angiotensin-converting enzyme II (ACE2) has been proposed to serve as the receptor for the entry of 2019-nCoV, which is the same as that for the severe acute respiratory syndrome. This study aimed to investigate the possible cause of kidney damage and the potential route of 2019-nCoV infection in the urinary system. METHODS: We used both published kidney and bladder cell atlas data and new independent kidney single-cell RNA sequencing data generated in-house to evaluate ACE2 gene expression in all cell types in healthy kidneys and bladders. The Pearson correlation coefficients between ACE2 and all other genes were first generated. Then, genes with r values larger than 0.1 and P values smaller than 0.01 were deemed significant co-expression genes with ACE2. RESULTS: Our results showed the enriched expression of ACE2 in all subtypes of proximal tubule (PT) cells of the kidney. ACE2 expression was found in 5.12%, 5.80%, and 14.38% of the proximal convoluted tubule cells, PT cells, and proximal straight tubule cells, respectively, in three published kidney cell atlas datasets. In addition, ACE2 expression was also confirmed in 12.05%, 6.80%, and 10.20% of cells of the proximal convoluted tubule, PT, and proximal straight tubule, respectively, in our own two healthy kidney samples. For the analysis of public data from three bladder samples, ACE2 expression was low but detectable in bladder epithelial cells. Only 0.25% and 1.28% of intermediate cells and umbrella cells, respectively, had ACE2 expression. CONCLUSION: This study has provided bioinformatics evidence of the potential route of 2019-nCoV infection in the urinary system.

The Promise of Aggregation-Induced Emission Luminogens for Detecting COVID-19.

The long-term pandemic of coronavirus disease 2019 (COVID-19) requires sensitive and accurate diagnostic assays to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and SARS-CoV-2 antibodies in infected individuals. Currently, RNA of SARS-CoV-2 virus is mainly detected by reverse transcription-polymerase chain reaction (RT-PCR)-based nucleic acid assays, while SARS-CoV-2 antigen and antibody are identified by immunological assays. Both nucleic acid assays and immunological assays rely on the luminescence signals of specific luminescence probes for qualitative and quantitative detection. The exploration of novel luminescence probes will play a crucial role in improving the detection sensitivity of the assays. As innate probes, aggregation-induced emission (AIE) luminogens (AIEgens) exhibit negligible luminescence in the free state but enhanced luminescence in the aggregated or restricted states. Moreover, AIEgen-based nanoparticles (AIE dots) offer efficient luminescence, good biocompatibility and water solubility, and superior photostability. Both AIEgens and AIE dots have been widely used for high-performance detection of biomolecules and small molecules, chemical/biological imaging, and medical therapeutics. In this review, the availability of AIEgens and AIE dots in nucleic acid assays and immunological assays are enumerated and discussed. By building a bridge between AIE materials and COVID-19, we hope to inspire researchers to use AIE materials as a powerful weapon against COVID-19.

Epidemiological characteristics of imported and domestic COVID-19 cases in Taiwan: a retrospective study (preprint)

Background: This study aimed to elaborate Taiwan’s epidemiological characteristics of 2020 COVID-19 in human, temporal, and geographical dimensions. Methods: Big data for cases from January to May 2020 were obtained from the public database of Taiwan Centers for Disease Control (CDC) in June 2020. The data were used to analyze and compare differences, correlations, and trends in human, temporal, and geographical characteristics of imported and domestic COVID-19 cases.Results: During the study period, 443 cases were confirmed, with a mortality rate of 1.6%. The epidemiological features indicated that most cases (87.6%) were imported. No difference was observed between sexes, but significant differences were observed in age groups (p = 0.002). The age group of 20¬–29 years accounted for the highest proportion of imported cases (40.7%), with an odds ratio (OR) of 2.748, whereas the age group of 50–59 years had the largest proportion of domestic cases (23.6%, OR = 2.770). March 2020 displayed the highest proportion of imported cases (78.1%, OR = 4.278). A significant difference was observed in different regions (p = 0.003), with northern Taiwan exhibiting the highest proportion of both imported and domestic cases (63.4% and 80.0%); in particular, domestic cases in northern Taiwan had an OR of 2.309. Conclusion: This is the first report comparing domestic and imported cases of COVID-19 from surveillance data from the Taiwan CDC during January-May 2020. The study also highlights the importance of longitudinal and geographically extended studies in understanding the implications of COVID-19 transmission for Taiwan’s population.

A digital protein microarray for COVID-19 cytokine storm monitoring.

Despite widespread concern regarding cytokine storms leading to severe morbidity in COVID-19, rapid cytokine assays are not routinely available for monitoring critically ill patients. We report the clinical application of a digital protein microarray platform for rapid multiplex quantification of cytokines from critically ill COVID-19 patients admitted to the intensive care unit (ICU) at the University of Michigan Hospital. The platform comprises two low-cost modules: (i) a semi-automated fluidic dispensing/mixing module that can be operated inside a biosafety cabinet to minimize the exposure of the technician to the virus infection and (ii) a 12-12-15 inch compact fluorescence optical scanner for the potential near-bedside readout. The platform enabled daily cytokine analysis in clinical practice with high sensitivity (<0.4 pg mL-1), inter-assay repeatability (∼10% CV), and rapid operation providing feedback on the progress of therapy within 4 hours. This test allowed us to perform serial monitoring of two critically ill patients with respiratory failure and to support immunomodulatory therapy using the selective cytopheretic device (SCD). We also observed clear interleukin-6 (IL-6) elevations after receiving tocilizumab (IL-6 inhibitor) while significant cytokine profile variability exists across all critically ill COVID-19 patients and to discover a weak correlation between IL-6 to clinical biomarkers, such as ferritin and C-reactive protein (CRP). Our data revealed large subject-to-subject variability in patients' response to COVID-19, reaffirming the need for a personalized strategy guided by rapid cytokine assays.

A Digital Protein Microarray for COVID-19 Cytokine Storm Monitoring (preprint)

Despite widespread concern for cytokine storms leading to severe morbidity in COVID-19, rapid cytokine assays are not routinely available for monitoring critically ill patients. We report the clinical application of a machine learning-based digital protein microarray platform for rapid multiplex quantification of cytokines from critically ill COVID-19 patients admitted to the intensive care unit (ICU) at the University of Michigan Hospital. The platform comprises two low-cost modules: (i) a semi-automated fluidic dispensing/mixing module that can be operated inside a biosafety cabinet to minimize the exposure of technician to the virus infection and (ii) a 12-12-15 inch compact fluorescence optical scanner for the potential near-bedside readout. The platform enabled daily cytokine analysis in clinical practice with high sensitivity (<0.4pg/mL), inter-assay repeatability (~10% CV), and near-real-time operation with a 10 min assay incubation. A cytokine profiling test with the platform allowed us to observe clear interleukin-6 (IL-6) elevations after receiving tocilizumab (IL-6 inhibitor) while significant cytokine profile variability exists across all critically ill COVID-19 patients and to discover a weak correlation between IL-6 to clinical biomarkers, such as Ferritin and CRP. Our data revealed large subject-to-subject variability in a patient's response to anti-inflammatory treatment for COVID-19, reaffirming the need for a personalized strategy guided by rapid cytokine assays.