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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-332958

ABSTRACT

As SARS-CoV-2 Omicron and other variants of concern continue spreading around the world, development of antibodies and vaccines to confer broad and protective activity is a global priority. Here, we report on the identification of a special group of nanobodies from immunized alpaca with exceptional breadth and potency against diverse sarbecoviruses including SARS-CoV-1, Omicron BA.1, and BA.2. Crystal structure analysis of one representative nanobody, 3-2A2-4, revealed a highly conserved epitope between the cryptic and the outer face of the receptor binding domain (RBD). The epitope is readily accessible regardless of RBD in up or down conformation and distinctive from the receptor ACE2 binding site. Passive delivery of 3-2A2-4 protected K18-hACE2 mice from infection of authentic SARS-CoV-2 Delta and Omicron. This group of nanobodies and the epitope identified should provide invaluable reference for the development of next generation antibody therapies and vaccines against wide varieties of SARS-CoV-2 infection and beyond.

2.
J Chem Inf Model ; 2022 Apr 11.
Article in English | MEDLINE | ID: covidwho-1783923

ABSTRACT

The cell entry of SARS-CoV-2 has emerged as an attractive drug development target. We previously reported that the entry of SARS-CoV-2 depends on the cell surface heparan sulfate proteoglycan (HSPG) and the cortex actin, which can be targeted by therapeutic agents identified by conventional drug repurposing screens. However, this drug identification strategy requires laborious library screening, which is time consuming, and often limited number of compounds can be screened. As an alternative approach, we developed and trained a graph convolutional network (GCN)-based classification model using information extracted from experimentally identified HSPG and actin inhibitors. This method allowed us to virtually screen 170,000 compounds, resulting in ∼2000 potential hits. A hit confirmation assay with the uptake of a fluorescently labeled HSPG cargo further shortlisted 256 active compounds. Among them, 16 compounds had modest to strong inhibitory activities against the entry of SARS-CoV-2 pseudotyped particles into Vero E6 cells. These results establish a GCN-based virtual screen workflow for rapid identification of new small molecule inhibitors against validated drug targets.

3.
J Med Virol ; 94(5): 1893-1905, 2022 05.
Article in English | MEDLINE | ID: covidwho-1777573

ABSTRACT

Bamlanivimab is routinely used in the treatment of coronavirus disease 2019 (COVID-19) worldwide. We performed a meta-analysis to investigate the efficacy and safety of bamlanivimab treatment in patients with COVID-19. We searched articles from Web of Science, PubMed, Embase, the Cochrane Library, and medRxiv between January 30, 2020 and August 5, 2021. We selected randomized clinical trials (RCTs) and observational studies with a control group to assess the efficiency of bamlanivimab in treating patients with COVID-19. Our meta-analysis retrieved three RCTs and seven cohort studies including 14 461 patients. Bmlanivimab may help outpatients to prevent hospitalization or emergency department visits (RR 0.41, 95%CI 0.29-0.58), reduce ICU admission (RR 0.47, 95%CI 0.23-0.92), and mortality (RR 0.32, 95%CI 0.13-0.77) from the disease. The combination of bamlanivimab and etesevimab may have a greater potential for positive treatment outcomes. Bamlanivimab has demonstrated clinical efficacy on mild or moderate ill patients with COVID-19 to prevent hospitalization, reduce severity, and mortality from the disease. Combinations of bamlanivimab and etesevimab have a significant relative risk reduction for COVID-related hospitalization or death for patients than the monotherapy 700 mg group. Well-designed clinical trials to identify the clinical and biochemical characteristics in the COVID-19 patients' population that could benefit from bamlanivimab or plus etesevimab are warranted in the future.


Subject(s)
COVID-19 , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing , COVID-19/drug therapy , Humans , SARS-CoV-2 , Treatment Outcome
4.
Proc Natl Acad Sci U S A ; 119(16): e2117142119, 2022 Apr 19.
Article in English | MEDLINE | ID: covidwho-1774040

ABSTRACT

SignificanceCOVID-19 is a deadly rampaging infectious disease with over 480 million cases worldwide. Unfortunately, effective therapies remain very limited. Novel antiviral agents are urgently needed to combat this global healthcare crisis. Here, we elucidate the structural basis for replicase polyprotein cleavage and substrate specificity of SARS-CoV-2 main protease (Mpro). Through analyzing a series of high-resolution structures of SARS-CoV-2 Mpro throughout the proteolytic process, we demonstrate the molecular mechanism of Mpro in proteolytic processing that confers substrate specificity. Substrate selectivity is revealed using structures of the H41A mutant in complex with six individual native cleavage substrates. Our study underscores the mechanistic function of Mpro in the viral life cycle, which provides structural insights to develop effective inhibitors against this essential target of SARS-CoV-2.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/chemistry , Endopeptidases , Humans , Peptide Hydrolases/genetics , Polyproteins/genetics , Protease Inhibitors/chemistry , SARS-CoV-2/genetics , Substrate Specificity
5.
Tourism Tribune ; 36(8):15-26, 2021.
Article in Chinese | CAB Abstracts | ID: covidwho-1771991

ABSTRACT

Virtual museums, virtual exhibitions, and other virtual reality (VR) forms have been developing significantly during the COVID-19 pandemic. VR has been widely used in planning, management, marketing, education, heritage preservation, and other tourism-related areas. It has attracted some scholars' attention and related studies have also gradually increased. However, the relationship between VR tourism experience and on-site tourism needs to be further explored. It is likely important to solve the following questions: what are the main factors affecting the VR tourist behavior and what is the transformation mechanism between VR tourism and on-site tourism? This study developed a theoretical framework to conceptualize VR tourism experience, VR attitude, VR intention, and actual tourism activities in the context of COVID-19 pandemic based on the theory of planned behavior (TPB). To examine the theoretical model, the Likert 7-scale was used to design the questionnaire. Via social network service, surveys were widely distributed to the potential VR tourists such as the surfers of tourism portals. There were 568 questionnaires collected, and 358 of them were effective samples. Using SPSS 26.0 and AMOS 22.0, factor analyses and structural equation modeling were employed to empirically test the hypotheses. The Bootstrap method was further applied to examine the transformation mechanism of tourists' VR behavioral intention to actual tourism behavior. The results suggest: (1) VR tourism experience, perceptual behavioral control, and subjective norm could significantly influence VR tourist attitude, but only VR tourism experience and attitude could directly affect the onsite tourism intention. (2) VR tourism experience was the most influential factor to promote actual tourism intention. It is likely that VR tourism experience could bring relevant information about the destination to potential tourists and further affect their perceptions. This may reduce the external control effect on the on-site tourism activities. (3) Tourists' attitude was not a significant mediator between the VR tourism experience and actual tourism intention. The development of VR tourism is still in the early stage with limited in-depth experience contents, which still needs more efforts to promote the on-site tourism activities by changing the attitude of VR tourists. (4) the COVID-19 pandemic did not show a statistically significant influence on tourists' attitude or actual tourism intention. It is thus believed that the anxiety and fear brought by the COVID-19 did not play a great role in the intention of tourism activities. This research provide both a new theoretical perspective and an empirical evidence for the transformation and combination of VR tourism and actual tourism activities in the future. The findings also sheds some light on tourism recovery and development after the COVID-19 pandemic.

6.
J Med Chem ; 65(6): 4590-4599, 2022 03 24.
Article in English | MEDLINE | ID: covidwho-1740391

ABSTRACT

Identification of anti-SARS-CoV-2 compounds through traditional high-throughput screening (HTS) assays is limited by high costs and low hit rates. To address these challenges, we developed machine learning models to identify compounds acting via inhibition of the entry of SARS-CoV-2 into human host cells or the SARS-CoV-2 3-chymotrypsin-like (3CL) protease. The optimal classification models achieved good performance with area under the receiver operating characteristic curve (AUC-ROC) values of >0.78. Experimental validation showed that the best performing models increased the assay hit rate by 2.1-fold for viral entry inhibitors and 10.4-fold for 3CL protease inhibitors compared to those of the original drug repurposing screens. Twenty-two compounds showed potent (<5 µM) antiviral activities in a SARS-CoV-2 live virus assay. In conclusion, machine learning models can be developed and used as a complementary approach to HTS to expand compound screening capacities and improve the speed and efficiency of anti-SARS-CoV-2 drug discovery.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Repositioning , Humans , Protease Inhibitors/pharmacology
7.
iScience ; 25(4): 104043, 2022 Apr 15.
Article in English | MEDLINE | ID: covidwho-1734555

ABSTRACT

With the rapid emergence and spread of SARS-CoV-2 variants, development of vaccines with broad and potent protectivity has become a global priority. Here, we designed a lipid nanoparticle-encapsulated, nucleoside-unmodified mRNA (mRNA-LNP) vaccine encoding the trimerized receptor-binding domain (RBD trimer) and showed its robust capability in inducing broad and protective immune responses against wild-type and major variants of concern (VOCs) in the mouse model of SARS-CoV-2 infection. The protectivity was correlated with RBD-specific B cell responses especially the long-lived plasma B cells in bone marrow, strong ability in triggering BCR clustering, and downstream signaling. Monoclonal antibodies isolated from vaccinated animals demonstrated broad and potent neutralizing activity against VOCs tested. Structure analysis of one representative antibody identified a novel epitope with a high degree of conservation among different variants. Collectively, these results demonstrate that the RBD trimer mRNA vaccine serves as a promising vaccine candidate against SARS-CoV-2 variants and beyond.

8.
Front Psychol ; 13: 814869, 2022.
Article in English | MEDLINE | ID: covidwho-1731835

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has fueled anti-Asian, especially anti-Chinese sentiments worldwide, which may negatively impact diasporic Chinese youths' adjustment and prosocial development. This study examined the association between compassion, discrimination and prosocial behaviors in diasporic Chinese youths during the COVID-19 pandemic. 360 participants participated and completed the multi-country, cross-sectional, web-based survey between April 22 and May 9, 2020, the escalating stage of the pandemic. This study found compassion as prosocial behaviors' proximal predictor, while discrimination independently predicted participation in volunteering, and could potentially enhance the association between compassion and charitable giving. These findings suggest that prosociality among young people is sensitive to social context, and that racial discrimination should be considered in future prosocial studies involving young members of ethnic and racial minorities.

9.
Proc Natl Acad Sci U S A ; 119(11): e2122954119, 2022 03 15.
Article in English | MEDLINE | ID: covidwho-1721790

ABSTRACT

SignificanceSARS-CoV-2 continues to evolve through emerging variants, more frequently observed with higher transmissibility. Despite the wide application of vaccines and antibodies, the selection pressure on the Spike protein may lead to further evolution of variants that include mutations that can evade immune response. To catch up with the virus's evolution, we introduced a deep learning approach to redesign the complementarity-determining regions (CDRs) to target multiple virus variants and obtained an antibody that broadly neutralizes SARS-CoV-2 variants.


Subject(s)
Broadly Neutralizing Antibodies/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Broadly Neutralizing Antibodies/pharmacology , COVID-19 Vaccines/immunology , Complementarity Determining Regions , Deep Learning , Epitopes/immunology , Humans , Immunotherapy/methods , Neutralization Tests/methods , Protein Domains , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
12.
Cell Mol Life Sci ; 79(3): 142, 2022 Feb 20.
Article in English | MEDLINE | ID: covidwho-1707928

ABSTRACT

As a result of cross-species transmission in December 2019, the coronavirus disease 2019 (COVID-19) became a serious endangerment to human health and the causal agent of a global pandemic. Although the number of infected people has decreased due to effective management, novel methods to treat critical COVID-19 patients are still urgently required. This review describes the origins, pathogenesis, and clinical features of COVID-19 and the potential uses of mesenchymal stem cells (MSCs) in therapeutic treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients. MSCs have previously been shown to have positive effects in the treatment of lung diseases, such as acute lung injury, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, lung cancer, asthma, and chronic obstructive pulmonary disease. MSC mechanisms of action involve differentiation potentials, immune regulation, secretion of anti-inflammatory factors, migration and homing, anti-apoptotic properties, antiviral effects, and extracellular vesicles. Currently, 74 clinical trials are investigating the use of MSCs (predominately from the umbilical cord, bone marrow, and adipose tissue) to treat COVID-19. Although most of these trials are still in their early stages, the preliminary data are promising. However, long-term safety evaluations are still lacking, and large-scale and controlled trials are required for more conclusive judgments regarding MSC-based therapies. The main challenges and prospective directions for the use of MSCs in clinical applications are discussed herein. In summary, while the clinical use of MSCs to treat COVID-19 is still in the preliminary stages of investigation, promising results indicate that they could potentially be utilized in future treatments.


Subject(s)
COVID-19/therapy , Clinical Trials as Topic/statistics & numerical data , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/cytology , SARS-CoV-2/isolation & purification , COVID-19/virology , Humans
13.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-325219

ABSTRACT

In the middle of March, the World Health Organization declared the outbreak of COVID-19 caused by SARS-CoV-2 infection a global pandemic. While China experienced a dramatic decline in daily growth rate of COVID-19, multiple importations of new cases from other countries and their related local infections caused a rapid rise. Between March 12 and April 15, we collected nasopharyngeal samples from 109 imported cases from 25 countries and 69 local cases in Guangzhou, China. In order to characterize the transmission patterns and genetic evolution of this virus among different populations, we sequenced the genome of SARS-CoV-2. The imported viral strains were assigned to lineages distributed in Europe (33.0%), America (17.4%), Africa (25.7%), or Southeast/West Asia (23.9%). Importantly, 10 imported cases from Africa formed two novel sub-lineages not identified in global tree previously. A detailed analysis showed that the imported viral strains from Philippines and Pakistan were closely related and within the same sub-lineage, whereas Ethiopia had varied lineages in the African phylogenetic tree. In spite of the diversity of imported SARS-CoV-2, 60 of 69 local infections could be traced back to two specific small lineages imported from Africa. A combined genetic and epidemiological analysis revealed a high-resolution transmission network of the imported SARS-CoV-2 in local communities, which might help inform the public health response and genomic surveillance in other cities and regions. Finally, we observed in-frame deletions on seven loci of SARS-CoV-2 genome, some of which were intra-host mutations, and they exhibited no enrichment on the S protein. Our findings provide new insight into the viral phylodynamics of SARS-CoV-2 and beta coronavirus.

14.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-325084

ABSTRACT

The development of an effective vaccine against SARS-CoV-2, the causative agent of pandemic coronavirus disease-2019 (COVID-19), is a global priority. Here, we present three chimpanzee adenovirus vaccines that express either the full-length spike (ChAdTS-S), or receptor-binding domain (RBD) with two different signal sequences (ChAdTS-RBD and ChAdTS-RBDs). Single-dose intranasal or intramuscular immunization induced robust and sustained neutralizing antibody responses in BALB/c mice, with ChAdTS-S being superior to ChAdTS-RBD and ChAdTS-RBDs. Intranasal immunization appeared to induce a predominately Th2-based response whereas intramuscular administration resulted in a predominately Th1 response. The neutralizing activity against several circulating SARS-CoV-2 variants remained unaffected for mice serum but reduced for rhesus macaque serum. Importantly, immunization with ChAdTS-S via either route induced protective immunity against high-dose challenge with live SARS-CoV-2 in rhesus macaques. Vaccinated macaques demonstrated dramatic decreases in viral RNA in the lungs and nasal swabs, as well as reduced lung pathology compared to the control animals. Similar protective effects were also found in a golden Syrian hamster model of SARS-CoV-2 infection. Taken together, these results confirm that ChAdTS-S can induce protective immune responses in experimental animals, meriting further development toward a human vaccine against SARS-CoV-2.

15.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-324221

ABSTRACT

Background: Bamlanivimab is routinely used in the treatment of coronavirus disease 2019 (COVID-19) in worldwide. We performed a meta-analysis to investigate the efficacy and safety of bamlanivimab treatment in patients with COVID-19. Methods: We searched articles from Web of Science, PubMed, Embase, the Cochrane Library and MedRxiv between 30 January 2020 and August 5, 2021. We selected randomized clinical trials (RCTs) and observational studies with a control group to assess the efficiency of bamlanivimab in treating patients with COVID-19. Results: Our meta-analysis retrieved 3 RCTs and 7 cohort studies including 14461 patients. Bmlanivimab may help outpatients to prevent hospitalization or emergency department visit (RR 0.41 95%CI 0.29 to 0.58), reduce ICU admission (RR 0.47 95%CI 0.23 to 0.92) and mortality (RR 0.32 95%CI 0.13 to 0.77) from the disease. The combination of bamlanivimab and etesevimab may had a greater potential for positive treatment outcome. Conclusion: Bamlanivimab has demonstrated clinical efficacy on mild or moderate ill patients with COVID-19 to prevent hospitalization, reduce severity and mortality from the disease . Combinations of two or more monoclonal antibody increase the effect. Well-designed clinical trials to identify the clinical and biochemical characteristics in COVID-19 patients’ population that could benefit from bamlanivimab are warranted in the future.Funding Statement: None to declare. Declaration of Interests: The authors declared there are no competing interests.

16.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-323700

ABSTRACT

Background: During the novel coronavirus pneumonia (COVID-19) outbreak, the internet became the main channel for the public to access all kinds of information. Through search engines and other media, people can aquire information about the epidemic situation in real time. Baidu, currently the top online search tool in China, has developed an internet search trends gathering and analysis tool called Baidu Index. The aim of this study was to understand the public’s focus on the epidemic and their most pressing needs through analysis of the Chinese internet usage during the first month of the outbreak, which was also the most severe period. Method: The data period selected was from January 23, 2020 to February 22, 2020. Through Baidu index, we identified hot search terms related to COVID-19 which were grouped into four categories. Searching trend analysis was obtained depicting the quantities with which each category was searched. Next, we selected the category with the highest search volume, and obtained data regarding geographic and demographic characteristics. Finally, we explored Wuhan residents’ interest in COVID-19 by tracking their online seeking behavior. Results: The public was most concerned about news of "latest developments of epidemic". The remaining categories in descending order of attention received were "basic information of disease", "extended information" and "diagnosis and treatment of the novel coronavirus pneumonia". The mobile search volume was dominant. People searching for "latest developments of epidemic" mostly came from economically developed regions with a large floating population. The group with the maximum concern were men aged 20-49. The most searched terms by Wuhan residents were "how to use a thermometer", "n95 mask", "testing kit" and "nucleic acid testing". Conclusion: Through big data from internet, we can accurately understand public concerns and needs during the epidemic. If this data is used in media coverage, public health policy decision-making, and personal epidemic prevention education, it will certainly play an important role. Other countries and regions in the early stages of the epidemic can also benefit from China's experience.

17.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-321373

ABSTRACT

Background: To explore the long-term trajectories considering pneumonia volumes and lymphocyte counts with individual data in COVID-19. Methods: A cohort of 257 convalescent COVID-19 patients (131 male and 126 females) were included. Group-based multi-trajectory modelling was applied to identify different trajectories in terms of pneumonia lesion percentage and lymphocyte counts covering the time from onset to post-discharge follow-ups. We studied the basic characteristics and disease severity associated with the trajectories. Results: We characterised four distinct trajectory subgroups. (1) Group 1 (13.9%), pneumonia increased until a peak lesion percentage of 1.9% (IQR 0.7~4.4) before absorption. The slightly decreased lymphocyte rapidly recovered to the top half of the normal range. (2) Group 2 (44.7%), the peak lesion percentage was 7.2% (IQR 3.2~12.7). The abnormal lymphocyte count restored to normal soon. (3) Group 3 (26.0%), the peak lesion percentage reached 14.2% (IQR 8.5~19.8). The lymphocytes continuously dropped to 0.75 × 10 9 /L after one day post-onset before slowly recovering. (4) Group 4 (15.4%), the peak lesion percentage reached 41.4% (IQR 34.8~47.9), much higher than other groups. Lymphopenia was aggravated until the lymphocytes declined to 0.80 × 10 9 /L on the fourth day and slowly recovered later. Patients in the higher order groups were older and more likely to have hypertension and diabetes (all P values < 0.05), and have more severe disease. Conclusions: Our findings provide new insights to understand the heterogeneous natural courses of COVID-19 patients and the associations of distinct trajectories with disease severity, which is essential to improve the early risk assessment, patient monitoring, and follow-up schedule.

18.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-320704

ABSTRACT

Forest fires impact on soil, water and biota resources has been widely researched. Although forest fires profoundly impact the atmosphere and air quality across the ecosystems, much less research has been developed to examine its impact on the current pandemic. In-situ air pollution data were utilized to examine the effects of the 2020 forest fire on atmosphere and coronavirus (COVID 19) casualties. The spatiotemporal concentrations of particulate matter (PM2.5 and PM10) and Nitrogen Dioxide (NO2) were collected from August 1 to October 30 for 2020 (fire year) and 2019 (reference year). Both spatial (Multiscale Geographically Weighted Regression) and non spatial (negative binomial regression) regression analysis was performed to assess the adverse effects of fire emission on human health. The in situ data led measurements showed that the maximum increases in PM2.5, PM10, and NO2 concentrations were clustered in the West Coastal fire-prone states during the August 1 to October 30 period. The average concentration of particulate matter (PM2.5 and PM10) and NO2 were increased in all the fire states affected badly by forest fires. The average PM2.5 concentration over the period was recorded as 7.9, 6.3, 5.5, and 5.2 for California, Colorado, Oregon, and Washington in 2019, which was increased up to 24.9, 13.4, 25, and 17 in 2020. Both spatial and non-spatial regression models exhibited a statistically significant association between fire emission and COVID 19 incidents. A total of 30 models were developed for analyzing the spatial non-stationary and local association between the predictor and response factors. All these spatial models have demonstrated a statistically significant association between fire emissions and COVID counts. More thorough research is needed to better understand the complex association between forest fire and human health.

19.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-320325

ABSTRACT

COVID-19 has impacted nations differently based on their policy implementations. The effective policy requires taking into account public information and adaptability to new knowledge. Epidemiological models built to understand COVID-19 seldom provide the policymaker with the capability for adaptive pandemic control (APC). Among the core challenges to be overcome include (a) inability to handle a high degree of non-homogeneity in different contributing features across the pandemic timeline, (b) lack of an approach that enables adaptive incorporation of public health expert knowledge, and (c) transparent models that enable understanding of the decision-making process in suggesting policy. In this work, we take the early steps to address these challenges using Knowledge Infused Policy Gradient (KIPG) methods. Prior work on knowledge infusion does not handle soft and hard imposition of varying forms of knowledge in disease information and guidelines to necessarily comply with. Furthermore, the models do not attend to non-homogeneity in feature counts, manifesting as partial observability in informing the policy. Additionally, interpretable structures are extracted post-learning instead of learning an interpretable model required for APC. To this end, we introduce a mathematical framework for KIPG methods that can (a) induce relevant feature counts over multi-relational features of the world, (b) handle latent non-homogeneous counts as hidden variables that are linear combinations of kernelized aggregates over the features, and (b) infuse knowledge as functional constraints in a principled manner. The study establishes a theory for imposing hard and soft constraints and simulates it through experiments. In comparison with knowledge-intensive baselines, we show quick sample efficient adaptation to new knowledge and interpretability in the learned policy, especially in a pandemic context.

20.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-316228

ABSTRACT

Since December 2019, the world has been witnessing the gigantic effect of an unprecedented global pandemic called Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) - COVID-19. So far, 38,619,674 confirmed cases and 1,093,522 confirmed deaths due to COVID-19 have been reported. In the United States (US), the cases and deaths are recorded as 7,833,851 and 215,199. Several timely researches have discussed the local and global effects of the confounding factors on COVID-19 casualties in the US. However, most of these studies considered little about the time varying associations between and among these factors, which are crucial for understanding the outbreak of the present pandemic. Therefore, this study adopts various relevant approaches, including local and global spatial regression models and machine learning to explore the causal effects of the confounding factors on COVID-19 counts in the contiguous US. Totally five spatial regression models, spatial lag model (SLM), ordinary least square (OLS), spatial error model (SEM), geographically weighted regression (GWR) and multiscale geographically weighted regression (MGWR), are performed at the county scale to take into account the scale effects on modelling. For COVID-19 cases, ethnicity, crime, and income factors are found to be the strongest covariates and explain the maximum model variances. For COVID-19 deaths, both (domestic and international) migration and income factors play a crucial role in explaining spatial differences of COVID-19 death counts across counties. The local coefficient of determination (R2) values derived from the GWR and MGWR models are found very high over the Wisconsin-Indiana-Michigan (the Great Lake) region, as well as several parts of Texas, California, Mississippi and Arkansas.

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