Factors associated with resistance to SARS-CoV-2 infection discovered using large-scale medical record data and machine learning.

There have been over 621 million cases of COVID-19 worldwide with over 6.5 million deaths. Despite the high secondary attack rate of COVID-19 in shared households, some exposed individuals do not contract the virus. In addition, little is known about whether the occurrence of COVID-19 resistance differs among people by health characteristics as stored in the electronic health records (EHR). In this retrospective analysis, we develop a statistical model to predict COVID-19 resistance in 8,536 individuals with prior COVID-19 exposure using demographics, diagnostic codes, outpatient medication orders, and count of Elixhauser comorbidities in EHR data from the COVID-19 Precision Medicine Platform Registry. Cluster analyses identified 5 patterns of diagnostic codes that distinguished resistant from non-resistant patients in our study population. In addition, our models showed modest performance in predicting COVID-19 resistance (best performing model AUROC = 0.61). Monte Carlo simulations conducted indicated that the AUROC results are statistically significant (p < 0.001) for the testing set. We hope to validate the features found to be associated with resistance/non-resistance through more advanced association studies.

One Year of COVID-19 Vaccine Misinformation on Twitter: Longitudinal Study.

BACKGROUND: Vaccinations play a critical role in mitigating the impact of COVID-19 and other diseases. Past research has linked misinformation to increased hesitancy and lower vaccination rates. Gaps remain in our knowledge about the main drivers of vaccine misinformation on social media and effective ways to intervene. OBJECTIVE: Our longitudinal study had two primary objectives: (1) to investigate the patterns of prevalence and contagion of COVID-19 vaccine misinformation on Twitter in 2021, and (2) to identify the main spreaders of vaccine misinformation. Given our initial results, we further considered the likely drivers of misinformation and its spread, providing insights for potential interventions. METHODS: We collected almost 300 million English-language tweets related to COVID-19 vaccines using a list of over 80 relevant keywords over a period of 12 months. We then extracted and labeled news articles at the source level based on third-party lists of low-credibility and mainstream news sources, and measured the prevalence of different kinds of information. We also considered suspicious YouTube videos shared on Twitter. We focused our analysis of vaccine misinformation spreaders on verified and automated Twitter accounts. RESULTS: Our findings showed a relatively low prevalence of low-credibility information compared to the entirety of mainstream news. However, the most popular low-credibility sources had reshare volumes comparable to those of many mainstream sources, and had larger volumes than those of authoritative sources such as the US Centers for Disease Control and Prevention and the World Health Organization. Throughout the year, we observed an increasing trend in the prevalence of low-credibility news about vaccines. We also observed a considerable amount of suspicious YouTube videos shared on Twitter. Tweets by a small group of approximately 800 "superspreaders" verified by Twitter accounted for approximately 35% of all reshares of misinformation on an average day, with the top superspreader (@RobertKennedyJr) responsible for over 13% of retweets. Finally, low-credibility news and suspicious YouTube videos were more likely to be shared by automated accounts. CONCLUSIONS: The wide spread of misinformation around COVID-19 vaccines on Twitter during 2021 shows that there was an audience for this type of content. Our findings are also consistent with the hypothesis that superspreaders are driven by financial incentives that allow them to profit from health misinformation. Despite high-profile cases of deplatformed misinformation superspreaders, our results show that in 2021, a few individuals still played an outsized role in the spread of low-credibility vaccine content. As a result, social media moderation efforts would be better served by focusing on reducing the online visibility of repeat spreaders of harmful content, especially during public health crises.

The Clinical Observation of Inflammation Theory for Depression: The Initiative of the Formosa Long COVID Multicenter Study (FOCuS).

There is growing evidence that the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with increased risks of psychiatric sequelae. Depression, anxiety, cognitive impairments, sleep disturbance, and fatigue during and after the acute phase of COVID-19 are prevalent, long-lasting, and exerting negative consequences on well-being and imposing a huge burden on healthcare systems and society. This current review presented timely updates of clinical research findings, particularly focusing on the pathogenetic mechanisms underlying the neuropsychiatric sequelae, and identified potential key targets for developing effective treatment strategies for long COVID. In addition, we introduced the Formosa Long COVID Multicenter Study (FOCuS), which aims to apply the inflammation theory to the pathogenesis and the psychosocial and nutrition treatments of post-COVID depression and anxiety.

A Novel Y-Shaped, S-O-N-O-S-Bridged Cross-Link between Three Residues C22, C44, and K61 Is Frequently Observed in the SARS-CoV-2 Main Protease.

As the COVID-19 pathogen, SARS-CoV-2 relies on its main protease (MPro) for pathogenesis and replication. During crystallographic analyses of MPro crystals that were exposed to the air, a uniquely Y-shaped, S-O-N-O-S-bridged post-translational cross-link that connects three residues C22, C44, and K61 at their side chains was frequently observed. As a novel covalent modification, this cross-link serves potentially as a redox switch to regulate the catalytic activity of MPro, a demonstrated drug target of COVID-19. The formation of this linkage leads to a much more open active site that can potentially be targeted for the development of novel SARS-CoV-2 antivirals. The structural rearrangement of MPro by this cross-link indicates that small molecules that lock MPro in the cross-linked form can potentially be used with other active-site-targeting molecules such as paxlovid for synergistic effects in inhibiting SARS-CoV-2 viral replication.

Exposure to benzalkonium chloride disinfectants promotes antibiotic resistance in sewage sludge microbiomes.

Disinfectants are routinely used in human environments to control and prevent the transmission of microbial disease, and this is particularly true during the current COVID-19 crisis. However, it remains unclear whether the increased disinfectant loadings to wastewater treatment plants facilitate the dissemination of antibiotic resistance genes (ARGs) in sewage sludge microbiomes. Here, we investigated the impacts of benzalkonium chlorides (BACs), widely used disinfectants, on ARGs profiles and microbial community structures in sewage sludge by using high-throughput quantitative PCR and Illumina sequencing. A total of 147 unique ARGs and 39 mobile genetic elements (MGEs) were detected in all sewage sludge samples. Our results show that exposure to BACs disinfectants at environmentally relevant concentrations significantly promotes both the diversity and absolute abundance of ARGs in sludge microbiomes, indicating the co-selection of ARGs by BACs disinfectants. The enrichment of ARGs abundance varied from 2.15-fold to 3.63-fold compared to controls. In addition, BACs exposure significantly alters bacterial and protistan communities, resulting in dysbiosis of the sludge microbiota. The Mantel test and Procrustes analysis confirm that bacterial communities are significantly correlated with ARGs profiles under BACs treatments. The structural equation model explains 83.8 % of the total ARGs variation and further illustrates that the absolute abundance of MGEs exerts greater impacts on the variation of absolute abundance of ARGs than microbial communities under BACs exposure, suggesting BACs may promote antibiotic resistance by enhancing the horizontal gene transfer of ARGs across sludge microbiomes. Collectively, our results provide new insights into the proliferation of antibiotic resistance through disinfectant usage during the pandemic and highlight the necessity to minimize the environmental release of disinfectants into the non-target environment for combating antibiotic resistance.

Circular RNA cancer vaccines drive immunity in hard-to-treat malignancies.

Rationale: Messenger RNA (mRNA) vaccine outperforms other kinds of cancer immunotherapy due to its high response rates, easy preparation, and wide applicability, which is considered as one of the most promising forms of next-generation cancer therapies. However, the inherent instability and insufficient protein expression duration of mRNA limit the efficacy and widespread application of the vaccine. Methods: Here, we first tested the possibility of a novel circular RNA (circRNA) platform for protein expression and compare its duration with linear RNA. Then, we developed a lipid nanoparticle (LNP) system for circRNA delivery in vitro and in vivo. Next, the innate and adaptive immune response of circRNA-LNP complex was evaluated in vivo. The anti-tumor efficacy of circRNA-LNP was further confirmed in three tumor models. Finally, the possibility of combination therapy with circRNA-LNP and adoptive cell transfer therapy was further investigated in a late-stage tumor model. Results: We successfully increased the stability of the RNA vaccine by circularizing the linear RNA molecules to form highly stable circRNA molecules which exhibited durable protein expression ability. By encapsulating the antigen-coding circRNA in LNP enabling in vivo expression, we established a novel circRNA vaccine platform, which was capable of triggering robust innate and adaptive immune activation and showed superior anti-tumor efficacy in multiple mouse tumor models. Conclusions: Overall, our circRNA vaccine platform provides a novel prospect for the development of cancer RNA vaccines in a wide range of hard-to-treat malignancies.

Ileocolic Thrombophlebitis and Lymphadenitis Mimicking Acute Appendicitis as a Late Manifestation in a COVID-19 Patient: A Case Report

Coronavirus disease 2019 (COVID-19) is an infectious viral disease, manifesting primarily as a lung infection with fever and respiratory symptoms. However, it also has a wide range of gastrointestinal symptoms, including nausea, vomiting, abdominal pain, and diarrhea. Right lower quadrant (RLQ) abdominal pain is a common complaint for patients seeking care at emergency departments. In addition to appendicitis, the other possible causes include diverticular disease, epiploic appendagitis, Crohn’s disease, or mesenteric lymphadenitis, among others. Mesenteric ischemia is an uncommon, but crucial cause of abdominal pain, necessitating early diagnosis and treatment. Herein, we report a 47-year-old man who presented to our emergency department complaining of RLQ abdominal pain following recovery from COVID-19. CT was performed due to concern for acute appendicitis. However, mesenteric thrombophlebitis and lymphadenitis in the ileocolic branch were noted on CT. His abdominal pain improved after receiving anticoagulation therapy. This case describes an uncommon etiology of RLQ abdominal pain that should be considered as a late complication of COVID-19.

A systematic review and Bayesian network meta-analysis for comparative safety assessment of favipiravir interventions in hospitalized COVID-19 patients.

INTRODUCTION: COVID-19 is a coronavirus-based infectious illness that was first detected at the end of 2019 in Wuhan, China. The novel virus induces severe acute respiratory syndrome (SARS-CoV-2) and has spread globally, resulting in an ongoing pandemic. There is still a lack of evidence for direct comparison of favipiravir therapy. Network meta-analysis (NMA), may incorporate direct and indirect comparisons in a pooled computation while depending on strong assumptions and premises. This study provides evidence-based recommendations on the safety of currently used clinical pharmacological treatments compared to favipiravir for COVID-19 patients. METHODOLOGY: We conducted a systematic review and Bayesian NMA. We searched the primary databases and clinical trials center for reports of short-term, randomized controlled trials (RCTs) of favipiravir for COVID-19 treatment. The primary endpoints here considered were any adverse events observed or reported during the treatment cycle with estimates of odds ratio (OR) and 95% confidence interval (CI), until November 6, 2021. RESULTS: Between January 2020 and July 2021, 908 individuals were randomly assigned to one of the seven active prescription medication regimens or placebo in this study, generating seven direct comparisons on 12 data points. The safety of favipiravir over the four clinically efficacious monotherapies or combinations including tocilizumab, arbidol, lopinavir + ritonavir, and chloroquine remained unknown due to the lack of a significant difference and the limited sample size. CONCLUSIONS: Overall, comparative rankings could assist doctors and guideline developers in decision-making. We have also concluded that the safety of favipiravir requires further attention.

NO2 retrievals from NOAA-20 OMPS: Algorithm, evaluation, and observations of drastic changes during COVID-19.

We present the first NO2 measurements from the Nadir Mapper of Ozone Mapping and Profiler Suite (OMPS) instrument aboard the NOAA-20 satellite. NOAA-20 OMPS was launched in November 2017, with a nadir resolution of 17 × 13 km2 similar to the Ozone Monitoring Instrument (OMI). The retrieval of NOAA-20 NO2 vertical columns were achieved through the Direct Vertical Column Fitting (DVCF) algorithm, which was uniquely designed and successfully used to retrieve NO2 from OMPS aboard Suomi National Polar-orbiting Partnership (SNPP) spacecraft, predecessor to NOAA-20. Observations from NOAA-20 reveal a 20-40% decline in regional tropospheric NO2 in January-April 2020 due to COVID-19 lockdown, consistent with the findings from other satellite observations. The NO2 retrievals are preliminarily validated against ground-based Pandora spectrometer measurements over the New York City area as well as other U.S. Pandora locations. It shows OMPS total columns tend to be lower in polluted urban regions and higher in clean areas/episodes associated with relatively small NO2 total columns, but generally the agreement is within ±2.5 × 1015 molecules/cm2. Comparisons of stratospheric NO2 columns exhibit the excellent agreement between OMPS and OMI, validating OMPS capability in capturing the stratospheric background accurately. These results demonstrate the high sensitivity of OMPS to tropospheric NO2 and highlight its potential use for extending the long-term global NO2 record.

Clinical evaluation and application of detection of IgM and IgG antibodies against SARS-CoV-2 using a colloidal gold immunochromatography assay

The pandemic of the novel coronavirus (SARS-CoV-2) infection has seriously threated global public health, a rapid and easy operated method for coronavirus disease (COVID-19) diagnosis is needed. To evaluate the clinical application efficacy of the colloidal gold rapid test kit for detection of the IgM/IgG antibodies to SARS-CoV-2, a total of 304 clinical diagnosed case, 138 health donor (of which 114 showed SARS-CoV-2) viral RNA negative and 64 other fever patients with respiratory symptoms were selected for the study and the plasma or serum samples were tested for both IgM and IgG with the kit. The comparison of the detection coincidence of the samples from whole blood and plasma or serum were also performed;Furthermore, the time distribution of SARS-CoV-2 viral RNA and IgM/IgG antibodies detections were analyzed. The results showed that, of the 304 clinical diagnosed cases, 105 cases were positive for viral RNA detection, among which the detection sensitivity of IgM and IgG antibodies to SARS-CoV-2 by colloidal gold rapid assay was 76.2% (80/105) and 86.6% (91/105), respectively, and the overall coincidence rate of IgM/IgG antibody was 96.1% (101/105);and 73 cases were negative for both nucleic acid and antibody detection. Of the remaining 126 clinical diagnosed cases, the positive rate of IgM and IgG was 69.2% (87/126) and 98.3% (125/126), respectively, and the overall coincidence rate of IgM/IgG antibody was 100% (126/126). In detections for healthy and other fever patients, the specificity of IgM and IgG was 99% (200/202) and 98% (198/202), respectively, and the total coincidence rate of antibody detection results of homologous whole blood and plasma samples was 99%, indicating a high degree of consistency. In this study, the detection assay of SARS-CoV-2 antibodies using colloidal gold method showed satisfactory detection effect, and it could be used for clinical auxiliary diagnosis and epidemiological investigation, which could be applied in a wide range of scenarios and play a valuable role in the prevention and control of SARS-CoV-2 pandemic.

A systematic exploration of boceprevir-based main protease inhibitors as SARS-CoV-2 antivirals.

Boceprevir is an HCV NSP3 inhibitor that was explored as a repurposed drug for COVID-19. It inhibits the SARS-CoV-2 main protease (MPro) and contains an α-ketoamide warhead, a P1 ß-cyclobutylalanyl moiety, a P2 dimethylcyclopropylproline, a P3 tert-butylglycine, and a P4 N-terminal tert-butylcarbamide. By introducing modifications at all four positions, we synthesized 20 boceprevir-based MPro inhibitors including PF-07321332 and characterized their MPro inhibition potency in test tubes (in vitro) and 293T cells (in cellulo). Crystal structures of MPro bound with 10 inhibitors and cytotoxicity and antiviral potency of 4 inhibitors were characterized as well. Replacing the P1 site with a ß-(S-2-oxopyrrolidin-3-yl)-alanyl (Opal) residue and the warhead with an aldehyde leads to high in vitro potency. The original moieties at P2, P3 and the P4 N-terminal cap positions in boceprevir are better than other tested chemical moieties for high in vitro potency. In crystal structures, all inhibitors form a covalent adduct with the MPro active site cysteine. The P1 Opal residue, P2 dimethylcyclopropylproline and P4 N-terminal tert-butylcarbamide make strong hydrophobic interactions with MPro, explaining high in vitro potency of inhibitors that contain these moieties. A unique observation was made with an inhibitor that contains a P4 N-terminal isovaleramide. In its MPro complex structure, the P4 N-terminal isovaleramide is tucked deep in a small pocket of MPro that originally recognizes a P4 alanine side chain in a substrate. Although all inhibitors show high in vitro potency, they have drastically different in cellulo potency to inhibit ectopically expressed MPro in human 293T cells. In general, inhibitors with a P4 N-terminal carbamide or amide have low in cellulo potency. This trend is reversed when the P4 N-terminal cap is changed to a carbamate. The installation of a P3 O-tert-butyl-threonine improves in cellulo potency. Three molecules that contain a P4 N-terminal carbamate were advanced to cytotoxicity tests on 293T cells and antiviral potency tests on three SARS-CoV-2 variants. They all have relatively low cytotoxicity and high antiviral potency with EC50 values around 1 µM. A control compound with a nitrile warhead and a P4 N-terminal amide has undetectable antiviral potency. Based on all observations, we conclude that a P4 N-terminal carbamate in a boceprevir derivative is key for high antiviral potency against SARS-CoV-2.

Analysis of the close contact management mode and epidemiological characteristics of COVID-19 in Chengdu, China.

With the development of the novel coronavirus disease 2019 (COVID-19) epidemic and the increase in cases, as a potential source of infection, the risk of close contact has gradually increased. However, few studies have analyzed the tracking and management of cross-regional personnel. In this study, we hope to understand the effectiveness and feasibility of existing close contact management measures in Chengdu, so as to provide a reference for further prevention and control of the epidemic. The close contact management mode and epidemiological characteristics of 40,425 close contacts from January 22, 2020, to March 1, 2022, in Chengdu, China, were analyzed. The relationship with index cases was mainly co-passengers (57.58%) and relatives (7.20%), and the frequency of contact was mainly occasional contact (70.39%). A total of 400 (0.99%) close contacts were converted into cases, which were mainly found in the first and second nucleic acid tests (53.69%), and the contact mode was mainly by sharing transportation (63.82%). In terms of close contact management time, both the supposed ((11.93 ± 3.00) days vs. (11.92 ± 7.24) days) and actual ((13.74 ± 17.47) days vs. (12.60 ± 4.35) days) isolation times in Chengdu were longer than those of the outer cities (P < 0.001). For the local clustered epidemics in Chengdu, the relationship with indexed cases was mainly colleagues (12.70%). The tracing and management of close contacts is a two-way management measure that requires cooperation among departments. Enhancing existing monitoring and response capabilities can control the spread of the epidemic to a certain extent.

Boosting the Photothermal Conversion Efficiency of MXene Film by Porous Wood for Light-driven Soft Actuators

Ti3C2Tx (a typical MXene) has been widely used in light-driven actuators due to its outstanding photothermal conversion capability. However, the response speed of these actuators is always slow because the effective irradiated area is limited to their surface. Herein, we propose a wood-based composite material which is made by coating Ti3C2Tx on delignified wood (DW). The high porosity of DW leads to high loading of Ti3C2Tx and provides large irradiated areas, thus enhancing photothermal conversion efficiency. The delignification on wood can expose cellulose with highly hydrophilic surface for rapid diffusion of Ti3C2Tx suspension, and the hydroxy in cellulose can act as binding sites to form stable combination with Ti3C2Tx. Taking advantage of the good compressibility of DW, a simple densification is conducted on TDW (Ti3C2Tx/DW) to greatly shorten the distance between adjacent oxygen-enriched Ti3C2Tx nanosheets, enhancing the conjugation among nanosheets, thus endowing TDW with good flexibility and high heat transfer efficiency. Moreover, we manufacture a light-driven bilayer actuator comprised of TDW as the passive layer and low-density polyethylene (LDPE) as the active layer. Our light-driven actuator exhibits a tremendous angle variation of 160° at a light intensity of 120 mW/cm2. A series of devices based on the TDW/LDPE actuator are demonstrated, including simulated gestures, a four-finger soft gripper, and a bionic flower. Moreover, we propose a light-controlled smart switch which can be used on non-contact (COVID-19) or dangerous (blasting) occasions. Additionally, we present a finite element simulation to predict the bending deformation, which guides the accurate control of the devices.

A multi-pronged evaluation of aldehyde-based tripeptidyl main protease inhibitors as SARS-CoV-2 antivirals.

As an essential enzyme of SARS-CoV-2, the COVID-19 pathogen, main protease (MPro) is a viable target to develop antivirals for the treatment of COVID-19. By varying chemical compositions at both P2 and P3 positions and the N-terminal protection group, we synthesized 18 tripeptidyl MPro inhibitors that contained also an aldehyde warhead and ß-(S-2-oxopyrrolidin-3-yl)-alaninal at the P1 position. Systematic characterizations of these inhibitors were conducted, including their in vitro enzymatic inhibition potency, X-ray crystal structures of their complexes with MPro, their inhibition of MPro transiently expressed in 293T cells, and cellular toxicity and SARS-CoV-2 antiviral potency of selected inhibitors. These inhibitors have a large variation of determined in vitro enzymatic inhibition IC50 values that range from 4.8 to 650 nM. The determined in vitro enzymatic inhibition IC50 values reveal that relatively small side chains at both P2 and P3 positions are favorable for achieving high in vitro MPro inhibition potency, the P3 position is tolerable toward unnatural amino acids with two alkyl substituents on the α-carbon, and the inhibition potency is sensitive toward the N-terminal protection group. X-ray crystal structures of MPro bound with 16 inhibitors were determined. In all structures, the MPro active site cysteine interacts covalently with the aldehyde warhead of the bound inhibitor to form a hemithioacetal that takes an S configuration. For all inhibitors, election density around the N-terminal protection group is weak indicating possible flexible binding of this group to MPro. In MPro, large structural variations were observed on residues N142 and Q189. Unlike their high in vitro enzymatic inhibition potency, most inhibitors showed low potency to inhibit MPro that was transiently expressed in 293T cells. Inhibitors that showed high potency to inhibit MPro transiently expressed in 293T cells all contain O-tert-butyl-threonine at the P3 position. These inhibitors also exhibited relatively low cytotoxicity and high antiviral potency. Overall, our current and previous studies indicate that O-tert-butyl-threonine at the P3 site is a key component to achieve high cellular and antiviral potency for tripeptidyl aldehyde inhibitors of MPro.

Evolutionary and Structural Insights about Potential SARS-CoV-2 Evasion of Nirmatrelvir.

The U.S. FDA approval of PAXLOVID, a combination therapy of nirmatrelvir and ritonavir has significantly boosted our morale in fighting the COVID-19 pandemic. Nirmatrelvir is an inhibitor of the main protease (MPro) of SARS-CoV-2. Since many SARS-CoV-2 variants that resist vaccines and antibodies have emerged, a concern of acquired viral resistance to nirmatrelvir naturally arises. Here, possible mutations in MPro to confer viral evasion of nirmatrelvir are analyzed and discussed from both evolutionary and structural standpoints. The analysis indicates that those mutations will likely reside in the whole aa45-51 helical region and residues including M165, L167, P168, R188, and Q189. Relevant mutations have also been observed in existing SARS-CoV-2 samples. Implications of this analysis to the fight against future drug-resistant viral variants and the development of broad-spectrum antivirals are discussed as well.

Clinical prediction system of complications among patients with COVID-19: A development and validation retrospective multicentre study during first wave of the pandemic.

Clinical evidence suggests that some patients diagnosed with coronavirus disease 2019 (COVID-19) experience a variety of complications associated with significant morbidity, especially in severe cases during the initial spread of the pandemic. To support early interventions, we propose a machine learning system that predicts the risk of developing multiple complications. We processed data collected from 3,352 patient encounters admitted to 18 facilities between April 1 and April 30, 2020, in Abu Dhabi (AD), United Arab Emirates. Using data collected during the first 24 h of admission, we trained machine learning models to predict the risk of developing any of three complications after 24 h of admission. The complications include Secondary Bacterial Infection (SBI), Acute Kidney Injury (AKI), and Acute Respiratory Distress Syndrome (ARDS). The hospitals were grouped based on geographical proximity to assess the proposed system's learning generalizability, AD Middle region and AD Western & Eastern regions, A and B, respectively. The overall system includes a data filtering criterion, hyperparameter tuning, and model selection. In test set A, consisting of 587 patient encounters (mean age: 45.5), the system achieved a good area under the receiver operating curve (AUROC) for the prediction of SBI (0.902 AUROC), AKI (0.906 AUROC), and ARDS (0.854 AUROC). Similarly, in test set B, consisting of 225 patient encounters (mean age: 42.7), the system performed well for the prediction of SBI (0.859 AUROC), AKI (0.891 AUROC), and ARDS (0.827 AUROC). The performance results and feature importance analysis highlight the system's generalizability and interpretability. The findings illustrate how machine learning models can achieve a strong performance even when using a limited set of routine input variables. Since our proposed system is data-driven, we believe it can be easily repurposed for different outcomes considering the changes in COVID-19 variants over time.

Advanced Functions Embedded in the Second Version of Database, Global Evaluation of SARS-CoV-2/hCoV-19 Sequences 2.

The Global Evaluation of SARS-CoV-2/hCoV-19 Sequences 2 (GESS v2 https://shiny.ph.iu.edu/GESS_v2/) is an updated version of GESS, which has offered a handy query platform to analyze single-nucleotide variants (SNVs) on millions of high coverages and high-quality severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) complete genomes provided by the Global Initiative on Sharing Avian Influenza Data (GISAID). Including the tools in the first version, the GESS v2 is embedded with new functions, which allow users to search SNVs, given the viral nucleotide or amino acid sequence. The GESS v2 helps users to identify SNVs or SARS-CoV-2 lineages enriched in countries of user's interest and show the migration path of a selected lineage on a world map during specific time periods chosen by the users. In addition, the GESS v2 can recognize the dynamic variations of newly emerging SNVs in each month to help users monitor SNVs, which will potentially become dominant soon. More importantly, multiple sets of analyzed results about SNVs can be downloaded directly from the GESS v2 by which users can conduct their own independent research. With these significant updates, the GESS v2 will continue to serve as a public open platform for researchers to explore SARS-CoV-2 evolutionary patterns from the perspectives of the prevalence and impact of SNVs.

Online misinformation is linked to early COVID-19 vaccination hesitancy and refusal.

Widespread uptake of vaccines is necessary to achieve herd immunity. However, uptake rates have varied across U.S. states during the first six months of the COVID-19 vaccination program. Misbeliefs may play an important role in vaccine hesitancy, and there is a need to understand relationships between misinformation, beliefs, behaviors, and health outcomes. Here we investigate the extent to which COVID-19 vaccination rates and vaccine hesitancy are associated with levels of online misinformation about vaccines. We also look for evidence of directionality from online misinformation to vaccine hesitancy. We find a negative relationship between misinformation and vaccination uptake rates. Online misinformation is also correlated with vaccine hesitancy rates taken from survey data. Associations between vaccine outcomes and misinformation remain significant when accounting for political as well as demographic and socioeconomic factors. While vaccine hesitancy is strongly associated with Republican vote share, we observe that the effect of online misinformation on hesitancy is strongest across Democratic rather than Republican counties. Granger causality analysis shows evidence for a directional relationship from online misinformation to vaccine hesitancy. Our results support a need for interventions that address misbeliefs, allowing individuals to make better-informed health decisions.

Repurposing Halicin as a potent covalent inhibitor for the SARS-CoV-2 main protease.

The rapid spread of COVID-19 has caused a worldwide public health crisis. For prompt and effective development of antivirals for SARS-CoV-2, the pathogen of COVID-19, drug repurposing has been broadly conducted by targeting the main protease (MPro), a key enzyme responsible for the replication of virus inside the host. In this study, we evaluate the inhibition potency of a nitrothiazole-containing drug, halicin, and reveal its reaction and interaction mechanism with MPro. The in vitro potency test shows that halicin inhibits the activity of MPro an IC50 of 181.7 â€‹nM. Native mass spectrometry and X-ray crystallography studies clearly indicate that the nitrothiazole fragment of halicin covalently binds to the catalytic cysteine C145 of MPro. Interaction and conformational changes inside the active site of MPro suggest a favorable nucleophilic aromatic substitution reaction mechanism between MPro C145 and halicin, explaining the high inhibition potency of halicin towards MPro.

Evaluation of SARS-CoV-2 Main Protease Inhibitors Using a Novel Cell-Based Assay.

As an essential enzyme of SARS-CoV-2, main protease (MPro) triggers acute toxicity to its human cell host, an effect that can be alleviated by an MPro inhibitor. Using this toxicity alleviation, we developed an effective method that allows a bulk analysis of the cellular potency of MPro inhibitors. This novel assay is advantageous over an antiviral assay in providing precise cellular MPro inhibition information to assess an MPro inhibitor. We used this assay to analyze 30 known MPro inhibitors. Contrary to their strong antiviral effects and up to 10 µM, 11a, calpain inhibitor II, calpain XII, ebselen, bepridil, chloroquine, and hydroxychloroquine showed relatively weak to undetectable cellular MPro inhibition potency implicating their roles in interfering with key steps other than just the MPro catalysis in the SARS-CoV-2 life cycle. Our results also revealed that MPI5, MPI6, MPI7, and MPI8 have high cellular and antiviral potency. As the one with the highest cellular and antiviral potency among all tested compounds, MPI8 has a remarkable cellular MPro inhibition IC50 value of 31 nM that matches closely to its strong antiviral effect with an EC50 value of 30 nM. Therefore, we cautiously suggest exploring MPI8 further for COVID-19 preclinical tests.