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188 lines
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<meta content="width=device-width, initial-scale=1.0, user-scalable=yes" name="viewport"/>
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<title>21 May, 2022</title>
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<title>Covid-19 Sentry</title><meta content="width=device-width, initial-scale=1.0" name="viewport"/><link href="styles/simple.css" rel="stylesheet"/><link href="../styles/simple.css" rel="stylesheet"/><link href="https://unpkg.com/aos@2.3.1/dist/aos.css" rel="stylesheet"/><script src="https://unpkg.com/aos@2.3.1/dist/aos.js"></script></head>
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<h1 data-aos="fade-down" id="covid-19-sentry">Covid-19 Sentry</h1>
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<h1 data-aos="fade-right" data-aos-anchor-placement="top-bottom" id="contents">Contents</h1>
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<li><a href="#from-preprints">From Preprints</a></li>
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<li><a href="#from-clinical-trials">From Clinical Trials</a></li>
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<li><a href="#from-pubmed">From PubMed</a></li>
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<li><a href="#from-patent-search">From Patent Search</a></li>
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<h1 data-aos="fade-right" id="from-preprints">From Preprints</h1>
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<li><strong>Omicron breakthrough infections in vaccinated or previously infected hamsters</strong> -
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The second and third years of the SARS-CoV-2 pandemic have been marked by the repeated emergence and replacement of variants with genetic and phenotypic distance from the ancestral strains, the most recent examples being Delta and Omicron. Here we describe a hamster contact exposure challenge model to assess protection conferred by vaccination or prior infection against re-infection. We found that 2-doses of self-amplifying RNA vaccine based on the ancestral spike ameliorated weight loss following Delta infection and decreased viral loads, but had minimal effect on Omicron/BA.1 infection. Prior infection with ancestral or Alpha variant was partially protective against Omicron/BA.1 infection, whereas all animals previously infected with Delta and exposed to Omicron became infected, although shed less virus. We further tested whether prior infection with Omicron/BA.1 protected from re-infection with Delta or Omicron/BA.2. Omicron/BA.1 was protective against Omicron/BA.2, but not Delta reinfection, again showing Delta and Omicron have a very large antigenic distance. Indeed, cross-neutralisation assays with human antisera from otherwise immunonaive individuals (unvaccinated and no known prior infection), confirmed a large antigenic distance between Delta and Omicron. Prior vaccination followed by Omicron or Delta breakthrough infection led to a higher degree of cross-reactivity to all tested variants. To conclude, cohorts whose only immune experience of COVID is Omicron/BA.1 infection may be particularly vulnerable to future circulation of Delta or Delta-like derivatives. In contrast, repeated exposure to antigenically distinct spikes, via infection and or vaccination drives a more cross-reactive immune response, both in hamsters and people.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.05.20.492779v1" target="_blank">Omicron breakthrough infections in vaccinated or previously infected hamsters</a>
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<li><strong>Structural basis for substrate selection by the SARS-CoV-2 replicase</strong> -
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The SARS-CoV-2 RNA-dependent RNA polymerase coordinates viral RNA synthesis as part of an assembly known as the replication-transcription complex (RTC). Accordingly, the RTC is a target for clinically approved antiviral nucleoside analogs, including remdesivir. Faithful synthesis of viral RNAs by the RTC requires recognition of the correct nucleotide triphosphate (NTP) for incorporation into the nascent RNA. To be effective inhibitors, antiviral nucleoside analogs must compete with the natural NTPs for incorporation. How the SARS-CoV-2 RTC discriminates between the natural NTPs, and how antiviral nucleoside analogs compete, has not been discerned in detail. Here, we use cryo-electron microscopy to visualize the RTC bound to each of the natural NTPs in states poised for incorporation. Furthermore, we investigate the RTC with the active metabolite of remdesivir, remdesivir triphosphate (RDV-TP), highlighting the structural basis for the selective incorporation of RDV-TP over its natural counterpart ATP. Our results elucidate the suite of interactions required for NTP recognition, informing the rational design of antivirals. Our analysis also yields insights into nucleotide recognition by the nsp12 NiRAN, an enigmatic catalytic domain essential for viral propagation. The NiRAN selectively binds GTP, strengthening proposals for the role of this domain in the formation of the 5’ RNA cap.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.05.20.492815v1" target="_blank">Structural basis for substrate selection by the SARS-CoV-2 replicase</a>
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</div></li>
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<li><strong>SARS-CoV-2 Infects Peripheral and Central Neurons of Mice Before Viremia, Facilitated by Neuropilin-1</strong> -
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<div>
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Neurological symptoms are increasingly associated with COVID-19, suggesting that SARS-CoV-2 is neuroinvasive. Although studies have focused on neuroinvasion through infection of olfactory neurons and supporting cells or hematogenous spread, little attention has been paid to the susceptibility of the peripheral nervous system to infection or to alternative routes of neural invasion. We show that neurons in the central and peripheral nervous systems are susceptible to productive infection with SARS-CoV-2. Infection of K18-hACE2 mice, wild-type mice, and primary neuronal cultures demonstrates viral RNA, protein, and infectious virus in peripheral nervous system neurons, spinal cord, specific brain regions, and satellite glial cells. Moreover, we found that SARS-CoV-2 infects neurons at least in part via neuropilin-1. Our data show that SARS-CoV-2 rapidly invades and establishes productive infection in previously unassessed sites in the nervous system via direct invasion of neurons before viremia, which may underlie some cognitive and sensory symptoms associated with COVID-19.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.05.20.492834v1" target="_blank">SARS-CoV-2 Infects Peripheral and Central Neurons of Mice Before Viremia, Facilitated by Neuropilin-1</a>
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<li><strong>The spike-stabilizing D614G mutation interacts with S1/S2 cleavage site mutations to promote the infectious potential of SARS-CoV-2 variants</strong> -
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SARS-CoV-2 remained genetically stable during the first three months of the pandemic, before acquiring a D614G spike mutation that rapidly spread worldwide, and then generating successive waves of viral variants with increasingly high transmissibility. We set out to evaluate possible epistatic interactions between the early occurring D614G mutation and the more recently emerged cleavage site mutations present in spike of the Alpha, Delta, and Omicron variants of concern. The P681H/R mutations at the S1/S2 cleavage site increased spike processing and fusogenicity but limited its incorporation into pseudoviruses. In addition, the higher cleavage rate led to higher shedding of the spike S1 subunit, resulting in a lower infectivity of the P681H/R-carrying pseudoviruses compared to those expressing the Wuhan wild-type spike. The D614G mutation increased spike expression at the cell surface and limited S1 shedding from pseudovirions. As a consequence, the D614G mutation preferentially increased the infectivity of P681H/R-carrying pseudoviruses. This enhancement was more marked in cells where the endosomal route predominated, suggesting that more stable spikes could better withstand the endosomal environment. Taken together, these findings suggest that the D614G mutation stabilized S1/S2 association and enabled the selection of mutations that increased S1/S2 cleavage, leading to the emergence of SARS-CoV-2 variants expressing highly fusogenic spikes.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.05.20.492832v1" target="_blank">The spike-stabilizing D614G mutation interacts with S1/S2 cleavage site mutations to promote the infectious potential of SARS-CoV-2 variants</a>
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</div></li>
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<li><strong>Deep mutational scanning identifies SARS-CoV-2 Nucleocapsid escape mutations of currently available rapid antigen tests</strong> -
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Widespread and frequent testing is critical to prevent the spread of COVID-19, and rapid antigen tests are the diagnostic tool of choice in many settings. With new viral variants continuously emerging and spreading rapidly, the effect of mutations on antigen test performance is a major concern. In response to the spread of variants the National Institutes of Health’s Rapid Acceleration of Diagnostics (RADx) initiative created a Variant Task Force to assess the impact of emerging SARS-CoV-2 variants on in vitro diagnostic testing. To evaluate the impact of mutations on rapid antigen tests we developed a lentivirus-mediated mammalian surface-display platform for the SARS-CoV-2 Nucleocapsid protein, the target of the majority of rapid antigen tests. We employed deep mutational scanning (DMS) to directly measure the effect of all possible Nucleocapsid point mutations on antibody binding by 17 diagnostic antibodies used in 11 commercially available antigen tests with FDA emergency use authorization (EUA). The results provide a complete map of the antibodies’ epitopes and their susceptibility to mutational escape. This approach identifies linear epitopes, conformational epitopes, as well as allosteric escape mutations in any region of the Nucleocapsid protein. All 17 antibodies tested exhibit distinct escape mutation profiles, even among antibodies recognizing the same folded domain. Our data predict no vulnerabilities of rapid antigen tests for detection of mutations found in currently and previously dominant variants of concern and interest. We confirm this using the commercial tests and sequence-confirmed COVID-19 patient samples. The antibody escape mutation profiles generated here serve as a valuable resource for predicting the performance of rapid antigen tests against past, current, as well as any possible future variants of SARS-CoV-2, establishing the direct clinical and public health utility of our system. Further, our mammalian surface-display platform combined with DMS is a generalizable platform for complete mapping of protein-protein interactions.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.05.19.492641v1" target="_blank">Deep mutational scanning identifies SARS-CoV-2 Nucleocapsid escape mutations of currently available rapid antigen tests</a>
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<li><strong>SARS-CoV-2 Spike protein suppresses CTL-mediated killing by inhibiting immune synapse assembly</strong> -
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CTL-mediated killing of virally infected or malignant cells is orchestrated at a specialized intercellular junction, the immune synapse (IS). We hypothesized that SARS-CoV-2 may target IS assembly in CTLs to escape killing. We show that primary human CD8+ T cells strongly upregulate the expression of ACE2, the Spike protein receptor, during differentiation to CTLs. CTL pre-incubation with the Wuhan or Omicron Spike variants inhibits IS assembly and function, as shown by defective synaptic accumulation of TCRs and tyrosine phosphoproteins as well as defective centrosome and lytic granule polarisation to the IS, resulting in impaired target cell killing. These defects were reversed by anti- Spike antibodies that interfere with ACE2 binding and were reproduced by ACE2 engagement with Angiotensin-II or an anti- ACE2 antibody, but not by the ACE2 product Ang (1-7). These results highlight a new strategy of immune evasion by SARS- CoV-2 based on the Spike-dependent, ACE2-mediated targeting of the lytic IS to prevent the elimination of infected cells.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.05.20.492764v1" target="_blank">SARS-CoV-2 Spike protein suppresses CTL-mediated killing by inhibiting immune synapse assembly</a>
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<li><strong>Revealing druggable cryptic pockets in the Nsp-1 of SARS-CoV-2 and other β-coronaviruses by simulations and crystallography</strong> -
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Non-structural protein 1 (Nsp1) is a main pathogenicity factor of alpha- and beta-coronaviruses. Nsp1 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suppresses the host gene expression by sterically blocking 40S host ribosomal subunits and promoting host mRNA degradation. This mechanism leads to the downregulation of the translation-mediated innate immune response in host cells, ultimately mediating the observed immune evasion capabilities of SARS-CoV-2. Here, by combining extensive Molecular Dynamics simulations, fragment screening and crystallography, we reveal druggable pockets in Nsp1. Structural and computational solvent mapping analyses indicate the partial crypticity of these newly discovered and druggable binding sites. The results of fragment-based screening via X-ray crystallography confirm the druggability of the major pocket of Nsp1. Finally, we show how the targeting of this pocket could disrupt the Nsp1-mRNA complex and open a novel avenue to design new inhibitors for other Nsp1s present in homologous beta- coronaviruses.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.05.20.492819v1" target="_blank">Revealing druggable cryptic pockets in the Nsp-1 of SARS-CoV-2 and other β-coronaviruses by simulations and crystallography</a>
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<li><strong>Highly divergent white-tailed deer SARS-CoV-2 with potential deer-to-human transmission</strong> -
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Wildlife reservoirs of SARS-CoV-2 may enable viral adaptation and spillback from animals to humans. In North America, there is evidence of unsustained spillover of SARS-CoV-2 from humans to white-tailed deer (Odocoileus virginianus), but no evidence of transmission from deer to humans. Through a biosurveillance program in Ontario, Canada we identified a new and highly divergent lineage of SARS-CoV-2 in white-tailed deer. This lineage is the most divergent SARS-CoV-2 lineage identified to date, with 76 consensus mutations (including 37 previously associated with non-human animal hosts) and signatures of considerable evolution and transmission within wildlife. Phylogenetic analysis also revealed an epidemiologically linked human case. Together, our findings represent the first clear evidence of sustained evolution of SARS-CoV-2 in white-tailed deer and of deer-to-human transmission.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.02.22.481551v2" target="_blank">Highly divergent white-tailed deer SARS-CoV-2 with potential deer-to-human transmission</a>
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<li><strong>Covid-19 Vaccine Acceptance Among People Incarcerated in Connecticut State Jails</strong> -
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Objective: To assess the Connecticut Department of Corrections (DOC) COVID-19 vaccine program within jails. Methods: We conducted a retrospective cohort analysis among people who were incarcerated in a DOC-operated jail between February 2 and November 8, 2021, and were eligible for vaccination at the time of incarceration (intake). We compared the vaccination rates before and after incarceration using an age-adjusted survival analysis with a time-varying exposure of incarceration and an outcome of vaccination. Results: During the study period, 3,716 people spent at least 1 night in jail and were eligible for vaccination at intake. Of these residents, 136 were vaccinated prior to incarceration, 2,265 had a recorded vaccine offer, and 476 were vaccinated while incarcerated. The age-adjusted hazard of vaccination following incarceration was significantly higher than prior to incarceration (12.5; 95% CI: 10.2-15.3). Conclusions: We found that residents were more likely to become vaccinated in jail than the community. Though these findings highlight the utility of vaccination programs within jails, the low level of vaccination in this population speaks to the need for additional program development within jails and the community.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.05.19.22275339v1" target="_blank">Covid-19 Vaccine Acceptance Among People Incarcerated in Connecticut State Jails</a>
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<li><strong>Jinhua Qinggan Granules for Nonhospitalized COVID-19 Patients: a Double-Blind, Placebo-Controlled, Randomized Controlled Trial</strong> -
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Background: Key findings from the World Health Organization Expert Meeting on Evaluation of Traditional Chinese Medicine in treating COVID-19 reported that TCMs are beneficial, particularly for mild-to-moderate cases. The efficacy of Jinhua Qinggan Granules (JHQG) in COVID-19 patients with mild symptoms has yet to be clearly defined. Methods: We conducted a phase 2/3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with JHQR in mild, nonhospitalized, laboratory-confirmed COVID-19 patients. Participants were randomly assigned to receive 5g/sacket of JHQG or placebo granules orally thrice daily for 10 days. The primary outcomes were the improvement in clinical symptoms and proportion tested negative on viral PCR after treatment. Secondary outcomes were the time to recovery from clinical symptoms and changes in white blood cells (WBC) and acute phase reactants (C-reactive protein (CRP) and ferritin) 10 days after treatment. Results: A total of 300 patients were randomly assigned to receive JHQG (150 patients) and placebo (150 patients). Baseline characteristics were similar in the two groups. In the modified intention-to-treat analysis, JHQG showed greater clinical efficacy (82.67%) after 10 days of treatment compared with the placebo group (10.74%) (rate difference: 71.93%; 95% CI 64.09 - 79.76). The proportion of patients with a negative PCR after treatment were comparable (rate difference: -4.67%; 95% CI -15.76 - 6.42). While all changes in WBC, ferritin, and CRP levels showed a statistically significant decline in JHQG (p<=0.044) after treatment, but not the latter in placebo (p=0.077). The median time to recovery of COVID-19 related symptoms including cough, sputum, sore throat, dyspnea, headache, nasal obstruction, fatigue, and myalgia were shorter in the JHQG group compared to the placebo group (P<0.001 for all). 3 patients experienced mild to moderate adverse events during the treatment period in the JHQG group. Findings were similar between the modified intention-to-treat and the per-protocol analysis that included only patients who reported 100% adherence to the assigned regimen. Conclusions: JHQG is a safe and effective TCM for the treatment of mild COVID-19 patients.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.05.16.22275074v2" target="_blank">Jinhua Qinggan Granules for Nonhospitalized COVID-19 Patients: a Double-Blind, Placebo-Controlled, Randomized Controlled Trial</a>
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<li><strong>Behaviour, booster vaccines and waning immunity: modelling the medium-term dynamics of SARS-CoV-2 transmission in England in the Omicron era</strong> -
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England has experienced a heavy burden of COVID-19, with multiple waves of SARS-CoV-2 transmission since early 2020 and high infection levels following the emergence and spread of Omicron variants since late 2021. In response to rising Omicron cases, booster vaccinations were accelerated and offered to all adults in England. Using a model fitted to more than 2 years of epidemiological data, we project potential dynamics of SARS-CoV-2 infections, hospital admissions and deaths in England to December 2022. We consider key uncertainties including future behavioural change and waning immunity, and assess the effectiveness of booster vaccinations in mitigating SARS-CoV-2 disease burden between October 2021 and December 2022. If no new variants emerge, SARS-CoV-2 transmission is expected to decline, with low levels remaining in the coming months. The extent to which projected SARS-CoV-2 transmission resurges later in 2022 depends largely on assumptions around waning immunity and to some extent, behaviour and seasonality.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2021.11.22.21266584v2" target="_blank">Behaviour, booster vaccines and waning immunity: modelling the medium-term dynamics of SARS-CoV-2 transmission in England in the Omicron era</a>
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<li><strong>A social media-based framework for quantifying temporal changes to wildlife viewing intensity: Case study of sea turtles before and during COVID-19</strong> -
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Documenting how human pressure on wildlife changes over time is important to minimise potential adverse effects through implementing appropriate management and policy actions; however, obtaining objective measures of these changes and their potential impacts is often logistically challenging, particularly in the natural environment. Here, we developed a modular stochastic model that infers the ratio of actual viewing pressure on wildlife in consecutive time periods (years) using social media, as this medium is widespread and easily accessible. Pressure was calculated from the number of times individual animals appeared in social media in pre-defined time windows, accounting for time-dependent variables that influence them (e.g. number of people with access to social media). Formulas for the confidence intervals of viewing pressure ratios were rigorously developed and validated, and corresponding uncertainty was quantified. We applied the developed framework to calculate changes to wildlife viewing pressure on loggerhead sea turtles (Caretta caretta) at Zakynthos island (Greece) before and during the COVID-19 pandemic (2019-2021) based on 2646 social media entries. Our model ensured temporal comparability across years of social media data grouped in time window sizes, by correcting for the interannual increase of social media use. Optimal sizes for these windows were delineated, reducing uncertainty while maintaining high time-scale resolution. The optimal time window was around 7-days during the peak tourist season when more data were available in all three years, and >15 days during the low season. In contrast, raw social media data exhibited clear bias when quantifying changes to viewing pressure, with unknown uncertainty. The framework developed here allows widely-available social media data to be used objectively when quantifying temporal changes to wildlife viewing pressure. Its modularity allowed viewing pressure to be quantified for all data combined, or subsets of data (different groups, situations or locations), and could be applied to any site supporting wildlife exposed to tourism.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.05.19.492636v1" target="_blank">A social media-based framework for quantifying temporal changes to wildlife viewing intensity: Case study of sea turtles before and during COVID-19</a>
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<li><strong>Annual prevalence of non-communicable diseases and identification of vulnerable populations following the Fukushima disaster and COVID-19 pandemic</strong> -
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Disasters, pandemics, and their response measures can have secondary effects on the physical and psychological health of affected populations. Identifying populations vulnerable to these effects is beneficial for promoting effective health and prevention strategies. Using health insurance receipt data from 2009 to 2020, we assessed changes in prevalence of major non-communicable diseases (NCDs), including hypertension, hyperlipidemia, diabetes, and mental disorders, among affected populations before and after the Fukushima disaster and coronavirus disease (COVID-19) outbreak in Japan. Furthermore, age and sex groups with the largest increases in prevalence after these events were identified. The participants of this study were members of the Employees9 Health Insurance scheme, including employees of companies and their dependent family members. The dataset was provided by JMDC Inc. The annual age-adjusted prevalence of each disease was used to calculate the ratio of disease prevalence before and after the events. After the Fukushima disaster, hypertension, hyperlipidemia, and diabetes generally increased over a 9-year period in Fukushima Prefecture. The increase in the prevalence rate of these three NCDs and mental disorders were the highest among females aged 40-74 years compared to males and the other age groups. The prevalence of all four diseases increased after the COVID-19 outbreak in Japan, with marked increase in males aged 0-39 years. Populations that have experienced secondary health effects such as NCDs are unique to each disaster or pandemic, and it is important to provide tailor-made public health support among populations in accordance to the type of disasters and pandemic.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.05.18.22275293v1" target="_blank">Annual prevalence of non-communicable diseases and identification of vulnerable populations following the Fukushima disaster and COVID-19 pandemic</a>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Prevalence and determinants of mental well-being and satisfaction with life among university students amidst COVID-19 pandemic</strong> -
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Background: The COVID-19 pandemic has caused a slew of mental illnesses due to a lack of cures and vaccinations, as well as concerns about students9 well-being and satisfaction with life, resulting in psychological symptoms and dissatisfaction with their lives. As students are highly susceptible to mental health issues, researchers discovered that perceived SWL and MWB decreased. The present study investigated the prevalence and determinants of mental well- being and satisfaction with life among university students in Bangladesh. Methods: An e-survey based cross-sectional study was carried out from February to April 2021 among 660 students. A purposive sampling technique was utilized in the study. Self-reported mental well-being and satisfaction with life psychological tools were also used. The e-questionnaire survey was conducted with informed consent and questions were related to socio-demographics, satisfaction with life, and mental well-being scales. Descriptive statistics and multiple regression analyses were performed. The data were rechecked and analyzed with the R programming language. Results: The prevalence estimates of mental well-being and satisfaction with life were 27% and 13% respectively. In a total of 660 participants, 58.2% of them were male and the rest of them were female (41.8%). Among the participants, 22.5% suffer the worst conditions regarding their financial conditions, and 16.5% badly seek a job for livelihood. Conclusion: The present findings revealed that the COVID-19 pandemic and longtime educational institution closure significantly affect the students mental health. Students mental well-being was in vulnerable conditions and their satisfaction with life was extremely poor. A comprehensive student psychological support service should be expanded to help students mental health.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.05.18.22275203v1" target="_blank">Prevalence and determinants of mental well-being and satisfaction with life among university students amidst COVID-19 pandemic</a>
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<li><strong>Real-world effectiveness of molnupiravir and nirmatrelvir/ritonavir among COVID-19 inpatients during Hong Kong’s Omicron BA.2 wave: an observational study</strong> -
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Background Real-world evidence on the effectiveness of oral antivirals in mild-to-moderate COVID-19 patients is urgently needed. This retrospective cohort study aims to evaluate the clinical and virologic outcomes associated with molnupiravir and nirmatrelvir/ritonavir use in COVID-19 patients during a pandemic wave dominated by the Omicron BA.2 variant. Methods We analyzed data from a territory-wide retrospective cohort of hospitalized patients with confirmed diagnosis of SARS-CoV-2 infection from 26th February 2022 to 26th April 2022 in Hong Kong. Oral antiviral users were matched with controls using propensity-score matching in a ratio of 1:4. Study outcomes were a composite outcome of disease progression (all-cause mortality, initiation of invasive mechanical ventilation [IMV], or intensive care unit admission) and their individual outcomes, and lower viral load of cycle threshold (Ct) value ≥30 cycles. Hazard ratios (HR) of event outcomes were estimated using Cox regression models. Results Among 40,776 hospitalized patients with SARS- CoV-2 infection over a mean follow-up of 41.3 days with 925,713 person-days, 2,359 and 1,000 patients not initially requiring oxygen therapy were initiated with molnupiravir and nirmatrelvir/ritonavir, respectively. The crude incidence rates of all-cause mortality and IMV were 22.24 and 1.06 events per 10,000 person-days among molnupiravir users, 11.04 and 1.75 events per 10,000 person-days among nirmatrelvir/ritonavir users. Oral antiviral use was associated with a significantly lower risk of the composite outcome of disease progression (molnupiravir: HR=0.53, 95%CI=0.46-0.62, p<0.001; nirmatrelvir/ritonavir: HR=0.33, 95%CI=0.24-0.46, p<0.001) than non-use, which was consistently observed for all-cause mortality (molnupiravir: HR=0.55, 95%CI=0.47-0.63, p<0.001; nirmatrelvir/ritonavir: HR=0.32, 95%CI=0.23-0.45, p<0.001). Molnupiravir users had lower risks of IMV (HR=0.31, 95%CI=0.16-0.61, p<0.001). Time to achieving lower viral load was significantly shorter among oral antiviral users than matched controls (molnupiravir: HR=1.21, 95%CI=1.07-1.37, p=0.002; nirmatrelvir/ritonavir: HR=1.25, 95%CI=1.04-1.50, p=0.015). Amongst survivors, nirmatrelvir/ritonavir had shorter length of hospital stay (-0.70 days, 95%CI=-1.37 to -0.04, p=0.039) than matched controls. Head-to-head comparison of molnupiravir and nirmatrelvir/ritonavir reported higher risk of mortality (HR=1.53 95%CI=1.01-2.31, p=0.047) and longer length of hospital stay (0.83 days, 95%CI=0.07-1.58, p=0.032) for molnupiravir users. Conclusions Against Omicron BA.2, initiation of novel oral antiviral treatment in hospitalized patients not requiring any oxygen therapy was associated with lower risks of disease progression and all-cause mortality, in addition to achieving low viral load faster.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.05.19.22275291v1" target="_blank">Real-world effectiveness of molnupiravir and nirmatrelvir/ritonavir among COVID-19 inpatients during Hong Kong’s Omicron BA.2 wave: an observational study</a>
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<h1 data-aos="fade-right" id="from-clinical-trials">From Clinical Trials</h1>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>The Role of Glutathione Deficiency and MSIDS Variables in Long COVID-19</strong> - <b>Condition</b>: COVID-19<br/><b>Intervention</b>: Dietary Supplement: NAC (N-acetyl cysteine) , Alpha lipoic acid (ALA), liposomal glutathione (GSH)<br/><b>Sponsors</b>: University of California, Irvine; Hudson Valley Healing Arts Center<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Study to Evaluate the Efficacy of IN STI-9199 in Treating Symptomatic COVID-19 in Outpatient Adults and Adolescents</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Drug: STI-9199; Drug: Placebo<br/><b>Sponsor</b>: <br/>
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Sorrento Therapeutics, Inc.<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Study to Evaluate the Safety and Immunogenicity of Omicron COVID-19 Vaccine (Vero Cell), Inactivated in Population 18 Years Old of Age and Above</strong> - <b>Condition</b>: COVID-19<br/><b>Intervention</b>: Biological: Omicron COVID-19 Vaccine (Vero Cell), Inactivated<br/><b>Sponsors</b>: China National Biotec Group Company Limited; Beijing Institute of Biological Products Co Ltd.; Shulan (Hangzhou) Hospital<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Study on Sequential Immunization of Omicron Inactivated COVID-19 Vaccine and Prototype Inactivated COVID-19 Vaccine in Population Aged 18 Years Old and Above</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: Omicron COVID-19 Vaccine (Vero Cell), Inactivated; Biological: COVID-19 Vaccine (Vero Cell), Inactivated<br/><b>Sponsors</b>: <br/>
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China National Biotec Group Company Limited; Beijing Institute of Biological Products Co Ltd.; Hunan Provincial Center for Disease Control and Prevention<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Neuro-inflammation and Post-infectious Fatigue in Individuals With and Without COVID-19</strong> - <b>Condition</b>: COVID-19<br/><b>Intervention</b>: Radiation: [18F]DPA-714 positron emission tomography (PET) scan<br/><b>Sponsors</b>: Amsterdam UMC, location VUmc; ZonMw: The Netherlands Organisation for Health Research and Development<br/><b>Enrolling by invitation</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Phase II Safety Single-arm Study of CDK4/6 Inhibition With Palbociclib in Hospitalized, Moderate COVID-19 Cases to Prevent Thromboinflammation</strong> - <b>Condition</b>: COVID-19<br/><b>Intervention</b>: Drug: Palbociclib<br/><b>Sponsor</b>: biotx.ai GmbH<br/><b>Active, not recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Phase I Clinical Trial of COVID-19 mRNA Vaccine in Adults Aged 18 Years and Older</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: COVID-19 mRNA vaccine; Biological: Placebo<br/><b>Sponsor</b>: CanSino Biologics Inc.<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Phase II Clinical Trial of COVID-19 mRNA Vaccine in Adults Aged 18 Years and Older</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: COVID-19 mRNA vaccine; Biological: Placebo<br/><b>Sponsor</b>: CanSino Biologics Inc.<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>THEMBA II T-Cell Vaccine: Vaccination With saRNA COVID-19 Vaccines</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: AAHI-SC2 Vaccine; Biological: AAHI- SC3 Vaccine; Biological: EUA or approved vaccine<br/><b>Sponsor</b>: ImmunityBio, Inc.<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>To Evaluate SSD8432/Ritonavir in Adults With COVID-19</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Drug: SSD8432 dose; Drug: SSD8432 placebo<br/><b>Sponsor</b>: Jiangsu Simcere Pharmaceutical Co., Ltd.<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Study to Evaluate the Efficacy and Safety of DXP604 in Patients With Mild to Moderate COVID-19</strong> - <b>Condition</b>: COVID-19<br/><b>Intervention</b>: Biological: DXP604<br/><b>Sponsor</b>: <br/>
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Wuhan Institute of Biological Products Co., Ltd<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Evaluation of SSD8432 and Ritonavir in Adult Subjects With COVID-19 Placebo-Controlled, Phase II Clinical Study</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Drug: SSD8432 dose1; Drug: SSD8432 dose2; Drug: SSD8432Placebo<br/><b>Sponsor</b>: Jiangsu Simcere Pharmaceutical Co., Ltd.<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Sequential Immunization of Two Doses of Inactivated COVID-19 Vaccine (Omicron) in Vaccinated Population Aged 18 Years and Above</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: BIBP Omicron Inactivated COVID-19 vaccine (Vero Cell); Biological: WIBP Omicron Inactivated COVID-19 vaccine (Vero Cell); Biological: COVID-19 Vaccine (Vero Cell), Inactivated<br/><b>Sponsors</b>: China National Biotec Group Company Limited; Beijing Institute of Biological Products Co Ltd.; Wuhan Institute of Biological Products Co., Ltd; The University of Hong Kong<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Immunogenicity and Safety of Booster Immunization of COVID-19 Vaccine (Vero Cell), Inactivated (Omicron Variant) in Healthy People Aged 18 Years and Above</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: COVID-19 Vaccine (Vero cell), Inactivated (Omicron variant); Biological: COVID-19 Vaccine (Vero cell), Inactivated (CZ strain)<br/><b>Sponsor</b>: <br/>
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Sinovac Research and Development Co., Ltd.<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>To Evaluate SSD8432/ Ritonavir in Adults With COVID-19</strong> - <b>Condition</b>: COVID-19 Patients<br/><b>Interventions</b>: Drug: SSD8432 dose 1/Ritonavir; Drug: SSD8432 dose 2/Ritonavir<br/><b>Sponsor</b>: Jiangsu Simcere Pharmaceutical Co., Ltd.<br/><b>Recruiting</b></p></li>
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</ul>
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<h1 data-aos="fade-right" id="from-pubmed">From PubMed</h1>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Disease-associated dysbiosis and potential therapeutic role of Akkermansia muciniphila, a mucus degrading bacteria of gut microbiome</strong> - The unique functionality of Akkermansia muciniphila in gut microbiota indicates it to be an indispensable microbe for human welfare. The importance of A. muciniphila lies in its potential to convert mucin into beneficial by-products, regulate intestinal homeostasis and maintain gut barrier integrity. It is also known to competitively inhibit other mucin-degrading bacteria and improve metabolic functions and immunity responses in the host. It finds a pivotal perspective in various diseases and…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Expanding the spectrum of the hyperferritinemic syndrome, from pathogenic mechanisms to clinical observations, and therapeutic implications</strong> - From the introduction of hyperferritinemic syndrome concept, a growing body of evidence has suggested the role of ferritin as a pathogenic mediator and a relevant clinical feature in the management of patients with inflammatory diseases. From a pathogenic point of view, ferritin may directly stimulate the aberrant immune response by triggering the production of pro-inflammatory mediators in inducing a vicious pathogenic loop and contributing to the occurrence of cytokine storm syndrome. The…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Longitudinal analyses reveal distinct immune response landscapes in lung and intestinal tissues from SARS- CoV-2-infected rhesus macaques</strong> - The pathological and immune response of individuals with COVID-19 display different dynamics in lung and intestine. Here, we depict the single-cell transcriptional atlas of longitudinally collected lung and intestinal tissue samples from SARS-CoV-2-infected monkeys at 3 to 10 dpi. We find that intestinal enterocytes are degraded at 3 days post- infection but recovered rapidly, revealing that infection has mild effects on the intestine. Crucially, we observe suppression of the inflammatory…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>In vitro characterization of the furin inhibitor MI-1851: Albumin binding, interaction with cytochrome P450 enzymes and cytotoxicity</strong> - The substrate-analog furin inhibitor MI-1851 can suppress the cleavage of SARS-CoV-2 spike protein and consequently produces significant antiviral effect on infected human airway epithelial cells. In this study, the interaction of inhibitor MI-1851 was examined with human serum albumin using fluorescence spectroscopy and ultrafiltration techniques. Furthermore, the impacts of MI-1851 on human microsomal hepatic cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6 and 3A4 activities were assessed based on…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Folic acid: a potential inhibitor against SARS-CoV-2 nucleocapsid protein</strong> - CONTEXT: Coronavirus disease 2019 is a global pandemic. Studies suggest that folic acid has antiviral effects. Molecular docking shown that folic acid can act on SARS-CoV-2 Nucleocapsid Phosphoprotein (SARS-CoV-2 N).</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>HDAC Inhibition as Potential Therapeutic Strategy to Restore the Deregulated Immune Response in Severe COVID-19</strong> - The COVID-19 pandemic has had a devastating impact worldwide and has been a great challenge for the scientific community. Vaccines against SARS-CoV-2 are now efficiently lessening COVID-19 mortality, although finding a cure for this infection is still a priority. An unbalanced immune response and the uncontrolled release of proinflammatory cytokines are features of COVID-19 pathophysiology and contribute to disease progression and worsening. Histone deacetylases (HDACs) have gained interest in…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Intranasal Delivery of Thermostable Subunit Vaccine for Cross-Reactive Mucosal and Systemic Antibody Responses Against SARS-CoV-2</strong> - Despite the remarkable efficacy of currently approved COVID-19 vaccines, there are several opportunities for continued vaccine development against SARS-CoV-2 and future lethal respiratory viruses. In particular, restricted vaccine access and hesitancy have limited immunization rates. In addition, current vaccines are unable to prevent breakthrough infections, leading to prolonged virus circulation. To improve access, a subunit vaccine with enhanced thermostability was designed to eliminate the…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Importance of Influenza Anti-Hemagglutinin Antibodies During the SARS-CoV-2 Pandemic in the 2019/2020 Epidemic Season in Poland</strong> - BACKGROUND The aim of this study was to determine the level of anti-hemagglutinin antibodies in the serum of recovered patients during the SARS-CoV-2 pandemic in the 2019/2020 epidemic season in Poland, and the course of COVID-19. MATERIAL AND METHODS The material for the study consisted of the sera of COVID-19 convalescents obtained from the following 9 Regional Blood Donation and Blood Supply Centers located in 8 voivodeships. The hemagglutination inhibition reaction assay (HAI) using 8 viral…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Nanocomposites of Graphene Oxide-Silver Nanoparticles for Enhanced Antibacterial Activity: Mechanism of Action and Medical Textiles Coating</strong> - The resistance of microorganisms to antibiotics is a crucial problem for which the application of nanomaterials is among a growing number of solutions. The aim of the study was to create a nanocomposite (composed of graphene oxide and silver nanoparticles) with a precise mode of antibacterial action: what enables textiles to be coated in order to exhibit antibacterial properties. A characterization of nanomaterials (silver nanoparticles and graphene oxide) by size distribution, zeta potential…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Ginkgolic acid and anacardic acid are reversible inhibitors of SARS-CoV-2 3-chymotrypsin-like protease</strong> - Because of the emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in different regions of the world, the battle with infectious coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has been seesawing. Therefore, the identification of antiviral drugs is of particular importance. In order to rapidly identify inhibitors for SARS-CoV-2 3-chymotrypsin-like protease (3CL^(pro)), an enzyme essential for viral replication, we combined the fluorescence polarization (FP)…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Broad-spectrum CRISPR-mediated inhibition of SARS-CoV-2 variants and endemic coronaviruses in vitro</strong> - A major challenge in coronavirus vaccination and treatment is to counteract rapid viral evolution and mutations. Here we demonstrate that CRISPR-Cas13d offers a broad-spectrum antiviral (BSA) to inhibit many SARS-CoV-2 variants and diverse human coronavirus strains with >99% reduction of the viral titer. We show that Cas13d-mediated coronavirus inhibition is dependent on the crRNA cellular spatial colocalization with Cas13d and target viral RNA. Cas13d can significantly enhance the therapeutic…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>SARS-CoV-2 Omicron sublineages show comparable cell entry but differential neutralization by therapeutic antibodies</strong> - The Omicron variant of SARS-CoV-2 evades antibody-mediated neutralization with unprecedented efficiency. At least three Omicron sublineages have been identified-BA.1, BA.2, and BA.3-and BA.2 exhibits increased transmissibility. However, it is currently unknown whether BA.2 differs from the other sublineages regarding cell entry and antibody-mediated inhibition. Here, we show that BA.1, BA.2, and BA.3 enter and fuse target cells with similar efficiency and in an ACE2-dependent manner. However,…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Inhibition of IRAK4 dysregulates SARS-CoV-2 spike protein-induced macrophage inflammatory and glycolytic reprogramming</strong> - Escalated innate immunity plays a critical role in SARS-CoV-2 pathology; however, the molecular mechanism is incompletely understood. Thus, we aim to characterize the molecular mechanism by which SARS-CoV-2 Spike protein advances human macrophage (Mϴ) inflammatory and glycolytic phenotypes and uncover novel therapeutic strategies. We found that human Mϴs exposed to Spike protein activate IRAK4 phosphorylation. Blockade of IRAK4 in Spike protein-stimulated Mϴs nullifies signaling of IRAK4, AKT,…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>ZBP1-dependent inflammatory cell death, PANoptosis, and cytokine storm disrupt IFN therapeutic efficacy during coronavirus infection</strong> - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), continues to cause significant morbidity and mortality in the ongoing global pandemic. Understanding the fundamental mechanisms that govern innate immune and inflammatory responses during SARS-CoV-2 infection is critical for developing effective therapeutic strategies. While IFN-based therapies are generally expected to be beneficial during viral infection, clinical trials…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Clofoctol inhibits SARS-CoV-2 replication and reduces lung pathology in mice</strong> - Drug repurposing has the advantage of shortening regulatory preclinical development steps. Here, we screened a library of drug compounds, already registered in one or several geographical areas, to identify those exhibiting antiviral activity against SARS-CoV-2 with relevant potency. Of the 1,942 compounds tested, 21 exhibited a substantial antiviral activity in Vero-81 cells. Among them, clofoctol, an antibacterial drug used for the treatment of bacterial respiratory tract infections, was…</p></li>
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<h1 data-aos="fade-right" id="from-patent-search">From Patent Search</h1>
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