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<title>14 October, 2023</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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<ul>
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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>Nanobodies against SARS-CoV-2 non-structural protein Nsp9 inhibit viral replication by targeting innate immunity</strong> -
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Nanobodies are emerging as critical tools for drug design. Several have been recently created to serve as inhibitors of SARS-Cov-2 entry in the host cell by targeting surface-exposed Spike protein. However, due to the high frequency of mutations that affect Spike, these nanobodies may not target it to their full potential and as a consequence, inhibition of viral entry may not be efficient. Here we have established a pipeline that instead targets highly conserved viral proteins that are made only after viral entry into the host cell when the SARS-Cov-2 RNA-based genome is translated. As proof of principle, we designed nanobodies against the SARS-CoV-2 non-structural protein Nsp9, required for viral genome replication. To find out if this strategy efficiently blocks viral replication, one of these anti-Nsp9 nanobodies, 2NSP23, previously characterized using immunoassays and NMR spectroscopy for epitope mapping, was encapsulated into lipid nanoparticles (LNP) as mRNA. We show that this nanobody, hereby referred to as LNP-mRNA-2NSP23, is internalized and translated in HEK293 cells. We next infected HEK293-ACE2 cells with multiple SARS-CoV-2 variants and subjected them to LNP-mRNA-2NSP23 treatment. Analysis of total RNA isolated from infected cells treated or untreated with LNP-mRNA-2NSP23 using qPCR and RNA deep sequencing shows that the LNP-mRNA-2NSP23 nanobody protects HEK293-ACE2 cells and suppresses replication of several SARS-CoV-2 variants. These observations indicate that following translation, the nanobody 2NSP23 inhibits viral replication by targeting Nsp9 in living cells. We speculate that LNP-mRNA-2NSP23 may be translated into an innovative technology to generate novel antiviral drugs highly efficient across coronaviruses.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.10.12.561992v1" target="_blank">Nanobodies against SARS-CoV-2 non-structural protein Nsp9 inhibit viral replication by targeting innate immunity</a>
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</div></li>
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<li><strong>Akaluc bioluminescence offers superior sensitivity to track in vivo dynamics of SARS-CoV-2 infection</strong> -
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Monitoring in vivo viral dynamics can improve our understanding of pathogenicity and tissue tropism. For positive-sense, single-stranded RNA viruses, several studies have attempted to monitor viral kinetics in vivo using reporter genomes. The application of such recombinant viruses can be limited by challenges in accommodating bioluminescent reporter genes in the viral genome. Conventional luminescence also exhibits relatively low tissue permeability and thus less sensitivity for visualization in vivo. Here we show that unlike NanoLuc bioluminescence, the improved method, termed AkaBLI, allows visualization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Syrian hamsters. By successfully incorporating a codon-optimized Akaluc luciferase gene into the SARS-CoV-2 genome, we visualized in vivo infection, including the tissue-specific differences associated with particular variants. Additionally, we could evaluate the efficacy of neutralizing antibodies and mRNA vaccination by monitoring changes in Akaluc signals. Overall, AkaBLI is an effective technology for monitoring viral dynamics in live animals.
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</div>
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<div class="article-link article-html-link">
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.10.12.561993v1" target="_blank">Akaluc bioluminescence offers superior sensitivity to track in vivo dynamics of SARS-CoV-2 infection</a>
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<li><strong>Reference materials for SARS-CoV-2 molecular diagnostic quality control: validation of encapsulated synthetic RNAs for room temperature storage and shipping</strong> -
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The Coronavirus pandemic unveiled the unprecedented need for diagnostic tests to rapidly detect the presence of pathogens in the population. Real-time RT-PCR and other nucleic acid amplification techniques are accurate and sensitive molecular techniques that necessitate positive controls. To meet this need, Twist Bioscience has developed and released synthetic RNA controls. However, RNA is an inherently unstable molecule needing cold storage, costly shipping, and resource-intensive logistics. Imagene provides a solution to this problem by encapsulating dehydrated RNA inside metallic capsules filled with anhydrous argon, allowing room temperature and eco-friendly storage and shipping. Here, RNA controls produced by Twist were encapsulated (RNAshells) and distributed to several laboratories that used them for COVID-19 detection tests by amplification. One RT-LAMP procedure, four different RT-PCR devices and six different PCR kits were used. The amplification targets were genes E, N; RdRp, Sarbeco-E and Orf1a/b. RNA retrieval was satisfactory, and the detection was reproducible. RNA stability was checked by accelerated aging. The results for a 10-year equivalent storage time at 25 {degrees}C were not significantly different from those for unaged samples. This room temperature RNA stability allows the preparation and distribution of large strategic batches which can be stored for a long time and used for standardization processes between detection sites. Moreover, it makes it also possible to use these controls for single use and in the field where large differences in temperature can occur. Consequently, this type of encapsulated RNA controls, processed at room temperature, can be used as reference materials for the SARS-Cov-2 virus as well as for other pathogens detection.
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<div class="article-link article-html-link">
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.08.28.555008v2" target="_blank">Reference materials for SARS-CoV-2 molecular diagnostic quality control: validation of encapsulated synthetic RNAs for room temperature storage and shipping</a>
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</div></li>
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<li><strong>homeRNA self-blood collection by exposed close contacts enables high-frequency temporal profiling of the pre-symptomatic host immune kinetics to respiratory viral infection</strong> -
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<b>Background</b> Host immunity is critical in determining outcomes of acute respiratory viral infections (ARVIs). However, detailed kinetics of host immune responses following natural exposures are poorly understood. Investigating the host response during the pre–symptomatic phase of viral infection is challenging, and prior work has largely relied on human challenge studies. In this prospective longitudinal study, we utilized a self-blood collection tool (<i>home</i>RNA) to profile the host response during pre–symptomatic ARVIs in recently exposed adults and present a study framework for the conduct of large–scale longitudinal mechanistic studies. <b>Methods</b> We prospectively recruited non–symptomatic adults with recent exposure to ARVIs who subsequently tested negative (exposed uninfected) and positive for respiratory pathogens. Study participants performed self–collection of blood and nasal swabs across a 4–week observation window. Daily monitoring of symptoms, viral load, and blood transcriptional responses was performed for the first week followed by weekly monitoring of blood transcriptional responses and symptoms. Nasal swabs were assayed for respiratory pathogens including SARS–CoV–2. Immune kinetics from 132 longitudinal blood samples (8 SARS–CoV–2 infected and 4 exposed uninfected) were profiled at high temporal resolution for 773 host response genes. <b>Findings</b> 68 participants across 26 U.S. states completed the study between June 2021 – April 2022, with 97.6% of scheduled longitudinal blood collections (n=691), 97.9% of nasal swabs (n=466) and 97.2% of symptom surveys (n=688) returned. SARS-CoV-2 infection was confirmed in 25% of the participants (n=17) Expression of host immediate early genes (IEGs) involved in AP-1 transcriptional complex and prostaglandin biosynthesis along with genes encoding the early T-cell activation antigen (<i>CD69</i>), pyrogenic cytokines (IL-6, MIP-1β, and IFN-γ), cytotoxic cell receptors and granule proteins, and interferon-induced GTPases were detected in the periphery prior to onset of viral shedding in the nasal passage. Upon onset of viral shedding, robust induction of interferon stimulated genes (ISGs) were observed. We also observed elevated expression of the host defense peptides <i>DEFA4, LCN2, LTF, BPI</i> (HDPs) in exposed uninfected individuals. <b>Interpretation</b> Signatures of T–cell responses prior to nasal viral shedding followed by robust induction of innate ISGs upon onset of viral shedding suggests that T–cell derived immune memory may play a role in pathogen control during early phases of the infection. Elevated levels of HDPs in exposed uninfected individuals suggest a potential role for neutrophil–mediated immunity in host defense during pathogen exposure. Finally, we demonstrated that unsupervised self–collection and stabilization of blood using <i>home</i>RNA can be used to study early host immune kinetics to natural ARVIs at a temporal resolution comparable to that of human challenge studies.
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<div class="article-link article-html-link">
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.10.12.23296835v1" target="_blank">homeRNA self-blood collection by exposed close contacts enables high-frequency temporal profiling of the pre-symptomatic host immune kinetics to respiratory viral infection</a>
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<li><strong>Estimating the potential impact and diagnostic requirements for SARS-CoV-2 test-and-treat programs</strong> -
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Oral antivirals have the potential to reduce the public health burden of COVID-19. However, now that we have exited the emergency phase of the COVID-19 pandemic, declining SARS-CoV-2 clinical testing rates (average testing rates = ≪10 tests/100,000 people/day in low-and-middle income countries; <100 tests/100,000 people/day in high-income countries; September 2023) make the development of effective test-and-treat programs challenging. We used an agent-based model to investigate how testing rates and strategies affect the use and effectiveness of oral antiviral test-to-treat programs in four country archetypes of different income levels and demographies. We find that in the post-emergency phase of the pandemic, in countries where low testing rates are driven by limited testing capacity, significant population-level impact of test-and-treat programs can only be achieved by both increasing testing rates and prioritizing individuals with greater risk of severe disease. However, for all countries, significant reductions in severe cases with antivirals are only possible if testing rates were substantially increased with high willingness of people to seek testing. Comparing the potential population-level reductions in severe disease outcomes of test-to-treat programs and vaccination shows that test-and-treat strategies are likely substantially more resource intensive requiring very high levels of testing (>>100 tests/100,000 people/day) and antiviral use suggesting that vaccination should be a higher priority.
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</p>
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.10.05.22280727v2" target="_blank">Estimating the potential impact and diagnostic requirements for SARS-CoV-2 test-and-treat programs</a>
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<li><strong>Adolescents’ future orientation and anticipatory emotion regulation in daily life during the COVID-19 pandemic: An experience sampling study</strong> -
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The COVID-19 pandemic posed a challenge to young people’s positive future orientation and mental health. The current study’s objective was to understand the role of daily-life future orientation and anticipatory emotion regulation in mental health during the pandemic. We used the Experience Sampling Method to investigate Belgian adolescents’ (aged 13 – 21) daily life future orientation and anticipatory emotion regulation in relation to psychopathology symptoms in 2020 (N = 136, 121 females) and 2021 (N = 53, 48 females). Adolescents generally perceived immediate future events more positively than negatively throughout the pandemic. However, differences in future orientation between phases of the pandemic were also observed. Higher psychopathology symptom levels were associated with looking forward to future events less and dreading them more early in the pandemic and with perceiving immediate future events as less positive in a later phase of the pandemic. Furthermore, the expected intensity and importance of immediate future events were related to anticipatory emotion regulation in daily life during the pandemic. The results suggest that adolescents with higher psychopathology symptoms perceived the immediate future more negatively during the first year of the COVID-19 pandemic. Therefore, clinical interventions to target future orientation during a crisis could be beneficial in supporting and improving young people’s mental health.
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🖺 Full Text HTML: <a href="https://osf.io/preprints/psyarxiv/mh7au/" target="_blank">Adolescents’ future orientation and anticipatory emotion regulation in daily life during the COVID-19 pandemic: An experience sampling study</a>
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<li><strong>Antecedents and consequences of telework during the COVID-19 pandemic: A natural experiment in Japan</strong> -
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With the outbreak of the COVID-19 pandemic, companies around the world have been introducing telework. However, Japan stands out for its low rate of telework implementation, and it seems there may be cultural factors that have hindered telework use in Japan during the pandemic. In this study, we aim to clarify the antecedents and consequences of telework in Japan, making use of the natural experiment created by the COVID-19 pandemic to examine the following two questions: (1) What socio-psychological factors in workplaces were important for introducing telework in the first place? and (2) How did the implementation of telework subsequently influence socio-psychological factors in these workplaces? Three waves of an online survey were conducted among the same employees working for Japanese companies before and during the pandemic. We found that telework in Japan was more readily introduced in organizations characterized by meritocracy. We also found that the introduction of telework in Japanese companies did not have any negative effects but instead increased levels of independence, organizational commitment and perceived hierarchy mutability. We discuss how telework interacts with culture at both societal and organizational levels.
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🖺 Full Text HTML: <a href="https://osf.io/preprints/psyarxiv/rxn4u/" target="_blank">Antecedents and consequences of telework during the COVID-19 pandemic: A natural experiment in Japan</a>
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<li><strong>An ethnographic analysis virtual peer review panels</strong> -
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In the early months of the COVID-19 pandemic, many research funding organisations were faced with the choice of suspending or else continuing their decision-making processes, including peer review panels, virtually. Although seen part of a longer drive to make peer review more cost and time efficient, it is still not fully understood how peer review panels, more commonly operating in a face-to-face (F2F) setting, function in a virtual environment. Using a series of observation of 4 peer review panels conducted virtually during 2020 at the Research Council of Norway (Forskningsrådet), this research explores the move from face-to-face to virtual panel deliberation and how panellists behaved in this new environment. Despite the virtual panels arguably conducted more efficiently, saving time and money by panellists participating from their home-settings, a number of behaviours around the role of the Panel Chair, and the collective presence during the decision-making process, suggest alternations as to how panels reached and confirmed consensus in the virtual environment. Deliberate mechanisms to confirm consensus was required during panels thus suggesting a more onerous workload mid, and post-panel work for Panel Chairs and managers. In addition, whereas a majority of panel members had experience working together in the past, the introduction of new panel members was restricted in an online environment, leading to instances where new panel members would lead discussions, and present conflicting information during evaluations. These preliminary results indicate that more information is needed about how the virtual environment influences peer review processes before a more permanent change is adopted by funding agencies.
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🖺 Full Text HTML: <a href="https://osf.io/preprints/socarxiv/fbkr6/" target="_blank">An ethnographic analysis virtual peer review panels</a>
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<li><strong>Virtual Simulated Placements in Healthcare Education: A scoping review</strong> -
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Abstract Introduction A virtual simulated placement (VSP) is a computer-generated version of a practice placement. COVID-19 drove increased adoption of virtual technology in clinical education. Accordingly, the number of VSP publications increased from 2020. This review aims to determine the scope of this literature to inform future research questions. Objective Assess the range and types of evidence related to VSPs across the healthcare professions. Inclusion criteria Studies that focussed on healthcare students participating in VSPs. Hybrid, augmented reality (AR) and mixed reality (MR) placements were excluded. Methods Fourteen databases were searched, limited to English, and dated from 1st January 2020. Supplementary searches were employed, and an updated search was conducted on 9th July 2023. Themes were synthesised using the PAGER framework to highlight patterns, advances, gaps, evidence for practice and research recommendations. Results Twenty-eight papers were reviewed. All VSPs were designed in response to pandemic restrictions. Students were primarily from medicine and nursing. Few publications were from developing nations. There was limited stakeholder involvement in the VSP designs and a lack of robust research designs, consistent outcome measures, conceptual underpinnings, and immersive technologies. Despite this, promising trends for student experience, knowledge, communication, and critical thinking skills using VSPs have emerged. Conclusion. This review maps the VSP evidence across medicine, nursing, midwifery and allied health. Before a systematic review is feasible across healthcare, allied health and midwifery research require greater representation. Based on the highlighted gaps, other areas for future research are suggested.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.10.12.23296932v1" target="_blank">Virtual Simulated Placements in Healthcare Education: A scoping review</a>
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<li><strong>A nationwide study of 331 rare diseases among 58 million individuals: prevalence, demographics, and COVID-19 outcomes</strong> -
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Background: The Global Burden of Disease study has provided key evidence to inform clinicians, researchers, and policy makers across common diseases, but no similar effort with single study design exists for hundreds of rare diseases. Consequently, many rare conditions lack population-level evidence including prevalence and clinical vulnerability. This has led to the absence of evidence-based care for rare diseases, prominently in the COVID-19 pandemic. Method: This study used electronic health records (EHRs) of more than 58 million people in England, linking nine National Health Service datasets spanning healthcare settings for people alive on Jan 23, 2020. Starting with all rare diseases listed in Orphanet, we quality assured and filtered down to analyse 331 conditions with ICD-10 or SNOMED-CT mappings clinically validated in our dataset. We report 1) population prevalence, clinical and demographic details of rare diseases, and 2) investigate differences in mortality with SARs-CoV-2. Findings: Among 58,162,316 individuals, we identified 894,396 with at least one rare disease. Prevalence data in Orphanet originates from various sources with varying degrees of precision. Here we present reproducible age and gender-adjusted estimates for all 331 rare diseases, including first estimates for 186 (56.2%) without any reported prevalence estimate in Orphanet. We identified 49 rare diseases significantly more frequent in females and 62 in males. Similarly we identified 47 rare diseases more frequent in Asian as compared to White ethnicity and 22 with higher Black to white ratios as compared to similar ratios in population controls. 37 rare diseases were overrepresented in the white population as compared to both Black and Asian ethnicities. In total, 7,965 of 894,396 (0.9%) of rare-disease patients died from COVID-19, as compared to 141,287 of 58,162,316 (0.2%) in the full study population. Eight rare diseases had significantly increased risks for COVID-19-related mortality in fully vaccinated individuals, with bullous pemphigoid (8.07[3.01-21.62]) being worst affected. Interpretation: Our study highlights that National-scale EHRs provide a unique resource to estimate detailed prevalence, clinical and demographic data for rare diseases. Using COVID-19-related mortality analysis, we showed the power of large-scale EHRs in providing insights to inform public health decision-making for these often neglected patient populations.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.10.12.23296948v1" target="_blank">A nationwide study of 331 rare diseases among 58 million individuals: prevalence, demographics, and COVID-19 outcomes</a>
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<li><strong>Mathematical modeling of SARS-CoV-2 variant substitutions in European countries: Transmission dynamics and epidemiological insights</strong> -
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Background: Countries across Europe have faced similar evolutions of SARS-CoV-2 VOCs, including the Alpha, Delta, and Omicron variants. Materials and Methods: We used data from GISAID and applied a robust, automated mathematical substitution model to study the dynamics of COVID-19 variants across Europe over a period of more than two years, from late 2020 to early 2023. This model identifies variant substitution patterns and distinguishes between residual and dominant behavior. We used weekly sequencing data from 19 European countries to estimate the increase in transmissibility (∆β) between consecutive SARS-CoV-2 variants. In addition, we focused on large countries with separate regional outbreaks and complex scenarios of multiple competing variants. Results: Our model accurately reproduced the observed substitution patterns between the Alpha, Delta, and Omicron major variants. We estimated the daily variant prevalence and calculated ∆β between variants, revealing that: (i) ∆β increased progressively from the Alpha to the Omicron variant; (ii) ∆β showed a high degree of variability within Omicron variants; (iii) a higher ∆β was associated with a later emergence of the variant within a country; (iv) a higher degree of immunization of the population against previous variants was associated with a higher ∆β for the Delta variant; (v) larger countries exhibited smaller ∆β, suggesting regionally diverse outbreaks within the same country; and finally (vi) the model reliably captures the dynamics of competing variants, even in complex scenarios. Conclusions: The use of mathematical models allows for the precise and reliable estimation of daily cases of each variant. By quantifying ∆β, we have tracked the spread of the different variants across Europe, highlighting a robust increase in transmissibility trend from Alpha to Omicron. On the other hand, we have shown that the country-level increases in transmissibility can always be influenced by the geographical characteristics of the country and the timing of the emergence of the variant.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.10.12.23296888v1" target="_blank">Mathematical modeling of SARS-CoV-2 variant substitutions in European countries: Transmission dynamics and epidemiological insights</a>
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<li><strong>Evolution of SARS-CoV-2 in the RhineNeckar/Heidelberg Region 01/2021 07/2023</strong> -
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At the beginning of 2021 the monitoring of the circulating variants of SARS-CoV-2 was established in Germany in accordance with the Corona Surveillance Act (discontinued after July 2023) to allow a better containment of the pandemic, because certain amino acid exchanges (especially) in the spike protein lead to higher transmission as well as a reduced vaccination efficacy. Therefore, our group performed whole genome sequencing applying the ARTIC protocol (currently V4) on Illumina9s NextSeq 500 platform (and starting in May 2023 on the MiSeq DX platform) for SARS-CoV-2 positive specimen from patients of the Heidelberg University Hospital (and associated hospitals) as well as the Public health office in Rhine-Neckar/Heidelberg region. Our group sequenced a total of 26,795 SARS-CoV-2-positive samples between January 2021 and July 2023 - valid sequences, according to the requirements for sequence upload to the German electronic sequencing data hub (DESH) operated by the Robert Koch Institute (RKI), could be determined for 24,852 samples, while the lineage/clade could be identified for 25,912 samples. While the year 2021 was very dynamic and changing regarding the circulating variants in the Rhine-Neckar/Heidelberg region with the initial non-variant of concerns, followed by A.27.RN and the rise of B.1.1.7 in winter/spring and its displacement by B.1.617.2 in spring/summer, which remained almost exclusive until the beginning of December and the first B.1.1.529 incidences, which rose to a proportion of 40 percent by the end of 2021 (and superseded B.1.617.2 by January 2022 with a proportion of over 90 percent). The years 2022 and 2023 were then dominated by B.1.1.529 and its numerous sublineages, especially BA.5 and BA.2, and more recently by the rise of recombinant variants, such as XBB.1.5. By the end of July 2023 (and since calendar week 20) the proportion of the recombinant variants amounted to 100 percent of all circulating variants in the Rhine-Neckar/Heidelberg region.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.10.12.23296928v1" target="_blank">Evolution of SARS-CoV-2 in the RhineNeckar/Heidelberg Region 01/2021 07/2023</a>
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<li><strong>Sarbecovirus disease susceptibility is conserved across viral and host models</strong> -
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Coronaviruses have caused three severe epidemics since the start of the 21st century: SARS, MERS and COVID-19. The severity of the ongoing COVID-19 pandemic and increasing likelihood of future coronavirus outbreaks motivates greater understanding of factors leading to severe coronavirus disease. We screened ten strains from the Collaborative Cross mouse genetic reference panel and identified strains CC006/TauUnc (CC006) and CC044/Unc (CC044) as coronavirus-susceptible and resistant, respectively, as indicated by variable weight loss and lung congestion scores four days post-infection. We generated a genetic mapping population of 755 CC006xCC044 F2 mice and exposed the mice to one of three genetically distinct mouse-adapted coronaviruses: clade 1a SARS-CoV MA15 (n=391), clade 1b SARS-CoV-2 MA10 (n=274), and clade 2 HKU3-CoV MA (n=90). Quantitative trait loci (QTL) mapping in SARS-CoV- and SARS-CoV-2-infected F2 mice identified genetic loci associated with disease severity. Specifically, we identified seven loci associated with variation in outcome following infection with either virus, including one, HrS45, that is present in both groups. Three of these QTL, including HrS45, were also associated with HKU3-CoV MA outcome. HrS45 overlaps with a QTL previously reported by our lab that is associated with SARS-CoV outcome in CC011xCC074 F2 mice and is also syntenic with a human chromosomal region associated with severe COVID-19 outcomes in humans GWAS. The results reported here provide: (a) additional support for the involvement of this locus in SARS-CoV MA15 infection, (b) the first conclusive evidence that this locus is associated with susceptibility across the Sarbecovirus subgenus, and (c) demonstration of the relevance of mouse models in the study of coronavirus disease susceptibility in humans.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.10.11.561544v1" target="_blank">Sarbecovirus disease susceptibility is conserved across viral and host models</a>
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<li><strong>Sex-Specific Development of ssRNA Virus Receptor Gene Expression in the Human Brain</strong> -
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Viral infection severity often varies with host factors such as age and sex. The pathogenesis of infections caused by a broad range of viruses, from neurotropic viruses like Rabies and Zika to respiratory viruses such as influenza and SARS-CoV-2, differ between the sexes and across the lifespan. Typically, older males are more susceptible to severe acute outcomes, while females are more vulnerable to the post-acute sequelae of infections. All of these complications can include neuroinflammation, stroke, cognitive dysfunction, and delirium. While these symptoms can be secondary to infection, recent studies suggest that even peripheral infections can lead to neuropathological changes in the brain. However, few studies have characterized the expression of viral receptors in the human brain or examined age- or sex-related differences in such expression. In this study, we used a publicly accessible transcriptomic database to assess the impact of age and sex on the expression of 67 viral host factor genes, associated with ten virus families. Analyzing data from 15 brain areas (n=33, F=14, M=19, age:4 mo-80 yrs), we determined the lifespan trajectory for each gene in each area via LOESS regressions. We used unsupervised hierarchical clustering to determine if a brain-wide pattern or virus family pattern can be detected. Using Dense-tSNE, a dimension-reduction and visualization technique, we discovered four distinct developmental trajectories, clustering the areas into two mixed-sex subcortical clusters and one each of male and female cortical clusters. Applying Differential Expression Sliding Window Analysis (DeSWAN), we identified the genes driving these age- and sex-related differences. Many sex differences were noted in childhood, potentially impacting the brain's susceptibility to viral infections and underscoring a broader dimorphic organization of male and female brains. These insights contribute to our understanding of sex-specific responses to viral infections, offering the potential for more personalized treatment strategies.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.10.11.561925v1" target="_blank">Sex-Specific Development of ssRNA Virus Receptor Gene Expression in the Human Brain</a>
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<li><strong>Modelling the impact of population mobility, post-infection immunity and vaccination on SARS-CoV-2 transmission in the Dominican Republic</strong> -
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COVID-19 epidemic dynamics are driven by a complex interplay of factors including population behaviour, government interventions, new variants, vaccination campaigns and immunity from prior infections. We aimed to quantify the epidemic drivers of SARS-CoV-2 dynamics in the Dominican Republic, an upper-middle income country of 10.8 million people, and assess the impact of the vaccination campaign implemented in February 2021 in saving lives and averting hospitalisations. We used an age-structured, multi-variant transmission dynamic model to characterise epidemic drivers in the Dominican Republic and explore counterfactual scenarios around vaccination coverage and population mobility. We fit the model to reported deaths, hospital bed occupancy, ICU bed occupancy and seroprevalence data until December 2021 and simulated epidemic trajectories under different counterfactual vaccination scenarios. We estimate that vaccination averted 5040 hospital admissions (95% CrI: 4750 - 5350), 1500 ICU admissions (95% CrI: 1420 - 1590) and 544 deaths (95% CrI: 488 - 606) in the first 6 months of the campaign. We also found that early vaccination with Sinovac-CoronaVac was preferable to delayed vaccination using a product with higher efficacy. We investigated the trade-off between changes in vaccination coverage and population mobility to understand how much relaxation of social distancing measures vaccination was able to 9buy9 in the later stages of a pandemic. We found that if no vaccination had occurred, an additional decrease of 10-20% in population mobility would have been required to maintain the same death and hospitalisation outcomes. We found SARS-CoV-2 transmission dynamics in the Dominican Republic were driven by substantial accumulation of immunity during the first two years of the pandemic but that, despite this, vaccination was essential in enabling a return to pre-pandemic mobility levels without incurring considerable additional morbidity and mortality.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.10.05.23296586v2" target="_blank">Modelling the impact of population mobility, post-infection immunity and vaccination on SARS-CoV-2 transmission in the Dominican Republic</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>Improving Post COVID-19 Syndrome With Hyperbaric Oxygen Treatments</strong> - <b>Conditions</b>: Post COVID-19 Condition; Post-COVID-19 Syndrome; Post-COVID Syndrome; COVID-19; Fatigue; Fatigue Syndrome, Chronic <br/><b>Interventions</b>: Device: Monoplace Hyperbaric Chamber (Class III medical device). <br/><b>Sponsors</b>: Sunnybrook Health Sciences Centre <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>Education of Medical Staff to Post Acute Covid susTained sYmptoms</strong> - <b>Conditions</b>: Post-acute COVID-19 Syndrome <br/><b>Interventions</b>: Other: Training in the management of functional disorders; Other: Reimbursement of 3 long consultations <br/><b>Sponsors</b>: Assistance Publique - Hôpitaux de Paris; ANRS, Emerging Infectious Diseases <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>Pharmacist Management of Paxlovid eVisits</strong> - <b>Conditions</b>: COVID-19; Quality of Care <br/><b>Interventions</b>: Other: Pharmacist Care; Other: AFM Pool Care <br/><b>Sponsors</b>: Kaiser Permanente <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>ACTIVATE in Public Housing</strong> - <b>Conditions</b>: Pneumonia; Influenza; Varicella Zoster; Meningitis; COVID-19; Vaccine Hesitancy <br/><b>Interventions</b>: Behavioral: Increasing Willingness and Uptake of Influenza, Pneumonia, Meningitis, HZV, and COVID-19 Vaccination <br/><b>Sponsors</b>: Charles Drew University of Medicine and Science <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>Effects of a Home-Based Exercise Intervention in Subjects With Long COVID</strong> - <b>Conditions</b>: Long COVID-19; Post-COVID-19 Syndrome <br/><b>Interventions</b>: Other: home-based concurrent exercise <br/><b>Sponsors</b>: University of Vienna <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>Early Awake Alterning Prone Positioning Combined With Non-invasive Oxygen Therapy in Patients With COVID-19.</strong> - <b>Conditions</b>: COVID-19 Pneumonia <br/><b>Interventions</b>: Other: Prone position; Other: Standard treatment <br/><b>Sponsors</b>: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran <br/><b>Terminated</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>tDCS in the Management of Post-COVID Disorders</strong> - <b>Conditions</b>: Long COVID <br/><b>Interventions</b>: Device: Transcranial Direct Current Stimulation (tDCS); Behavioral: Motor Training; Behavioral: Cognitive Training <br/><b>Sponsors</b>: Universidade Federal de Pernambuco; São Paulo State University <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>Equity Evaluation of Fact Boxes on Informed COVID-19 and Influenza Vaccination Decisions - Study Protocol</strong> - <b>Conditions</b>: COVID-19; Influenza <br/><b>Interventions</b>: Other: Fact box <br/><b>Sponsors</b>: Harding Center for Risk Literacy <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 of the Vector Vaccine GamCovidVac-M (Altered Antigenic Composition)</strong> - <b>Conditions</b>: COVID-19 <br/><b>Interventions</b>: Biological: GamCovidVac-M vector vaccine for the prevention of COVID-19 with altered antigenic composition <br/><b>Sponsors</b>: Gamaleya Research Institute of Epidemiology and Microbiology, Health Ministry of the Russian Federation <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 of the Vector Vaccine GamCovidVac for the Prevention of COVID-19 With Altered Antigenic Profile With Participation of Adult Volunteers</strong> - <b>Conditions</b>: COVID-19 <br/><b>Interventions</b>: Biological: GamCovidVac vector vaccine for the prevention of COVID-19 (with altered antigenic profile) <br/><b>Sponsors</b>: Gamaleya Research Institute of Epidemiology and Microbiology, Health Ministry of the Russian Federation <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>Exercise Interventions in Post-acute Sequelae of Covid-19</strong> - <b>Conditions</b>: COVID-19 <br/><b>Interventions</b>: Behavioral: Exercise <br/><b>Sponsors</b>: University of Virginia <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>Effects of Cacao FLAvonoids in LOng Covid Patients (FLALOC)</strong> - <b>Conditions</b>: Long Covid19; Fatigue Syndrome, Chronic <br/><b>Interventions</b>: Dietary Supplement: Flavonoids <br/><b>Sponsors</b>: Guillermo Ceballos Reyes; Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado <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>The Efficacy of the 2023-2024 Updated COVID-19 Vaccines Against COVID-19 Infection</strong> - <b>Conditions</b>: COVID-19; Vaccine-Preventable Diseases; SARS CoV 2 Infection; Upper Respiratory Tract Infection; Upper Respiratory Disease <br/><b>Interventions</b>: Biological: Novavax COVID-19 vaccine (2023-2024 formula XBB containing); Biological: Pfizer COVID-19 mRNA vaccine (2023-2024 formula XBB containing) <br/><b>Sponsors</b>: Sarang K. Yoon, DO, MOH; Westat; Novavax <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>Motivational Interviewing for Vaccine Uptake in Latinx Adults</strong> - <b>Conditions</b>: Vaccine Hesitancy <br/><b>Interventions</b>: Other: EHR alert; Behavioral: Motivational Interviewing; Behavioral: Warm hand off to nurse <br/><b>Sponsors</b>: Boston College; East Boston Neighborhood Health Center; Harvard School of Public Health (HSPH); Boston Children’s Hospital; National Institute of Nursing Research (NINR) <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>Clinical Trial to Evaluate the Safety of RQ-01 in SARS-CoV-2 Positive Subjects</strong> - <b>Conditions</b>: COVID-19; Infectious Disease; Symptomatic COVID-19 Infection Laboratory-Confirmed; SARS CoV 2 Infection <br/><b>Interventions</b>: Combination Product: RQ-001; Other: Placebo <br/><b>Sponsors</b>: Red Queen Therapeutics, Inc.; PPD <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>2-thiouridine is a broad-spectrum antiviral nucleoside analogue against positive-strand RNA viruses</strong> - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are causing significant morbidity and mortality worldwide. Furthermore, over 1 million cases of newly emerging or re-emerging viral infections, specifically dengue virus (DENV), are known to occur annually. Because no virus-specific and fully effective treatments against these or many other viruses have been approved, there is an urgent need for novel, effective therapeutic agents. Here, we identified 2-thiouridine (s2U) as…</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>Distinct motifs in the E protein are required for SARS-CoV-2 virus particle formation and lysosomal deacidification in host cells</strong> - Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is a major public health concern, but the mechanisms underlying its viral particle formation are not well understood. In this study, we established a system for producing virus-like particles (VLPs) by expressing four structural proteins that make up SARS-CoV-2 virus particles in cells and used a spike (S) protein fused with the HiBiT peptide as a marker for evaluating VLP production. Using this system, we confirmed that the E protein…</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 in vitro SARS-CoV-2 inactivation by a new quaternary ammonium compound: Bromiphen bromide</strong> - The pneumonia (COVID-19) outbreak caused by the novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which unpredictably exploded in late December of 2019 has stressed the importance of being able to control potential pathogens with the aim of limiting their spread. Although vaccines are well known as a powerful tool for ensuring public health and controlling the pandemic, disinfection and hygiene habits remain crucial to prevent infection from spreading 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>An aggregation-induced emission sensor combined with UHPLC-Q-TOF/MS for fast identification of anticoagulant active ingredients from traditional Chinese medicine</strong> - Xuebijing injection (XBJ) has a good therapeutic effect on the patients with severe coronavirus disease, but the material basis of XBJ with the anticoagulant effect to improve the coagulopathy and thromboembolism is still unclear. Herein, we developed a new strategy based on aggregation-induced emission (AIE) for monitoring thrombin activity and screening thrombin inhibitors from XBJ. The molecule AIE(603) and the thrombin substrate peptide S-2238 were formed into AIE nanoparticle (AIENP) which…</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>Targeting Cyclophilin A and CD147 to Inhibit Replication of SARS-CoV-2 and SARS-CoV-2-Induced Inflammation</strong> - Identification and development of effective therapeutics for COVID-19 are still urgently needed. The CD147/Spike interaction is involved in the SARS-CoV-2 invasion process, in addition to ACE2. Cyclophilin A (CyPA), the extracellular ligand of CD147, has been found to play a role in the infection and replication of coronaviruses. In this study, our results show that CyPA inhibitors such as Cyclosporine A (CsA) and STG-175 can suppress the intracellular replication of SARS-CoV-2 by inhibiting 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>Multifunctional natural derived carbon quantum dots from Withania somnifera (L.) - Antiviral activities against SARS-CoV-2 pseudoviron</strong> - Natural carbon dots (NCQDs) are expediently significant in the photo-, nano- and biomedical spheres owing to their facile synthesis, optical and physicochemical attributes. In the present study, three NCQDs are prepared and optimized from Withania somnifera (ASH) by one-step hydrothermal (bottom-up) method: HASHP (without dopant), nitrogen doped HASHNH(3) (surface passivation using ammonia) and HASHEDA (surface passivation with ethylenediamine). The HR-TEM images reveal that HASHP, HASNH(3),…</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>4-Octyl itaconate reduces influenza A replication by targeting the nuclear export protein CRM1</strong> - In recent years, especially since the outbreak of the severe acute respiratory syndrome coronavirus 2 pandemic, the cell-permeable itaconate derivative 4-octyl itaconate (4-OI) has gained traction as a potential antiviral agent. Here, we demonstrate that 4-OI inhibits replication of multiple influenza A viruses (IAV) by restricting nuclear export of viral ribonucleoproteins, a key step in the IAV replication cycle. This nuclear retention is achieved by deactivation and subsequent degradation of…</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>Exploration of phenolic acid derivatives as inhibitors of SARS-CoV-2 main protease and receptor binding domain: potential candidates for anti-SARS-CoV-2 therapy</strong> - Severe acute respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) is the etiological virus of Coronavirus Disease 2019 (COVID-19) which has been a public health concern due to its high morbidity and high mortality. Hence, the search for drugs that incapacitate the virus via inhibition of vital proteins in its life cycle is ongoing due to the paucity of drugs in clinical use against the virus. Consequently, this study was aimed at evaluating the potentials of natural phenolics against the Main…</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>The Apolipoprotein E neutralizing antibody inhibits SARS-CoV-2 infection by blocking cellular entry of lipoviral particles</strong> - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal agent for coronavirus disease 2019 (COVID-19). Although vaccines have helped to prevent uncontrolled viral spreading, our understanding of the fundamental biology of SARS-CoV-2 infection remains insufficient, which hinders effective therapeutic development. Here, we found that Apolipoprotein E (ApoE), a lipid binding protein, is hijacked by SARS-CoV-2 for infection. Preincubation of SARS-CoV-2 with a neutralizing antibody…</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>Unnatural Endotype B PPAPs as Novel Compounds with Activity against <em>Mycobacterium tuberculosis</em></strong> - Pre-SARS-CoV-2, tuberculosis was the leading cause of death by a single pathogen. Repetitive exposure of Mycobacterium tuberculosis(Mtb) supported the development of multidrug- and extensively drug-resistant strains, demanding novel drugs. Hyperforin, a natural type A polyprenylated polycyclic acylphloroglucinol from St. John’s wort, exhibits antidepressant and antibacterial effects also against Mtb. Yet, Hyperforin’s instability limits the utility in clinical practice. Here, we present photo-…</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 reconstitution of SARS-CoV-2 Nsp1-induced mRNA cleavage reveals the key roles of the N-terminal domain of Nsp1 and the RRM domain of eIF3g</strong> - SARS CoV-2 nonstructural protein 1 (Nsp1) is the major pathogenesis factor that inhibits host translation using a dual strategy of impairing initiation and inducing endonucleolytic cleavage of cellular mRNAs. To investigate the mechanism of cleavage, we reconstituted it in vitro on β-globin, EMCV IRES, and CrPV IRES mRNAs that use unrelated initiation mechanisms. In all instances, cleavage required Nsp1 and only canonical translational components (40S subunits and initiation factors), arguing…</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>Lipid droplets in Zika neuroinfection: Potential targets for intervention?</strong> - Lipid droplets (LD) are evolutionarily conserved lipid-enriched organelles with a diverse array of cell- and stimulus-regulated proteins. Accumulating evidence demonstrates that intracellular pathogens exploit LD as energy sources, replication sites, and part of the mechanisms of immune evasion. Nevertheless, LD can also favor the host as part of the immune and inflammatory response to pathogens. The functions of LD in the central nervous system have gained great interest due to their presence…</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>Tetherin antagonism by SARS-CoV-2 ORF3a and spike protein enhances virus release</strong> - The antiviral restriction factor, tetherin, blocks the release of several different families of enveloped viruses, including the Coronaviridae. Tetherin is an interferon-induced protein that forms parallel homodimers between the host cell and viral particles, linking viruses to the surface of infected cells and inhibiting their release. We demonstrate that SARS-CoV-2 infection causes tetherin downregulation and that tetherin depletion from cells enhances SARS-CoV-2 viral titres. We investigate…</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>Characterization of pre-existing anti-PEG and anti-AGAL antibodies towards PRX-102 in patients with Fabry disease</strong> - Polyethylene glycol (PEG)ylated drugs are used for medical treatment, since PEGylation either decreases drug clearance or/and shields the protein from undesirable immunogenicity. PEGylation was implemented in a new enzyme replacement therapy for Fabry disease (FD), pegunigalsidase-alfa (PRX-102). However, exposure to PEG via life-style products and vaccination can result in the formation of anti-PEG antibodies. We demonstrate the de novo formation of functional anti-PEG antibodies in a healthy…</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>W254 in furin functions as a molecular gate promoting anti-viral drug binding: Elucidation of putative drug tunneling and docking by non-equilibrium molecular dynamics</strong> - Furins are serine endoproteases that process precursor proteins into their biologically active forms, and they play essential roles in normal metabolism and disease presentation, including promoting expression of bacterial virulence factors and viral pathogenesis. Thus, furins represent vital targets for development of antimicrobial and antiviral therapeutics. Recent experimental evidence indicated that dichlorophenyl (DCP)-pyridine “BOS” drugs (e.g., BOS-318) competitively inhibit human furin…</p></li>
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</ul>
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<h1 data-aos="fade-right" id="from-patent-search">From Patent Search</h1>
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