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188 lines
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<title>22 April, 2021</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>Pathways to regional housing recovery from COVID-19</strong> -
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<div>
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This research examines the consequences of COVID-19 for households in regional Australia, and considers that post-pandemic recovery models designed for large cities such as Sydney or Melbourne may not work in regional areas or less-urbanised states like South Australia or Tasmania.
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<div class="article-link article-html-link">
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🖺 Full Text HTML: <a href="https://osf.io/preprints/socarxiv/rbx49/" target="_blank">Pathways to regional housing recovery from COVID-19</a>
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<li><strong>Associations between mobility and socio-economic indicators vary across the timeline of the Covid-19 pandemic</strong> -
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Covid-19 interventions are greatly affecting patterns of human mobility. Changes in mobility during Covid-19 have differed across socio-economic gradients during the first wave. We use fine-scale network mobility data in Ontario, Canada to study the association between three different mobility measures and four socio-economic indicators throughout the first and second wave of Covid-19 (January to December 2020). We find strong associations between mobility and the socio-economic indicators and that relationships between mobility and other socio-economic indicators vary over time. We further demonstrate that understanding how mobility has changed in response to Covid-19 varies considerably depending on how mobility is measured. Our findings have important implications for understanding how mobility data should be used to study interventions across space and time. Our results support that Covid-19 non-pharmaceutical interventions have resulted in geographically disparate responses to mobility and quantifying mobility changes at fine geographical scales is crucial to understanding the impacts of Covid-19.
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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://osf.io/preprints/socarxiv/tca34/" target="_blank">Associations between mobility and socio-economic indicators vary across the timeline of the Covid-19 pandemic</a>
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</div></li>
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<li><strong>FACT subunit SUPT16H associates with BRD4 and contributes to silencing of antiviral interferon signaling</strong> -
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<div>
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FACT (FAcilitates Chromatin Transcription) is a heterodimeric protein complex composed of SUPT16H and SSRP1, and a histone chaperone participating in chromatin remodeling during gene transcription. FACT complex is profoundly regulated, and contributes to both gene activation and suppression. Here we reported that SUPT16H, a subunit of FACT, is acetylated at lysine 674 (K674) of middle domain (MD), which involves TIP60 histone acetyltransferase. Such acetylation of SUPT16H is recognized by bromodomain protein BRD4, which promotes protein stability of SUPT16H. We further demonstrated that SUPT16H-BRD4 associates with histone modification enzymes (EZH2, HDAC1) and affects histone marks (H3K9me3, H3K27me3 and H3ac). BRD4 is known to profoundly regulate interferon (IFN) signaling, while such function of SUPT16H has never been explored. Surprisingly, our results revealed that SUPT16H genetic knockdown via RNAi or pharmacological inhibition by using its inhibitor, curaxin 137 (CBL0137), results in the induction of IFNs and interferon-stimulated genes (ISGs). Through this mechanism, CBL0137 is shown to efficiently inhibit infection of multiple viruses, including Zika, influenza, and SARS-CoV-2. Furthermore, we demonstrated that CBL0137 also causes the remarkable activation of IFN signaling in natural killer (NK) cells, which promotes the NK-mediated killing of virus-infected cells in a co-culture system using human primary NK cells. Overall, our studies unraveled the previously un-appreciated role of FACT complex in regulating IFN signaling in both epithelial and NK cells, and also proposed the novel application of CBL0137 to treat viral infections.
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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/10.1101/2021.04.21.440833v1" target="_blank">FACT subunit SUPT16H associates with BRD4 and contributes to silencing of antiviral interferon signaling</a>
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</div></li>
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<li><strong>Eicosanoid signaling as a therapeutic target in middle-aged mice with severe COVID-19</strong> -
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<div>
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Coronavirus disease 2019 (COVID-19) is especially severe in aged populations. Resolution of the COVID-19 pandemic has been advanced by the recent development of SARS-CoV-2 vaccines, but vaccine efficacy is partly compromised by the recent emergence of SARS-CoV-2 variants with enhanced transmissibility. The emergence of these variants emphasizes the need for further development of anti-SARS-CoV-2 therapies, especially in aged populations. Here, we describe the isolation of a new set of highly virulent mouse-adapted viruses and use them to test a novel therapeutic drug useful in infections of aged animals. Initially, we show that many of the mutations observed in SARS-CoV-2 during mouse adaptation (at positions 417, 484, 501 of the spike protein) also arise in humans in variants of concern (VOC). Their appearance during mouse adaptation indicates that immune pressure is not required for their selection. Similar to the human infection, aged mice infected with mouse-adapted SARS-CoV-2 develop more severe disease than young mice. In murine SARS, in which severity is also age-dependent, we showed that elevated levels of an eicosanoid, prostaglandin D2 (PGD2) and of a phospholipase, PLA2G2D, contributed to poor outcomes in aged mice. Using our virulent mouse-adapted SARS-CoV-2, we show that infection of middle-aged mice lacking expression of DP1, a PGD2 receptor, or PLA2G2D are protected from severe disease. Further, treatment with a DP1 antagonist, asapiprant, protected aged mice from a lethal infection. DP1 antagonism is one of the first interventions in SARS-CoV-2-infected animals that specifically protects aged animals, and demonstrates that the PLA2G2D-PGD2/DP1 pathway is a useful target for therapeutic interventions.
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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/10.1101/2021.04.20.440676v1" target="_blank">Eicosanoid signaling as a therapeutic target in middle-aged mice with severe COVID-19</a>
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</div></li>
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<li><strong>MARCH8 targets cytoplasmic lysine residues of various viral envelope glycoproteins</strong> -
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<div>
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The host transmembrane protein MARCH8 is a RING finger E3 ubiquitin ligase that downregulates various host transmembrane proteins, such as MHC-II. We have recently reported that MARCH8 expression in virus-producing cells impairs viral infectivity by reducing virion incorporation of not only HIV-1 envelope glycoproteins but also vesicular stomatitis virus G-glycoprotein through two different pathways. However, the MARCH8 inhibition spectrum remains largely unknown. Here, we investigate the antiviral spectrum of MARCH8 using HIV-1 pseudotyped with a variety of viral envelope glycoproteins. Pseudotyping experiments revealed that viral envelopes derived from the rhabdovirus, arenavirus, coronavirus, and togavirus (alphavirus) families were sensitive to MARCH8-mediated inhibition. Lysine mutations at the cytoplasmic tails of rabies virus-G, lymphocytic choriomeningitis virus glycoproteins, SARS-CoV and SARS-CoV-2 spike proteins, and Chikungunya virus and Ross River virus E2 proteins conferred resistance to MARCH8. Immunofluorescence showed impaired downregulation of the mutants of these viral envelopes by MARCH8, followed by lysosomal degradation, suggesting that MARCH8-mediated ubiquitination leads to intracellular degradation of these envelopes. Indeed, rabies virus-G and Chikungunya virus E2 proteins proved to be clearly ubiquitinated. We conclude that MARCH8 has inhibitory activity on a variety of viral envelope glycoproteins whose cytoplasmic lysine residues are targeted by this antiviral factor.
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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/10.1101/2021.04.20.440588v1" target="_blank">MARCH8 targets cytoplasmic lysine residues of various viral envelope glycoproteins</a>
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</div></li>
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<li><strong>Rapid and Efficient Inactivation of SARS-CoV-2 from Surfaces using UVC Light Emitting Diode Device</strong> -
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<div>
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Efforts are underway to develop countermeasures to prevent the environmental spread of COVID-19 pandemic caused by SARS-CoV-2. Physical decontamination methods like Ultraviolet radiation has shown to be promising. Here, we describe a novel device emitting ultraviolet C radiation (UVC), called NuvaWave, to rapidly and efficiently inactivate SARS-CoV-2. SARS-CoV-2 was dried on a chambered glass slides and introduced in a NuvaWave robotic testing unit. The robot simulated waving NuvaWave over the virus at a pre-determined UVC radiation dose of 1, 2, 4 and 8 seconds. Post-UVC exposure, virus was recovered and titered by plaque assay in Vero E6 cells. We observed that relative control (no UVC exposure), exposure of the virus to UVC for one or two seconds resulted in a >2.9 and 3.8 log10 reduction in viral titers, respectively. Exposure of the virus to UVC for four or eight seconds resulted in a reduction of greater than 4.7-log10 reduction in viral titers. The NuvaWave device inactivates SARS-CoV-2 on surfaces to below the limit of detection within one to four seconds of UVC irradiation. This device can be deployed to rapidly disinfect surfaces from SARS-CoV-2, and to assist in mitigating its spread in a variety of settings.
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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/10.1101/2021.04.20.440654v1" target="_blank">Rapid and Efficient Inactivation of SARS-CoV-2 from Surfaces using UVC Light Emitting Diode Device</a>
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</div></li>
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<li><strong>Characterization of the Second Wave of COVID-19 in India</strong> -
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Background: The second wave of COVID-19 is affecting most of the world. The scenario is very grim in India where the daily count on April 15, 2021 itself is double of the first peak. The epidemic evolution there is quite complex due to regional inhomogeneities. In this paper, we characterize the virus spread in the ongoing second wave in India, as well as study the dynamical evolution of epidemic from the beginning of the pandemic. Methods: Variations in the effective reproduction number (Rt) in India are taken as a quantifiable measure of the virus transmissibility and are compared with those of other countries where the second wave is already over. Further, characteristics of COVID-19 spread are analyzed for Indian states by estimating test positivity and case fatality rates. Finally, forecasts and actionable inputs are provided based on mathematical and epidemiological models. Results: Effective reproduction number for almost every state in India has value greater than 1 indicating the presence of the second wave. An exponential fit on recent data indicates that the infection rate is much higher than the first wave however the case fatality rate is lower. Preliminary estimates with the SIR model suggest the peak for the second wave to occur in mid-May 2021 with daily count exceeding 0.35 million. Conclusions: The spread of the second wave is much faster than the first wave. Hence, quick and effective administrative intervention is needed to arrest the rapid growth of the epidemic.
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</p>
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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.medrxiv.org/content/10.1101/2021.04.17.21255665v1" target="_blank">Characterization of the Second Wave of COVID-19 in India</a>
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<li><strong>Human Taste Cells Express ACE2: A Portal for SARS-CoV-2 Infection</strong> -
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<div>
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Loss and changes in taste and smell are well-reported symptoms of SARS-CoV-2 infection. The virus targets cells for entry by high affinity binding of its spike protein to cell-surface angiotensin-converting enzyme- 2 (ACE2). It was not known whether ACE2 is expressed on taste receptor cells (TRCs) nor if TRCs are infected directly. Using an in-situ hybridization (ISH) probe and an antibody specific to ACE2, it seems evident that ACE2 is present on a subpopulation of specialized TRCs, namely, PLC{beta}2 positive, Type II cells in taste buds in taste papillae. Fungiform papillae (FP) of a SARS-CoV-2+ patient exhibiting symptoms of COVID-19, including taste changes, were biopsied. Based on ISH, replicating SARS-CoV-2 was present in Type II cells of this patient. Therefore, taste Type II cells provide a portal for viral entry that predicts vulnerabilities to SARS-CoV-2 in the oral cavity. The continuity and cell turnover of the FP taste stem cell layer of the patient were disrupted during infection and had not fully recovered 6 weeks post symptom onset. Another patient suffering post-COVID-19 taste disturbances also had disrupted stem cells. These results indicate that a COVID-19 patient who experienced taste changes had replicating virus in their taste buds and that SARS-CoV-2 infection results in deficient stem cell turnover needed for differentiation into TRCs.
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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/10.1101/2021.04.21.440680v1" target="_blank">Human Taste Cells Express ACE2: A Portal for SARS-CoV-2 Infection</a>
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</div></li>
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<li><strong>Deep time course proteomics of SARS-CoV and SARS-CoV-2-infected human lung epithelial cells (Calu-3) reveals strong induction of interferon-stimulated gene (ISG) expression by SARS-CoV-2 in contrast to SARS-CoV</strong> -
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<div>
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SARS-CoV and SARS-CoV-2 infections are characterized by remarkable differences, including contagiosity and case fatality rate. The underlying mechanisms are not well understood, illustrating major knowledge gaps of coronavirus biology. In this study, protein expression of SARS-CoV- and SARS-CoV-2-infected human lung epithelial cell line Calu-3 was analysed using data-independent acquisition mass spectrometry (DIA-MS). This resulted in the so far most comprehensive map of infection-related proteome-wide expression changes in human cells covering the quantification of 7478 proteins across 4 time points. Most notably, the activation of interferon type-I response was observed, which surprisingly is absent in other recent proteome studies, but is known to occur in SARS-CoV-2-infected patients. The data reveal that SARS-CoV-2 triggers interferon-stimulated gene (ISG) expression much stronger than SARS-CoV, which reflects the already described differences in interferon sensitivity. Potentially, this may be caused by the enhanced expression of viral M protein of SARS-CoV in comparison to SARS-CoV-2, which is a known inhibitor of type I interferon expression. This study expands the knowledge on the host response to SARS-CoV-2 infections on a global scale using an infection model, which seems to be well suited to analyse innate immunity.
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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/10.1101/2021.04.21.440783v1" target="_blank">Deep time course proteomics of SARS-CoV and SARS-CoV-2-infected human lung epithelial cells (Calu-3) reveals strong induction of interferon-stimulated gene (ISG) expression by SARS-CoV-2 in contrast to SARS-CoV</a>
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</div></li>
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<li><strong>Immune Correlates of Protection by mRNA-1273 Immunization against SARS-CoV-2 Infection in Nonhuman Primates</strong> -
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<div>
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Immune correlates of protection can be used as surrogate endpoints for vaccine efficacy. The nonhuman primate (NHP) model of SARS-CoV-2 infection replicates key features of human infection and may be used to define immune correlates of protection following vaccination. Here, NHP received either no vaccine or doses ranging from 0.3-100 micrograms of mRNA-1273, a mRNA vaccine encoding the prefusion-stabilized SARS-CoV-2 spike (S-2P) protein encapsulated in a lipid nanoparticle. mRNA-1273 vaccination elicited robust circulating and mucosal antibody responses in a dose-dependent manner. Viral replication was significantly reduced in bronchoalveolar lavages and nasal swabs following SARS-CoV-2 challenge in vaccinated animals and was most strongly correlated with levels of anti-S antibody binding and neutralizing activity. Consistent with antibodies being a correlate of protection, passive transfer of vaccine-induced IgG to naive hamsters was sufficient to mediate protection. Taken together, these data show that mRNA-1273 vaccine-induced humoral immune responses are a mechanistic correlate of protection against SARS-CoV-2 infection in NHP.
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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/10.1101/2021.04.20.440647v1" target="_blank">Immune Correlates of Protection by mRNA-1273 Immunization against SARS-CoV-2 Infection in Nonhuman Primates</a>
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<li><strong>Comparative Analysis of Emerging B.1.1.7+E484K SARS-CoV-2 isolates from Pennsylvania</strong> -
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<div>
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Rapid whole genome sequencing of SARS-CoV-2 has presented the ability to detect new emerging variants of concern in near real time. Here we report the genome of a virus isolated in Pennsylvania in March 2021 that was identified as lineage B.1.1.7 (VOC-202012/01) that also harbors the E484K spike mutation, which has been shown to promote escape from neutralizing antibodies in vitro. We compare this sequence to the only 5 other B.1.1.7+E484K genomes from Pennsylvania, all of which were isolated in mid March. Beginning in February 2021, only a small number (n=60) of isolates with this profile have been detected in the US, and only a total of 253 have been reported globally (first in the UK in December 2020). Comparative genomics of all currently available high coverage B.1.1.7+E484K genomes (n=235) available on GISAID suggested the existence of 7 distinct groups or clonal complexes (CC; as defined by GNUVID) bearing the E484K mutation raising the possibility of 7 independent acquisitions of the E484K spike mutation in each background. Phylogenetic analysis suggested the presence of at least 3 distinct clades of B.1.1.7+E484K circulating in the US, with the Pennsylvanian isolates belonging to two distinct clades. Increased genomic surveillance will be crucial for detection of emerging variants of concern that can escape natural and vaccine induced immunity.
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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/10.1101/2021.04.21.440801v1" target="_blank">Comparative Analysis of Emerging B.1.1.7+E484K SARS-CoV-2 isolates from Pennsylvania</a>
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<li><strong>GIVE Statistic for Goodness of Fit in Instrumental Variables Models with Application to COVID Data</strong> -
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Since COVID-19 outbreak, scientists have been interested to know whether there is any impact of the Bacillus Calmette-Guerin (BCG) vaccine against COVID-19 mortality or not. It becomes more relevant as a large population in the world may have latent tuberculosis infection (LTBI), for which a person may not have active tuberculosis but persistent immune responses stimulated by Mycobacterium tuberculosis antigens, and that means, both LTBI and BCG generate immunity against COVID- 19. In order to understand the relationship between LTBI and COVID-19 mortality, this article proposes a measure of goodness of fit, viz., Goodness of Instrumental Variable Estimates (GIVE) statistic, of a model obtained by Instrumental Variables estimation. The GIVE helps in finding the appropriate choice of instruments, which provides a better fitted model. In the course of study, the large sample properties of the GIVE statistic are investigated. As indicated before, the COVID-19 data is analysed using the GIVE statistic, and moreover, simulation studies are also conducted to show the usefulness of the GIVE statistic.
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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/10.1101/2021.04.18.440376v1" target="_blank">GIVE Statistic for Goodness of Fit in Instrumental Variables Models with Application to COVID Data</a>
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</div></li>
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<li><strong>Recognition of Divergent Viral Substrates by the SARS-CoV-2 Main Protease</strong> -
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<div>
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The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease (COVID-19), is an ideal target for pharmaceutical inhibition. It is required for infection, it cleaves the viral polyprotein at multiple sites, and it is conserved among coronaviruses and distinct from human proteases. We present crystal structures of SARS-CoV-2 Mpro bound to two viral substrate peptides. The structures show how Mpro recognizes substrates and how the peptide sequence can dictate catalytic efficiency by influencing the position of the scissile bond. One peptide, constituting the junction between viral non-structural proteins 8 and 9 (nsp8/9), has P1’ and P2’ residues that are unique among SARS-CoV-2 cleavage sites but conserved among nsp8/9 junctions in coronaviruses. Mpro cleaves nsp8/9 inefficiently, and amino acid substitutions at P1’ or P2’ can enhance catalysis. Visualization of Mpro with intact substrates provides new templates for antiviral drug design and suggests that the coronavirus lifecycle selects for finely tuned substrate-dependent catalytic parameters.
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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/10.1101/2021.04.20.440716v1" target="_blank">Recognition of Divergent Viral Substrates by the SARS-CoV-2 Main Protease</a>
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<li><strong>Prediction of COVID-19 cases during Tokyo’s Olympic and Paralympic Games</strong> -
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
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Tokyo9s Olympic and Paralympic Games set to begin in late July 2021 without spectators from abroad, but vaccine rollout has been slow in Japan compared to other developed countries. In this study, COVID-19 epidemic curve in Tokyo is developed based on weekly reported data from January 23, 2020 until April 16, 2021. The maximum daily number of the infected cases in Tokyo in August 2021 would be 7,991 if the current pace of vaccinations (1/1,000 per day). This daily number is greater than the highest daily cases (2,447) recorded on January 7, 2021. However, if the rollout pace could be doubled (1/500 per day), the peak daily new cases would be 4,470 in August. If it could be quadrupled (1/250 per day), the peak would be noted at 2,128 in July and the highest number in August would be 1,977. If vaccine rollout could not be enhanced, the cancellation might be an acceptable decision, since health is the most precious to our Olympians.
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</p>
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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/10.1101/2021.04.21.21255676v1" target="_blank">Prediction of COVID-19 cases during Tokyo’s Olympic and Paralympic Games</a>
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<li><strong>Results Availability and Timeliness of Registered COVID-19 Clinical Trials: A Cross-Sectional Study</strong> -
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
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Objective: To examine how and when the results of COVID-19 clinical trials are disseminated Design: Cross-sectional bibliographic study Setting: The COVID-19 clinical trial landscape Participants: 285 registered interventional clinical trials for the treatment and prevention of COVID-19 completed by 30 June 2020 Main outcome measures: Overall reporting and reporting by dissemination route (i.e., by journal article, preprint, or results on a registry); time to reporting by dissemination route. Results: Following automated and manual searches of the COVID-19 literature, we located 41 trials (14%) with results spread across 47 individual results publications published by 15 August 2020. The most common dissemination route was preprints (n = 25) followed by journal articles (n = 18), and results on a registry (n = 2). Of these, four trials were available as both a preprint and journal publication. The cumulative incidence of any reporting surpassed 20% at 119 days from completion. Sensitivity analyses using alternate dates available and definitions of results did not appreciably change the reporting percentage. Expanding minimum follow-up time to 3 months increased the overall reporting percentage to 19%. Conclusion: COVID-19 trials completed during the first six months of the pandemic did not consistently yield rapid results in the literature or on clinical trial registries. Our findings suggest that the COVID-19 response may be seeing quicker results disclosure compared to non-emergency conditions. Issues with the reliability and timeliness of trial registration data may impact our estimates. Ensuring registry data is accurate should be a priority for the research community during a pandemic. Data collection is underway for Phase 2 of the DIRECCT study expanding our trial population to those completed anytime in 2020.
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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/10.1101/2021.04.07.21255071v2" target="_blank">Results Availability and Timeliness of Registered COVID-19 Clinical Trials: A Cross-Sectional 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>Oestrogen Treatment for COVID-19 Symptoms</strong> - <b>Condition</b>: COVID-19<br/><b>Intervention</b>: Drug: Transdermal estradiol gel<br/><b>Sponsors</b>: Hamad Medical Corporation; Laboratoires Besins International<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 Study in the Treatment of Patients With Moderate Course of COVID-19</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Drug: COVID-globulin; Drug: Placebo<br/><b>Sponsor</b>: Microgen<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 Effects of a Multi-factorial Rehabilitation Program for Healthcare Workers Suffering From Post-COVID-19 Fatigue Syndrome</strong> - <b>Condition</b>: COVID-19<br/><b>Intervention</b>: Other: Exercise<br/><b>Sponsor</b>: Medical 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>Omega-3 Oil Use in COVID-19 Patients in Qatar</strong> - <b>Condition</b>: COVID-19<br/><b>Intervention</b>: Drug: Omega 3 fatty acid<br/><b>Sponsor</b>: Hamad Medical Corporation<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>Safety and Immunogenicity of the Inactivated Koçak-19 Inaktif Adjuvanlı COVID-19 Vaccine Compared to Placebo</strong> - <b>Condition</b>: COVID-19 Vaccine<br/><b>Interventions</b>: Biological: Koçak-19 Inaktif Adjuvanlı COVID-19 Vaccine 4 µg/0.5 ml Vaccine; Biological: Koçak-19 Inaktif Adjuvanlı COVID-19 Vaccine 6 µg/0.5 ml Vaccine; Biological: Placebo<br/><b>Sponsor</b>: Kocak Farma<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 of Intravenous Ampion in Adult COVID-19 Patients Requiring Supplemental Oxygen</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: Ampion; Other: Saline<br/><b>Sponsor</b>: Ampio Pharmaceuticals. 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>A Study to Evaluate the Efficacy, Safety and Immunogenicity of SARS-CoV-2 Vaccine (Vero Cells), Inactivated in Healthy Adults Aged 18 Years and Older (COVID-19)</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: SARS-CoV-2 Vaccine (Vero Cells), Inactivated; Biological: Placebo<br/><b>Sponsors</b>: Shenzhen Kangtai Biological Products Co., LTD; Beijing Minhai Biotechnology 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>Efficacy and Safety of Oral Immunotherapy With GcMAF in Hospitalized Patients With COVID-19 Pneumonia</strong> - <b>Condition</b>: COVID-19 Pneumonia<br/><b>Intervention</b>: Dietary Supplement: Saisei Maf capsules<br/><b>Sponsor</b>: Dr. Spadera Lucrezia<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>Safety and Efficacy of Hyperbaric Oxygen Therapy for Long COVID Syndrome</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Drug: Hyperbaric oxygen; Procedure: Sham treatment<br/><b>Sponsors</b>: Karolinska University Hospital; Karolinska Institutet; Karolinska Trial Alliance<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 Phase 2 Study to Evaluate Biomarker Change, Efficacy, Pharmacokinetics, Safety and Tolerability of Telacebec (Q203) in Covid-19 Patients</strong> - <b>Condition</b>: COVID-19 Virus Infection<br/><b>Interventions</b>: Drug: Telacebec; Drug: COVID-19 Standard of care<br/><b>Sponsor</b>: Qurient 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>Virgin Coconut Oil as Adjunctive Therapy for Hospitalized COVID-19 Patients</strong> - <b>Condition</b>: Covid19<br/><b>Intervention</b>: Drug: Virgin Coconut Oil<br/><b>Sponsors</b>: University of the Philippines; Philippine Coconut Authority; Philippine Council for Health Research & Development<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>Rehabilitation for Patients With Persistent Symptoms Post COVID-19</strong> - <b>Condition</b>: Covid19<br/><b>Intervention</b>: Other: Concentrated rehabilitation for patients with persistent symptoms post COVID-19<br/><b>Sponsors</b>: Western Norway University of Applied Sciences; Helse-Bergen HF<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>Safety and Immunogenicity of Demi-dose of Two Covid-19 mRNA Vaccines in Healthy Population</strong> - <b>Condition</b>: Covid19<br/><b>Intervention</b>: Diagnostic Test: immunogenicity after first and second dose<br/><b>Sponsors</b>: Sciensano; Mensura EDPB; Institute of Tropical Medicine, Belgium; Erasme University Hospital<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>Efficacy of FES Cycling After a Severe Form of COVID-19</strong> - <b>Condition</b>: Person With a Severe Form of COVID-19 That Caused an Acute Distress Respiratory Syndrome Treated by Mechanical Ventilation in Intensive Care Unit<br/><b>Interventions</b>: Behavioral: Physical therapy that include a standardized cycling training with functional electrical stimulation; Behavioral: Physical therapy that include a standardized cycling training with no additional functional electrical stimulation<br/><b>Sponsor</b>: Hospices Civils de Lyon<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 Phase III Clinical Study of a SARS-CoV-2 Messenger Ribonucleic Acid (mRNA) Vaccine Candidate Against COVID-19 in Population Aged 18 Years and Above</strong> - <b>Conditions</b>: COVID-19; SARS-CoV-2<br/><b>Interventions</b>: Biological: SARS-CoV-2 mRNA Vaccine; Biological: Placebo<br/><b>Sponsors</b>: Walvax Biotechnology Co., Ltd.; Abogen Biosciences Co., Ltd.; Yuxi Walvax Biotechnology Co., Ltd.<br/><b>Not yet 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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<ul>
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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>Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers: potential allies in the COVID-19 pandemic instead of a threat?</strong> - Angiotensin-converting enzyme 2 (ACE2) is the leading player of the protective renin-angiotensin system (RAS) pathway but also the entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). RAS inhibitors seemed to interfere with the ACE2 receptor, and their safety was addressed in COVID-19 patients. Pedrosa et al. (Clin. Sci. (Lond.) (2021), 135, 465-481) showed in rats that captopril and candesartan up-regulated ACE2 expression and the protective RAS pathway in lung…</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 antiviral activity of the anti-HCV drugs daclatasvir and sofosbuvir against SARS-CoV-2, the aetiological agent of COVID-19</strong> - CONCLUSIONS: Daclatasvir, alone or in combination with sofosbuvir, at higher doses than used against HCV, may be further fostered as an anti-COVID-19 therapy.</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 international, interlaboratory ring trial confirms the feasibility of an open-source, extraction-less “direct” RT-qPCR method for reliable detection of SARS-CoV-2 RNA in clinical samples</strong> - Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) is used worldwide to test and trace the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). “Extraction-less” or “direct” real time-reverse transcription polymerase chain reaction (RT-PCR) is an open-access qualitative method for SARS-CoV-2 detection from nasopharyngeal or oral pharyngeal samples with the potential to generate actionable data more quickly, at a lower cost, and with fewer experimental…</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>Rapalogs downmodulate intrinsic immunity and promote cell entry of SARS-CoV-2</strong> - Infection by SARS-CoV-2 generally causes mild symptoms but can lead to severe disease and death in certain populations, including the immunocompromised. Drug repurposing efforts are underway to identify compounds that interfere with SARS-CoV-2 replication or the immunopathology it can elicit. Rapamycin is among those being currently tested in clinical trials for impacts on COVID-19 severity. While rapamycin and rapamycin analogs (rapalogs) are FDA-approved for use as mTOR inhibitors in multiple…</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>CRISPR/Cas-New Molecular Scissors in Diagnostics and Therapeutics of COVID-19</strong> - The current pandemic of COVID-19, with its climbing number of cases and deaths, has us searching for tools for rapid, reliable, and affordable methods of detection on one hand, and novel, improved therapeutic strategies on the other. The currently employed RT-PCR method, despite its all-encompassing utility, has its shortcomings. Newer diagnostic tools, based on the Clustered Regularly Interspaced Short Palindromic Repeats/Cas(CRISPR-Cas) system, with its better diagnostic accuracy measures,…</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>Structurally modified compounds of hydroxychloroquine, remdesivir and tetrahydrocannabinol against main protease of SARS-CoV-2, a possible hope for COVID-19: Docking and Molecular Dynamics Simulation studies</strong> - Now a days, more than 200 countries faces the health crisis due to epidemiological disease COVID-19 caused by SARS-CoV-2 virus. It will cause a very high impact on world’s economy and global health sector. Earlier the structure of main protease (M^(pro)) protein was deposited in the RCSB protein repository. Hydroxychloroquine (HCQ) and remdesivir were found to effective in treatment of COVID-19 patients. Here we have performed docking and molecule dynamic (MD) simulation study of HCQ 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>SARS-CoV-2 spike protein dictates syncytium-mediated lymphocyte elimination</strong> - The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is highly contagious and causes lymphocytopenia, but the underlying mechanisms are poorly understood. We demonstrate here that heterotypic cell-in-cell structures with lymphocytes inside multinucleate syncytia are prevalent in the lung tissues of coronavirus disease 2019 (COVID-19) patients. These unique cellular structures are a direct result of SARS-CoV-2 infection, as the expression of the SARS-CoV-2 spike glycoprotein is…</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 in silico mechanism of hVKOR interaction with acetaminophen and its metabolite, as well as N-acetyl cysteine: caution on application in COVID-19 patients</strong> - Acetaminophen and N-acetyl cysteine (NAC) are being used as supportive care in patients suffering from coronavirus disease 2019 (COVID-19). The coagulopathy and cerebral hemorrhage have been recently reported in these patients. Prolonged acetaminophen use increases the international normalized ratio (INR) and the risk of bleeding among patients taking anti-coagulants. Inhibition of vitamin K epoxide reductase (VKOR) by acetaminophen and NAC in chronic applications has been reported, 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>Successful treatment of vaccine-induced prothrombotic immune thrombocytopenia (VIPIT)</strong> - Cases of unusual thrombosis and thrombocytopenia after administration of the ChAdOx1 nCoV-19 vaccine (AstraZeneca) have been reported. The term vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) was coined to reflect this new phenomenon. In vitro experiments with VIPIT patient sera indicated that high dose intravenous immunoglobulins (IVIG) competitively inhibit the platelet activating properties of ChAdOx1 nCoV-19 vaccine induced antibodies. Here, we report a case of a 62-year-old…</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>Antibody Affinity Governs the Inhibition of SARS-CoV-2 Spike/ACE2 Binding in Patient Serum</strong> - The humoral immune response plays a key role in suppressing the pathogenesis of SARS-CoV-2. The molecular determinants underlying the neutralization of the virus remain, however, incompletely understood. Here, we show that the ability of antibodies to disrupt the binding of the viral spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor on the cell, the key molecular event initiating SARS-CoV-2 entry into host cells, is controlled by the affinity of these antibodies to the 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>A crystallography-based investigation of weak interactions for drug design against COVID-19</strong> - Interactions between proteins and small molecules play important roles in the inhibition of protein function. However, a lack of proper knowledge about non-covalent interactions can act as a barrier towards gaining a complete understanding of the factors that control these associations. To find effective molecules for COVID-19 inhibition, we have quantitatively investigated 143 X-ray crystal structures of the SARS-CoV-2 M^(pro) protein of coronavirus with covalently or non-covalently bound small…</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 role of IL-6 and IL-6 blockade in COVID-19</strong> - INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a dysregulated hyperinflammatory response.</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>Interleukin-6: obstacles to targeting a complex cytokine in critical illness</strong> - Circulating concentrations of the pleiotropic cytokine interleukin-6 (IL-6) are known to be increased in pro-inflammatory critical care syndromes, such as sepsis and acute respiratory distress syndrome. Elevations in serum IL-6 concentrations in patients with severe COVID-19 have led to renewed interest in the cytokine as a therapeutic target. However, although the pro-inflammatory properties of IL-6 are widely known, the cytokine also has a series of important physiological 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>Interactions between SARS coronavirus 2 papain-like protease and immune system: a potential drug target for the treatment of COVID-19</strong> - Coronaviruses (CoVs) are a large family of respiratory viruses which can cause mild to moderate upper respiratory tract infections. Recently, new coronavirus named as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified which is a major threat to public health. Innate immune responses play a vital role in a host’s defense against viruses. Interestingly, CoVs have evolved elaborate strategies to evade the complex system of sensors and signaling molecules to suppress…</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>Acute Cardiac Injury in Coronavirus Disease 2019 and Other Viral Infections-A Systematic Review and Meta-Analysis</strong> - CONCLUSIONS: Acute cardiac injury may be associated with whether the virus binds angiotensin-converting enzyme-2. Acute cardiac injury occurs in half of critically ill coronavirus disease 2019 patients, but only 12% of patients infected by viruses that do not bind to angiotensin-converting enzyme-2.</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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<ul>
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<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Compositions and methods for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection</strong> - - <a href="https://patentscope.wipo.int/search/en/detail.jsf?docId=AU321590214">link</a></p></li>
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<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>5-(4-TERT-BUTOXY PHENYL)-3-(4N-OCTYLOXYPHENYL)-4,5-DIHYDROISOXAZOLE MOLECULE (C-I): A PROMISING DRUG FOR SARS-COV-2 (TARGET I) AND BLOOD CANCER (TARGET II)</strong> - The present invention relates to a method ofmolecular docking of crystalline compound (C-I) with SARS-COV 2 proteins and its repurposing with proteins of blood cancer, comprising the steps of ; employing an algorithmto carry molecular docking calculations of the crystalized compound (C-I); studying the compound computationally to understand the effect of binding groups with the atoms of the amino acids on at least four target proteins of SARS-COV 2; downloading the structure of the proteins; removing water molecules, co enzymes and inhibitors attached to the enzymes; drawing the structure using Chem Sketch software; converting the mol file into a PDB file; using crystalized compound (C-I) for comparative and drug repurposing with two other mutated proteins; docking compound into the groove of the proteins; saving format of docked molecules retrieved; and filtering and docking the best docked results. - <a href="https://patentscope.wipo.int/search/en/detail.jsf?docId=IN320884617">link</a></p></li>
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<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>AQUEOUS ZINC OXIDE NANOSPRAY COMPOSITIONS</strong> - Disclosed herein is aqueous zinc oxide nano spray compositions comprising zinc oxide nanoparticles and a synthetic surfactant for controlling the spread of Covid-19 virus. - <a href="https://patentscope.wipo.int/search/en/detail.jsf?docId=IN321836709">link</a></p></li>
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<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>一种肝素类药物组合物、喷鼻剂及其制备方法及应用</strong> - 本发明公开了一种肝素类药物组合物、喷鼻剂及其制备方法及应用。该肝素类药物组合物包括肝素钠和阿比朵尔。本发明中的肝素类药物组合物首次采用肝素钠和阿比朵尔联合使用，普通肝素钠联合1μM/L以上的阿比朵尔病毒抑制效率显著高于单独普通肝素钠或单独阿比多尔组（p<0.05）。 - <a href="https://patentscope.wipo.int/search/en/detail.jsf?docId=CN321712860">link</a></p></li>
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<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>USING CLINICAL ONTOLOGIES TO BUILD KNOWLEDGE BASED CLINICAL DECISION SUPPORT SYSTEM FOR NOVEL CORONAVIRUS (COVID-19) WITH THE ADOPTION OF TELECONFERENCING FOR THE PRIMARY HEALTH CENTRES/SATELLITE CLINICS OF ROYAL OMAN POLICE IN SULTANATE OF OMAN</strong> - - <a href="https://patentscope.wipo.int/search/en/detail.jsf?docId=AU320796026">link</a></p></li>
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<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>抗SARS-COV-2中和抗体</strong> - 本公开提供了针对SARS‑COV‑2的新颖中和抗体和其抗原结合片段。还提供了包括其的药物组合物和试剂盒以及其用途。 - <a href="https://patentscope.wipo.int/search/en/detail.jsf?docId=CN321712812">link</a></p></li>
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<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Peptides and their use in diagnosis of SARS-CoV-2 infection</strong> - - <a href="https://patentscope.wipo.int/search/en/detail.jsf?docId=AU319943278">link</a></p></li>
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<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Method and compositions for treating coronavirus infection</strong> - A method of treating viral infection, such as viral infection caused by a virus of the Coronaviridae family, is provided. A composition having at least oleandrin is used to treat viral infection. - <a href="https://patentscope.wipo.int/search/en/detail.jsf?docId=AU319943054">link</a></p></li>
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<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">**一种4-肟-5<code>-（2-甲基丙酰基）尿苷的制备方法** - 本发明公开了一种4‑肟‑5</code>‑（2‑甲基丙酰基）尿苷的制备方法，包括：S1：在酸存在条件下，使得化合物1和2,2‑二甲氧基丙烷在有机溶剂中反应得到化合物2；S2：在碱存在条件下，使得化合物2在有机溶剂中反应得到化合物3；S3：在羟胺水溶液存在条件下使化合物3在有机溶剂中反应得到化合物4；S4：在酸存在条件下使化合物4在有机溶剂中反应得到化合物I。本发明制备得到的结晶性能良好的固体，且制备条件简单，转化率以及原子经济性好。 - <a href="https://patentscope.wipo.int/search/en/detail.jsf?docId=CN321712529">link</a></p></li>
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<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>一种COVID-19假病毒及其制备方法和用途</strong> - 本发明涉及生物技术领域，特别是涉及一种COVID‑19假病毒及其制备方法和用途本发明，所述COVID‑19假病毒由外壳蛋白质粒与辅助质粒经病毒包装而成，所述外壳蛋白质粒包括表达COVID‑19 S蛋白的质粒、表达COVID‑19 M蛋白的质粒和表达COVID‑19 E蛋白的质粒。本发明的COVID‑19假病毒采用三质粒系统包装，以S/M/E蛋白替代表达VSV‑G蛋白，比仅含有S蛋白的假病毒感染能力更强、灵敏度更高。而且，COVID‑19假病毒携带两种荧光报告基团，不同的荧光报告基团可应用于不同的场景，使得COVID‑19假病毒应用时更简便。 - <a href="https://patentscope.wipo.int/search/en/detail.jsf?docId=CN321712520">link</a></p></li>
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</ul>
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