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213 lines
54 KiB
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<meta content="width=device-width, initial-scale=1.0, user-scalable=yes" name="viewport"/>
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<title>30 August, 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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<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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</ul>
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<h1 data-aos="fade-right" id="from-preprints">From Preprints</h1>
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<li><strong>How to run behavioural experiments online: best practice suggestions for cognitive psychology and neuroscience</strong> -
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The combination of a replication crisis, global COVID-19 pandemic, and recent technological advances have accelerated the on-going transition of research in cognitive psychology and behavioural neuroscience to the online realm. When participants cannot be tested in-person in the laboratory, data of acceptable quality can be collected online still. While conducting research online has many advantages and generic advice on their infrastructure and implementation exists, numerous pitfalls can hinder researchers addressing their research question appropriately or even result in unusable data. Here, we present detailed best practice suggestions that span the range from initial study design to the final interpretation of the data. These suggestions take a critical look at issues regarding the recruitment of typical and (sub)clinical samples, their comparison, and the importance of context dependency for each part of a study. We illustrate our suggestions by means of a recent online study investigating cognitive working memory skills in adult dyslexia.
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🖺 Full Text HTML: <a href="https://psyarxiv.com/nt67j/" target="_blank">How to run behavioural experiments online: best practice suggestions for cognitive psychology and neuroscience</a>
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</div></li>
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<li><strong>Lockdown Lives: A longitudinal study of inter-relationships amongst feelings of loneliness, social contacts and solidarity during the COVID-19 lockdown in early 2020.</strong> -
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We examine how social contacts and feelings of solidarity shape experiences of loneliness during the COVID-19 lockdown in early 2020. From the PsyCorona database, we obtained longitudinal data from 23 countries, collected between March and May 2020. Results demonstrated that, although online contacts help to reduce feelings of loneliness, people who feel more lonely are less likely to use that strategy. Solidarity played only a small role in shaping feelings of loneliness during lockdown. Thus, it seems we must look beyond the current focus on online contact and solidarity to help people address feelings of loneliness during lockdown. Finally, online contacts did not function as a substitute for face-to-face contacts outside the home - in fact, more frequent online contact in earlier weeks predicted more frequent face-to-face contacts in later weeks. As such, this work provides relevant insight into how individuals manage the impact of restrictions on their social lives.
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🖺 Full Text HTML: <a href="https://psyarxiv.com/hx5kt/" target="_blank">Lockdown Lives: A longitudinal study of inter-relationships amongst feelings of loneliness, social contacts and solidarity during the COVID-19 lockdown in early 2020.</a>
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</div></li>
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<li><strong>Hydrogel-based slow release of a receptor-binding domain subunit vaccine elicits neutralizing antibody responses against SARS-CoV-2</strong> -
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The development of effective vaccines that can be rapidly manufactured and distributed worldwide is necessary to mitigate the devastating health and economic impacts of pandemics like COVID-19. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, which mediates host cell entry of the virus, is an appealing antigen for subunit vaccines because it is efficient to manufacture, highly stable, and a target for neutralizing antibodies. Unfortunately, RBD is poorly immunogenic. While most subunit vaccines are commonly formulated with adjuvants to enhance their immunogenicity, we found that clinically-relevant adjuvants Alum, AddaVax, and CpG/Alum were unable to elicit neutralizing responses following a prime-boost immunization. Here we show that sustained delivery of an RBD subunit vaccine comprising CpG/Alum adjuvant in an injectable polymer-nanoparticle (PNP) hydrogel elicited potent anti-RBD and anti-spike antibody titers, providing broader protection against SARS-CoV-2 variants of concern compared to bolus administration of the same vaccine and vaccines comprising other clinically-relevant adjuvant systems. Notably, a SARS-CoV-2 spike-pseudotyped lentivirus neutralization assay revealed that hydrogel-based vaccines elicited potent neutralizing responses when bolus vaccines did not. Together, these results suggest that slow delivery of RBD subunit vaccines with PNP hydrogels can significantly enhance the immunogenicity of RBD and induce neutralizing humoral immunity.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2021.03.31.437792v3" target="_blank">Hydrogel-based slow release of a receptor-binding domain subunit vaccine elicits neutralizing antibody responses against SARS-CoV-2</a>
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</div></li>
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<li><strong>Opaganib in COVID-19 pneumonia: Results of a randomized, placebo-controlled Phase 2a trial</strong> -
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Rationale: Opaganib, an oral sphingosine kinase-2 inhibitor with antiviral and anti-inflammatory properties, was shown to inhibit SARS-CoV-2 replication in vitro. We thus considered that opaganib could be beneficial for moderate to severe COVID-19 pneumonia. Objectives: To evaluate the effect of opaganib on supplemental oxygen requirements, time to hospital discharge and its safety in COVID-19 pneumonia hospitalized patients requiring supplemental oxygen. Methods: This Phase 2a, randomized, double-blind, placebo-controlled study, was conducted between July and December 2020 in eight sites in the USA. Forty-two enrolled patients received opaganib (n=23) or placebo (n=19) added to standard of care for up to 14 days and were followed up for 28 days after their last dose of investigational product. Main Results: By Day 14, 50.0% of patients in the opaganib and 22.2% in the placebo group no longer required supplemental oxygen for at least 24 hours, while 86.4% and 55.6%, respectively, were discharged from hospital. The relative decrease in total supplemental oxygen requirement from baseline to Day 14 was 61.6% in the opaganib versus 46.7% in the placebo arms. The incidence of ≥ Grade 3 treatment-emergent adverse events was 17.4% and 33.3% in the opaganib and placebo groups, respectively. Three deaths occurred in each group. Conclusions: In this proof-of-concept study, patients receiving oral opaganib required less supplemental oxygen, resulting in earlier hospital discharge, with no safety concerns arising. These findings support further evaluation of opaganib in this population.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2021.08.23.21262464v1" target="_blank">Opaganib in COVID-19 pneumonia: Results of a randomized, placebo-controlled Phase 2a trial</a>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Role of Emotion in Child Maltreatment Risk during the COVID-19 Pandemic</strong> -
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Purpose: Preliminary research early in the COVID-19 pandemic suggested children appeared to be at increased risk for child maltreatment, particularly as parents struggled with mental health and economic strains. To identify the potential affective elements that may contribute to such increased maltreatment risk, the current study focused on whether maternal worry about children’s behavior specifically and maternal anger were related to increased risk for neglect or physical or psychological aggression six months into the pandemic. Method: The racially diverse sample included 193 mothers who completed an online survey during late September-early October 2020. Results: Mothers’ reported increases in neglect and physical and psychological aggression during the pandemic were significantly related with established measures of maltreatment risk. Furthermore, path models indicated that maternal anger and worry about children’s behavior, as well as their interaction, were significantly related to indicators of physical aggression risk and neglect during the pandemic, but only maternal anger related to increased psychological aggression during the pandemic. Conclusions: Maternal worry and anger about children’s behavior may be exacerbating risk for maltreatment under the stressful conditions of the COVID-19 pandemic. Findings suggest affective reactions of both parental worry and anger focused on child behavior warrants greater empirical attention and consideration in intervention efforts.
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🖺 Full Text HTML: <a href="https://psyarxiv.com/cgznf/" target="_blank">Role of Emotion in Child Maltreatment Risk during the COVID-19 Pandemic</a>
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<li><strong>Young children’s ability to make predictions about novel illnesses</strong> -
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Understanding disease transmission is a complex problem highlighted by the COVID-19 pandemic. These studies test whether 3- to 6-year-old children in the United States use information about social interactions to predict disease transmission. Before and during COVID-19, children predicted illness would spread through close interactions. Older children outperformed younger children, with no associations between task performance and pandemic experience. Children did not predict that being hungry or tired would similarly spread through close interactions. Participants include 196 3—6-year-olds (53% girls, 47% boys; 68% White, 9% Black, 7% Asian, 6% Hispanic or Latinx), with medium-sized effects (d=0.6, ηp2=0.3). These findings suggest that thinking about social interaction supports young children’s predictions about illness, with noted limitations regarding children’s real-world avoidance of disease-spreading behaviors.
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🖺 Full Text HTML: <a href="https://psyarxiv.com/6s3c8/" target="_blank">Young children’s ability to make predictions about novel illnesses</a>
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<li><strong>The effectiveness of SARS-CoV-2 vaccination in preventing severe illness and death- real-world data from a cohort of patients hospitalized with COVID-19.</strong> -
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Background: Due to the unprecedented speed of SARS-CoV-2 vaccine development, their efficacy trials and issuance of emergency use approvals and marketing authorizations, additional scientific questions remain that need to be answered regarding vaccine effectiveness, vaccination regimens and the need for booster doses. While long-term studies on the correlates of protection, vaccine effectiveness, and enhanced surveillance are awaited, studies on breakthrough infections help us understand the nature and course of this illness among vaccinated individuals and guide in public health preparedness. Methods: This observational cohort study aimed at comparing the differences in clinical, biochemical parameters and the hospitalization outcomes of 53 fully vaccinated individuals with those of unvaccinated (1,464) and partially vaccinated (231) individuals, among a cohort of 2,080 individuals hospitalized with SARS-CoV-2 infection. Results: Completing the course of vaccination protected individuals from developing severe COVID-19 as evidence by lower proportions of those with hypoxia, abnormal levels of inflammatory markers, requiring ventilatory support and death compared to unvaccinated and partially vaccinated individuals. There were no differences in these outcomes among patients who received either vaccine type approved in India. Conclusion: With a current rate of only 9.5% of the Indian population being fully vaccinated, efforts should be made to improve the vaccination rates as a timely measure to prepare for the upcoming waves of this highly transmissible pandemic. Vaccination rates of the communities may also guide in the planning of the health needs and appropriate use of medical resources.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2021.08.26.21262705v1" target="_blank">The effectiveness of SARS-CoV-2 vaccination in preventing severe illness and death- real-world data from a cohort of patients hospitalized with COVID-19.</a>
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<li><strong>Integrating Health Behavior Theories to Predict COVID-19 Vaccine Acceptance: Differences between Medical Students and Nursing Students</strong> -
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Abstract Background: This study aimed to explore behavioral-related factors predicting the intention of getting a COVID-19 vaccine among medical and nursing students using an integrative model combining the Health Belief Model (HBM) and the Theory of Planned Behavior (TPB). Methods: A cross-sectional online survey was conducted among medical and nursing students aged > 18 years in their clinical years in Israel between 27 August and 28 September 2020. Hierarchical logistic regression was used to predict acceptance of a COVID-19 vaccine. Results: A total number of 628 participants completed the survey. Medical students expressed higher intentions of getting vaccinated against COVID-19 than nursing students (88.1% vs. 76.2%, p < 0.01). The integrated model based on HBM and TPB was able to explain 66% of the variance (adjusted R2 = 0.66). Participants were more likely to be willing to get vaccinated if they reported higher levels of perceived susceptibility, benefits, barriers, cues to action, attitude, self-efficacy and anticipated regret. Two interaction effects revealed that male nurses had a higher intention of getting vaccinated than did female nurses and that susceptibility is a predictor of the intention of getting vaccinated only among nurses. Conclusions: This study demonstrates that both models considered (i.e., HBM and TPB) are important for predicting the intention of getting a COVID-19 vaccine among medical and nursing students, and can help better guide intervention programs, based on components from both models. Our findings also highlight the importance of paying attention to a targeted group of female nurses, who expressed low vaccine acceptance. Keywords: SARS Coronavirus; Health Belief Model; healthcare workers; Theory of Planned Behavior; vaccine acceptance
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2021.05.18.21257416v2" target="_blank">Integrating Health Behavior Theories to Predict COVID-19 Vaccine Acceptance: Differences between Medical Students and Nursing Students</a>
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<li><strong>A Community-Based Participatory Research to Assess the Feasibility of Ayurveda Intervention in Patients with Mild- to-Moderate COVID-19</strong> -
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Innovative strategies are required to manage COVID-19 in the communities. Back to Roots was a collaborative, community-based pilot intervention project in the British Asian community. To assess the efficacy and safety of Ayurveda intervention in relieving symptoms of mild-to-moderate COVID-19, a community based participatory research framework was used. Twenty-eight patients were enrolled with confirmed COVID-19 clinical stages of mild-to-moderate COVID-19, symptomatic, and between 20 to 70 years of age. Routine management was followed by all patients managing at home, additionally patents taking Ayurveda intervention for 14 consecutive days. The efficacy and safety of Ayurveda intervention were evaluated. There were suggestions of Ayurveda9s advantage in improved symptoms relief, clinical recovery in 7 days. However, a control group was not included but data triangulations from separate usual care found the difference statistically significant. Ayurveda intervention may potentially have a beneficial effect on patients with COVID‐19, especially for those with mild to moderate symptoms. A further definitive large‐scale clinical trial is necessary.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2021.01.20.21250198v2" target="_blank">A Community-Based Participatory Research to Assess the Feasibility of Ayurveda Intervention in Patients with Mild-to-Moderate COVID-19</a>
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<li><strong>Comparison of Antibody Levels in Response to SARS-CoV-2 Infection and Vaccination Type in a Midwestern Cohort</strong> -
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We present preliminary data in an ongoing observational study reporting SARS-CoV-2 spike protein reactive antibody levels from a convenience cohort of over 200 individuals in Kansas City. We observe stable antibody levels over 11 months in individuals who recovered from COVID19 infection caused by SARS-CoV-2. Our data revealed higher-than recovered levels from naive individuals vaccinated with Pfizer or Moderna vaccines and similar-to recovered levels from Johnson & Johnson (J&J) recipients. For all vaccines, inoculation after recovery resulted in higher antibody levels than vaccination alone. Responses to Pfizer and Moderna vaccines decreased over time from high initial levels but at the time of publication remain higher than those for recovered or J&J recipients. Within our limited cohort we did not see strong demographic trends other than higher antibody levels in recovered female individuals.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2021.08.16.21262036v2" target="_blank">Comparison of Antibody Levels in Response to SARS-CoV-2 Infection and Vaccination Type in a Midwestern Cohort</a>
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<li><strong>County-Level Estimates of Excess Mortality associated with COVID-19 in the United States</strong> -
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Background: The COVID-19 pandemic in the U.S. has been largely monitored on the basis of death certificates containing reference to COVID-19. However, prior analyses reveal that a significant percentage of excess deaths associated with the pandemic were not directly assigned to COVID-19. Methods: In the present study, we estimate a generalized linear model of expected mortality in 2020 based on historical trends in deaths by county of residence between 2011 and 2019. We use the results of the model to generate estimates of excess mortality and excess deaths not assigned to COVID-19 for 1,470 county-sets in the U.S. representing 3,138 counties. Results: During 2020, more than one- fourth of U.S. residents (91.2 million) lived in counties where less than 75% of excess deaths were assigned to COVID-19. Across the country, we estimated that 439,698 excess deaths occurred in 2020, among which 86.7% were assigned to COVID-19. Some regions (Mideast, Great Lakes, New England, and Far West) reported the most excess deaths in large central metros, whereas other regions (Southwest, Southeast, Plains, and Rocky Mountains) reported the highest excess mortality in nonmetro areas. The proportion assigned to COVID-19 was lowest in large central metro areas (79.3%) compared to medium or small metros (87.4%), nonmetro areas (89.4%) and large fringe metros (95.2%). Regionally, the proportion of excess deaths assigned to COVID-19 was lowest in the Southeast (81.1%), Far West (81.2%), Southwest (82.6%), and Rocky Mountains (85.2%). Across the regions, the number of excess deaths exceeded the number of directly assigned COVID-19 deaths in the majority of counties. The exception to this was in New England, which reported more directly assigned COVID-19 deaths than excess deaths in large central metro areas, large fringe metros, and medium or small metros. Conclusions: Across the U.S., many counties had substantial numbers of excess deaths that were not accounted for in direct COVID-19 death counts. Estimates of excess mortality at the local level can inform the allocation of resources to areas most impacted by the pandemic and contribute to positive protective behavior feedback loops (i.e. increases in mask-wearing and vaccine uptake).
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2021.04.23.21255564v5" target="_blank">County-Level Estimates of Excess Mortality associated with COVID-19 in the United States</a>
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<li><strong>Predicting mortality in SARS-COV-2 (COVID-19) positive patients in the inpatient setting using a Novel Deep Neural Network</strong> -
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Background The second-wave of CVOID-19 pandemic is anticipated to be worse than the initial one and will strain the healthcare systems even more during the winter months. Our aim was to develop a machine learning-based model to predict mortality using the Neo-V framework. We hypothesized this novel machine learning approach could be applied to COVID-19 patients to predict mortality successfully and high accuracy. Methods The current Deep-Neo-V model is built on our previously statistically rigorous machine learning framework [Fahad-Liaqat-Ahmad Intensive Machine (FLAIM) framework] that evaluates the statistically significant risk factors, generate new combined variables and then supply these risk factors to deep neural network to predict mortality in RT-PCR positive COVID-19 patients in the inpatient setting. We analyzed adult patients (≥18 years) admitted to the Aga Khan University Hospital with a working diagnosis of COVID-19 infection (n=1228). We excluded patients that were negative on COVID-19 on RT-PCR, had incomplete or missing health records. The first phase selection of risk factor was done using Cox-regression univariate and multivariate analyses. In the second phase, we generated new variables and tested those statistically significant for mortality and in the third and final phase we applied deep neural networks and other traditional machine learning models like Decision Tree Model, k-nearest neighbor models and others. Results A total of 1228 cases were diagnosed as a COVID-19 infection, we excluded 14 patients after the exclusion criteria and (n=)1214 patients were analyzed. We observed that several clinical and laboratory-based variables were statistically significant for both univariate and multivariate analyses while others were not. With most significant being septic shock (hazard ratio [HR], 4.30; 95% confidence interval [CI], 2.91-6.37), supportive treatment (HR, 3.51; 95% CI, 2.01-6.14), abnormal international normalized ratio (INR) (HR, 3.24; 95% CI, 2.28-4.63), admission to the intensive care unit (ICU) (HR, 3.24; 95% CI, 2.22-4.74), treatment with invasive ventilation (HR, 3.21; 95% CI, 2.15-4.79) and laboratory lymphocytic derangement (HR, 2.79; 95% CI, 1.6-4.86). Machine learning results showed our DNN (Neo-V) model outperformed all conventional models (Neo-V) and Deep-FLAIM models with test set accuracy of 99.53%, sensitivity of 89.87%, and specificity of 95.63%; positive predictive value, 50.00%; negative predictive value, 91.05%; and area under the curve of the receiver-operator curve of 88.5. Conclusion Our novel Deep-Neo-V model outperformed all other machine learning models. The model is easy to implement, user friendly and with high accuracy.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2020.12.13.20247254v3" target="_blank">Predicting mortality in SARS-COV-2 (COVID-19) positive patients in the inpatient setting using a Novel Deep Neural Network</a>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>State- and County-Level COVID-19 Public Health Orders in California: Constructing a Dataset and Describing Their Timing, Content, and Stricture</strong> -
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Without vaccines, non-pharmaceutical interventions have been the most widely used approach to controlling the spread of COVID-19 epidemics. Various jurisdictions have implemented public health orders as a means of reducing effective contacts and controlling their local epidemics. Multiple studies have examined the effectiveness of various orders (e.g. use of face masks) for epidemic control. However, orders occur at different timings across jurisdictions and some orders on the same topic are stricter than others. We constructed a county-level longitudinal data set of more than 2,400 public health orders issues by California and its 58 counties pertaining to its 40 million residents. First, we describe methods used to construct the dataset that enables the characterization of the evolution over time of California state- and county-level public health orders dealing with COVID-19 from January 1, 2020 through June 30,</p></div></li>
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<li>Public health orders are both an interesting and important outcome in their own right and also a key input into analyses looking at how such orders may impact COVID-19 epidemics. To construct the dataset, we developed and executed a search strategy to identify COVID-19 public health orders over this time period for all relevant jurisdictions. We characterized each identified public health order in terms of the timing of when it was announced, went into effect and (potentially) expired. We also adapted an existing schema to describe the topic(s) each public health order dealt with and the level of stricture each imposed, applying it to all identified orders. Finally, as an initial assessment, we examined the patterns of public health orders within and across counties, focusing on the timing of orders, the rate of increase and decrease in stricture, and on variation and convergence of orders within regions.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2020.11.08.20224915v8" target="_blank">State- and County-Level COVID-19 Public Health Orders in California: Constructing a Dataset and Describing Their Timing, Content, and Stricture</a>
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<li><strong>Prolonged SARS-CoV-2 infection in patients with lymphoid malignancies</strong> -
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ABSTRACT Coronavirus disease 2019 (COVID-19) infection results in high mortality rates in patients with hematologic malignancies. Persistent and/or recurrent COVID-19 has not yet been demonstrated in this population. We identified patients with B-cell lymphomas as having a particularly high risk for persistent SARS-CoV-2 positivity. Subsequent analysis of patients with lymphoid malignancies and COVID-19 identified discrete risk factors for severity of primary infection as compared to disease chronicity. Active therapy and diminished T-cell counts were key drivers of acute mortality in lymphoma patients with COVID-19 infection. Conversely, B-cell depleting therapy was the primary driver of re-hospitalization for COVID-19. In patients with persistent SARS-CoV-2 positivity, we observed high levels of viral entropy consistent with intrahost viral evolution, particularly in patients with impaired CD8+ T-cell immunity. These results suggest that persistent COVID-19 infection is likely to remain a risk in patients with impaired adaptive immunity and that additional therapeutic strategies are needed to enable viral clearance in this high-risk population. Statement of Significance We establish persistent symptomatic COVID-19 infection as a novel clinical syndrome in patients with lymphoid malignancies and identify B-cell depletion as the key immunologic driver of persistent infection. Furthermore, we demonstrate ongoing intrahost viral evolution in patients with persistent COVID-19 infection, particularly in patients with impaired CD8+ T-cell immunity.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2021.08.25.21262417v1" target="_blank">Prolonged SARS-CoV-2 infection in patients with lymphoid malignancies</a>
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<li><strong>Antibodies anti-SARS-CoV2 time-course in patients and vaccinated subjects: an evaluation of the harmonization of two different methods</strong> -
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The time-course of antibodies anti SARS-CoV2 is not yet well elucidated, especially in people who underwent a vaccination campaign. In this study we measured antibodies anti-S1 and anti-RBD with two different methods both in patients and in vaccinated subjects. 108 specimens from 48 patients diagnosed as COVID-19 affected (time from the onset of symptoms from 3 to 368 days) and 60 specimens from 20 vaccinated subjects (collected after 14 days from the first dose, 14 days and 3 months after a second dose of Comirnaty) were evaluated. We used an ELISA method that measure IgG against anti-Spike 1 and a chemiluminescence immunoassays that measure IgG anti-RBD. In the patients, antibodies concentrations tend to decline after a few months with both methods, but persist relatively high up to nearly a year after symptoms. In vaccinated subjects, antibodies were already detectable after the first dose, but after the booster they show a significant increase. However, the decrease is rapid, given that after 3 months after the second vaccination they are reduced to less than a quarter. The conversion of the results into BAU units improves the relationship between the two methods. However, in vaccinated subjects there was no evidence of proportional error after the conversion, while in the patients the difference between the two methods remained significant.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2021.08.28.21262543v1" target="_blank">Antibodies anti-SARS-CoV2 time-course in patients and vaccinated subjects: an evaluation of the harmonization of two different methods</a>
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</div></li>
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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>A Phase III Study to Evaluate the Efficacy and Safety of Proxalutamide (GT0918) in Hospitalized Subjects With COVID-19</strong> - <b>Condition</b>: Covid19<br/><b>Interventions</b>: Drug: GT0918; Drug: Standard of care; Drug: Matching placebo<br/><b>Sponsor</b>: Suzhou Kintor Pharmaceutical Inc,<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Study of PF-07321332/Ritonavir in Non-hospitalized Low-Risk Adult Participants With COVID-19</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Drug: PF-07321332; Drug: Ritonavir; Drug: Placebo<br/><b>Sponsor</b>: Pfizer<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>Targeting de Novo Pyrimidine Biosynthesis by Leflunomide for the Treatment of COVID-19 Virus Disease</strong> - <b>Condition</b>: COVID-19<br/><b>Intervention</b>: Drug: leflunomide<br/><b>Sponsor</b>: <br/>
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Ashford and St. Peter’s Hospitals NHS Trust<br/><b>Active, not recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Andrographis Paniculata vs Boesenbergia Rotunda vs Control in Asymptomatic COVID-19</strong> - <b>Condition</b>: Covid19<br/><b>Interventions</b>: Drug: Andrographis Paniculata; Drug: Boesenbergia; Other: Standard supportive treatment<br/><b>Sponsors</b>: Mahidol University; Ministry of Health, Thailand<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 PJS-539 for Adult Patients With COVID-19.</strong> - <b>Conditions</b>: Covid19; COVID-19 Pneumonia<br/><b>Interventions</b>: Drug: PJS-539 Dose 1; Drug: PJS-539 Dose 2; Drug: Placebo<br/><b>Sponsors</b>: Hospital do Coracao; Covicept<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>Enhancing COVID Rehabilitation With Technology</strong> - <b>Condition</b>: Covid19<br/><b>Interventions</b>: Behavioral: NexJ Connected Wellness; Other: Usual Care<br/><b>Sponsors</b>: University of Ottawa; Canadian Institutes of Health Research (CIHR); Ottawa Hospital Research Institute<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Phase I/II Clinical Trial of Recombinant COVID-19 Vaccine (Sf9 Cells) in Children and Adolescents</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: Recombinant COVID-19 vaccine (Sf9 cells); Other: Placebo control<br/><b>Sponsors</b>: WestVac Biopharma Co., Ltd.; West China 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>Treatment of Covid-19 With a Herbal Compound, Xagrotin</strong> - <b>Condition</b>: Covid19<br/><b>Intervention</b>: Combination Product: Xagrotin<br/><b>Sponsors</b>: <br/>
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Biomad AS; Directorate of health of Sulaimani, Iraq -KRG<br/><b>Completed</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>Philippine Trial to Determine Efficacy and Safety of Favipiravir for COVID-19</strong> - <b>Condition</b>: Covid19<br/><b>Interventions</b>: Combination Product: Favipiravir + Standard of Care; Procedure: Standard of Care<br/><b>Sponsors</b>: University of the Philippines; Department of Health, Philippines<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>Evaluation of the Effects of Bradykinin Antagonists on Pulmonary Manifestations of COVID-19 Infections (AntagoBrad- Cov Study).</strong> - <b>Condition</b>: Covid19<br/><b>Interventions</b>: Drug: C1 Inhibitor Human; Drug: Icatibant Injection; Other: Placebo<br/><b>Sponsor</b>: GCS Ramsay Santé pour l’Enseignement et la Recherche<br/><b>Completed</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>Combination of Dietary Supplements Curcumin, Quercetin and Vitamin D for Early Symptoms of COVID-19</strong> - <b>Condition</b>: Covid19<br/><b>Interventions</b>: Drug: Standard of care; Dietary Supplement: combination of curcumin, quercetin and Vitamin D<br/><b>Sponsor</b>: Ayub Teaching 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>Evaluation of Safety and Immunogenicity of a Novel Vaccine for Prevention of Covid-19 in Adults Previously Immunized</strong> - <b>Condition</b>: Covid19<br/><b>Intervention</b>: Biological: A vaccine composed of a recombinant S1 antigen<br/><b>Sponsors</b>: Hospital do Coracao; Farmacore Biotecnologia Ltda<br/><b>Withdrawn</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>Preventive Dendritic Cell Vaccine, AV-COVID-19, in Subjects Not Actively Infected With COVID-19</strong> - <b>Condition</b>: COVID-19<br/><b>Intervention</b>: Biological: AV-COVID-19<br/><b>Sponsors</b>: <br/>
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Aivita Biomedical, Inc.; PT AIVITA Biomedika Indonesia; Kariadi Hospital; Central Army Hospital RSPAD Gatot Soebroto<br/><b>Completed</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Phase 3 Clinical Study Evaluating Nitric Oxide Nasal Spray (NONS) Efficacy To Treat and Prevent the Exacerbation of Infection in Individuals With Documented Asymptomatic or Mild COVID-19</strong> - <b>Condition</b>: Covid19<br/><b>Intervention</b>: Drug: to be given as a treatment<br/><b>Sponsor</b>: <br/>
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Salmaniya Medical Complex<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 Phase I Study to Determine Safety and Immunogenicity of the Candidate COVID-19 Vaccine AZD1222 Delivered by Aerosol in Healthy Adult Volunteers</strong> - <b>Conditions</b>: Covid19; SARS-CoV-2 Infection<br/><b>Interventions</b>: Biological: 1x10^9 vp AZD1222; Biological: 5x10^9 vp AZD1222; Biological: 1x10^10 vp AZD1222<br/><b>Sponsors</b>: Imperial College London; University of Oxford; AstraZeneca<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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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Identification of Natural Inhibitors Against SARS-CoV-2 Drugable Targets Using Molecular Docking, Molecular Dynamics Simulation, and MM-PBSA Approach</strong> - The present study explores the SARS-CoV-2 drugable target inhibition efficacy of phytochemicals from Indian medicinal plants using molecular docking, molecular dynamics (MD) simulation, and MM-PBSA analysis. A total of 130 phytochemicals were screened against SARS-CoV-2 Spike (S)-protein, RNA-dependent RNA polymerase (RdRp), and Main protease (M^(pro)). Result of molecular docking showed that Isoquercetin potentially binds with the active site/protein binding site of the Spike, RdRP, and Mpro…</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 overview of potential inhibitors targeting non-structural proteins 3 (PL(pro) and Mac1) and 5 (3CL(pro)/M(pro)) of SARS-CoV-2</strong> - There is an urgent need to develop effective treatments for the coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The rapid spread of SARS-CoV-2 has resulted in a global pandemic that has not only affected the daily lives of individuals but also had a significant impact on the global economy and public health. Although extensive research has been conducted to identify inhibitors targeting SARS-CoV-2, there are still no effective…</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>DAMPening COVID-19 Severity by Attenuating Danger Signals</strong> - COVID-19 might lead to multi-organ failure and, in some cases, to death. The COVID-19 severity is associated with a “cytokine storm.” Danger-associated molecular patterns (DAMPs) are proinflammatory molecules that can activate pattern recognition receptors, such as toll-like receptors (TLRs). DAMPs and TLRs have not received much attention in COVID-19 but can explain some of the gender-, weight- and age-dependent effects. In females and males, TLRs are differentially expressed, likely…</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 Silico Identification of MicroRNAs targeting the Key nucleator of Stress Granules, G3BP: Promising Therapeutics for SARS-CoV-2 Infection</strong> - Stress granules (SGs) are non-membrane ribonucleoprotein condensates formed in response to environmental stress conditions via liquid-liquid phase separation (LLPS). SGs are involved in the pathogenesis of aging and aging-associated diseases, cancers, viral infection, and several other diseases. GTPase-activating protein (SH3 domain)-binding protein 1 and 2 (G3BP1/2) is a key component and commonly used marker of SGs. Recent studies have shown that SARS-CoV-2 nucleocapsid protein via…</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 silico molecular docking of SARS-CoV-2 surface proteins with microbial non-ribosomal peptides: identification of potential drugs</strong> - Outbreak of COVID-19 by SARS-CoV-2 infection caused severe acute respiratory syndrome that has been declared a public health emergency of international concern. To control infections, there is urgent need to develop an effective therapeutic strategy. COVID-19 viral spike glycoprotein and proteases play major role in viral entry and mediating virus replication and spread and thus can serve as potential antiviral drug target. Being highly specific, efficacious and safe, peptides hold their place…</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 silico screening of FDA approved drugs against ACE2 receptor: potential therapeutics to inhibit the entry of SARS-CoV-2 to human cells</strong> - An unknown coronavirus that emerged sometime at the end of 2019 in China, the novel SARS-CoV-2, now called COVID-19, has spread all over the world. Several efforts have been made to prevent or treat this disease, though not with success. The initiation of COVID-19 viral infection involves specific binding of SARS-CoV-2 to the host surface of the receptor, ACE2. The ACE2- SARS-CoV-2 complex then gets transferred into the endosomes where the endosomal acidic proteases cleave the S protein present…</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>Digital PCR can augment the interpretation of RT-qPCR Cq values for SARS-CoV-2 diagnostics</strong> - Coronavirus disease 2019 (COVID-19) is an infectious, acute respiratory disease caused mainly by person-to-person transmission of the coronavirus SARS-CoV-2. Its emergence has caused a world-wide acute health crisis, intensified by the challenge of reliably identifying individuals likely to transmit the disease. Diagnosis is hampered by the many unknowns surrounding this disease, including those relating to infectious viral burden. This uncertainty is exacerbated by disagreement surrounding 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>In vitro data suggest that Indian variant B.1.617 of SARS-CoV-2 escapes neutralization by both receptor affinity and immune evasion</strong> - CONCLUSION: Our data suggest that the newly emerged SARS-CoV-2 variant B.1.617, as well as the better-studied variants B.1.351 and P.1 (all containing a mutation at position E484) display increased transmissibility both due their higher affinity for the cell receptor ACE2 and their ability to partially bypass immunity generated against the wild-type virus. For variant B.1.36 (with a point mutation at position N440), only increased affinity seems to play a role.</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 Favipiravir in Moderate COVID-19 Pneumonia Patients without Oxygen Therapy: A Randomized, Phase III Clinical Trial</strong> - CONCLUSIONS: The results suggested favipiravir may be one of options for moderate COVID-19 pneumonia treatment. However, the risk of adverse events, including hyperuricemia, should be carefully considered.</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>Suppressive Monocytes Impair MAIT Cells Response via IL-10 in Patients with Severe COVID-19</strong> - Immune cell responses are strikingly altered in patients with severe coronavirus disease 2019 (COVID-19), but the immunoregulatory process in these individuals is not fully understood. In this study, 23 patients with mild and 22 patients with severe COVID-19 and 6 asymptomatic carriers of COVID-19 were enrolled, along with 44 healthy controls (HC). Peripheral immune cells in HC and patients with COVID-19 were comprehensively profiled using mass cytometry. We found that in patients with severe…</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>All-Trans Retinoic Acid Exhibits Antiviral Effect against SARS-CoV-2 by Inhibiting 3CLpro Activity</strong> - The pandemic of COVID-19 caused by SARS-CoV-2 continues to spread despite the global efforts taken to control it. The 3C-like protease (3CLpro), the major protease of SARS-CoV-2, is one of the most interesting targets for antiviral drug development because it is highly conserved among SARS-CoVs and plays an important role in viral replication. Herein, we developed high throughput screening for SARS-CoV-2 3CLpro inhibitor based on AlphaScreen. We screened 91 natural product compounds and found…</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>Antiviral Activity of Umifenovir In Vitro against a Broad Spectrum of Coronaviruses, Including the Novel SARS-CoV-2 Virus</strong> - An escalating pandemic of the novel SARS-CoV-2 virus is impacting global health, and effective antivirals are needed. Umifenovir (Arbidol) is an indole-derivative molecule, licensed in Russia and China for prophylaxis and treatment of influenza and other respiratory viral infections. It has been shown that umifenovir has broad spectrum activity against different viruses. We evaluated the sensitivity of different coronaviruses, including the novel SARS-CoV-2 virus, to umifenovir using in vitro…</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 Novel Frameshifting Inhibitor Having Antiviral Activity against Zoonotic Coronaviruses</strong> - Recent outbreaks of zoonotic coronaviruses, such as Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have caused tremendous casualties and great economic shock. Although some repurposed drugs have shown potential therapeutic efficacy in clinical trials, specific therapeutic agents targeting coronaviruses have not yet been developed. During coronavirus replication, a replicase gene cluster, including RNA-dependent RNA…</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>IFN-λ1 Displays Various Levels of Antiviral Activity In Vitro in a Select Panel of RNA Viruses</strong> - Type III interferons (lambda IFNs) are a quite new, small family of three closely related cytokines with interferon-like activity. Attention to IFN-λ is mainly focused on direct antiviral activity in which, as with IFN-α, viral genome replication is inhibited without the participation of immune system cells. The heterodimeric receptor for lambda interferons is exposed mainly on epithelial cells, which limits its possible action on other cells, thus reducing the likelihood of developing…</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>Non-Nucleotide RNA-Dependent RNA Polymerase Inhibitor That Blocks SARS-CoV-2 Replication</strong> - SARS-CoV-2 has caused an extensive pandemic of COVID-19 all around the world. Key viral enzymes are suitable molecular targets for the development of new antivirals against SARS-CoV-2 which could represent potential treatments of the corresponding disease. With respect to its essential role in the replication of viral RNA, RNA-dependent RNA polymerase (RdRp) is one of the prime targets. HeE1-2Tyr and related derivatives were originally discovered as inhibitors of the RdRp of flaviviruses. Here,…</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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<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Anti-Sars-Cov-2 Neutralizing Antibodies</strong> - - <a href="https://patentscope.wipo.int/search/en/detail.jsf?docId=AU333857732">link</a></p></li>
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<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Expression Vector for Anti-Sars-Cov-2 Neutralizing Antibodies</strong> - - <a href="https://patentscope.wipo.int/search/en/detail.jsf?docId=AU333857737">link</a></p></li>
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<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>DEVELOPMENT OF CNN SCHEME FOR COVID-19 DISEASE DETECTION USING CHEST RADIOGRAPH</strong> - - <a href="https://patentscope.wipo.int/search/en/detail.jsf?docId=AU333857177">link</a></p></li>
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<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>SARS-COV-2 BINDING PROTEINS</strong> - - <a href="https://patentscope.wipo.int/search/en/detail.jsf?docId=AU333402004">link</a></p></li>
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<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A PROCESS FOR PREPARING MONTELUKAST SODIUM FOR TREATING COVID 19 PATIENTS</strong> - - <a href="https://patentscope.wipo.int/search/en/detail.jsf?docId=AU333857132">link</a></p></li>
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<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>IDENTIFICATION OF ANTI-COVID 19 AGENT SOMNIFERINE AS INHIBITOR OF MPRO & ACE2-RBD INTERACTION</strong> - - <a href="https://patentscope.wipo.int/search/en/detail.jsf?docId=AU333857079">link</a></p></li>
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<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Deep Learning Based System For Detection of Covid-19 Disease of Patient At Infection Risk.</strong> - - <a href="https://patentscope.wipo.int/search/en/detail.jsf?docId=AU333857030">link</a></p></li>
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<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>자외선살균등</strong> - 본 발명은 사람의 의복이나 사용한 마스크 등에 부착하여 있다 호흡기로 유입되어 감염을 유발할 수 있는 COVID-19와 같은 유해균류를 간편하게 살균하기 위한 휴대용 자와선살균등에 관한 것이다. 반감기가 길고 인체에 유해한 오존을 발생하지 않으면서 탁월한 살균능력이 있는 250~265nm(최적은 253.7nm) 파장의 자외선을 발광하는 자외선램프를 본 발명의 막대형의 자외선살균등 광원으로 사용하고 비광원부를 손으로 잡고 의복이나 사용한 마스크 등 유해균류가 부착되었을 것으로 의심되는 곳에 자외선을 조사하여 간편하게 유해균류를 살균하므로써 감염을 예방하기 위한 휴대용 자외선살균등에 관함 것이다. - <a href="https://patentscope.wipo.int/search/en/detail.jsf?docId=KR332958765">link</a></p></li>
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<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Protein chip and kit for detecting the SARS-CoV-2 S antigen</strong> - - <a href="https://patentscope.wipo.int/search/en/detail.jsf?docId=AU333400883">link</a></p></li>
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<li><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>桑黄和百蕊草复方作为新型冠状病毒治疗药物或抗病毒制剂的用途</strong> - 本发明公开了桑黄和百蕊草复方作为新型冠状病毒治疗药物或抗病毒制剂的用途。本发明提供了桑黄和百蕊草的应用：在制备治疗新型冠状病毒所致疾病的药物中的应用；在制备治疗新型冠状病毒感染的药物中的应用；在制备预防新型冠状病毒所致疾病的药物中的应用；在制备预防新型冠状病毒感染的药物中的应用；在制备新型冠状病毒抑制剂中的应用。发明人在前期研究发现桑黄和百蕊草具有抗新冠病毒的作用效果。进一步的，将百蕊草提取物与桑黄提取物组合使用，组合药物的毒性并没有增加，同时百蕊草有很强的抗炎作用，桑黄具有调节人体免疫力作用，这种组合药物对于治疗新冠肺炎病人是理想的选择药物。 - <a href="https://patentscope.wipo.int/search/en/detail.jsf?docId=CN333965968">link</a></p></li>
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