190 lines
50 KiB
HTML
190 lines
50 KiB
HTML
<!DOCTYPE html>
|
||
<html lang="" xml:lang="" xmlns="http://www.w3.org/1999/xhtml"><head>
|
||
<meta charset="utf-8"/>
|
||
<meta content="pandoc" name="generator"/>
|
||
<meta content="width=device-width, initial-scale=1.0, user-scalable=yes" name="viewport"/>
|
||
<title>15 January, 2023</title>
|
||
<style>
|
||
code{white-space: pre-wrap;}
|
||
span.smallcaps{font-variant: small-caps;}
|
||
span.underline{text-decoration: underline;}
|
||
div.column{display: inline-block; vertical-align: top; width: 50%;}
|
||
div.hanging-indent{margin-left: 1.5em; text-indent: -1.5em;}
|
||
ul.task-list{list-style: none;}
|
||
</style>
|
||
<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>
|
||
<body>
|
||
<h1 data-aos="fade-down" id="covid-19-sentry">Covid-19 Sentry</h1>
|
||
<h1 data-aos="fade-right" data-aos-anchor-placement="top-bottom" id="contents">Contents</h1>
|
||
<ul>
|
||
<li><a href="#from-preprints">From Preprints</a></li>
|
||
<li><a href="#from-clinical-trials">From Clinical Trials</a></li>
|
||
<li><a href="#from-pubmed">From PubMed</a></li>
|
||
<li><a href="#from-patent-search">From Patent Search</a></li>
|
||
</ul>
|
||
<h1 data-aos="fade-right" id="from-preprints">From Preprints</h1>
|
||
<ul>
|
||
<li><strong>APPRAISE: Fast, accurate ranking of engineered proteins by receptor binding propensity using structural modeling</strong> -
|
||
<div>
|
||
Deep learning-based methods for protein structure prediction have achieved unprecedented accuracy. However, the power of these tools to guide the engineering of protein-based therapeutics remains limited due to a gap between the ability to predict the structures of candidate proteins and the ability to assess which of those proteins are most likely to bind to a target receptor. Here we bridge this gap by introducing Automated Pairwise Peptide-Receptor AnalysIs for Screening Engineered proteins (APPRAISE), a method for predicting the receptor binding propensity of engineered proteins. After generating models of engineered proteins competing for binding to a target using an established structure-prediction tool such as AlphaFold2-multimer or ESMFold, APPRAISE performs a rapid (under 1 CPU second per model) scoring analysis that takes into account biophysical and geometrical constraints. As a proof-of-concept, we demonstrate that APPRAISE can accurately classify receptor-dependent vs. receptor-independent engineered adeno-associated viral vectors, as well as diverse classes of engineered proteins such as miniproteins targeting the SARS-CoV-2 spike protein, nanobodies targeting a G-protein-coupled receptor, and peptides that specifically bind to transferrin receptor and PD-L1. With its high accuracy, interpretability, and generalizability, APPRAISE has the potential to expand the utility of current structural prediction and accelerate protein engineering for biomedical applications.
|
||
</div>
|
||
<div class="article-link article-html-link">
|
||
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.01.11.523680v1" target="_blank">APPRAISE: Fast, accurate ranking of engineered proteins by receptor binding propensity using structural modeling</a>
|
||
</div></li>
|
||
<li><strong>Incipient parallel evolution of SARS-CoV-2 Deltacron variant in South Brazil</strong> -
|
||
<div>
|
||
With the coexistence of multiple lineages and increased international travel, recombination and gene flow are likely to become increasingly important in the adaptive evolution of SARS-CoV-2. This could result in the incipient parallel evolution of multiple recombinant lineages. However, identifying recombinant lineages is challenging, and the true extent of recombinant evolution in SARS-CoV-2 may be underestimated. This study describes the first SARS-CoV-2 Deltacron recombinant case identified in Brazil. We demonstrate that the recombination breakpoint is at the beginning of Spike gene (S). The 5’ genome portion (circa 22 kb) resembles the AY.101 lineage (VOC Delta), and the 3’ genome portion (circa 8 kb nucleotides) is most similar to the BA.1.1 lineage (VOC Omicron). Furthermore, evolutionary genomic analyses indicate that the new strain emerged after a single recombination event between lineages of diverse geographical locations in December 2021 in South Brazil. This Deltacron, named AYBA-RS, is one out of almost 30 recombinants described this year. The submission of only four sequences in the GISAID database suggests that this Brazilian lineage had a minor epidemiological impact. On the other hand, the recent emergence of this and various other Deltacron recombinant lineages (i.e., XD, XF, and XS) suggests that gene flow and recombination may play an increasingly important role in the COVID-19 pandemic. We explain the evolutionary and population genetic theory that support this assertion, and we conclude that this stresses the need for continued genomic and epidemiological surveillance. This is particularly important for countries where multiple variants are present, as well as for countries that receive significant inbound international travel.
|
||
</div>
|
||
<div class="article-link article-html-link">
|
||
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.10.06.511203v2" target="_blank">Incipient parallel evolution of SARS-CoV-2 Deltacron variant in South Brazil</a>
|
||
</div></li>
|
||
<li><strong>Variations in COVID-19 impacts by social vulnerability in Philadelphia, June 2020-December 2022</strong> -
|
||
<div>
|
||
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
|
||
Introduction: The study objective was to elucidate the relationship between social vulnerability and COVID-19 impacts in Philadelphia between June 2020 and December 2022. Methods: Using publicly available COVID-19 case, test, hospitalization, and mortality data for Philadelphia (June 7, 2020-December 31, 2022) and area-level social vulnerability data, we compared the incidence, test positivity, hospitalization, and mortality rates in high and low vulnerability neighborhoods of Philadelphia, characterized as scoring above or below the national median score on the social vulnerability index. We used linear mixed effects models to test the association between social vulnerability and COVID-19 incidence, test positivity, hospitalization, and mortality rates, adjusting for time and age distribution. Results: 90.4% of Philadelphians (n = 1,430,153) live in neighborhoods classified as socially vulnerable, based on scoring above the national median score on the social vulnerability index. COVID-19 incidence, hospitalization, and mortality rates were significantly elevated in the more vulnerable communities, with p < 0.05, p < 0.005, and p < 0.001, respectively. The relative risks of COVID-19-related incidence, hospitalization, and death, comparing the more vulnerable neighborhoods to the less vulnerable neighborhoods, were 1.11 (95%CI: 1.10-1.12), 2.07 (95%CI: 1.93-2.20), and 2.06 (95%CI: 1.78-2.38), respectively. Thus, between June 7, 2020 and December 31, 2022, 32,573 COVID-19 cases, 9,409 hospitalizations, and 1,967 deaths would have been avoided in Philadelphias more vulnerable communities had they experienced the same rates of incidence, hospitalization, and death as the less vulnerable Philadelphia communities. Conclusions: These results highlight the disparate morbidity and mortality experienced by people living in more vulnerable neighborhoods in a large US city. Importantly, our findings illustrate the importance of designing public health policies and interventions with an equity-driven approach, with greater resources and more intensive prevention strategies applied in socially vulnerable communities.
|
||
</p>
|
||
</div>
|
||
<div class="article-link article-html-link">
|
||
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.01.13.23284488v1" target="_blank">Variations in COVID-19 impacts by social vulnerability in Philadelphia, June 2020-December 2022</a>
|
||
</div></li>
|
||
<li><strong>Occupational Determinants of COVID-19 Cumulative Incidence and Vaccination Rate in the United States</strong> -
|
||
<div>
|
||
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
|
||
Objective We aim to study the relationship between occupation distribution within each county and COVID-19 cumulative incidence and vaccination rate in the United States. Methods We collected county-level data from January 22, 2020 up to December 25, 2021. We fit multivariate linear models to find the relationship of the percentage of people employed by 23 main occupations. Results Counties with more health-related jobs, office support roles, community service, sales, production and material moving occupations had higher COVID-19 cumulative incidence. During the uptick of the Delta COVID variant (stratified period July 1-Dec 25), counties with more transportation occupations had significantly more COVID-19 cumulative incidence than before. Significance Understanding the association between occupations and COVID-19 cumulative incidence on an ecological level can provide information for precision public health strategies for prevention and protecting vulnerable workers.
|
||
</p>
|
||
</div>
|
||
<div class="article-link article-html-link">
|
||
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.01.13.22274536v1" target="_blank">Occupational Determinants of COVID-19 Cumulative Incidence and Vaccination Rate in the United States</a>
|
||
</div></li>
|
||
<li><strong>SARS-CoV-2 VARIANT PREVALENCE ESTIMATION USING WASTEWATER SAMPLES</strong> -
|
||
<div>
|
||
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
|
||
The present work describes a statistical model to account for sequencing information of SARS-CoV-2 variants in wastewater samples. The model expresses the joint probability distribution of the number of genomic reads corresponding to mutations and non-mutations in every locus in terms of the variant proportions and the joint mutation distribution within every variant. Since the variant joint mutation distribution can be estimated using GISAID data, the only unknown parameters in the model are the variant proportions. These are estimated using maximum likelihood. The method is applied to monitor the evolution of variant proportions using genomic data coming from wastewater samples collected in A Coruna (NW Spain) in the period May 2021 - March 2022. Although the procedure is applied assuming independence among the number of reads along the genome, it is also extended to account for Markovian dependence of counts along loci in the aggregated information coming from wastewater samples.
|
||
</p>
|
||
</div>
|
||
<div class="article-link article-html-link">
|
||
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.01.13.23284507v1" target="_blank">SARS-CoV-2 VARIANT PREVALENCE ESTIMATION USING WASTEWATER SAMPLES</a>
|
||
</div></li>
|
||
<li><strong>Coverage of primary and booster vaccination against COVID-19 by socioeconomic level: A nationwide cross-sectional registry study</strong> -
|
||
<div>
|
||
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
|
||
High and equitable COVID-19 vaccination coverage is important for pandemic control and prevention of health inequity. However, little is known about socioeconomic correlates of booster vaccination coverage. In this cross-sectional study of all Norwegian adults in the national vaccination program (N = 4,190,655), we use individual-level registry data to examine coverage by levels of household income and education of primary (≥2 doses) and booster (≥3 doses) vaccination against COVID-19. We stratify the analyses by age groups with different booster recommendations and report relative risk ratios (RR) for vaccination by 25 August 2022. In the 18-44 years group, individuals with highest vs. lowest education had 94% vs. 79% primary coverage (adjusted RR (adjRR) 1.15, 95%CI 1.14-1.15) and 67% vs. 38% booster coverage (adjRR 1.55, 95% CI 1.55-1.56), while individuals with highest vs. lowest income had 94% vs. 81% primary coverage (adjRR 1.10, 95%CI 1.10-1.10) and 60% vs. 43% booster coverage (adjRR 1.23, 95%CI 1.22-1.24). In the ≥45 years group, individuals with highest vs. lowest education had 96% vs. 92% primary coverage (adjRR 1.02, 95%CI 1.02-1.02) and 88% vs. 80% booster coverage (adjRR 1.09, 95%CI 1.09-1.09), while individuals with highest vs. lowest income had 98% vs. 82% primary coverage (adjRR 1.16, 95%CI 1.16-1.16) and 92% vs. 64% booster coverage (adjRR 1.33, 95%CI 1.33-1.34). In conclusion, we document large socioeconomic inequalities in COVID-19 vaccination coverage, especially for booster vaccination, even though all vaccination was free-of-charge. The results highlight the need to tailor information and to target underserved groups for booster vaccination.
|
||
</p>
|
||
</div>
|
||
<div class="article-link article-html-link">
|
||
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.01.13.23284467v1" target="_blank">Coverage of primary and booster vaccination against COVID-19 by socioeconomic level: A nationwide cross-sectional registry study</a>
|
||
</div></li>
|
||
<li><strong>The Last Confirmed Case is Not the Last Infection and Catastrophic Outbreaks do Not Require Transmission</strong> -
|
||
<div>
|
||
Efforts made to prevent transmission of the infectious agent that causes an infectious disease in its capacity as a pathogen are praised and victory is declared after the last case of the expected outcomes of the event in which this disease occurs is confirmed. After all, it is assumed that such expected outcomes of the event in which the pathogen causes the infectious disease are manifestations of this disease and therefore that the last confirmed case in which such outcomes are observed is the last case of infection. But the results obtained by visualizing the reality in which the immunological concepts which have eluded us since the birth of the repeatedly proven germ theory are represented reveal that outcomes of the event in which the pathogen causes the infectious disease are not manifestations of this disease but rather consequences of the co-manifestation of different diseases in the spectrum of the infectious disease. These results enable us to account for the differences between such outcomes which, for instance, in patients with COVID-19 that the current theory of infectious disease pathogenesis expects to produce outcomes that affect the upper respiratory disease, include unexpected conditions such as the chronic ones seen in Long COVID patients and in patients with mpox, which this theory logically deduced to be a skin-affecting disease, include deadly conditions like encephalitis with the consequence that outcomes with such deadly conditions are attributed to underlying conditions even after Spain’s health ministry reported deaths from such outcomes in healthy individuals. And the consequence of the same results is that the last cases of expected outcomes such as those that affect the skin of individuals who are infected with the mpox virus are not the last cases of infection but rather the last cases in which such outcomes appear as the sterile causes of the non-infectious diseases that co-manifest with the infectious disease for the emergence of such outcomes disappear from the population in which undetected spread of the infectious agent occurred long before the widespread appearance of such expected outcomes that called attention to this pathogen or an earlier form of the pathogen, such as the smallpox virus, which is assumed to have been eradicated. It follows in the reality which was visualized to obtain these results that even as the disappearance of such outcomes is being celebrated, the sterile causes of non-infectious diseases which co-manifest with the infectious disease for the emergence of unexpected deadly outcomes, such as those with encephalitis and toxic shock, may be appearing in the population which is already harboring the pathogen silently. And without exciting cause or warning, such deadly outcomes will become widespread in our populations and will decimate them if the only treatments available at the time are still those that reduce viral replication which are unable to bring about the remission of such outcomes. Instead of celebrating the disappearance of cases when the sterile causes of the non-infectious diseases that co-manifest with mpox for the emergence of those expected skin-affecting outcomes disappear, we ought to quickly elucidate the conditions that permit the immunological mechanisms of infection and vaccination to bring about uneventful exposure to such sterile causes even after deadly outcomes of such events have already appeared as achieved by the vaccines of William Coley and Julius Wagner-Jauregg in some cases even at a time when nothing was known about the nature of such immunological mechanisms and the remission that followed therapeutic infection in such cases was attributed to fever.
|
||
</div>
|
||
<div class="article-link article-html-link">
|
||
🖺 Full Text HTML: <a href="https://osf.io/gb7ky/" target="_blank">The Last Confirmed Case is Not the Last Infection and Catastrophic Outbreaks do Not Require Transmission</a>
|
||
</div></li>
|
||
<li><strong>Changes to Family Caregiving of Older Adults and Adults with Disabilities during COVID-19</strong> -
|
||
<div>
|
||
The strict restrictions to reduce the spread of COVID-19 have disrupted the lives of many at-risk people and their family caregivers. This study explored how family caregivers perceived that family caregiving had changed during COVID-19 and the strategies they used to cope with these changes. We conducted 52 semi-structured interviews with family caregivers of adults over age 65 or adults with disabilities and analyzed the data through an inductive thematic analysis. Caregivers perceive the largest COVID-19-related caregiving changes to be limited social and physical contacts, changed caregiving tasks, reduced services and supports, and a new focus on vigilance and safety. Caregivers made numerous changes to caregiving, including keeping connected, keeping relatives occupied, getting support and services in new ways, and reducing caregiver stress.
|
||
</div>
|
||
<div class="article-link article-html-link">
|
||
🖺 Full Text HTML: <a href="https://osf.io/preprints/socarxiv/pb6ry/" target="_blank">Changes to Family Caregiving of Older Adults and Adults with Disabilities during COVID-19</a>
|
||
</div></li>
|
||
<li><strong>Structure-based discovery of inhibitors of the SARS-CoV-2 Nsp14 N7-methyltransferase</strong> -
|
||
<div>
|
||
An under-explored target for SARS-CoV-2 is non-structural protein 14 (Nsp14), a crucial enzyme for viral replication that catalyzes the methylation of N7-guanosine of the viral RNA at 5-prime-end; this enables the virus to evade the host immune response by mimicking the eukaryotic post-transcriptional modification mechanism. We sought new inhibitors of the S-adenosyl methionine (SAM)-dependent methyltransferase (MTase) activity of Nsp14 with three large library docking strategies. First, up to 1.1 billion make-on-demand (tangible) lead-like molecules were docked against the enzyme SAM site, seeking reversible inhibitors. On de novo synthesis and testing, three inhibitors emerged with IC50 values ranging from 6 to 43 M, each with novel chemotypes. Structure-guided optimization and in vitro characterization supported their non-covalent mechanism. In a second strategy, docking a library of 16 million tangible fragments revealed nine new inhibitors with IC50 values ranging from 12 to 341 M and ligand efficiencies from 0.29 to 0.42. In a third strategy, a newly created library of 25 million tangible, virtual electrophiles were docked to covalently modify Cys387 in the SAM binding site. Seven inhibitors emerged with IC50 values ranging from 3.2 to 39 M, the most potent being a reversible aldehyde. Initial optimization of a second series yielded a 7 M acrylamide inhibitor. Three inhibitors characteristic of the new series were tested for selectivity against 30 human protein and RNA MTases, with one showing partial selectivity and one showing high selectivity. Overall, 32 inhibitors encompassing eleven chemotypes had IC50 values <50 M and 5 inhibitors in four chemotypes had IC50 values <10 M. These molecules are among the first non-SAM-like inhibitors of Nsp14, providing multiple starting points for optimizing towards antiviral activity.
|
||
</div>
|
||
<div class="article-link article-html-link">
|
||
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.01.12.523677v1" target="_blank">Structure-based discovery of inhibitors of the SARS-CoV-2 Nsp14 N7-methyltransferase</a>
|
||
</div></li>
|
||
<li><strong>Pathogenesis of Breakthrough Infections with SARS-CoV-2 Variants in Syrian Hamsters</strong> -
|
||
<div>
|
||
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, has evolved into multiple variants. Animal models are important to understand variant pathogenesis, particularly for those with mutations that have significant phenotypic or epidemiological effects. Here, cohorts of naive or previously infected Syrian hamsters (Mesocricetus auratus) were infected with variants to investigate viral pathogenesis and disease protection. Naive hamsters infected with SARS-CoV-2 variants had consistent clinical outcomes, tissue viral titers, and pathology, while hamsters that recovered from initial infection and were reinfected demonstrated less severe clinical disease and lung pathology than their naive counterparts. Males had more frequent clinical signs than females in most variant groups, but few sex variations in tissue viral titers and lung pathology were observed. These findings support the use of Syrian hamsters as a SARS-CoV-2 model and highlight the importance of considering sex differences when using this species.
|
||
</div>
|
||
<div class="article-link article-html-link">
|
||
🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.01.12.523876v1" target="_blank">Pathogenesis of Breakthrough Infections with SARS-CoV-2 Variants in Syrian Hamsters</a>
|
||
</div></li>
|
||
<li><strong>Burden, Causation, and Particularities of long-COVID in African populations: A rapid systematic review</strong> -
|
||
<div>
|
||
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
|
||
Background: The global estimated prevalence of long COVID-19 is 43%, and the most common symptoms found globally are fatigue, confusion, or lack of confusion, and dyspnea, with prevalence rates of 23%, 14%, and 13%, respectively. However, long COVID still lacks an overall review in African populations. The aim of this review was to determine the prevalence of long COVID, its most common symptoms, comorbidities, and pathophysiological mechanisms. Methods: A systematic review of long COVID in African populations was conducted. The random effects model was used to calculate the pooled prevalence rates (95% CI). If the results could not be pooled, a narrative synthesis was performed. Results: We included 14 studies from 7 African countries, totaling 6,030 previously SARS-CoV-2 infected participants and 2,954 long COVID patients. Long COVID had a pooled prevalence of 41% [26%-56%]. Fatigue, dyspnea, and confusion or lack of concentration were the most common symptoms, with prevalence rates (95% CI) of 41% [26%-56%], 25% [12%-38%], and 40% [12%-68%], respectively. Long COVID was associated with advanced age, being female, more than three long COVID symptoms in the acute phase, initial fatigue and dyspnea, post-recovery stress, sadness, and sleep disturbances, and loss of appetite at symptoms onset, mild, moderate, and severe, pre-existing obesity, hypertension, diabetes mellitus, and the presence of any chronic illness (P ≤0.05). According to our review, high micro clot and platelet poor plasma (PPP) viscosity explain the pathophysiology of long COVID. Conclusion: Long COVID prevalence in Africa was comparable to the global prevalence. However, the prevalence of the most common symptoms was higher in Africa. Comorbidities associated with long COVID may lead to additional complications in African populations due to hypercoagulation and thrombosis.
|
||
</p>
|
||
</div>
|
||
<div class="article-link article-html-link">
|
||
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.01.13.23284305v1" target="_blank">Burden, Causation, and Particularities of long-COVID in African populations: A rapid systematic review</a>
|
||
</div></li>
|
||
<li><strong>Effectiveness of Paxlovid - a review</strong> -
|
||
<div>
|
||
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
|
||
Paxlovid is an oral treatment for mild to moderate COVID-19 cases with a high risk for severe course of the disease. For this review, we have performed a comprehensive literature review. We present a summary of currently available data on Paxlovid9s ability to reduce the risk of progressing to a severe disease state. Our findings can be concluded as follows: data from the time when the Delta-variant was dominant shows that Paxlovid reduced the risk of hospitalization or death by 87.8% for unvaccinated, non-hospitalized high-risk individuals. Data from the time when the Omicron variant was dominant found decreased risk reductions, varying between 41% and 46%, combining various vaccination statuses. However, one study, which differentiated by age, found that the administration of Paxlovid reduced the risk of hospitalization by 67% for individuals aged 65 and older, but only by 27% for individuals aged 40-64. From the available data, one can conclude that Paxlovid cannot substitute vaccination, but its low manufacturing cost as well as its easy administration make it a valuable tool in fighting COVID-19, especially for countries with a low vaccination rate.
|
||
</p>
|
||
</div>
|
||
<div class="article-link article-html-link">
|
||
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.01.13.23284506v1" target="_blank">Effectiveness of Paxlovid - a review</a>
|
||
</div></li>
|
||
<li><strong>A Scoping Review of Factors used to Explain Disparities in COVID-19 Vaccination Intentions and Uptake among People of Color: United States, December 1, 2020-April 30, 2021</strong> -
|
||
<div>
|
||
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
|
||
Background: Vaccine access, coupled with the belief that vaccines are important, beneficial, and safe, plays a pivotal role in achieving high levels of vaccination to reduce the spread and severity of COVID-19 in the United States (U.S.) and globally. Many factors can influence vaccine intentions and uptake. Methods: We conducted a scoping review of factors (e.g., access-related factors, racism) known to influence vaccine intentions and uptake, using publications from various databases and websites published December 1, 2020-April 30, 2021. Descriptive statistics were used to present results. Results: Overall, 1094 publications were identified through the database search, of which 133 were included in this review. Among the publications included, over 60% included mistrust in vaccines and vaccine-safety concerns, 43% included racism/discrimination, 35% included lack of vaccine access (35%), and 8% had no contextual factors when reporting on vaccine intentions and disparities in vaccine uptake. Conclusions: Findings revealed during a critical period when there was a well-defined goal for adult COVID-19 vaccination in the U.S., some publications included several contextual factors while others provided limited or no contextual factors when reporting on disparities in vaccine intentions and uptake. Failing to contextualize inequities and other factors that influence vaccine intentions and uptake might be perceived as placing responsibility for vaccination status on the individual, consequently, leaving social and structural inequities that impact vaccination rates and vaccine confidence, among people of color, intact.
|
||
</p>
|
||
</div>
|
||
<div class="article-link article-html-link">
|
||
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.01.12.23284499v1" target="_blank">A Scoping Review of Factors used to Explain Disparities in COVID-19 Vaccination Intentions and Uptake among People of Color: United States, December 1, 2020-April 30, 2021</a>
|
||
</div></li>
|
||
<li><strong>Estimates of COVID-19 deaths in Mainland China after abandoning zero COVID policy</strong> -
|
||
<div>
|
||
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
|
||
Background: China witnessed a surge of Omicron infections after abandoning zero COVID strategies on December 7, 2022. The authorities report very sparse deaths based on very restricted criteria, but massive deaths are speculated. Methods: We aimed to estimate the COVID-19 fatalities in Mainland China until summer 2023 using the experiences of Hong Kong and of South Korea in 2022 as prototypes. Both these locations experienced massive Omicron waves after having had very few SARS-CoV-2 infections during 2020-2021. We estimated age-stratified infection fatality rates (IFRs) in Hong Kong and South Korea during 2022 and extrapolated to the population age structure of Mainland China. We also accounted separately for deaths of residents in long-term care facilities in both Hong Kong and South Korea. Results: IFR estimates in non-elderly strata were modestly higher in Hong Kong than South Korea and projected 987,455 and 619,549 maximal COVID-19 deaths, respectively, if the entire China population was infected. Expected COVID-19 deaths in Mainland China until summer 2023 ranged from 49,962 to 691,219 assuming 25-70% of the non-elderly population being infected and variable protection of elderly (from none to three-quarter reduction in fatalities). The main analysis (45% of non-elderly population infected and fatality impact among elderly reduced by half) estimated 152,886-249,094 COVID-19 deaths until summer 2023. Large uncertainties exist regarding potential changes in dominant variant, health system strain, and impact on non-COVID-19 deaths. Conclusions: The most critical factor that can affect total COVID-19 fatalities in China is the extent to which the elderly can be protected.
|
||
</p>
|
||
</div>
|
||
<div class="article-link article-html-link">
|
||
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2022.12.29.22284048v3" target="_blank">Estimates of COVID-19 deaths in Mainland China after abandoning zero COVID policy</a>
|
||
</div></li>
|
||
<li><strong>Diagnostic performance of lateral flow immunoassays for COVID-19 antibodies in Peruvian population</strong> -
|
||
<div>
|
||
<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
|
||
Background Serological assays have been used in seroprevalence studies to inform the dynamics of COVID-19. Lateral flow immunoassay (LFIA) tests are a very practical technology to use for this objective; however, one of their challenges may be variable diagnostic performance. Given the numerous available LFIA tests, evaluation of their accuracy is critical before real-world implementation. Methods We performed a retrospective diagnostic evaluation study to independently determine the diagnostic accuracy of 4 different antibody-detection LFIA tests. The sample panel was comprised of specimens collected and stored in biobanks; specifically, specimens that were RT-PCR positive for SARS-CoV-2 collected at various times throughout the COVID-19 disease course and those that were collected before the pandemic, during 2018 or earlier, from individuals with upper respiratory symptoms but were negative for tuberculosis. Clinical performance (sensitivity and specificity) was analyzed overall, and subset across individual antibody isotypes, and days from symptoms onset. Results A very high specificity (98% - 100%) was found for all four tests. Overall sensitivity was variable, ranging from 29% [95% CI: 21%-39%] to 64% [95% CI: 54%-73%]. When considering detection of IgM only, the highest sensitivity was 42% [95% CI: 32%-52%], compared to 57% [95% CI: 47%-66%] for IgG only. When the analysis was restricted to at least 15 days since symptom onset, across any isotype, the sensitivity reached 90% for all four brands. Conclusion All four LFIA tests proved effective for identifying COVID-19 antibodies when two conditions were met: 1) at least 15 days have elapsed since symptom onset and 2) a sample is considered positive when either IgM or IgG is present. With these considerations, the use of this assays could help in seroprevalence studies or further exploration of its potential uses.
|
||
</p>
|
||
</div>
|
||
<div class="article-link article-html-link">
|
||
🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.01.13.23284518v1" target="_blank">Diagnostic performance of lateral flow immunoassays for COVID-19 antibodies in Peruvian population</a>
|
||
</div></li>
|
||
</ul>
|
||
<h1 data-aos="fade-right" id="from-clinical-trials">From Clinical Trials</h1>
|
||
<ul>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Digital Tools to Expand COVID-19 Testing in Exposed Individuals in Cameroon</strong> - <b>Condition</b>: COVID-19<br/><b>Intervention</b>: Other: Digital based contact tracing<br/><b>Sponsors</b>: Elizabeth Glaser Pediatric AIDS Foundation; Find<br/><b>Recruiting</b></p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Postural Changes and Severe COVID-19</strong> - <b>Condition</b>: COVID-19<br/><b>Intervention</b>: Behavioral: Postural interventions based on pulmonary imaging<br/><b>Sponsor</b>: Wuhan Union Hospital, China<br/><b>Recruiting</b></p></li>
|
||
<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 Jaktinib in Patients With COVID-19 Pneumoia</strong> - <b>Condition</b>: COVID-19 Pneumonia<br/><b>Interventions</b>: Drug: Jaktinib; Drug: Placebo<br/><b>Sponsor</b>: First Affiliated Hospital of Zhejiang University<br/><b>Not yet recruiting</b></p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Awaken Prone Positioning Ventinlation in COVID-19 Patients</strong> - <b>Condition</b>: COVID-19<br/><b>Intervention</b>: Procedure: Awaken prone positioning ventilation<br/><b>Sponsor</b>: Southeast University, China<br/><b>Enrolling by invitation</b></p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Effect of a Traditional Chinese Medicine Formulation on COVID-19 Infection</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Drug: Traditional Chinese Medicine Formulation; Other: Placebo Treatment<br/><b>Sponsor</b>: First Affiliated Hospital Xi’an Jiaotong University<br/><b>Not yet recruiting</b></p></li>
|
||
<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 SHEN26 Capsule in Patients With Mild to Moderate COVID-19</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Drug: SHEN26 dose 1; Drug: SHEN26 dose 2; Drug: SHEN26 placebo<br/><b>Sponsor</b>: Shenzhen Kexing Pharmaceutical Co., Ltd.<br/><b>Recruiting</b></p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Study on the Safety and Efficacy of Meplazumab for Injection in Severe Patients With COVID-19</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: Meplazumab for injection; Other: Normal saline<br/><b>Sponsor</b>: Jiangsu Pacific Meinuoke Bio Pharmaceutical Co Ltd<br/><b>Not yet recruiting</b></p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Bright Light Therapy for Post-COVID-19 Fatigue</strong> - <b>Condition</b>: Post COVID-19 Condition<br/><b>Interventions</b>: Device: Bright light therapy; Device: Dim red light therapy<br/><b>Sponsor</b>: Chinese University of Hong Kong<br/><b>Not yet recruiting</b></p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Study on the Safety and Efficacy of Meplazumab for Injection in Adults With Mild and Moderate COVID-19 Infections</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: Meplazumab foe injection; Other: Normal saline<br/><b>Sponsor</b>: Jiangsu Pacific Meinuoke Bio Pharmaceutical Co Ltd<br/><b>Not yet recruiting</b></p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Evaluate the Efficacy and Safety of FB2001 for Inhalation in Patients With Mild to Moderate COVID-19</strong> - <b>Condition</b>: Mild to Moderate COVID-19<br/><b>Interventions</b>: Drug: FB2001; Drug: FB2001 placebo<br/><b>Sponsor</b>: Frontier Biotechnologies Inc.<br/><b>Recruiting</b></p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>UC-MSCs in the Treatment of Severe and Critical COVID-19 Patients</strong> - <b>Conditions</b>: Mesenchymal Stem Cell; COVID-19 Pneumonia<br/><b>Interventions</b>: Biological: umbilical cord mesenchymal stem cells; Drug: paxlovid<br/><b>Sponsor</b>: Shanghai East Hospital<br/><b>Recruiting</b></p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>An Investigator Initiated, Randomized, Double-blinded, Placebo-controlled Clinical Trial to Evaluate the Safety, Immunogenicity and Efficacy of the Recombinant Two-component COVID-19 Vaccine (CHO Cell) in Adults Aged 18 Years and Older</strong> - <b>Condition</b>: Prevention of COVID-19 Caused by SARS-CoV-2<br/><b>Intervention</b>: Biological: randomized, double-blinded, placebo-controlled<br/><b>Sponsor</b>: Yu Qin<br/><b>Active, not recruiting</b></p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Evaluate the Efficacy and Safety of Azvudine in Preventing SARS-Cov-2 Infection in Ousehold in China</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Drug: Azvudine; Drug: Placebo<br/><b>Sponsors</b>: Shanghai Henlius Biotech; Huashan Hospital; Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd.; HeNan Sincere Biotech Co., Ltd<br/><b>Recruiting</b></p></li>
|
||
<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 Positive Emotions With Long COVID-19</strong> - <b>Condition</b>: Post-Acute COVID-19 Syndrome<br/><b>Intervention</b>: Behavioral: Microdosing of mindfulness<br/><b>Sponsor</b>: University of California, Davis<br/><b>Not yet recruiting</b></p></li>
|
||
<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 Outcome of Covid Patients Discharged Home on Oxygen Therapy</strong> - <b>Condition</b>: COVID-19<br/><b>Intervention</b>: Other: Phone satisfaction questionnaire<br/><b>Sponsor</b>: Centre Hospitalier René Dubos<br/><b>Not yet recruiting</b></p></li>
|
||
</ul>
|
||
<h1 data-aos="fade-right" id="from-pubmed">From PubMed</h1>
|
||
<ul>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Flavonoids from the roots and rhizomes of Sophoratonkinensis and their in vitro anti-SARS-CoV-2 activity</strong> - Acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had caused a global pandemic since 2019, and posed a serious threat to global health security. Traditional Chinese medicine (TCM) has played an indispensable role in the battle against the epidemic. Many components originated from TCMs were found to inhibit the production of SARS-CoV-2 3C-like protease (3CLpro) and papain-like protease (PLpro), which are two promising therapeutic targets to inhibit…</p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Immunogenicity and safety in healthy adults of full dose versus half doses of COVID-19 vaccine (ChAdOx1-S or BNT162b2) or full-dose CoronaVac administered as a booster dose after priming with CoronaVac: a randomised, observer-masked, controlled trial in Indonesia</strong> - BACKGROUND: Inactivated COVID-19 vaccines effectively prevent death, but their effectiveness for preventing infection or severe illness is known to decrease within 3-6 months following the second priming dose. Here we aimed to evaluate the immunogenicity and safety of three potential booster vaccines administered as a full-dose homologous booster or full-dose or half-dose heterologous boosters among individuals primed with CoronaVac.</p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Preclinical development of kinetin as a safe error-prone SARS-CoV-2 antiviral able to attenuate virus-induced inflammation</strong> - Orally available antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are necessary because of the continuous circulation of new variants that challenge immunized individuals. Because severe COVID-19 is a virus-triggered immune and inflammatory dysfunction, molecules endowed with both antiviral and anti-inflammatory activity are highly desirable. We identified here that kinetin (MB-905) inhibits the in vitro replication of SARS-CoV-2 in human hepatic and pulmonary cell…</p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Why did air quality experience little improvement during the COVID-19 lockdown in megacities, northeast China?</strong> - To inhibit the COVID-19 (Coronavirus disease 2019) outbreak, unprecedented nationwide lockdowns were implemented in China in early 2020, resulting in a marked reduction of anthropogenic emissions. However, reasons for the insignificant improvement in air quality in megacities of northeast China, including Shenyang, Changchun, Jilin, Harbin, and Daqing, were scarcely reported. We assessed the influences of meteorological conditions and changes in emissions on air quality in the five megacities…</p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Multi-target activity of copper complexes; antibacterial, DNA binding, and molecular docking with SARS-CoV-2 receptor</strong> - A series of pendant-armed mixed-ligand copper(II) complexes of the type [CuL^(1-3)(diimine)] (1-6) have been synthesized by the reaction of pendant-armed ligands N,N-bis(2-(((E)-2-hydroxy-5-methylbenzylidene)amino)ethyl)benzamide (H(2)L(1)), N,N-bis(2-(((E)-2-hydroxy-5-methylbenzylidene)amino)ethyl)-4-nitrobenzamide (H(2)L(2)) and N,N-bis(2-(((E)-2-hydroxy-5-methylbenzylidene)amino)ethyl)-3,5-dinitrobenzamide (H(2)L(3)) with diimine = 2,2’-bipyridyl (bpy) or 1,10-phenanthroline (phen) in the…</p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Lidocaine inhibits influenza a virus replication by up-regulating IFNα4 via TBK1-IRF7 and JNK-AP1 signaling pathways</strong> - Influenza A viruses (IAV), significant respiratory pathogenic agents, cause seasonal epidemics and global pandemics in intra- and interannual cycles. Despite effective therapies targeting viral proteins, the continuous generation of drug-resistant IAV strains is challenging. Therefore, exploring novel host-specific antiviral treatment strategies is urgently needed. Here, we found that lidocaine, widely used for local anesthesia and sedation, significantly inhibited H1N1(PR8) replication in…</p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Soluble Signal Inhibitory Receptor on Leukocytes-1 Is Released from Activated Neutrophils by Proteinase 3 Cleavage</strong> - Signal inhibitory receptor on leukocytes-1 (SIRL-1) is an immune inhibitory receptor expressed on human granulocytes and monocytes that dampens antimicrobial functions. We previously showed that sputum neutrophils from infants with severe respiratory syncytial virus (RSV) bronchiolitis have decreased SIRL-1 surface expression compared with blood neutrophils and that SIRL-1 surface expression is rapidly lost from in vitro activated neutrophils. This led us to hypothesize that activated…</p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Toll-Like Receptor 4-Dependent Platelet-Related Thrombosis in SARS-CoV-2 Infection</strong> - CONCLUSIONS: The study identifies 2 TLR4-dependent and independent pathways promoting platelet-dependent thrombus growth and suggests inhibition of TLR4. or p47phox as a tool to counteract thrombosis in SARS-CoV-2.</p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>How to achieve carbon neutrality while maintaining economic vitality: An exploration from the perspective of technological innovation and trade openness</strong> - The significant drop in global carbon emissions in 2020 was credited to the enormous loss of economic activity from the impact of COVID-19. The challenge is now to reduce carbon emissions without causing massive disruption and damage to economic production. To achieve carbon neutrality while maintaining economic vitality, the impact of technological innovation and trade openness must be considered. This paper sets technological innovation and trade openness as core variables and establishes two…</p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Molecular mechanisms in chloroquine-exposed muscle cells elucidated by combined proteomic and microscopic studies</strong> - CONCLUSION: We demonstrated that CQ exposure (secondarily) impacts biological processes beyond lysosomal function and linked a variety of proteins with known roles in the manifestation of other neuromuscular diseases.</p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Predicting the systemic exposure and lung concentration of nafamostat using physiologically-based pharmacokinetic modeling</strong> - Nafamostat has been actively studied for its neuroprotective activity and effect on various indications, such as coronavirus disease 2019 (COVID-19). Nafamostat has low water solubility at a specific pH and is rapidly metabolized in the blood. Therefore, it is administered only intravenously, and its distribution is not well known. The main purposes of this study are to predict and evaluate the pharmacokinetic (PK) profiles of nafamostat in a virtual healthy population under various dosing…</p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Pharmacokinetic/Pharmacodynamic Modeling of Dexamethasone Anti-Inflammatory and Immunomodulatory Effects in LPS-Challenged Rats: A Model for Cytokine Release Syndrome</strong> - Dexamethasone (DEX) is a potent synthetic glucocorticoid used for the treatment of variety of inflammatory and immune-mediated disorders. The RECOVERY clinical trial revealed benefits of DEX therapy in COVID-19 patients. Severe SARS-CoV-2 infection leads to an excessive inflammatory reaction commonly known as a cytokine release syndrome that is associated with activation of the toll like receptor 4 (TLR4) signaling pathway. The possible mechanism of action of DEX in the treatment of COVID-19 is…</p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>P2Y12 Inhibition Suppresses Proinflammatory Platelet-Monocyte Interactions</strong> - BACKGROUND: Monocyte-platelet aggregates (MPAs) represent the crossroads between thrombosis and inflammation, and targeting this axis may suppress thromboinflammation. While antiplatelet therapy (APT) reduces platelet-platelet aggregation and thrombosis, its effects on MPA and platelet effector properties on monocytes are uncertain.</p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>4-Aminoquinolines modulate RNA structure and function: Pharmacophore implications of a conformationally restricted polyamine</strong> - RNA structure plays an important role in regulating cellular function and there is a significant emerging interest in targeting RNA for drug discovery. Here we report the identification of 4-aminoquinolines as modulators of RNA structure and function. Aminoquinolines have a broad range of pharmacological activities, but their specific mechanism of action is often not fully understood. Using electrophoretic mobility shift assays and enzymatic probing we identified 4-aminoquinolines that bind the…</p></li>
|
||
<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Sleep as a protective factor of children’s executive functions: A study during COVID-19 confinement</strong> - Confinements due to the COVID-19 outbreak affected sleep and mental health of adults, adolescents and children. Already preschool children experienced acutely worsened sleep, yet the possible resulting effects on executive functions remain unexplored. Longitudinally, sleep quality predicts later behavioral-cognitive outcomes. Accordingly, we propose children’s sleep behavior as essential for healthy cognitive development. By using the COVID-19 confinement as an observational-experimental…</p></li>
|
||
</ul>
|
||
<h1 data-aos="fade-right" id="from-patent-search">From Patent Search</h1>
|
||
|
||
|
||
<script>AOS.init();</script></body></html> |