05 April, 2021

Differences in risk for SARS-CoV-2 infection among healthcare workers -

Healthcare workers (HCWs) are a risk group for SARS-CoV-2 infection, but which healthcare work that conveys risk and to what extent such risk can be prevented is not clear. Starting on April 24th, 2020, all employees at work (n=15,300) at the Karolinska University Hospital, Stockholm, Sweden were invited and 92% consented to participate in a SARS-CoV-2 cohort study. Complete SARS-CoV-2 serology was available for n=12,928 employees and seroprevalences were analyzed by age, sex, profession, patient contact, and hospital department. Relative risks were estimated to examine the association between type of hospital department as a proxy for different working environment exposure and risk for seropositivity, adjusting for age, sex, sampling week, and profession. Wards that were primarily responsible for COVID-19 patients were at increased risk (adjusted OR 1.95 (95% CI 1.65-2.32) with the notable exception of the infectious diseases and intensive care units (adjusted OR 0.86 (95% CI 0.66-1.13)), that were not at increased risk despite being highly exposed. Several units with similar types of work varied greatly in seroprevalences. Among the professions examined, nurse assistants had the highest risk (adjusted OR 1.62 (95% CI 1.38-1.90)). Although healthcare workers, in particular nurse assistants, who attend to COVID-19 patients are a risk group for SARS-CoV-2 infection, several units caring for COVID-19 patients had no excess risk. Large variations in seroprevalences among similar units suggest that healthcare work-related risk of SARS-CoV-2 infection may be preventable.

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Smoking modulates different secretory subpopulations expressing SARS-CoV-2 entry genes in the nasal and bronchial airways -

Coronavirus Disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which infects host cells with help from the Viral Entry (VE) proteins ACE2, TMPRSS2, and CTSL. Proposed risk factors for viral infection, as well as the rate of disease progression, include age, sex, chronic obstructive pulmonary disease, cancer, and cigarette smoking. To investigate whether the proposed risk factors increase viral infection by modulation of the VE genes, we examined gene expression profiles of 796 nasal and 1,673 bronchial samples across four lung cancer screening cohorts containing individuals without COVID-19. Smoking was the only clinical factor reproducibly associated with the expression of any VE gene across cohorts. ACE2 expression was significantly up-regulated with smoking in the bronchus but significantly down-regulated with smoking in the nose. Furthermore, expression of individual VE genes were not correlated between paired nasal and bronchial samples from the same patients. Single-cell RNA-seq of nasal brushings revealed that an ACE2 gene module was detected in a variety of nasal secretory cells with the highest expression in the C15orf48+ secretory cells, while a TMPRSS2 gene module was most highly expressed in nasal keratinizing epithelial cells. In contrast, single-cell RNA-seq of bronchial brushings revealed that ACE2 and TMPRSS2 gene modules were most enriched in MUC5AC+ bronchial goblet cells. The CTSL gene module was highly expressed in immune populations of both nasal and bronchial brushings. Deconvolution of bulk RNA-seq showed that the proportion of MUC5AC+ goblet cells was increased in current smokers in both the nose and bronchus but proportions of nasal keratinizing epithelial cells, C15orf48+ secretory cells, and immune cells were not associated with smoking status. The complex association between VE gene expression and smoking in the nasal and bronchial epithelium revealed by our results may partially explain conflicting reports on the association between smoking and SARS-CoV-2 infection.

🖺 Full Text HTML: Smoking modulates different secretory subpopulations expressing SARS-CoV-2 entry genes in the nasal and bronchial airways

A novel variant of interest of SARS-CoV-2 with multiple spike mutations is identified from travel surveillance in Africa -

At the end of 2020, the Network for Genomic Surveillance in South Africa (NGS-SA) detected a SARS-CoV-2 variant of concern (VOC) in South Africa (501Y.V2 or PANGO lineage B.1.351)1. 501Y.V2 is associated with increased transmissibility and resistance to neutralizing antibodies elicited by natural infection and vaccination2,3. 501Y.V2 has since spread to over 50 countries around the world and has contributed to a significant resurgence of the epidemic in southern Africa. In order to rapidly characterize the spread of this and other emerging VOCs and variants of interest (VOIs), NGS-SA partnered with the Africa Centres for Disease Control and Prevention and the African Society of Laboratory Medicine through the Africa Pathogen Genomics Initiative to strengthen SARS-CoV-2 genomic surveillance across the region. Here, we report the first genomic surveillance results from Angola, which has had 21 500 reported cases and around 500 deaths from COVID-19 up to March 2021 (Supplemental Fig S1). On 15 January 2021, in response to the international spread of VOCs, the government instituted compulsory rapid antigen testing of all passengers arriving at the main international airport, in addition to the existing requirement to present a negative PCR test taken within 72 hours of travel. All individuals with a positive antigen test are isolated in a government facility for a minimum of 14 days and require two negative RT-PCR tests at least 48 hours apart for de-isolation, whilst all travelers with a negative test on arrival proceed to mandatory self-quarantine for 10 days followed by a repeat test. In March 2021, we received 118 nasopharyngeal swab samples collected between June 2020 and February 2021, a number of which were from incoming air travelers (Supplemental Fig S1). From these, we produced 73 high quality genomes (>80% coverage), 14 of which were known VOCs/VOIs (seven 501Y.V2/B.1.351, six B.1.1.7, one B.1.525), 44 of which were C.16 (a common lineage circulating in Portugal), and twelve of which were other lineages (Supplemental Fig S2). In addition, we detected a new VOI in three incoming travelers from Tanzania who were tested together at the airport in mid-February. The three genomes from these passengers were almost identical and presented highly divergent sequences within the A lineage (Figure 1A & 1B). The GISAID database contains nine other sequences reported to be sampled from cases involving travel from Tanzania, two of which are basal to the three sampled in Angola (Figure 1A, Supplemental Table S1). This new VOI, temporarily designated A.VOI.V2, has 31 amino acid substitutions (11 in spike) and three deletions (all in spike) (Figure 1C & 1D). The spike mutations include three substitutions in the receptor-binding domain (R346K, T478R and E484K); five substitutions and three deletions in the N-terminal domain, some of which are within the antigenic supersite (Y144Δ, R246M, SYL247-249Δ and W258L)4; and two substitutions adjacent to the S1/S2 cleavage site (H655Y and P681H). Several of these mutations are present in other VOCs/VOIs and are evolving under positive selection.

🖺 Full Text HTML: A novel variant of interest of SARS-CoV-2 with multiple spike mutations is identified from travel surveillance in Africa

Predictive modeling of COVID-19 New Confirmed Cases in Algeria using Artificial Neural Network -

This study investigates the potential of a simple artificial neural network for the prediction of COVID-19 New Confirmed Cases in Algeria (CNCC). Four different ANN models were built (GRNN, RBFNN, ELM, and MLP). The performance of the predictive models is evaluated based on four numerical parameters, namely root mean squared error (RMSE), mean absolute error (MAE), Nash-Sutcliffe efficiency (NSE), and Pearson correlation coefficient (R). Taylor diagram was also used to examine the similarities and differences between the observed and predicted values obtained from the proposed models. The results showed the potential of the multi-layer perceptron neural network (MLPNN) which exhibited a high level of accuracy in comparison to the other models.

🖺 Full Text HTML: Predictive modeling of COVID-19 New Confirmed Cases in Algeria using Artificial Neural Network

RELATIONSHIP OF LIVER ENZYME LEVELS WITH THE CLINICAL COURSE OF COVID-19 -

Introduction: Covid 19 infection, which can affect many systems in the human body, can cause organ dysfunction. High liver serum enzymes can be found in covid-19 patients, and many factors cause this stop. Patients with high levels of liver enzymes that require invasive mechanical ventilation during their follow-up were examined, and it was aimed to determine whether it was among the predictive indicators of mortality. MATERIAL AND METHODS: Patients infected with covid 19 who were hospitalized in the intensive care unit between March 30 and December 1, 2020 according to the criteria of hospitalization in the intensive care unit, clinical trials such as age, gender, length of stay, additional diseases, liver enzyme levels and whether invasive mechanical ventilation is required their characteristics were recorded and analyzed retrospectively and compared. RESULTS: Data were collected from 111 patients whose liver enzyme levels were measured from 131 patients included in the study. It was found that aspartate transaminase, alanine aminotransferase, and gamma-glutamyl transferase levels were statistically higher in the invasive mechanical ventilation group compared to the patients who did not undergo invasive mechanical ventilation. CONCLUSION: Alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase levels were statistically higher in COVID19-infected patients who were treated in intensive care and undergoing invasive mechanical ventilation. These enzymes are easily accessible and are shown among predictive values in mortality.

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Factors associated with nonessential workplace attendance during the Covid-19 pandemic in the UK in early 2021: evidence from cross-sectional surveys -

Background and aims: Working from home where possible is important in reducing spread of Covid-19. In early 2021, a quarter of people in England who believed they could work entirely from home reported attending their workplace. To inform interventions to reduce this, this study examined associated factors. Methods: Data from the ongoing CORSAIR survey series of nationally representative samples of people in the UK aged 16+ years in January-February 2021 were used. The study sample was 1422 respondents who reported that they could work completely from home. The outcome measure was self-reported workplace attendance at least once during the preceding week. Factors of interest were analysed in three blocks: 1) sociodemographic variables, 2) variables relating to circumstances of respondents, and 3) psychological variables. Results: 26.8% (95%CI=24.5%-29.1%) of respondents reported having attended their workplace at least once in the preceding week. Sociodemographic variables and living circumstances significantly independently predicted non-essential workplace attendance: male gender (OR=1.85,95%CI=1.33-2.58), dependent children in the household (OR=1.65,95%CI=1.17-2.32), financial hardship (OR=1.14,95%CI=1.08-1.21), socio-economic grade C2DE (OR=1.74, 95%CI=1.19-2.53), working in sectors such as health or social care (OR=4.18, 95%CI=2.56-6.81), education and childcare (OR=2.45, 95%CI=1.45-4.14) and key public service (OR=3.78, 95%CI=1.83-7.81), and having been vaccinated (OR=2.08,95%CI=1.33-3.24). Conclusions: Non-essential workplace attendance in the UK in early 2021 during the Covid-19 pandemic was significantly independently associated with a range of sociodemographic variables and personal circumstances. Having been vaccinated, financial hardship, socio-economic grade C2DE, having a dependent child at home, working in certain key sectors were associated with higher likelihood of workplace attendance.

🖺 Full Text HTML: Factors associated with nonessential workplace attendance during the Covid-19 pandemic in the UK in early 2021: evidence from cross-sectional surveys

Determining the cutoff points of the 5C scale for assessment of COVID-19 vaccines psychological antecedents among the Arab population: A multinational study -

Background: One of the newly faced challenges during the COVID-19 is vaccine hesitancy (VH). The validated 5C scale, which assesses five psychological antecedents of vaccination, could be effective in exploring COVID-19 VH. This study aimed to determine a statistically valid cutoff point for the 5C sub-scales among the Arab population. Methods: A cross-sectional study was conducted among 446 subjects from three Arab countries (Egypt, United Arab Emirates UAE, and Jordan). Information regarding sociodemographics, clinical history, COVID-19 infection and vaccination history, and 5C scale were collected online. The 5C scores were analyzed to define the cutoff points using the receiver operating characteristic curve (ROC) and to verify the capability of the questionnaire to differentiate whether responders are hesitant or non-hesitant to accept vaccination. ROC curve analysis was conducted setting for previous vaccine administration as a response, with the predictors being the main five domains of the 5C questionnaire. The mean score of each sub-scale was compared with COVID-19 vaccine intake Results: The mean age of the studied population was 37+11, 42.9% were males, 44.8% from Egypt, 21.1% from Jordan, and 33.6% from UAE. Statistically significant differences between vaccinated and unvaccinated participants, respectively, were detetd in the median score of confidence [6.0(1.3) versus 4.7(2.0)], complacency [(2.7(2.0) versus 3.0(2.0), constraints [1.7(1.7) versus 3.7(2.3)], and collective responsibility [6.7(1.7) versus 5.7(1.7)]. The area under the curve of the five scales was 0.72, 0.60, 0.76, 0.66, 0.66 for confidence, complacency, constraints, calculation, and collective responsibility at cutoff values of 5.7, 4.7, 6.0, 6.3, and 6.2, respectively. Conclusion the Arabic validated version of the 5C scale has a good discriminatory power to predict COVID-19 vaccines antecedent.

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GUIdEStaR (G-quadruplex, uORF, IRES, Epigenetics, Small RNA, Repeats), the integrated matadatabase: transcript-indexed binary information creation for chaining with neural network analysis -

GUIdEStaR integrates existing databases of important compositional and structural elements of sequences- various types of G-quadruplex, upstream open reading frame (uORF), Internal Ribosome Entry Site (IRES), epigenetic modification (histone protein and RNA), and repeats. It contains binary information (presence/absence of the elements) that are organized into 5 regions (5’UTR, 3’UTR, exon, intron, and biological region) per transcript and per gene. These elements are highly interdependent in controlling functional interaction of a gene. The database contains information of approx. 40,000 genes and 320,000 transcripts, where each transcript has 845 presence/absence information. Recently, artificial intelligence (AI) based analysis of sequencing data has been gaining popularity in the area of bioinformatics. To create a dataset that can be used as an input to AI methods, GUIdEStaR comes with example Java codes. Here, we demonstrates the database usage with three neural network classification examples- 1) small RNA example for identifying the attributes that are unique to transcription factor (TF) genes mediated by small RNAs originated from SARS-CoV-2 vs. from human, 2) cell membrane receptor study for classifying virus interacting vs. non-interacting receptors, and 3) receptors targeted by nonsense mediated mRNA decay (NMD) vs. of non-target. GUIdEStaR is freely available at www.guidestar.kr and https://sourceforge.net/projects/guidestar.

🖺 Full Text HTML: GUIdEStaR (G-quadruplex, uORF, IRES, Epigenetics, Small RNA, Repeats), the integrated matadatabase: transcript-indexed binary information creation for chaining with neural network analysis

Preprints in motion: tracking changes between posting and journal publication -

Amidst the COVID-19 pandemic, preprints in the biomedical sciences are being posted and accessed at unprecedented rates, drawing widespread attention from the general public, press and policymakers for the first time. This phenomenon has sharpened longstanding questions about the reliability of information shared prior to journal peer review. Does the information shared in preprints typically withstand the scrutiny of peer review, or are conclusions likely to change in the version of record? We assessed preprints that had been posted and subsequently published in a journal between 1st January and 30th April 2020, representing the initial phase of the pandemic response. We utilised a combination of automatic and manual annotations to quantify how an article changed between the preprinted and published version. We found that the total number of figure panels and tables changed little between preprint and published articles. Moreover, the conclusions of 6% of non-COVID-19-related and 15% of COVID-19-related abstracts undergo a discrete change by the time of publication, but the majority of these changes do not reverse the main message of the paper.

🖺 Full Text HTML: Preprints in motion: tracking changes between posting and journal publication

Sex differences in lung imaging and SARS-CoV-2 antibody responses in a COVID-19 golden Syrian hamster model -

In the ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), more severe outcomes are reported in males compared with females, including hospitalizations and deaths. Animal models can provide an opportunity to mechanistically interrogate causes of sex differences in the pathogenesis of SARS-CoV-2. Adult male and female golden Syrian hamsters (8-10 weeks of age) were inoculated intranasally with 105 TCID50 of SARS-CoV-2/USA-WA1/2020 and euthanized at several time points during the acute (i.e., virus actively replicating) and recovery (i.e., after the infectious virus has been cleared) phases of infection. There was no mortality, but infected male hamsters experienced greater morbidity, losing a greater percentage of body mass, developing more extensive pneumonia as noted on chest computed tomography, and recovering more slowly than females. Treatment of male hamsters with estradiol did not alter pulmonary damage. Virus titers in respiratory tissues, including nasal turbinates, trachea, and lungs, and pulmonary cytokine concentrations, including IFNb and TNFa, were comparable between the sexes. However, during the recovery phase of infection, females mounted two-fold greater IgM, IgG, and IgA responses against the receptor-binding domain of the spike protein (S-RBD) in both plasma and respiratory tissues. Female hamsters also had significantly greater IgG antibodies against whole inactivated SARS-CoV-2 and mutant S-RBDs, as well as virus neutralizing antibodies in plasma. The development of an animal model to study COVID-19 sex differences will allow for a greater mechanistic understanding of the SARS-CoV-2 associated sex differences seen in the human population.

🖺 Full Text HTML: Sex differences in lung imaging and SARS-CoV-2 antibody responses in a COVID-19 golden Syrian hamster model

Membrane lectins enhance SARS-CoV-2 infection and influence the neutralizing activity of different classes of antibodies -

Investigating the mechanisms of SARS-CoV-2 cellular infection is key to better understand COVID-19 immunity and pathogenesis. Infection, which involves both cell attachment and membrane fusion, relies on the ACE2 receptor that is paradoxically found at low levels in the respiratory tract, suggesting that additional mechanisms facilitating infection may exist. Here we show that C-type lectin receptors, DC-SIGN, L-SIGN and the sialic acid-binding Ig-like lectin 1 (SIGLEC1) function as auxiliary receptors by enhancing ACE2-mediated infection and modulating the neutralizing activity of different classes of spike-specific antibodies. Antibodies to the N-terminal domain (NTD) or to the conserved proteoglycan site at the base of the Receptor Binding Domain (RBD), while poorly neutralizing infection of ACE2 over-expressing cells, effectively block lectin-facilitated infection. Conversely, antibodies to the Receptor Binding Motif (RBM), while potently neutralizing infection of ACE2 over-expressing cells, poorly neutralize infection of cells expressing DC-SIGN or L-SIGN and trigger fusogenic rearrangement of the spike promoting cell-to-cell fusion. Collectively, these findings identify a lectin-dependent pathway that enhances ACE2-dependent infection by SARS-CoV-2 and reveal distinct mechanisms of neutralization by different classes of spike-specific antibodies.

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Recovery from acute SARS-CoV-2 infection and development of anamnestic immune responses in T cell-depleted rhesus macaques -

Severe COVID-19 has been associated with T cell lymphopenia 1,2, but no causal effect of T cell deficiency on disease severity has been established. To investigate the specific role of T cells in recovery from SARS-CoV-2 infections we studied rhesus macaques that were depleted of either CD4+, CD8+ or both T cell subsets prior to infection. Peak virus loads were similar in all groups, but the resolution of virus in the T cell-depleted animals was slightly delayed compared to controls. The T cell-depleted groups developed virus-neutralizing antibody responses and also class-switched to IgG. When re-infected six weeks later, the T cell-depleted animals showed anamnestic immune responses characterized by rapid induction of high-titer virus-neutralizing antibodies, faster control of virus loads and reduced clinical signs. These results indicate that while T cells play a role in the recovery of rhesus macaques from acute SARS-CoV-2 infections, their depletion does not induce severe disease, and T cells do not account for the natural resistance of rhesus macaques to severe COVID-19. Neither primed CD4+ or CD8+ T cells appeared critical for immunoglobulin class switching, the development of immunological memory or protection from a second infection.

🖺 Full Text HTML: Recovery from acute SARS-CoV-2 infection and development of anamnestic immune responses in T cell-depleted rhesus macaques

Structure and dynamics of SARS-CoV-2 proofreading exoribonuclease ExoN -

High-fidelity replication of the large RNA genome of coronaviruses (CoVs) is mediated by a 3’-to-5’ exoribonuclease (ExoN) in non-structural protein 14 (nsp14), which excises nucleotides including antiviral drugs mis-incorporated by the low-fidelity viral RNA-dependent RNA polymerase (RdRp) and has also been implicated in viral RNA recombination and resistance to innate immunity. Here we determined a 1.6-[A] resolution crystal structure of SARS-CoV-2 ExoN in complex with its essential co-factor, nsp10. The structure shows a highly basic and concave surface flanking the active site, comprising several Lys residues of nsp14 and the N-terminal amino group of nsp10. Modeling suggests that this basic patch binds to the template strand of double-stranded RNA substrates to position the 3’ end of the nascent strand in the ExoN active site, which is corroborated by mutational and computational analyses. Molecular dynamics simulations further show remarkable flexibility of multi-domain nsp14 and suggest that nsp10 stabilizes ExoN for substrate RNA-binding to support its exoribonuclease activity. Our high-resolution structure of the SARS-CoV-2 ExoN-nsp10 complex serves as a platform for future development of anti-coronaviral drugs or strategies to attenuate the viral virulence.

🖺 Full Text HTML: Structure and dynamics of SARS-CoV-2 proofreading exoribonuclease ExoN

Some Mathematics for the Method of Pooled PCR Test -

At the time of the worldwide COVID-19 disaster, the author learned about the pooled (RT-) PCR test from the news. From the common sense of individual tests, the idea of mixing multiple samples seems taboo, however in fact many samples can be tested with a smaller number of tests by the method. As a retired researcher of mathematical engineering, the author was deeply interested in the idea and absorbed in the mathematical formulation and intensive analysis of the method. Later, he found that the original basic equation was already proposed in the old (1943) treatise [1] and so many related research works have been done and available as materials on the web [2], although many of those seem to be based on qualitative or intuitive analysis. In that sense, some of the analysis here seems to be already known in the field, but some results might be novel, such as boundary conditions, derivation of limit values, estimation of infection rate and adaptive optimization scheme of pool test, strict extension to multi-stage pool test, and explicit derivation of asymptotic approximate solutions of optimal pooling number and achieved efficiency measure, etc. In any case, he decided to put it together here as a material rather than a formal treatise, hoping that the results here would be useful for deeper mathematical insights into and better understanding of the pool inspection, and also in its actual practice.

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Rapid, point-of-care molecular diagnostics with Cas13 -

Rapid nucleic acid testing is a critical component of a robust infrastructure for increased disease surveillance. Here, we report a microfluidic platform for point-of-care, CRISPR-based molecular diagnostics. We first developed a nucleic acid test which pairs distinct mechanisms of DNA and RNA amplification optimized for high sensitivity and rapid kinetics, linked to Cas13 detection for specificity. We combined this workflow with an extraction-free sample lysis protocol using shelf-stable reagents that are widely available at low cost, and a multiplexed human gene control for calling negative test results. As a proof-of-concept, we demonstrate sensitivity down to 40 copies/μL of SARS-CoV-2 in unextracted saliva within 35 minutes, and validated the test on total RNA extracted from patient nasal swabs with a range of qPCR Ct values from 13-35. To enable sample-to-answer testing, we integrated this diagnostic reaction with a single-use, gravity-driven microfluidic cartridge followed by real-time fluorescent detection in a compact companion instrument. We envision this approach for Diagnostics with Coronavirus Enzymatic Reporting (DISCoVER) will incentivize frequent, fast, and easy testing.

🖺 Full Text HTML: Rapid, point-of-care molecular diagnostics with Cas13

Covid-19 Sentry

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From Preprints

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