Cerebral venous sinus thrombosis following ChAdOx1 nCoV-19 AstraZeneca COVID-19 vaccine.

A woman in her mid-twenties was admitted with headache, ultimately leading to a diagnosis of cerebral venous sinus thrombosis 10 days after receiving a first dose of the AstraZeneca ChAdOx1 nCoV-19 vaccine (Vaxzevria). We report this case from clinical investigations to outcomes and discuss the issues raised by it regarding the ChAdOx1 nCoV-19 vaccine.

Targeting an evolutionarily conserved "E-L-L" motif in spike protein to identify a small molecule fusion inhibitor against SARS-CoV-2.

As newer variants of SARS-CoV-2 continue to pose major threats to global human health and economy, identifying novel druggable antiviral targets is the key toward sustenance. Here, we identify an evolutionarily conserved "Ex3Lx6L" ("E-L-L") motif present within the HR2 domain of all human and nonhuman coronavirus spike (S) proteins that play a crucial role in stabilizing its postfusion six-helix bundle (6-HB) structure and thus, fusion-mediated viral entry. Mutations within this motif reduce the fusogenicity of the S protein without affecting its stability or membrane localization. We found that posaconazole, an FDA-approved drug, binds to this "E-L-L" motif and impedes the formation of 6-HB, thus effectively inhibiting SARS-CoV-2 infection in cells. While posaconazole exhibits high efficacy in blocking S protein-mediated viral entry, mutations within the "E-L-L" motif rendered the protein completely resistant to the drug, establishing its specificity toward this motif. Our data demonstrate that posaconazole restricts early stages of infection through specific inhibition of membrane fusion and viral genome release into the host cell and is equally effective toward all major variants of concerns of SARS-CoV-2, including Beta, Kappa, Delta, and Omicron. Together, we show that this conserved essential "E-L-L" motif is an ideal target for the development of prophylactic and therapeutic interventions against SARS-CoV-2.

SARS-CoV-2 infection increases the gene expression profile for Alzheimer's disease risk.

The coronavirus disease 2019 (COVID-19) pandemic has caused over 600,000,000 infections globally thus far. Up to 30% of individuals with mild to severe disease develop long COVID, exhibiting diverse neurologic symptoms including dementias. However, there is a paucity of knowledge of molecular brain markers and whether these can precipitate the onset of Alzheimer's disease (AD). Herein, we report the brain gene expression profiles of severe COVID-19 patients showing increased expression of innate immune response genes and genes implicated in AD pathogenesis. The use of a mouse-adapted strain of SARS-CoV-2 (MA10) in an aged mouse model shows evidence of viral neurotropism, prolonged viral infection, increased expression of tau aggregator FKBP51, interferon-inducible gene Ifi204, and complement genes C4 and C5AR1. Brain histopathology shows AD signatures including increased tau-phosphorylation, tau-oligomerization, and α-synuclein expression in aged MA10 infected mice. The results of gene expression profiling of SARS-CoV-2-infected and AD brains and studies in the MA10 aged mouse model taken together, for the first time provide evidence suggesting that SARS-CoV-2 infection alters expression of genes in the brain associated with the development of AD. Future studies of common molecular markers in SARS-CoV-2 infection and AD could be useful for developing novel therapies targeting AD.

An improved, simple and field-deployable CRISPR-Cas12a assay for the detection of SARS-CoV-2.

AIMS: The RT-PCR is the most popular confirmatory test for SARS-CoV-2. It is sensitive, but high instrumentation cost makes it difficult for use outside routine clinical setup. This has necessitated the development of alternative methods such as CRISPR-based DETECTR method which uses lateral flow technology. Although accurate and sensitive, this method is limited by complex steps and recurrent cost of high-quality lateral flow strips. The main goal of this study was to improve the Cas12a-based SARS-CoV-2 DETECTR method and develop a portable and field-deployable system to reduce the recurring consumable cost. METHODS AND RESULTS: Specific regions of N and E genes from SARS-CoV-2 virus and human RNase P (internal control) were reverse transcribed (RT) and amplified by loop-mediated isothermal amplification (LAMP). The amplified products were detected by a Cas12a-based trans-cleavage reaction that generated a fluorescent signal which could be easily visualized by naked eye. Detection of internal control, RNase P gene was improved and optimized by redesigning RT-LAMP primers. A number of steps were reduced by combining the reagents related to the detection of Cas12a trans-cleavage reaction into a single ready-to-use mix. A portable, cost-effective battery-operated instrument, CRISPR-CUBE was developed to run the assay and visualize the outcome. The method and instrument were validated using both contrived and patient samples. CONCLUSIONS: The simplified CRISPR-based SARS-CoV-2 detection and instrument developed in this study, along with improved design for internal control detection allows for easier, more definitive viral detection requiring only reagents, consumables and the battery operable CRISPR-CUBE. SIGNIFICANCE AND IMPACT OF STUDY: Significant improvement in Cas12 method, coupled with simple visualization of end point makes the method and instrument deployable at the point-of-care (POC) for SARS-CoV-2 detection, without any recurrent cost for the lateral flow strips which is used in other POC methods.

Ultrafast-UV laser integrating cavity device for inactivation of SARS-CoV-2 and other viruses.

Ultraviolet (UV) irradiation-based methods used for viral inactivation have provided an important avenue targeting severe acute respiratory-syndrome coronavirus-2 (SARS-CoV-2) virus. A major problem with state-of-the-art UV inactivation technology is that it is based on UV lamps, which have limited efficiency, require high power, large doses, and long irradiation times. These drawbacks limit the use of UV lamps in air filtering systems and other applications. To address these limitations, herein we report on the fabrication of a device comprising a pulsed nanosecond 266 nm UV laser coupled to an integrating cavity (LIC) composed of a UV reflective material, polytetrafluoroethylene. Previous UV lamp inactivation cavities were based on polished walls with specular reflections, but the diffuse reflective UV ICs were not thoroughly explored for virus inactivation. Our results show that LIC device can inactivate several respiratory viruses including SARS-CoV-2, at ~ 1 ms effective irradiation time, with > 2 orders of magnitude higher efficiency compared to UV lamps. The demonstrated 3 orders of magnitude cavity enhancement relative to direct exposure is crucial for the development of efficient real-time UV air and water purification systems. To the best of our knowledge this is the first demonstration of LIC application for broad viral inactivation with high efficiency.

Deep Learning Based Intelligent Screening Mechanism

Facial recognition is widely used for identification of people as one of the biometric authentications. Biometric authentication consists of two types physiological and behavioral features. In physiological biometrics, faces, iris, and fingerprints are used for identifying the person. In behavioral biometrics, their characteristic features namely voice, DNA and hand writing is used. While using facial recognition, an individual can be identified using the previously trained model using deep learning based on the Haar cascade algorithm. Biometric authentication has been generally used for surveillance purposes. However, due to the COVID 19 pandemic, people of each nation are in need to wear face masks for their safety. Our project uses deep learning and open cv to recognize the person and to identify whether he wears a face mask or not by using transfer learning techniques and convolution neural network. One large dataset of people with mask and people without a mask was used as a training model. Our project was able to achieve an accuracy of 96.8% during the training and testing phase. © 2022 IEEE.

Study of novel COVID-19 data using graph energy centrality: a soft computing approach

The propagation of the new pandemic COVID-19 is more likely linked to human social relations and activities. A social network can be used to describe these human relationships and activities. Understanding the dynamic properties of disease dissemination through diverse social networks is critical for effective and efficient infection prevention and control. With the frequent emergence and spread of infectious diseases and their impact on large areas of the population, there is growing interest in modelling these complex epidemic behaviour. Such an approach could provide a stronger decision-making method to tackle and control disease. In this paper, a transmission network is developed using the South Korean data, and the study of the network is carried out using graph energy centrality. This measure of centrality allows us to recognise the primary cause of the spread of the virus within the established network by ranking the nodes of the network based on graph energy. The identified primary cause can then be isolated, which can prevent further spread of infection. We have also considered the Novel_Corona_Virus_2019_Dataset from Johns Hopkins University to analyse epidemiological data around the world.

Targeting an evolutionarily conserved "E-L-L" motif in the spike protein to develop a small molecule fusion inhibitor against SARS-CoV-2 (preprint)

As newer variants of SARS-CoV-2 continue to pose major threats to global human health and economy, identifying novel druggable antiviral targets is the key towards sustenance. Here, we identify an evolutionary conserved E-L-L motif present within the HR2 domain of all human and non-human coronavirus spike (S) proteins that play a crucial role in stabilizing the post-fusion six-helix bundle (6-HB) structure and thus, fusion-mediated viral entry. Mutations within this motif reduce the fusogenicity of the S protein without affecting its stability or membrane localization. We found that posaconazole, an FDA-approved drug, binds to this E-L-L motif resulting in effective inhibition of SARS-CoV-2 infection in cells. While posaconazole exhibits high efficacy towards blocking S protein-mediated viral entry, mutations within the E-L-L motif rendered the protein completely resistant to the drug, establishing its specificity towards this motif. Our data demonstrate that posaconazole restricts early stages of infection through specific inhibition of membrane fusion and viral genome release into the host cell and is equally effective towards all major variants of concerns of SARS-CoV-2 including beta, kappa, delta, and omicron. Together, we show that this conserved essential E-L-L motif is an ideal target for the development of prophylactic and therapeutic interventions against SARS-CoV-2.

Identification of SARS-CoV-2 Spike Palmitoylation Inhibitors That Results in Release of Attenuated Virus with Reduced Infectivity.

The spike proteins of enveloped viruses are transmembrane glycoproteins that typically undergo post-translational attachment of palmitate on cysteine residues on the cytoplasmic facing tail of the protein. The role of spike protein palmitoylation in virus biogenesis and infectivity is being actively studied as a potential target of novel antivirals. Here, we report that palmitoylation of the first five cysteine residues of the C-terminal cysteine-rich domain of the SARS-CoV-2 S protein are indispensable for infection, and palmitoylation-deficient spike mutants are defective in membrane fusion. The DHHC9 palmitoyltransferase interacts with and palmitoylates the spike protein in the ER and Golgi and knockdown of DHHC9 results in reduced fusion and infection of SARS-CoV-2. Two bis-piperazine backbone-based DHHC9 inhibitors inhibit SARS-CoV-2 S protein palmitoylation and the resulting progeny virion particles released are defective in fusion and infection. This establishes these palmitoyltransferase inhibitors as potential new intervention strategies against SARS-CoV-2.

Activation of Intracellular Complement in Lungs of Patients With Severe COVID-19 Disease Decreases T-Cell Activity in the Lungs.

A novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), arose late in 2019, with disease pathology ranging from asymptomatic to severe respiratory distress with multi-organ failure requiring mechanical ventilator support. It has been found that SARS-CoV-2 infection drives intracellular complement activation in lung cells that tracks with disease severity. However, the cellular and molecular mechanisms responsible remain unclear. To shed light on the potential mechanisms, we examined publicly available RNA-Sequencing data using CIBERSORTx and conducted a Ingenuity Pathway Analysis to address this knowledge gap. In complement to these findings, we used bioinformatics tools to analyze publicly available RNA sequencing data and found that upregulation of complement may be leading to a downregulation of T-cell activity in lungs of severe COVID-19 patients. Thus, targeting treatments aimed at the modulation of classical complement and T-cell activity may help alleviate the proinflammatory effects of COVID-19, reduce lung pathology, and increase the survival of COVID-19 patients.

Inhibition of SARS-CoV-2 spike protein palmitoylation reduces virus infectivity (preprint)

Spike glycoproteins of almost all enveloped viruses are known to undergo post-translational attachment of palmitic acid moieties. The precise role of such palmitoylation of the spike protein in membrane fusion and infection is not completely understood. Here, we report that palmitoylation of the first five cysteine residues of the c-terminal cysteine-rich domain of the SARS-CoV-2 spike are indispensable for infection and palmitoylation deficient spike mutants are defective in trimerization and subsequent membrane fusion. The DHHC9 palmitoyltransferase interacts with and palmitoylates the spike protein in the ER and Golgi, and knockdown of DHHC9 results in reduced fusion and infection of SARS-CoV-2. Two bis-piperazine backbone-based DHHC9 inhibitors inhibit SARS-CoV-2 spike protein palmitoylation and the resulting progeny virion particles released are defective in fusion and infection. This establishes these palmitoyltransferase inhibitors as potential new intervention strategies against SARS-CoV-2.

Modelling and optimal control of multi strain epidemics, with application to COVID-19.

Reinfection and multiple viral strains are among the latest challenges in the current COVID-19 pandemic. In contrast, epidemic models often consider a single strain and perennial immunity. To bridge this gap, we present a new epidemic model that simultaneously considers multiple viral strains and reinfection due to waning immunity. The model is general, applies to any viral disease and includes an optimal control formulation to seek a trade-off between the societal and economic costs of mitigation. We validate the model, with and without mitigation, in the light of the COVID-19 epidemic in England and in the state of Amazonas, Brazil. The model can derive optimal mitigation strategies for any number of viral strains, whilst also evaluating the effect of distinct mitigation costs on the infection levels. The results show that relaxations in the mitigation measures cause a rapid increase in the number of cases, and therefore demand more restrictive measures in the future.

SARS-CoV-2 Immuno-Pathogenesis and Potential for Diverse Vaccines and Therapies: Opportunities and Challenges.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a novel coronavirus that emerged from Wuhan, China in late 2019 causing coronavirus disease-19 (COVID-19). SARS-CoV-2 infection begins by attaching to angiotensin-converting enzyme 2 receptor (ACE2) via the spike glycoprotein, followed by cleavage by TMPRSS2, revealing the viral fusion domain. Other presumptive receptors for SARS-CoV-2 attachment include CD147, neuropilin-1 (NRP1), and Myeloid C-lectin like receptor (CLR), each of which might play a role in the systemic viral spread. The pathology of SARS-CoV-2 infection ranges from asymptomatic to severe acute respiratory distress syndrome, often displaying a cytokine storm syndrome, which can be life-threatening. Despite progress made, the detailed mechanisms underlying SARS-CoV-2 interaction with the host immune system remain unclear and are an area of very active research. The process's key players include viral non-structural proteins and open reading frame products, which have been implicated in immune antagonism. The dysregulation of the innate immune system results in reduced adaptive immune responses characterized by rapidly diminishing antibody titers. Several treatment options for COVID-19 are emerging, with immunotherapies, peptide therapies, and nucleic acid vaccines showing promise. This review discusses the advances in the immunopathology of SARS-CoV-2, vaccines and therapies under investigation to counter the effects of this virus, as well as viral variants.

Outcome of COVID-19-positive children with heart disease and grown-ups with congenital heart disease: A multicentric study from India.

BACKGROUND: Outcome data of children with heart disease who acquired COVID-19 infection are limited. AIMS: We sought to analyze outcome data and identify risk factors associated with mortality in children with heart disease and grown-ups with congenital heart disease (GUCH) who had a laboratory-confirmed COVID-19 infection. SETTINGS AND DESIGN: This is a retrospective, multicentric, observational study. MATERIALS AND METHODS: The study included children with heart disease and GUCH population, who presented with either symptomatic or asymptomatic COVID-19 infection to any of the participating centers. COVID-19-negative patients admitted to these centers constituted the control group. RESULTS: From 24 pediatric cardiac centers across India, we included 94 patients with a median age of 12.5 (interquartile range 3-96) months and 49 (52.1%) patients were males. Majority (83 patients, 88.3%) were children. One-third of the patients (n = 31, 33.0%) had acyanotic congenital heart disease, and 41.5% (n = 39) were cyanotic, with > 80% of the patients being unoperated. Only 30 (31.9%) patients were symptomatic for COVID-19 infection, while the rest were incidentally detected positive on screening. A total of 13 patients died (case fatality rate: 13.8%). The in-hospital mortality rate among hospitalized patients was significantly higher among COVID-19-positive cases (13 of 48; 27.1%) as compared to COVID-negative admissions (9.2%) during the study period (P < 0.001). On multivariate analysis, the independent predictors of mortality among COVID-19-positive cases were severity of illness at admission (odds ratio [OR]: 535.7, 95% confidence interval [CI]: 6.9-41,605, P = 0.005) and lower socioeconomic class (OR: 29.5, 95% CI: 1.1-814.7, P = 0.046). CONCLUSIONS: Children with heart disease are at a higher risk of death when they acquire COVID-19 infection. Systematic preventive measures and management strategies are needed for improving the outcomes.

SARS-CoV-2-Induced Gut Microbiome Dysbiosis: Implications for Colorectal Cancer.

The emergence of a novel coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), in December 2019 led to a worldwide pandemic with over 170 million confirmed infections and over 3.5 million deaths (as of May 2021). Early studies have shown higher mortality rates from SARS-CoV-2 infection in cancer patients than individuals without cancer. Herein, we review the evidence that the gut microbiota plays a crucial role in health and has been linked to the development of colorectal cancer (CRC). Investigations have shown that SARS-CoV-2 infection causes changes to the gut microbiota, including an overall decline in microbial diversity, enrichment of opportunistic pathogens such as Fusobacterium nucleatum bacteremia, and depletion of beneficial commensals, such as the butyrate-producing bacteria. Further, these changes lead to increased colonic inflammation, which leads to gut barrier disruption, expression of genes governing CRC tumorigenesis, and tumor immunosuppression, thus further exacerbating CRC progression. Additionally, a long-lasting impact of SARS-CoV-2 on gut dysbiosis might result in a greater possibility of new CRC diagnosis or aggravating the condition in those already afflicted. Herein, we review the evidence relating to the current understanding of how infection with SARS-CoV-2 impacts the gut microbiota and the effects this will have on CRC carcinogenesis and progression.

SARS-CoV-2 antibody seroprevalence in NHS healthcare workers in a large double-sited UK hospital.

We determined the seroprevalence of SARS-CoV-2 antibodies in NHS healthcare workers (HCWs) in a cross-sectional study from a large general hospital located in a double-sited rural and semi-rural area. The sample size of 3,119 HCWs (mean age 43±13) consisted of 75.2% women, 61.1% White individuals and predominantly (62.4%) asymptomatic individuals. Seroprevalence of SARS-CoV-2 antibodies was 19.7%. Determinants of seropositivity were preceding symptomatic infection and non-White ethnicity. Regardless of staff role or sex, multivariate regression analysis revealed that non-White HCWs were three times (odds ratio [OR] 3.12, 95% confidence interval [CI] 2.53-3.86, P<0.001) more likely to have antibodies than White staff, and seven times (OR 7.10, 95% CI 5.72-8.87, P<0.001) more likely if there was a history of preceding symptoms. We report relatively high rates of seropositivity in all NHS healthcare workers. Non-White symptomatic HCWs were significantly more likely to be seropositive than their colleagues, independent of age, sex or staff role.

Changing Pattern of Congenital Heart Disease Care During COVID-19 Pandemic.

OBJECTIVE: To study the impact of coronavirus disease 2019 (COVID-19) pandemic on the utilization of pediatric cardiac care services and to determine the role of teleconsultation services in delivering healthcare in this subset of population. METHODS: It was a retrospective, observational study. All children who attended pediatric cardiology outpatient/teleconsultation services or were admitted to pediatric cardiology ward between April 1, 2019 to July 31, 2019 and April 1, 2020 to July 31, 2020, were recruited in the study. Data for patients who underwent surgery or catheter intervention for congenital heart disease were also recorded and analyzed. Comparisons were drawn between the statistics during the two time-periods. RESULTS: Physical outpatient services were discontinued and were replaced by teleconsultations from April 2020. Inpatient admissions during COVID-19 pandemic (n = 66) decreased by two-thirds as compared to the admissions during similar period in 2019 (n = 189). Similarly, the percentage decrease during these 4 mo of pandemic were 84% for catheter interventions, 90% for total congenital heart disease (CHD) surgeries, and 40% for emergency CHD surgeries. The number of patients availing successful teleconsultation was 1079, which was only 15% of the total number of patients attending physical outpatient services (n = 7176) during the corresponding period in the year 2019. During the pandemic, systematic teleconsultation and local evaluation and investigations aided in better management of patients with CHD. CONCLUSIONS: The utilization of cardiovascular services for CHD has reduced significantly during COVID-19 pandemic, for both out- and inpatient care. Teleconsultation services have streamlined the follow-up care to some extent and have helped in noncontact triaging of these patients for further care.

Modelling and Optimal Control of Multi Strain Epidemics, with Application to COVID-19 (preprint)

This work introduces a novel epidemiological model that simultaneously considers multiple viral strains, reinfections due to waning immunity response over time and an optimal control formulation. This enables us to derive optimal mitigation strategies over a prescribed time horizon under a more realistic framework that does not imply perennial immunity and a single strain, although these can also be derived as particular cases of our formulation. The model also allows estimation of the number of infections over time in the absence of mitigation strategies under any number of viral strains. We validate our approach in the light of the COVID-19 epidemic and present a number of experiments to shed light on the overall behaviour under one or two strains in the absence of sufficient mitigation measures. We also derive optimal control strategies for distinct mitigation costs and evaluate the effect of these costs on the optimal mitigation measures over a two-year horizon. The results show that relaxations in the mitigation measures cause a rapid increase in the number of cases, which then demand more restrictive measures in the future.

Current trends and challenges in laboratory investigation of the covid-19 pandemic

The ongoing virus impact in the whole world is COVID19 infection has led to unprecedented crisis paving to outrage of the world citizens. The highly contagious virus started its spread from the China during the month of late November 2019 and spread to all over the world. The COVID-19 pandemic led catastrophe and earlier episodes of similar epidemic SARS outbreaks in China and Middle East interrogate the preparedness in handling such predicament. The major symptomatic manifestations of patients are not so accurate and vary from one person to another and higher frequency of asymptomatic cases often misled diagnosis, unless the CT chest scan findings affirms the disease progress into fatal SARS. Disambiguation over the other viral respiratory illnesses similar to COVID-19 needs to be meticulously handled by emphasize on simultaneous co-detection of multiple viral pathogens. Henceforth, robust diagnostic tools are necessitated to substantiate suspected cases and to screen large population in less time. This review would keenly focus on the challenging prime requisite for accurate laboratory testing of the infection and the potentials of various techniques in investigating the pandemic.