Covid-19 Sentry

Contents

• From Preprints
• From Clinical Trials
• From PubMed
• From Patent Search

From Preprints

• Analytic modeling and risk assessment of aerial transmission of SARS-CoV-2 virus through vaping expirations in shared micro-environments -
  Background. E-cigarettes are an important harm reduction tool that provides smokers an alternative for nicotine consumption that is much safer than smoking. It is important to asses its safety under preventive and containment measures undertaken during the COVID-19 pandemic. Methods. We develop a theoretical risk model to assess the contagion risk by aerial trans mission of the SARS-CoV-2 virus carried by e–cigarette aerosol (ECA) in shared indoor spaces, a home and restaurant scenarios, with natural and mechanical ventilation, with and without face masks. We also provide the theoretical elements to explain the visibility of exhaled ECA, which has important safety implications. Results. In a home or restaurant scenarios bystanders exposed to ECA expirations by an infectious vaper (and not wearing face masks) face a 1% increase of risk of contagion with respect to a “control case” scenario defined by exclusively rest breathing without vaping. This relative added risk becomes 5 - 17% for high intensity vaping, 44 - 176% and over 260% for speaking for various periods or coughing (all without vaping). Mechanical ventilation significantly decrease infective emissions but keep the same proportionality in risk percentages. Face masks of common usage effectively protect wearers from respiratory droplets and droplet nuclei possibly emitted by mask-less vapers as long as they avoid direct exposure to the visible exhaled vaping jet. Conclusions. Vaping emissions in shared indoor spaces involve only a minuscule added risk of COVID-19 contagion with respect to the already existing (unavoidable) risk from continuous breathing, significantly less than speaking or coughing. Protection of bystanders from this contagion does not require extra preventive measures besides those already recommended (1.5 meters separation and wearing face masks).
  🖺 Full Text HTML: Analytic modeling and risk assessment of aerial transmission of SARS-CoV-2 virus through vaping expirations in shared micro-environments
• Nirmatrelvir Resistant SARS-CoV-2 Variants with High Fitness in Vitro -
  The oral protease inhibitor nirmatrelvir is expected to play a pivotal role for prevention of severe cases of coronavirus disease 2019 (COVID-19). To facilitate monitoring of potentially emerging resistance, we studied severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) escape from nirmatrelvir. Resistant variants selected in cell culture harbored different combinations of substitutions in the SARS-CoV-2 main protease (Mpro). Reverse genetic studies in a homologous infectious cell culture system revealed up to 80-fold resistance conferred by the combination of substitutions L50F and E166V. Resistant variants had high fitness increasing the likelihood of occurrence and spread of resistance. Molecular dynamics simulations revealed that E166V and L50F+E166V weakened nirmatrelvir-Mpro binding. The SARS-CoV-2 polymerase inhibitor remdesivir retained activity against nirmatrelvir resistant variants and combination of remdesivir and nirmatrelvir enhanced treatment efficacy compared to individual compounds. These findings have implications for monitoring and ensuring treatment programs with high efficacy against SARS-CoV-2 and potentially emerging coronaviruses.
  🖺 Full Text HTML: Nirmatrelvir Resistant SARS-CoV-2 Variants with High Fitness in Vitro
• Development of an Escape-resistant SARS CoV-2 Neutralizing Synthetic Nanobody -
  An emerging COVID-19 pandemic resulted in a global crisis, but also accelerated vaccine development and antibody discovery. In this work, we identified a number of nanomolar-range affinity VHH binders to SARS-CoV-2 variants of concern (VoC) receptor binding domains (RBD), by screening synthetic humanized antibody library with more than 1e11 diversity. In order to explore the most robust and fast method for affinity improvement, we performed affinity maturation by CDR1 and CDR2 shuffling and avidity engineering by multivalent trimeric VHH fusion protein construction. As a result, H7-Fc and G12x3-Fc binders were developed with the affinities in nM and pM range respectively. Importantly, their affinities are weakly influenced by SARS-CoV-2 VoC mutations. The plaque reduction neutralization test (PRNT) resulted in IC50 = 100 ngand 9.6 ngfor H7-Fc and G12x3-Fc antibodies respectively for emerging Omicron variant. Therefore, these VHH could expand the present landscape of SARS-CoV-2 neutralization binders with the therapeutic potential for present and future SARS-CoV-2 variants.
  🖺 Full Text HTML: Development of an Escape-resistant SARS CoV-2 Neutralizing Synthetic Nanobody
• The substitutions L50F, E166A and L167F in SARS-CoV-2 3CLpro are selected by a protease inhibitor in vitro and confer resistance to nirmatrelvir -
  The SARS-CoV-2 main protease (3CLpro) has an indispensable role in the viral life cycle and is a therapeutic target for the treatment of COVID-19. The potential of 3CLpro-inhibitors to select for drug-resistant variants needs to be established. Therefore SARS-CoV-2 was passaged in vitro in the presence of increasing concentrations of ALG-097161, a probe compound designed in the context of a 3CLpro drug discovery program. We identified a combination of amino acid substitutions in 3CLpro (L50F E166A L167F) that is associated with > 20x increase in EC50 values for ALG-097161, nirmatrelvir (PF-07321332) and PF-00835231. While two of the single substitutions (E166A and L167F) provide low-level resistance to the inhibitors in a biochemical assay, the triple mutant results in the highest levels of resistance (6- to 72-fold). All substitutions are associated with a significant loss of enzymatic 3CLpro activity, suggesting a reduction in viral fitness. Structural biology analysis indicates that the different substitutions reduce the number of inhibitor/enzyme interactions while the binding of the substrate is maintained. These observations will be important for the interpretation of resistance development to 3CLpro inhibitors in the clinical setting.
  🖺 Full Text HTML: The substitutions L50F, E166A and L167F in SARS-CoV-2 3CLpro are selected by a protease inhibitor in vitro and confer resistance to nirmatrelvir
• Within-host diversity improves phylogenetic and transmission reconstruction of SARS-CoV-2 outbreaks -
  Accurate inference of who infected whom in an infectious disease outbreak is critical for the delivery of effective infection prevention and control. The increased resolution of pathogen whole-genome sequencing has significantly improved our ability to infer transmission events. Despite this, transmission inference often remains limited by the lack of genomic variation between the source case and infected contacts. Although within-host genetic diversity is common among a wide variety of pathogens, conventional whole-genome sequencing phylogenetic approaches to reconstruct outbreaks exclusively use consensus sequences, which consider only the most prevalent nucleotide at each position and therefore fail to capture low frequency variation within samples. We hypothesized that including within-sample variation in a phylogenetic model would help to identify who infected whom in instances in which this was previously impossible. Using whole-genome sequences from SARS-CoV-2 multi-institutional outbreaks as an example, we show how within-sample diversity is stable among repeated serial samples from the same host, is transmitted between those cases with known epidemiological links, and how this improves phylogenetic inference and our understanding of who infected whom. Our technique is applicable to other infectious diseases and has immediate clinical utility in infection prevention and control.
  🖺 Full Text HTML: Within-host diversity improves phylogenetic and transmission reconstruction of SARS-CoV-2 outbreaks
• Neutralization of Omicron sublineages and Deltacron SARS-CoV-2 by 3 doses of BNT162b2 vaccine or BA.1 infection -
  Distinct SARS-CoV-2 Omicron sublineages have evolved showing increased fitness and immune evasion than the original Omicron variant BA.1. Here we report the neutralization activity of sera from BNT162b2 vaccinated individuals or unimmunized Omicron BA.1-infected individuals against Omicron sublineages and Deltacron variant (XD). BNT162b2 post-dose 3 immune sera neutralized USA-WA1/2020, Omicron BA.1-, BA.2-, BA.2.12.1-, BA.3-, BA.4/5-, and XD-spike SARS-CoV-2s with geometric mean titers (GMTs) of 1335, 393, 298, 315, 216, 103, and 301, respectively; thus, BA.4/5 SARS-CoV-2 spike variant showed the highest propensity to evade vaccine neutralization compared to the original Omicron variants BA.1. BA.1-convalescent sera neutralized USA-WA1/2020, BA.1-, BA.2-, BA.2.12.1-, BA.3-, BA.4/5-, and Deltacron-spike SARS-CoV-2s with GMTs of 15, 430, 110, 109, 102, 25, and 284, respectively. The low neutralization titers of vaccinated sera or convalescent sera from BA.1 infected individuals against the emerging and rapidly spreading Omicron BA.4/5 variants provide important results for consideration in the selection of an updated vaccine in the current Omicron wave.
  🖺 Full Text HTML: Neutralization of Omicron sublineages and Deltacron SARS-CoV-2 by 3 doses of BNT162b2 vaccine or BA.1 infection
• GABA-receptors are a new druggable target for limiting disease severity, lung viral load, and death in SARS-CoV-2 infected mice -
  GABA-receptors (GABA-Rs) are well-known neurotransmitter receptors in the central nervous system. GABA-Rs are also expressed by immune cells and lung epithelial cells and GABA-R agonists/potentiators reduce inflammatory immune cell activities and limit acute lung injuries. Notably, plasma GABA levels are reduced in hospitalized COVID-19 patients. Hence, GABA-R agonists may have therapeutic potential for treating COVID-19. Here, we show that oral GABA treatment initiated just after SARS-CoV-2 infection, or 2 days later near the peak of lung viral load, reduced disease severity, lung coefficient index, and death rates in K18-hACE2 mice. GABA-treated mice had a reduced viral load in their lungs and displayed shifts in their serum cytokine and chemokine levels that are associated with better outcomes in COVID-19 patients. Thus, GABA-R activation had multiple beneficial effects in this mouse model which are also desirable for the treatment of COVID-19. A number of GABA-R agonists are safe for human use and can be readily tested in clinical trials with COVID-19 patients. We also discuss their potential for limiting COVID-19-associated neuroinflammation.
  🖺 Full Text HTML: GABA-receptors are a new druggable target for limiting disease severity, lung viral load, and death in SARS-CoV-2 infected mice
• Predicting clinical outcomes of SARS-CoV-2 drug treatments with a high throughput human airway on chip platform -
  Despite the relatively common observation of therapeutic efficacy in discovery screens with immortalized cell lines, the vast majority of drug candidates do not reach clinical development. Candidates that do move forward often fail to demonstrate efficacy when progressed from animal models to humans. This dilemma highlights the need for new drug screening technologies that can parse drug candidates early in development with regard to predicted relevance for clinical use. PREDICT96-ALI is a high-throughput organ-on-chip platform incorporating human primary airway epithelial cells in a dynamic tissue microenvironment. Here we demonstrate the utility of PREDICT96-ALI as an antiviral screening tool for SARS-CoV-2, combining the high-throughput functionality of a 96-well plate format in a high containment laboratory with the relevant biology of primary human tissue. PREDICT96-ALI resolved differential efficacy in five antiviral compounds over a range of drug doses. Complementary viral genome quantification and immunofluorescence microscopy readouts achieved high repeatability between devices and replicate plates. Importantly, results from testing the three antiviral drugs currently available to patients (nirmatrelvir, molnupiravir, and remdesivir) tracked with clinical outcomes, demonstrating the value of this technology as a prognostic drug discovery tool.
  🖺 Full Text HTML: Predicting clinical outcomes of SARS-CoV-2 drug treatments with a high throughput human airway on chip platform
• Assessing the effects of data drift on the performance of machine learning models used in clinical sepsis prediction -

  Background Data drift can negatively impact the performance of machine learning algorithms (MLAs) that were trained on historical data. As such, MLAs should be continuously monitored and tuned to overcome the systematic changes that occur in the distribution of data. In this paper, we study the extent of data drift and provide insights about its characteristics for sepsis onset prediction. This study will help elucidate the nature of data drift for prediction of sepsis and similar diseases. This may aid with the development of more effective patient monitoring systems that can stratify risk for dynamic disease states in hospitals. Methods We devise a series of simulations that measure the effects of data drift in patients with sepsis. We simulate multiple scenarios in which data drift may occur, namely the change in the distribution of the predictor variables (covariate shift), the change in the statistical relationship between the predictors and the target (concept shift), and the occurrence of a major healthcare event (major event) such as the COVID-19 pandemic. We measure the impact of data drift on model performances, identify the circumstances that necessitate model retraining, and compare the effects of different retraining methodologies and model architecture on the outcomes. We present the results for two different MLAs, eXtreme Gradient Boosting (XGB) and Recurrent Neural Network (RNN). Results Our results show that the properly retrained XGB models outperform the baseline models in all simulation scenarios, hence signifying the existence of data drift. In the major event scenario, the area under the receiver operating characteristic curve (AUROC) at the end of the simulation period is 0.811 for the baseline XGB model and 0.868 for the retrained XGB model. In the covariate shift scenario, the AUROC at the end of the simulation period for the baseline and retrained XGB models is 0.853 and 0.874 respectively. In the concept shift scenario and under the mixed labeling method, the retrained XGB models perform worse than the baseline model for most simulation steps. However, under the full relabeling method, the AUROC at the end of the simulation period for the baseline and retrained XGB models is 0.852 and 0.877 respectively. The results for the RNN models were mixed, suggesting that retraining based on a fixed network architecture may be inadequate for an RNN. We also present the results in the form of other performance metrics such as the ratio of observed to expected probabilities (calibration) and the normalized rate of positive predictive values (PPV) by prevalence, referred to as lift, at a sensitivity of 0.8. Conclusion Our simulations reveal that retraining periods of a couple of months or using several thousand patients are likely to be adequate to monitor machine learning models that predict sepsis. This indicates that a machine learning system for sepsis prediction will probably need less infrastructure for performance monitoring and retraining compared to other applications in which data drift is more frequent and continuous. Our results also show that in the event of a concept shift, a full overhaul of the sepsis prediction model may be necessary because it indicates a discrete change in the definition of sepsis labels, and mixing the labels for the sake of incremental training may not produce the desired results.

  🖺 Full Text HTML: Assessing the effects of data drift on the performance of machine learning models used in clinical sepsis prediction
• Post-acute COVID-19 cognitive impairment and decline uniquely associate with kynurenine pathway activation: a longitudinal observational study -

  Cognitive impairment and function post-acute mild to moderate COVID-19 are poorly understood. We report findings of 128 prospectively studied SARS-CoV-2 positive patients. Cognition and olfaction were assessed at 2-, 4- and 12-months post-diagnosis. Lung function, physical and mental health were assessed at 2-month post diagnosis. Blood cytokines, neuro-biomarkers, and kynurenine pathway (KP) metabolites were measured at 2-, 4-, 8- and 12-months. Mild to moderate cognitive impairment (demographically corrected) was present in 16%, 23%, and 26%, at 2-, 4- and 12-months post diagnosis, respectively. Overall cognitive performance mildly, but significantly (p<.001) declined. Cognitive impairment was more common in those with anosmia (p=.05), but only at 2 months. KP metabolites quinolinic acid, 3-hydroxyanthranilic acid, and kynurenine were significantly (p<.001) associated with cognitive decline. The KP as a unique biomarker offers a potential therapeutic target for COVID-19-related cognitive impairment.

  🖺 Full Text HTML: Post-acute COVID-19 cognitive impairment and decline uniquely associate with kynurenine pathway activation: a longitudinal observational study
• Precarious employment and associations with health during COVID-19: a nationally representative survey in Wales, UK -

  Background The COVID-19 pandemic had an early impact on employment, with the United States (US) and the United Kingdom (UK) experiencing more severe immediate labour market impacts than other Western countries. Emerging evidence from the initial phase of the pandemic highlighted that job losses were experienced more by those holding atypical contracts. Furthermore, it is predicted that this associated unemployment will increase precarious employment arrangements during the COVID-19 pandemic. In this paper we seek to answer the following research questions: I. What is the prevalence of precarious employment in Wales and are there differences in employment precariousness by socio-demographic characteristics and self-reported health status? II. Which domains are the main contributing factors of precarious employment in Wales? III. Which domains of precarious employment are associated with poorer health? IV. Haves there been changes in job quality (as reflected by precarious employment domains) during the COVID pandemic (between February 2020 and Winter 2020/2021)? Methods Data was collected from a national household survey carried out in May/June 2020, with a sample of 1,032 residents in Wales and follow-up responses from 429 individuals collected between November 2020 and January 2021. To examine the associations between experiencing precarious employment or the separate domains of employment precariousness and socio-demographics and health, chi-squared analyses and logistic regression models (multinomial and binary) were used. To determine longitudinal changes in precarious employment experienced by socio-demographic groups and furlough status, McNemars test was used. The data is presented as proportion of respondents or adjusted odds ratios (aOR) and 95% confidence intervals following logistic regression. Results Overall, pre-pandemic, one in four respondents were determined to be in precarious employment (26.5%). A higher proportion of females (28.3%) and those aged 18-29 years (41.0%) were in precarious employment in February 2020. In addition, a greater percentage of individuals who reported poorer health across all self-reported measures were in precarious employment compared to those reporting better health. Worse perceived treatment at work was twice as likely in those who reported a pre-existing condition (aOR 2.45 95% CI [1.33-4.49]), poorer general health (aOR 2.33 95% CI [1.22-4.47]) or low mental wellbeing (aOR 2.81 95% CI [1.34-5.88]) when compared to their healthier counterparts. Those calculated to have high wage precariousness were three times more likely to report low mental wellbeing (aOR 3.12 95% CI [1.54-6.32]). In the subsample, there was an observed increase in the prevalence of precarious employment, with this being attributable to lower affordability of wages and a perceived increase in vulnerability at work. The subgroups that were most impacted by this decrease in job quality were females and the 30-39 years age group. Implications Improving the vulnerability and wages domains, through the creation and provision of secure, adequately paid job opportunities has the potential to reduce the prevalence of precarious employment in Wales. In turn, these changes would improve the health and wellbeing of the working age population, some of which are already adversely impacted by the COVID-19 pandemic.

  🖺 Full Text HTML: Precarious employment and associations with health during COVID-19: a nationally representative survey in Wales, UK
• Rapid adaptation of established high-throughput molecular testing infrastructure for detection of monkeypoxvirus. -

  Background: Since May 2022, a rising number of monkeypox-cases has been reported in non-endemic countries of the northern hemisphere. In contrast to previous clusters, infections seem predominantly driven by human-to-human transmission, rather than animal sources. In this study, we adapted two published qPCR assays (non-variola orthopoxvirus and monkeypoxvirus specific) for use as a lab-developed dual-target monkeypoxvirus-test on widely used automated high-throughput PCR-systems (cobas5800/6800/8800). Methods: Selected assays were checked for in-silico inclusivity and exclusivity in current orthopoxvirus sequences, as well as for multiplex compatibility. Analytic performance was determined by serial dilution of monkeypoxvirus reference material, quantified by digital PCR. Cross reactivity was ruled out through a clinical exclusivity set containing various bloodborne and respiratory pathogens. Clinical performance was compared to a commercial manual RUO-kit using clinical remnant samples. Results: Analytic lower limit of detection (LoD) was determined as 4.795 dcp/ml (CI95%: 3.598 - 8.633 dcp/ml) for both assays combined, with a dynamic range of at least 5 log-steps. The assay showed 100% positive and negative agreement with the manual RUO orthopoxvirus PCR test kit in clinical swab samples. Discussion: While the full extend of the ongoing monkeypox outbreak remains to be established, the WHO and local health authorities are calling for increased awareness and efforts to limit further spread. For this, timely and scalable PCR tests are an important prerequisite. The assay presented here allows streamlined high-throughput molecular testing for monkeypoxvirus on existing hardware, broadly established previously for SARS-CoV-2 diagnostics.

  🖺 Full Text HTML: Rapid adaptation of established high-throughput molecular testing infrastructure for detection of monkeypoxvirus.
• Non-pharmacological therapies for post-viral syndromes, including Long COVID: A systematic review -

  Background: Post-viral syndromes (PVS), including Long COVID, are symptoms sustained from weeks to years following an acute viral infection. Non-pharmacological treatments for these symptoms are poorly understood. This review summarises evidence for the effectiveness of non-pharmacological treatments for symptoms of PVS. It also summarises the symptoms and health impacts of PVS in individuals recruited to studies evaluating treatments. Methods and findings: We conducted a systematic review to evaluate the effectiveness of non-pharmacological interventions for PVS, as compared to either standard care, alternative non-pharmacological therapy, or placebo. The outcomes of interest were changes in symptoms, exercise capacity, quality of life (including mental health and wellbeing), and work capability. We searched five databases (Embase, MEDLINE, PsycINFO, CINAHL, MedRxiv) for randomised controlled trials (RCTs) published between 1st January 2001 to 29th October 2021. We anticipated that there would be few RCTs specifically pertaining to Long COVID, so we also included observational studies only if they assessed interventions in individuals where the viral pathogen was SARS-COV-2. Relevant outcome data were extracted, study quality appraised using the Cochrane Risk of Bias tool, and the findings were synthesised narratively. Quantitative synthesis was not planned due to substantial heterogeneity between the studies. Overall, five studies of five different interventions (Pilates, music therapy, telerehabilitation, resistance exercise, neuromodulation) met the inclusion criteria. Aside from music-based intervention, all other selected interventions demonstrated some support in the management of PVS in some patients. Conclusions: In this study, we observed a lack of robust evidence evaluating non-pharmacological treatments for PVS, including Long COVID. Considering the prevalence of prolonged symptoms following acute viral infections, there is an urgent need for clinical trials evaluating the effectiveness and cost-effectiveness of non-pharmacological treatments for patients with PVS as well as what may work for certain sub-groups of patients with differential symptom presentation. Registration: The study protocol was registered with PROSPERO [CRD42021282074] in October 2021 and published in BMJ Open in 2022. Keywords: Post-viral syndromes, PVS, COVID-19, Long COVID, post-COVID-19 condition, post-acute sequelae of SARS-CoV-2 infection (PASC), rehabilitation, systematic review, non-pharmacological intervention

  🖺 Full Text HTML: Non-pharmacological therapies for post-viral syndromes, including Long COVID: A systematic review
• Hospitalization, death, and probable reinfection in Peruvian healthcare workers infected with SARS-CoV-2: a national retrospective cohort study -

  OBJECTIVE: To determine if the occupation is a risk factor for probable reinfection, hospitalization, and death from COVID 19 in Peruvian healthcare workers infected with SARS CoV2. MATERIAL AND METHODS: Retrospective cohort study. Healthcare workers who presented SARS CoV 2 infection between March 1, 2020, and August 9, 2021, were included. Occupational cohorts were reconstructed from the following sources of information: the National Epidemiological Surveillance System, molecular tests (NETLAB), results of serology and antigen tests (SICOVID 19), National Registry of Health Personnel (INFORHUS), and National Information System of Deaths (SINADEF). The incidence of probable reinfection, hospitalization, and death from COVID 19 was obtained in the cohorts of health auxiliaries and technicians, nursing staff, obstetricians, physicians, and other healthcare workers. Using a log-binomial generalized linear model, we evaluated whether the occupation was a risk factor for probable reinfection, hospitalization, and death from COVID 19, obtaining the adjusted relative risk (RR AJ). RESULTS: 90,672 healthcare workers were included. 8.1% required hospitalization, 1.7% died from COVID 19, and 2.0% had probable reinfection. A similar incidence of probable reinfection was found in the 5 cohorts (1.9% to 2.2%). Physicians had a higher incidence of hospitalization (13.2%) and death (2.6%); however, they were also those who presented greater susceptibility linked to non-occupational variables such as age and comorbidities. The multivariate analysis found that physicians (RR=1.691; CI 95: 1.556 to 1.837) had a higher risk of hospitalization and that the occupation of health technician and the assistant was the only one that constituted a risk factor for mortality from COVID-19 (RR =1.240; 95% CI: 1.052 to 1.463). CONCLUSIONS: Peruvian health technicians and auxiliaries have a higher risk of death from COVID-19 linked to their occupation, while doctors have higher mortality due to non-occupational factors. Physicians had a higher risk of hospitalization independent of the presence of comorbidities and age; likewise, all occupations had a similar risk of probable reinfection.

  🖺 Full Text HTML: Hospitalization, death, and probable reinfection in Peruvian healthcare workers infected with SARS-CoV-2: a national retrospective cohort study
• Modeling the Omicron Dynamics and Development in China: with a Deep Learning Enhanced Compartmental Model -

  Background: Compartmental models dominate epidemic modeling. Estimations of transmission parameters between compartments are typically done through stochastic parameterization processes that depend upon detailed statistics on transmission characteristics, which are economically and resource-wide expensive to collect. Objectives: We apply deep learning techniques as a lower data dependency alternative to estimate transmission parameters of a customized compartmental model, for the purpose of simulating the dynamics of the Omicron phase of the COVID-19 epidemics and projecting its further development in China and subregions within the country. Methods: We construct a compartmental model, and develop a multivariate, multistep deep learning methodology to estimate the model9s transmission parameters. We then feed the estimated transmission parameters to the compartmental model to predict the development of the COVID-19 epidemics in China and subregions within the country for 28 days. Results: In China (excluding Hong Kong and Taiwan), the daily Omicron infection increase is between 60 and 260 in the 28-day forecast period between June 4 and July 1, 2022. On July 1, 2022, there would be 768,622 cumulative confirmed cases and 591 cumulative deceased cases. The CFR would stabilize at 0.077%. Assuming a 25% infection rate, the total deaths with Omicron would be up to 280,000 without non-pharmaceutical intervention (NPI). Conclusions: Current compartmental models require stochastic parameterization to estimate the transmission parameters. These models9 effectiveness depends upon detailed statistics on transmission characteristics. As an alternative, deep learning techniques are effective in estimating these stochastic parameters with greatly reduced dependency on data particularity.

  🖺 Full Text HTML: Modeling the Omicron Dynamics and Development in China: with a Deep Learning Enhanced Compartmental Model

From Clinical Trials

• Phase I Clinical Trial of Safety, Tolerance and Immunogenicity of GEN2-Recombinant COVID-19 Vaccine (CHO Cells) in Healthy People Aged 18 and Above - Condition:   COVID-19 Pneumonia
  Interventions:   Biological: Experimental Vaccine 1;   Biological: Experimental Vaccine 2;   Biological: Experimental Vaccine 3;   Biological: placebo
  Sponsors:   National Vaccine and Serum Institute, China;   Lanzhou Institute of Biological Products Co., Ltd;   Beijing Institute of Biological Products Co Ltd.
  Not yet recruiting

• A Study to Assess the Safety and Immunogenicity of a COVID-19 Vaccine Booster in Healthy Adults - Condition:   COVID-19
  Intervention:   Biological: Prime-2-CoV_Beta
  Sponsors:   University Hospital Tuebingen;   FGK Clinical Research GmbH;   VisMederi srl;   Staburo GmbH;   Viedoc Technologies AB
  Not yet recruiting

• Eucalyptus Oil as Adjuvant Therapy for Coronavirus Disease 19 (COVID-19) - Condition:   COVID-19
  Interventions:   Drug: Eucalyptus Oil;   Drug: Standard COVID medication
  Sponsors:   Hasanuddin University;   Ministry of Agriculture, Republic of Indonesia
  Completed

• Study of Oral High/Low-dose Cepharanthine Compared With Placebo in Non Hospitalized Adults With COVID-19 - Condition:   Asymptomatic COVID-19
  Interventions:   Drug: Cepharanthine;   Drug: Placebo
  Sponsors:   Shanghai Jiao Tong University School of Medicine;   YUNNAN BAIYAO GROUP CO.,LTD
  Not yet recruiting

• α-synuclein Seeding Activity in the Olfactory Mucosa in COVID-19 - Condition:   COVID-19
  Intervention:   Other: Real-time Quaking-Induced Conversion (RT-QuIC)
  Sponsor:   Medical University Innsbruck
  Recruiting

• Randomized, Single-blinded, Multicenter Trial Comparing the Immune Response to a 2nd Booster Dose of COVID-19 mRNA Vaccine (Pfizer-BioNTech) or Sanofi /GSK B.1.351 Adjuvanted Vaccine in Adults - Condition:   COVID-19 Vaccines
  Interventions:   Biological: 2nd booster with Comirnaty® (Pfizer-BioNTech);   Biological: CoV2 preS dTM adjuvanted vaccine (B.1.351), Sanofi/GSK
  Sponsors:   Assistance Publique - Hôpitaux de Paris;   IREIVAC/COVIREIVAC Network
  Not yet recruiting

• Immunogenicity and Safety of a Third Dose of COVID-19 Vaccine(Vero Cell), Inactivated in the Elderly - Condition:   COVID-19
  Intervention:   Biological: COVID-19 Vaccine (Vero cell), Inactivated
  Sponsor:   Sinovac Research and Development Co., Ltd.
  Active, not recruiting

• Efficacy, Safety and Immunogenicity Study of the Recombinant Two-component COVID-19 Vaccine (CHO Cell)(Recov) - Condition:   COVID-19
  Interventions:   Biological: Recombinant two-component COVID-19 vaccine (CHO cell);   Biological: Placebo
  Sponsor:   Jiangsu Rec-Biotechnology Co., Ltd.
  Not yet recruiting

• A Phase 1a Trial to Evaluate the Safety and Immunogenicity of a SARS-CoV-2 mRNA Chimera Vaccine Against COVID-19 - Condition:   COVID-19
  Interventions:   Biological: RQ3013;   Biological: Comirnaty
  Sponsors:   Walvax Biotechnology Co., Ltd.;   Shanghai RNACure Biopharma Co., Ltd.
  Not yet recruiting

• A Phase 1b Trial to Evaluate the Safety and Immunogenicity of a SARS-CoV-2 mRNA Chimera Vaccine Against COVID-19 - Condition:   COVID-19
  Interventions:   Biological: RQ3013;   Biological: Comirnaty
  Sponsors:   Walvax Biotechnology Co., Ltd.;   Shanghai RNACure Biopharma Co., Ltd.
  Not yet recruiting

• Treatment of COVID-19 Post-acute Cognitive Impairment Sequelae With tDCS - Conditions:   Cognitive Impairment;   Post-Acute Sequelae of SARS-CoV-2 Infection;   COVID-19
  Interventions:   Procedure: Active tDCS and cognitive training;   Procedure: Sham tDCS and cognitive training
  Sponsors:   University of Sao Paulo;   Fundação de Amparo à Pesquisa do Estado de São Paulo
  Not yet recruiting

• Inhibition of Bradykinin in COVID-19 Infection With Icatibant - Condition:   SARS CoV 2 Infection
  Interventions:   Drug: Icatibant;   Drug: 0.9% Sodium Chloride Injection
  Sponsors:   Belfast Health and Social Care Trust;   Queen’s University, Belfast
  Recruiting

• Effect of Prone Positioning on the Severity of COVID-19 Pneumonia and Acute Respiratory Distress Syndrome. - Conditions:   COVID-19 Acute Respiratory Distress Syndrome;   COVID-19 Pneumonia;   Prone Positioning
  Intervention:   Other: Prone Positioning Maneuver
  Sponsors:   Ayub Medical College, Abbottabad;   Ayub Teaching Hospital
  Completed

• Long Haul COVID Rehabilitation & Recovery Research Program - Condition:   Long Haul COVID or Post Acute Sequella of COVID - PASC (U09.9)
  Intervention:   Other: Virtual vs On Site Pulmonary Rehabilitation
  Sponsor:   Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
  Recruiting

• Evaluation of the Immunogenicity and Safety of Sputnik V and BBIBP-CorV Vaccines for COVID-19 in Adult in Guinea - Conditions:   COVID-19;   Vaccine Adverse Reaction;   Sars-CoV-2 Infection;   Healthy Volunteer
  Interventions:   Biological: BBIBP-CorV;   Biological: Sputnik V
  Sponsors:   ANRS, Emerging Infectious Diseases;   CEPI;   Alliance for International Medical Action;   Centre National de Formation et de Recherche en Sante Rurale;   Institut National de la Santé Et de la Recherche Médicale, France;   APHP;   Agence Nationale de Sécurité Sanitaire de la Guinée (ANSS Guinée);   Innovative clinical research network in vaccinology (IREIVAC)
  Recruiting

From PubMed

• Parsing the role of NSP1 in SARS-CoV-2 infection - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to shutoff of protein synthesis, and nsp1, a central shutoff factor in coronaviruses, inhibits cellular mRNA translation. However, the diverse molecular mechanisms employed by nsp1 as well as its functional importance are unresolved. By overexpressing various nsp1 mutants and generating a SARS-CoV-2 mutant, we show that nsp1, through inhibition of translation and induction of mRNA degradation, targets translated cellular mRNA and…

• Outcomes with Direct and Indirect Thrombin Inhibition during Extracorporeal Membrane Oxygenation for COVID-19 - Anticoagulation during extracorporeal membrane oxygenation (ECMO) for Coronovirus Disease 2019 (COVID-19) can be performed by direct or indirect thrombin inhibitors but differences in outcomes with these agents are uncertain. A retrospective, multicenter study was conducted. All consecutive adult patients with COVID-19 placed on ECMO between March 1, 2020 and April 30, 2021 in participating centers, were included. Patients were divided in groups receiving either a direct thrombin inhibitor (DTI)…

• Supporting Cells of the Human Olfactory Epithelium Co-Express the Lipid Scramblase TMEM16F and ACE2 and May Cause Smell Loss by SARS-CoV-2 Spike-Induced Syncytia - CONCLUSION: Our results provide the first evidence that TMEM16F is expressed in human olfactory supporting cells and indicate that syncytia formation, that could be blocked by niclosamide, is one of the pathogenic mechanisms worth investigating in COVID-19 smell loss.

• Novel cleavage sites identified in SARS-CoV-2 spike protein reveal mechanism for cathepsin L-facilitated viral infection and treatment strategies - The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important target for vaccine and drug development. However, the rapid emergence of variant strains with mutated S proteins has rendered many treatments ineffective. Cleavage of the S protein by host proteases is essential for viral infection. Here, we discovered that the S protein contains two previously unidentified Cathepsin L (CTSL) cleavage sites (CS-1 and CS-2). Both sites are highly conserved among…

• Performance analysis among multiple fully automated anti-SARS-CoV-2 antibody measurement reagents: A potential indicator for the correlation of protection in the antibody titer - CONCLUSIONS: The performance observed for each anti-SARS-CoV-2 antibody detection reagent was sufficient. The reference values based on the inhibition rate of sVNT have potential as indicators of the correlation of protection and are expected to be leveraged in automated antibody tests.

• Review of Anti-inflammatory and Antiviral Therapeutics for Hospitalized Patients Infected with Severe Acute Respiratory Syndrome Coronavirus 2 - Severe acute respiratory syndrome coronavirus 2 infection leads to dysregulation of immune pathways. Therapies focusing on suppressing cytokine activity have some success. Current evidence supports the use of dexamethasone in hospitalized patients requiring oxygen to decrease mortality. Interleukin-6 inhibitors, like tocilizumab and sarilumab, are also beneficial in hypoxemic patients, if used early. Janus kinase inhibition in combination with glucocorticoids is emerging as a potential…

• Epitope Mapping of an Anti-Chinese/Golden Hamster Podoplanin Monoclonal Antibody - Chinese hamster (Cricetulus griseus) and golden hamster (Mesocricetus auratus) are important animal models of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, which affect several organs, including respiratory tract, lung, and kidney. Podoplanin (PDPN) is a marker of lung type I alveolar cells, kidney podocytes, and lymphatic endothelial cells. The development of anti-PDPN monoclonal antibodies (mAbs) for these animals is essential to evaluate the pathogenesis by…

• Efferocytosis of SARS-CoV-2-infected dying cells impairs macrophage anti-inflammatory functions and clearance of apoptotic cells - COVID-19 is a disease of dysfunctional immune responses, but the mechanisms triggering immunopathogenesis are not established. The functional plasticity of macrophages allows this cell type to promote pathogen elimination and inflammation or suppress inflammation and promote tissue remodeling and injury repair. During an infection, the clearance of dead and dying cells, a process named efferocytosis, can modulate the interplay between these contrasting functions. Here, we show that engulfment of…

• Melatonin and multiple sclerosis: antioxidant, anti-inflammatory and immunomodulator mechanism of action - CONCLUSION: Melatonin could exert a beneficial effect in people suffering from MS, running as a promising candidate for the treatment of this disease. However, more research in human is needed to help understand the possible interaction between melatonin and certain sex hormones, such as estrogens, to know the potential therapeutic efficacy in both men and women.

• Interleukin-6 Elevation Is a Key Pathogenic Factor Underlying COVID-19-Associated Heart Rate-Corrected QT Interval Prolongation - CONCLUSION: For the first time, we demonstrated that in severe COVID-19, systemic inflammatory activation can per se promote QTc prolongation via IL-6 elevation, leading to ventricular electric remodeling. Despite being transitory, such modifications may significantly contribute to arrhythmic events and associated poor outcomes in COVID-19. These findings provide a further rationale for current anti-inflammatory treatments for COVID-19, including IL-6-targeted therapies.

• Severe acute respiratory syndrome coronavirus 2 infection: Role of interleukin-6 and the inflammatory cascade - Since December 2019, a novel coronavirus that represents a serious threat to human lives has emerged. There is still no definite treatment for severe cases of the disease caused by this virus, named coronavirus disease 2019 (COVID-19). One of the most considered treatment strategies targets the exaggerated immune regulator, and interleukin (IL)-6 is a crucial pro-inflammatory mediator. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cases show an elevated level of IL-6 related to…

• Omicron BA.1 and BA.2 Neutralizing Activity Following Pre-Exposure Prophylaxis with Tixagevimab plus Cilgavimab in Vaccinated Solid Organ Transplant Recipients - Neutralizing antibody responses are attenuated in many solid organ transplant recipients (SOTRs) despite SARS-CoV-2 vaccination. Pre-exposure prophylaxis (PrEP) with the monoclonal antibody combination Tixagevimab and Cilgavimab (T+C) might augment immunoprotection, yet activity against Omicron sublineages in vaccinated SOTRs is unknown. Vaccinated SOTRs who received 300+300mg T+C (either single dose or two 150+150mg doses) within a prospective observational cohort submitted pre- and…

• The DNA glycosylase NEIL2 plays a vital role in combating SARS-CoV-2 infection - Compromised DNA repair capacity of individuals could play a critical role in the severity of SARS-CoV-2 infection-induced COVID-19. We therefore analyzed the expression of DNA repair genes in publicly available transcriptomic datasets of COVID-19 patients and found that the level of NEIL2, an oxidized base specific mammalian DNA glycosylase, is particularly low in the lungs of COVID-19 patients displaying severe symptoms. Downregulation of pulmonary NEIL2 in CoV-2-permissive animals and…

• Inhibition of major histocompatibility complex-I antigen presentation by sarbecovirus ORF7a proteins - Viruses employ a variety of strategies to escape or counteract immune responses, including depletion of cell surface major histocompatibility complex class I (MHC-I), that would ordinarily present viral peptides to CD8+ cytotoxic T cells. As part of a screen to elucidate biological activities associated with individual SARS-CoV-2 viral proteins, we found that ORF7a reduced cell surface MHC-I levels by approximately 5-fold. Nevertheless, in cells infected with SARS-CoV-2, surface MHC-I levels…

• A dual role for CRTH2 in acute lung injury - Acute respiratory distress syndrome (ARDS) is a life-threatening clinical condition defined by rapid onset respiratory failure following acute lung injury (ALI). Its increased incidence due to COVID-19 and high mortality rate (∼40%) make the study of ARDS pathogenesis a crucial research priority. CRTH2 is a G protein-coupled receptor with established roles in type 2 immunity and well-characterized inhibitors. Prior studies have shown it also promotes neutrophilic inflammation, indicating that…

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