Abstract Background The coronavirus nonstructural protein 5 (Nsp5) is a cysteine protease required for processing the viral polyprotein and is therefore crucial for viral replication. Nsp5 from several coronaviruses have also been found to cleave host proteins, disrupting molecular pathways involved in innate immunity. Nsp5 from the recently emerged SARS-CoV-2 virus interacts with and can cleave human proteins, which may be relevant to the pathogenesis of COVID-19. Based on the continuing global pandemic, and emerging understanding of coronavirus Nsp5-human protein interactions, we set out to predict what human proteins are cleaved by the coronavirus Nsp5 protease using a bioinformatics approach. Results Using a previously developed neural network trained on coronavirus Nsp5 cleavage sites (NetCorona), we made predictions of Nsp5 cleavage sites in all human proteins. Structures of human proteins in the Protein Data Bank containing a predicted Nsp5 cleavage site were then examined, generating a list of 92 human proteins with a highly predicted and accessible cleavage site. Of those, 48 are expected to be found in the same cellular compartment as Nsp5. Analysis of this targeted list of proteins revealed molecular pathways susceptible to Nsp5 cleavage and therefore relevant to coronavirus infection, including pathways involved in mRNA processing, cytokine response, cytoskeleton organization, and apoptosis. Conclusions This study combines predictions of Nsp5 cleavage sites in human proteins with protein structure information and protein network analysis. We predicted cleavage sites in proteins recently shown to be cleaved in vitro by SARS-CoV-2 Nsp5, and we discuss how other potentially cleaved proteins may be relevant to coronavirus mediated immune dysregulation. The data presented here will assist in the design of more targeted experiments, to determine the role of coronavirus Nsp5 cleavage of host proteins, which is relevant to understanding the molecular pathology of coronavirus infection.
Modeling complex chemical reaction networks has inspired a considerable body of research and a variety of approaches to modeling nonlinear pathways are being developed. Here, a general methodology is formulated to convert an arbitrary reaction network into its equivalent electrical analog. The topological equivalence of the electrical analog is mathematically established for unimolecular reactions using Kirchhoff's laws. The modular approach is generalized to bimolecular and nonlinear autocatalytic reactions. It is then applied to simulate the dynamics of nonlinear autocatalytic networks without making simplifying assumptions, such as use of the quasi-steady state/Bodenstein approximation or the absence of nonlinear steps in the intermediates. This is among the few papers that quantify the dynamics of a nonlinear chemical reaction network by generating and simulating an electrical network analog. As a realistic biological application, the early phase of the spread of COVID-19 is modeled as an autocatalytic process and the predicted dynamics are in good agreement with experimental data. The rate-limiting step of viral transmission is identified, leading to novel mechanistic insights.
IntroductionMajor advancements in technology have led to considerations how telemedicine (TM) and other technology platforms can be meaningfully integrated in treatment for psychiatric disorders. The COVID-19 pandemic has placed a further focus on use of TM in psychiatry. Despite the widespread use of TM, little is known about its effect compared with traditional in-person (IP) consultation. The objective of this systematic review is to examine if individual psychiatric outpatient interventions for adults using TM are comparable to IP in terms of (1) psychopathology outcomes, (2) levels of patient satisfaction, (3) working alliance and (4) dropout from treatment.Methods and analysisThis review will only include randomised controlled trials for adult participants with mood disorders, anxiety or personality disorders. The primary outcome is psychopathology, and secondary outcomes include patient satisfaction, treatment alliance and dropout rate. Systematic searches were conducted in MEDLINE, APA PsycINFO, Embase, Web of Science and CINAHL. The inverse-variance method will be used to conduct the meta-analysis. Effect sizes will be calculated as standardised mean difference (Hedges’ g) for the primary outcome, mean difference for patient satisfaction and working alliance, and risk ratio for the dropout rate. Effect sizes will be supplemented with 95% CI. We will calculate the I² statistic to quantify heterogeneity and Chi-square statistic (χ²) to test for heterogeneity for the primary outcome. Potential clinical and methodological heterogeneity moderators will be assessed in subgroup and sensitivity analysis. The risk of bias will be assessed by Cochrane Risk of Bias Tool V.2, and confidence in cumulative evidence will be assessed by Grading of Recommendations Assessment, Development and Evaluation.Ethics and disseminationNo ethical approval is required for this systematic review protocol. Data sets will be deposited in the Zenodo repository. The findings of this study will be published in a peer-review scientific journal.PROSPERO registration numberCRD42021256357.
Countries: United Kingdom, Finland, Denmark, Netherlands, Norway, Germany
Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Peer reviewed
The COVID-19 pandemic emphasized the importance of rapid, portable, and on-site testing technologies necessary for resource-limited settings for effective testing and screening to reduce spreading of the infection. Realizing this, we developed a fluorescence-based point-of-care (fPOC) detection system with real-time reverse transcriptase loop-mediated isothermal amplification for rapid and quantitative detection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. The system is built based on the Arduino platform compatible with commercially available open-source hardware–software and off-the-shelf electronic components. The fPOC system comprises of three main components: 1) an instrument with integrated heaters, 2) optical detection components, and 3) an injection-molded polymeric cartridge. The system was tested and experimentally proved to be able to use for fast detection of the SARS-CoV-2 virus in real-time in less than 30 min. Preliminary results of testing the performance of the fPOC revealed that the fPOC could detect the SARS-CoV-2 virus at a limit of detection (LOD50%) at two to three copies/microliter (15.36 copies/reaction), which was comparable to reactions run on a standard commercial thermocycler. The performance of the fPOC was evaluated with 12 SARS-CoV-2 clinical throat swab samples that included seven positive and five negative samples, as confirmed by reverse transcription–polymerase chain reaction. The fPOC showed 100% agreement with the commercial thermocycler. This simple design of the fPOC system demonstrates the potential to greatly enhance the practical applicability to develop a totally integrated point-of-care system for rapid on-site screening of the SARS-CoV-2 virus in the management of the pandemic.
The ability to rewire ties in communication networks is vital for large-scale human cooperation and the spread of new ideas. We show that lack of researcher co-location during the COVID-19 lockdown caused the loss of more than 4,800 weak ties -- ties between distant parts of the social system that enable the flow of novel information -- over 18 months in the email network of a large North American university. Furthermore, we find that the re-introduction of partial co-location through a hybrid work mode led to a partial regeneration of weak ties. We quantify the effect of co-location in forming ties through a model based on physical proximity, which is able to reproduce all empirical observations. Results indicate that employees who are not co-located are less likely to form ties, weakening the spread of information in the workplace. Such findings could contribute to a better understanding of the spatio-temporal dynamics of human communication networks, and help organizations that are moving towards the implementation of hybrid work policies evaluate the minimum amount of in-person interaction necessary for a productive work environment. 19 pages, ~2500 words, 6 main figures. Supplementary information included as appendix. v3/v4 cleaned supplementary info. First two authors are co-first
Uffe Vest Schneider; Maria Wendelboe Forsberg; Thomas Daell Leineweber; Christel Barker Jensen; Khaled Ghathian; Charlotte Nielsen Agergaard; Kasper Kjersgaard Mortensen; Arieh Cohen; Charlotte Sværke Jørgensen; Helene Larsen; +24 more
Uffe Vest Schneider; Maria Wendelboe Forsberg; Thomas Daell Leineweber; Christel Barker Jensen; Khaled Ghathian; Charlotte Nielsen Agergaard; Kasper Kjersgaard Mortensen; Arieh Cohen; Charlotte Sværke Jørgensen; Helene Larsen; Matilde Bøgelund Hansen; Ulla Saleme; Anders Koch; Nikolai Søren Kirkby; Thomas Kallemose; Marie Louise Schaadt; Frederikke Holm Jensen; Rikke Lind Jørgensen; Chih Man German Ma; Nina Steenhard; Jenny Dahl Knudsen; Jan Gorm Lisby; John Eugenio Coia; Svend Ellermann-Eriksen; Lennart Friis-Hansen; David Fuglsang-Damgaard; Jens Otto Jarløv; Ulrich Stab Jensen; Sanne Jespersen; Ea Sofie Marmolin; Lene Nielsen; Xiaohui Chen Nielsen; Anel Ramic; Lars Jørgen Østergaard;
Background: The SARS-CoV-2 pandemic has resulted in massive testing by Rapid Antigen Tests (RAT) without solid independent data regarding clinical performance being available. Thus, decision on purchase of a specific RAT may rely on manufacturer-provided data and limited peer-reviewed data. Methods: This study consists of two parts. In the retrospective analytical part, 33 RAT from 25 manufacturers were compared to RT-PCR on 100 negative and 204 positive deep oropharyngeal cavity samples divided into four groups based on RT-PCR Cq levels. In the prospective clinical part, nearly 200 individuals positive for SARS-CoV-2 and nearly 200 individuals negative for SARS-CoV-2 by routine RT-PCR testing were retested within 72 h for each of 44 included RAT from 26 manufacturers applying RT-PCR as the reference method.Results: The overall analytical sensitivity differed significantly between the 33 included RAT; from 2.5% (95% CI 0.5–4.8) to 42% (95% CI 35–49). All RAT presented analytical specificities of 100%. Likewise, the overall clinical sensitivity varied significantly between the 44 included RAT; from 2.5% (95% CI 0.5–4.8) to 94% (95% CI 91–97). All RAT presented clinical specificities between 98 and 100%. Conclusion: The study presents analytical as well as clinical performance data for 44 commercially available RAT compared to the same RT-PCR test. The study enables identification of individual RAT that has significantly higher sensitivity than other included RAT and may aid decision makers in selecting between the included RAT. Funding: The study was funded by a participant fee for each test and the Danish Regions.
Signe de Place Knudsen; Saud Abdulaziz Alomairah; Caroline Borup Roland; Anne Dsane Jessen; Ida-Marie Hergel; Tine D Clausen; Jakob Eg Larsen; Gerrit van Hall; Andreas Kryger Jensen; Stig Molsted; +3 more
Signe de Place Knudsen; Saud Abdulaziz Alomairah; Caroline Borup Roland; Anne Dsane Jessen; Ida-Marie Hergel; Tine D Clausen; Jakob Eg Larsen; Gerrit van Hall; Andreas Kryger Jensen; Stig Molsted; Jane M Bendix; Ellen Løkkegaard; Bente Stallknecht;
Background Physical activity (PA) during pregnancy is an effective and safe way to improve maternal health in uncomplicated pregnancies. However, compliance with PA recommendations remains low among pregnant women. Objective The purpose of this study was to evaluate the effects of offering structured supervised exercise training (EXE) or motivational counseling on PA (MOT) during pregnancy on moderate-to-vigorous intensity physical activity (MVPA) level. Additionally, complementary measures of PA using the Pregnancy Physical Activity Questionnaire (PPAQ) and gold standard doubly labeled water (DLW) technique were investigated. The hypotheses were that both EXE and MOT would increase MVPA in pregnancy compared with standard care (CON) and that EXE would be more effective than MOT. In addition, the association between MVPA and the number of sessions attended was explored. Methods A randomized controlled trial included 220 healthy, inactive pregnant women with a median gestational age of 12.9 (IQR 9.4-13.9) weeks. A total of 219 women were randomized to CON (45/219), EXE (87/219), or MOT (87/219). The primary outcome was MVPA (minutes per week) from randomization to the 29th gestational week obtained by a wrist-worn commercial activity tracker (Vivosport, Garmin International). PA was measured by the activity tracker throughout pregnancy, PPAQ, and DLW. The primary outcome analysis was performed as an analysis of covariance model adjusting for baseline PA. Results The average MVPA (minutes per week) from randomization to the 29th gestational week was 33 (95% CI 18 to 47) in CON, 50 (95% CI 39 to 60) in EXE, and 40 (95% CI 30 to 51) in MOT. When adjusted for baseline MVPA, participants in EXE performed 20 (95% CI 4 to 36) minutes per week more MVPA than participants in CON (P=.02). MOT was not more effective than CON; EXE and MOT also did not differ. MVPA was positively associated with the number of exercise sessions attended in EXE from randomization to delivery (P=.04). Attendance was higher for online (due to COVID-19 restrictions) compared with physical exercise training (P=.03). Adverse events and serious adverse events did not differ between groups. Conclusions Offering EXE was more effective than CON to increase MVPA among pregnant women, whereas offering MOT was not. MVPA in the intervention groups did not reach the recommended level in pregnancy. Changing the intervention to online due to COVID-19 restrictions did not affect MVPA level but increased exercise participation. Trial Registration ClinicalTrials.gov NCT03679130; https://clinicaltrials.gov/ct2/show/NCT03679130 International Registered Report Identifier (IRRID) RR2-10.1136/bmjopen-2020-043671
AbstractRecent global trade disruptions, due to blockage of the Suez Canal and cascading effects of COVID-19, have altered the movement patterns of commercial ships and may increase worldwide invasions of marine non-indigenous species. Organisms settle on the hulls and underwater surfaces of vessels and can accumulate rapidly, especially when vessels remain stationary during lay-ups and delays. Once present, organisms can persist on vessels for long-periods (months to years), with the potential to release propagules and seed invasions as ships visit ports across the global transportation network. Shipborne propagules also may be released in increasing numbers during extended vessel residence times at port or anchor. Thus, the large scale of shipping disruptions, impacting thousands of vessels and geographic locations and still on-going for over two years, may elevate invasion rates in coastal ecosystems in the absence of policy and management efforts to prevent this outcome. Concerted international and national biosecurity actions, mobilizing existing frameworks and tools with due diligence, are urgently needed to address a critical gap and abate the associated invasion risks.
AbstractEffective vaccines protect individuals by not only reducing the susceptibility to infection, but also reducing the infectiousness of breakthrough infections in vaccinated cases. To disentangle the vaccine effectiveness against susceptibility to infection (VES) and vaccine effectiveness against infectiousness (VEI), we took advantage of Danish national data comprising 24,693 households with a primary case of SARS-CoV-2 infection (Delta Variant of Concern, 2021) including 53,584 household contacts. In this setting, we estimated VES as 61% (95%-CI: 59-63), when the primary case was unvaccinated, and VEI as 31% (95%-CI: 26-36), when the household contact was unvaccinated. Furthermore, unvaccinated secondary cases with an infection exhibited a three-fold higher viral load compared to fully vaccinated secondary cases with a breakthrough infection. Our results demonstrate that vaccinations reduce susceptibility to infection as well as infectiousness, which should be considered by policy makers when seeking to understand the public health impact of vaccination against transmission of SARS-CoV-2.