Impact of Divalent Metal Ions on Regulation of Trans-Cleavage Activity of CRISPR-Cas13a: A Combined Experimental and Computational Study.

CRISPR-LbuCas13a has emerged as a revolutionary tool for in vitro diagnosis. Similar to other Cas effectors, LbuCas13a requires Mg2+ to maintain its nuclease activity. However, the effect of other divalent metal ions on its trans-cleavage activity remains less explored. Herein, we addressed this issue by combining experimental and molecular dynamics simulation analysis. In vitro studies showed that both Mn2+ and Ca2+ could replace Mg2+ as cofactors of LbuCas13a. In contrast, Ni2+ , Zn2+ , Cu2+ , or Fe2+ inhibits the cis- and trans-cleavage activity, while Pb2+ does not affect it. Importantly, molecular dynamics simulations confirmed that calcium, magnesium, and manganese hydrated ions have a strong affinity to nucleotide bases, thus stabilizing the conformation of crRNA repeat region and enhancing the trans-cleavage activity. Finally, we showed that combination of Mg2+ and Mn2+ can further enhance the trans-cleavage activity to allow amplified RNA detection, revealing its potential advantage for in vitro diagnosis.

COVID-19 and liver dysfunction in children: Current views and new hypotheses.

Coronavirus disease 2019 (COVID-19) poses an extremely serious global impact on public healthcare for individuals of all ages, including children. Increasing evidence has shown that liver abnormalities are commonly found in children with COVID-19, and age-related features in innate and adaptive response have been demonstrated. However, there are few reports and studies on COVID-19 related liver injury in children, and the data are scattered. So that many contradictions have arose. This situation is not only due to the serious ethical issues in studying pediatric patients with COVID-19, but also because of the short duration and wide coverage of the COVID-19 epidemic, the severity and complexity of clinical cases varied, as did the inclusion criteria for case reporting and patient outcomes. Therefore, we totaled the incidences, characteristics and pathomechanism of liver injury in children since the COVID-19 outbreak. The etiology of COVID-19-related liver injury is divided into three categories: (1) The direct mechanism involves severe acute respiratory syndrome coronavirus 2 binding to angiotensin-converting enzyme 2 in the liver or bile duct to exert direct toxicity; (2) the indirect mechanisms include an inflammatory immune response and hypoxia; and (3) COVID-19-related treatments, such as mechanical ventilation and antiviral drugs, may cause liver injury. In summary, this minireview provides fundamental insights into COVID-19 and liver dysfunction in children.

CHEC-UP: A Digital Intervention to Reduce Disparities in Well-Child and Immunization Completion in Community Health

Objective Well-child visits and immunizations among children in the U.S. declined at the pandemic's onset and vulnerable populations have been disproportionately affected. This pilot project tested an innovative mechanism to use chatbots to engage caregivers in evidence-based preventive care for children. Design We used artificial intelligence (AI)-enabled chatbots to personalize messages and facilitate appointment scheduling over a five-month period. Chatbots introduced a novel way to connect vulnerable populations to care and challenged traditional convention of provider-patient engagement. Setting The pilot study was conducted at a Community Health Center in Chicago, Illinois that serves roughly 10,500 children, and 82% of patients are racial and/or ethnic minorities. Participants We targeted outreach to 250 English and Spanish-speaking families with children 0-17 years of age for proactive outreach using chatbots promoting well-child visit completion and up-to-date immunization status;moreover, a special emphasis was placed on the 0-2 age group as the first two years represent a critical time for primary prevention of vaccine-preventable diseases. Interventions The intervention focused on pre-visit engagement by launching an AI-enabled chatbot to deliver personalized messages and facilitate appointment scheduling via mobile devices. CHEC-UP also provided evidence-based anticipatory guidance prior to an appointment. Coaching in preparation for the visit with trusted information has the potential to educate, improve confidence and promote shared decisions between the parent and provider. Patient experience was measured via surveys deployed via the chatbot. Main Outcome Measures & Results Chatbots facilitated a relative increase in well-child visits and immunizations by 27% in the intervention group. Well-child visits and immunizations in the intervention group increased 13% compared to the control group. Survey results and patient interviews indicated a high level of patient satisfaction using the chatbot. In addition to a favorable perception of the chatbots, patients also identified future use cases for chatbots. Conclusions Engaging patients with chatbots improved vaccination and well-child uptake. Patients were highly satisfied with chatbot engagement. By engaging patients and caregivers, chatbots present the potential to proactively engage patients in care and optimize vaccination uptake and realize one of societies' greatest public health achievements: decreasing the spread of communicable diseases.

At-Home COVID-19 Rapid Antigen Test Down to 0.03 pg mL-1 of Nucleocapsid Protein.

Rapid and ultra-sensitive detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for early screening and management of COVID-19. Currently, the real-time reverse transcription polymerase chain reaction (rRT-PCR) is the primary laboratory method for diagnosing SARS-CoV-2. It is not suitable for at-home COVID-19 diagnostic test due to the long operating time, specific equipment, and professional procedures. Here an all-printed photonic crystal (PC) microarray with portable device for at-home COVID-19 rapid antigen test is reported. The fluorescence-enhanced effect of PC amplifies the fluorescence intensity of the labeled probe, achieving detection of nucleocapsid (N-) protein down to 0.03 pg mL-1 . A portable fluorescence intensity measurement instrument gives the result (negative or positive) by the color of the indicator within 5 s after inserting the reacted PC microarray test card. The N protein in inactivated virus samples (with cycle threshold values of 26.6-40.0) can be detected. The PC microarray provides a general and easy-to-use method for the timely monitoring and eventual control of the global coronavirus pandemic.

Comparative efficacy of face-to-face and internet-based cognitive behavior therapy for generalized anxiety disorder: A meta-analysis of randomized controlled trial

Objective The study aimed to ascertain the comparative efficacy of these two forms on reducing anxiety scores of scales in patients with a generalized anxiety disorder (GAD) by examining the available evidence for face-to-face cognitive behavior therapy (CBT) and internet-based cognitive behavior therapy (ICBT). Moreover, this study attempted to determine whether ICBT can obtain similar benefits as CBT for GAD patients during coronavirus disease 2019 (COVID-19) due to the quarantine policy and the requirement of social distance. Methods This meta-analysis was registered with the International Prospective Register of Systematic Reviews (PROSPERO) according to the guidelines in the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement (registration number CRD42021241938). Therefore, a meta-analysis of randomized controlled trials (RCTs) examining CBT or ICBT was conducted in this study to treat GAD patients diagnosed with DMS-IV. The researchers searched PubMed, MEDLINE, Embase, PsycINFO, and the Cochrane Database of Systematic Reviews for relevant studies published from 2000 to July 5, 2022. Evidence from RCTs was synthesized by Review Manager 5.4 as mean difference (MD) for change in scores of scales through a random-effects meta-analysis. Results A total of 26 trials representing 1,687 participants were pooled. The results demonstrated that ICBT and CBT were very close in the effect size of treating GAD (MD = −2.35 vs. MD = −2.79). Moreover, they still exhibited a similar response (MD = −3.45 vs. MD = −2.91) after studies with active control were removed. Conclusion Regarding the treatment of GAD, ICBT can achieve a similar therapeutic effect as CBT and could be CBT's candidate substitute, especially in the COVID-19 pandemic era, since the internet plays a crucial role in handling social space constraints. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=241938, identifier CRD42021241938.

A flexible, efficient, and scalable platform to produce circular RNAs as new therapeutics (preprint)

Messenger RNA (mRNA) has recently emerged as a new drug modality with great therapeutic potential. However, linear mRNAs are relatively unstable and also require base modification to reduce their immunogenicity, imposing a limitation to the broad application. With improved stability, the circular RNA (circRNA) presents a better alternative for prolonged expression of the proteins, however the in vitro circularization of RNA at a large scale is technically challenging. Here we developed a new self-catalyzed system to efficiently produce circRNAs in a co-transcriptional fashion. By rational sequence design, we can efficiently produce scarless circRNAs that do not contain foreign sequences. The resulting circRNAs are very stable and have low immunogenicity, enabling prolonged protein translation in different cells without cellular toxicity. The circRNAs generated from this platform can be encapsulated in lipid nanoparticles and efficiently delivered into mice to direct robust protein expression. Finally, the circRNAs encoding RBD of SARS-CoV-2 S protein induced strong antibody productions, with neutralization antibody titers higher than the preclinical data from the linear mRNAs. Collectively, this study provided a general platform for efficient production of circRNAs, demonstrating the potential of circRNAs as the new generation of mRNA therapy.

A broad-spectrum antiviral fusion protein, Pheromonicin demonstrated protective efficacy against SARS-CoV-2 variants in vitro and in vivo models (preprint)

The unprecedented coronavirus disease (COVID-19) epidemic has created a worldwide public health emergency, and there is an urgent need to develop an effective antiviral drug to control this severe infectious disease. Here, we found that the E, or M membrane proteins of coronavirus could be targeted by a 28-residue antibody mimetic by fusing two antibody Fab complementarity-determining regions (VHCDR1 and VLCDR3) through a cognate framework region (VHFR2) of the antibodies which recognize the coronavirus E or M proteins. We constructed a fusion protein, pheromonicin-covid-19 (PMC-covid-19), by linking colicin Ia, a bactericidal molecule produced by E.coli which kills target cells by forming a voltage-dependent channel in target lipid bilayers, to that antibody mimetic. The E, or M protein/antibody mimetic interaction initiated the formation of irreversible PMC-covid-19 channel in the covid-19 envelope and infected host cell membrane resulting in leakage of cellular contents. PMC-covid-19 demonstrates broad-spectrum protective efficacy against tested variants of coronavirus severe acute respiratory syndrome (p<0.01-0.0001). PMC-covid-19 significantly altered outcomes of in vivo fatal covid-19 challenge infection without evident toxicity, making it an appropriate candidate for further clinical evaluation.

Development and implementation of an “Internet+” management plan for cancer patients with wounds/stomas during the coronavirus disease 2019 pandemic

To explore the practical application and effect of the management plan for cancer patients with wounds/stomas based on the ?Internet+? model during the coronavirus disease 2019 (COVID-19) pandemic. Based on the specific situation during the COVID-19 pandemic, we established the ?Internet+? management team for cancer patients with wounds/stomas. After systematical literature search and brainstorming analysis, we developed a management plan for cancer patients with wounds/stomas based on the ?Internet+? model. Then, we included cancer patients with wounds/stomas who needed follow-up visits or consultations at Jiangsu Cancer Hospital from January 25 to April 30, 2020. A total of 304 patients were participated in the study. The effects of the plan were evaluated including patient satisfaction, the proportion of patients who did not need to go to the hospital for treatment, the proportion of patients with improved symptoms and the rate of the patients or nurses contracted COVID-19. After the implementation of the plan, 56.3% of the patients mastered the relevant self-care methods under the guidance of specialist nurses and did not need to go to the hospital for treatment. A total of 89.5% of the patients showed improvement in symptoms, and 99.4% of the patients were satisfied with the online treatment. None of the patients or nurses contracted COVID-19. The ?Internet+? management plan for cancer patients with wounds/stomas during the COVID-19 pandemic had supported epidemic prevention and control in medical institutions and reduced the risk of cross infection. In addition, this type of plan effectively improved disease symptoms in the patients, and their level of satisfaction was high.

An Extended COVID-19 Epidemiological Model with Vaccination and Multiple Interventions for Controlling COVID-19 Outbreaks in the UK (preprint)

ABSTRACT For controlling the first wave of the UK COVID-19 pandemic in 2020, a plethora of hypothetical COVID-19 models has been developed for simulating how diseases spread under different non-pharmaceutical interventions like suppression and mitigation and providing useful guidance to UK policymakers. While many models demonstrate their effectiveness on predicting and controlling the spread of COVID-19, they rarely consider consequence of incorporating the effects of potential SARS-CoV-2 variants and implementing vaccine interventions in large-scale. By December 2020, the second wave in the UK appeared to be much more aggressive with many more cases as one potentially more contagious SARS-CoV-2 variant was detected in the UK since September 2020. Meanwhile, UK has begun their first mass vaccination campaign on 8 December 2020, where three vaccines were in use including Pfizer, BioNTech and Moderna. Thus, these new issues pose an emergent need to build up advanced models for accessing effectiveness of taking both vaccination and multiple interventions for controlling COVID-19 outbreaks and balancing healthcare demands. Targeting at this problem, we conducted a feasibility study by defining a new mathematical model SEMCVRD (Susceptible [S], Exposed [E] (infected but asymptomatic), Mild [M] and Critical [C] (mild cases, severe and critical cases), [V] (vaccinated), Recovered [R] and Deceased [D]), containing two importantly new features: the combined infection of the mutant strain and the original strain and the addition of a new group who have been vaccinated. The model was fitted and evaluated with a public COVID-19 dataset including daily new infections, new deaths and daily vaccination in the UK from February 2020 to February 2021. Based on the simulation results, 1) we find under the assumption that the vaccine is equivalently effective against both the original strain and new variants of COVID-19, if the UK government implements insensitive suppression intervention for 13 weeks, COVID-19 epidemic will be controlled by the first week of April 2021 and nearly ended by the first week of May 2021. It shows that taking both vaccine and suppression interventions can effectively inhibit the spread and infection of the new mutant virus. 2) we suggest implementing a 3-weeks phased and progressive lifting intervention strategy up to a low intensity mitigation level for effectively controlling COVID-19 outbreaks in the UK. By implementing this strategy, the total number of infections in the UK will be limited to 4.2 million and the total number of deaths in the UK is 135 thousand, by the end of June 2021. The epidemic will nearly end in the early of June 2021, and the UK will not experience a shortage of medical resources. 3) On the assumption that UK has a capability of providing 600 thousand vaccinations every day, a 3-weeks phased and progressive lifting intervention strategy up to a moderate intensity mitigation level can end the epidemic by the end of May 2021. This strategy would reduce the overall infections and deaths of COVID-19 outbreaks, and balance healthcare demand in the UK.

MFL_COVID19: Quantifying Country-based Factors affecting Case Fatality Rate in Early Phase of COVID-19 Epidemic via Regularised Multi-task Feature Learning (preprint)

Recent outbreak of COVID-19 has led a rapid global spread around the world. Many countries have implemented timely intensive suppression to minimize the infections, but resulted in high case fatality rate (CFR) due to critical demand of health resources. Other country-based factors such as sociocultural issues, ageing population etc., has also influenced practical effectiveness of taking interventions to improve morality in early phase. To better understand the relationship of these factors across different countries with COVID-19 CFR is of primary importance to prepare for potentially second wave of COVID-19 infections. In the paper, we propose a novel regularized multi-task learning based factor analysis approach for quantifying country-based factors affecting CFR in early phase of COVID-19 epidemic. We formulate the prediction of CFR progression as a ML regression problem with observed CFR and other countries-based factors. In this formulation, all CFR related factors were categorized into 6 sectors with 27 indicators. We proposed a hybrid feature selection method combining filter, wrapper and tree-based models to calibrate initial factors for a preliminary feature interaction. Then we adopted two typical single task model (Ridge and Lasso regression) and one state-of-the-art MTFL method (fused sparse group lasso) in our formulation. The fused sparse group Lasso (FSGL) method allows the simultaneous selection of a common set of country-based factors for multiple time points of COVID-19 epidemic and also enables incorporating temporal smoothness of each factor over the whole early phase period. Finally, we proposed one novel temporal voting feature selection scheme to balance the weight instability of multiple factors in our MTFL model.

Tobacco smoking cessation in mental health services during the COVID-19 pandemic.

Tobacco smoking is more prevalent among people who experience mental illness. It is therefore a prominent issue for psychiatric inpatient units. The COVID-19 pandemic has meant that many psychiatric inpatient units are no longer granting leave and outdoor smoking breaks, prompting the question of whether to allow tobacco smoking or enforce smoking bans in mental health services. There is currently mixed evidence that tobacco smoking is associated with a higher risk of developing COVID-19 and poorer outcomes for COVID-19 cases, potentially due to current small sample sizes. Considering the benefits of smoking cessation in this vulnerable population, the current pandemic should be used as an opportunity to further enforce smoking cessation in mental health facilities and encourage nicotine replacement therapy alongside cessation counseling.

Optimized Laboratory Detection Strategy for COVID-19 Patients Reduces the Rate of Missed Diagnosis (preprint)

Background: Novel coronavirus pneumonia (NCP) is an emerging, highly contagious community acquired pneumonia (CAP) caused by severe acute SARS-CoV-2. Nucleic acid test currently played a crucial role in diagnosis of suspected COVID-19 patients. However, a high false-negative rate of this “gold standard” test has been reported and posed a major setback in blocking the spread of the virus. We here aim to describe an optimized laboratory detection strategy to reduce the false negative rate. Methods: Suspected NCP patients were asked to collect both coughed up specimen and pharyngeal swab. Samples from the same patient were mixed and tested at a single pool. SARS-CoV-2 was then detected by real-time RT-PCR using two different detection kits. Only if both results were negative was the test reported as negative. The patients will be excluded after two consecutive negative tests at 24 hour intervals. We also used multiplex PCR to detect 13 common respiratory tract pathogens (RTP). Results: Using this strategy, we confirmed 85 SARS-CoV-2 infections from 181 suspected patients, and 94.12% of patients were positive in the first test. The 96 excluded patients were followed up, and no additional NCP was found. We also found that 31.25% patients in 96 non-NCP patients were infected with at least one RTP that may cause CAP. Conclusion: Our studies suggest that dual reagents screening with pooled coughed up specimen and pharyngeal swab samples reduced the false negative rate of nucleic acid testing. During the epidemic of NCP in Anhui province, there was a certain proportion of infection and co-infection of other common pathogens of CAP. In comparison with SARS-CoV-2 detection alone, combining multiple pathogen detection reduces the rate of miss diagnosis.

Digestive Manifestations in Patients Hospitalized with COVID-19 (preprint)

BackgroundThe prevalence and significance of digestive manifestations in COVID-19 remain uncertain. MethodsConsecutive patients hospitalized with COVID-19 were identified across a geographically diverse alliance of medical centers in North America. Data pertaining to baseline characteristics, symptomatology, laboratory assessment, imaging, and endoscopic findings from the time of symptom onset until discharge or death were manually abstracted from electronic health records to characterize the prevalence, spectrum, and severity of digestive manifestations. Regression analyses were performed to evaluate the association between digestive manifestations and severe outcomes related to COVID-19. ResultsA total of 1992 patients across 36 centers met eligibility criteria and were included. Overall, 53% of patients experienced at least one gastrointestinal symptom at any time during their illness, most commonly diarrhea (34%), nausea (27%), vomiting (16%), and abdominal pain (11%). In 74% of cases, gastrointestinal symptoms were judged to be mild. In total, 35% of patients developed an abnormal alanine aminotransferase or total bilirubin level; these were elevated to less than 5 times the upper limit of normal in 77% of cases. After adjusting for potential confounders, the presence of gastrointestinal symptoms at any time (odds ratio 0.93, 95% confidence interval 0.76-1.15) or liver test abnormalities on admission (odds ratio 1.31, 95% confidence interval 0.80-2.12) were not independently associated with mechanical ventilation or death. ConclusionsAmong patients hospitalized with COVID-19, gastrointestinal symptoms and liver test abnormalities were common but the majority were mild and their presence was not associated with a more severe clinical course

Nomogram for Prediction of fatal outcome in Patients with Severe COVID-19: A Multicenter Study (preprint)

Background & Aims: To develop an effective model of predicting fatalOutcome in the severe coronavirus disease 2019 (COVID-19) patients.Methods: Between February 20, 2020 and April 4, 2020, consecutive COVID-19 patients from three designated hospitals were enrolled in this study. Independent high- risk factors associated with death were analyzed using Cox proportional hazard model. A prognostic nomogram was constructed to predict the survival of severe COVID-19 patients.Results: There were 124 severe patients in the training cohort, and there were 71 and 76 severe patients in the two independent validation cohorts, respectively. Multivariate Cox analysis indicated that age ≥ 70 years (HR 1.184, 95% CI 1.061-1.321), Panting(breathing rate ≥ 30/min) (HR 3.300, 95% CI 2.509-6.286), lymphocyte count < 1.0 × 109/L (HR 2.283, 95% CI 1.779-3.267), and IL-6 >10pg/mL (HR 3.029, 95% CI 1.567-7.116) were independent high-risk factors associated with fatal outcome. We developed the nomogram for identifying survival of severe COVID-19 patients in the training cohort (AUC 0.900, [95% CI 0.841-0.960], sensitivity 95.5%, specificity 77.5%); in validation cohort 1 (AUC 0.811, [95% CI 0.763-0.961], sensitivity 77.3%, specificity 73.5); in validation cohort 2 (AUC 0.862, [95% CI 0.698-0.924], sensitivity 92.9%, specificity 64.5%). The calibration curve for probability of death indicated a good consistence between prediction by the nomogram and the actual observation. The prognosis of severe COVID-19 patients with high levels of interleukin-6 (IL-6) receiving tocilizumab was better than that of those patients without tocilizumab both in the training and validation cohorts, but without difference (p = 0.105 for training cohort, p = 0.133 for validation cohort 1, and p = 0.210 for validation cohort 2).Conclusions: This nomogram could help clinicians to identify severe patients who have high risk of death, and to develop more appropriate treatment strategies to reduce the mortality of severe patients. Tocilizumab may improve the prognosis of severe COVID-19 patients with high levels of IL-6.

Nomogram for Prediction of fatal outcome in Patients with Severe COVID-19 Pneumonia: A Multicenter Study (preprint)

Background & Aims: To develop an effective model of predicting fatal Outcome in the severe coronavirus disease 2019 (COVID-19) patients.Methods: Between February 20, 2020 and April 4, 2020, consecutive COVID-19 patients from three designated hospitals were enrolled in this study. Independent high- risk factors associated with death were analyzed using Cox proportional hazard model. A prognostic nomogram was constructed to predict the survival of severe COVID-19 patients.Results: There were 124 severe patients in the training cohort, and there were 71 and 76 severe patients in the two independent validation cohorts, respectively. Multivariate Cox analysis indicated that age ≥ 70 years (HR 1.184, 95% CI 1.061-1.321), Panting(breathing rate ≥ 30/min) (HR 3.300, 95% CI 2.509-6.286), lymphocyte count < 1.0 × 109/L (HR 2.283, 95% CI 1.779-3.267), and IL-6 >10pg/mL (HR 3.029, 95% CI 1.567-7.116) were independent high-risk factors associated with fatal outcome. We developed the nomogram for identifying survival of severe COVID-19 patients in the training cohort (AUC 0.900, [95% CI 0.841-0.960], sensitivity 95.5%, specificity 77.5%); in validation cohort 1 (AUC 0.862, [95% CI 0.763-0.961], sensitivity 92.9%, specificity 64.5%); in validation cohort 2 (AUC 0.811, [95% CI 0.698-0.924], sensitivity 77.3%, specificity 73.5%). The calibration curve for probability of death indicated a good consistence between prediction by the nomogram and the actual observation. Conclusions: This nomogram could help clinicians to identify severe patients who have high risk of death, and to develop more appropriate treatment strategies to reduce the mortality of severe patients.

The effect of multiple interventions to balance healthcare demand for controlling COVID-19 outbreaks: a modelling study (preprint)

BackgroundRecent outbreak of a novel coronavirus disease 2019 (COVID-19) has led a rapid global spread around the world. For controlling COVID-19 outbreaks, many countries have implemented two non-pharmaceutical interventions: suppression like immediate lock-downs in cities at epicentre of outbreak; or mitigation that slows down but not stopping epidemic for reducing peak healthcare demand. Both interventions have apparent pros and cons; the effectiveness of any one intervention in isolation is limited. It is crucial but hard to know how and when to take which level of interventions tailored to the specific situation in each country. We aimed to conduct a feasibility study for robustly accessing the effect of multiple interventions to control the number and distribution of infections, growth of deaths, peaks and lengths of COVID-19 breakouts in the UK and other European countries, accounting for balance of healthcare demand. MethodsWe developed a model to attempt to infer the impact of mitigation, suppression and multiple rolling interventions for controlling COVID-19 outbreaks in the UK. Our model assumed that each intervention has equivalent effect on the reproduction number R across countries and over time; where its intensity was presented by average-number contacts with susceptible individuals as infectious individuals; early immediate intensive intervention led to increased health need and social anxiety. We considered two important features: direct link between Exposed and Recovered population, and practical healthcare demand by separation of infections into mild, moderate and critical cases. Our model was fitted and calibrated with date on cases of COVID-19 in Wuhan to estimate how suppression intervention impacted on the number and distribution of infections, growth of deaths over time during January 2020, and April 2020. We combined the calibrated model with data on the cases of COVID-19 in London and non-London regions in the UK during February 2020 and April 2020 to estimate the number and distribution of infections, growth of deaths, and healthcare demand by using multiple interventions. We applied the calibrated model to the prediction of infection and healthcare resource changes in other 6 European countries based on actual measures they have implemented during this period. FindingsWe estimated given that 1) By the date (5th March 2020) of the first report death in the UK, around 7499 people would have already been infected with the virus. After taking suppression on 23rd March, the peak of infection in the UK would have occurred between 28th March and 4th April 2020; the peak of death would have occurred between 18th April and 24th April 2020. 2) By 29th April, no significant collapse of health system in the UK have occurred, where there have been sufficient hospital beds for severe and critical cases. But in the Europe, Italy, Spain and France have experienced a 3 weeks period of shortage of hospital beds for severe and critical cases, leading to many deaths outside hospitals. 3) One optimal strategy to control COVID-19 outbreaks in the UK is to take region-level specific intervention. If taking suppression with very high intensity in London from 23rd March 2020 for 100 days, and 3 weeks rolling intervention between very high intensity and high intensity in non-London regions. The total infections and deaths in the UK were limited to 9.3 million and 143 thousand; the peak time of healthcare demand was due to the 96th day (12th May, 2020), where it needs hospital beds for 68.9 thousand severe and critical cases. 4) If taking a simultaneous 3 weeks rolling intervention between very high intensity and high intensity in all regions of the UK, the total infections and deaths increased slightly to 10 million and 154 thousand; the peak time of healthcare occurs at the 97th day (13th May, 2020), where it needs equivalent hospital beds for severe and critical cases of 73.5 thousand. 5) If too early releasing intervention intensity above moderate level and simultaneously implemented them in all regions of the UK, there would be a risk of second wave, where the total infections and deaths in the UK possibly reached to 23.4 million and 897 thousand. InterpretationConsidering social and economic costs in controlling COVID-19 outbreaks, long-term suppression is not economically viable. Our finding suggests that rolling intervention is an optimal strategy to effectively and efficiently control COVID-19 outbreaks in the UK and potential other countries for balancing healthcare demand and morality ratio. As for huge difference of population density and social distancing between different regions in the UK, it is more appropriate to implement regional level specific intervention with varied intensities and maintenance periods. We suggest an intervention strategy to the UK that take a consistent suppression in London for 100 days and 3 weeks rolling intervention in other regions. This strategy would reduce the overall infections and deaths of COVID-19 outbreaks, and balance healthcare demand in the UK.

Broad-spectrum virucidal activity of bacterial secreted lipases against flaviviruses, SARS-CoV-2 and other enveloped viruses (preprint)

Viruses are the major aetiological agents of acute and chronic severe human diseases that place a tremendous burden on global public health and economy; however, for most viruses, effective prophylactics and therapeutics are lacking, in particular, broad-spectrum antiviral agents. Herein, we identified 2 secreted bacterial lipases from a Chromobacterium bacterium, named Chromobacterium antiviral effector-1 (CbAE-1) and CbAE-2, with a broad-spectrum virucidal activity against dengue virus (DENV), Zika virus (ZIKV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human immunodeficiency virus (HIV) and herpes simplex virus (HSV). The CbAEs potently blocked viral infection in the extracellular milieu through their lipase activity. Mechanistic studies showed that this lipase activity directly disrupted the viral envelope structure, thus inactivating infectivity. A mutation of CbAE-1 in its lipase motif fully abrogated the virucidal ability. Furthermore, CbAE-2 presented low toxicity in vivo and in vitro, highlighting its potential as a broad-spectrum antiviral drug.

Susceptibility of tree shrew to SARS-CoV-2 infection (preprint)

Since SARS-CoV-2 became a pandemic event in the world, it has not only caused huge economic losses, but also a serious threat to global public health. Many scientific questions about SARS-CoV-2 and COVID-19 were raised and urgently need to be answered, including the susceptibility of animals to SARS-CoV-2 infection. Here we tested whether tree shrew, an emerging experimental animal domesticated from wild animal, is susceptible to SARS-CoV-2 infection. No clinical signs were observed in SARS-CoV-2 inoculated tree shrews during this experiment except the increasing body temperature (above 39{degrees} C) particular in female animals during infection. Low levels of virus shedding and replication in tissues occurred in all three age groups, each of which showed his own characteristics. Histopathological examine revealed that pulmonary abnormalities were mild but the main changes although slight lesions were also observed in other tissues. In summary, tree shrew is not susceptible to SARS-CoV-2 infection and may not be a suitable animal for COVID-19 related researches.

COVID-19 diagnosis and study of serum SARS-CoV-2 specific IgA, IgM and IgG by a quantitative and sensitive immunoassay (preprint)

Background. The pandemic of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is causing great loss. Detecting viral RNAs is standard approach for SARS-CoV-2 diagnosis with variable success. Currently, studies describing the serological diagnostic methods are emerging, while most of them just involve the detection of SARS-CoV-2-specific IgM and IgG by ELISA or flow immunoassay with limited accuracy. Methods. Diagnostic approach depends on chemiluminescence immunoanalysis (CLIA) for detecting IgA, IgM and IgG specific to SARS-CoV-2 nucleocapsid protein (NP) and receptor-binding domain (RBD) was developed. The approach was tested with 216 sera from 87 COVID-19 patients and 483 sera from SARS-CoV-2 negative individuals. The diagnostic accuracy was evaluated by receiver operating characteristic (ROC) analysis. Concentration kinetics of RBD-specific serum antibodies were characterized. The relationship of serum RBD-specific antibodies and disease severity was analyzed. Results. The diagnostic accuracy based on RBD outperformed those based on NP. Adding IgA to a conventional serological test containing IgM and IgG improves sensitivity of SARS-CoV-2 diagnosis at early stage. CLIA for detecting RBD-specific IgA, IgM and IgG showed diagnostic sensitivities of 98.6%, 96.8% and 96.8%, and specificities of 98.1%, 92.3% and 99.8%, respectively. Median concentration of IgA and IgM peaked during 16-20 days after illness onset at 8.84 g/mL and 7.25 g/mL, respectively, while IgG peaked during 21-25 days after illness onset at 16.47 g/mL. Furthermore, the serum IgA level positively correlates with COVID-19 severity. Conclusion. CLIA for detecting SARS-CoV-2 RBD-specific IgA, IgM and IgG in blood provides additional values for diagnosing and monitoring of COVID-19.