Deep Dynamic Epidemiological Modelling for COVID-19 Forecasting in Multi-level Districts (preprint)

Objective: COVID-19 has spread worldwide and made a huge influence across the world. Modeling the infectious spread situation of COVID-19 is essential to understand the current condition and to formulate intervention measurements. Epidemiological equations based on the SEIR model simulate disease development. The traditional parameter estimation method to solve SEIR equations could not precisely fit real-world data due to different situations, such as social distancing policies and intervention strategies. Additionally, learning-based models achieve outstanding fitting performance, but cannot visualize mechanisms. Methods: Thus, we propose a deep dynamic epidemiological (DDE) method that combines epidemiological equations and deep-learning advantages to obtain high accuracy and visualization. The DDE contains deep networks to fit the effect function to simulate the ever-changing situations based on the neural ODE method in solving variants' equations, ensuring the fitting performance of multi-level areas. Results: We introduce four SEIR variants to fit different situations in different countries and regions. We compare our DDE method with traditional parameter estimation methods (Nelder-Mead, BFGS, Powell, Truncated Newton Conjugate-Gradient, Neural ODE) in fitting the real-world data in the cases of countries (the USA, Columbia, South Africa) and regions (Wuhan in China, Piedmont in Italy). Our DDE method achieves the best Mean Square Error and Pearson coefficient in all five areas. Further, compared with the state-of-art learning-based approaches, the DDE outperforms all techniques, including LSTM, RNN, GRU, Random Forest, Extremely Random Trees, and Decision Tree. Conclusion: DDE presents outstanding predictive ability and visualized display of the changes in infection rates in different regions and countries.

A survey of health status of healthcare providers in a square cabin hospital during the new corona omicron outbreak: A cross-sectional study

Background The coronavirus omicron variant outbroke in early 2022 in Shanghai. Although previous studies indicated that long working hours in a square cabin hospital might increase the risk of mental health among frontline healthcare providers, few studies have investigated whether the mental health risk could be reduced among well-trained professionals following the new guidelines. Objective This study aimed to investigate the health situation of frontline healthcare providers in Shanghai square cabin during the omicron variant circulation. Methods An online survey was used to evaluate those healthcare providers working in the square cabin hospitals from March 1, 2022, to May 31, 2022. The first online survey was conducted and emailed to the health providers on April 1. The second survey was conducted and sent to the nonrespondents on May 31. Overall, 142 frontline healthcare providers completed the online survey. Their mental health was assessed by the Insomnia Severity Index Scale, the Generalized Anxiety Disorder Scale, the Patient Health Questionnaire-9, and the Psychological Resilience Scale. We estimated multiple clinical systems and identified factors associated with those symptoms among participants. Multivariable logistic regression models were used to assess the risk factors of these symptoms. Results Overall, 66.20%, 45.07%, and 27.46% of frontline healthcare providers in Shanghai City reported symptoms of insomnia, depression, and anxiety, respectively. In addition, the most common symptoms included dry eyes (57.75%), lumbar muscle strain (47.18%), dry mouth (35.92%), itching (31.69%), headache (29.58%), and sore throat (28.87%) among the frontline healthcare providers. There was no statistical difference in symptoms by gender, age, personnel category, or job position (p > 0.05). Conclusion In the case of an unexpected pandemic, the mental health of healthcare providers is not optimistic. This situation still exists more than 2 years after the global outbreak of the COVID-19 pandemic. Therefore, the physical and mental health of long-term healthcare providers working in a square cabin hospital still needs monitoring.

Research progress of origin traceability technology for food and drug homologous products

The idea of 'food and drug homology' plays a very important role in Chinese history. Especially, in the COVID-19 epidemic situation, 'food and drug homology' products improved health as medicated diet, thus promoting traditional Chinese drugs industry becomingmoreinternational. However, the quality of food and drug homology products were uneven, intermingled quality products and fake ones happen occasionally. In recent years, traceability technology for food and drug homologous products has gradually become a research hotspot due to the complex and diverse means of adulteration of food and drug homologous products. The aim of the development of origin traceability technology is to protect the 'genuineness' and 'distinctiveness' of food and drug homologous products. At the same time, it protects the rights and interests of consumersand protects the authenticity of food and drug homologous products and the healthy development of the food and drug homologous industry. Based on the basic data of journals and master's and doctoral dissertations collected from CNKI, Web of Sciences and Pud Med till June 2021, this paper analyzed the development trend of traceability technology in the application of global food and drug homologous products. The source, classification, origin traceability technology and application progress in food and drug homologous products were summarized in order to provide a theoretical basis for future research on origin traceability technology for food and drug homologous products.

Development of a thermostable SARS-CoV-2 variant-based bivalent protein vaccine with cross-neutralizing potency against Omicron subvariants

SARS-CoV-2 variants have posed significant challenges to the hopes of using ancestral strain-based vaccines to address the risk of breakthrough infection by variants. We designed and developed a bivalent vaccine based on SARS-CoV-2 Alpha and Beta variants (named SCTV01C). SCTV01C antigens were stable at 25 oC for at least 6 months. In the presence of a squalene-based oil-in-water adjuvant SCT-VA02B, SCTV01C showed significant protection efficacy against antigen-matched Beta variant, with favorable safety profiles in rodents. Notably, SCTV01C exhibited cross-neutralization capacity against Omicron subvariants (BA.1, BA.1.1, BA.2, BA.3, and BA.4/5) in mice, superior to a WT (D614G)-based vaccine, which reinforced our previously published findings that SCTV01C exhibited broad-spectrum neutralizing potencies against over a dozen pre-Omicron variants and the Omicron BA.1 variant. In summary, variant-based multivalent protein vaccine could be a platform approach to address the challenging issues of emerging variants, vaccine hesitancy and the needs of affordable and thermal stable vaccines.

Genetic screening for hypertension and COVID-19 reveals functional variant of SPEG associated with severe COVID-19 in female (preprint)

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused more than 6.4 million deaths worldwide and is still spreading among global populations. The prevalent comorbidity between hypertension and severe COVID-19 suggests common genetic factors may affect the outcome of both diseases. As both hypertension and severe COVID-19 demonstrate sex-specific prevalence, common genetic factors among the two diseases may display gender-based differential associations. By evaluating COVID-19 association signals of 172-candidate hypertension single nucleotide polymorphisms derived from more than one million European individuals in two severe COVID-19 genome-wide association studies from UK BioBank with European ancestry, we revealed one functional cis expression quantitative trait locus of SPEG (rs12474050) associating with both hypertension and severe COVID-19 in female. The risk allele of rs12474050*T is correlated with lower SPEG expression in muscle-skeletal, heart-atrial appendage, and heart-left ventricle; among these tissues the SPEG expression is higher in female than in male COVID-19 patients. Further analysis revealed SPEG is mainly expressed in cardiomyocytes in heart and is upregulated upon SARS-CoV-2 infection, with significantly higher folder change of SPEG expression observed in female compared to male COVID-19 patients. Taken together, our analyses strongly suggest the involvement of SPEG in both hypertension and severe COVID-19 in female, which provides new insights for sex-specific effect of severe COVID-19 in female.

Recent developments in the immunopathology of COVID-19 (preprint)

There has been an important change in the clinical characteristics and immune profile of COVID-19 patients during the pandemic thanks to the extensive vaccination programs. Here, we highlight recent studies on COVID-19, from the clinical and immunological characteristics to the protective and risk factors for severity and mortality of COVID-19. The efficacy COVID-19 vaccines and potential allergic reactions after administration are also discussed. The occurrence of new variants of concerns such as Omicron BA.2, BA.4 and BA.5 and the global administration of COVID-19 vaccines have changed the clinical scenario of COVID-19. Multisystem inflammatory syndrome in children (MIS-C) has been identified as an important cause of death of children with COVID-19. Perturbations in immunity of T cells, B cells, and mast cells, as well as autoantibodies and metabolic reprogramming may contribute to the long-term symptoms of COVID-19. Atopic diseases, such as allergic asthma and rhinitis, have been shown to be associated with a lower susceptibility and better outcomes of COVID-19. At the beginning of pandemic, EAACI developed guidelines that provided timely information for the management of allergic diseases and preventive measures to reduce transmission in the allergic clinics. The global distribution of COVID-19 vaccines and emerging SARS-CoV-2 variants with reduced pathogenic potential dramatically decreased the morbidity, severity, and mortality of COVID-19. Nevertheless, breakthrough infection remains a challenge for disease control. Hypersensitivity reactions (HSR) to COVID-19 vaccines are low compared to other vaccines, and these were addressed in EAACI statements that provided indications for the management of allergic reactions, including anaphylaxis to COVID-19 vaccines. We have gained a depth knowledge and experience in the over 2 years since the start of the pandemic, and yet a full eradication of SARS-CoV-2 is not on the horizon. Novel strategies are warranted to prevent severe disease in high-risk groups, the development of MIS-C and long COVID.

Will People Accept a Third Booster Dose of the COVID-19 Vaccine? A Cross-Sectional Study in China

Objective The coronavirus disease 2019 (COVID-19) vaccines are considered to be an effective way to prevent the spread of the infection. Our previous study has shown that about 75% of healthcare workers (HCWs) in China were willing to receive the vaccine when it became available. Here, we examined the acceptance of a third booster dose among Chinese people and identified the influencing factors. Methods A cross-sectional online survey was conducted and the snowball sampling method was utilized. An online questionnaire was provided to all the participants in the form of a quick response (QR) code. The questionnaire included general demographic information, views on vaccines, the General Health Questionnaire-12 (GHQ-12), and the Depression, Anxiety, and Stress Scale-21 (DASS-21). The univariate analysis was done between all the variables and our dependent variable. Then, we used the multivariate logistic regression model to examine the influencing factors of the third booster dose acceptance. Results We collected 1,062 complete answers. Of these, 90.39% (n = 960) declared that they would accept the booster dose. Knowing more about the vaccine and recognizing the efficacy of vaccines were significantly associated with greater acceptance of the booster dose. People willing to take the booster dose had better psychological health. A belief that the booster dose could prevent severe infection caused by COVID-19 and enhance the effectiveness of the first two doses were the main contributing factors to vaccine acceptance. Vaccine hesitancy was mainly due to a low perceived risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and rapid mutation of SARS-CoV-2. Conclusion This study revealed that Chinese people were very receptive to the third booster dose, which is an inspiring result. More positive attitudes regarding COVID-19 vaccination were supported by its efficacy and few side effects.

To mask, or not to mask, Alice and Bob's dating dilemma (preprint)

Face masking in current COVID-19 pandemic seems to be a deceivingly simple decision-making problem due to its multifaceted nature. Questions arising from masking span biomedicine, epidemiology, physics, and human behaviors. While science has shown masks work generally, human behaviors (particularly under influences of politics) complicate the problem significantly given science generally assumes rationality and our minds are not always rational and/or honest. Minding minds, a legitimate concern, can also make masking legitimately confusing. To disentangle the potential confusions, particularly, the ramifications of irrationality and dishonesty, here we resort to evolutionary game theory. Specifically, we formulate and analyze the masking problem with a fictitious pair of young lovers, Alice and Bob, as a Sir Philip Sydney (SPS) evolutionary game, inspired by the handicap principle in evolutionary biology and cryptography figures in computer science. With the proposed ABD (Alice and Bob's dating dilemma) as an asymmetric four-by-four strategic-form game, 16 strategic interactions were identified, and six of which may reach equilibriums with different characteristics such as separating, pooling, and polymorphic hybrid, being Nash, evolutionarily stable or neutrally stable. The six equilibrium types seem to mirror the diverse behaviors of mask believers, skeptics, converted, universal masking, voluntarily masking, coexisted and/or divided world of believers and skeptics. We suggest that the apparently simple ABD game is sufficiently general not only for studying masking policies for populations (via replicator dynamics), but also for investigating other complex decision-making problems with COVID-19 pandemic including lockdown vs. reopening, herd immunity vs. quarantines, and aggressive tracing vs. privacy protection.

Tongue Coating in COVID-19 Patients: A Case-Control Study (preprint)

It has been suggested that COVID-19 patients have distinct tongue features, which may help to monitor the development of their condition. To determine if there was any specific tongue coating feature in COVID-19, this study investigated the difference in tongue coating between COVID-19 subjects and subjects with other acute inflammatory diseases characterized by fever. Tongue images taken with smartphones from three age-matched groups, namely, COVID group (n=92), non-COVID febrile group (n=92), and normal control group (n=92), were analyzed by two blinded raters according to a tongue coating scoring scheme, which assessed the levels of thick fur, slimy or greasy fur, discolored fur and composite index of tongue coating. Compared with control, significant increases in all coating indexes were found in the COVID group (P<0.001), as well as in the non-COVID febrile group (P<0.001). However, no difference was observed between COVID and non-COVID febrile groups for all coating indexes measured. In COVID-19 subjects, their scores of coating indexes had weak but significant correlations with certain inflammatory biomarkers, including WBC and neutrophil - lymphocyte ratio. It is concluded that COVID-19 subjects have pathological tongue coating patterns that are associated with inflammatory responses, and these coating patterns can help to indicate the direction of disease development.

Global Cold-Chain Related SARS-CoV-2 Transmission (preprint)

The COVID-19 pandemic poses a great threat to human society. SARS-CoV-2 is mainly transmitted through social contact; however, it is highly debated whether cold-chain related transmission has occurred and can be identified in the epidemic areas of COVID-19. Here, we provide a new method and distinguish two transmission routes by detecting a lineage-specific reduction of SARS-CoV-2 mutation rate. After analyzing 1,610,125 SARS-CoV-2 genomic sequences, we find that two outbreaks in Xinfadi-Beijing and Auckland are cold-chain related and respectively caused by two mutation-dormant variants. A Dalian outbreak in July 2020 and a Yingkou outbreak ten months later are epidemiologically connected and derived from a cold-chain related variant. Mutation-dormant variants are detected during the spread of spike D614G variant and the Delta Variant of Concern. Cold-chain contaminations repeatedly caused by epidemiologically connected patients are also found and have resulted in infections. Moreover, the COVID-19 outbreak in Wuhan is likely to be cold-chain related. A systematic identification reveals that the frequency of cold-chain related transmission is in the order of magnitude of 0.1-10%. Our results indicate that that cold-chain related transmission is rare but happens globally.

Clinicopathological and Immunological Features of Patients With New Onset Kidney Disease After Inactivated SARS-CoV-2 Vaccination: An Observational Cohort Study (preprint)

Background: The onset of various kidney diseases have been reported after COVID-19 vaccination. However, detailed clinical and pathological examination of kidney injury in patients receiving inactivated vaccines are lacking.Methods: We screened and analyzed patients with newly diagnosed kidney diseases after inactivated SARS-CoV-2 vaccination in Peking University First Hospital from January 2021 to August 2021. We obtained samples of blood, urine, and renal biopsy tissues. Clinical and laboratory information, as well as light microscopy, immunostaining and ultrastructural observation were described. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein and Nucleoprotein were stained using immune-fluorescence technique in the kidney biopsy samples. SARS-CoV-2 specific antibodies were tested using magnetic particle chemiluminescence immunoassay.Findings: The study group included 17 patients, including immune complex mediated kidney diseases (IgA nephropathy, membranous nephropathy and lupus nephritis), podocytopathy (minimal change disease and focal segmental glomerulosclerosis) and others (antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, anti-GBM nephritis, acute tubulointerstitial nephritis, and thrombotic microangiopathy). Seven patients (41.18%) developed renal disease after the first dose and 10 (58.82%) after the second dose. We found no definitive evidence of SARS-CoV-2 Spike protein or Nucleoprotein deposition in the kidney biopsy samples. Serological markers implicated abnormal immune responses in predisposed individuals. Treatment and follow-up (median = 86 days) showed that biopsy diagnosis informed treatment and prognosis in all patients.Interpretation: We observed various kidney diseases following inactivated SARS-CoV-2 vaccine administration. Our findings provide an evidence against direct vaccine protein deposition as the major pathomechanism, but implicate abnormal immune responses in predisposed individuals. These findings expand our understanding of inactivated SARS-CoV-2 vaccine renal safety.Funding: This study was funded by National Natural Science Foundation of China (91742205, 82170711, 81800636, 82070733, 81625004), Clinical Medicine Plus X—Young Scholars Project of Peking University (PKU2021LCXQ017), the Fundamental Research Funds for the Central Universities, CAMS Innovation Fund for Medical Sciences (2019-I2M-5-046), Yunnan Provincial Science and Technology Department (202102AA100051 and 202003AC100010, China), and Beijing Young Scientist Program (BJJWZYJH01201910001006).Declaration of Interest: The authors declare no competing interests.Ethical Approval: This study was approved by the institutional review board of Peking University First Hospital (2021-352) and the Committee on Human Subject Research and Ethics of Yunnan University (CHSRE2021020). Written Informed Consent Form was obtained from each participant.

A vimentin-targeting oral compound with host-directed antiviral and anti-inflammatory actions addresses multiple features of COVID-19 and related diseases (preprint)

Damage in COVID-19 results from both the SARS-CoV-2 virus and its triggered overreactive host immune responses. Therapeutic agents that focus solely on reducing viral load or hyperinflammation fail to provide satisfying outcomes in all cases. Although viral and cellular factors have been extensively profiled to identify potential anti-COVID targets, new drugs with significant efficacy remain to be developed. Here, we report the potent preclinical efficacy of ALD-R491, a vimentin-targeting small molecule compound, in treating COVID-19 through its host-directed antiviral and anti-inflammatory actions. We found that by altering the physical properties of vimentin filaments, ALD-491 affected general cellular processes as well as specific cellular functions relevant to SARS-CoV-2 infection. Specifically, ALD-R491 reduced endocytosis, endosomal trafficking, and exosomal release, thus impeding the entry and egress of the virus; increased the microcidal capacity of macrophages, thus facilitating the pathogen clearance; and enhanced the activity of regulatory T cells, therefore suppressing the overreactive immune responses. In cultured cells, ALD-R491 potently inhibited the SARS-CoV-2 spike protein and human ACE2-mediated pseudoviral infection. In aged mice with ongoing, productive SARS-CoV-2 infection, ALD-R491 reduced disease symptoms as well as lung damage. In rats, ALD-R491 also reduced bleomycin-induced lung injury and fibrosis. Our results indicate a unique mechanism and significant therapeutic potential for ALD-R491 against COVID-19. We anticipate that ALD-R491, an oral, fast-acting, and non-toxic agent targeting the cellular protein with multipart actions, will be convenient, safe, and broadly effective, regardless of viral mutations, for patients with early- or late-stage disease, post-COVID complications and other related diseases. IMPORTANCEWith the Delta variant currently fueling a resurgence of new infections in the fully-vaccinated population, developing an effective therapeutic drug is especially critical and urgent in fighting COVID-19. In contrast to the many efforts to repurpose existing drugs or address only one aspect of COVID-19, we are developing a novel agent with first-in-class mechanism-of-actions that address both the viral infection and the overactive immune system in the pathogenesis of the disease. Unlike virus-directed therapeutics that may lose efficacy due to viral mutations and immunosuppressants that require ideal timing to be effective, this agent, with its unique host-directed antiviral and anti-inflammatory actions, can work against all variants of the virus, be effective during all stages of the disease, and even resolve post-disease damage and complications. A further development of the compound will provide an important tool in the fight against COVID-19, its complications, as well as future outbreaks of new viruses.

Systemic Anticoagulation is Associated With Decreased Mortality in COVID-19 Patients: A Propensity Score-Matched Cohort Study (preprint)

Background: Accumulating evidence has revealed that coagulopathy and widespread thrombosis in the lung are common in patients with Coronavirus Disease 2019 (COVID-19). This raises questions about the efficacy and safety of systemic anticoagulation (AC) in COVID-19 patients. Method: This single-center, retrospective, cohort study unselectively reviewed 2272 patients with COVID-19 admitted to the Tongji Hospital between Jan 25 and Mar 23, 2020. Propensity score-matching between patients adjusted for potential covariates was carried out with the patients divided into two groups depending on whether or not they had received AC treatment (AC group, ³7 days of treatment; non-AC group, no treatment). This yielded 164 patients in each group. Result: In-hospital mortality of the AC group was significantly lower than that of the non-AC group (14.0% vs. 28.7%, P =0.001). Treatment with AC was associated with a significantly lower probability of in-hospital death (adjusted HR=0.273, 95% CI, 0.154 to 0.484, P<0.001). The incidence of major bleeding and thrombocytopenia in the two groups was not significantly different. Subgroup analysis showed the following factors were associated with a significantly lower in-hospital mortality in patients who had received AC treatment; severe cases (13.2% vs. 24.6%, P=0.018), critical cases (20.0% vs 82.4%, P=0.003), patients with a D-dimer level ≥0.5 μg/mL (14.8% vs. 33.8, P<0.001), and moderate (16.7% vs. 60.0%, P=0.003) or severe acute respiratory distress syndrome (ARDS) cases at admission (33.3% vs. 86.7%, P=0.004). During the hospital stay, critical cases (38.3% vs. 76.7%, P<0.001) and severe ARDS cases (36.5% vs. 76.3%, P<0.001) who received AC treatment had significantly lower in-hospital mortality. Conclusions: AC treatment decreases the risk of in-hospital mortality, especially in critically ill patients, with no additional significant, major bleeding events or thrombocytopenia being observed.Trials registration - ChiCTR2000039855

A blood atlas of COVID-19 defines hallmarks of disease severity and specificity (preprint)

Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete understanding of potentially druggable immune mediators of disease. To advance this, we present a comprehensive multi-omic blood atlas in patients with varying COVID-19 severity and compare with influenza, sepsis and healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity revealed cells, their inflammatory mediators and networks as potential therapeutic targets, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Tensor and matrix decomposition of the overall dataset revealed feature groupings linked with disease severity and specificity. Our systems-based integrative approach and blood atlas will inform future drug development, clinical trial design and personalised medicine approaches for COVID-19.

Pregnancy with Atypical Pulmonary Tuberculosis During the COVID-19 Outbreak: A Case Report (preprint)

Background: During pregnancy, due to reduced immunological resistance, the probability of tuberculosis infection is increased, easily leading to the occurrence of tuberculosis; thus, pregnancy with tuberculosis is a risk to the health of pregnant women with infectious diseases. However, the clinical symptoms of pregnancy with pulmonary tuberculosis are atypical, often confused with the physiological reactions of pregnancy, and there is a lack of clinical awareness, especially in the context of the global COVID-19 pandemic. Specifically, atypical lung lesions are prone to misdiagnosis or delayed diagnosis.Case presentation: A 21-year-old woman was infected with Mycobacterium tuberculosis during the third trimester of pregnancy. The diagnosis and treatment of the patient are reported.Conclusion: The interaction between tuberculosis and pregnancy is a double-edged sword. Increasing awareness of tuberculosis among doctors is essential, and early diagnosis and standardized treatment are key to improving the outcome of pregnancy.

Antiviral biomaterials

Summary Viral infections remain one of the leading causes of mortality worldwide, responsible for millions of deaths every year. The application of antiviral drugs, along with symptomatic treatment, is the primary modality of clinical antiviral therapy. Nevertheless, the severe side effects of antiviral drugs, such as gastrointestinal, hepatic, renal, and/or hematopoietic damages, can affect compliance and may even interrupt treatment. Moreover, drug resistance due to frequent viral mutations and single antiviral mechanisms often leads to therapeutic failure. The introduction of biomaterials into antiviral therapy provides distinct advantages and unique mechanisms. Antiviral biomaterials work in various ways, such as physical adsorption of viruses, binding to viruses as entry inhibitors, induction of irreversible viral deformation, interference with viral nucleic acid replication, and blockage of viral release from infected cells, among others. This review offers an overview of state-of-the-art advances in antiviral biomaterials featuring different mechanisms and discusses their challenges and opportunities in clinical translations.

A SARS-CoV-2 targeted siRNA-nanoparticle therapy for COVID-19 (preprint)

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in humans. Despite several emerging vaccines, there remains no verifiable therapeutic targeted specifically to the virus. Here we present a highly effective siRNA therapeutic against SARS-CoV-2 infection using a novel lipid nanoparticle delivery system. Multiple small-interfering RNAs (siRNAs) targeting highly conserved regions of the SARS-CoV-2 virus were screened and three candidate siRNAs emerged that effectively inhibit virus by greater than 90% either alone or in combination with one another. We simultaneously developed and screened two novel lipid nanoparticle formulations for the delivery of these candidate siRNA therapeutics to the lungs, an organ that incurs immense damage during SARS-CoV-2 infection. Encapsulation of siRNAs in these LNPs followed by in vivo injection demonstrated robust repression of virus in the lungs and a pronounced survival advantage to the treated mice. Our LNP-siRNA approaches are scalable and can be administered upon the first sign of SARS-CoV-2 infection in humans. We suggest that an siRNA-LNP therapeutic approach could prove highly useful in treating COVID-19 disease as an adjunctive therapy to current vaccine strategies.

Clinical characteristics and laboratory indicator analysis of 67 COVID-19 pneumonia patients in Suzhou, China (preprint)

Background: Sudden exacerbations and respiratory failure are major causes of death in patients with severe coronavirus disease 2019(COVID-19) pneumonia, but indicators for the prediction and treatment of severe patients are still lacking.MethodsA retrospective analysis of 67 collected cases was conducted and included approximately 67 patients with COVID-19 pneumonia who were admitted to the Suzhou Fifth People’s Hospital from January 1, 2020 to February 8, 2020. The epidemiological, clinical and imaging characteristics as well as laboratory data of the 67 patients were analyzed.ResultsThe study found that fibrinogen(FIB) was increased in 45 (65.2%) patients, and when FIB reached a critical value of 4.805 g/L, the sensitivity and specificity、DA, helping to distinguish general and severe cases, were 100% and 14%、92.9%, respectively, which were significantly better than those for lymphocyte count and myoglobin. Chest CT images indicated that the cumulative number of lung lobes with lesions in severe patients was significantly higher than that in general patients (P<0.05), and the cumulative number of lung lobes with lesions was negatively correlated with lymphocyte count and positively correlated with myoglobin and FIB. Our study also found that there was no obvious effect of hormone therapy in patients with severe COVID-19.ConclusionsBased on the retrospective analysis, FIB was found to be increased in severe patients and was better than lymphocyte count and myoglobin in distinguishing general and severe patients. The study also suggested that hormone treatment has no significant effect on COVID-19.

Worldwide tracing of mutations and the evolutionary dynamics of SARS-CoV-2 (preprint)

Understanding the mutational and evolutionary dynamics of SARS-CoV-2 is essential for treating COVID-19 and the development of a vaccine. Here, we analyzed publicly available 15,818 assembled SARS-CoV-2 genome sequences, along with 2,350 raw sequence datasets sampled worldwide. We investigated the distribution of inter-host single nucleotide polymorphisms (inter-host SNPs) and intra-host single nucleotide variations (iSNVs). Mutations have been observed at 35.6% (10,649/29,903) of the bases in the genome. The substitution rate in some protein coding regions is higher than the average in SARS-CoV-2 viruses, and the high substitution rate in some regions might be driven to escape immune recognition by diversifying selection. Both recurrent mutations and human-to-human transmission are mechanisms that generate fitness advantageous mutations. Furthermore, the frequency of three mutations (S protein, F400L; ORF3a protein, T164I; and ORF1a protein, Q6383H) has gradual increased over time on lineages, which provides new clues for the early detection of fitness advantageous mutations. Our study provides theoretical support for vaccine development and the optimization of treatment for COVID-19. We call researchers to submit raw sequence data to public databases.

A deep learning framework for high-throughput mechanism-driven phenotype compound screening (preprint)

ABSTRACT Target-based high-throughput compound screening dominates conventional one-drug-one-gene drug discovery process. However, the readout from the chemical modulation of a single protein is poorly correlated with phenotypic response of organism, leading to high failure rate in drug development. Chemical-induced gene expression profile provides an attractive solution to phenotype-based screening. However, the use of such data is currently limited by their sparseness, unreliability, and relatively low throughput. Several methods have been proposed to impute missing values for gene expression datasets. However, few existing methods can perform de novo chemical compound screening. In this study, we propose a mechanism-driven neural network-based method named DeepCE (Deep Chemical Expression) which utilizes graph convolutional neural network to learn chemical representation and multi-head attention mechanism to model chemical substructure-gene and gene-gene feature associations. In addition, we propose a novel data augmentation method which extracts useful information from unreliable experiments in L1000 dataset. The experimental results show that DeepCE achieves the superior performances not only in de novo chemical setting but also in traditional imputation setting compared to state-of-the-art baselines for the prediction of chemical-induced gene expression. We further verify the effectiveness of gene expression profiles generated from DeepCE by comparing them with gene expression profiles in L1000 dataset for downstream classification tasks including drug-target and disease predictions. To demonstrate the value of DeepCE, we apply it to patient-specific drug repurposing of COVID-19 for the first time, and generate novel lead compounds consistent with clinical evidences. Thus, DeepCE provides a potentially powerful framework for robust predictive modeling by utilizing noisy omics data as well as screening novel chemicals for the modulation of systemic response to disease.