The impact of intervention to the incidence of natural focus diseases during the outbreak of COVID-19 in Jiangsu Province, China (preprint)

Doxorubicin (DOX) is a well-known chemotherapeutic drug for most malgnencies including breast cancer and leukemia whilst the usage of DOX is limited owing to its cardiotoxicity. The present study analyzed the effects of crocin on doxorubicin’s cardiotoxic efect in rat myocardium and searched their mechanistic interaction in the pathogenesis of DOX-induced myocardial toxicity. Forty rats were divided into four groups; (a) control (received normal saline as a dose of 1 ml/kg by ip for 15 days), (b) Crocin (received crocin as a dose of 40 mg/kg/24h by ip for 15 days), (c) DOX (received DOX as a dose of 2 mg/kg/48h by ip in six injection, cumulative dose 12 mg/kg), and (d) DOX+Crocin (received DOX as a dose of 2 mg/kg/48h by ip in six injection and crocin as a dose of 40 mg/kg/24h ip for 15 days). According to the present study, DOX administration caused significant increases in lipid indices (triglyseride, low-dencity lipoproteins and very low-dencity lipoproteins) as well as cardiac markers (Creatine kinase-muscle/brain and Cardiac Troponin I). Morever, DOX caused significant increases in oxidative stress parameters (malondialdehyde and total oxidant status) as well as decreases in antioxidant defense systems (glutathione, superoxide dismutase, catalase and total antioxidant status). The present study also demonstrated that co-administration of crocin with DOX significantly ameliorated the lipid profile and biochemical parameters in rats receiving DOX. The results were supported by histopathological and immunohistochemical evaluations. Taken together, our results reveal that crocin might be a cardioprotective agent in DOX treated patients for cancer.

Control Measures During the COVID-19 Outbreak Reduced the Transmission of Hand, Foot, and Mouth Disease (preprint)

Background: Control measures during the coronavirus disease 2019 (COVID-19) outbreak may have limited the spread of infectious diseases. This study aimed to analyse the impact of COVID-19 on the spread of hand, foot, and mouth disease (HFMD) in China. Methods: A mathematical model was established to fit the reported data of HFMD in six selected cities in mainland China from 2015 to 2020. The absolute difference (AD) and relative difference (RD) between the reported incidence in 2020, and simulated maximum, minimum, or median incidence of HFMD in 2015-2019 were calculated. Findings: The incidence and Reff of HFMD have decreased in six selected cities since the outbreak of COVID-19, and in the second half of 2020, the incidence and R eff of HFMD have rebounded. The results show that the total attack rate (TAR) in 2020 was lower than the maximum, minimum, and median TAR fitted in previous years in six selected cities (except Changsha city). For the maximum, median, minimum fitted TAR, the range of RD (%) is 42·20-99·20%, 36·35-98·41% 48·35-96·23% (except Changsha city) respectively. Interpretation: Based on the incidence data of six cities from 2015 to 2019, the SEIAR model demonstrated a significant effect on the incidence of HFMD. During the period of COVID-19, the incidence and R eff of HFMD decreased, the prevention and control measures taken during the period of COVID-19, such as school suspension, home quarantine, closing all kinds of leisure places, wearing masks, advocating frequent hand washing, etc., have not only effectively suppressed the spread of COVID-19 epidemic, but also have significantly contributed to the containment of HFMD transmission.Funding Statement: This study was partly supported by the Bill & Melinda Gates Foundation (INV-005834).Declaration of Interests: The authors declare no conflicts of interests.

The Impact of Intervention to Routine Surveillance of Natural Focal Diseases During the Outbreak of COVID-19 in Jiangsu Province, China (preprint)

Background: With the strength intervention of China, the outbreak of Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) had a great control effect. The measures may influence the development and progression of others infectious diseases.Method: The data of daily coronavirus virus disease 2019 (COVID-19) confirmed cases from January 3, 2020 to April 30, 2020 and natural focal disease cases from January, 2005 to April, 2020 were collected from Jiangsu Provincial Center for Disease Control and Prevention (Jiangsu Provincial CDC). We describe and compare the data of natural focal diseases from January to April, 2020 with the same months from 2015 to 2019 in the four aspects: trend of incidence, regional, age and sex distribution. Nonparametric tests were used to analyzed to the difference between the duration from onset of illness to date of diagnosis of natural focal diseases and the same period of the previous year. Results: The incidence of malaria in February (0.9 per 10,000,000 people), March (0.3 per 10,000,000 people) and April (0.1 per 10,000,000 people) 2020 less than the lower limit for range of February (1.6-4.5 per 10,000,000 people), March (0.8-3.3 per 10,000,000 people) and April (1.0-2.9 per 10,000,000 people) from 2015 to 2019 respectively. The incidence of brucellosis in February was 0.9 (per 10,000,000 people), less than the lower limit for the range from 2015 to 2019 (1.6-4.5 per 10,000,000 people). The incidence of hemorrhagic fever (HF) in March was 1.0 (per 10,000,000 people), less than the lower limit for the range from 2015 to 2019 (1.4-2.6 per 10,000,000 people). However, the incidence of Severe Fever with Thrombocytopenia Syndrome (SEFT) in March was 0.3 (per 10,000,000 people), higher than the upper limit for the range from 2015 to 2019 (0.0-0.1 per 10,000,000 people). Furthermore, we respectively observed the incidence with various degree of reduction in male, 20-60 years old and both rural and urban areas. Conclusions: In Jiangsu province, the incidence of natural focal diseases decreased during the outbreak of COVID-19 in 2020, especially malaria, HF and SEFT. The impact of interventions were felt most by male individuals within the age group of 20-50 years. The interventions for COVID-19 may control the epidemics of natural focal diseases.

Forecasting the Effectiveness of Interventions to Control the Second Wave of COVID-19 Outbreaks: A Modelling Study in 12 Countries of 6 Regions (preprint)

Background: In most countries, it is hard to effectively control coronavirus disease 2019 (COVID-19). This study conducted the most comprehensive evaluation of the effects of pharmacological (like vaccination, pharmacotherapy ) and non-pharmacological (like isolation, social distancing and mask-wearing) interventions taken singly or in combination for the first time globally.Methods: We estimate that across these 12 countries that are different but presentative, interventions prevented or delayed roughly millions of confirmed cases. This study constructs mathematical model, which interventions includes vaccination, pharmacotherapy, isolation, social distancing and mask-wearing , and analyses the effect of these interventions used alone and in combination.Findings: The basic reproduction number (R0) of each country mostly range from 3 to 5. In terms of the effect of single intervention, for countries such as China, South Korea, Thailand, US, South Africa and Algeria, it is preferred to recommend these countries to adopt isolation to prevent and control the second wave of COVID-19 outbreak, while for countries such as Russia, UK, Saudi Arabia, India and Brazil, wearing masks is the best choice. Especially pharmacotherapy can play a good role in Iran. When combinations with different interventions were taken, the situation was different. For US, Brazil and Algeria, the combination of “Vaccination & Isolation & Wearing mask” is recommended in these countries to prevent and control the development of COVID-19, and the combination of “Isolation & Social distancing & Wearing mask” is recommended in UK and China. For the rest, we suggest that Russia, Iran, Saudi Arabia, India, Thailand and South Africa take the intervention measures of “Vaccination & Medical treatment & Isolation & Wearing mask”, “Vaccination & Medical treatment”, “Vaccination & Social distancing & Wearing mask”, “Medical treatment & Social distancing & Wearing mask”, “Vaccination & Medical Treatment & Isolation”, “Vaccination & Medical Treatment & Wearing mask”, respectively to deal with the second wave of outbreaks that may come by the end of this year.Interpretation: Our model is operable and selective for the prevention and control of epidemic situations in various countries. These findings may help policy makers in the 180+ countries where COVID-19 has been reported around the world to identify the most effective and socioeconomically acceptable measures to prevent and control the second wave of COVID-19 epidemic, and inform if when these policies should be deployed, intensified or replaced.Funding: This study was partly supported by the Bill & Melinda Gates Foundation (INV-005834), the Science and Technology Program of Fujian Province (No: 2020Y0002), the Xiamen New Coronavirus Prevention and Control Emergency Tackling Special Topic Program (No: 3502Z2020YJ03), and the Open Research Fund of State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics (SKLVD2019KF005).Declaration of Interests: The authors declare no competing interests.

Transferrin receptor is another receptor for SARS-CoV-2 entry (preprint)

Angiotensin-converting enzyme 2 (ACE2) has been suggested as a receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry to cause coronavirus disease 2019 (COVID-19). However, no ACE2 inhibitors have shown definite beneficiaries for COVID-19 patients, applying the presence of another receptor for SARS-CoV-2 entry. Here we show that ACE2 knockout dose not completely block virus entry, while TfR directly interacts with virus Spike protein to mediate virus entry and SARS-CoV-2 can infect mice with over-expressed humanized transferrin receptor (TfR) and without humanized ACE2. TfR-virus co-localization is found both on the membranes and in the cytoplasma, suggesting SARS-CoV-2 transporting by TfR, the iron-transporting receptor shuttling between cell membranes and cytoplasma. Interfering TfR-Spike interaction blocks virus entry to exert significant anti-viral effects. Anti-TfR antibody (EC50 16.6 nM) shows promising anti-viral effects in mouse model. Collectively, this report indicates that TfR is another receptor for SARS-CoV-2 entry and a promising anti-COVID-19 target.

Transferrin receptor is another receptor for SARS-CoV-2 entry (preprint)

Angiotensin-converting enzyme 2 (ACE2) has been suggested as a receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry to cause coronavirus disease 2019 (COVID-19). However, no ACE2 inhibitors have shown definite beneficiaries for COVID-19 patients, applying the presence of another receptor for SARS-CoV-2 entry. Here we show that ACE2 knockout dose not completely block virus entry, while TfR directly interacts with virus Spike protein to mediate virus entry and SARS-CoV-2 can infect mice with over-expressed humanized transferrin receptor (TfR) and without humanized ACE2. TfR-virus co-localization is found both on the membranes and in the cytoplasma, suggesting SARS-CoV-2 transporting by TfR, the iron-transporting receptor shuttling between cell membranes and cytoplasma. Interfering TfR-Spike interaction blocks virus entry to exert significant anti-viral effects. Anti-TfR antibody (EC50 ∼16.6 nM) shows promising anti-viral effects in mouse model. Collectively, this report indicates that TfR is another receptor for SARS-CoV-2 entry and a promising anti-COVID-19 target.

Effectiveness of Pharmacological Interventions to Control COVID-19: An Age-Specific Modelling Study (preprint)

Background: Novel coronavirus disease 2019 (COVID-19) causes an immense disease burden. Only drugs or vaccines can eliminate the virus. Methods: We adopted our age-specific transmission model by susceptible-exposed-infectious -critically ill-asymptomatic-removed (SEICAR) model. Effects of different drug types were simulated by changing transmission rate (β), critical case fatality rate (fc), and disease duration of each age group. Evaluation indexes were based on outbreak duration(OD), cumulative number of cases(CNC), total attack rate(TAR), peak date(PD), number of peak cases(NPC), and case fatality rate(f). Findings: When without intervention, changing in β and disease duration, as the age increased, OD decreased, TAR increased, PD advanced, CCN and NPC initially increased and then decreased, while f decreased first and then increased. When disease duration and β remained unchanged, changing fc did not affect the epidemic. All age groups had 40% shorter disease duration but unchanged fc, while β was reduced by 60%, which reduced TAR of group 1 (≤14 years) from 2·35% to 0·09%; f of group 4 (≥65 years) was reduced from 1·04% to 0·05%. Interpretation: Drugs had different age-dependent effects. If a drug can control the disease duration or β of all age groups, younger people would have the fastest transmission control and seniors will have the best improvement in disease severity. Funding: The Bill & Melinda Gates Foundation (INV-005834); the Science and Technology Program of Fujian Province (No: 2020Y0002), and the Xiamen New Coronavirus Prevention and Control Emergency Tackling Special Topic Program (No: 3502Z2020YJ03).Declaration of Interests: The authors declare no competing interests.

The relationship between key natural and social factors and the transmission of novel coronavirus disease 2019 in China (preprint)

Background Novel coronavirus disease 2019 (COVID-19) has become a global pandemic. This study aims to explore the relationship between key natural and social factors and the transmission of COVID-19 in China.Methods This study collected the number of confirmed cases of COVID-19 in 21 provinces and cities in China as of February 28, 2020. Three provinces were included in the sample: Hainan, Guizhou, and Qinghai. The 18 cities included Shanghai, Tianjin and so on. Key natural factors comprised monthly average temperatures in the January and February 2020 and spatial location as determined by longitude and latitude. Social factors were population density, Gross Domestic Product (GDP), number of medical institutions and health practitioners; as well as the per capita values for GDP, medical institutions, and health practitioners. Excel was used to collate the data and draw the temporal and spatial distribution map of the prevalence rate (PR) and the proportion of local infection (PLI). The influencing factors were analyzed by SPSS 21.0 statistical software, and the relationship between the dependent and independent variables was simulated by 11 models. Finally, we choose the exponential model according to the value of R2 and the applicability of the model.Results The temporal and spatial distribution of the PR varies across the 21 provinces and cities identified. The PR generally decreases with distance from Hubei, except in the case of Shenzhen City, where the converse is observed. The results of the exponential model simulation show that the monthly minimum, median, and maximum average temperatures in January and February, and the latitude and population density are significant and thus will affect the PLI. The corresponding values of R2 are 0.297, 0.322, 0.349, 0.290, 0.314, 0.339, 0.344, and 0.301. The effects of other factors were not statistically significant.Conclusions Among the selected key natural and social factors, higher temperatures may decrease the transmission of COVID-19. From this analysis, it is evident that if the temperature decreases by 1℃, the average PLI increases by 0.01. Further, it was established that locations at more northern latitudes had a higher PLI, and population density showed an inverse relationship with PLI.

Epidemiological characteristics and the effectiveness of countermeasures to control coronavirus disease 2019 in Ningbo City, China (preprint)

Background: A novel coronavirus (SARS-CoV-2) has spread widely and led to high disease burden around the world. This study aimed to explore key parameters of SARS-CoV-2 infection and to assess the effectiveness of interventions to control the coronavirus disease 2019 (COVID-19).Methods: A susceptible – exposed – infectious – asymptomatic – recovered (SEIAR) model was developed for the assessment. Data of symptomatic and asymptomatic infection of SARS-CoV-2 were collected to calculate the key parameters of the model in Ningbo City, China.Results: A total of 157 confirmed COVID-19 cases (including 51 imported cases and 106 secondary cases) and 30 asymptomatic infections were reported in Ningbo City. The proportion of asymptomatic has an increasing trend. The proportion of asymptomatic of elder people was lower than younger people, and the difference was statistical significant (Fisher’s Exact Test, P = 0.034). There were 22 clusters associated with 167 SARS-CoV-2 infections, among which 29 cases were asymptomatic, with a proportion of 17.37%. We found that the secondary attack rate of asymptomatic was almost the same as that of symptomatic cases, and no significance was observed (χ2 = 1.350, P = 0.245) by Kruskal-Wallis test. The effective reproduction number (Reff) was 1.43 which revealed that the transmissibility of SARS-CoV-2 was moderate. If the interventions were not strengthened, the duration of the outbreak would last about 16 months with a simulated attack rate of 44.15%. The total attack rate and duration of the outbreak would increase along with the increasing delay of intervention.Conclusions: SARS-CoV-2 had moderate transmissibility in Ningbo City, China. Asymptomatic infection has the same transmissibility as symptomatic. The integrated interventions were implemented at different stages during the outbreak, which found to be exceedingly effective in China.

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.

Comparison of SARS-CoV-2 infections among 3 species of non-human primates (preprint)

COVID-19, caused by SARS-CoV-2 infection, has recently been announced as a pandemic all over the world. Plenty of diagnostic, preventive and therapeutic knowledges have been enriched from clinical studies since December 2019. However, animal models, particularly non-human primate models, are urgently needed for critical questions that could not be answered in clinical patients, evaluations of anti-viral drugs and vaccines. In this study, two families of non-human primates, Old world monkeys (12 Macaca mulatta, 6 Macaca fascicularis) and New world monkeys (6 Callithrix jacchus), were experimentally inoculated with SARS-CoV-2. Clinical signs were recorded. Samples were collected for analysis of viral shedding, viremia and histopathological examination. Increased body temperature was observed in 100% (12/12) M. mulatta, 33.3% (2/6) M. fascicularis and none (0/6) of C. jacchus post inoculation of SARS-CoV-2. All of M. mulatta and M. fascicularis showed chest radiographic abnormality. Viral genomes were detected in nasal swabs, throat swabs, anal swabs and blood from all 3 species of monkeys. Viral shedding from upper respiratory samples reached the peak between day 6 and day 8 post inoculation. From necropsied M. mulatta and M. fascicularis, the tissues showing virus positive were mainly lung, weasand, bronchus and spleen. No viral genome was seen in any of tissues from 2 necropsied C. jacchus. Severe gross lesions and histopathological changes were observed in lung, heart and stomach of SARS-CoV-2 infected animals. In summary, we have established a NHP model for COVID-19, which could be used to evaluate drugs and vaccines, and investigate viral pathogenesis. M. mulatta is the most susceptible to SARS-CoV-2 infection, followed by M. fascicularis and C. jacchus. One Sentence SummaryM. mulatta is the most susceptible to SARS-CoV-2 infection as compared to M. fascicularis and C. jacchus.