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A novel coronavirus disease (COVID-19) caused by SARS-CoV-2 has been pandemic worldwide. The genetic dynamics of quasispecies afford RNA viruses a great fitness on cell tropism and host range. However, no quasispecies data of SARS-CoV-2 have been reported yet. To explore quasispecies haplotypes and its transmission characteristics, we carried out single-molecule real-time (SMRT) sequencing of the full-length of SARS-CoV-2 spike gene within 14 RNA samples from 2 infection clusters, covering first-to third-generation infected-patients. We observed a special quasispecies structure of SARS-CoV-2 (modeled as One-King): one dominant haplotype (mean abundance ~70.15%) followed by numerous minor haplotypes (mean abundance < 0.10%). We not only discovered a novel dominant haplotype of F1040 but also realized that minor quasispecies were also worthy of attention. Notably, some minor haplotypes (like F1040 and currently pandemic one G614) could potentially reveal adaptive and converse into the dominant one. However, minor haplotypes exhibited a high transmission bottleneck (~6% could be stably transmitted), and the new adaptive/dominant haplotypes were likely originated from genetic variations within a host rather than transmission. The evolutionary rate was estimated as 2.68-3.86 x 10-3 per site per year, which was larger than the estimation at consensus genome level. The One-King model and conversion event expanded our understanding of the genetic dynamics of SARS-CoV-2, and explained the incomprehensible phenomenon at the consensus genome level, such as limited cumulative mutations and low evolutionary rate. Moreover, our findings suggested the epidemic strains may be multi-host origin and future traceability would face huge difficulties.
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BackgroundA pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spreading over the world. However, the viral dynamics, host serologic responses, and their associations with clinical manifestations, have not been well described in prospective cohort. MethodsWe conducted a prospective cohort and enrolled 67 COVID-19 patients admitting between Jan 26 and Feb 5, 2020. Clinical specimens including nasopharyngeal swab, sputum, blood, urine and stool were tested periodically according to standardized case report form with final follow-up on February 27. The routes and duration of viral shedding, antibody response, and their associations with disease severity and clinical manifestations were systematically evaluated. Coronaviral particles in clinical specimens were observed by transmission electron microscopy (TEM). ResultsThe median duration of SARS-CoV-2 RNA shedding were 12 (3-38), 19 (5-37), and 18 (7-26) days in nasopharyngeal swabs, sputum and stools, respectively. Only 13 urines (5.6%) and 12 plasmas (5.7%) were viral positive. Prolonged viral shedding was observed in severe patients than that of non-severe patients. Cough but not fever, aligned with viral shedding in clinical respiratory specimens, meanwhile the positive stool-RNA appeared to align with the proportion who concurrently had cough and sputum production, but not diarrhea. Typical coronaviral particles could be found directly in sputum by TEM. The anti-nucleocapsid-protein IgM started on day 7 and positive rate peaked on day 28, while that of IgG was on day 10 and day 49 after illness onset. IgM and IgG appear earlier, and their titers are significantly higher in severe patients than non-severe patients (p<0.05). The weak responders for IgG had a significantly higher viral clearance rate than that of strong responders (p= 0.011). ConclusionsNasopharyngeal, sputum and stools rather than blood and urine, were the major shedding routes for SARS-CoV-2, and meanwhile sputum had a prolonged viral shedding. Symptom cough seems to be aligned with viral shedding in clinical respiratory and fecal specimens. Stronger antibody response was associated with delayed viral clearance and disease severity. Summary boxesO_ST_ABSWhat is already known on this topicC_ST_ABSAs a newly appearing infectious disease, early efforts have focused on virus identification, describing the epidemiologic characteristics, clinical course, prognostics for critically illed cases and mortality. Among COVID-19 cases reported in mainland China (72 314 cases, updated through February 11, 2020), 81% are mild, 14% are severe, and 5% are critical. The estimated overall case fatality rate (CFR) is 2.3%. Some case series reported had shown that SARS-CoV-2 could shed in upper/lower respiratory specimens, stools, blood and urines of patients. However, important knowledge gaps remain, particularly regarding full kinetics of viral shedding and host serologic responses in association with clinical manifestations and host factors. What this study addsThe incubation period has no change after spreading out of Wuhan, and has no sex or age differences, however, children had prolonged incubation period. Due to early recognition and intervention, COVID-19 illness of Chongqing cohort is milder than that of Wuhan patients reported. This prospective cohort study on SARS-CoV-2 infection shows clearly that the viral and serological kinetics were related in duration of infection, disease severity, and clinical manifestations of COVID-19. Our data demonstrate that nasopharyngeal, sputum and stools are major shedding routes for SARS-CoV-2, and stronger NP antibody response is associated with delayed viral clearance and disease severity.
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Objective@#To survey the children under 7 years of age in nine cities of China for a better understanding of the current situation of childhood stunting.@*Methods@#According to a stratified cluster sampling design, a cross-sectional survey on children under 7 years of age was carried out in 9 cities (Beijing, Harbin and Xi′an in northern China; Shanghai, Nanjing and Wuhan in central China; and Guangzhou, Fuzhou and Kunming in southern China) from June to November in 2016. A total of 110 499 children were recruited. Height of children was evaluated using the growth standards for Chinese children (2009 edition) .Children with height less than the 3rd percentile of the growth standards were considered as stunting, and children with height between the 3rd and 10th percentiles of the growth standards were considered as relatively short stature. Chi-square test was used for comparison between data of boys and girls, urban and suburban, as well as among different ages and regions.@*Results@#Totally 113 084 children under 7 years of age should be investigated and actually 110 499 children were investigated, with a rate of 97.7%. The prevalence of stunting was 1.9% (2 141/110 499) among all the children. The prevalence of stunting in urban children (1.6%, 904/55 524) was lower than that in suburban children (2.3%, 1 237/54 975, χ2=56.246, P<0.01). The gender difference in stunting prevalence was not statistically significant (1.9% (1 121/57 921) in boys and 1.9% (1 020/52 578) in girls, χ2=0.003, P=0.965). The prevalence of stunting decreased with age for children younger than 3 years, from 1.8% (312/17 080) in 0-<1 year of age group to 1.2% (168/13 740) in 2-<3 years of age group, but increased to 2.2% (240/11 073) at 6-<7 years group. Comparison among different regions showed that the stunting prevalence in southern region was higher than those in the central and northern regions (0.9% (193/20 374) in northern urban, 0.8% (154/18 486) in central urban, and 3.3% (557/16 664) in southern urban children), showing a statistical significance (χ2=437.736, P<0.01); 1.1% (241/21 924) in northern suburban, 1.4% (227/16 775) in central suburban and 4.7% (769/16 276) in southern suburban children, showing a statistical significance (χ2=646.533, P<0.01). In urban areas, the difference between the central and northern regions showed no statistical significance (χ2=1.429, P=0.232) and the stunting prevalence of central Chinese children was slightly higher than that of northern Chinese children in suburban areas (χ2=5.130, P=0.024). Among the nine cities, the stunting prevalence of Guangzhou (6.1%, 613/10 019) was higher than those of other cities (χ2=1 559.64, P<0.01). Among the stunting children, 78.4% (1 679/2 141) were classified as borderline or mild and only 7.2% (154/2 141) were classified as severe. The prevalence of relatively short stature was 5.2% (5 721/110 499).@*Conclusions@#The prevalence of stunting among children under 7 years of age in nine cities of China is low and most of the stunting children were classified as mild; the prevalence of stunting in suburban children is higher than that in urban children; the gender difference show no statistical significance; and the prevalence of stunting in southern Chinese children is higher than those in central and northern Chinese children.
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Objective To understand the levels of exposure to traffic-related air pollutants including nitrogen dioxide (NO2),PM10 and PM2.5,and the relationship between the exposure to air pollutants during pre-pregnancy or early pregnancy and birth defects.Methods Data on air pollution and birth defects from 2013 to 2015 was collected.A case-crossover design was employed to analyze the exposure-response relationship between traffic-related air pollutants and birth defects.Results A total of 4 235 pregnant women were studied.During the study period,the daily average concentrations of ambient NO2,PM10 and PM25 appeared as 60.83 μg/m3,104.94 μg/m3 and 103.88 μ.tg/m3,respectively,with the concentration of PM2.5 larger than the 2nd version of Standard National Ambient Air Quality Standard.In addition,there were strong correlations seen between each of the pollutants (P＜0.01).After adjustment for the influence of meteorological factors,it was found that the exposure to high level of NO2 and PM10 during pre-pregnancy or early pregnancy increased the risk on birth defects (P＜0.05).Conclusion Levels of exposure to adverse environmental factors during pre-pregnancy or early pregnancy could increase the risk of birth defects,suggesting that in these sensitive periods,women should try to avoid being exposed to high concentration of traffic-related air pollutants as NO2,PM10 etc.in order to reduce the risk of birth defects.
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Objective To understand the levels of exposure to traffic-related air pollutants including nitrogen dioxide (NO2),PM10 and PM2.5,and the relationship between the exposure to air pollutants during pre-pregnancy or early pregnancy and birth defects.Methods Data on air pollution and birth defects from 2013 to 2015 was collected.A case-crossover design was employed to analyze the exposure-response relationship between traffic-related air pollutants and birth defects.Results A total of 4 235 pregnant women were studied.During the study period,the daily average concentrations of ambient NO2,PM10 and PM25 appeared as 60.83 μg/m3,104.94 μg/m3 and 103.88 μ.tg/m3,respectively,with the concentration of PM2.5 larger than the 2nd version of Standard National Ambient Air Quality Standard.In addition,there were strong correlations seen between each of the pollutants (P＜0.01).After adjustment for the influence of meteorological factors,it was found that the exposure to high level of NO2 and PM10 during pre-pregnancy or early pregnancy increased the risk on birth defects (P＜0.05).Conclusion Levels of exposure to adverse environmental factors during pre-pregnancy or early pregnancy could increase the risk of birth defects,suggesting that in these sensitive periods,women should try to avoid being exposed to high concentration of traffic-related air pollutants as NO2,PM10 etc.in order to reduce the risk of birth defects.
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Objective To analyze the trend of birth defects and air pollution in Xi'an and discuss the correlation between air pollution exposure and birth defects.Methods Time series multiplication model was used to decompose the time series of birth defects and concentration of air pollutants to describe their long-term trend and seasonal variations.The rank correlation and cross-correlation between birth defects and air pollutants were analyzed by ecological approach.Results During 2010-2015,the results of air pollution analysis in Xi'an showed that the overall trend of NO2 increased in 2013 and then fluctuated at a high level.Generally,SO2 showed a trend of slow decline,but there were two peaks in 2012 and 2013.The overall trend of PM10 had two small peaks in 2013 and 2014,and during the rest of the time the change was stable.The overall trend of PM2.5 showed a slow decline,but after 2015 it showed a slight increase.Analysis of the birth defects during 2010-2015 in Xi'an showed that the long-term trend of total birth defects and congenital heart disease increased in 2010-2014,but then decreased rapidly.The long-term trend of cleft lip and palate and neural tube defects fluctuated at a low level.Analysis of the correlation between air pollutants and birth defects showed that total birth defects and congenital heart disease were positively correlated with NO2 at 3 months before pregnancy and early 3 months of pregnancy.Congenital heart disease 3 months before pregnancy had a positive correlation with PM10.Conclusion Birth defects and air pollution in Xi'an have trend variations and seasonal regularity.There is a positive correlation of women's exposure to NO2 3 months before pregnancy and the first 3 months of pregnancy with the incidence of congenital heart disease.
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Objective To analyze the spatial distribution characteristics of birth defects and air pollution in Xi'an and the correlation between air pollution exposure and birth defects.Methods In this study,we calculated the mean and median concentration of air pollutants in Xi'an between 2010 and 2015 to describe their concentration trends.Then we analyzed quartile range to describe their discrete trend.The spatial distribution of air pollution in the whole study area was calculated by inverse distance weighted spatial interpolation method to describe its overall occurrence level.The global trend was analyzed to describe the main body change pattern in the birth defect space.The total number of birth defects in the districts and counties of Xi'an between 2010 and 2015 was calculated and the incidence of birth defects was calculated according to the monitoring data of live births.Correlation between birth defects and air pollution was analyzed by rank correlation analysis.Results The spatial distribution of air pollutants in Xi'an between 2010 and 2015 was as follows:the concentration of SO2 was relatively high in Lianhu District,Yanta District,Baqiao District,Beilin District,and Xincheng District.The concentration of NO2 was relatively high in Yanta District,Baqiao District,Lianhu District,Beilin District,and Xincheng District.The concentration of PM10 was relatively high in Baqiao District,Yanta District,Xincheng District,Weiyang District,and Yanliang District.In Baqiao District,Xincheng District,Lianhu District,Weiyang District,and Gaoling District,the concentration of PM2.5 was relatively high.The total number of birth defects was 6 858 cases in Xi'an between 2010 and 2015,and the total number of perinatal births was 752 142 cases,with the incidence of 91.18 (1/10 000).The spatial distribution of birth defects from the west to the east direction and from south to north direction was generally characterized of inverted U type.The birth defects were positively correlated with NO2 concentration.Conclusion There are obvious regional differences in air pollution and birth defects in Xi'an.Birth defects may be related to NO2.
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Objective To study the effects of air pollution including sulphur dioxide (SO2),nitrogen dioxide (NO2) and PM10 in Xi'an on birth defects.Methods We collected the birth defects data from Xi'an Maternal and Child Health Hospital,meteorological data from Xi'an Bureau of Meteorology,and the air pollution data from Xi'an Environment Monitoring Station from 2010 to 2015.Generalized additive model (GAM) was used to explore the relationship between air pollution and birth defects after adjusting the effects of long-term and seasonal trend,temperature,and relative humidity.Results The monthly average birth defects were 89 cases;the monthly average concentration of SO2,NO2 and PM10 was 34.05 μg/m3,45.13 μg/m3,and 96.77 μg/m3,respectively.In the GAM,the monthly average temperature was 13.57 ℃ and the relative humidity was 63.20％.The three kinds of air pollutants all had a certain lag effect in 10 months,which reached the maximum.With an increase of concentration by 10 μg/m3 in three air pollutants,the relative risks and confidence interval of SO2,NO2,and PM10 were 1.060 (1.023-1.097),1.033 (1.014-1.052) and 1.018 (1.007-1.029),with significant differences (P＜0.05).Conclusion Exposure to SO2,NO2,and PM10 may be associated with the risk of birth defects.
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Objective To investigate the dynamic epidemiological characteristics of perinatal birth defects in Xi'an so as to provide scientific evidence for the priority of future birth defect prevention.Methods We made a statistical description of the data of perinatal birth defects from 2010 to 2015 reported by all the maternity hospitals in Xi'an.Results The incidence of birth defects in Xi'an from 2010 to 2015 was 89.62/104 (87.60/104,91.74/ 104) and had an annual ascending tendency (x2-157.13,P＜0.01).The top five main birth defects in a descending order were congenital heart disease (26.53/104),polydactyly (13.10/104),total cleft lip (11.42/104),neural tube defects (6.06 /104),and congenital hydrocephalus (5.08/104),accounting for 69.39％ of the total number of birth defects.And the incidence of congenital heart diseases showed a year-by-year ascending trend (x2=837.65,P＜ 0.01).The incidence of birth defects was higher in urban areas than in rural areas (OR 1.108,95％ CI:1.056-1.162).The birth defects were more frequently seen in males than in females (OB=1.151,95％ CI:1.097-1.208).Mother's age ＜20 (OR=1.764,95％ CI..1.532-2.032) and mother'sage≥35 (OR=1.283,95％ CI:1.179-1.395) also were risk factors for birth defects.Up to 72.54％ of the defects were live births.There were 52.83％ cases diagnosed by ultrasound and 46.24％ ones by clinical examination.The prenatal diagnosis rate was 33.20％.Conclusion The incidence of perinatal birth defects in Xi'an from 2010 to 2015 showed an annual ascending trend.We should improve the prenatal diagnosis level of all monitored hospitals in order to reduce incidence of birth defects and increase the quality of population.
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Objective To predict the incidence of birth defects in Xi'an using the auto-regressive integrated moving average product seasonal model.Methods In Xi'an,the trend of the incidence of birth defects was analyzed and tested from October 2009 to August 2015.Using the data from September to December 2015,the actual birth defects were compared with the model fitting data to evaluate the predictive performance of the model.Multiple seasonal ARIMA model was then fitted under time series to predict the incidence of birth defects in 2016.Results Seasonal effect was seen in the incidence of birth defects in Xi'an.A multiple seasonal ARIMA(0,0,1) (0,1,1)12 was established.The mean of absolute error and the relative error were 9.5 and 0.084,respectively,when compared to the simulated number of patients from September to December in 2015,suggesting that ARIMA (0,0,1) (0,1,1)12 has a better predictive ability.Results under the prediction of multiple seasonal ARIMA model showed that the number of patients in 2016 was similar to that of 2015 in Xi'an,with a slight increase and a decrease in the peak value.Conclusion Multiple seasonal ARIMA(0,0,1)(0,1,1)12 model could be used to successfully predict the incidence of birth defects in Xi'an.
