Impact of quarantine on the 2003 SARS outbreak: a retrospective modeling study

During the 2003 Severe Acute Respiratory Syndrome (SARS) outbreak, traditional intervention measures such as quarantine and border control were found to be useful in containing the outbreak. We used laboratory verified SARS case data and the detailed quarantine data in Taiwan, where over 150,000 people were quarantined during the 2003 outbreak, to formulate a mathematical model which incorporates Level A quarantine (of potentially exposed contacts of suspected SARS patients) and Level B quarantine (of travelers arriving at borders from SARS affected areas) implemented in Taiwan during the outbreak. We obtain the average case fatality ratio and the daily quarantine rate for the Taiwan outbreak. Model simulations is utilized to show that Level A quarantine prevented approximately 461 additional SARS cases and 62 additional deaths, while the effect of Level B quarantine was comparatively minor, yielding only around 5% reduction of cases and deaths. The combined impact of the two levels of quarantine had reduced the case number and deaths by almost a half. The results demonstrate how modeling can be useful in qualitative evaluation of the impact of traditional intervention measures for newly emerging infectious diseases outbreak when there is inadequate information on the characteristics and clinical features of the new disease-measures which could become particularly important with the looming threat of global flu pandemic possibly caused by a novel mutating flu strain, including that of avian variety.     

Congruent epidemic models for unstructured and structured populations: analytical reconstruction of a 2003 SARS outbreak

Both the threat of bioterrorism and the natural emergence of contagious diseases underscore the importance of quantitatively understanding disease transmission in structured human populations. Over the last few years, researchers have advanced the mathematical theory of scale-free networks and used such theoretical advancements in pilot epidemic models. Scale-free contact networks are particularly interesting in the realm of mathematical epidemiology, primarily because these networks may allow meaningfully structured populations to be incorporated in epidemic models at moderate or intermediate levels of complexity. Moreover, a scale-free contact network with node degree correlation is in accord with the well-known preferred mixing concept. The present author describes a semi-empirical and deterministic epidemic modeling approach that (a) focuses on time-varying rates of disease transmission in both unstructured and structured populations and (b) employs probability density functions to characterize disease progression and outbreak controls. Given an epidemic curve for a historical outbreak, this modeling approach calls for Monte Carlo calculations (that define the average new infection rate) and solutions to integro-differential equations (that describe outbreak dynamics in an aggregate population or across all network connectivity classes). Numerical results are obtained for the 2003 SARS outbreak in Taiwan and the dynamical implications of time-varying transmission rates and scale-free contact networks are discussed in some detail.     

Simulating the SARS outbreak in Beijing with limited data

We propose a mathematical model to simulate the SARS outbreak in Beijing. The model consists of six subpopulations, namely susceptible, exposed, quarantined, suspect, probable and removed, as China started to report SARS cases as suspect and probable separately from April 27 and cases transferred from suspect class to probable class from May 2. By simplifying the model to a two-compartment suspect-probable model and a single-compartment probable model and using limited data, we are able to simulate the SARS outbreak in Beijing. We estimate that the reproduction number varies from 1.0698 to 3.2524 and obtain certain important epidemiological parameters.     

A network-based approach for resistance transmission in bacterial populations

Horizontal transfer of mobile genetic elements (conjugation) is an important mechanism whereby resistance is spread through bacterial populations. The aim of our work is to develop a mathematical model that quantitatively describes this process, and to use this model to optimize antimicrobial dosage regimens to minimize resistance development. The bacterial population is conceptualized as a compartmental mathematical model to describe changes in susceptible, resistant, and transconjugant bacteria over time. This model is combined with a compartmental pharmacokinetic model to explore the effect of different plasma drug concentration profiles. An agent-based simulation tool is used to account for resistance transfer occurring when two bacteria are adjacent or in close proximity. In addition, a non-linear programming optimal control problem is introduced to minimize bacterial populations as well as the drug dose. Simulation and optimization results suggest that the rapid death of susceptible individuals in the population is pivotal in minimizing the number of transconjugants in a population. This supports the use of potent antimicrobials that rapidly kill susceptible individuals and development of dosage regimens that maintain effective antimicrobial drug concentrations for as long as needed to kill off the susceptible population. Suggestions are made for experiments to test the hypotheses generated by these simulations.     

SARS冠状病毒分离培养和鉴定的实验研究

建立严重急性呼吸综合征(SARS)冠状病毒分离、培养方法,为SARS冠状病毒动物模型的建立提供实验依据,并根据病毒在体内存活的时间确定检测指标。选用已鉴定为SARS冠状病毒的毒株,经过鼻腔接种感染恒河猴。定期采集咽拭子标本,分离血清或血浆,用Vero细胞进行病毒培养、分离。结果显示,在SARS冠状病毒感染恒河猴后2、5、7天,可以从拭子中分离到病毒,5～15天可在猴肺、脾、肝、肾和淋巴组织中分离到病毒,并用免疫荧光法和RT-PCR方法进行了确定。首次实验证实了SARS冠状病毒可在恒河猴体内复制。SARS病毒的成功分离是SARS冠状病毒动物模型建立的主要依据,在进行疫苗安全性和药效评价等工作中,病毒分离可作为药物筛选、疫苗评价的重要指标。     

The effect of intrinsic stochasticity on transmitted HIV drug resistance patterns

Estimates of transmitted HIV drug-resistance prevalence vary widely among and within epidemiological surveys. Interpretation of trends from available survey data is therefore difficult. Because the emergence of drug-resistance involves small populations of infected drug-resistant individuals, the role of stochasticity (chance events) is likely to be important. The question addressed here is: how much variability in transmitted HIV drug-resistance prevalence patterns arises due to intrinsic stochasticity alone, i.e., if all starting conditions in the different epidemics surveyed were identical? This ‘thought experiment’ gives insight into the minimum expected variabilities within and among epidemics. A simple stochastic mathematical model was implemented. Our results show that stochasticity alone can generate a significant degree of variability and that this depends on the size and variation of the pool of new infections when drug treatment is first introduced. The variability in transmitted drug-resistance prevalence within an epidemic (i.e., the temporal variability) is large when the annual pool of all new infections is small (fewer than 200, typical of the HIV epidemics in Central European and Scandinavian countries) but diminishes rapidly as that pool grows. Epidemiological surveys involving hundreds of new infections annually are therefore needed to allow meaningful interpretation of temporal trends in transmitted drug-resistance prevalence within individual epidemics. The stochastic variability among epidemics shows a similar dependence on the pool of new infections if treatment is introduced after endemic equilibrium is established, but can persist even when there are more than 10,000 new infections annually if drug therapy is introduced earlier. Stochastic models may therefore have an important role to play in interpreting differences in transmitted drug-resistance prevalence trends among epidemiological surveys.     

严重急性呼吸综合征(SARS)冠状病毒抗体的检测及其临床意义

To investigate the k inetics of antibody to SARS coronavirus in SARS patients and its clinical implication,ELISA was used to dete ct antibody to SARS coronavirus(SA RS CoV),RT-PCR was used to detect the SARS CoV RNA and,besides,the C D+4 and CD+8 T cells in peripheral blood of SARS patients and healthy controls were assayed by flowcytom etryThe results showed that SARS CoV IgM were first detected from da y 7 to day 47 after SARS onset,wit h average at day 193±101SARS Co V IgG were first detected from day 4 to day 47 after SARS onset,with average at day 207±101,and the p roduction of SARS CoV IgG was corr elated with CD+4 T cell number(P<005),but had no relationship with SARS CoV RNAMost SARS patients pr oduced SARS CoV antibody,IgM produ ced almost at the same time wit h IgGSARS CoV IgG is a protective antibody against SARS CoV and the titer of IgG may be used as an ind ex indicating the specific immunit y production in SARS patients     

广东地区SARS-COV细胞培养模型的建立和初步应用

目的：建立中国广东地区SARS—CoV细胞培养模型。方法：通过将SARS—CoV广东地区分离株GD322在Vero E6细胞中连续传代,检测TCID50,获得稳定的细胞模型。利用此细胞培养模型,对不同温度、紫外线等条件下SARS-CoV的存活时间进行了比较。对重组人复合干扰素α抗病毒效果进行了筛查。结果与结论：SARS—CoV对外界环境抵抗力比普通冠状病毒强,对重组人复合干扰素α有较高的敏感性,抑制指数达4．9。     

SARS流行病传染动力学研究

Logistic确定型增长模型可被用来描述严重急性呼吸道综合症（SARS）的流行规律,通过对部分国家、地区及中国内地部分省市的数据进行拟合,及其对拟合结果的分析,揭示了各个地区SARS传染力不均匀的现象,以及在控制措施上的差异所带来的不同效果.同时,还对超级传播现象（SSEs）等问题进行了讨论.     

Control of onchocerciasis in Africa: threshold shifts, breakpoints and rules for elimination

Control of onchocerciasis in Africa is currently based on annual community-directed treatment with ivermectin (CDTI) which has been assumed to be not efficient enough to bring about elimination. However, elimination has recently been reported to have been achieved by CDTI alone in villages of Senegal and Mali, reviving debate on the eradicability of onchocerciasis in Africa. We investigate the eradicability of onchocerciasis by examining threshold shifts and breakpoints predicted by a stochastic transmission model that has been fitted extensively to data. We show that elimination based on CDTI relies on shifting the threshold biting rate to a level that is higher than the annual biting rate. Breakpoints become relevant in the context of when to stop CDTI. In order for the model to predict a good chance for CDTI to eliminate onchocerciasis, facilitating factors such as the macrofilaricidal effect of ivermectin must be assumed. A chart predicting the minimum efficacy of CDTI required for elimination, dependent on the annual biting rate, is provided. Generalisable recommendations into strategies for the elimination of onchocerciasis are derived, particularly referring to the roles of vectors, the residual infection rate under control, and a low-spreader problem originating from patients with low parasite burdens.     

Epidemiology and control of onchocerciasis: The threshold biting rate of savannah onchocerciasis in Africa

Control of onchocerciasis currently focuses on community-directed treatment with the microfilaricide ivermectin which effectively kills Onchocerca volvulus microfilariae in the human host. The feasibility of elimination by this control strategy has recently been reported for some foci in Africa which has rekindled discussions on evaluating the threshold conditions of elimination of onchocerciasis. We developed a stochastic model based on a master equation which predicts, based on data from West and Central Africa, that elimination of savannah onchocerciasis can be expected around a threshold biting rate of 730 bites per person per year, ranging region-specifically roughly from 230 to 2300 bites per person and year. The threshold values give rise to optimism that elimination of onchocerciasis is feasible, but the associated measures of parasite prevalence and density suggest that onchocerciasis can remain endemic at very low infection intensities. Endemicity at a low level is a risk factor for elimination strategies, and we point to the necessity of investigating these issues on the basis of breakpoints which refer to threshold conditions based on parasite prevalence and density.     

冠状病毒的新成员--SARS-CoV的基因组特性

2003年3月,人类发现一种新的冠状病毒SARS-CoV,这种病毒是非典型性肺炎(SARS)的病原体。SARS-CoV的基因组序列已经由包括中国科学家在内的全世界的科研人员测定完成。该文对国际报道的SARS病源的基因序列进行了收录,阐述了SARS-CoV基因组的基本特性：SARS-CoV的基因组长约28-30kb,与冠状病毒科的基因组长度相符合,其中包括11个编码序列,基因组的组织方式也与其他冠状病毒类似,从表面蛋白(S蛋白)、外膜蛋白(M蛋白)和核蛋白(N蛋白)上看,SARS病毒与其他冠状病毒的对应蛋白进化关系接近。同时发现,在某些区域,SARS病毒的基因序列与其他冠状病毒存在相当大的差异,具有自身比较保守的基因组序列结构。而且氨基酸的序列也与其他冠状病毒有很大程度的不同。基因信息的冗余分析表明,SARS-CoV具有较低的冗余度,即发生变异的可能性比较大。虽然SARS-CoV外表与冠状病毒类似,亲缘关系未超出冠状病毒科界限,但由于蛋白基因与氨基酸的序列与其他冠状病毒有本质不同,因此可能不是其他冠状病毒的变异体,而是一种与冠状病毒类似、但早已独立存在、此前未被人类所认识的新病毒。     

严重急性呼吸综合征(SARS)患者不同组织中冠状病毒的分离和鉴定

严重急性呼吸综合征(SARS)自2002年11月在中国广东爆发后,已迅速蔓延成为全球性传染疾患。为了了解SARS冠状病毒的特征,对先前SARS冠状病毒PCR检测呈阳性的来自广东的3份尸检肺组织标本、2份尸检脾组织标本：来自北京的2份咽拭子标本和1份血清标本,利用10种不同的细胞系分离病毒。结果显示,上述标本在感染细胞后,分别可在293、Vero—E6、Vero、RD和HeLa细胞系中产生细胞病变(CPE)。不同标本在上述细胞系中致CPE的能力不同,但CPE出现的时间和病变形态学特征无显著性差异。以恢复期SARS病人血清为抗体,用间接免疫荧光法对感染后细胞培养的检测,冠状病毒RT-_PCR对感染后细胞RNA的检测,初步证明分离的病毒为冠状病毒。结果再次证明冠状病毒为SARS的病原,它具有较广泛的器官分布和细胞感染能力。血清中SARS冠状病毒的分离,高度提示在SARS发病过程中存在有病毒血症。     

Network-based analysis of comorbidities risk during an infection: SARS and HIV case studies

Background

Infections are often associated to comorbidity that increases the risk of medical conditions which can lead to further morbidity and mortality. SARS is a threat which is similar to MERS virus, but the comorbidity is the key aspect to underline their different impacts. One UK doctor says "I’d rather have HIV than diabetes" as life expectancy among diabetes patients is lower than that of HIV. However, HIV has a comorbidity impact on the diabetes.

Results

We present a quantitative framework to compare and explore comorbidity between diseases. By using neighbourhood based benchmark and topological methods, we have built comorbidity relationships network based on the OMIM and our identified significant genes. Then based on the gene expression, PPI and signalling pathways data, we investigate the comorbidity association of these 2 infective pathologies with other 7 diseases (heart failure, kidney disorder, breast cancer, neurodegenerative disorders, bone diseases, Type 1 and Type 2 diabetes). Phenotypic association is measured by calculating both the Relative Risk as the quantified measures of comorbidity tendency of two disease pairs and the ϕ-correlation to measure the robustness of the comorbidity associations. The differential gene expression profiling strongly suggests that the response of SARS affected patients seems to be mainly an innate inflammatory response and statistically dysregulates a large number of genes, pathways and PPIs subnetworks in different pathologies such as chronic heart failure (21 genes), breast cancer (16 genes) and bone diseases (11 genes). HIV-1 induces comorbidities relationship with many other diseases, particularly strong correlation with the neurological, cancer, metabolic and immunological diseases. Similar comorbidities risk is observed from the clinical information. Moreover, SARS and HIV infections dysregulate 4 genes (ANXA3, GNS, HIST1H1C, RASA3) and 3 genes (HBA1, TFRC, GHITM) respectively that affect the ageing process. It is notable that HIV and SARS similarly dysregulated 11 genes and 3 pathways. Only 4 significantly dysregulated genes are common between SARS-CoV and MERS-CoV, including NFKBIA that is a key regulator of immune responsiveness implicated in susceptibility to infectious and inflammatory diseases.

Conclusions

Our method presents a ripe opportunity to use data-driven approaches for advancing our current knowledge on disease mechanism and predicting disease comorbidities in a quantitative way.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2105-15-333) contains supplementary material, which is available to authorized users.     

Modelling parasite aggregation: disentangling statistical and ecological approaches

The overdispersion in macroparasite infection intensity among host populations is commonly simulated using a constant negative binomial aggregation parameter. We describe an alternative to utilising the negative binomial approach and demonstrate important disparities in intervention efficacy projections that can come about from opting for pattern-fitting models that are not process-explicit. We present model output in the context of the epidemiology and control of soil-transmitted helminths due to the significant public health burden imposed by these parasites, but our methods are applicable to other infections with demonstrable aggregation in parasite numbers among hosts.     

SARS及其病原体研究进展

严重急性呼吸道综合症(SARS)的病原体己被认定为一种新的冠状病毒-SARS冠状病毒。关于SARS冠状病毒的基因组和蛋白组研究也已取得重要进展,这为探索SARS病毒的来源与进化、研制SARS诊断试剂、开发SARS疫苗和治疗药物奠定了坚实基础。本文对严重急性呼吸道综合症病原学研究取得的一些进展进行了综述。     

Emergent heterogeneity in declining tuberculosis epidemics

Tuberculosis is a disease of global importance: over 2 million deaths are attributed to this infectious disease each year. Even in areas where tuberculosis is in decline, there are sporadic outbreaks which are often attributed either to increased host susceptibility or increased strain transmissibility and virulence. Using two mathematical models, we explore the role of the contact structure of the population, and find that in declining epidemics, localized outbreaks may occur as a result of contact heterogeneity even in the absence of host or strain variability. We discuss the implications of this finding for tuberculosis control in low incidence settings.     

Population dynamics of live-attenuated virus vaccines

Viruses contained in live-attenuated virus vaccines (LAVV) can be transmitted between individuals, resulting in secondary or contact vaccinations. This fact has been exploited successfully in the use of the Oral Polio Vaccine (OPV) to better control wild-type polio viruses. In this work we analyze general LAVV vaccination models for infections that confer lifelong immunity. We consider both standard (continuous) vaccination strategies and pulse vaccination programs (where mass vaccination is carried out at regular intervals). For continuous vaccination, we provide a complete global analysis of a very general compartmental ordinary differential equation LAVV model. We find that the threshold vaccination level required for the eradication of wild-type virus depends on the basic reproduction numbers of both the wild-type and vaccine viruses, but is otherwise independent of the distributions of the durations in each of the sequence of stages of disease progression (e.g., latent, infectious, etc.). Furthermore, even for vaccine viruses with reproduction numbers below one, which would naturally fade from the population upon cessation of vaccination, there can be a significant reduction in the threshold vaccination level. The dependence of the threshold vaccination level on the virus reproduction numbers largely generalizes to the pulse vaccination model. For shorter pulsing periods there is negligible difference in threshold vaccination level as compared to continuous vaccination campaigns. Thus, we conclude that current policy in many countries to employ annual pulsed OPV vaccination does not significantly diminish the benefits of contact vaccination.     

SARS冠状病毒Nsp14基因的克隆与表达

对SARS冠状病毒的非结构蛋白Nsp14的基因全长进行了克隆表达。根据公布的SARS冠状病毒的非结构蛋白Nsp14的基因序列设计引物,用PCR的方法把该基因从SARS冠状病毒的cDNA片段中扩增出来,经限制性内切酶BamHI与XhoI双酶切后插入到原核表达载体pET30a( )中,建成重组载体pET30a-Exo。重组载体转化大肠杆菌并进行诱导表达,通过原核表达的方法得到了该蛋白。这为该蛋白的进一步研究奠定了基础。