Modeling the effect of information quality on risk behavior change and the transmission of infectious diseases

How the quality of information about the prevalence of an infectious disease affects individuals’ incentives to adopt self-protective actions to reduce the risk of infection is studied using an economic/game-theoretic model of epidemics. In the model, agents make inferences regarding the current prevalence of a disease by observing the health status of a subset of the population. Therefore, the higher the number of agents whose infection status can be observed, the better one’s information about the current prevalence is. In particular, it is assumed that an agent’s estimate of the current prevalence depends on observations of the current health status of other agents and on the agent’s estimate of past prevalence, and that the agent places more weight on the current observations in forming an estimate of the prevailing prevalence when the number of observations increases. It is shown that the likelihood of eradicating an infectious disease through behavioral changes depends critically on the amount of information that individuals have access to, which also determines whether prevalence will be relatively stable or will exhibit cyclical patterns over time. Increasing the amount of information that individuals possess may lower the likelihood of eradication.     

Neuraminidase inhibitors for treatment of human and avian strain influenza: A comparative modeling study

Treatment of seasonal influenza viral infections using antivirals such as neuraminidase inhibitors (NAIs) has been proven effective if administered within 48 h post-infection. However, there is growing evidence that antiviral treatment of infections with avian-derived strains even as late as 6 days post-infection (dpi) can significantly reduce infection severity and duration. Using a mathematical model of in-host influenza viral infections which can capture the kinetics of both a short-lived, typical, seasonal infection and a severe infection exhibiting sustained viral titer, we explore differences in the effects of NAI treatment on both types of influenza viral infections. Comparison of our model's behavior against experimental data from patients naturally infected with avian strains yields estimates for the times at which patients were infected that are consistent with those reported by the patients, and estimates of drug efficacies that are lower for patients who died than for those who recovered. In addition, our model suggests that the sustained, high, viral titers often seen in more severe influenza virus infections are the reason why antiviral treatment delayed by as much as 6 dpi will still lead to reduced viral titers and shortened illness. We conclude that NAIs may be an effective and beneficial treatment strategy against more severe strains of influenza virus characterized by high, sustained, viral titers. We believe that our mathematical model will be an effective tool in guiding treatment of severe influenza viral infections with antivirals.     

A dynamical model of human immune response to influenza A virus infection

We present a simplified dynamical model of immune response to uncomplicated influenza A virus (IAV) infection, which focuses on the control of the infection by the innate and adaptive immunity. Innate immunity is represented by interferon-induced resistance to infection of respiratory epithelial cells and by removal of infected cells by effector cells (cytotoxic T-cells and natural killer cells). Adaptive immunity is represented by virus-specific antibodies. Similar in spirit to the recent model of Bocharov and Romanyukha [1994. Mathematical model of antiviral immune response. III. Influenza A virus infection. J. Theor. Biol. 167, 323-360], the model is constructed as a system of 10 ordinary differential equations with 27 parameters characterizing the rates of various processes contributing to the course of disease. The parameters are derived from published experimental data or estimated so as to reproduce available data about the time course of IAV infection in a na?ve host. We explore the effect of initial viral load on the severity and duration of the disease, construct a phase diagram that sheds insight into the dynamics of the disease, and perform sensitivity analysis on the model parameters to explore which ones influence the most the onset, duration and severity of infection. To account for the variability and speed of adaptation of the adaptive response to a particular virus strain, we introduce a variable that quantifies the antigenic compatibility between the virus and the antibodies currently produced by the organism. We find that for small initial viral load the disease progresses through an asymptomatic course, for intermediate value it takes a typical course with constant duration and severity of infection but variable onset, and for large initial viral load the disease becomes severe. This behavior is robust to a wide range of parameter values. The absence of antibody response leads to recurrence of disease and appearance of a chronic state with nontrivial constant viral load.     

Public avoidance and epidemics: insights from an economic model

In this paper, we present a mathematical model of infectious disease transmission in which people can engage in public avoidance behavior to minimize the likelihood of acquiring an infection. The framework employs the economist's theory of utility maximization to model people's decision regarding their level of public avoidance. We derive the reproductive number of a disease which determines whether an endemic equilibrium exists or not. We show that when the contact function exhibits saturation, an endemic equilibrium must be unique. Otherwise, multiple endemic equilibria that differ in disease prevalence can coexist, and which one the population gets to depends on initial conditions. Even when a unique endemic equilibrium exists, people's preferences and the initial conditions may determine whether the disease will eventually die out or become endemic. Public health policies that increase the recovery rate or encourage self-quarantine by infected people can be beneficial to the community by lowering disease prevalence. However, it is also possible for these policies to worsen the situation and cause prevalence to rise since these measures give people less incentive to engage in public avoidance behavior. We also show that implementing policies that result in a higher level of public avoidance behavior in equilibrium does not necessarily lower prevalence and can result in more infections.     

Coinfection can trigger multiple pandemic waves

Sequences of epidemic waves have been observed in past influenza pandemics, such as the Spanish influenza. Possible explanations may be sought either in mechanisms altering the structure of the network of contacts, such as those induced by changes in the rates of movement of people or by public health measures, or in the genetic drift of the influenza virus, since the appearance of new strains can reduce or eliminate herd immunity. The pandemic outbreaks may also be influenced by coinfection with other acute respiratory infections (ARI) that increase transmissibility of influenza virus (by coughing, sneezing, running nose). In fact, some viruses (e.g., Rhinovirus and Adenovirus) have been found to induce “clouds” of bacteria and increase the transmissibility of Staphylococcus aureus. Moreover, Rhinovirus and Adenovirus were detected in patients during past pandemics, and their presence is linked to superspreading events. In this paper, by assuming increased transmissibility in coinfected individuals, we propose and study a model where multiple pandemic waves are triggered by coinfection with ARI. The model agrees well with mortality excess data during the 1918 pandemic influenza, thereby providing indications for potential pandemic mitigation.     

Modeling resistance to genetic control of insects

The sterile insect technique is an area-wide pest control method that reduces pest populations by releasing mass-reared sterile insects which compete for mates with wild insects. Modern molecular tools have created possibilities for improving and extending the sterile insect technique. As with any new insect control method, questions arise about potential resistance. Genetic RIDL^®1 (Release of Insects carrying a Dominant Lethal) technology is a proposed modification of the technique, releasing insects that are homozygous for a repressible dominant lethal genetic construct rather than being sterilized by irradiation. Hypothetical resistance to the lethal mechanism is a potential threat to RIDL strategies' effectiveness. Using population genetic and population dynamic models, we assess the circumstances under which monogenic biochemically based resistance could have a significant impact on the effectiveness of releases for population control. We assume that released insects would be homozygous susceptible to the lethal genetic construct and therefore releases would have a built-in element of resistance dilution. We find that this effect could prevent or limit the spread of resistance to RIDL constructs; the outcomes are subject to competing selective forces deriving from the fitness properties of resistance and the release ratio. Resistance that is spreading and capable of having a significant detrimental impact on population reduction is identifiable, signaling in advance a need for mitigating action.     

Modeling an immune response to influenza A virus infection in alveolar epithelial cells

Influenza A viruses (IAV) have been the cause of several influenza pandemics in history and are a significant threat for the next global pandemic. Hospitalized influenza patients often have excess interferon production and a dysregulated immune response to the IAV infection. Obtaining a better understanding of the mechanisms of IAV infection that induce these harmful effects would help drug developers and health professionals create more effective treatments for IAV infection and improve patient outcomes. IAV stimulates viral sensors and receptors expressed by alveolar epithelial cells, like RIG-I and toll-like receptor 3 (TLR3). These two pathways coordinate with one another to induce expression of type III interferons to combat the infection. Presented here is a queuing theory-based model of these pathways that was designed to analyze the timing and amount of interferons produced in response to IAV single stranded RNA and double-stranded RNA detection. The model accurately represents biological data showing the necessary coordination of the RIG-I and TLR3 pathways for effective interferon production. This model can serve as the framework for future studies of IAV infection and identify new targets for potential treatments.     

微生态制剂防治儿童感染性腹泻的有效性评价

目的 对微生态制剂防治儿童感染性腹泻的有效性和安全性进行分析研究。方法 选取2017年3月到2018年3月间我院收治的132例感染性腹泻患儿为研究对象,依据随机数字表法分为对照组（n=66）与观察组（n=66）。对照组患儿施以常规药物防治,观察组患儿应用益生菌进行防治。对两组患者的治疗效果、腹泻持续时间、治疗后病情、血常规与肝功能情况进行比较分析。结果 观察组患儿治疗总有效率（96.97%）明显高于对照组（86.36%）。观察组患儿腹泻持续时间为（2.41±1.08）d,明显少于对照组的（3.67±1.89）d。观察组患儿治疗3 d后腹泻频率≤2次/d的发生率为24.24%,低于对照组的60.61%。观察组患儿治疗后脱水发生率为3.03%,低于对照组的22.73%。观察组患儿血常规与肝功能水平明显高于对照组,差异均有统计学意义（P＜0.05）。结论 在儿童感染性腹泻中应用微生态制剂有助于提高治疗效果,缩短腹泻持续时间,促进大便恢复正常,且具有较高的安全性,可有效促进患儿康复。     

Spontaneous behavioural changes in response to epidemics

We study how spontaneous reduction in the number of contacts could develop, as a defensive response, during an epidemic and affect the course of infection events. A model is proposed which couples an SIR model with selection of behaviours driven by imitation dynamics. Therefore, infection transmission and population behaviour become dynamical variables that influence each other. In particular, time scales of behavioural changes and epidemic transmission can be different. We provide a full qualitative characterization of the solutions when the dynamics of behavioural changes is either much faster or much slower than that of epidemic transmission. The model accounts for multiple outbreaks occurring within the same epidemic episode. Moreover, the model can explain “asymmetric waves”, i.e., infection waves whose rising and decaying phases differ in slope. Finally, we prove that introduction of behavioural dynamics results in the reduction of the final attack rate.     

Modeling the transmission dynamics and control of hepatitis B virus in China

Hepatitis B is a potentially life-threatening liver infection caused by the hepatitis B virus (HBV) and is a major global health problem. HBV is the most common serious viral infection and a leading cause of death in mainland China. Around 130 million people in China are carriers of HBV, almost a third of the people infected with HBV worldwide and about 10% of the general population in the country; among them 30 million are chronically infected. Every year, 300,000 people die from HBV-related diseases in China, accounting for 40-50% of HBV-related deaths worldwide. Despite an effective vaccination program for newborn babies since the 1990s, which has reduced chronic HBV infection in children, the incidence of hepatitis B is still increasing in China. We propose a mathematical model to understand the transmission dynamics and prevalence of HBV infection in China. Based on the data reported by the Ministry of Health of China, the model provides an approximate estimate of the basic reproduction number R₀=2.406. This indicates that hepatitis B is endemic in China and is approaching its equilibrium with the current immunization program and control measures. Although China made a great progress in increasing coverage among infants with hepatitis B vaccine, it has a long and hard battle to fight in order to significantly reduce the incidence and eventually eradicate the virus.     

某院感染科病房住院患者常见病原菌分布及耐药性分析

目的 对感染科病房住院患者临床常见病原菌的分布及其耐药性进行分析,为临床预防和治疗感染性疾病提供依据。方法 回顾性分析中国医科大学附属第一医院感染科病房2012年1月至2016年12月住院患者体液及组织样本中分离的病原菌,对其耐药情况进行分析。结果 5年中感染科共分离出非重复病原菌1 266株,其中革兰阴性菌786株,占62.09%,分离率居前3位的是大肠埃希菌、肺炎克雷伯菌以及铜绿假单胞菌,分别占17.22%、15.24%和10.58%;革兰阳性菌480株,占37.91%,分离率居前3位的是屎肠球菌、草绿色链球菌以及金黄色葡萄球菌,分别占9.79%、7.50%和6.00%。产超广谱β-内酰胺酶（ESBLs）大肠埃希菌和肺炎克雷伯菌检出率分别为66.7%和28.8%。大肠埃希菌对亚胺培南和美罗培南的耐药率分别为0.95%和3.79%,肺炎克雷伯菌对亚胺培南和美罗培南的耐药率分别为2.80%和2.80%。结论 我院感染科病房住院患者感染病原菌以革兰阴性菌为主,为有效的控制和避免耐药菌感染的发生,临床应根据药敏试验结果合理应用抗菌药物。     

An individual-based model of hepatitis A transmission

Viral hepatitis A, as other endemic diseases, represents a public health priority worldwide. To study long-time scale human pathogens through individual-based simulations, the development of a dynamic network of contacts is required. In this work, we introduce an individual-based model accounting for the birth and death of the individuals, the generation of new households, and the educational career of the individuals, in order to investigate viral hepatitis A dynamics in the most affected Italian areas. Intervention options such as targeted vaccination, social distancing measures (e.g., closure of day care centers and kindergartens) and improvements in standards of living and hygiene are evaluated. Results show that a very low vaccination coverage is sufficient to control hepatitis A in Italy, while its elimination is not possible since new cases are continuously imported from high endemicity areas outside the country. Finally, the considered social distancing measures can be counterproductive since the fraction of recovered individuals does not decline while the age at infection increases, thus augmenting the probability of developing acute symptoms.     

Modeling hepatitis C virus dynamics: liver regeneration and critical drug efficacy

Mathematical models for hepatitis C viral (HCV) RNA kinetics have provided a means of evaluating the antiviral effectiveness of therapy, of estimating parameters such as the rate of HCV RNA clearance, and they have suggested mechanism of action against HCV for both interferon and ribavirin. Nevertheless, the model that was originally formulated by Neumann et al. [1998. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science 282 (5386), 103-107] is unable to explain all of the observed HCV RNA profiles under treatment e.g., a triphasic viral decay and a viral rebound to baseline values after the cessation of therapy. Further, the half-life of productively HCV-infected cells, estimated from the second phase HCV RNA decline slope, is very variable and sometimes zero with no clear understanding of why. We show that extending the original model by including hepatocyte proliferation yields a more realistic model without any of these deficiencies. Further, we define and characterize a critical drug efficacy, such that for efficacies above the critical value HCV is ultimately cleared, while for efficacies below it, a new chronically infected viral steady-state level is reached.     

Flavone-resistant Leishmania donovani Overexpresses LdMRP2 Transporter in the Parasite and Activates Host MRP2 on Macrophages to Circumvent the Flavone-mediated Cell Death

In parasites, ATP-binding cassette (ABC) transporters represent an important family of proteins related to drug resistance and other biological activities. Resistance of leishmanial parasites to therapeutic drugs continues to escalate in developing countries, and in many instances, it is due to overexpressed ABC efflux pumps. Progressively adapted baicalein (BLN)-resistant parasites (pB²⁵R) show overexpression of a novel ABC transporter, which was classified as ABCC2 or Leishmania donovani multidrug resistance protein 2 (LdMRP2). The protein is primarily localized in the flagellar pocket region and in internal vesicles. Overexpressed LdABCC2 confers substantial BLN resistance to the parasites by rapid drug efflux. The BLN-resistant promastigotes when transformed into amastigotes in macrophage cells cannot be cured by treatment of macrophages with BLN. Amastigote resistance is concomitant with the overexpression of macrophage MRP2 transporter. Reporter analysis and site-directed mutagenesis assays demonstrated that antioxidant response element 1 is activated upon infection. The expression of this phase II detoxifying gene is regulated by NFE2-related factor 2 (Nrf2)-mediated antioxidant response element activation. In view of the fact that the signaling pathway of phosphoinositol 3-kinase controls microfilament rearrangement and translocation of actin-associated proteins, the current study correlates with the intricate pathway of phosphoinositol 3-kinase-mediated nuclear translocation of Nrf2, which activates MRP2 expression in macrophages upon infection by the parasites. In contrast, phalloidin, an agent that prevents depolymerization of actin filaments, inhibits Nrf2 translocation and Mrp2 gene activation by pB²⁵R infection. Taken together, these results provide insight into the mechanisms by which resistant clinical isolates of L. donovani induce intracellular events relevant to drug resistance.     

pH-dependent tetramerization and amantadine binding of the transmembrane helix of M2 from the influenza A virus

The M2 proton channel from the influenza A virus is a small protein with a single transmembrane helix that associates to form a tetramer in vivo. This protein forms proton-selective ion channels, which are the target of the drug amantadine. Here, we propose a mechanism for the pH-dependent association, and amantadine binding of M2, based on studies of a peptide representing the M2 transmembrane segment in dodecylphosphocholine micelles. Using analytical ultracentrifugation, we find that the sedimentation curves for the peptide depend on its concentration in the micellar phase. The data are well-described by a monomer-tetramer equilibrium, and the binding of amantadine shifts the monomer-tetramer equilibrium toward tetrameric species. Both tetramerization and the binding of amantadine lead to increases in the magnitude of the ellipticity at 223 nm in the circular dichroism spectrum of the peptide. The tetramerization and binding of amantadine are more favorable at elevated pH, with a pK(a) that is assigned to a His side chain, the only ionizable residue within the transmembrane helix. Our results, interpreted quantitatively in terms of a reversible monomer and tetramer protonation equilibrium model, suggest that amantadine competes with protons for binding to the deprotonated tetramer, thereby stabilizing the tetramer in a slightly altered conformation. This model accounts for the observed inhibition of proton flux by amantadine. Additionally, our measurements suggest that the M2 tetramer is substantially protonated at neutral pH and that both singly and doubly protonated states could be involved in M2's proton conduction at more acidic pHs.     

Ion channel activity of influenza A virus M2 protein: characterization of the amantadine block.

The influenza A virus M2 integral membrane protein has ion channel activity which can be blocked by the antiviral drug amantadine. The M2 protein transmembrane domain is highly conserved in amino acid sequence for all the human, swine, equine, and avian strains of influenza A virus, and thus, known amino acid differences could lead to altered properties of the M2 ion channel. We have expressed in oocytes of Xenopus laevis the M2 protein of human influenza virus A/Udorn/72 and the avian virus A/chicken/Germany/34 (fowl plague virus, Rostock) and derivatives of the Rostock ion channel altered in the presumed pore region. The pH of activation of the M2 ion channels and amantadine block of the M2 ion channels were investigated. The channels were found to be activated by pH in a similar manner but differed in their apparent Kis for amantadine block.     

A dynamic model for tuberculosis transmission and optimal treatment strategies in South Korea

We have developed a dynamic model for tuberculosis (TB) transmission in South Korea using a SEIR model with the time-dependent parameters. South Korea ranked the highest TB incidence among members of the Organization for Economic Cooperation and Development (OECD) in 2005 yr. The observed data from the Korea Center for Disease Control and Prevention (KCDC) shows a certain rise of active-TB incidence individuals after 2001 yr. Because of this sudden jump, we have considered two different periods for best fitting the model: prior to 2001 yr and posterior to 2001 yr. The least-squares fitting has been used for estimating model parameters to the observed data of active-TB incidence. Our model agrees well with the observed data. In this work, we also propose optimal treatment strategies of TB model in South Korea for the future. We have considered three control mechanisms representing distancing, case finding and case holding efforts. Optimal control programs have been proposed in various scenarios, in order to minimize the number of exposed and infectious individuals and the cost of implementing the control treatment.     

Evidence of intra-segmental homologous recombination in influenza A virus

The evolution of influenza viruses is remarkably dynamic. Influenza viruses evolve rapidly in sequence and undergo frequent reassortment of different gene segments. Homologous recombination, although commonly seen as an important component of dynamic genome evolution in many other organisms, is believed to be rare in influenza. In this study, 256 gene segments from 32 influenza A genomes were examined for homologous recombination, three recombinant H1N1 strains were detected and they most likely resulted from one recombination event between two closely rated parental sequences. These findings suggest that homologous recombination in influenza viruses tends to take place between strains sharing high sequence similarity. The three recombinant strains were isolated at different time periods and they form a clade, indicating that recombinant strains could circulate. In addition, the simulation results showed that many recombinant sequences might not be detectable by currently existing recombinant detection programs when the parental sequences are of high sequence similarity. Finally, possible ways were discussed to improve the accuracy of the detection for recombinant sequences in influenza.