Antiviral resistance and the control of pandemic influenza: the roles of stochasticity, evolution and model details

Antiviral drugs, most notably the neuraminidase inhibitors, are an important component of control strategies aimed to prevent or limit any future influenza pandemic. The potential large-scale use of antiviral drugs brings with it the danger of drug resistance evolution. A number of recent studies have shown that the emergence of drug-resistant influenza could undermine the usefulness of antiviral drugs for the control of an epidemic or pandemic outbreak. While these studies have provided important insights, the inherently stochastic nature of resistance generation and spread, as well as the potential for ongoing evolution of the resistant strain have not been fully addressed. Here, we study a stochastic model of drug resistance emergence and consecutive evolution of the resistant strain in response to antiviral control during an influenza pandemic. We find that taking into consideration the ongoing evolution of the resistant strain does not increase the probability of resistance emergence; however, it increases the total number of infecteds if a resistant outbreak occurs. Our study further shows that taking stochasticity into account leads to results that can differ from deterministic models. Specifically, we find that rapid and strong control cannot only contain a drug sensitive outbreak, it can also prevent a resistant outbreak from occurring. We find that the best control strategy is early intervention heavily based on prophylaxis at a level that leads to outbreak containment. If containment is not possible, mitigation works best at intermediate levels of antiviral control. Finally, we show that the results are not very sensitive to the way resistance generation is modeled.     

Novel 5-methyl-2-phenylphenanthridium derivatives as FtsZ-targeting antibacterial agents from structural simplification of natural product sanguinarine

A novel series of 5-methyl-2-phenylphenanthridium derivatives were displayed outstanding activity against a panel of antibiotic-sensitive and -resistant bacteria strains compared with their precursor sanguinarine, ciprofloxacin and oxacillin sodium. Compounds 7?l, 7m and 7n were found to display the most effective activity against five sensitive strains (0.06–2?μg/mL) and three resistant strains (0.25–4?μg/mL). The kinetic profiles indicated that compound 7l possessed the strongest bactericidal effect on S. aureus ATCC25923, with the MBC value of 16?μg/mL. The cell morphology and the FtsZ polymerization assays indicated that these compounds inhibited the bacterial proliferation by interfering the function of bacterial FtsZ. The SARs showed that all the 4-methyl-substituted 5-methyl-2-phenylphenanthridium subseries could be further investigated as the FtsZ-targeting antibacterial agents.     

The structural error-in-equation model to evaluate individual bioequivalence

Individual bioequivalence is assessed using an extension of the classical structural equation model, known as the error-in-equation model. This procedure estimates the relationship between individual means, as well as the variance-covariance parameters, of the bioavailabilities measurement model, by considering individual means related through a straight line with a random term, whereas the classical structural equation considers a deterministic linear relationship. We discuss the implications of this approach in terms of the bioavailabilities measurement model and how to test the overall hypothesis of individual bioequivalence. Both models are compared in a simulation study and a case example is presented.     

The evolving epidemiology of monkeypox virus

Monkeypox, caused by the monkeypox virus (MPXV), is a zoonotic disease endemic mainly in West and Central Africa. As of 27 September 2022, human monkeypox has occurred in more than 100 countries (mostly in non-endemic regions) and caused over 66,000 confirmed cases, which differs from previous epidemics that mainly affected African countries. Due to the increasing number of confirmed cases worldwide, the World Health Organization (WHO) has declared the monkeypox outbreak as a Public Health Emergency of International Concern on July 23, 2022. The international outbreak of human monkeypox represents a novel route of transmission for MPXV, with genital lesions as the primary infection, and the emergence of monkeypox in the current outbreak is also new, as novel variants emerge. Clinical physicians and scientists should be aware of this emerging situation, which presents a different scenario from previous outbreaks. In this review, we will discuss the molecular virology, evasion of antiviral immunity, epidemiology, evolution, and detection of MPXV, as well as prophylaxis and treatment strategies for monkeypox. This review also emphasizes the integration of relevant epidemiological data with genomic surveillance data to obtain real-time data, which could formulate prevention and control measures to curb this outbreak.     

N-(3,5-Dichloro-4-(2,4,6-trichlorophenoxy)phenyl)benzenesulfonamide: A new dual-target inhibitor of mitochondrial complex II and complex III via structural simplification

Mitochondrial complex II and complex III are two promising targets for the development of numerous pharmaceuticals and pesticides. Although tremendous inhibitors of either complex II or complex III were identified, compounds which are capable of prohibiting the activities of both complexes have been rarely reported. Since multi-target drugs can interact with several drug targets simultaneously, we were keen on discovering new and potent dual-target inhibitors of both complex II and complex III. Therefore, a new series of structurally simplified sulfonamides bearing a diaryl ether scaffold were designed and synthesized in this paper. Afterwards, the biological activities of the newly synthesized compounds were evaluated. The results implied that several compounds demonstrated outstanding potency against succinate-cytochrome c reductase (SCR, a mixture of complex II and complex III). Further studies confirmed that N-(3,5-Dichloro-4-(2,4,6-trichlorophenoxy)phenyl)benzenesulfonamide (3f), a representative compound herein, was identified as a dual-target inhibitor of both complexes. Furthermore, computational simulations were also performed to have a better understanding about binding of 3f to the enzyme complexes, which concluded that 3f should bind to complex II and the Q_o site of complex III. Consequently, we harbor the idea that this work can be beneficial for the synthesis and discovery of more dual- or multi-target inhibitors.     

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.     

Campus drinking: an epidemiological model

The drinking behaviours of college students have posed significant public health concerns for several generations. However, the dynamics of campus drinking have not been analysed using mathematical models. An epidemiological model capturing the dynamics of campus drinking is used to study how the ‘disease’ of drinking is spread on campus. The model suggests that the reproductive numbers are not sufficient to predict whether drinking behaviour will persist on campus and that the pattern of recruiting new members plays a significant role in the reduction of campus alcohol problems. In particular, campus alcohol abuse may be reduced by minimizing the ability of problem drinkers to directly recruit non-drinkers.     

猪流感病毒在世界范围内的流行情况及公共卫生意义

猪流感病毒(Swine influenza virus, SIV)是引起猪的急性呼吸道疾病的重要原发病原之一, 常常与其他病原体混合感染造成更严重的损害。目前, 猪流感(Swine influenza, SI)已遍布美洲、亚洲、欧洲和非洲, 是规模化养猪场普遍存在且难以根除的群发性疾病。猪在流感病毒的种间传播和遗传进化中起着重要的作用, 猪可被禽流感病毒和人流感病毒感染, 因此, 猪被认为是人、禽和/或猪流感病毒通过基因重排产生新的亚型流感病毒的“混合器”。SIV不仅危害猪群, 而且同时具有感染人和禽的潜力。目前世界范围内猪群中流行的SIV亚型主要有3种：H1N1、H3N2和H1N2, 其中包括古典H1N1、类禽H1N1、类人H3N2、基因重排的H3N2和多基因型的H1N2亚型。研究表明, 禽流感病毒、人H3N2亚型病毒和古典猪H1N1亚型病毒在我国猪群中共存, 为产生含有禽流感病毒基因片段的重排病毒创造了条件, 这将对养猪业以及人类公共卫生都具有潜在的威胁。     

猪流感病毒在世界范围内的流行情况及公共卫生意义

猪流感病毒(Swine influenza virus,SIV)是引起猪的急性呼吸道疾病的重要原发病原之一,常常与其他病原体混合感染造成更严重的损害.目前,猪流感(Swine influenza,SI)已遍布美洲、亚洲、欧洲和非洲,是规模化养猪场普遍存在且难以根除的群发性疾病.猪在流感病毒的种间传播和遗传进化中起着重要的作用,猪可被禽流感病毒和人流感病毒感染,因此,猪被认为是人、禽和/或猪流感病毒通过基因重排产生新的亚型流感病毒的"混合器".SIV不仅危害猪群,而且同时具有感染人和禽的潜力.目前世界范围内猪群中流行的SIV亚型主要有3种:H1N1、H3N2和H1N2,其中包括古典H1N1、类禽H1N1、类人H3N2、基因重排的H3N2和多基因型的H1N2亚型.研究表明,禽流感病毒、人H3N2亚型病毒和古典猪H1N1亚型病毒在我国猪群中共存,为产生含有禽流感病毒基因片段的重排病毒创造了条件,这将对养猪业以及人类公共卫生都具有潜在的威胁.     

A threshold result for an epidemiological model

A threshold parameter R ₀ is identified for an SIRS epidemiological model which has nonlinear incidence and a distributed delay for transfer out of the removed class. For R ₀ < 1, the disease free equilibrium is proved to be the global attractor for all solutions.Research supplied in part by NSERC A-8965     

A structural constitutive model for the human lens capsule

Published data on the mechanical performance of the human lens capsule when tested under uniaxial and biaxial conditions are reviewed. It is concluded that two simple phenomenological constitutive models (namely a linear elastic model and a Fung-type hyperelastic model) are unable to provide satisfactory representations of the mechanical behaviour of the capsule for both of these loading conditions. The possibility of resolving these difficulties using a structural constitutive model for the capsule, of a form that is inspired by the network of collagen IV filaments that exist within the lens capsule, is explored. The model is implemented within a rectangular periodic cell. Prescribed stretches are imposed on the periodic cell and the network is allowed to deform in a non-affine manner. The performance of the constitutive model correlates well with previously published test data. One possible application of the model is in the development of a multi-scale analysis of the mechanics of the human lens capsule.     

Data-based dynamic compartment model: Modeling of E. coli fed-batch fermentation in a 600 m3 bubble column

Mathematical modeling is a powerful and inexpensive approach to provide a quantitative basis for improvements that minimize the negative effects of bioreactor heterogeneity. For a model to accurately represent a heterogeneous system, a flow model that describes how mass is channeled between different zones of the bioreactor volume is necessary. In this study, a previously developed compartment model approach based on data from flow-following sensor devices was further developed to account for dynamic changes in volume and flow rates and thus enabling simulation of the widely used fed-batch process. The application of the dynamic compartment model was demonstrated in a study of an industrial fermentation process in a 600 m³ bubble column bioreactor. The flow model was used to evaluate the mixing performance by means of tracer simulations and was coupled with reaction kinetics to simulate concentration gradients in the process. The simulations showed that despite the presence of long mixing times and significant substrate gradients early in the process, improving the heterogeneity did not lead to overall improvements in the process. Improvements could, however, be achieved by modifying the dextrose feeding profile.     

胶州市2001—2010年肾综合征出血热流行病学分析

对胶州市2001—2010年肾综合征出血热疫情资料进行了描述性流行病学分析。2001—2010年胶州市肾综合征出血热年发病率3.34/10万～11.96/10万,近三年呈逐年下降趋势。男、女性别比为2.91∶1;以青壮年发病为主,40～49岁组发病率为最高(22.69/10万),10～19岁组发病率最低(0.26/10万);农民所占比例最高,其次为工人。全市发病率最高的是东部镇。肾综合征出血热严重危害胶州市人民健康,应列为防治重点,在抓好爱国卫生健康教育的同时,需进一步扩大疫苗接种范围。     

Oscillations in an epidemiological model based on asynchronous probabilistic cellular automaton

Consider a contagious disease affecting a host population composed of two groups with distinct habits. At each time step, each individual of this population can be in one of two states: susceptible (S) or infective (I). Here, a SIS epidemic model based on cellular automaton (CA) is proposed to study the disease spreading in such a population. In this model, the state transitions are described by probabilistic rules and each group has its own schedule to update the states of its individuals. We also propose a set of difference equations (DE) to analyze this population dynamics and we show how these two approaches (CA and DE) can be equivalent. We noticed that oscillations can be found in the composition of the group with more active social life, but not in the composition of the other group.     

International travel in times of the COVID-19 pandemic: The case of German school breaks

The COVID-19 pandemic has triggered severe global restrictions on international travel with the intention of limiting the spread of SARS-CoV-2 across countries. This paper studies the causal effect of the partial relaxation of these travel restrictions in Europe on the COVID-19 incidence in Germany during the summer months of 2020. It exploits the staggered start of the summer school breaks across German states as an exogenous shock to the travel opportunities of the population. While the school breaks also increased mobility within Germany, the event-study type regressions precisely control for domestic mobility and local COVID-19-related restrictions. The intention-to-treat effects of the relaxed travel restrictions show a significant and sizable increase of the COVID-19 incidence in German counties during the later weeks of the school breaks. Part of the increase can be attributed to a mandatory testing regime for travel returnees from high-incidence areas.     

类器官组织在感染性疾病研究中的应用

类器官(organoid)是体外3D培养组织干细胞所形成的多功能细胞团,具有自身增殖和多向分化的能力,在空间和结构上与来源器官组织的基因、结构和功能相似,可用于模拟体内组织细胞生长、分化及器官形成过程,在药物筛选与评价、生物医学材料及组织工程等方面具有重要的应用潜能.当前在感染性疾病研究方面,越来越多数据表明不同类器官...     

The structural identifiability of the susceptible infected recovered model with seasonal forcing

In this paper, it is shown that the SIR epidemic model, with the force of infection subject to seasonal variation, and a proportion of either the prevalence or the incidence measured, is unidentifiable unless certain key system parameters are known, or measurable. This means that an uncountable number of different parameter vectors can, theoretically, give rise to the same idealised output data. Any subsequent parameter estimation from real data must be viewed with little confidence as a result. The approach adopted for the structural identifiability analysis utilises the existence of an infinitely differentiable transformation that connects the state trajectories corresponding to parameter vectors that give rise to identical output data. When this approach proves computationally intractable, it is possible to use the converse idea that the existence of a coordinate transformation between states for particular parameter vectors implies indistinguishability between these vectors from the corresponding model outputs.     

The effect of seasonal host birth rates on population dynamics: the importance of resonance

Many of the simple mathematical models currently in use often fail to capture important biological factors. Here we extend current models of insect-pathogen interactions to include seasonality in the birth rate. In particular, we consider the SIR model with self-regulation when applied to specific cases--rabbit haemorrhagic disease and fox rabies. In this paper, we briefly summarize the results of the model with a constant time-independent birth rate, a, which we then replace with the time dependent birth rate a(t), to investigate how this effects the dynamics of the host population. We can split parameter space into an area in which the model without seasonality has no oscillations, in which case a simple averaging rule predicts the behaviour. Alternatively, in the area where oscillations to the equilibrium do occur in the non-seasonal model, disease persistence is more complicated and we get more complex dynamical behaviour in this case. We apply resonance techniques to discover the structure of the subharmonic modes of the SIR model with self-regulation. We then look at whether many biological systems are likely to display these "resonant" dynamics and find that we would expect them to be widespread.