Modeling the impact of immigration on the epidemiology of tuberculosis

This paper presents two new theoretical frameworks to investigate the impact of immigration on the transmission dynamics of tuberculosis. For the basic model, we present new analysis on the existence and stability of equilibria. Then, we use numerical simulations of the model to illustrate the behavior of the system. We apply the model to Canadian reported data on tuberculosis and observe a good agreement between the model prediction and the data. For the extended model, which incorporated the recruitment of the latent and infectious in immigrants to the basic model, we find that the usual threshold condition does not apply and a unique equilibrium exists for all parameter values. This indicates that the disease does not disappear and becomes endemic in host areas. This finding is also supported by numerical simulations with the extended model. Our study suggests that immigrants have a considerable influence on the overall transmission dynamics behavior of tuberculosis.     

Compartmental neural simulations with spatial adaptivity

Since their inception, computational models have become increasingly complex and useful counterparts to laboratory experiments within the field of neuroscience. Today several software programs exist to solve the underlying mathematical system of equations, but such programs typically solve these equations in all parts of a cell (or network of cells) simultaneously, regardless of whether or not all of the cell is active. This approach can be inefficient if only part of the cell is active and many simulations must be performed. We have previously developed a numerical method that provides a framework for spatial adaptivity by making the computations local to individual branches rather than entire cells (Rempe and Chopp, SIAM Journal on Scientific Computing, 28: 2139–2161, 2006). Once the computation is reduced to the level of branches instead of cells, spatial adaptivity is straightforward: the active regions of the cell are detected and computational effort is focused there, while saving computations in other regions of the cell that are at or near rest. Here we apply the adaptive method to four realistic neuronal simulation scenarios and demonstrate its improved efficiency over non-adaptive methods. We find that the computational cost of the method scales with the amount of activity present in the simulation, rather than the physical size of the system being simulated. For certain problems spatial adaptivity reduces the computation time by up to 80%.     

Crystal structure determination and dynamic studies of Mycobacterium tuberculosis Cytidine deaminase in complex with products

Cytidine deaminase (CDA) is a key enzyme in the pyrimidine salvage pathway. It is involved in the hydrolytic deamination of cytidine or 2′-deoxycytidine to uridine or 2′-deoxyuridine, respectively. Here we report the crystal structures of Mycobacterium tuberculosis CDA (MtCDA) in complex with uridine (2.4 Å resolution) and deoxyuridine (1.9 Å resolution). Molecular dynamics (MD) simulation was performed to analyze the physically relevant motions involved in the protein–ligand recognition process, showing that structural flexibility of some protein regions are important to product binding. In addition, MD simulations allowed the analysis of the stability of tetrameric MtCDA structure. These findings open-up the possibility to use MtCDA as a target in future studies aiming to the rational design of new inhibitor of MtCDA-catalyzed chemical reaction with potential anti-proliferative activity on cell growth of M. tuberculosis, the major causative agent of tuberculosis.     

Branching stochastic processes with immigration in analysis of renewing cell populations

This paper considers the utility of a new class of stochastic branching processes with non-homogeneous immigration in modeling complex renewing cell systems. Such systems typically include the population of stem cells that provides an inexhaustible supply of cells necessary for maintaining the cellular composition of a tissue. A stem cell may be induced to transform (differentiate) into a progenitor cell. Progenitor cells retain the ability to proliferate and their function is believed to provide a quick proliferative response to an increased demand for cells in the population. There may be several sub-types of progenitor cells. Terminally differentiated cells do not divide under normal conditions; they are responsible for maintaining tissue-specific functions. Recent advancements in experimental techniques offer considerable scope for quantitative studies of in vivo cell kinetics based on stochastic modeling of renewing cell populations. However, no ready-made theory is currently available to take full advantage of these advancements. This paper introduces such a theory with a special focus on its feasibility in biological applications.     

Heparin-binding hemagglutinin HBHA from Mycobacterium tuberculosis affects actin polymerisation

HBHA is a mycobacterial cell surface protein that mediates adhesion to epithelial cells and that has been implicated in the dissemination of Mycobacterium tuberculosis (Mtb) from the site of primary infection. In this work, we demonstrate that HBHA is able to bind G-actin whereas its shorter form, deprived of the lysine-rich C-terminal region (HBHAΔC), does not bind. Consistently, interaction of actin with HBHA is competitive with heparin binding. Notably, we also observe that HBHA, but not HBHAΔC, clearly hampers G-actin polymerisation into F-actin filaments. Since Mtb escapes from the phagosome into the cytosol of host cells, where it can persist and replicate, HBHA is properly localised on the bacterial surface to regulate the dynamic process of cytoskeleton formation driven by actin polymerisation and depolymerisation.     

Estimating lead time and overdiagnosis associated with PSA screening from prostate cancer incidence trends

Summary .   The introduction of the prostate-specific antigen (PSA) test has led to dramatic changes in the incidence of prostate cancer in the United States. In this article, we use information on the increase and subsequent decline in prostate cancer incidence following the adoption of PSA to estimate the lead time associated with PSA screening. The lead time is a key determinant of the likelihood of overdiagnosis, one of the main costs associated with the PSA test. Our approach conceptualizes observed incidence as the sum of the secular trend in incidence, which reflects incidence in the absence of PSA, and the excess incidence over and above the secular trend, which is a function of population screening patterns and the unknown lead time. We develop a likelihood model for the excess incidence given the secular trend and use it to estimate the mean lead time under specified distributional assumptions. We also develop a likelihood model for observed incidence and use it to simultaneously estimate the mean lead time together with a smooth secular trend. Variances and confidence intervals are estimated via a parametric bootstrap. Our results indicate an average lead time of approximately 4.59 years (95% confidence interval [3.24, 5.93]) for whites and 6.78 years [5.42, 8.20] for blacks with a corresponding secular trend estimate that is fairly flat after the introduction of PSA screening. These estimates correspond to overdiagnosis frequencies of approximately 22.7% and 34.4% for screen-detected whites and blacks, respectively. Our results provide the first glimpse of a plausible secular trend in prostate cancer incidence and suggest that, in the absence of PSA screening, disease incidence would not have continued its historic increase, rather it would have leveled off in accordance with changes in prostate patterns of care unrelated to PSA.     

Minimizing the dependency ratio in a population with below-replacement fertility through immigration

Many industrialized countries face fertility rates below replacement level, combined with declining mortality especially in older ages. Consequently, the populations of these countries have started to age. One important indicator of age structures is the dependency ratio which is the ratio of the nonworking age population to the working age population. In this work we find the age-specific immigration profile that minimizes the dependency ratio in a stationary population with below-replacement fertility. It is assumed that the number of immigrants per age is limited. We consider two alternative policies. In the first one, we fix the total number of people who annually immigrate to a country. In the second one, we prescribe the size of the receiving country’s population. For both cases we provide numerical results for the optimal immigration profile, for the resulting age structure of the population, as well as for the dependency ratio.     

Approach to equilibrium in age structured populations with an increasing recruitment process

This paper considers a model for the dynamics of an age structured population subject to a density dependent factor which regulates the recruitment. Certain properties of biological interest are obtained and the stability of the equilibrium age distributions is investigated. Finally some applications to known fishery models are considered.Work done under the contract 80.02333.01 of C.N.R.     

Modeling disease incidence data with spatial and spatio temporal dirichlet process mixtures

Disease incidence or mortality data are typically available as rates or counts for specified regions, collected over time. We propose Bayesian nonparametric spatial modeling approaches to analyze such data. We develop a hierarchical specification using spatial random effects modeled with a Dirichlet process prior. The Dirichlet process is centered around a multivariate normal distribution. This latter distribution arises from a log-Gaussian process model that provides a latent incidence rate surface, followed by block averaging to the areal units determined by the regions in the study. With regard to the resulting posterior predictive inference, the modeling approach is shown to be equivalent to an approach based on block averaging of a spatial Dirichlet process to obtain a prior probability model for the finite dimensional distribution of the spatial random effects. We introduce a dynamic formulation for the spatial random effects to extend the model to spatio-temporal settings. Posterior inference is implemented through Gibbs sampling. We illustrate the methodology with simulated data as well as with a data set on lung cancer incidences for all 88 counties in the state of Ohio over an observation period of 21 years.     

Theorizing transnational immigration: a critical review of current efforts

During the past decade, transnationalism has entered the lexicon of migration scholars. As with other terms used in the study of immigration and ethnicity, this concept suffers from ambiguity as a result of competing definitions that fail to specify the temporal and spatial parameters of the term and to adequately locate it vis-à-vis older concepts such as assimilation and cultural pluralism. This article offers a review and critique of the ways the term has come to be employed at the hands of key spokespersons that have articulated the most sustained theoretical rationales to date for transnationalism as a conceptual construct to account for new immigrant identities and communities. The conclusion of the essay offers in schematic form an alternative assessment of transnationalism that locates it as one potential subset of assimilation theory, rather than as an alternative to it.     

Threshold behaviour of a SIR epidemic model with age structure and immigration

We consider a SIR age-structured model with immigration of infectives in all epidemiological compartments; the population is assumed to be in demographic equilibrium between below-replacement fertility and immigration; the spread of the infection occurs through a general age-dependent kernel. We analyse the equations for steady states; because of immigration of infectives a steady state with a positive density of infectives always exists; however, a quasi-threshold theorem is proved, in the sense that, below the threshold, the density of infectives is close to 0, while it is away from 0, above the threshold; furthermore, conditions that guarantee uniqueness of steady states are obtained. Finally, we present some numerical examples, inspired by the Italian demographic situation, that illustrate the threshold-like behaviour, and other features of the stationary solutions and of the transient. Supported in part by FIRB project RBAU01K7M2 “Metodi dell’Analisi Matematica in Biologia, Medicina e Ambiente” of the Italian Ministero Istruzione Università e Ricerca     

Polymorphism in NOD2, Crohn's disease, and susceptibility to pulmonary tuberculosis

The nucleotide oligomerization binding domain 2 gene (NOD2) encodes an intracellular receptor for bacterial components, which is expressed in monocytes and is associated with Crohn's Disease (CD). This finding, along with epidemiological evidence, supports a role for infection in the pathogenesis of CD. Speculation that mycobacteria are involved in CD led us to investigate NOD2 in susceptibility to tuberculosis (TB), a global public health problem caused by Mycobacterium tuberculosis. CD-associated NOD2 variants were absent in a case-control study of 640 Gambians, where CD is rare. Novel NOD2 promoter polymorphisms were identified but showed no association with TB in this African population sample.     

Inaugural structure from the DUF3349 superfamily of proteins, Mycobacterium tuberculosis Rv0543c

The first structure for a member of the DUF3349 (PF11829) family of proteins, Rv0543c from Mycobacterium tuberculosis, has been determined using NMR-based methods and some of its biophysical properties characterized. Rv0543c is a 100 residue, 11.3 kDa protein that both size exclusion chromatography and NMR spectroscopy show to be a monomer in solution. The structure of the protein consists of a bundle of five α-helices, α1 (M1 – Y16), α2 (P21 – C33), α3 (S37 – G52), α4 (G58 – H65) and α5 (S72 – G87), held together by a largely conserved group of hydrophobic amino acid side chains. Heteronuclear steady-state {¹H}–¹⁵N NOE, T₁, and T₂ values are similar through-out the sequence indicating that the backbones of the five helices are in a single motional regime. The thermal stability of Rv0543c, characterized by circular dichroism spectroscopy, indicates that Rv0543c irreversibly unfolds upon heating with an estimated melting temperature of 62.5 °C. While the biological function of Rv0543c is still unknown, the presence of DUF3349 proteins predominately in Mycobacterium and Rhodococcus bacterial species suggests that Rv0543 may have a biological function unique to these bacteria, and consequently, may prove to be an attractive drug target to combat tuberculosis.     

Spatial models of virus-immune dynamics

To date, the majority of theoretical models describing the dynamics of infectious diseases in vivo are based on the assumption of well-mixed virus and cell populations. Because many infections take place in solid tissues, spatially structured models represent an important step forward in understanding what happens when the assumption of well-mixed populations is relaxed. Here, we explore models of virus and virus-immune dynamics where dispersal of virus and immune effector cells was constrained to occur locally. The stability properties of our spatial virus-immune dynamics models remained robust under almost all biologically plausible dispersal schemes, regardless of their complexity. The various spatial dynamics were compared to the basic non-spatial dynamics and important differences were identified: When space was assumed to be homogeneous, the dynamics generated by non-spatial and spatially structured models differed substantially at the peak of the infection. Thus, non-spatial models may lead to systematic errors in the estimates of parameters underlying acute infection dynamics. When space was assumed to be heterogeneous, spatial coupling not only changed the equilibrium properties of the uncoupled populations but also equalized the dynamics and thereby reduced the likelihood of dynamic elimination of the infection. In line with experimental and clinical observations, long-lasting oscillation periods were virtually absent. When source-sink dynamics were considered, the long-term outcome of the infection depended critically on the degree of spatial coupling. The infection collapsed when emigration from source sites became too large. Finally, we discuss the implications of spatially structured models on medical treatment of infectious diseases, and note that a huge gap exists in data accurately describing infection dynamics in solid tissues.     

The impact of immigration on unemployment and earnings among racial minorities in the United States

The existing immigration literature presents inconsistencies and contradictions. Some studies suggest that immigration has no effect on the earnings and employment levels of native‐born minorities, while others offer contrary evidence. In an effort to make more progress, a study was done to examine the impact of immigration on unemployment and earnings among racial minorities in the US. Employing United States census data covering 1940 to 1980, and using states and a sample of metropolitan statistical areas as units of analysis, this study found that increases in immigration in some periods of US history had significant negative effects on employment levels among racial minorities in the United States. Specifically, results of the regression analysis showed that, in 1970, a standard deviation change in immigration increased unemployment among minorities by nearly 14 per cent, while in 1980 unemployment increased by nearly 10 per cent, given a standard deviation increase in immigration. With regard to earnings, the study found that immigration decreases minority income. In 1980 a one per cent increase in immigration reduced racial minority earnings, on average, by nearly $25.32. Analysis also showed that low skill levels among minorities, as well as family breakdown may in part be responsible for high minority unemployment and low earnings. For example, in 1980 a one per cent increase in divorce reduced minority earnings, on average, by $65.89. Low minority skill levels reduced earnings by $104 on average. However, the deleterious effects of immigration on racial minority unemployment and earnings remain even after adjusting for the potentially confounding effects of skill levels and divorce. Policy implications of the findings are discussed at length, and suggestions are proposed for future research.     

Estimation of rates of births, deaths, and immigration from mark-recapture data

Summary .  The analysis of mark–recapture data is undergoing a period of development and expansion. Here we contribute to that by presenting a model which includes both births and immigration, as well as the usual deaths. Data come from a long-term study of the willow tit ( Parus montanus ), where we can assume that all births are recorded, and hence immigrants can also be identified as birds captured as adults for the first time. We model the rates of immigration, birth rate per parent, and death rates of juveniles and adults. Using a hierarchical model allows us to incorporate annual variation in these parameters. The model is fitted to the data using Markov chain Monte Carlo, as a Bayesian analysis. In addition to the model fitting, we also check several aspects of the model fit, in particular whether survival varies with age or immigrant status, and whether capture probability is affected by previous capture history. The latter check is important, as independence of capture histories is a key assumption that simplifies the model considerably. Here we find that the capture probability depends strongly on whether the individual was captured in the previous year.     

肝硬化合并结核病患者的临床特征

目的 分析肝硬化合并结核病患者的临床特征,为该类患者的治疗提供参考。 方法 回顾性分析2014年9月至2017年7月于浙江大学医学院附属第一医院住院的肝硬化合并结核病患者的相关资料,总结患者的临床特征。 结果 共收治68例肝硬化合并结核病患者,其中男性50例(73.5%),女性18例(26.5%),平均年龄(59.9±13.7)岁。在所有患者中,肝硬化最常见的原因是HBV感染(46例,67.7%)和酒精(9例,13.2%)。肺结核(43例)、结核性腹膜炎(13例)、结核性胸膜炎(12例)是最常见的结核类型,此外骨关节结核、结核性脑膜炎、结核性心包炎、泌尿系结核、肠结核、淋巴结结核均可见。该类患者常见临床表现为乏力、腹胀,出现发热的患者不足半数,有盗汗表现的更为罕见。 结论 肝硬化患者并发结核后可使病情复杂化,增加治疗难度。此外部分患者临床表现不典型,需提高警惕,避免漏诊。     

Inequality,low-intensity immigration and human capital formation in the regions of Chile, 1820-1939

This article traces inequality and numeracy development in the regions of Chile during the 19th and early 20th century. Inequality, measured with anthropometric methods, was associated with a lower speed of human capital formation. Not all talents received the necessary education to make full use of their talent for the regional economy, especially in the south in the early period. However, Chile became slightly less unequal over time and more numerate during the late 19th century. In addition, we study the correlates of low-intensity immigration in Chile. Regions with a relatively high share of North European migrants developed faster in terms of numeracy.     

Exploration of the intercellular heterogeneity of topotecan uptake into human breast cancer cells through compartmental modelling

A mathematical multi-cell model for the in vitro kinetics of the anti-cancer agent topotecan (TPT) following administration into a culture medium containing a population of human breast cancer cells (MCF-7 cell line) is described. This non-linear compartmental model is an extension of an earlier single-cell type model and has been validated using experimental data obtained using two-photon laser scanning microscopy (TPLSM). A structural identifiability analysis is performed prior to parameter estimation to test whether the unknown parameters within the model are uniquely determined by the model outputs. The full model has 43 compartments, with 107 unknown parameters, and it was found that the structural identifiability result could not be established even when using the latest version of the symbolic computation software Mathematica. However, by assuming that a priori knowledge is available for certain parameters, it was possible to reduce the number of parameters to 81, and it was found that this (Stage Two) model was globally (uniquely) structurally identifiable. The identifiability analysis demonstrated how valuable symbolic computation is in this context, as the analysis is far too lengthy and difficult to be performed by hand.