Processes underlying rabies virus incursions across US–Canada Border as revealed by whole-genome phylogeography

Disease control programs aim to constrain and reduce the spread of infection. Human disease interventions such as wildlife vaccination play a major role in determining the limits of a pathogen’s spatial distribution. Over the past few decades, a raccoon-specific variant of rabies virus (RRV) has invaded large areas of eastern North America. Although expansion into Canada has been largely prevented through vaccination along the US border, several outbreaks have occurred in Canada. Applying phylogeographic approaches to 289 RRV whole-genome sequences derived from isolates collected in Canada and adjacent US states, we examined the processes underlying these outbreaks. RRV incursions were attributable predominantly to systematic virus leakage of local strains across areas along the border where vaccination has been conducted but also to single stochastic events such as long-distance translocations. These results demonstrate the utility of phylogeographic analysis of pathogen genomes for understanding transboundary outbreaks

Application of high-throughput sequencing to whole rabies viral genome characterisation and its use for phylogenetic re-evaluation of a raccoon strain incursion into the province of Ontario

Raccoon rabies remains a serious public health problem throughout much of the eastern seaboard of North America due to the urban nature of the reservoir host and the many challenges inherent in multi-jurisdictional efforts to administer co-ordinated and comprehensive wildlife rabies control programmes. Better understanding of the mechanisms of spread of rabies virus can play a significant role in guiding such control efforts. To facilitate a detailed molecular epidemiological study of raccoon rabies virus movements across eastern North America, we developed a methodology to efficiently determine whole genome sequences of hundreds of viral samples. The workflow combines the generation of a limited number of overlapping amplicons covering the complete viral genome and use of high throughput sequencing technology. The value of this approach is demonstrated through a retrospective phylogenetic analysis of an outbreak of raccoon rabies which occurred in the province of Ontario between 1999 and 2005. As demonstrated by the number of single nucleotide polymorphisms detected, whole genome sequence data were far more effective than single gene sequences in discriminating between samples and this facilitated the generation of more robust and informative phylogenies that yielded insights into the spatio-temporal pattern of viral spread. With minor modification this approach could be applied to other rabies virus variants thereby facilitating greatly improved phylogenetic inference and thus better understanding of the spread of this serious zoonotic disease. Such information will inform the most appropriate strategies for rabies control in wildlife reservoirs

Emergence of Arctic-like Rabies Lineage in India

Progenitors of Arctic-like rabies viruses, which now circulate extensively in India, may have been responsible for the emergence of the Arctic rabies lineage

Caracterización molecular y biológica del virus de la rabia que circula en zorrillos de México enfocado a la variante del gen de la fosfoproteína (P)

The objective of this work was to characterize molecularly rabies viruses from Mexican skunks, by comparison of a portion of the viral P gene sequence with corresponding regions from other skunk-adapted rabies virus variants and with other genotype 1 rabies viruses that circulate in the Americas. Furthermore, incubation period and histopathologic lesions after virus inoculation by the intra-cerebral route in mice was characterized. According to the results of phylogenetic studies the Mexican skunk strains (Antigenic Variant (AV) 8 and AV10) are evolutionarily quite distinct. The AV10 isolate from South Baja California is quite closely related to the viruses that circulate in Californian skunks, while the AV8 isolate from San Luis Potosí was most closely related to the South central skunk strain that circulates in southern states such as Texas. These variations were reflected in some biological properties of both strains in mice.El objetivo de este estudio fue la caracterización molecular y biológica del virus de la rabia en zorrillos de México, comparando una porción de la secuencia viral del gen P, con regiones correspondientes de variantes de virus rábico adaptadas en zorrillos y pertenecientes al genotipo 1 (virus de la rabia "clásica"), que circulan en América. Como parte de la caracterización biológica se incluyó el periodo de incubación y las lesiones histopatológicas después de la inoculación del virus por ví­a intracerebral en ratones. De acuerdo a los resultados de estudios filogenéticos, las cepas de zorrillo mexicano (variante antigénica (AV8 y AV10) son muy distintas en cuanto a su evolución. El aislado AV10 de Baja California Sur está muy relacionado con los virus que circulan en zorrillos de California, mientras que el aislado AV8 de San Luis Potosí­ tuvo mayor relación con la cepa del zorrillo del Centro/Sur que circula en los estados del sur, como Texas. Estas variantes se reflejaron en algunas propiedades biológicas de ambas cepas en ratones

Towards Enhanced Diagnosis of Diseases using Statistical Analysis of Genomic Copy Number Data

Genomic copy number data are a rich source of information about the biological systems they are collected from. They can be used for the diagnoses of various diseases by identifying the locations and extent of aberrations in DNA sequences. However, copy number data are often contaminated with measurement noise which drastically affects the quality and usefulness of the data. The objective of this project is to apply some of the statistical filtering and fault detection techniques to improve the accuracy of diagnosis of diseases by enhancing the accuracy of determining the locations of such aberrations. Some of these techniques include multiscale wavelet-based filtering and hypothesis testing based fault detection. The filtering techniques include Mean Filtering (MF), Exponentially Weighted Moving Average (EWMA), Standard Multiscale Filtering (SMF) and Boundary Corrected Translation Invariant filtering (BCTI). The fault detection techniques include the Shewhart chart, EWMA and Generalized Likelihood Ratio (GLR). The performance of these techniques is illustrated using Monte Carlo simulations and through their application on real copy number data. Based on the Monte Carlo simulations, the non-linear filtering techniques performed better than the linear techniques, with BCTI performing with the least error . At an SNR of 1, BCTI technique had an average mean squared error of 2.34% whereas mean filtering technique had the highest error of 5.24%. As for the fault detection techniques, GLR had the lowest missed detection rate of 1.88% at a fixed false alarm rate of around 4%. At around the same false alarm rate, the Shewhart chart had the highest missed detection of 67.4%. Furthermore, these techniques were applied on real genomic copy number data sets. These included data from breast cancer cell lines (MPE600) and colorectal cancer cell lines (SW837)

Genetic Tracking of the Raccoon Variant of Rabies Virus in Eastern North America

AbstractTo gain insight into the incursion of the raccoon variant of rabies into the raccoon population in three Canadian provinces, a collection of 192 isolates of the raccoon rabies virus (RRV) strain was acquired from across its North American range and was genetically characterized. A 516-nucleotide segment of the non-coding region between the G and L protein open reading frames, corresponding to the most variable region of the rabies virus genome, was sequenced. This analysis identified 119 different sequences, and phylogenetic analysis of the dataset supports the documented history of RRV spread. Three distinct geographically restricted RRV lineages were identified. Lineage 1 was found in Florida, Alabama and Georgia and appears to form the ancestral lineage of the raccoon variant of rabies. Lineage 2, represented by just two isolates, was found only in Florida, while the third lineage appears broadly distributed throughout the rest of the eastern United States and eastern Canada. In New York State, two distinct spatially segregated variants were identified; the one occupying the western and northern portions of the state was responsible for an incursion of raccoon rabies into the Canadian province of Ontario. Isolates from New Brunswick and Quebec form distinct, separate clusters, consistent with their independent origins from neighboring areas of the United States. The data are consistent with localized northward incursion into these three separate areas with no evidence of east–west viral movement between the three Canadian provinces

Enzootic Rabies Elimination from Dogs and Reemergence in Wild Terrestrial Carnivores, United States

Independent enzootics in wild terrestrial carnivores resulted from spillover events from long-term enzootics associated with dogs

Numerical solutions of random mean square Fisher-KPP models with advection

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Development and diagnostic validation of the Brisbane Evidence-Based Language Test

Purpose: To describe the development and determine the diagnostic accuracy of the Brisbane Evidence-Based Language Test in detecting aphasia. Methods: Consecutive acute stroke admissions (n = 100; mean = 66.49y) participated in a single (assessor) blinded cross-sectional study. Index assessment was the ∼45 min Brisbane Evidence-Based Language Test. The Brisbane Evidence-Based Language Test is further divided into four 15–25 min Short Tests: two Foundation Tests (severe impairment), Standard (moderate) and High Level Test (mild). Independent reference standard included the Language Screening Test, Aphasia Screening Test, Comprehensive Aphasia Test and/or Measure for Cognitive-Linguistic Abilities, treating team diagnosis and aphasia referral post-ward discharge. Results: Brisbane Evidence-Based Language Test cut-off score of ≤ 157 demonstrated 80.8% (LR+ =10.9) sensitivity and 92.6% (LR− =0.21) specificity. All Short Tests reported specificities of ≥ 92.6%. Foundation Tests I (cut-off ≤ 61) and II (cut-off ≤ 51) reported lower sensitivity (≥ 57.5%) given their focus on severe conditions. The Standard (cut-off ≤ 90) and High Level Test (cut-off ≤ 78) reported sensitivities of ≥ 72.6%. Conclusion: The Brisbane Evidence-Based Language Test is a sensitive assessment of aphasia. Diagnostically, the High Level Test recorded the highest psychometric capabilities of the Short Tests, equivalent to the full Brisbane Evidence-Based Language Test. The test is available for download from brisbanetest.org. Implications for rehabilitation: Aphasia is a debilitating condition and accurate identification of language disorders is important in healthcare. Language assessment is complex and the accuracy of assessment procedures is dependent upon a variety of factors. The Brisbane Evidence-Based Language Test is a new evidence-based language test specifically designed to adapt to varying patient need, clinical contexts and co-occurring conditions. In this cross-sectional validation study, the Brisbane Evidence-Based Language Test was found to be a sensitive measure for identifying aphasia in stroke