Cholangiocarcinoma: Epidemiology and risk factors

Cholangiocarcinoma (CCA) is a heterogeneous disease arising from a complex interaction between host-specific genetic background and multiple risk factors. Globally, CCA incidence rates exhibit geographical variation, with much higher incidence in parts of the Eastern world compared to the West. These differences are likely to reflect differences in geographical risk factors as well as genetic determinants. Of note, over the past few decades, the incidence rates of CCA appear to change and subtypes of CCA appear to show distinct epidemiological trends. These trends need to be interpreted with caution given the issues of diagnosis, recording and coding of subtypes of CCA. Epidemiological evidences suggest that in general population some risk factors are less frequent but associated with a higher CCA risk, while others are more common but associated with a lower risk. Moreover, while some risk factors are shared by intrahepatic and both extrahepatic forms, others seem more specific for one of the two forms. Currently some pathological conditions have been clearly associated with CCA development, and other conditions are emerging; however, while their impact in increasing CCA risk as single etiological factors has been provided in many studies, less is known when two or more risk factors co-occur in the same patient. Moreover, despite the advancements in the knowledge of CCA aetiology, in Western countries about 50% of cases are still diagnosed without any identifiable risk factor. It is therefore conceivable that other still undefined etiologic factors are responsible for the recent increase of CCA (especially iCCA) incidence worldwide

Comparative Pathogenesis of an Avian H5N2 and a Swine H1N1 Influenza Virus in Pigs

Pigs are considered intermediate hosts for the transmission of avian influenza viruses (AIVs) to humans but the basic organ pathogenesis of AIVs in pigs has been barely studied. We have used 42 four-week-old influenza naive pigs and two different inoculation routes (intranasal and intratracheal) to compare the pathogenesis of a low pathogenic (LP) H5N2 AIV with that of an H1N1 swine influenza virus. The respiratory tract and selected extra-respiratory tissues were examined for virus replication by titration, immunofluorescence and RT-PCR throughout the course of infection. Both viruses caused a productive infection of the entire respiratory tract and epithelial cells in the lungs were the major target. Compared to the swine virus, the AIV produced lower virus titers and fewer antigen positive cells at all levels of the respiratory tract. The respiratory part of the nasal mucosa in particular showed only rare AIV positive cells and this was associated with reduced nasal shedding of the avian compared to the swine virus. The titers and distribution of the AIV varied extremely between individual pigs and were strongly affected by the route of inoculation. Gross lung lesions and clinical signs were milder with the avian than with the swine virus, corresponding with lower viral loads in the lungs. The brainstem was the single extra-respiratory tissue found positive for virus and viral RNA with both viruses. Our data do not reject the theory of the pig as an intermediate host for AIVs, but they suggest that AIVs need to undergo genetic changes to establish full replication potential in pigs. From a biomedical perspective, experimental LP H5 AIV infection of pigs may be useful to examine heterologous protection provided by H5 vaccines or other immunization strategies, as well as for further studies on the molecular pathogenesis and neurotropism of AIVs in mammals

A Bayesian approach to quantifying the effects of mass poultry vaccination upon the spatial and temporal dynamics of H5N1 in Northern Vietnam.

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A Complete Analysis of HA and NA Genes of Influenza A Viruses

BACKGROUND: More and more nucleotide sequences of type A influenza virus are available in public databases. Although these sequences have been the focus of many molecular epidemiological and phylogenetic analyses, most studies only deal with a few representative sequences. In this paper, we present a complete analysis of all Haemagglutinin (HA) and Neuraminidase (NA) gene sequences available to allow large scale analyses of the evolution and epidemiology of type A influenza. METHODOLOGY/PRINCIPAL FINDINGS: This paper describes an analysis and complete classification of all HA and NA gene sequences available in public databases using multivariate and phylogenetic methods. CONCLUSIONS/SIGNIFICANCE: We analyzed 18,975 HA sequences and divided them into 280 subgroups according to multivariate and phylogenetic analyses. Similarly, we divided 11,362 NA sequences into 202 subgroups. Compared to previous analyses, this work is more detailed and comprehensive, especially for the bigger datasets. Therefore, it can be used to show the full and complex phylogenetic diversity and provides a framework for studying the molecular evolution and epidemiology of type A influenza virus. For more than 85% of type A influenza HA and NA sequences into GenBank, they are categorized in one unambiguous and unique group. Therefore, our results are a kind of genetic and phylogenetic annotation for influenza HA and NA sequences. In addition, sequences of swine influenza viruses come from 56 HA and 45 NA subgroups. Most of these subgroups also include viruses from other hosts indicating cross species transmission of the viruses between pigs and other hosts. Furthermore, the phylogenetic diversity of swine influenza viruses from Eurasia is greater than that of North American strains and both of them are becoming more diverse. Apart from viruses from human, pigs, birds and horses, viruses from other species show very low phylogenetic diversity. This might indicate that viruses have not become established in these species. Based on current evidence, there is no simple pattern of inter-hemisphere transmission of avian influenza viruses and it appears to happen sporadically. However, for H6 subtype avian influenza viruses, such transmissions might have happened very frequently and multiple and bidirectional transmission events might exist

Eurasian Tree Sparrows, Risk for H5N1 Virus Spread and Human Contamination through Buddhist Ritual: An Experimental Approach

Background: The Highly Pathogenic Avian Influenza H5N1 virus has dramatically spread throughout Southeast Asia since its first detection in 1997. Merit Release Birds, such as the Eurasian Tree Sparrow, are believed to increase one's positive karma when kissed and released during Buddhist rituals. Since these birds are often in close contact with both poultry and humans, we investigated their potential role in the spread of H5N1 virus. Methodology/Principal Findings: Seven series of experiments were conducted in order to investigate the possible interactions between inoculated and exposed birds, including sparrow/sparrow, sparrow/chicken, duck/sparrow. Daily and post-mortem samples collected were tested for H5N1 virus by real-time RT-PCR and egg inoculation. When directly inoculated, Eurasian Tree Sparrows were highly susceptible to the H5N1 virus, with a fatality rate approaching 100% within 5 days post-inoculation. Although transmission of fatal infection between sparrows did not occur, seroconversion of the exposed birds was observed. Up to 100% chickens exposed to inoculated sparrows died of H5N1 infection, depending on the caging conditions of the birds, while a fatality rate of 50% was observed on sparrows exposed to infected ducks. Large quantities of H5N1 virus were detected in the sparrows, particularly in their feathers, from which infectious particles were recovered. Conclusions/Significance: Our study indicates that under experimental conditions, Eurasian Tree Sparrows are susceptible to H5N1 infection, either by direct inoculation or by contact with infected poultry. Their ability to transmit H5N1 infection to other birds is also demonstrated, suggesting that the sparrows may play a role in the dissemination of the virus. Finally, the presence of significant quantities of H5N1 virus on sparrows' feathers, including infectious particles, would suggest that Merit Release Birds represent a risk for human contamination in countries where avian influenza virus is circulating and where this religious ritual is practiced. © 2011 Gutiérrez et al.published_or_final_versio

Flying Over an Infected Landscape: Distribution of Highly Pathogenic Avian Influenza H5N1 Risk in South Asia and Satellite Tracking of Wild Waterfowl

Highly pathogenic avian influenza (HPAI) H5N1 virus persists in Asia, posing a threat to poultry, wild birds, and humans. Previous work in Southeast Asia demonstrated that HPAI H5N1 risk is related to domestic ducks and people. Other studies discussed the role of migratory birds in the long distance spread of HPAI H5N1. However, the interplay between local persistence and long-distance dispersal has never been studied. We expand previous geospatial risk analysis to include South and Southeast Asia, and integrate the analysis with migration data of satellite-tracked wild waterfowl along the Central Asia flyway. We find that the population of domestic duck is the main factor delineating areas at risk of HPAI H5N1 spread in domestic poultry in South Asia, and that other risk factors, such as human population and chicken density, are associated with HPAI H5N1 risk within those areas. We also find that satellite tracked birds (Ruddy Shelduck and two Bar-headed Geese) reveal a direct spatio-temporal link between the HPAI H5N1 hot-spots identified in India and Bangladesh through our risk model, and the wild bird outbreaks in May–June–July 2009 in China (Qinghai Lake), Mongolia, and Russia. This suggests that the continental-scale dynamics of HPAI H5N1 are structured as a number of persistence areas delineated by domestic ducks, connected by rare transmission through migratory waterfowl

Influenza A H5N1 Immigration Is Filtered Out at Some International Borders

Geographic spread of highly pathogenic influenza A H5N1, the bird flu strain, appears a necessary condition for accelerating the evolution of a related human-to-human infection. As H5N1 spreads the virus diversifies in response to the variety of socioecological environments encountered, increasing the chance a human infection emerges. Genetic phylogenies have for the most part provided only qualitative evidence that localities differ in H5N1 diversity. For the first time H5N1 variation is quantified across geographic space.We constructed a statistical phylogeography of 481 H5N1 hemagglutinin genetic sequences from samples collected across 28 Eurasian and African localities through 2006. The MigraPhyla protocol showed southern China was a source of multiple H5N1 strains. Nested clade analysis indicated H5N1 was widely dispersed across southern China by both limited dispersal and long distance colonization. The UniFrac metric, a measure of shared phylogenetic history, grouped H5N1 from Indonesia, Japan, Thailand and Vietnam with those from southeastern Chinese provinces engaged in intensive international trade. Finally, H5N1's accumulative phylogenetic diversity was greatest in southern China and declined beyond. The gradient was interrupted by areas of greater and lesser phylogenetic dispersion, indicating H5N1 migration was restricted at some geopolitical borders. Thailand and Vietnam, just south of China, showed significant phylogenetic clustering, suggesting newly invasive H5N1 strains have been repeatedly filtered out at their northern borders even as both countries suffered recurring outbreaks of endemic strains. In contrast, Japan, while successful in controlling outbreaks, has been subjected to multiple introductions of the virus.The analysis demonstrates phylogenies can provide local health officials with more than hypotheses about relatedness. Pathogen dispersal, the functional relationships among disease ecologies across localities, and the efficacy of control efforts can also be inferred, all from viral genetic sequences alone

A case-control study to identify risk factors associated with avian influenza subtype H9N2 on commercial poultry farms in Pakistan

A 1:1 matched case-control study was conducted to identify risk factors for avian influenza subtype H9N2 infection on commercial poultry farms in 16 districts of Punjab, and 1 administrative unit of Pakistan. One hundred and thirty-three laboratory confirmed positive case farms were matched on the date of sample submission with 133 negative control farms. The association between a series of farm-level characteristics and the presence or absence of H9N2 was assessed by univariable analysis. Characteristics associated with H9N2 risk that passed the initial screening were included in a multivariable conditional logistic regression model. Manual and automated approaches were used, which produced similar models. Key risk factors from all approaches included selling of eggs/birds directly to live bird retail stalls, being near case/infected farms, a previous history of infectious bursal disease (IBD) on the farm and having cover on the water storage tanks. The findings of current study are in line with results of many other studies conducted in various countries to identify similar risk factors for AI subtype H9N2 infection. Enhancing protective measures and controlling risks identified in this study could reduce spread of AI subtype H9N2 and other AI viruses between poultry farms in Pakistan