Genotype-specific sensitivity of the hepatitis C virus (HCV) to interferon-ribavirin (IFN-RBV) combination therapy and reduced HCV response to IFN-RBV as infection progresses from acute to chronic infection suggest that HCV genetic factors and intrahost HCV evolution play important roles in therapy outcomes. HCV polyprotein sequences (n ‫؍‬ 40) from 10 patients with unsustainable response (UR) (breakthrough and relapse) and 10 patients with no response (NR) following therapy were identified through the Virahep-C study. Bayesian networks (BNs) were constructed to relate interrelationships among HCV polymorphic sites to UR/NR outcomes. All models showed an extensive interdependence of HCV sites and strong connections (P < 0.003) to therapy response. Although all HCV proteins contributed to the networks, the topological properties of sites differed among proteins. E2 and NS5A together contributed ϳ40% of all sites and ϳ62% of all links to the polyprotein BN. The NS5A BN and E2 BN predicted UR/NR outcomes with 85% and 97.5% accuracy, respectively, in 10-fold cross-validation experiments. The NS5A model constructed using physicochemical properties of only five sites was shown to predict the UR/NR outcomes with 83.3% accuracy for 6 UR and 12 NR cases of the HALT-C study. Thus, HCV adaptation to IFN-RBV is a complex trait encoded in the interrelationships among many sites along the entire HCV polyprotein. E2 and NS5A generate broad epistatic connectivity across the HCV polyprotein and essentially shape intrahost HCV evolution toward the IFN-RBV resistance. Both proteins can be used to accurately predict the outcomes of IFN-RBV therapy.Hepatitis C virus (HCV) is the major etiologic agent of blood-borne non-A, non-B hepatitis (25). Chronic HCV infection is an established risk factor for the development of liver diseases, such as fibrosis, cirrhosis, and hepatocellular carcinoma (33,124,125). Approximately 70% to 80% of HCVinfected patients fail to clear the virus and progress to chronicity (89a). At present, there are no preventive vaccines against HCV. The current, accepted therapeutic approach to treating chronic hepatitis C infection involves a 24-or 48-week course of pegylated alpha interferon (IFN-␣) combined with ribavirin (RBV) (i.e. IFN-RBV therapy) (48, 52). Because only 50% to 70% of chronically infected patients develop a sustained virologic response (SVR) to this treatment (48,52,55,80) and because patient intolerance to such therapy is common (61, 68, 120), the development and application of other therapeutic approaches using antiviral compounds that act against HCV more efficaciously and yet generate lower rates of adverse effects are major clinical management and public health objectives. Therapeutic failure presents in two forms: (i) complete resistance to treatment (no response [NR]) and (ii) unsustainable response (UR), which is characterized by an increase in HCV load observed during therapy after an initial period of decline in viral load (breakthrough) or observed after cessation of therapy (relapse)...

BackgroundPattern of Dengue periodic epidemics through the years along with sporadic cases of Dengue hemorrhagic fever followed by a severe 2011 epidemic of Dengue fever in Pakistan make Pakistan a Dengue endemic country. To study the entry and evolution of dengue virus serotype 2 (DENV-2) in Pakistan, we sequenced three full length genomes and 24 complete envelope sequences of DENV-2 from the years 2010, 2011 and 2013 collected from Punjab province of Pakistan.MethodsPhylogenetic and Bayesian phylogeographic analyses was applied to three full genome sequences as well as 24 envelope sequences to study the spatiotemporal dynamics of DENV-2 in Pakistan.ResultsMost of the DENV-2 viruses from the years 2008 to 2013 formed a monophyletic Pakistani clade in IVb sublineage of cosmopolitan genotype except one 2008 DENV-2 strain. Phylogeographic analysis revealed that this 2008 DENV-2 strain was rooted to India 25.4 years ago with a location probability of 0.88. However Pakistani clade rooted back to Sri Lanka 12.6 years ago with a location probability of 0.57.ConclusionDENV-2 genotype IV was introduced in Pakistan in two time events. First event was introduction from India to Pakistan in the late 1980s (around 1986), and second event was introduction from Sri Lanka to Pakistan around 2000. The later introduction event was responsible for major outbreaks in the Punjab region of Pakistan, including major 2011 outbreak. After the second Introduction event, DENV-2 circulated locally in the region forming a distinct Sublineage within the IVb cosmopolitan genotype of DENV-2.Electronic supplementary materialThe online version of this article (doi:10.1186/s12985-015-0371-8) contains supplementary material, which is available to authorized users.

Mental health nurses frequently draw on self-disclosure practices within their working relationships. These 'confessional' acts can in turn be predicated on traditional assumptions of moral authority exercised by more senior colleagues. More broadly, attention has been drawn to the increasing significance of 'technologies of the self' inside neo-liberal regimes of governance. Through various forms of self-disclosure people are obliged 'to speak the truth about themselves'. By publically declaring themselves as 'fit for purpose' nurses are required to be reflexive, self-monitoring individuals, capable of constructing their own identities and biographies, and guided by expert knowledges. In this way, risk becomes a form of governance, as the individuals continually find themselves balancing risks and opportunities. Foucault's insights into the importance of 'care of the self' and 'surveillance of the self' to systems of social order and governance, such as mental health services, are significant in identifying nursing as a potential form of confessional practice. 'Reflective practice' and 'clinical supervision' are therefore 'technologies', functioning as 'modes of surveillance', and as 'confessional practices'. So 'clinical supervision' may be understood as part of a process of 'governance' that does not necessarily empower nurses, but can act to guide, correct and modify ways in which they conduct themselves.

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