Identification of a residue in hepatitis C virus E2 glycoprotein that determines scavenger receptor BI and CD81 receptor dependency and sensitivity to neutralizing antibodies.

Hepatitis C virus (HCV) infection is dependent on at least three coreceptors: CD81, scavenger receptor BI (SR-BI), and claudin-1. The mechanism of how these molecules coordinate HCV entry is unknown. In this study we demonstrate that a cell culture-adapted JFH-1 mutant, with an amino acid change in E2 at position 451 (G451R), has a reduced dependency on SR-BI. This altered receptor dependency is accompanied by an increased sensitivity to neutralization by soluble CD81 and enhanced binding of recombinant E2 to cell surface-expressed and soluble CD81. Fractionation of HCV by density gradient centrifugation allows the analysis of particle-lipoprotein associations. The cell culture-adapted mutation alters the relationship between particle density and infectivity, with the peak infectivity occurring at higher density than the parental virus. No association was observed between particle density and SR-BI or CD81 coreceptor dependence. JFH-1 G451R is highly sensitive to neutralization by gp-specific antibodies, suggesting increased epitope exposure at the virion surface. Finally, an association was observed between JFH-1 particle density and sensitivity to neutralizing antibodies (NAbs), suggesting that lipoprotein association reduces the sensitivity of particles to NAbs. In summary, mutation of E2 at position 451 alters the relationship between particle density and infectivity, disrupts coreceptor dependence, and increases virion sensitivity to receptor mimics and NAbs. Our data suggest that a balanced interplay between HCV particles, lipoprotein components, and viral receptors allows the evasion of host immune responses

Reducing Uncertainty in PHM by Accounting for Human Factors - A Case Study in the Biopharmaceutical Industry

The ultimate goal of prognostics within Through-life Engineering Services (TES) is to accurately predict the remaining useful life (RUL) of components. Prognostic frameworks inherently presume that there is predictability in the failure rate of the system, i.e. a system experiencing exclusively stochastic failure events cannot, by definition, be predictable. Prediction model uncertainties must be bound in some logical way. Therefore, to achieve an accurate prognostic model, uncertainty must first be reduced through the identification and elimination of the root causes of random failure events. This research investigates human error in maintenance activities as a major cause of random failure events, using a case study from the biopharmaceutical industry. Elastomer failures remain the number one contamination risk in this industry and data shows unexplained variability in the lifetime of real components when compared to accelerated lifetime testing in the lab environment. Technician error during installation and maintenance activities of elastomers is one possible cause for this and this research explores how these errors can be eliminated, reduced, or accounted for within the reliability modeling process. The initial approach followed was to improve technician training in order to reduce errors and thereby reduce the variability of random failure events. Subsequent data has shown an improvement in key metrics with failures now more closely matching data from lab testing. However, there is scope for further improvements and future research will explore the role of performance influencing factors in the maintenance task to identify additional causes of variation. These factors may then be incorporated as a process variable in a prognostics and health management (PHM) model developed for the system. The paper will present these data fusion approaches accounting for human factors as a roadmap to improving PHM model reliability

Neutralizing Antibody-Resistant Hepatitis C Virus Cell-to-Cell Transmission

Hepatitis C virus (HCV) can initiate infection by cell-free particle and cell-cell contact-dependent transmission. In this study we use a novel infectious coculture system to examine these alternative modes of infection. Cell-to-cell transmission is relatively resistant to anti-HCV glycoprotein monoclonal anti- bodies and polyclonal immunoglobulin isolated from infected individuals, providing an effective strategy for escaping host humoral immune responses. Chimeric viruses expressing the structural proteins rep- resenting the seven major HCV genotypes demonstrate neutralizing antibody-resistant cell-to-cell trans- mission. HCV entry is a multistep process involving numerous receptors. In this study we demonstrate that, in contrast to earlier reports, CD81 and the tight-junction components claudin-1 and occludin are all essential for both cell-free and cell-to-cell viral transmission. However, scavenger receptor BI (SR-BI) has a more prominent role in cell-to-cell transmission of the virus, with SR-BI-specific antibodies and small-molecule inhibitors showing preferential inhibition of this infection route. These observations highlight the importance of targeting host cell receptors, in particular SR-BI, to control viral infection and spread in the liver

Neutralizing antibody response during acute and chronic hepatitis C virus infection

Little is known about the role of Abs in determining the outcome of hepatitis C virus (HCV) infection. By using infectious retroviral pseudotypes bearing HCV glycoproteins, we measured neutralizing Ab (nAb) responses during acute and chronic HCV infection. In seven acutely infected health care workers, only two developed a nAb response that failed to associate with viral clearance. In contrast, the majority of chronically infected patients had nAbs. To determine the kinetics of strain-specific and crossreactive nAb emergence, we studied patient H, the source of the prototype genotype 1a H77 HCV strain. An early weak nAb response, specific for the autologous virus, was detected at seroconversion. However, neutralization of heterologous viruses was detected only between 33 and 111 weeks of infection. We also examined the development of nAbs in 10 chimpanzees infected with H77 clonal virus. No nAb responses were detected in three animals that cleared virus, whereas strain-specific nAbs were detected in six of the seven chronically infected animals after approximately 50 weeks of infection. The delayed appearance of high titer crossreactive nAbs in chronically infected patients suggests that selective mechanism(s) may operate to prevent the appearance of these Abs during acute infection. The long-term persistence of these nAbs in chronically infected patients may regulate viral replication

The SPORTSMART study: a pilot randomised controlled trial of sexually transmitted infection screening interventions targeting men in football club settings

Background: Uptake of chlamydia screening by men in England has been substantially lower than by women. Non-traditional settings such as sports clubs offer opportunities to widen access. Involving people who are not medically trained to promote screening could optimise acceptability. Methods: We developed two interventions to explore the acceptability and feasibility of urine-based sexually transmitted infection (STI) screening interventions targeting men in football clubs. We tested these interventions in a pilot cluster randomised control trial. Six clubs were randomly allocated, two to each of three trial arms: team captain-led and poster STI screening promotion; sexual health adviser-led and poster STI screening promotion; and poster-only STI screening promotion (control/comparator). Primary outcome was test uptake. Results: Across the three arms, 153 men participated in the trial and 90 accepted the offer of screening (59%, 95% CI 35% to 79%). Acceptance rates were broadly comparable across the arms: captain-led: 28/56 (50%); health professional-led: 31/46 (67%); and control: 31/51 (61%). However, rates varied appreciably by club, precluding formal comparison of arms. No infections were identified. Process evaluation confirmed that interventions were delivered in a standardised way but the control arm was unintentionally ‘enhanced’ by some team captains actively publicising screening events. Conclusions: Compared with other UK-based community screening models, uptake was high but gaining access to clubs was not always easy. Use of sexual health advisers and team captains to promote screening did not appear to confer additional benefit over a poster-promoted approach. Although the interventions show potential, the broader implications of this strategy for UK male STI screening policy require further investigation

Public art today. How public art sheds light on the future of the theory of commons

Public art and common goods, although belonging to apparently distant realms of inquiry, share a long history and, inevitably, an evolving meaning. This chapter investigates the evolution of the practice of public art with the objective to obtain a viable understanding of how the value of public art is produced today. With a focus on the future of public art, this chapter investigates three public art cases. The results of the qualitative analysis of these public art experiences are interpreted from an institutional economics perspective. The combination of public art and the theory of commons sheds light on what seems to be the most important attributes of common goods in the current debate, that is the social practices that constitute the act of making the commons.</p

What prompts young adults in Ireland to attend health services for STI testing?

<p>Abstract</p> <p>Background</p> <p>In-depth understanding of the factors that prompt young adults to attend health services for sexually transmitted infection (STI) testing are needed to underpin sexual health programes. We conducted a qualitative study to identify and explore why young adults (18–29 years) in Ireland attended specialist and community health services for STI testing; the factors that supported/undermined their decisions to seek STI testing; and any factors that led to delay in seeking STI testing.</p> <p>Methods</p> <p>Semi-structured interviews with 30 adults (21 women, 9 men). Young adults were recruited from General Practice (GP) practices, Third Level College health services, Family Planning clinics and specialist STI treatment services for men who have sex with men (MSM). Interview questions examined why respondents decided to go for STI testing, whether they acted upon this desire immediately or decided to wait, and what they felt were important barriers/enablers to their health-seeking attempts. Interviews were thematically analyzed using standard qualitative techniques.</p> <p>Results</p> <p>Respondents sought STI testing for one of four reasons: they had reached a transitional moment in their lives (they were either about to stop using condoms with their sexual partner or were emerging from a period of their lives where they had a series of risky sexual relationships); they had had unprotected sex with a casual partner; they had symptoms of infection; and/or they were required to do so by their employer. Catalytic factors included media and government health promotion campaigns and knowing someone with an STI. However, many respondents delayed seeking testing. Reasons included respondents' concerns about stigma and that they would be judged by healthcare professionals, and feelings of invulnerability. Importantly, several respondents who waited up to four weeks to make an appointment after their initial decision to seek STI testing did not view this as delay.</p> <p>Conclusion</p> <p>Sexual health promotion campaigns for young people should address the reasons why they delay testing, specifically through measures to avoid stigma (supply-side) and reassure young adults (demand-side). Strategies to increase testing-uptake should focus on these four key opportunities – young adults leaving relationships, those entering relationships where condoms will not be used, those who have had unprotected sex and those with STI-related symptoms.</p