Prevalence of genital human papillomavirus DNA in a sample of senior school-aged women in the Australian Capital Territory

Background: A strong association between persistent infection with oncogenic types of human papillomavirus (HPV) and cervical cancer is well established. Small numbers of international studies examining adolescent HPV infection and the risk factors associated are published, but there is currently no evidence on the prevalence and risk factors for HPV in an Australian, sexually active female adolescent population. Methods: To provide prevalence and risk factors for HPV in a female sexually active, senior high school population in the Australian Capital Territory (ACT), a convenience sample of 161, 16–19-year-old females attending a senior high school was evaluated. The sample formed part of a larger sample recruited for a study of sexually transmitted infections and blood-borne viruses in senior high school students. A clinical record was used to collect information about sexual and other risk behaviours, while self-collected vaginal swabs were tested for HPV DNA detection and genotyping using polymerase chain reaction. Results: The prevalence of HPV DNA in this sample overall was 11.2%, with multiple genotypes in 38%. No statistically significant associations were found between HPV DNA and the number of male partners, age of coitarche, time since first sexually active, condom use, smoking or alcohol intake. Conclusions: This is the first Australian study that has examined the prevalence and risk factors for genital HPV in this demographic group. The prevalence of HPV infection is slightly lower than reported in similar age groups overseas and is lower than other Australian studies in older women and those attending sexual health centres. Of HPV-positive young women, high-risk genotypes were found in over half, with more than one-third of HPV existing as multiple genotypes. Large community-based prevalence studies are needed to guide the development of recommendations for the vaccination of young women against HPV and to support other health promotion initiatives.

Knowledge of human papillomavirus (HPV) and the HPV vaccine in a national sample of Australian men and women

Background: Human papillomavirus (HPV) knowledge has rarely been investigated in the context of a national vaccination program. The present study investigated HPV knowledge after the introduction of a national HPV vaccination program in Australia using a national sample of men and women. Methods: Questions assessing HPV knowledge were part of a broader national study of health and relationships administered via a computer-assisted telephone interview. These findings are from wave four of the study, conducted between 2007 and 2008. Knowledge questions about HPV included its association with cervical cancer, genital warts and abnormal Pap tests. Results: A total of 2634 women and 2556 men between the ages of 18 and 70 were interviewed. Overall, 62.8% (95% confidence interval (CI): 60.8–64.7%) of women and 38.3% (95% CI: 36.3–40.4%) of men had heard of HPV. Of these, 66.0% (95% CI: 64.1–67.9%) correctly answered that HPV is associated with cervical cancer, 50.2% (95% CI: 48.2–52.1%) answered that HPV is associated with abnormal Pap tests and 44.5% (95% CI:42.5–46.5%) answered that HPV causes warts. Predictors of good knowledge included being female, aged between 26 and 45, holding higher education levels and older age at first sex. Ever having a Pap test was also associated with awareness about HPV. Conclusion: One of the highest levels of knowledge about HPV in Australia to date is reported in the present study. Knowledge about the association between HPV and cervical cancer was particularly high, especially when compared with knowledge of the association with genital warts. This appears to be a consequence of the marketing of the HPV vaccine as a vaccination against cervical cancer.

Cost-effectiveness of a bivalent human papillomavirus vaccination program in Japan

Background Human papillomavirus (HPV) vaccines and their widespread adoption have the potential to relieve a large part of the burden of cervical cancer morbidity and mortality, particularly in countries that have low screening rates or, like Japan, lack a cohesive universal screening program. An economic evaluation was conducted to assess the cost-effectiveness of introducing a bivalent HPV vaccination program in Japan from a healthcare perspective. METHODS: A Markov model of the natural history of HPV infection that incorporates both vaccination and screening was developed for Japan. The modelled intervention, a bivalent HPV vaccine with a 100% lifetime vaccine efficacy and 80% vaccine coverage, given to a cohort of 12-year-old Japanese girls in conjunction with the current screening program, was compared with screening alone in terms of costs and effectiveness. A discount rate of 5% was applied to both costs and utilities where relevant. RESULTS: Vaccination alongside screening compared with screening alone is associated with an incremental cost-effectiveness ratio (ICER) of US$20315 per quality-adjusted-life-year gained if 80% coverage is assumed. The ICER at 5% coverage with the vaccine plus screening, compared with screening alone, is US$1158. CONCLUSION: The cost-effectiveness results suggest that the addition of a HPV vaccination program to Japan's cervical cancer screening program is highly likely to prove a cost-effective way to reduce the burden of cervical cancer, precancerous lesions and HPV16/18-related diseases.

Targeting hepatitis B virus and human papillomavirus induced carcinogenesis : novel patented therapeutics

Viral infections leading to carcinogenesis tops the risk factors list for the development of human cancer. The decades of research has provided ample scientific evidence that directly links 10-15% of the worldwide incidence of human cancers to the infections with seven human viruses. Moreover, the insights gained into the molecular pathogenetic and immune mechanisms of hepatitis B virus (HBV) and human papillomavirus (HPV) viral transmission to tumour progression, and the identification of their viral surface antigens as well as oncoproteins have provided the scientific community with opportunities to target these virus infections through the development of prophylactic vaccines and antiviral therapeutics. The preventive vaccination programmes targeting HBV and high risk HPV infections, linked to hepatocellular carcinoma (HCC) and cervical cancer respectively have been recently reported to alter age-old cancer patterns on an international scale. In this review, with an emphasis on HBV and HPV mediated carcinogenesis because of the similarities and differences in their global incidence patterns, viral transmission, mortality, molecular pathogenesis and prevention, we focus on the development of recently identified HBV and HPV targeting innovative strategies resulting in several patents and patent applications.

HPV.edu study protocol: a cluster randomised controlled evaluation of education, decisional support and logistical strategies in school-based human papillomavirus (HPV) vaccination of adolescents

BACKGROUND: The National Human Papillomavirus (HPV) Vaccination Program in Australia commenced in 2007 for females and in 2013 for males, using the quadrivalent HPV vaccine (HPV 6,11,16,18). Thus far, we have demonstrated very substantial reductions in genital warts and in the prevalence of HPV among young Australian women, providing early evidence for the success of this public health initiative. Australia has a long history of school-based vaccination programs for adolescents, with comparatively high coverage. However, it is not clear what factors promote success in a school vaccination program. The HPV.edu study aims to examine: 1) student knowledge about HPV vaccination; 2) psycho-social outcomes and 3) vaccination uptake.

METHODS/DESIGN: HPV.edu is a cluster randomised trial of a complex intervention in schools aiming to recruit 40 schools with year-8 enrolments above 100 students (approximately 4400 students). The schools will be stratified by Government, Catholic, and Independent sectors and geographical location, with up to 20 schools recruited in each of two states, Western Australia (WA) and South Australia (SA), and randomly allocated to intervention or control (usual practice). Intervention schools will receive the complex intervention which includes an adolescent intervention (education and distraction); a decisional support tool for parents and adolescents and logistical strategies (consent form returns strategies, in-school mop-up vaccination and vaccination-day guidelines). Careful process evaluation including an embedded qualitative evaluation will be undertaken to explore in depth possible mechanisms for any observed effect of the intervention on primary and secondary outcomes.

DISCUSSION: This study is the first to evaluate the relative effectiveness of various strategies to promote best practice in school-based vaccination against HPV. The study aims to improve vaccination-related psychosocial outcomes, including adolescent knowledge and attitudes, decision-making involvement, self-efficacy, and to reduce fear and anxiety. The study also aims to improve school vaccination program logistics including reduction in time spent vaccinating adolescents and increased number of consent forms returned (regardless of decision). Less anxiety in adolescents will likely promote more efficient vaccination, which will be more acceptable to teachers, nurses and parents. Through these interventions, it is hoped that vaccination uptake will be increased.

The impact of stigma on couples managing a sexually transmitted infection

Recent research has indicated that the stigma surrounding sexually transmitted infections (STIs) creates a psychological and emotional burden for individuals with these conditions. It would be expected that the stigma of having a STI would also alter the dynamics of an intimate relationship. This paper reviews the literature on the impact of STIs on intimate relationships, and considers the relevance of this research to both clinicians and researchers. In particular, the types of relationships in which the presence of a STI may have a varying degree of impact are examined. Since disclosure of a STI would also be expected to impact on a relationship, an overview of the factors involved in the disclosure of a STI to a partner is also considered. Finally, the implications of this research for both clinicians and researchers are discussed.

Alterations in microRNAs miR-21 and let-7a correlate with aberrant STAT3 signaling and downstream effects during cervical carcinogenesis

BACKGROUND: Present study provides clinical evidence of existence of a functional loop involving miR-21 and let-7a as potential regulators of aberrant STAT3 signaling recently reported by our group in an experimental setup (Shishodia et al. BMC Cancer 2014, 14:996). The study is now extended to a set of cervical tissues that represent natural history of human papillomavirus (HPV)-induced tumorigenic transformation. MATERIALS AND METHODS: Cervical tissues from histopathologically-confirmed pre-cancer (23) and cancer lesions (56) along with the normal control tissues (23) were examined for their HPV infection status, expression level of miR-21 & let-7a and STAT3 & pSTAT3 (Y705) by PCR-based genotyping, quantitative real-time PCR and immunoblotting. RESULTS: Analysis of cancer tissues revealed an elevated miR-21 and reduced let-7a expression that correspond to the level of STAT3 signaling. While miR-21 showed direct association, let-7a expression was inversely related to STAT3 expression and its activation. In contrast, a similar reciprocal expression kinetics was absent in LSIL and HSIL tissues which overexpressed let-7a. miR-21 was found differentially overexpressed in HPV16-positive lesions with a higher oncoprotein E6 level. Overexpression of miR-21 was accompanied by elevated level of other STAT3-regulated gene products MMP-2 and MMP-9. Enhanced miR-21 was found associated with decreased level of STAT3 negative regulator PTEN and negative regulator of MMPs, TIMP-3. CONCLUSION: Overall, our study suggests that the microRNAs, miR-21 and let-7a function as clinically relevant integral components of STAT3 signaling and are responsible for maintaining activated state of STAT3 in HPV-infected cells during cervical carcinogenesis.

Options for change in the Australian cervical cancer screening program in context of HPV detection and vaccination

Introduction:
Cervical cancer screening has been implemented for over a decade in Australia and has significantly reduced the mortality and morbidity of the disease. The emergence of new technologies for cervical cancer, such as the Human Papillomavirus (HPV) vaccine and DNA testing has encouraged debate regarding the effective use of resources in cervical cancer prevention. The present study evaluates the cost-effectiveness, from a health sector perspective, of various screening strategies in the era of these new technologies.

Methods:
A stochastic epidemiological model using a discrete event and continuous algorithm was developed to describe the natural history of cervical cancer. By allowing one member of the cohort into the model at a time, this micro-simulation model encompasses the characteristics of heterogeneity and can track individual life histories. To evaluate the cost-effectiveness of the HPV vaccine a Markov model was built to simulate the effect on the incidence of HPV and subsequent cervical cancer. A number of proposed screening strategies were evaluated with the stochastic model for the application of HPV DNA testing, with changes in the screening interval and target population. Health outcomes were measured by Disability-Adjusted Life-Years (DALYs), adjusted for application within an evaluation setting (i.e. the mortality component of the DALY was adjusted by a disability weight when early mortality due to cervical cancer is avoided). Costs in complying with the Australian updated guidelines were assessed by pathway analysis to estimate the resources associated with cervical cancer and its pre-cancerous lesion treatment. Sensitivity analyses were performed to investigate the key parameters that influenced the cost-effectiveness results.

Results:
Current practice has already brought huge health gain by preventing more than 4,000 deaths and saving more than 86,000 life-years in a cohort of a million women. Any of the alternative screening strategies alter the total amount of health gain by a small margin compared to current practice. The results of incremental analyses of the alternative screening strategies compared to current practice suggest the adoption of the HPV DNA test as a primary screening tool every 3 years commencing at age 18, or the combined pap smear/HPV test every 3 years commencing at age 25, are more costly than current practice but with reasonable ICERs (AUD$1,810 per DALY and AUD$18,600 per DALY respectively). Delaying commencement of Pap test screening to age 25 is less costly than current practice, but involves considerable health loss. The sensitivity analysis shows, however, that the screening test accuracy has a significant impact on these conclusions. Threshold analysis indicates that a sensitivity ranging from 0.80 to 0.86 for the combined test in women younger than 30 is required to produce an acceptable incremental cost-effectiveness ratio.

Conclusions:
The adoption of HPV and combined test with an extended screening interval is more costly but affordable, resulting in reasonable ICERs. They appear good value for money for the Australian health care system, but need more information on test accuracy to make an informed decision. Potential screening policy change under current Australian HPV Vaccination Program is current work in progress. A Markov model is built to simulate the effect on the incidence of HPV and subsequent cervical cancer. Adoption of HPV DNA test as a primary screening tool in the context of HPV vaccination is under evaluation.

First probable Australian cases of human infection with Rickettsia felis (cat-flea typhus)

Human infection with Rickettsia felis has been reported in most parts of the world, and R. felis has recently been confirmed in cat fleas in Western Australia. The clinical presentations of R. typhi and R. felis are similar, and in the past, the incidence of R. felis infection may have been underestimated. We describe the first reported cases of probable human R. felis infection in Australia. Two adults and three children in Victoria contracted a rickettsial disease after exposure to fleas from kittens. Molecular testing of fleas demonstrated the presence of R. felis but not R. typhi.

Inhibition of A/Human/Hubei/3/2005 (H3N2) influenza virus infection by silver nanoparticles in vitro and in vivo

Abstract
Silver nanoparticles (AgNPs) have attracted much attention as antimicrobial agents and have demonstrated efficient inhibitory activity against various viruses, including human immunodeficiency virus, hepatitis B virus, and Tacaribe virus. In this study, we investigated if AgNPs could have antiviral and preventive effects in A/Human/Hubei/3/2005 (H3N2) influenza virus infection. Madin-Darby canine kidney cells infected with AgNP-treated H3N2 influenza virus showed better viability (P,0.05 versus influenza virus control) and no obvious cytopathic effects compared with an influenza virus control group and a group treated with the solvent used for preparation of the AgNPs. Hemagglutination assay indicated that AgNPs could significantly inhibit growth of the influenza virus in Madin-Darby canine kidney cells (P,0.01 versus the influenza virus control). AgNPs significantly reduced cell apoptosis induced by H3N2 influenza virus at three different treatment pathways (P,0.05 versus influenza virus control). H3N2 influenza viruses treated with AgNPs were analyzed by transmission electron microscopy and found to interact with each other, resulting in destruction of morphologic viral structures in a time-dependent manner in a time range of 30 minutes to 2 hours. In addition, intranasal AgNP administration in mice significantly enhanced survival after infection with the H3N2 influenza virus. Mice treated with AgNPs showed lower lung viral titer levels and minor pathologic lesions in lung tissue, and had a marked survival benefit during secondary intranasal passage in vivo. These results provide evidence that AgNPs have beneficial effects in preventing H3N2 influenza virus infection both in vitro and in vivo, and demonstrate that AgNPs can be used as potential therapeutics for inhibiting outbreaks of influenza.

Novel targeting of PEGylated liposomes for codelivery of TGF-β1 siRNA and four antitubercular drugs to human macrophages for the treatment of mycobacterial infection: a quantitative proteomic study

Tuberculosis (TB) is still a major public health issue in developing countries, and its chemotherapy is compromised by poor drug compliance and severe side effects. This study aimed to synthesize and characterize new multimodal PEGylated liposomes encapsulated with clinically commonly used anti-TB drugs with linkage to small interfering RNA (siRNA) against transforming growth factor-β1 (TGF-β1). The novel NP-siRNA liposomes could target THP-1-derived human macrophages that were the host cells of mycobacterium infection. The biological effects of the NP-siRNA liposomes were evaluated on cell cycle distribution, apoptosis, autophagy, and the gene silencing efficiency of TGF-β1 siRNA in human macrophages. We also explored the proteomic responses to the newly synthesized NP-siRNA liposomes using the stable isotope labeling with amino acids in cell culture approach. The results showed that the multifunctional PEGylated liposomes were successfully synthesized and chemically characterized with a mean size of 265.1 nm. The novel NP-siRNA liposomes functionalized with the anti-TB drugs and TGF-β1 siRNA were endocytosed efficiently by human macrophages as visualized by transmission electron microscopy and scanning electron microscopy. Furthermore, the liposomes showed a low cytotoxicity toward human macrophages. There was no significant effect on cell cycle distribution and apoptosis in THP-1-derived macrophages after drug exposure at concentrations ranging from 2.5 to 62.5 μg/mL. Notably, there was a 6.4-fold increase in the autophagy of human macrophages when treated with the NP-siRNA liposomes at 62.5 μg/mL. In addition, the TGF-β1 and nuclear factor-κB expression levels were downregulated by the NP-siRNA liposomes in THP-1-derived macrophages. The Ingenuity Pathway Analysis data showed that there were over 40 signaling pathways involved in the proteomic responses to NP-siRNA liposome exposure in human macrophages, with 160 proteins mapped. The top five canonical signaling pathways were eukaryotic initiation factor 2 signaling, actin cytoskeleton signaling, remodeling of epithelial adherens junctions, epithelial adherens junction signaling, and Rho GDP-dissociation inhibitor signaling pathways. Collectively, the novel synthetic targeting liposomes represent a promising delivery system for anti-TB drugs to human macrophages with good selectivity and minimal cytotoxicity.

Analysis of human breast milk cells: gene expression profiles during pregnancy, lactation, involution, and mastitic infection

The molecular processes underlying human milk production and the effects of mastitic infection are largely unknown because of limitations in obtaining tissue samples. Determination of gene expression in normal lactating women would be a significant step toward understanding why some women display poor lactation outcomes. Here, we demonstrate the utility of RNA obtained directly from human milk cells to detect mammary epithelial cell (MEC)-specific gene expression. Milk cell RNA was collected from five time points (24 h prepartum during the colostrum period, midlactation, two involutions, and during a bout of mastitis) in addition to an involution series comprising three time points. Gene expression profiles were determined by use of human Affymetrix arrays. Milk cells collected during milk production showed that the most highly expressed genes were involved in milk synthesis (e.g., CEL, OLAH, FOLR1, BTN1A1, and ARG2), while milk cells collected during involution showed a significant downregulation of milk synthesis genes and activation of involution associated genes (e.g., STAT3, NF-kB, IRF5, and IRF7). Milk cells collected during mastitic infection revealed regulation of a unique set of genes specific to this disease state, while maintaining regulation of milk synthesis genes. Use of conventional epithelial cell markers was used to determine the population of MECs within each sample. This paper is the first to describe the milk cell transcriptome across the human lactation cycle and during mastitic infection, providing valuable insight into gene expression of the human mammary gland.

A theoretical discussion of the impact of stigma on psychological adjustment to having a sexually transmissible infection

This paper provides a discussion of the utility of stigma theory as a conceptual framework for the interpretation and analysis of the psychological impact of contracting a sexually transmissible infection (STI). Most particularly, it focuses on those viral infections that cannot be medically cured, such as genital herpes and genital human papilloma virus. Recent research in the area of STIs suggests that the stigma associated with these conditions can hinder psychosocial and sexual adjustment post-diagnosis, and provides support for the use of stigma theory as a conceptual framework with which to analyse these experiences. This paper defines the concept of stigma and presents a theoretical overview of the process of stigmatisation. Three dimensions of stigma relevant to the experience of having a STI are then presented: the degree of concealability of the condition including the social consequences of concealing a condition; the origin of the condition; and the degree of peril presented by the condition. An overview of the way in which the presence of a stigmatising condition such as a STI may affect a person’s feelings of self and his/her intimate relationships is then presented. Finally, the implications of stigma theory as a conceptual framework for guiding future research in the area of personal and interpersonal reactions to STIs is discussed.