Doherty Institute - Research Publications
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ItemEvaluation of cardiovascular biomarkers In HIV-infected patients switching to abacavir or tenofovir based therapy(BIOMED CENTRAL LTD, 2011-10-04)BACKGROUND: Our objective was to evaluate and compare the effect of abacavir on levels of biomarkers associated with cardiovascular risk. METHODS: In an open-label randomized trial, HIV-infected patients were randomized 1:1 to switch from zidovudine/lamivudine to abacavir/lamivudine or tenofovir/emtricitabine. In the present analysis, we measured levels of interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), E-selectin, and myeloperoxidase (MPO) at baseline and 4, 12, and 48 weeks after randomization. D-dimer and fasting lipids were measured at baseline and weeks 12 and 48. Levels of biomarkers at all time points and changes from baseline were compared across study arms using Wilcoxon rank sum test. RESULTS: Of 40 included patients, 35 completed 48 weeks of randomized therapy and follow up. Levels of E-selectin (P=0.004) and sVCAM-1 (P=0.041) increased transiently from baseline to week 4 in the abacavir arm compared with the tenofovir arm, but no long-term increases were detected. We found no significant differences between study arms in the levels or changes in the levels of sICAM-1, MPO, d-dimer, IL-6, or hs-CRP. Levels of total cholesterol and high density lipoprotein (HDL) increased in the abacavir arm relative to the tenofovir arm, but no difference was found in total cholesterol/HDL ratio. CONCLUSION: In patients randomized to abacavir-based HIV-treatment transient increases were seen in the plasma levels of E-selectin and sVCAM-1 compared with treatment with tenofovir, but no difference between study arms was found in other biomarkers associated with endothelial dysfunction, inflammation, or coagulation. The clinical significance of these findings is uncertain. TRIAL REGESTRATION: Clinicaltrials.gov identifier: NCT00647244.
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ItemThe variant call format and VCFtools(OXFORD UNIV PRESS, 2011-08-01)SUMMARY: The variant call format (VCF) is a generic format for storing DNA polymorphism data such as SNPs, insertions, deletions and structural variants, together with rich annotations. VCF is usually stored in a compressed manner and can be indexed for fast data retrieval of variants from a range of positions on the reference genome. The format was developed for the 1000 Genomes Project, and has also been adopted by other projects such as UK10K, dbSNP and the NHLBI Exome Project. VCFtools is a software suite that implements various utilities for processing VCF files, including validation, merging, comparing and also provides a general Perl API. AVAILABILITY: http://vcftools.sourceforge.net
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ItemThe Utility of High-Resolution Melting Analysis of SNP Nucleated PCR Amplicons-An MLST Based Staphylococcus aureus Typing Scheme(PUBLIC LIBRARY SCIENCE, 2011-06-22)High resolution melting (HRM) analysis is gaining prominence as a method for discriminating DNA sequence variants. Its advantage is that it is performed in a real-time PCR device, and the PCR amplification and HRM analysis are closed tube, and effectively single step. We have developed an HRM-based method for Staphylococcus aureus genotyping. Eight single nucleotide polymorphisms (SNPs) were derived from the S. aureus multi-locus sequence typing (MLST) database on the basis of maximized Simpson's Index of Diversity. Only G↔A, G↔T, C↔A, C↔T SNPs were considered for inclusion, to facilitate allele discrimination by HRM. In silico experiments revealed that DNA fragments incorporating the SNPs give much higher resolving power than randomly selected fragments. It was shown that the predicted optimum fragment size for HRM analysis was 200 bp, and that other SNPs within the fragments contribute to the resolving power. Six DNA fragments ranging from 83 bp to 219 bp, incorporating the resolution optimized SNPs were designed. HRM analysis of these fragments using 94 diverse S. aureus isolates of known sequence type or clonal complex (CC) revealed that sequence variants are resolved largely in accordance with G+C content. A combination of experimental results and in silico prediction indicates that HRM analysis resolves S. aureus into 268 "melt types" (MelTs), and provides a Simpson's Index of Diversity of 0.978 with respect to MLST. There is a high concordance between HRM analysis and the MLST defined CCs. We have generated a Microsoft Excel key which facilitates data interpretation and translation between MelT and MLST data. The potential of this approach for genotyping other bacterial pathogens was investigated using a computerized approach to estimate the densities of SNPs with unlinked allelic states. The MLST databases for all species tested contained abundant unlinked SNPs, thus suggesting that high resolving power is not dependent upon large numbers of SNPs.
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ItemA Very Early-Branching Staphylococcus aureus Lineage Lacking the Carotenoid Pigment Staphyloxanthin(OXFORD UNIV PRESS, 2011)Here we discuss the evolution of the northern Australian Staphylococcus aureus isolate MSHR1132 genome. MSHR1132 belongs to the divergent clonal complex 75 lineage. The average nucleotide divergence between orthologous genes in MSHR1132 and typical S. aureus is approximately sevenfold greater than the maximum divergence observed in this species to date. MSHR1132 has a small accessory genome, which includes the well-characterized genomic islands, νSAα and νSaβ, suggesting that these elements were acquired well before the expansion of the typical S. aureus population. Other mobile elements show mosaic structure (the prophage ϕSa3) or evidence of recent acquisition from a typical S. aureus lineage (SCCmec, ICE6013 and plasmid pMSHR1132). There are two differences in gene repertoire compared with typical S. aureus that may be significant clues as to the genetic basis underlying the successful emergence of S. aureus as a pathogen. First, MSHR1132 lacks the genes for production of staphyloxanthin, the carotenoid pigment that confers upon S. aureus its characteristic golden color and protects against oxidative stress. The lack of pigment was demonstrated in 126 of 126 CC75 isolates. Second, a mobile clustered regularly interspaced short palindromic repeat (CRISPR) element is inserted into orfX of MSHR1132. Although common in other staphylococcal species, these elements are very rare within S. aureus and may impact accessory genome acquisition. The CRISPR spacer sequences reveal a history of attempted invasion by known S. aureus mobile elements. There is a case for the creation of a new taxon to accommodate this and related isolates.
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ItemAustralian general practitioner chlamydia testing rates among young people(AUSTRALASIAN MED PUBL CO LTD, 2011-03-07)OBJECTIVE: To describe the proportion of 16-29-year-olds tested for chlamydia by Australian general practitioners in a 12-month period. DESIGN AND SETTING: Between October 2007 and September 2008, the national chlamydia testing rate in 16-29-year-olds was calculated by dividing the number of Medicare-reimbursed chlamydia tests by two denominators: (i) Medicare-reimbursed GP consultations; and (ii) estimated resident populations adjusted for the proportion who were sexually active. MAIN OUTCOME MEASURES: GP chlamydia testing rates in 16-29-year-olds per 100 patients attending a GP consultation and per 100 sexually active population, by patient age and sex, state/territory of residence, and remoteness area. RESULTS: Among the estimated Australian population of 16-29-year-olds, 85.6% of females and 64.4% of males had at least one GP consultation in the 12-month period. The national GP chlamydia testing rate per 100 patients was 8.9% (95% CI, 8.88%-8.94%). The national GP chlamydia testing rate per 100 sexually active population was 8.0% (95% CI, 7.92%-7.98%). The rate per 100 sexually active population was higher in females (12.5%) compared with males (3.7%) (P < 0.01); higher in 20-24-year-olds (9.0%) compared with 16-19-year-olds (8.7%) and 25-29-year-olds (6.6%) (P < 0.01); higher in those living in non-metropolitan areas (11.0%) compared with metropolitan areas (8.4%) (P < 0.01); and highest in those living in the Northern Territory (21.4%) compared with other jurisdictions (P < 0.01). CONCLUSIONS: Despite clinical guidelines recommending annual chlamydia testing for sexually active 15-29-year-olds, our analysis showed that a high proportion of young people aged 16-29 years attend a GP each year, but few of the sexually active population in this age group were tested for chlamydia in general practice. Strategies are needed to support GPs to enhance chlamydia testing in young people.
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ItemSources, perceived usefulness and understanding of information disseminated to families who entered home quarantine during the H1N1 pandemic in Victoria, Australia: a cross-sectional study(BMC, 2011-01-04)BACKGROUND: Voluntary home quarantine of cases and close contacts was the main non-pharmaceutical intervention used to limit transmission of pandemic (H1N1) 2009 influenza (pH1N1) in the initial response to the outbreak of the disease in Australia. The effectiveness of voluntary quarantine logically depends on affected families having a clear understanding of what they are being asked to do. Information may come from many sources, including the media, health officials, family and friends, schools, and health professionals. We report the extent to which families who entered home quarantine received and used information on what they were supposed to do. Specifically, we outline their sources of information; the perceived usefulness of each source; and associations between understanding of recommendations and compliance. METHODS: Cross-sectional survey administered via the internet and computer assisted telephone interview to families whose school children were recommended to go into home quarantine because they were diagnosed with H1N1 or were a close contact of a case. The sample included 314 of 1157 potentially eligible households (27% response rate) from 33 schools in metropolitan Melbourne. Adjusting for clustering within schools, we describe self-reported 'understanding of what they were meant to do during the quarantine period'; source of information (e.g. health department) and usefulness of information. Using logistic regression we examine whether compliance with quarantine recommendations was associated with understanding and the type of information source used. RESULTS: Ninety per cent understood what they were meant to do during the quarantine period with levels of understanding higher in households with cases (98%, 95% CI 93%-99% vs 88%, 95% CI 84%-91%, P = 0.006). Over 87% of parents received information about quarantine from the school, 63% from the health department and 44% from the media. 53% of households were fully compliant and there was increased compliance in households that reported that they understood what they were meant to do (Odds Ratio 2.27, 95% CI 1.35-3.80). CONCLUSIONS: It is critical that public health officials work closely with other government departments and media to provide clear, consistent and simple information about what to do during quarantine as high levels of understanding will maximise compliance in the quarantined population.
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ItemDiagnosis and Antiviral Intervention Strategies for Mitigating an Influenza Epidemic(PUBLIC LIBRARY SCIENCE, 2011-02-04)BACKGROUND: Many countries have amassed antiviral stockpiles for pandemic preparedness. Despite extensive trial data and modelling studies, it remains unclear how to make optimal use of antiviral stockpiles within the constraints of healthcare infrastructure. Modelling studies informed recommendations for liberal antiviral distribution in the pandemic phase, primarily to prevent infection, but failed to account for logistical constraints clearly evident during the 2009 H1N1 outbreaks. Here we identify optimal delivery strategies for antiviral interventions accounting for logistical constraints, and so determine how to improve a strategy's impact. METHODS AND FINDINGS: We extend an existing SEIR model to incorporate finite diagnostic and antiviral distribution capacities. We evaluate the impact of using different diagnostic strategies to decide to whom antivirals are delivered. We then determine what additional capacity is required to achieve optimal impact. We identify the importance of sensitive and specific case ascertainment in the early phase of a pandemic response, when the proportion of false-positive presentations may be high. Once a substantial percentage of ILI presentations are caused by the pandemic strain, identification of cases for treatment on syndromic grounds alone results in a greater potential impact than a laboratory-dependent strategy. Our findings reinforce the need for a decentralised system capable of providing timely prophylaxis. CONCLUSIONS: We address specific real-world issues that must be considered in order to improve pandemic preparedness policy in a practical and methodologically sound way. Provision of antivirals on the scale proposed for an effective response is infeasible using traditional public health outbreak management and contact tracing approaches. The results indicate to change the transmission dynamics of an influenza epidemic with an antiviral intervention, a decentralised system is required for contact identification and prophylaxis delivery, utilising a range of existing services and infrastructure in a "whole of society" response.
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ItemGenome-wide association study identifies susceptibility loci for dengue shock syndrome at MICB and PLCE1(NATURE PUBLISHING GROUP, 2011-11)Hypovolemic shock (dengue shock syndrome (DSS)) is the most common life-threatening complication of dengue. We conducted a genome-wide association study of 2,008 pediatric cases treated for DSS and 2,018 controls from Vietnam. Replication of the most significantly associated markers was carried out in an independent Vietnamese sample of 1,737 cases and 2,934 controls. SNPs at two loci showed genome-wide significant association with DSS. We identified a susceptibility locus at MICB (major histocompatibility complex (MHC) class I polypeptide-related sequence B), which was within the broad MHC region on chromosome 6 but outside the class I and class II HLA loci (rs3132468, P(meta) = 4.41 × 10(-11), per-allele odds ratio (OR) = 1.34 (95% confidence interval: 1.23-1.46)). We identified associated variants within PLCE1 (phospholipase C, epsilon 1) on chromosome 10 (rs3765524, P(meta) = 3.08 × 10(-10), per-allele OR = 0.80 (95% confidence interval: 0.75-0.86)). We identify two loci associated with susceptibility to DSS in people with dengue, suggesting possible mechanisms for this severe complication of dengue.
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ItemAbsence of cross-reactive antibodies to influenza A (H1N1) 2009 before and after vaccination with 2009 Southern Hemisphere seasonal trivalent influenza vaccine in children aged 6 months-9 years: a prospective study(WILEY-BLACKWELL PUBLISHING, INC, 2011-01)BACKGROUND: Early outbreaks of the pandemic influenza A (H1N1) 2009 virus predominantly involved young children, who fuelled transmission through spread in homes and schools. Seroprevalence studies conducted on stored serum collections indicated low levels of antibody to the novel strain in this age group, leading many to recommend priority immunisation of paediatric populations. OBJECTIVES: In a prospective study, we sought evidence of cross-reactive antibodies to the pandemic virus in children who were naïve to seasonal influenza vaccines, at baseline and following two doses of the 2009 Southern Hemisphere trivalent influenza vaccine (TIV). PATIENTS/METHODS: Twenty children were recruited, with a median age of 4 years (interquartile range 3-5 years); all received two age appropriate doses of TIV. Paired sera were collected pre- and post-vaccination for the assessment of vaccine immunogenicity, using haemagglutination inhibition and microneutralisation assays against vaccine-related viruses and influenza A (H1N1) 2009. RESULTS: Robust responses to H3N2 were observed regardless of age or pre-vaccination titre, with 100% seroconversion. Fewer seroconverted to the seasonal H1N1 component. Only two children were weakly seropositive (HI titre 40) to the pandemic H1N1 strain at study entry, and none showed evidence of seroconversion by HI assay following TIV administration. CONCLUSIONS: Administration of 2009 Southern Hemisphere TIV did little to elicit cross-reactive antibodies to the pandemic H1N1 virus in children, in keeping with assay results on stored sera from studies of previous seasonal vaccines. Our findings support the recommendations for influenza A (H1N1) 2009 vaccination of children in preparation for the 2010 winter season.
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ItemUnderstanding mortality in the 1918-1919 influenza pandemic in England and Wales(WILEY-BLACKWELL, 2011-03)BACKGROUND: The causes of recurrent waves in the 1918-1919 influenza pandemic are not fully understood. OBJECTIVES: To identify the risk factors for influenza onset, spread and mortality in waves 1, 2 and 3 (summer, autumn and winter) in England and Wales in 1918-1919. METHODS: Influenza mortality rates for 333 population units and putative risk factors were analysed by correlation and by regressions weighted by population size and adjusted for spatial trends. RESULTS: For waves 1 and 3, influenza mortality was higher in younger, northerly and socially disadvantaged populations experiencing higher all-cause mortality in 1911-1914. Influenza mortality was greatest in wave 2, but less dependent on underlying population characteristics. Wave duration was shorter in areas with higher influenza mortality, typically associated with increasing population density. Regression analyses confirmed the importance of geographical factors and pre-pandemic mortality for all three waves. Age effects were complex, with the suggestion that younger populations with greater mortality in wave 1 had lesser mortality in wave 2. CONCLUSIONS: Our findings suggest that socially disadvantaged populations were more vulnerable, that older populations were partially protected by prior immunity in wave 1 and that exposure of (younger) populations in one wave could protect against mortality in the subsequent wave. An increase in viral virulence could explain the greater mortality in wave 2. Further modelling of causal processes will help to explain, in considerable detail, how social and geographical factors, season, pre-existing and acquired immunity and virulence affected viral transmission and pandemic mortality in 1918-1919.