Doherty Institute - Research Publications
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Enablers and barriers to primary healthcare for Aboriginal and Torres Strait Islander adolescents: study protocol for participatory mixed-methods research that builds on WHO global standards.
INTRODUCTION: One-third of Australia's Aboriginal and Torres Strait Islander population are adolescents. Recent data highlight their health needs are substantial and poorly met by existing services. To design effective models of primary healthcare, we need to understand the enablers and barriers to care for Aboriginal and Torres Strait Islander adolescents, the focus of this study. METHODS AND ANALYSIS: This protocol was codesigned with Apunipima Cape York Health Council that supports the delivery of primary healthcare for 11 communities in Far North Queensland. We framed our study around the WHO global standards for high-quality health services for adolescents, adding an additional standard around culturally safe care. The study is participatory and mixed methods in design and builds on the recommended WHO assessment tools. Formative qualitative research with young people and their communities (exploring concepts in the WHO recommended quantitative surveys) seeks to understand demand-side enablers and barriers to care, as well as preferences for an enhanced response. Supply-side enablers and barriers will be explored through: a retrospective audit of clinic data (to identify current reasons for access and what can be strengthened); an objective assessment of the adolescent friendliness of clinical spaces; anonymous feedback from adolescent clients around quality of care received and what can be improved; and surveys and qualitative interviews with health providers to understand their perspectives and needs to provide enhanced care. This codesigned project has been approved by Apunipima Cape York Health Council and Far North Queensland Human Research Ethics Committee. DISSEMINATION AND IMPLICATIONS: The findings from this project will inform a codesigned accessible and responsive model of primary healthcare for Aboriginal and Torres Strait Islander adolescents.
Real-world application of the Xpert (R) HBV viral load assay on serum and dried blood spots
As we strive towards the WHO goal of elimination of viral hepatitis as a public health threat by 2030, implementation of reliable, accurate diagnostic assays is crucial to identify those at risk of disease progression and those at risk of transmission. Ironically those at greatest risk of chronic hepatitis B are often in resource-poor regions with limited access to testing, collection, storage, and/or transportation of peripheral blood. The Xpert® HBV Viral Load assay provides an easy to use, convenient means of measuring load on GeneXpert platforms. In this study, the Xpert assay is evaluated against four commercially available high-throughput assays for Hepatitis B virus (HBV) loads. In addition application of dried blood spots (DBS) for estimation of viral load is assessed on real-world samples collected from a remote Pacific Island, Kiribati. A total of 107 serum/plasma samples were tested in the Xpert HBV load assay and compared with the Abbott m2000, Alinity m, and Roche Cobas CAP/CTM and 6800. Fifty-three DBS were tested in the Xpert assay and compared with matching serum samples. Overall 82% serum/plasma samples demonstrated good correlation between the Xpert and Roche and Abbott assays, to within 0.5 log10 IU/ml. The greatest discrepancies were seen at the limits of quantification of all assays. About 85.4% DBS gave estimable viral loads to within 1 log10 IU/ml of the serum load. The Xpert HBV viral load assay is recommended for all settings but particularly useful for resource-poor settings. Utility of DBS with the Xpert assay provides a simple means for testing in remote settings.
HBV variants are common in the 'immune-tolerant' phase of chronic hepatitis B
Nucleos(t)ide analogues (NUC) treatment prevents progression of liver fibrosis in subjects with chronic hepatitis B (CHB). However, risk of hepatocellular carcinoma (HCC) persists despite viral suppression. Specific HBV variants have been associated with adverse outcomes, including HCC; however, the frequency of these variants during the seemingly benign immunotolerant (IT) phase is unknown. Next-generation sequencing and detailed virological characterization on a cohort of treatment-naïve IT subjects were performed to determine the frequency of clinically relevant viral variants. Samples from 97 subjects (genotype B/C 55%/45%, median HBV-DNA 8.5 log10 IU/mL, median HBsAg 4.8 log10 IU/mL, median HBeAg 3.6 log10 PEIU/mL) were analysed. Despite subjects being in the IT phase, clinically relevant HBV variants were common at baseline, particularly in the basal core promoter (BCP, overlaps the hepatitis B X (HBx) gene), precore and PreS regions. BCP/HBx variants were independently associated with lower baseline HBeAg, HBsAg and HBV-DNA titres. Precore variants were independently associated with higher baseline ALT. Increased viral diversity was associated with increased age and lower HBV-DNA, HBsAg and HBeAg levels. Low-level (<5%) drug resistance-associated amino acid substitutions in the HBV reverse transcriptase were detected in 9 (9%) subjects at pre-treatment but were not associated with reduced antiviral activity. Future studies should evaluate whether the detection of HBV variant during IT CHB is predictive of progression to immune clearance and poor prognosis, and whether early initiation of antiviral therapy during IT CHB to prevent the selection of HBV variants is clinically beneficial.
Multi-site assessment of rapid, point-of-care antigen testing for the diagnosis of SARS-CoV-2 infection in a low-prevalence setting: A validation and implementation study
Background: In Australia, COVID-19 diagnosis relies on RT-PCR testing which is relatively costly and time-consuming. To date, few studies have assessed the performance and implementation of rapid antigen-based SARS-CoV-2 testing in a setting with a low prevalence of COVID-19 infections, such as Australia. Methods: This study recruited participants presenting for COVID-19 testing at three Melbourne metropolitan hospitals during a period of low COVID-19 prevalence. The Abbott PanBioTM COVID-19 Ag point-of-care test was performed alongside RT-PCR. In addition, participants with COVID-19 notified to the Victorian Government were invited to provide additional swabs to aid validation. Implementation challenges were also documented. Findings: The specificity of the Abbott PanBioTM COVID-19 Ag test was 99.96% (95% CI 99.73 - 100%). Sensitivity amongst participants with RT-PCR-confirmed infection was dependent upon the duration of symptoms reported, ranging from 77.3% (duration 1 to 33 days) to 100% in those within seven days of symptom onset. A range of implementation challenges were identified which may inform future COVID-19 testing strategies in a low prevalence setting. Interpretation: Given the high specificity, antigen-based tests may be most useful in rapidly triaging public health and hospital resources while expediting confirmatory RT-PCR testing. Considering the limitations in test sensitivity and the potential for rapid transmission in susceptible populations, particularly in hospital settings, careful consideration is required for implementation of antigen testing in a low prevalence setting. Funding: This work was funded by the Victorian Department of Health and Human Services. The funder was not involved in data analysis or manuscript preparation.
Effect of aspirin on deaths associated with sepsis in healthy older people (ANTISEPSIS): a randomised, double-blind, placebo-controlled primary prevention trial
(ELSEVIER SCI LTD, 2021-02-01)
BACKGROUND: Sepsis is a serious global health issue and a major cause of death and disability. The availability of a simple, community-based preventive strategy could substantially reduce the burden of sepsis. We aimed to establish whether low-dose aspirin reduced deaths or hospital admissions associated with sepsis in older people. METHODS: ANTISEPSIS was a substudy of ASPREE (a randomised controlled primary prevention trial of low-dose aspirin [100 mg per day] compared with placebo in community dwelling older adults conducted in Australia and the USA), with the Australian cohort included in the ANTISEPSIS substudy. Inclusion criteria were participants aged at least 70 years who did not have major illnesses. Participants were block randomised (1:1) via a centralised web portal and stratified by general practice and age. Participants, investigators, and staff were masked to the intervention. Teams of clinical specialist investigators assessed potential sepsis events to establish if they satisfied the primary endpoint of death associated with sepsis. The analyses were by intention-to-treat with univariate survival analysis methods, the log-rank test, and Cox proportional hazards regression. This study is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000349741. RESULTS: Between March 10, 2010, and Dec 24, 2014, of 20 288 individuals assessed for eligibility, 16 703 participants aged 70 years and older at trial entry were enrolled and followed up for a median of 4·6 years (IQR 3·6-5·6). 8322 (49·8%) participants were assigned to receive aspirin and 8381 (50·2%) to placebo. 203 deaths were considered to be associated with sepsis. Univariate analysis showed similar rates of death associated with sepsis in the two study groups (hazard ratio for aspirin vs placebo 1·08, 95% CI 0·82-1·43; p=0·57). Adverse events were previously reported in the ASPREE trial. INTERPRETATION: Daily low-dose aspirin treatment did not reduce deaths associated with sepsis in community dwelling older adults. Our findings do not support the use of aspirin as a primary prevention strategy to reduce the burden of sepsis in this population. FUNDING: National Health and Medical Research Council of Australia, National Institutes of Health, Monash University.
Buruli ulcer: a new case definition for Victoria
(AUSTRALIAN GOVERNMENT, DEPT HEALTH & AGEING, 2020-12-21)
Abstract: Laboratory-confirmed infection with Mycobacterium ulcerans is currently notifiable to health departments in several jurisdictions. Accurate surveillance is imperative to understanding current and emerging areas of endemicity and to facilitate research into a neglected tropical disease with poorly-understood transmission dynamics. The state of Victoria currently reports some of the highest numbers of M. ulcerans cases in the world each year, with 340 cases notified in 2018 (an incidence of 5.5 per 100,000 population). In May 2019, a group of clinical, laboratory and public health experts met to discuss a new case definition for the surveillance of M. ulcerans disease in Victoria, incorporating clinical and epidemiological elements. The new case definition supports important public health messaging and actions for residents and visitors to popular tourist areas in Victoria.
Multiply spliced HIV RNA is a predictive measure of virus production ex vivo and in vivo following reversal of HIV latency
BACKGROUND: One strategy being pursued to clear latently infected cells that persist in people living with HIV (PLWH) on antiretroviral therapy (ART) is to activate latent HIV infection with a latency reversing agent (LRA). Surrogate markers that accurately measure virus production following an LRA are needed. METHODS: We quantified cell-associated unspliced (US), multiply spliced (MS) and supernatant (SN) HIV RNA by qPCR from total and resting CD4+ T cells isolated from seven PLWH on ART before and after treatment ex vivo with different LRAs, including histone deacetylase inhibitors (HDACi). MS and plasma HIV RNA were also quantified from PLWH on ART (n-11) who received the HDACi panobinostat. FINDINGS: In total and resting CD4+ T cells from PLWH on ART, detection of US RNA was common while detection of MS RNA was infrequent. Primers used to detect MS RNA, in contrast to US RNA, bound sites of the viral genome that are commonly mutated or deleted in PLWH on ART. Following ex vivo stimulation with LRAs, we identified a strong correlation between the fold change increase in SN and MS RNA, but not the fold change increase in SN and US RNA. In PLWH on ART who received panobinostat, MS RNA was significantly higher in samples with detectable compared to non0detectable plasma HIV RNA. INTERPRETATION: Following administration of an LRA, quantification of MS RNA is more likely to reflect an increase in virion production and is therefore a better indicator of meaningful latency reversal. FUNDING: NHMRC, NIH DARE collaboratory.