ORCID Profile
0000-0003-0791-7228
Current Organisation
University of Newcastle Australia
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Publisher: Wiley
Date: 25-03-2019
DOI: 10.5694/MJA2.50117
Abstract: To examine the effectiveness of different strategies for recruiting participants for a large Australian randomised controlled trial (RCT), the Australian Study for the Prevention through Immunisation of Cardiovascular Events (AUSPICE). Men and women aged 55-60 years with at least two cardiovascular risk factors (hypertension, hypercholesterolaemia, overweight/obesity) were recruited for a multicentre placebo-controlled RCT assessing the effectiveness of 23-valent pneumococcal polysaccharide vaccine (23vPPV) for preventing cardiovascular events. Invitations were mailed by the Australian Department of Human Services to people in the Medicare database aged 55-60 years reminders were sent 2 weeks later. Invitees could respond in hard copy or electronically. Direct recruitment was supplemented by asking invitees to extend the invitation to friends and family (snowball s ling) and by Facebook advertising. Proportions of invitees completing screening questionnaire and recruited for participation in the RCT. 21 526 of 154 992 invited people (14%) responded by completing the screening questionnaire, of whom 4725 people were eligible and recruited for the study. Despite the minimal study burden (one questionnaire, one clinic visit), the overall participation rate was 3%, or an estimated 10% of eligible persons. Only 16% of eventual participants had responded within 2 weeks of the initial invitation letter (early responders) early and late responders did not differ in their demographic or medical characteristics. Socio-economic disadvantage did not markedly influence response rates. Facebook advertising and snowball s ling did not increase recruitment. Trial participation rates are low, and multiple concurrent methods are needed to maximise recruitment. Social media strategies may not be successful in older age groups. Australian New Zealand Clinical Trials Registry, ACTRN12615000536561.
Publisher: American Association for Cancer Research (AACR)
Date: 17-08-2022
DOI: 10.1158/2767-9764.CRC-22-0128
Abstract: Drug repurposing offers the opportunity for chemotherapy to be used to reestablish sensitivity to immune checkpoint blockade (ICB) therapy. Here we investigated the clinical and translational aspects of an early phase II study of azacitidine and carboplatin priming for anti-PDL1 immunotherapy (avelumab) in patients with advanced ICB-resistant melanoma. A total of 20 participants with ICB-resistant metastatic melanoma received 2 × 4-week cycles of azacitidine and carboplatin followed by ICB rechallenge with anti-PD-L1 avelumab. The primary objective was overall response rate after priming and ICB rechallenge. Secondary objectives were clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Translational correlation analysis of HLA-A and PD-L1 expression, RNA sequencing, and reduced representation bisulfite sequencing of biopsies at baseline, after priming and after six cycles of avelmuab was performed. The overall response rate (ORR) determined after azacitidine and carboplatin priming was 10% (2/20) with two partial responses (PR). The ORR determined after priming followed by six cycles of avelumab (week 22) was 10%, with 2 of 20 participants achieving immune partial response (iPR). The CBR for azacitidine and carboplatin priming was 65% (13/20) and after priming followed by six cycles of avelumab CBR was 35% (n = 7/20). The median PFS was 18.0 weeks [95% confidence interval (CI): 14.87–21.13 weeks] and the median OS was 47.86 weeks (95% CI: 9.67–86.06 weeks). Translational correlation analysis confirmed HLA-A generally increased after priming with azacitidine and carboplatin, particularly if it was absent at the start of treatment. Average methylation of CpGs across the HLA-A locus was decreased after priming and T cells, in particular CD8+, showed the greatest increase in infiltration. Priming with azacitidine and carboplatin can induce disease stabilization and resensitization to ICB for metastatic melanoma. There are limited treatments for melanoma once resistance to ICB occurs. Chemotherapy induces immune-related responses and may be repurposed to reinstate the response to ICB. This study provides the first evidence that chemotherapy can provide clinical benefit and increase OS for ICB-resistant melanoma.
Publisher: Elsevier BV
Date: 11-2018
DOI: 10.1016/J.VACCINE.2018.10.064
Abstract: The pneumococcal polysaccharide vaccine (PPV) has been associated with reduced risk of cardiovascular events in human observational studies. Animal studies suggest that the phosphorylcholine epitope in the Streptococcus pneumoniae cell wall is structurally similar to oxidized low-density lipoprotein (oxLDL), hence PPV induces the production of antibodies that cross-react with anti-oxLDL and may cause regression of atherosclerotic plaque. We set out to determine the strength of association between PPV administration and reduction in cardiovascular events. A longitudinal, population-based cohort study of older Australians, from the Hunter Community Study, with up to 11 years of follow-up. We included participants aged ≥ 65 years at baseline (2004-2008), without a history of cardiovascular disease (CVD). History of PPV administration at baseline was the main exposure of interest. "Total number of hospital bed-days with CVD primary diagnosis" was one of the main outcomes measured. Models were adjusted for age, diabetes, alcohol intake, and smoking status. Influenza vaccine was the control exposure used and fracture bed-days was the control outcome used, to investigate the potential for residual confounding. 91 of the total 1074 participants (mean age = 72, male = 45%) experienced a CVD event during follow-up. PPV (regardless of influenza vaccine) was associated with a significant reduction in CVD bed-day, (n = 863, incident rate ratio, IRR = 0.65, 95%CI: 0.45-0.94, p = 0.02), but influenza vaccine (regardless of PPV) was not (n = 864, IRR = 0.86, 95%CI: 0.54-1.35, p = 0.51). Furthermore, PPV adjusted for influenza vaccine remained associated with CVD bed-days (IRR = 0.64, 95%CI: 0.43-0.96, p = 0.03) but was not associated with fracture bed-days (IRR = 0.75, 95%CI: 0.28-2.00, p = 0.56). PPV demonstrated a 35% reduction in CVD bed-days. This finding was robust to residual confounding, using a control exposure and a control outcome, eliminating the concern for healthy-user bias. A large double-blinded placebo-controlled RCT is underway to confirm our finding and to explore the proposed mechanism of action (ACTRN12615000536561).
Publisher: Springer Science and Business Media LLC
Date: 17-12-2011
DOI: 10.1007/S11096-011-9594-Y
Abstract: Evidence from pivotal clinical trials conducted more than a decade ago supports the use of antithrombotic therapy, particularly warfarin, for stroke prevention in atrial fibrillation (AF). Despite the wide dissemination of this evidence since that time, there is anecdotal evidence that utilisation of therapy remains suboptimal, especially in the target elderly population, which is reflected in the development of practice tools such as the TAG Clinical Indicator ('Antithrombotics in AF' Indicator 1.6, 2007). Therefore, the objective of this study was to determine the current utilisation of antithrombotic therapy for elderly patients with AF in the local setting, and to compare this utilisation with the results of a prior audit (AUDIT 1), as well as against the recommendations of the TAG Clinical Indicator (TAG IND). A major teaching hospital in Sydney, Australia. A retrospective audit (AUDIT 2) of medical records of hospital inpatients (aged 65 years, with a significant diagnosis of AF), pertaining to admissions over the 12-month period 1st June 2006-31st May 2007, was conducted. Proportion of patients receiving antithrombotic therapy at the point of discharge from hospital. A total of 201 patients (mean age 79.8 ± 7.8 years) were reviewed in AUDIT 2. Most (85%) patients received antithrombotic therapy (vs. 79.2%, AUDIT 1), with "warfarin ± antiplatelets" most frequently (46.3%) used (vs. 34.5%, AUDIT 1), followed by "aspirin ± other antiplatelet" (33.3% AUDIT 2 vs. 43.1% AUDIT 1). Patients aged 80 years were significantly less likely to receive warfarin therapy, compared to those <80 years (40.2% vs. 52.5%, P = 0.01). Of those patients who were deemed 'eligible' for warfarin according to AUDIT 2 (n = 155), only 55.0% of patients were actually prescribed this treatment. Results obtained by AUDIT 2 and TAG IND were overall comparable. Whilst there have been temporal improvements in the overall utilisation of antithrombotic therapy, including warfarin, there are still significant gaps in the translation of evidence from clinical trials to clinical practice. Further sustainable intervention is warranted to help apply treatment recommendations to the target population.
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.ATHEROSCLEROSIS.2022.02.011
Abstract: Observational studies have demonstrated that the pneumococcal polysaccharide vaccine (PPV) is associated with reduced risk of cardiovascular events. This may be mediated through IgM antibodies to OxLDL, which have previously been associated with cardioprotective effects. The Australian Study for the Prevention through Immunisation of Cardiovascular Events (AUSPICE) is a double-blind, randomised controlled trial (RCT) of PPV in preventing ischaemic events. Participants received PPV or placebo once at baseline and are being followed-up for incident fatal and non-fatal myocardial infarction or stroke over 6 years. A subgroup of participants at one centre (Canberra n = 1,001) were evaluated at 1 month and 2 years post immunisation for changes in surrogate markers of atherosclerosis, as pre-specified secondary outcomes: high-sensitive C-reactive protein (CRP), pulse wave velocity (PWV), and carotid intima-media thickness (CIMT). In addition, 100 participants were randomly selected in each of the intervention and control groups for measurement of anti-pneumococcal antibodies (IgG, IgG2, IgM) as well as anti-OxLDL antibodies (IgG and IgM to CuOxLDL, MDA-LDL, and PC-KLH). Concentrations of anti-pneumococcal IgG and IgG2 increased and remained high at 2 years in the PPV group compared to the placebo group, while IgM increased and then declined, but remained detectable, at 2 years. There were statistically significant increases in all anti-OxLDL IgM antibodies at 1 month, which were no longer detectable at 2 years there was no increase in anti-OxLDL IgG antibodies. There were no significant changes in CRP, PWV or CIMT between the treatment groups at the 2-year follow-up. PPV engenders a long-lasting increase in anti-pneumococcal IgG, and to a lesser extent, IgM titres, as well as a transient increase in anti-OxLDL IgM antibodies. However, there were no detectable changes in surrogate markers of atherosclerosis at the 2-year follow-up. Long-term, prospective follow-up of clinical outcomes is continuing to assess if PPV reduces CVD events.
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.AHJ.2016.04.003
Abstract: Research has shown that vaccination with Streptococcus pneumoniae reduced the extent of atherosclerosis in experimental animal models. It is thought that phosphorylcholine lipid antigens in the S. pneumoniae cell wall induce the production of antibodies that cross-react with oxidized low-density lipoprotein, a component of atherosclerotic plaques. These antibodies may bind to and facilitate the regression of the plaques. Available data provide evidence that similar mechanisms also occur in humans, leading to the possibility that pneumococcal vaccination protects against atherosclerosis. A systematic review and meta-analysis, including 8 observational human studies, of adult pneumococcal polysaccharide vaccination for preventing cardiovascular disease in people older than 65 years, showed a 17% reduction in the odds (odds ratio 0.83, 95% CI 0.71-0.97) of having an acute coronary syndrome event. The AUSPICE is a multicenter, randomized, placebo-controlled, double-blind, clinical trial to formally test whether vaccination with the pneumococcal polysaccharide vaccine protects against cardiovascular events (fatal and nonfatal acute coronary syndromes and ischemic strokes). Cardiovascular outcomes will be obtained during 4 to 5 years of follow-up, through health record linkage with state and national administrative data sets. This is the first registered randomized controlled trial (on US, World Health Organization, Australia and New Zealand trial registries) to be conducted to test whether vaccination with the pneumococcal polysaccharide vaccine will reduce cardiovascular events. If successful, vaccination can be readily extended to at-risk groups to reduce the risk of cardiovascular diseases.
Publisher: BMJ
Date: 06-2015
Publisher: Elsevier BV
Date: 03-2021
No related grants have been discovered for Shu Ren.