Publications by authors named "Max Moldovan"

37 Publications

Contribution of facility level factors to variation in antibiotic use in long-term care facilities: a national cohort study.

J Antimicrob Chemother 2021 Apr;76(5):1339-1348

University of South Australia, UniSA Allied Health and Human Performance, Adelaide, South Australia, Australia.

Objectives: To examine national variation in systemic antibiotic use in long-term care facilities (LTCFs) and identify facility characteristics associated with antibiotic utilization.

Methods: This retrospective cohort study included 312 375 residents of 2536 Australian LTCFs between 2011 and 2016. LTCFs were categorized as low, medium or high antibiotic use facilities according to tertiles of DDDs of systemic antibiotics dispensed per 1000 resident-days. Multivariable logistic regression estimated the associations between facility characteristics (ownership, size, location, medication quality indicator performance, prevalence of after-hours medical practitioner services) and antibiotic use (low versus high).

Results: LTCFs in the lowest and highest antibiotic use categories received a median of 54.3 (IQR 46.5-60.5) and 106.1 (IQR 95.9-122.3) DDDs/1000 resident-days, respectively. Compared with not-for-profit LTCFs in major cities, government-owned non-metropolitan LTCFs were less likely to experience high antibiotic use [adjusted OR (aOR) 0.47, 95% CI 0.24-0.91]. LTCFs with 69-99 residents were less likely to experience high antibiotic use (aOR 0.69, 95% CI 0.49-0.97) than those with 25-47 residents annually. Greater prevalence of medical practitioner services accessed after-hours was associated with high antibiotic use [aOR 1.10 (per 10% increase in after-hours services), 95% CI 1.01-1.21]. South Australian LTCFs (aOR 2.17, 95% CI 1.38-3.39) were more likely, while Queensland (0.43, 95% CI 0.30-0.62) and Western Australian (aOR 0.34, 95% CI 0.21-0.57) LTCFs were less likely to experience high antibiotic use than New South Wales LTCFs.

Conclusions: Considerable facility level variation in systemic antibiotic use was observed across Australian LTCFs. Identification of facility characteristics associated with antibiotic use provides a basis for targeted stewardship initiatives.
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http://dx.doi.org/10.1093/jac/dkab007DOI Listing
April 2021

Salvage systemic therapy for advanced gastric and oesophago-gastric junction adenocarcinoma.

Cochrane Database Syst Rev 2020 11 19;11:CD012078. Epub 2020 Nov 19.

Medical Oncology, The Queen Elizabeth Hospital and University of Adelaide, Woodville, Adelaide, Australia.

Background: Salvage systemic therapy has become the new standard of care in patients with advanced gastric and oesophago-gastric junction (OGJ) adenocarcinoma, following disease progression on first-line fluoropyrimidine and platinum-containing chemotherapy. Pharmacological agents proven to be effective in this setting include both chemotherapy and biological therapy, however, the consensus on the best salvage systemic therapy has not been reached.

Objectives: To assess the effects of systemic chemotherapy and biological therapy, either alone or in combination, on overall survival (OS) and progression-free survival (PFS) in patients with advanced gastric and OGJ adenocarcinoma, whose disease has progressed on, or relapsed after first-line fluoropyrimidine and platinum-containing chemotherapy. Adverse events (AEs), tumour response rate (TRR) and quality of life (QoL) associated with systemic chemotherapy and/or biological therapy were additionally assessed.

Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, trial registries and proceedings of the major oncology conferences up to October 2020. We additionally handsearched the reference lists of studies. No language restriction was applied.

Selection Criteria: We included randomised controlled trials (RCTs) comparing salvage systemic therapy (chemotherapy and/or biological therapy) and either another type of salvage systemic therapy, placebo, best supportive care (BSC) or no treatment in patients with gastric and OGJ adenocarcinoma refractory to first-line fluoropyrimidine and platinum-containing chemotherapy.

Data Collection And Analysis: Two review authors independently performed selection of eligible studies and the primary author extracted study characteristics and outcome data from included studies. We assessed the quality and risk of bias of eligible studies according to the Cochrane Handbook for Systematic Reviews of Interventions. We expressed pooled estimates of effect using hazard ratio (HR) calculated using an inverse variance random-effects model for time-to-event data, and risk ratio (RR) calculated using Mantel-Haenszel random-effects model for binary data. The certainty of evidence was graded using GRADEpro.

Main Results: We identified 17 RCTs with 5110 participants for inclusion in this review. Tweenty-nine studies are ongoing and twenty studies are awaiting classification. No studies examined the following comparisons: chemotherapy combined with biological therapy versus placebo, BSC or no treatment, chemotherapy combined with biological therapy versus biological therapy, biological therapy versus biological therapy and chemotherapy combined with biological therapy versus chemotherapy combined with biological therapy. Chemotherapy versus placebo, best supportive care or no treatment Chemotherapy probably improves OS (HR = 0.66, 95% CI 0.52 to 0.83, moderate-certainty evidence) based on two studies involving 547 participants and improves PFS (HR = 0.57, 95% CI 0.47 to 0.69, high-certainty evidence) based on one study involving 507 participants over placebo and BSC. Chemotherapy probably increases serious AEs (SAEs) (RR = 1.38, 95% CI 1.20 to 1.59, moderate-certainty evidence) based on one study involving 503 participants. Biological therapy versus placebo, best supportive care or no treatment Biological therapy improves OS (HR = 0.55, 95% CI 0.41 to 0.73, high-certainty evidence) and probably improves PFS (HR = 0.33, 95% CI 0.19 to 0.57, moderate-certainty evidence) over placebo based on three studies involving 781 participants. There is currently insufficient evidence for increased SAEs from biological therapy (RR = 1.14, 95% CI 0.95 to 1.37, low-certainty evidence) based on two studies involving 638 participants. Chemotherapy versus biological therapy This comparison only considered immunotherapy. There is probably no evidence of a difference for OS (HR = 0.82, 95% CI 0.66 to 1.02, moderate-certainty evidence) between chemotherapy and immunotherapy, and immunotherapy probably reduces PFS (HR = 1.27, 95% CI 1.03 to 1.57, moderate-certainty evidence) based on one study involving 395 participants. SAEs may be less frequent with immunotherapy compared to chemotherapy (RR = 0.41, 95% CI 0.30 to 0.57, low-certainty evidence). Chemotherapy combined with biological therapy versus chemotherapy Addition of biological therapy to chemotherapy probably does not improve OS (HR = 0.93, 95% CI 0.83 to 1.04, moderate-certainty evidence) and we are uncertain whether it improves PFS (HR = 0.87, 95% CI 0.74 to 1.02, very low-certainty evidence) based on seven studies involving 2743 participants. We are similarly uncertain whether combined chemotherapy and biological therapy increases SAEs (RR = 1.17, 95% CI 0.95 to 1.44, very low-certainty evidence) based on four studies involving 1618 participants. Chemotherapy versus chemotherapy There is no evidence of a difference for OS and PFS between irinotecan and paclitaxel (HR = 1.13, 95% CI 0.86 to 1.48, low-certainty evidence for OS; HR = 1.14, 95% CI 0.88 to 1.48, low-certainty evidence for PFS) based on one study involving 219 participants. Similarly, there is no evidence to indicate improved OS and PFS from addition of another chemotherapy to docetaxel (HR = 1.05, 95% CI 0.72 to 1.54, low-certainty evidence for OS; HR = 0.75, 95% CI 0.52 to 1.09, low-certainty evidence for PFS) based on two studies involving 121 participants. Grade ≥ 3 neutropenia occurred commonly with both mono- and poly-chemotherapy except for docetaxel-S1 and EOX chemotherapy.

Authors' Conclusions: Survival outcome of patients with advanced gastric and OGJ adenocarcinoma whose disease progressed on first-line fluoropyrimidine and platinum-containing chemotherapy can be improved by chemotherapy and biological therapy. Biological therapy, in particular, achieves this without clear increase in SAEs or QoL impairment. Whether biological therapy is preferred over chemotherapy is still unclear and there is no evidence of a difference for OS outcome, although immunotherapy may be associated with less SAEs. Addition of biological therapy to chemotherapy and poly-chemotherapy are associated with frequent treatment-related toxicity without clear survival benefit.
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http://dx.doi.org/10.1002/14651858.CD012078.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094513PMC
November 2020

Development and validation of a frailty index based on Australian Aged Care Assessment Program data.

Med J Aust 2020 10 9;213(7):321-326. Epub 2020 Aug 9.

Registry of Senior Australians, South Australian Health and Medical Research Institute, Adelaide, SA.

Objectives: To develop and validate a frailty index, derived from aged care eligibility assessment data.

Design: Retrospective cohort study; analysis of the historical national cohort of the Registry of Senior Australians (ROSA).

Participants: 903 996 non-Indigenous Australians aged 65 years or more, living in the community and assessed for subsidised aged care eligibility during 2003-2013.

Main Outcome Measures: 44-item frailty index; summary statistics for frailty index score distribution; predictive validity with respect to mortality and entry into permanent residential aged care during the five years after assessment.

Results: The mean frailty index score during 2003-2013 was 0.20 (SD, 0.07; range, 0-0.41); the proportion of assessed older people with scores exceeding 0.20 increased from 32.1% in 2003-2005 to 75.0% in 2012-2013. The risks of death and entry into permanent residential aged care at one, three and five years increased with frailty index score level (at one year, high [over 0.35] v low scores [under 0.05]: hazard ratio for death, 5.99; 95% CI, 5.69-6.31; for entry into permanent residential aged care, 8.70; 95% CI, 8.32-9.11). The predictive validity (area under the receiver operating characteristic curve) of Cox proportional hazard models including age, sex, and frailty index score was 0.64 (95% CI, 0.63-0.64) for death and 0.63 (95% CI, 0.62-0.63) for entry into permanent residential aged care within one year of assessment.

Conclusions: We used Australian aged care eligibility assessment program data to construct and validate a frailty index. It can be employed in aged care research in Australia, but its application to aged care planning requires further investigation.
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http://dx.doi.org/10.5694/mja2.50720DOI Listing
October 2020

Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis.

Elife 2020 07 20;9. Epub 2020 Jul 20.

University of Adelaide Medical School and Freemasons Foundation Centre for Men's Health, University of Adelaide, Adelaide, Australia.

Fatty acid β-oxidation (FAO) is the main bioenergetic pathway in human prostate cancer (PCa) and a promising novel therapeutic vulnerability. Here we demonstrate therapeutic efficacy of targeting FAO in clinical prostate tumors cultured ex vivo, and identify encoding the rate-limiting enzyme for oxidation of polyunsaturated fatty acids (PUFAs), as robustly overexpressed in PCa tissues and associated with shorter relapse-free survival. is a negatively-regulated androgen receptor (AR) target gene and, therefore, may promote PCa cell survival and resistance to AR targeting therapeutics. DECR1 knockdown selectively inhibited β-oxidation of PUFAs, inhibited proliferation and migration of PCa cells, including treatment resistant lines, and suppressed tumor cell proliferation and metastasis in mouse xenograft models. Mechanistically, targeting of DECR1 caused cellular accumulation of PUFAs, enhanced mitochondrial oxidative stress and lipid peroxidation, and induced ferroptosis. These findings implicate PUFA oxidation via DECR1 as an unexplored facet of FAO that promotes survival of PCa cells.
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http://dx.doi.org/10.7554/eLife.54166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386908PMC
July 2020

Fatty Acid Oxidation Is an Adaptive Survival Pathway Induced in Prostate Tumors by HSP90 Inhibition.

Mol Cancer Res 2020 10 15;18(10):1500-1511. Epub 2020 Jul 15.

Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.

HSP90 is a molecular chaperone required for stabilization and activation of hundreds of client proteins, including many known oncoproteins. AUY922 (luminespib), a new-generation HSP90 inhibitor, exhibits potent preclinical efficacy against several cancer types including prostate cancer. However, clinical use of HSP90 inhibitors for prostate cancer has been limited by toxicity and treatment resistance. Here, we aimed to design an effective combinatorial therapeutic regimen that utilizes subtoxic doses of AUY922, by identifying potential survival pathways induced by AUY922 in clinical prostate tumors. We conducted a proteomic analysis of 30 patient-derived explants (PDE) cultured in the absence and presence of AUY922, using quantitative mass spectrometry. AUY922 significantly increased the abundance of proteins involved in oxidative phosphorylation and fatty acid metabolism in the PDEs. Consistent with these findings, AUY922-treated prostate cancer cell lines exhibited increased mitochondrial mass and activated fatty acid metabolism processes. We hypothesized that activation of fatty acid oxidation is a potential adaptive response to AUY922 treatment and that cotargeting this process will sensitize prostate cancer cells to HSP90 inhibition. Combination treatment of AUY922 with a clinical inhibitor of fatty acid oxidation, perhexiline, synergistically decreased viability of several prostate cancer cell lines, and had significant efficacy in PDEs. The novel drug combination treatment induced cell-cycle arrest and apoptosis, and attenuated the heat shock response, a known mediator of HSP90 treatment resistance. This combination warrants further preclinical and clinical investigation as a novel strategy to overcome resistance to HSP90 inhibition. IMPLICATIONS: Metabolic pathways induced in tumor cells by therapeutic agents may be critical, but targetable, mediators of treatment resistance.
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http://dx.doi.org/10.1158/1541-7786.MCR-20-0570DOI Listing
October 2020

National Trends in Antibiotic Use in Australian Residential Aged Care Facilities, 2005-2016.

Clin Infect Dis 2020 May 27. Epub 2020 May 27.

Registry of Senior Australians, Health Ageing Research Consortium, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.

Background: Understanding current patterns of antibiotic use in residential aged care facilities (RACFs) is essential to inform stewardship activities, but limited utilization data exist. This study examined changes in prevalence and consumption of antibiotics in Australian RACFs between 2005-2006 and 2015-2016.

Methods: This population-based, repeated cross-sectional analysis included all long-term permanent residents of Australian RACFs between July 2005 and June 2016 who were aged ≥ 65 years. The yearly prevalence rate of antibiotic use and number of defined daily doses (DDDs) of systemic antibiotics per 1000 resident-days were determined annually from linked pharmaceutical claims data. Trends were assessed using ordinary least squares regression.

Results: This study included 502 752 residents from 3218 RACFs, with 424.9 million resident-days analyzed. Antibiotics were dispensed on 5 608 126 occasions during the study period, of which 88% were for oral use. Cefalexin, amoxicillin-clavulanic acid, and trimethoprim were the most commonly dispensed antibiotics. The annual prevalence of antibiotic use increased from 63.8% (95% confidence interval [CI], 63.3%-64.4%) to 70.3% (95% CI, 69.9%-70.7%) between 2005-2006 and 2015-2016 (0.8% average annual increase, P < .001). There was a 39% relative increase in total consumption of systemic antibiotics, with utilization increasing from 67.6 to 93.8 DDDs/1000 resident-days during the study period (average annual increase of 2.8 DDDs/1000 resident-days, P < .001).

Conclusions: This nationwide study showed substantial increases in both prevalence of use and total consumption of antibiotics in Australian RACFs between 2005 and 2016. The increasingly widespread use of antibiotics in Australian RACFs is concerning and points to a need for enhanced efforts to optimize antibiotic use in this setting.
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http://dx.doi.org/10.1093/cid/ciaa436DOI Listing
May 2020

Using elastic nets to estimate frailty burden from routinely collected national aged care data.

J Am Med Inform Assoc 2020 03;27(3):419-428

South Australian Health and Medical Research Institute (SAHMRI), Registry of Senior Australians (ROSA), Adelaide, Australia.

Objectives: To (1) use an elastic net (EN) algorithm to derive a frailty measure from a national aged care eligibility assessment program; (2) compare the ability of EN-based and a traditional cumulative deficit (CD) based frailty measures to predict mortality and entry into permanent residential care; (3) assess if the predictive ability can be improved by using weighted frailty measures.

Materials And Methods: A Cox proportional hazard model based EN algorithm was applied to the 2003-2013 cohort of 903 996 participants for selecting items to enter an EN based frailty measure. The out-of-sample predictive accuracy was measured by the area under the curve (AUC) from Cox models fitted to 80% training and validated on 20% testing samples.

Results: The EN approach resulted in a 178-item frailty measure including items excluded from the 44-item CD-based measure. The EN based measure was not statistically significantly different from the CD-based approach in terms of predicting mortality (AUC 0.641, 95% CI: 0.637-0.644 vs AUC 0.637, 95% CI: 0.634-0.641) and permanent care entry (AUC 0.626, 95% CI: 0.624-0.629 vs AUC 0.627, 95% CI: 0.625-0.63). However, the weighted EN based measure statistically outperforms the weighted CD measure for predicting mortality (AUC 0.774, 95% CI: 0.771-0.777 vs AUC 0.757, 95% CI: 0.754-0.760) and permanent care entry (AUC 0.676, 95% CI: 0.673-0.678 vs AUC 0.671, 95% CI: 0.668-0.674).

Conclusions: The weighted EN and CD-based measures demonstrated similar prediction performance. The CD-based measure items are relevant to frailty measurement and easier to interpret. We recommend using the weighted and unweighted CD-based frailty measures.
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http://dx.doi.org/10.1093/jamia/ocz210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647260PMC
March 2020

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.

BMC Cardiovasc Disord 2019 10 29;19(1):240. Epub 2019 Oct 29.

Department Primary Care & Population Health, University College London, London, UK.

Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9.

Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration.

Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable.

Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.
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http://dx.doi.org/10.1186/s12872-019-1187-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820948PMC
October 2019

Changes in the Composition of the Gut Microbiota and the Blood Transcriptome in Preterm Infants at Less than 29 Weeks Gestation Diagnosed with Bronchopulmonary Dysplasia.

mSystems 2019 Oct 29;4(5). Epub 2019 Oct 29.

Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia

Bronchopulmonary dysplasia (BPD) is a common chronic lung condition in preterm infants that results in abnormal lung development and leads to considerable morbidity and mortality, making BPD one of the most common complications of preterm birth. We employed RNA sequencing and 16S rRNA gene sequencing to profile gene expression in blood and the composition of the fecal microbiota in infants born at <29 weeks gestational age and diagnosed with BPD in comparison to those of preterm infants that were not diagnosed with BPD. 16S rRNA gene sequencing, performed longitudinally on 255 fecal samples collected from 50 infants in the first months of life, identified significant differences in the relative levels of abundance of , and in the BPD infants in a manner that was birth mode dependent. Transcriptome sequencing (RNA-Seq) analysis revealed that more than 400 genes were upregulated in infants with BPD. Genes upregulated in BPD infants were significantly enriched for functions related to red blood cell development and oxygen transport, while several immune-related pathways were downregulated. We also identified a gene expression signature consistent with an enrichment of immunosuppressive CD71 early erythroid cells in infants with BPD. Intriguingly, genes that were correlated in their expression with the relative abundances of specific taxa in the microbiota were significantly enriched for roles in the immune system, suggesting that changes in the microbiota might influence immune gene expression systemically. Bronchopulmonary dysplasia (BPD) is a serious inflammatory condition of the lung and is the most common complication associated with preterm birth. A large body of evidence now suggests that the gut microbiota can influence immunity and inflammation systemically; however, the role of the gut microbiota in BPD has not been evaluated to date. Here, we report that there are significant differences in the gut microbiota of infants born at <29 weeks gestation and subsequently diagnosed with BPD, which are particularly pronounced when infants are stratified by birth mode. We also show that erythroid and immune gene expression levels are significantly altered in BPD infants. Interestingly, we identified an association between the composition of the microbiota and immune gene expression in blood in early life. Together, these findings suggest that the composition of the microbiota may influence the risk of developing BPD and, more generally, may shape systemic immune gene expression.
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http://dx.doi.org/10.1128/mSystems.00484-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819732PMC
October 2019

Does long-term use of antidiabetic drugs changes cancer risk?

Medicine (Baltimore) 2019 Oct;98(40):e17461

Department of Public Health and Community Medicine, Shaikh Khalifa Bin Zayed Al-Nahyan Medical College, Shaikh Zayed Medical Complex, Lahore, Pakistan.

Antidiabetic medications are commonly used around the world, but their safety is still unclear. The aim of this study was to investigate whether long-term use of insulin and oral antidiabetic medications is associated with cancer risk.We conducted a well-designed case-control study using 12 years of data from Taiwan's National Health Insurance Research Database and investigated the association between antidiabetic medication use and cancer risk over 20 years. We identified 42,500 patients diagnosed with cancer and calculated each patient's exposure to antidiabetic drugs during the study period. We matched cancer and noncancer subjects matched 1:6 by age, gender, and index date, and used Cox proportional hazard regression and conditional logistic regression, adjusted for potential confounding factors, that is, medications and comorbid diseases that could influence cancer risk during study period.Pioglitazone (adjusted odds ratio [AOR], 1.20; 95% confidence interval [CI], 1.05-1.38); and insulin and its analogs for injection, intermediate or long acting combined with fast acting (AOR, 1.22; 95% CI, 1.05-1.43) were significantly associated with a higher cancer risk. However, metformin (AOR, 1.00; 95% CI, 0.93-1.07), glibenclamide (AOR, 0.98; 95% CI, 0.92-1.05), acarbose (AOR, 1.06; 95% CI, 0.96-1.16), and others do not show evidence of association with cancer risk. Moreover, the risk for specific cancers among antidiabetic users as compared with nonantidiabetic medication users was significantly increased for pancreas cancer (by 45%), liver cancer (by 32%), and lung cancer (by 18%).Antidiabetic drugs do not seem to be associated with an increased cancer risk incidence except for pioglitazone, insulin and its analogs for injection, intermediate or long acting combined with fast acting.
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http://dx.doi.org/10.1097/MD.0000000000017461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783244PMC
October 2019

Transcriptional and metabolic rewiring of colorectal cancer cells expressing the oncogenic KRAS mutation.

Br J Cancer 2019 07 28;121(1):37-50. Epub 2019 May 28.

EMBL Australia Group, South Australian Health and Medical Research Institute, North Terrace, Adelaide, SA, 5000, Australia.

Background: Activating mutations in KRAS frequently occur in colorectal cancer (CRC) patients, leading to resistance to EGFR-targeted therapies.

Methods: To better understand the cellular reprogramming which occurs in mutant KRAS cells, we have undertaken a systems-level analysis of four CRC cell lines which express either wild type (wt) KRAS or the oncogenic KRAS allele (mtKRAS).

Results: RNAseq revealed that genes involved in ribosome biogenesis, mRNA translation and metabolism were significantly upregulated in mtKRAS cells. Consistent with the transcriptional data, protein synthesis and cell proliferation were significantly higher in the mtKRAS cells. Targeted metabolomics analysis also confirmed the metabolic reprogramming in mtKRAS cells. Interestingly, mtKRAS cells were highly transcriptionally responsive to EGFR activation by TGFα stimulation, which was associated with an unexpected downregulation of genes involved in a range of anabolic processes. While TGFα treatment strongly activated protein synthesis in wtKRAS cells, protein synthesis was not activated above basal levels in the TGFα-treated mtKRAS cells. This was likely due to the defective activation of the mTORC1 and other pathways by TGFα in mtKRAS cells, which was associated with impaired activation of PKB signalling and a transient induction of AMPK signalling.

Conclusions: We have found that mtKRAS cells are substantially rewired at the transcriptional, translational and metabolic levels and that this rewiring may reveal new vulnerabilities in oncogenic KRAS CRC cells that could be exploited in future.
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http://dx.doi.org/10.1038/s41416-019-0477-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738113PMC
July 2019

Identification of Novel Response and Predictive Biomarkers to Hsp90 Inhibitors Through Proteomic Profiling of Patient-derived Prostate Tumor Explants.

Mol Cell Proteomics 2018 08 9;17(8):1470-1486. Epub 2018 Apr 9.

¶Adelaide Medical School and Freemasons Foundation Centre for Men's Health, University of Adelaide, Adelaide, South Australia 5005, Australia.

Inhibition of the heat shock protein 90 (Hsp90) chaperone is a promising therapeutic strategy to target expression of the androgen receptor (AR) and other oncogenic drivers in prostate cancer cells. However, identification of clinically-relevant responses and predictive biomarkers is essential to maximize efficacy and treatment personalization. Here, we combined mass spectrometry (MS)-based proteomic analyses with a unique patient-derived explant (PDE) model that retains the complex microenvironment of primary prostate tumors. Independent discovery and validation cohorts of PDEs ( = 16 and 30, respectively) were cultured in the absence or presence of Hsp90 inhibitors AUY922 or 17-AAG. PDEs were analyzed by LC-MS/MS with a hyper-reaction monitoring data independent acquisition (HRM-DIA) workflow, and differentially expressed proteins identified using repeated measure analysis of variance (ANOVA; raw value <0.01). Using gene set enrichment, we found striking conservation of the most significantly AUY922-altered gene pathways between the discovery and validation cohorts, indicating that our experimental and analysis workflows were robust. Eight proteins were selectively altered across both cohorts by the most potent inhibitor, AUY922, including TIMP1, SERPINA3 and CYP51A (adjusted < 0.01). The AUY922-mediated decrease in secretory TIMP1 was validated by ELISA of the PDE culture medium. We next exploited the heterogeneous response of PDEs to 17-AAG in order to detect predictive biomarkers of response and identified PCBP3 as a marker with increased expression in PDEs that had no response or increased in proliferation. Also, 17-AAG treatment led to increased expression of DNAJA1 in PDEs that exhibited a cytostatic response, revealing potential drug resistance mechanisms. This selective regulation of DNAJA1 was validated by Western blot analysis. Our study establishes "proof-of-principle" that proteomic profiling of drug-treated PDEs represents an effective and clinically-relevant strategy for identification of biomarkers that associate with certain tumor-specific responses.
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http://dx.doi.org/10.1074/mcp.RA118.000633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072547PMC
August 2018

Frailty index from routine laboratory measurements correlates with leukocyte telomere length.

Geriatr Gerontol Int 2018 Apr;18(4):654-655

South Australian Health and Medical Research Institute, Adelaide, South Australia.

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http://dx.doi.org/10.1111/ggi.13257DOI Listing
April 2018

Dysregulated fibronectin trafficking by Hsp90 inhibition restricts prostate cancer cell invasion.

Sci Rep 2018 02 1;8(1):2090. Epub 2018 Feb 1.

Adelaide Medical School and Freemasons Foundation Centre for Men's Health, University of Adelaide, Adelaide, SA, 5000, Australia.

The molecular chaperone Hsp90 is overexpressed in prostate cancer (PCa) and is responsible for the folding, stabilization and maturation of multiple oncoproteins, which are implicated in PCa progression. Compared to first-in-class Hsp90 inhibitors such as 17-allylamino-demethoxygeldanamycin (17-AAG) that were clinically ineffective, second generation inhibitor AUY922 has greater solubility and efficacy. Here, transcriptomic and proteomic analyses of patient-derived PCa explants identified cytoskeletal organization as highly enriched with AUY922 treatment. Validation in PCa cell lines revealed that AUY922 caused marked alterations to cell morphology, and suppressed cell motility and invasion compared to vehicle or 17-AAG, concomitant with dysregulation of key extracellular matrix proteins such as fibronectin (FN1). Interestingly, while the expression of FN1 was increased by AUY922, FN1 secretion was significantly decreased. This resulted in cytosolic accumulation of FN1 protein within late endosomes, suggesting that AUY922 disrupts vesicular secretory trafficking pathways. Depletion of FN1 by siRNA knockdown markedly reduced the invasive capacity of PCa cells, phenocopying AUY922. These results highlight a novel mechanism of action for AUY922 beyond its established effects on cellular mitosis and survival and, furthermore, identifies extracellular matrix cargo delivery as a potential therapeutic target for the treatment of aggressive PCa.
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http://dx.doi.org/10.1038/s41598-018-19871-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794796PMC
February 2018

Benzodiazepines use and breast cancer risk: A population-based study and gene expression profiling evidence.

J Biomed Inform 2017 10 26;74:85-91. Epub 2017 Aug 26.

International Center for Health Information Technology (ICHIT), Taipei Medical University, Taipei, Taiwan; Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taiwan; Department of Dermatology, Wan-Fang Hospital, Taipei, Taiwan. Electronic address:

The aim of this study was to investigate whether long-term use of Benzodiazepines (BZDs) is associated with breast cancer risk through the combination of population-based observational and gene expression profiling evidence. We conducted a population-based case-control study by using 1998 to 2009year Taiwan National Health Insurance Research Database and investigated the association between BZDs use and breast cancer risk. We selected subjects age of >20years old and six eligible controls matched for age, sex and the index date (i.e., free of any cancer at the case diagnosis date) by using propensity scores. A bioinformatics analysis approach was also performed for the identification of oncogenesis effects of BZDs on breast cancer. We used breast cancer gene expression data from the Cancer Genome Atlas and perturbagen signatures of BZDs from the Library of Integrated Cellular Signatures database in order to identify the oncogenesis effects of BZDs on breast cancer. We found evidence of increased breast cancer risk for diazepam (OR, 1.16; 95%CI, 0.95-1.42; connectivity score [CS], 0.3016), zolpidem (OR, 1.11; 95%CI, 0.95-1.30; CS, 0.2738), but not for lorazepam (OR, 1.04; 95%CI, 0.89-1.23; CS, -0.2952) consistently in both methods. The finding for alparazolam was contradictory from the two methods. Diazepam and zolpidem trends showed association, although not statistically significant, with breast cancer risk in both epidemiological and bioinformatics analyses outcomes. The methodological value of our study is in introducing the way of combining epidemiological and bioinformatics approaches in order to answer a common scientific question. Combining the two approaches would be a substantial step towards uncovering, validation and further application of previously unknown scientific knowledge to the emerging field of precision medicine informatics.
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http://dx.doi.org/10.1016/j.jbi.2017.08.008DOI Listing
October 2017

Causal Associations of Adiposity and Body Fat Distribution With Coronary Heart Disease, Stroke Subtypes, and Type 2 Diabetes Mellitus: A Mendelian Randomization Analysis.

Circulation 2017 Jun 12;135(24):2373-2388. Epub 2017 May 12.

From Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, United Kingdom (C.E.D., G.F., D.P.-M., A.D.H., J.P.C.); Department of Mathematics and Statistics, Lancaster University, United Kingdom (T.M.P.); UCLGenetics Institute, University College London, United Kingdom (J.W.); Applied Statistical Methods in Medical Research Group, Universidad Catolica de San Antonio de Murcia, Spain (D.P.-M.); Social Genetic & Developmental Psychiatry, King's College London, United Kingdom (D.Z.); Institute of Cardiovascular Science, University College London, United Kingdom (J.E.L.E., T.S., A.D.H., S.E.H.); MRC Unit for Lifelong Health & Ageing at UCL, London, United Kingdom (A.W., D.K.); Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (H.R.W., M.J.C., P.B.M.); NIHR Barts Cardiovascular Biomedical Research Unit, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom (H.R.W., M.J.C., P.B.M.); Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, United Kingdom (S.M., J.F.P.); Department of Cardiology, Leiden University Medical Center, The Netherlands (S.T., W.J.); South Australian Health and Medical Research Institute, Adelaide (M.M., E.H.); EMBL Australia, Adelaide (M.M.); School of Social and Community Medicine, University of Bristol, United Kingdom (R.W.M., T.R.G., Y.B.-S., D.A.L., G.D.S.); Centre for Clinical Pharmacology, University College London, United Kingdom (R.S.); Institute for Social and Economic Research, University of Essex, Colchester, United Kingdom (M.K.); Centre for Population Health Research, School of Health Sciences and Sansom Institute, University of South Australia, Adelaide (E.H., A.Z.); Population, Policy & Practice, UCL Great Ormond Street Institute of Child Health, London, United Kingdom (E.H., C.P.); Department of Primary Care & Population Health, University College London, Royal Free Campus, United Kingdom (B.J.J.); MRC Integrative Epidemiology Unit, University of Bristol, United Kingdom (T.R.G., D.A.L., G.D.S.); Department of Women's Cancer, Institute for Women's Health, UCL, London, United Kingdom (A.G.-M., A.R., U.M.); Department of Clinical Epidemiology, Leiden University Medical Center, The Netherlands (R.d.M., D.O.M.-K.); Department of Internal Medicine, Section Gerontology and Geriatrics, Leiden University Medical Center, The Netherlands (R.N., S.T.); Interuniversity Cardiology Institute Netherlands, Utrecht (W.J.); Departments of Neurology and Public Health Sciences, University of Virginia, Charlottesville (B.B.W.); Department of Public Health and Primary Care, Leiden University Medical Center, The Netherlands (D.O.M.-K.); BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, United Kingdom (N.S.); Department of Epidemiology and Public Health, University College London, United Kingdom (M.K.); Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, United Kingdom (F.D.); Department of Health Sciences, University of Leicester, United Kingdom (F.D.); Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Population Health, Big Data Institute Building, University of Oxford, United Kingdom (M.V.H.); Medical Research Council Population Health Research Unit at the University of Oxford, United Kingdom (M.V.H.); and National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals, United Kingdom (M.V.H.).

Background: The implications of different adiposity measures on cardiovascular disease etiology remain unclear. In this article, we quantify and contrast causal associations of central adiposity (waist-to-hip ratio adjusted for body mass index [WHRadjBMI]) and general adiposity (body mass index [BMI]) with cardiometabolic disease.

Methods: Ninety-seven independent single-nucleotide polymorphisms for BMI and 49 single-nucleotide polymorphisms for WHRadjBMI were used to conduct Mendelian randomization analyses in 14 prospective studies supplemented with coronary heart disease (CHD) data from CARDIoGRAMplusC4D (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics; combined total 66 842 cases), stroke from METASTROKE (12 389 ischemic stroke cases), type 2 diabetes mellitus from DIAGRAM (Diabetes Genetics Replication and Meta-analysis; 34 840 cases), and lipids from GLGC (Global Lipids Genetic Consortium; 213 500 participants) consortia. Primary outcomes were CHD, type 2 diabetes mellitus, and major stroke subtypes; secondary analyses included 18 cardiometabolic traits.

Results: Each one standard deviation (SD) higher WHRadjBMI (1 SD≈0.08 U) associated with a 48% excess risk of CHD (odds ratio [OR] for CHD, 1.48; 95% confidence interval [CI], 1.28-1.71), similar to findings for BMI (1 SD≈4.6 kg/m; OR for CHD, 1.36; 95% CI, 1.22-1.52). Only WHRadjBMI increased risk of ischemic stroke (OR, 1.32; 95% CI, 1.03-1.70). For type 2 diabetes mellitus, both measures had large effects: OR, 1.82 (95% CI, 1.38-2.42) and OR, 1.98 (95% CI, 1.41-2.78) per 1 SD higher WHRadjBMI and BMI, respectively. Both WHRadjBMI and BMI were associated with higher left ventricular hypertrophy, glycemic traits, interleukin 6, and circulating lipids. WHRadjBMI was also associated with higher carotid intima-media thickness (39%; 95% CI, 9%-77% per 1 SD).

Conclusions: Both general and central adiposity have causal effects on CHD and type 2 diabetes mellitus. Central adiposity may have a stronger effect on stroke risk. Future estimates of the burden of adiposity on health should include measures of central and general adiposity.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.116.026560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515354PMC
June 2017

PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study.

Lancet Diabetes Endocrinol 2017 02 29;5(2):97-105. Epub 2016 Nov 29.

Centre for Population Health Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.

Background: Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk.

Methods: In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores.

Findings: Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m, -0·09 to 0·30).

Interpretation: PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins.

Funding: British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.
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http://dx.doi.org/10.1016/S2213-8587(16)30396-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266795PMC
February 2017

Serum 25-Hydroxyvitamin D Status and Longitudinal Changes in Weight and Waist Circumference: Influence of Genetic Predisposition to Adiposity.

PLoS One 2016 14;11(4):e0153611. Epub 2016 Apr 14.

Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospitals, the Capital Region, Copenhagen, Denmark.

Studies of the relationship between serum 25-hydroxyvitamin D (25(OH)D) and changes in measures of adiposity have shown inconsistent results, and interaction with genetic predisposition to obesity has rarely been examined. We examined whether 25(OH)D was associated with subsequent annual changes in body weight (ΔBW) or waist circumference (ΔWC), and whether the associations were modified by genetic predisposition to a high BMI, WC or waist-hip ratio adjusted for BMI (WHRBMI). The study was based on 10,898 individuals from the Danish Inter99, the 1958 British Birth Cohort and the Northern Finland Birth Cohort 1966. We combined 42 adiposity-associated Single Nucleotide Polymorphisms (SNPs) into four scores indicating genetic predisposition to BMI, WC and WHRBMI, or all three traits combined. Linear regression was used to examine the association between serum 25(OH)D and ΔBW or ΔWC, SNP-score × 25(OH)D interactions were examined, and results from the individual cohorts were meta-analyzed. In the meta-analyses, we found no evidence of an association between 25(OH)D and ΔBW (-9.4 gram/y per 10 nmol/L higher 25(OH)D [95% CI: -23.0, +4.3; P = 0.18]) or ΔWC (-0.06 mm/y per 10 nmol/L higher 25(OH)D [95% CI: -0.17, +0.06; P = 0.33]). Furthermore, we found no statistically significant interactions between the four SNP-scores and 25(OH)D in relation to ΔBW or ΔWC. Thus, in view of the narrow CIs, our results suggest that an association between 25(OH)D and changes in measures of adiposity is absent or marginal. Similarly, the study provided evidence that there is either no or very limited dependence on genetic predisposition to adiposity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0153611PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831693PMC
September 2016

Profiling phenome-wide associations: a population-based observational study.

J Am Med Inform Assoc 2015 Jul 5;22(4):896-9. Epub 2015 Feb 5.

Graduate Institute of Biomedical Informatics, College of Medicine Science and Technology; Department of Dermatology, Wan Fang Hospital, Taiwan. Taipei Medical University, Taipei, Taiwan

Objectives: To objectively characterize phenome-wide associations observed in the entire Taiwanese population and represent them in a meaningful, interpretable way.

Study Design: In this population-based observational study, we analyzed 782 million outpatient visits and 15 394 unique phenotypes that were observed in the entire Taiwanese population of over 22 million individuals. Our data was obtained from Taiwan's National Health Insurance Research Database.Results We stratified the population into 20 gender-age groups and generated 28.8 million and 31.8 million pairwise odds ratios from male and female subpopulations, respectively. These associations can be accessed online at http://associations.phr.tmu.edu.tw. To demonstrate the database and validate the association estimates obtained, we used correlation analysis to analyze 100 phenotypes that were observed to have the strongest positive association estimates with respect to essential hypertension. The results indicated that association patterns tended to have a strong positive correlation between adjacent age groups, while correlation estimates tended to decline as groups became more distant in age, and they diverged when assessed across gender groups.

Conclusions: The correlation analysis of pairwise disease association patterns across different age and gender groups led to outcomes that were broadly predicted before the analysis, thus confirming the validity of the information contained in the presented database. More diverse individual disease-specific analyses would lead to a better understanding of phenome-wide associations and empower physicians to provide personalized care in terms of predicting, preventing, or initiating an early management of concomitant diseases.
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http://dx.doi.org/10.1093/jamia/ocu019DOI Listing
July 2015

Death of siblings in childhood and subsequent mortality: prospective observational study.

Eur J Epidemiol 2014 Nov 30;29(11):859-61. Epub 2014 Oct 30.

MRC Integrative Epidemiology Unit (IEU), School of Social and Community Medicine, University of Bristol, Bristol, BS8 2PR, UK,

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http://dx.doi.org/10.1007/s10654-014-9962-8DOI Listing
November 2014

Identification of shared genes and pathways: a comparative study of multiple sclerosis susceptibility, severity and response to interferon beta treatment.

PLoS One 2013 28;8(2):e57655. Epub 2013 Feb 28.

School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.

Recent genome-wide association studies (GWAS) have successfully identified several gene loci associated with multiple sclerosis (MS) susceptibility, severity or interferon-beta (IFN-ß) response. However, due to the nature of these studies, the functional relevance of these loci is not yet fully understood. We have utilized a systems biology based approach to explore the genetic interactomes of these MS related traits. We hypothesised that genes and pathways associated with the 3 MS related phenotypes might interact collectively to influence the heterogeneity and unpredictable clinical outcomes observed. Individual genetic interactomes for each trait were constructed and compared, followed by prioritization of common interactors based on their frequencies. Pathway enrichment analyses were performed to highlight shared functional pathways. Biologically relevant genes ABL1, GRB2, INPP5D, KIF1B, PIK3R1, PLCG1, PRKCD, SRC, TUBA1A and TUBA4A were identified as common to all 3 MS phenotypes. We observed that the highest number of first degree interactors were shared between MS susceptibility and MS severity (p = 1.34×10(-79)) with UBC as the most prominent first degree interactor for this phenotype pair from the prioritisation analysis. As expected, pairwise comparisons showed that MS susceptibility and severity interactomes shared the highest number of pathways. Pathways from signalling molecules and interaction, and signal transduction categories were found to be highest shared pathways between 3 phenotypes. Finally, FYN was the most common first degree interactor in the MS drugs-gene network. By applying the systems biology based approach, additional significant information can be extracted from GWAS. Results of our interactome analyses are complementary to what is already known in the literature and also highlight some novel interactions which await further experimental validation. Overall, this study illustrates the potential of using a systems biology based approach in an attempt to unravel the biological significance of gene loci identified in large GWAS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057655PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585216PMC
August 2013

Profiling health-care accreditation organizations: an international survey.

Int J Qual Health Care 2013 Jul 13;25(3):222-31. Epub 2013 Feb 13.

Centre for Clinical Governance Research, Faculty of Medicine, University of New South Wales, 2052 Sydney, New South Wales,

Objective: To describe global patterns among health-care accreditation organizations (AOs) and to identify determinants of sustainability and opportunities for improvement.

Design: Web-based questionnaire survey.

Participants: Organizations offering accreditation services nationally or internationally to health-care provider institutions or networks at primary, secondary or tertiary level in 2010.

Main Outcome Measure: s) External relationships, scope and activity public information.

Results: Forty-four AOs submitted data, compared with 33 in a survey 10 years earlier. Of the 30 AOs that reported survey activity in 2000 and 2010, 16 are still active and stable or growing. New and old programmes are increasingly linked to public funding and regulation.

Conclusions: While the number of health-care AOs continues to grow, many fail to thrive. Successful organizations tend to complement mechanisms of regulation, health-care funding or governmental commitment to quality and health-care improvement that offer a supportive environment. Principal challenges include unstable business (e.g. limited market, low uptake) and unstable politics. Many organizations make only limited information available to patients and the public about standards, procedures or results.
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http://dx.doi.org/10.1093/intqhc/mzt011DOI Listing
July 2013

Economic evaluation of Australian acute care accreditation (ACCREDIT-CBA (Acute)): study protocol for a mixed-method research project.

BMJ Open 2013 8;3(2). Epub 2013 Feb 8.

Centre for Clinical Governance Research, Australian Institute of Health Innovation, University of New South Wales, Sydney, New South Wales, Australia.

Introduction: The Accreditation Collaborative for the Conduct of Research, Evaluation and Designated Investigations through Teamwork-Cost-Benefit Analysis (ACCREDIT-CBA (Acute)) study is designed to determine and make explicit the costs and benefits of Australian acute care accreditation and to determine the effectiveness of acute care accreditation in improving patient safety and quality of care. The cost-benefit analysis framework will be provided in the form of an interactive model for industry partners, health regulators and policy makers, accreditation agencies and acute care service providers.

Methods And Design: The study will use a mixed-method approach to identify, quantify and monetise the costs and benefits of accreditation. Surveys, expert panels, focus groups, interviews and primary and secondary data analysis will be used in cross-sectional and case study designs.

Ethics And Dissemination: The University of New South Wales Human Research Ethics Committee has approved this project (approval number HREC 10274). The results of the study will be reported via peer-reviewed publications, conferences and seminar resentations and will form part of a doctoral thesis.
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http://dx.doi.org/10.1136/bmjopen-2012-002381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586127PMC
February 2013

Comparison of health service accreditation programs in low- and middle-income countries with those in higher income countries: a cross-sectional study.

Int J Qual Health Care 2012 Dec 30;24(6):568-77. Epub 2012 Oct 30.

Faculty of Medicine, Centre for Clinical Governance Research, University of New South Wales, Sydney, NSW 2052, Australia.

Objective: The study aim was twofold: to investigate and describe the organizational attributes of accreditation programmes in low- and middle-income countries (LMICs) to determine how or to what extent these differ from those in higher-income countries (HICs) and to identify contextual factors that sustain or are barriers to their survival.

Design: Web-based questionnaire survey.

Participants: National healthcare accreditation providers and those offering international services. In total, 44 accreditation agencies completed the survey.

Main Outcome Measure(s): Income distinctions, accreditation programme features, organizational attributes and cross-national divergence.

Results: Accreditation programmes of LMICs exhibit similar characteristics to those of HICs. The consistent model of accreditation worldwide, centres on promoting improvements, applying standards and providing feedback. Where they do differ, the divergence is over specialized features rather than the general logic. LMICs were less likely than HICs to include an evaluation component to programmes, more likely to have certification processes for trainee surveyors and more likely to make decisions on the accreditation status based on a formulaic, mathematically oriented approach. Accreditation programme sustainability, irrespective of country characteristics, is influenced by ongoing policy support from government, a sufficient large healthcare market size, stable programme funding, diverse incentives to encourage participation in accreditation by Health Care Organizations as well as the continual refinement and improvement in accreditation agency operations and programme delivery.

Conclusions: Understanding the similarities, differences and factors that sustain accreditation programmes in LMICs, and HICs, can be applied to benefit programmes around the world. A flourishing accreditation programme is one element of the institutional basis for high-quality health care.
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http://dx.doi.org/10.1093/intqhc/mzs064DOI Listing
December 2012

A multimethod research investigation of consumer involvement in Australian health service accreditation programmes: the ACCREDIT-SCI study protocol.

BMJ Open 2012 10;2(5). Epub 2012 Oct 10.

Centre for Clinical Governance Research, Australian Institute of Health Innovation, University of New South Wales, Sydney, New South Wales, Australia.

Introduction: Health service accreditation programmes are a regulatory mechanism adopted to drive improvements inpatient safety and quality. Research investigating the benefits or limitations, of consumer involvement in accreditation programmes is negligible. To develop our knowledge in this area the ACCREDIT collaboration (Accreditation Collaborative for the Conduct of Research, Evaluation and Designated Investigations through Teamwork) has developed a research plan, known as the ACCREDIT-SCI (Standards of Consumer Involvement) study protocol. Two complementary studies have been designed: one, to examine the effectiveness of a standard for consumer participation and two, to explore how patient experiences vary across a range of settings with differing accreditation results.

Methods And Design: The research setting is the Australian healthcare system, and the two studies focus on three accreditation programmes in the primary, acute and aged care domains. The studies will use multimethods: document analysis; interviews and surveys. Participants will be stakeholders across the three domains including: policy officers; frontline healthcare professionals; accreditation agency personnel, including surveyors and healthcare consumers. Drawing on previous experience, the research team has developed purpose-designed tools. Data will be analysed using thematic, narrative and statistical (descriptive and inferential) procedures.

Ethics And Dissemination: The University of New South Wales Human Research Ethics Committee has approved the two studies (HREC 10274). Findings will be disseminated through seminars, conference presentations, academic publications and research partner websites. The findings will be formulated to facilitate uptake by policy and accreditation agency professionals, researchers and academics, and consumers, nationally and internationally.
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http://dx.doi.org/10.1136/bmjopen-2012-002024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488739PMC
October 2012

Narrative synthesis of health service accreditation literature.

BMJ Qual Saf 2012 Dec 4;21(12):979-91. Epub 2012 Oct 4.

Centre for Clinical Governance Research, Australian Institute of Health Innovation, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.

Aims: To systematically identify and synthesise health service accreditation literature.

Methods: A systematic identification and narrative synthesis of health service accreditation literature published prior to 2012 were conducted. The search identified 122 empirical studies that examined either the processes or impacts of accreditation programmes. Study components were recorded, including: dates of publication; research settings; levels of study evidence and quality using established rating frameworks; and key results. A content analysis was conducted to determine the frequency of key themes and subthemes examined in the literature and identify knowledge-gaps requiring research attention.

Results: The majority of studies (n=67) were published since 2006, occurred in the USA (n=60) and focused on acute care (n=79). Two thematic categories, that is, 'organisational impacts' and 'relationship to quality measures', were addressed 60 or more times in the literature. 'Financial impacts', 'consumer or patient satisfaction' and 'survey and surveyor issues' were each examined fewer than 15 times. The literature is limited in terms of the level of evidence and quality of studies, but highlights potential relationships among accreditation programmes, high quality organisational processes and safe clinical care.

Conclusions: Due to the limitations of the literature, it is not prudent to make strong claims about the effectiveness of health service accreditation. Nonetheless, several critical issues and knowledge-gaps were identified that may help stimulate and inform discussion among healthcare stakeholders. Ongoing effort is required to build upon the accreditation evidence-base by using high quality experimental study designs to examine the processes, effectiveness and financial value of accreditation programmes and their critical components in different healthcare domains.
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http://dx.doi.org/10.1136/bmjqs-2012-000852DOI Listing
December 2012

The standard of healthcare accreditation standards: a review of empirical research underpinning their development and impact.

BMC Health Serv Res 2012 Sep 20;12:329. Epub 2012 Sep 20.

Centre for Clinical Governance Research, Australian Institute of Health Innovation, University of New South Wales, Sydney, New South Wales 2052, Australia.

Background: Healthcare accreditation standards are advocated as an important means of improving clinical practice and organisational performance. Standard development agencies have documented methodologies to promote open, transparent, inclusive development processes where standards are developed by members. They assert that their methodologies are effective and efficient at producing standards appropriate for the health industry. However, the evidence to support these claims requires scrutiny. The study's purpose was to examine the empirical research that grounds the development methods and application of healthcare accreditation standards.

Methods: A multi-method strategy was employed over the period March 2010 to August 2011. Five academic health research databases (Medline, Psych INFO, Embase, Social work abstracts, and CINAHL) were interrogated, the websites of 36 agencies associated with the study topic were investigated, and a snowball search was undertaken. Search criteria included accreditation research studies, in English, addressing standards and their impact. Searching in stage 1 initially selected 9386 abstracts. In stage 2, this selection was refined against the inclusion criteria; empirical studies (n = 2111) were identified and refined to a selection of 140 papers with the exclusion of clinical or biomedical and commentary pieces. These were independently reviewed by two researchers and reduced to 13 articles that met the study criteria.

Results: The 13 articles were analysed according to four categories: overall findings; standards development; implementation issues; and impact of standards. Studies have only occurred in the acute care setting, predominately in 2003 (n = 5) and 2009 (n = 4), and in the United States (n = 8). A multidisciplinary focus (n = 9) and mixed method approach (n = 11) are common characteristics. Three interventional studies were identified, with the remaining 10 studies having research designs to investigate clinical or organisational impacts. No study directly examined standards development or other issues associated with their progression. Only one study noted implementation issues, identifying several enablers and barriers. Standards were reported to improve organisational efficiency and staff circumstances. However, the impact on clinical quality was mixed, with both improvements and a lack of measurable effects recorded.

Conclusion: Standards are ubiquitous within healthcare and are generally considered to be an important means by which to improve clinical practice and organisational performance. However, there is a lack of robust empirical evidence examining the development, writing, implementation and impacts of healthcare accreditation standards.
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http://dx.doi.org/10.1186/1472-6963-12-329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3520756PMC
September 2012

Evaluation of current Australian health service accreditation processes (ACCREDIT-CAP): protocol for a mixed-method research project.

BMJ Open 2012 4;2(4). Epub 2012 Aug 4.

Centre for Clinical Governance Research, Australian Institute of Health Innovation, University of New South Wales, Sydney, New South Wales, Australia.

Introduction: Accreditation programmes aim to improve the quality and safety of health services, and have been widely implemented. However, there is conflicting evidence regarding the outcomes of existing programmes. The Accreditation Collaborative for the Conduct of Research, Evaluation and Designated Investigations through Teamwork-Current Accreditation Processes (ACCREDIT-CAP) project is designed to address key gaps in the literature by evaluating the current processes of three accreditation programmes used across Australian acute, primary and aged care services.

Methods And Design: The project comprises three mixed-method studies involving documentary analyses, surveys, focus groups and individual interviews. Study samples will comprise stakeholders from across the Australian healthcare system: accreditation agencies; federal and state government departments; consumer advocates; professional colleges and associations; and staff of acute, primary and aged care services. Sample sizes have been determined to ensure results allow robust conclusions. Qualitative information will be thematically analysed, supported by the use of textual grouping software. Quantitative data will be subjected to a variety of analytical procedures, including descriptive and comparative statistics. The results are designed to inform health system policy and planning decisions in Australia and internationally.

Ethics And Dissemination: The project has been approved by the University of New South Wales Human Research Ethics Committee (approval number HREC 10274). Results will be reported to partner organisations, healthcare consumers and other stakeholders via peer-reviewed publications, conference and seminar presentations, and a publicly accessible website.
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http://dx.doi.org/10.1136/bmjopen-2012-001726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3449274PMC
October 2012

An empirical test of accreditation patient journey surveys: randomized trial.

Int J Qual Health Care 2012 Oct 11;24(5):495-500. Epub 2012 Jul 11.

Australian Institute of Health Innovation, University of New South Wales, Sydney, NSW, Australia.

Objective: To evaluate the effectiveness of utilizing the patient journey survey (PJS) method in healthcare accreditation processes.

Design: Randomized trial of the PJS method in parallel with the current accreditation survey (CAS) method of the Australian Council on Healthcare Standards (ACHS).

Setting: Acute healthcare organizations in Australia.

Participants: Seventeen organizations, 28 organizational staff, nine surveyors and 38 patients.

Main Outcome Measures: The results of each surveying method were compared. Participants provided feedback, via 18 interviews and 40 questionnaire surveys, about the benefits and disadvantages of a PJS compared to a CAS.

Results: The PJS method is not as comprehensive as the CAS method for accreditation assessment. In matched assessments the majority of items were rated lower by the PJS method than by the CAS. PJSs were shown to be appropriate for assessing mandatory clinical criteria, but were less effective for assessing corporate and support criteria. The two methods diverged in their final assessments of which organizations met the accreditation threshold. Participants endorsed the use of PJSs within accreditation processes.

Conclusions: The PJS methodology complements but is not a substitute for existing accreditation methods. There is significant stakeholder support for the inclusion of the PJS method within the current accreditation programme.
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http://dx.doi.org/10.1093/intqhc/mzs035DOI Listing
October 2012

An empirical test of short notice surveys in two accreditation programmes.

Int J Qual Health Care 2012 Feb 2;24(1):65-71. Epub 2011 Dec 2.

University of New South Wales, Kensington, NSW 2052, Australia.

Objective: To evaluate short notice surveys in accreditation programmes.

Design: Two trials using short notice surveys were conducted independently: a study of 20 healthcare organizations with the Australian Council on Healthcare Standards (ACHS) and a study of 7 general practices with the Australian General Practice Accreditation Limited (AGPAL). Participating organizations volunteered. ACHS and AGPAL selected 17 and 13 surveyors, respectively, and provided training for them on short notice surveys.

Methods: Each agency's short notice surveys were an abbreviated version of their current advanced notification surveys. Short notice surveys assessed accreditation programme criteria or indicators that corresponded to the Australian Commission on Safety and Quality in Health Care's priority issues. Fifteen (out of 45) ACHS criteria and 48 (out of 174) AGPAL indicators that aligned to the Commission's criteria were evaluated. Participating organizations were given 2 days notice prior to the short notice surveys. Ratings from the short notice surveys were compared with those from the most recent advanced notification surveys, and statistical tests were performed to detect differences and potential confounding factors. Surveyors and organizational staff completed a post-survey feedback questionnaire which was analysed thematically and by inferential statistics.

Results: The short notice survey approach overall produced ratings congruent with the advanced notification survey for both accreditation programmes. However, for both programmes short notice surveys assessed that more organizations would not reach the accreditation threshold as compared with the previous survey. Organizations in both programmes were judged to have achieved less successful performance against clinical standards by the short notice survey than the advanced notification survey. There was support from surveyors and organizational staff for short notice survey to be adopted. However, there were mixed views about the impact of short notice surveys and whether they validated trial participants' continuous improvement efforts.

Conclusions: The study demonstrated that short notice surveys are more critical in their assessment of clinical than administrative or corporate items. Short notice surveys, while broadly comparable with existing advanced notification survey practice, produced different accreditation outcomes for a significant proportion of the study organizations. The overall value and worth of short notice surveys remains to be proved.
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http://dx.doi.org/10.1093/intqhc/mzr074DOI Listing
February 2012