Provision of a comprehensive medicines review is associated with lower mortality risk for residents of aged care facilities: a retrospective cohort study.

BACKGROUND: no studies have examined the impact of residential medication management review (RMMR, a 24-year government subsidised comprehensive medicines review program) in Australian residential aged care facilities (RACFs) on hospitalisation or mortality. OBJECTIVE: to examine associations between RMMR provision in the 6-12 months after RACF entry and the 12-month risk of hospitalisation and mortality among older Australians in RACFs. DESIGN: retrospective cohort study. SUBJECTS: individuals aged 65-105 years taking at least one medicine, who entered an RACF in three Australian states between 1 January 2012 and 31 December 2015 and spent at least 6 months in the RACF (n = 57,719). METHODS: Cox regression models estimated adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for associations between RMMR provision and mortality. Adjusted subdistribution hazard ratios were estimated for associations between RMMR provision and next (i) emergency department (ED) presentation or unplanned hospitalisation or (ii) fall-related ED presentation or hospitalisation. RESULTS: there were 12,603 (21.8%) individuals who received an RMMR within 6-12 months of RACF entry, of whom 22.2% (95%CI 21.4-22.9) died during follow-up, compared with 23.3% (95%CI 22.9-23.7) of unexposed individuals. RMMR provision was associated with a lower risk of death due to any cause over 12-months (aHR 0.96, 95%CI 0.91-0.99), but was not associated with ED presentations or hospitalisations for unplanned events or falls. CONCLUSIONS: provision of an RMMR in the 6-12 months after RACF entry is associated with a 4.4% lower mortality risk over 12-months but was not associated with changes in hospitalisations for unplanned events or falls.

Medicines use before and after comprehensive medicines review among residents of long-term care facilities: a retrospective cohort study.

BACKGROUND: Residential Medication Management Review (RMMR) is a subsidized comprehensive medicines review program for individuals in Australian residential aged care facilities (RACFs). This study examined weekly trends in medicines use in the four months before and after an RMMR and among a comparison group of residents who did not receive an RMMR. METHODS: This retrospective cohort study included individuals aged 65 to 105 years who first entered permanent care between 1/1/2012 and 31/12/2016 in South Australia, Victoria, or New South Wales, and were taking at least one medicine. Individuals with an RMMR within 12 months of RACF entry were classified into one of three groups: (i) RMMR within 0 to 3 months, (ii) 3 to 6 months, or (iii) within 6 to 12 months of RACF entry. Individuals without RMMRs were included in the comparison group. Weekly trends in the number of defined daily doses per 1000 days were determined in the four months before and after the RMMR (or assigned index date in the comparison group) for 14 medicine classes. RESULTS: 113909 individuals from 1979 RACFs were included, of whom 55021 received an RMMR. Across all three periods examined, decreased use of statins and proton pump inhibitors was observed post-RMMR in comparison to those without RMMRs. Decreases in calcium channel blockers, benzodiazepines/zopiclone, and antidepressants were observed following RMMR provision in the 3-6 and 6-12 months after RACF entry. Negligible changes in antipsychotic use were also observed following an RMMR in the 6-12 months after RACF entry by comparison to those without RMMRs. No changes in use of opioids, ACE inhibitors/sartans, beta blockers, loop diuretics, oral anticoagulants, or medicines for osteoporosis, diabetes or the cognitive symptoms of dementia were observed post-RMMR. CONCLUSIONS: For six of the 14 medicine classes investigated, modest changes in weekly trends in use were observed after the provision of an RMMR in the 6-12 months after RACF entry compared to those without RMMRs. Findings suggest that activities such as medicines reconciliation may be prioritized when an RMMR is provided on RACF entry, with deprescribing more likely after an RMMR the longer a resident has been in the RACF.

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

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.

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

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.

The risk of fall-related hospitalisations at entry into permanent residential aged care.

BACKGROUND: Entering permanent residential aged care (PRAC) is a vulnerable time for individuals. While falls risk assessment tools exist, these have not leveraged routinely collected and integrated information from the Australian aged and health care sectors. Our study examined individual, system, medication, and health care related factors at PRAC entry that are predictors of fall-related hospitalisations and developed a risk assessment tool using integrated aged and health care data. METHODS: A retrospective cohort study was conducted on N = 32,316 individuals ≥65 years old who entered a PRAC facility (01/01/2009-31/12/2016). Fall-related hospitalisations within 90 or 365 days were the outcomes of interest. Individual, system, medication, and health care-related factors were examined as predictors. Risk prediction models were developed using elastic nets penalised regression and Fine and Gray models. Area under the receiver operating characteristics curve (AUC) assessed model discrimination. RESULTS: 64.2% (N = 20,757) of the cohort were women and the median age was 85 years old (interquartile range 80-89). After PRAC entry, 3.7% (N = 1209) had a fall-related hospitalisation within 90 days and 9.8% (N = 3156) within 365 days. Twenty variables contributed to fall-related hospitalisation prediction within 90 days and the strongest predictors included fracture history (sub-distribution hazard ratio (sHR) = 1.87, 95% confidence interval (CI) 1.63-2.15), falls history (sHR = 1.41, 95%CI 1.21-2.15), and dementia (sHR = 1.39, 95%CI 1.22-1.57). Twenty-seven predictors of fall-related hospitalisation within 365 days were identified, the strongest predictors included dementia (sHR = 1.36, 95%CI 1.24-1.50), history of falls (sHR = 1.30, 95%CI 1.20-1.42) and fractures (sHR = 1.28, 95%CI 1.15-1.41). The risk prediction models had an AUC of 0.71 (95%CI 0.68-0.74) for fall-related hospitalisations within 90 days and 0.64 (95%CI 0.62-0.67) for within 365 days. CONCLUSION: Routinely collected aged and health care data, when integrated at a clear point of action such as entry into PRAC, can identify residents at risk of fall-related hospitalisations, providing an opportunity for better targeting risk mitigation strategies.

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

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.

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

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.

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

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 (n = 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 p 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 p < 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.

Transcriptional and metabolic rewiring of colorectal cancer cells expressing the oncogenic KRASG13D mutation.

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 KRASG13D 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.

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

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.

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

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/m2; 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.

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

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.

Profiling health-care accreditation organizations: an international survey.

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.

Development of a Multivariable Prediction Model for Risk of Hospitalization With Pressure Injury After Entering Residential Aged Care.

OBJECTIVES: Although largely preventable, pressure injury is a major concern in individuals in permanent residential aged care (PRAC). Our study aimed to identify predictors and develop a prognostic model for risk of hospitalization with pressure injury (PI) using integrated Australian aged and health care data. DESIGN: National retrospective cohort study. SETTING AND PARTICIPANTS: Individuals ≥65 years old (N = 206,540) who entered 1797 PRAC facilities between January 1, 2009, and December 31, 2016. METHODS: PI, ascertained from hospitalization records, within 365 days of PRAC entry was the outcome of interest. Individual, medication, facility, system, and health care-related factors were examined as predictors. Prognostic models were developed using elastic nets penalized regression and Fine and Gray models. Area under the receiver operating characteristics curve (AUC) assessed model discrimination out-of-sample. RESULTS: Within 365 days of PRAC entry, 4.3% (n = 8802) of individuals had a hospitalization with PI. The strongest predictors for PI risk include history of PIs [sub-distribution hazard ratio (sHR) 2.41; 95% CI 1.77-3.29]; numbers of prior hospitalizations (having ≥5 hospitalizations, sHR 1.95; 95% CI 1.74-2.19); history of traumatic amputation of toe, ankle, foot and leg (sHR 1.72; 95% CI 1.44-2.05); and history of skin disease (sHR 1.54; 95% CI 1.45-1.65). Lower care needs at PRAC entry with respect to mobility, complex health care, and medication assistance were associated with lower risk of PI. The risk prediction model had an AUC of 0.74 (95% CI 0.72-0.75). CONCLUSIONS AND IMPLICATIONS: Our prognostic model for risk of hospitalization with PI performed moderately well and can be used by health and aged care providers to implement risk-based prevention plans at PRAC entry.

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

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.

Analysis of Australian newspaper coverage of medication errors.

OBJECTIVE: To investigate the frequency, style and reliability of newspaper reporting of medication errors. DESIGN: Content analysis of articles discussing medication errors that were published in the 10 most widely read Australian daily newspapers between January 2005 and January 2010. Main outcome measure(s) Newspaper source, article type, article topic, leading news actors, identified causes and solutions of medication errors and cited references. RESULTS: Ninety-two articles included discussion of medication errors, with the one national newspaper, The Australian, the main source of articles (n = 24). News items were the most frequent type of articles (n = 73), with the majority (n = 55) primarily focused on broader hospital problems. Government representatives, advocacy groups, researchers, health service staff and private industry groups were prominent news actors. A shortage of hospital resources was identified as the central cause of medication errors (n = 38), with efficient error reporting systems most frequently identified as a solution (n = 25). Government reports were cited on 39 occasions, with peer-reviewed publications infrequently cited (n = 4). CONCLUSION: Australian newspaper reporting of medication errors was relatively limited. Given the high prevalence of errors and the potential role consumers can play in identifying and preventing errors, there is a clear argument for increasing public awareness and understanding of issues relating to medication safety. Existing coverage of this issue is unrelated to research evidence. This suggests the need for patient safety researchers and advocacy groups to engage more strongly with the media as a strategy to increase the productive public discourse concerning medication errors and gain support for evidence-based interventions.

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

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.

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

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.

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

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.

Harnessing the Heterogeneity of Prostate Cancer for Target Discovery Using Patient-Derived Explants.

Prostate cancer is a complex and heterogeneous disease, but a small number of cell lines have dominated basic prostate cancer research, representing a major obstacle in the field of drug and biomarker discovery. A growing lack of confidence in cell lines has seen a shift toward more sophisticated pre-clinical cancer models that incorporate patient-derived tumors as xenografts or explants, to more accurately reflect clinical disease. Not only do these models retain critical features of the original tumor, and account for the molecular diversity and cellular heterogeneity of prostate cancer, but they provide a unique opportunity to conduct research in matched tumor samples. The challenge that accompanies these complex tissue models is increased complexity of analysis. With over 10 years of experience working with patient-derived explants (PDEs) of prostate cancer, this study provides guidance on the PDE method, its limitations, and considerations for addressing the heterogeneity of prostate cancer PDEs that are based on statistical modeling. Using inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) as an example of a drug that induces robust proliferative response, we demonstrate how multi-omics analysis in prostate cancer PDEs is both feasible and essential for identification of key biological pathways, with significant potential for novel drug target and biomarker discovery.