Retinoids induce growth arrest, differentiation, and cell death in many cancer cell types. One factor determining the sensitivity or resistance to the retinoid anticancer signal is the transcriptional response of retinoid-regulated target genes in cancer cells. We used cDNA microarray to identify 31 retinoid-regulated target genes shared by two retinoid-sensitive neuroblastoma cell lines, and then sought to determine the relevance of the target gene responses to the retinoid anticancer signal. The pattern of retinoid responsiveness for six of 13 target genes (RARbeta2, CYP26A1, CRBP1, RGS16, DUSP6, EGR1) correlated with phenotypic retinoid sensitivity, across a panel of retinoid-sensitive or -resistant lung and breast cancer cell lines. Retinoid treatment of MYCN transgenic mice bearing neuroblastoma altered the expression of five of nine target genes examined (RARbeta2, CYP26A1, CRBP1, DUSP6, PLAT) in neuroblastoma tumour tissue in vivo. In retinoid-sensitive neuroblastoma, lung and breast cancer cell lines, direct inhibition of retinoid-induced RARbeta2 expression blocked induction of only one of eight retinoid target genes (CYP26A1). DNA demethylation, histone acetylation, and exogenous overexpression of RARbeta2 partially restored retinoid-responsive CYP26A1 expression in RA-resistant MDA-MB-231 breast, but not SK-MES-1 lung, cancer cells. Combined, rather than individual, inhibition of DUSP6 and RGS16 was required to block retinoid-induced growth inhibition in neuroblastoma cells, through phosphorylation of extracellular-signal-regulated kinase. In conclusion, sensitivity to the retinoid anticancer signal is determined in part by the transcriptional response of key retinoid-regulated target genes, such as RARbeta2, DUSP6, and RGS16.

BACKGROUND: Concerns are often raised about the accuracy of microarray technologies and the degree of cross-platform agreement, but there are yet no methods which can unambiguously evaluate precision and sensitivity for these technologies on a whole-array basis. RESULTS: A methodology is described for evaluating the precision and sensitivity of whole-genome gene expression technologies such as microarrays. The method consists of an easy-to-construct titration series of RNA samples and an associated statistical analysis using non-linear regression. The method evaluates the precision and responsiveness of each microarray platform on a whole-array basis, i.e., using all the probes, without the need to match probes across platforms. An experiment is conducted to assess and compare four widely used microarray platforms. All four platforms are shown to have satisfactory precision but the commercial platforms are superior for resolving differential expression for genes at lower expression levels. The effective precision of the two-color platforms is improved by allowing for probe-specific dye-effects in the statistical model. The methodology is used to compare three data extraction algorithms for the Affymetrix platforms, demonstrating poor performance for the commonly used proprietary algorithm relative to the other algorithms. For probes which can be matched across platforms, the cross-platform variability is decomposed into within-platform and between-platform components, showing that platform disagreement is almost entirely systematic rather than due to measurement variability. CONCLUSION: The results demonstrate good precision and sensitivity for all the platforms, but highlight the need for improved probe annotation. They quantify the extent to which cross-platform measures can be expected to be less accurate than within-platform comparisons for predicting disease progression or outcome.

BACKGROUND: Assessment of array quality is an essential step in the analysis of data from microarray experiments. Once detected, less reliable arrays are typically excluded or "filtered" from further analysis to avoid misleading results. RESULTS: In this article, a graduated approach to array quality is considered based on empirical reproducibility of the gene expression measures from replicate arrays. Weights are assigned to each microarray by fitting a heteroscedastic linear model with shared array variance terms. A novel gene-by-gene update algorithm is used to efficiently estimate the array variances. The inverse variances are used as weights in the linear model analysis to identify differentially expressed genes. The method successfully assigns lower weights to less reproducible arrays from different experiments. Down-weighting the observations from suspect arrays increases the power to detect differential expression. In smaller experiments, this approach outperforms the usual method of filtering the data. The method is available in the limma software package which is implemented in the R software environment. CONCLUSION: This method complements existing normalisation and spot quality procedures, and allows poorer quality arrays, which would otherwise be discarded, to be included in an analysis. It is applicable to microarray data from experiments with some level of replication.

BACKGROUND: There are staff shortages nation-wide in residential aged care, which is only predicted to grow as the population ages in Australia. The aged care staff shortage is compounded in rural and remote areas where the health service workforce overall experiences difficulties in recruitment and retention. There is evidence that nurse practitioners fill important service gaps in aged care and rural health care but also evidence that barriers exist in introducing this extended practice role. METHODS: In 2018, 58 medical and direct care staff participated in interviews and focus groups about the implementation of an older person's nurse practitioner (OPNP) in aged care. All 58 interviewees had previously or currently worked in an aged care setting where the OPNP delivered services. The interviews were analysed using May's implementation theory framework to better understand staff perceptions of barriers and enablers when an OPNP was introduced to the workplace. RESULTS: The major perceived barrier to capacity of implementing the OPNP was a lack of material resources, namely funding of the role given the OPNP's limited ability to self-fund through access to the Medicare Benefits Schedule (MBS). Staff perceived that benefits included timely access to care for residents, hospital avoidance and improved resident health outcomes. CONCLUSION: Despite staff perceptions of more timely access to care for residents and improved outcomes, widespread implementation of the OPNP role may be hampered by a poor understanding of the role of an OPNP and the legislative requirement for a collaborative arrangement with a medical practitioner as well as limited access to the MBS. This study was not a registered trial.

The molecular basis for the inverse relationship between differentiation and tumorigenesis is unknown. The function of runx2, a master regulator of osteoblast differentiation belonging to the runt family of tumor suppressor genes, is consistently disrupted in osteosarcoma cell lines. Ectopic expression of runx2 induces p27KIP1, thereby inhibiting the activity of S-phase cyclin complexes and leading to the dephosphorylation of the retinoblastoma tumor suppressor protein (pRb) and a G1 cell cycle arrest. Runx2 physically interacts with the hypophosphorylated form of pRb, a known coactivator of runx2, thereby completing a feed-forward loop in which progressive cell cycle exit promotes increased expression of the osteoblast phenotype. Loss of p27KIP1 perturbs transient and terminal cell cycle exit in osteoblasts. Consistent with the incompatibility of malignant transformation and permanent cell cycle exit, loss of p27KIP1 expression correlates with dedifferentiation in high-grade human osteosarcomas. Physiologic coupling of osteoblast differentiation to cell cycle withdrawal is mediated through runx2 and p27KIP1, and these processes are disrupted in osteosarcoma.

INTRODUCTION: Overweight and obesity prevalence has increased significantly over the past two decades, currently impacting greater than 60% of Australians. It is unclear if a social perception of a healthy weight has been obscured by the increase in prevalence and thus has become inconsistent with the medical definitions. METHODS: An electronic questionnaire was distributed via email and social media using the authors' informal networks. Australian adults were eligible to participate. Participants were asked to categorise their own body size using medically accepted words and previously published silhouettes, before identifying underweight, healthy weight, overweight or obesity in a series ofsilhouettes. RESULTS: Eight hundred six questionnaires were completed, a majority of participants had attained a high level of education and were employed female health professionals. Under half the studied population had a Body Mass Index (BMI) corresponding to overweight or obese categories (n = 349, 47%). Accuracy in self-perceived weight status using medicalised words was higher among respondents with BMI corresponding to the healthy weight category (n = 311, 85%) and overweight category (n = 133, 74%) than for respondents with BMI corresponding to obesity (n = 79, 45%) or underweight (n = 5, 31%). A majority of respondents were able to accurately self-perceive their weight status using silhouettes (n = 469, 70%). Females were significantly more likely to be accurate in their self-perception than males, using both medicalised words (p = < 0.001) and silhouettes (p = 0.045). Respondents with a BMI corresponding to the obese category were significantly more likely to be accurate with weight status self-perception using silhouettes than words (87% versus 46% respectively, p = < 0.001). Less than half (41%) of respondents accurately perceived silhouettes corresponding to an overweight BMI and less than one in ten respondents (9%) accurately perceived the lower limit of the silhouettes corresponding to an obese BMI. CONCLUSIONS: Repondents were challenged to accurately perceive silhouettes corresponding to an obese BMI in themselves and others. Weight status misperception was more likely to exist among those with a BMI less than 18.5 or 30 or more (underweight BMI and obese BMI). Accuracy decreased as BMI increased. Respondents with a BMI in the obese category were significantly more likely to accurately self-perceive their weight status using silhouettes than medicalised words. Silhouettes may act as an effective visual cue in initiating weight related discussions.

BACKGROUND: High quality, contemporary data regarding patterns of chronic disease is essential for planning by health services, policy makers and local governments, but surprisingly scarce, including in rural Australia. This dearth of data occurs despite the recognition that rural Australians live with high rates of ill health, poor health behaviours and restricted access to health services. Crossroads-II is set in the Goulburn Valley, a rural region of Victoria, Australia 100-300 km north of metropolitan Melbourne. It is primarily an irrigated agricultural area. The aim of the study is to identify changes in the prevalence of key chronic health conditions including the extent of undiagnosed and undermanaged disease, and association with access to care, over a 15 year period. METHODS/DESIGN: This study is a 15 year follow up from the 2000-2003 Crossroads-I study (2376 households participated). Crossroads-II includes a similar face to face household survey of 3600 randomly selected households across four towns of sizes 6300 to 49,800 (50% sampled in the larger town with the remainder sampled equally from the three smaller towns). Self-reported health, health behaviour and health service usage information is verified and supplemented in a nested sub-study of 900 randomly selected adult participants in 'clinics' involving a range of additional questionnaires and biophysical measurements. The study is expected to run from October 2016 to December 2018. DISCUSSION: Besides providing epidemiological and health service utilisation information relating to different diseases and their risk factors in towns of different sizes, the results will be used to develop a composite measure of health service access. The importance of access to health services will be investigated by assessing the correlation of this measure with rates of undiagnosed and undermanaged disease at the mesh block level. Results will be shared with partner organisations to inform service planning and interventions to improve health outcomes for local people.

PURPOSE: The distress thermometer (DT) is commonly used in cancer care to improve detection of distress. The DT's recommended cut-off score of 4 or 5 has typically been established using the Hospital Anxiety and Depression Scale (HADS) by receiver operating characteristic curve analysis. The present analysis complements these studies by critically examining the use of the HADS to identify the DT's cut-off score and corroborating the DT's cut-off scores using item response theory (Rasch analysis). METHODS: The DT and HADS were completed by 340 patients with cancer. Rasch dimensionality analysis was performed on the HADS-Total, and test characteristic curves were examined to equate the DT and the HADS subscales. Identified DT cut-off scores were then examined for their sensitivity and specificity. RESULTS: Rasch analysis did not support the unidimensionality of HADS-Total. The test characteristic curves indicated that a cut-off score of ≥8 on the HADS-Anxiety and HADS-Depression subscales was equivalent to a score of 6 and 7 on the DT, respectively. However, a DT cut-off score of 5 resulted in the best balance between sensitivity and specificity across the HADS-Anxiety and HADS-Depression subscales. CONCLUSIONS: Despite being a popular practice, the present findings did not support combining the HADS-Anxiety and HADS-Depression subscales to identify the DT's cut-off score. Furthermore, these results inform the use of the DT as a preliminary screening tool and suggest that when a single screen is used, a DT cut-off score of 6 or 7 might be more appropriate than the typical cut-off score of 4.

Objective: To classify a rural community sample by their modifiable health behaviours and identify the prevalence of chronic conditions, poor self-rated health, obesity and hospital use. Method: Secondary analysis of a cross- sectional self-report questionnaire in the Hume region of Victoria, Australia. Cluster analysis using the two-step method was applied to responses to health behaviour items. Results: 1,259 questionnaires were completed. Overall 63% were overweight or obese. Three groups were identified: 'Healthy Lifestyle' (63%), 'Non Smoking, Unhealthy Lifestyle' (25%) and 'Smokers' (12%). 'Healthy lifestyle' were older and more highly educated than the other two groups while 'Non Smoking, Unhealthy Lifestyle' were more likely to be obese. 'Smokers' had the highest rate of poor self-rated health. Prevalence of chronic conditions was similar in each group (>20%). 'Smokers' were twice as likely to have had two or more visits to hospital in the preceding year even after adjustment for age, gender and education. Conclusion: High rates of overweight and obesity were identified but 'Smokers' were at the greatest risk for poor self-rated health and hospitalisation. Implications for Public Health: Within an environment of high rates of chronic ill health and obesity, primary care clinicians and public health policy makers must maintain their vigilance in encouraging people to quit smoking.

Executive Summary Storyline Education and income are inextricably linked to positive health outcomes. Australian Aboriginal people are known to have higher rates of unemployment than non-Aboriginal Australians and poorer health. In the Victorian regional town of Echuca, the local health service, Echuca Regional Health (ERH) has developed an Aboriginal Employment Plan (AEP) targeted to reach 2% employment of Aboriginal people by 2020. Aim Learning how to strengthen local employment opportunities at ERH for Aboriginal people was the aim of this study. Hunting and Gathering A qualitative research protocol was designed. Four distinct population groups with a strong interest in the growth of Aboriginal employment at ERH agreed to participate in focus groups and individual interviews: Yorta Yorta Elders, past and present Aboriginal employees, key community stakeholders and ERH Executive Officers. Conversations from the interviews and groups were thematically analysed with careful consideration of cultural meaning. Results Twenty four people participated in the study. Learnings were gathered from the past, present and the future. The past Local Aboriginal Elders recall birthing on the verandah of the health service, testament to a recent history of cultural inequality. In the face of segregation, Elders shared the memory of approaching the Matron to seek and subsequently achieve employment at the health service. Healing shifted from outside the building to within. First steps toward cultural inclusion. The present A contemporary rebuild of the health service provided an opportunity to physically demolish the old verandahs, powerfully symbolic of reconciling the wrongs of the past with a focus on building a culturally safe healing environment. Successes to date include: • the use of visual representations of culture; • leadership through Aboriginal Board membership; • mandatory online Cultural Awareness Training (CAT); • the development of Aboriginal employment pathways and strengthened relationships with the community; • the signing of a Memorandum of Understanding (MoU) with two local Aboriginal Community Controlled Health Organisations (ACCHOs). The Future Participants urged ERH to acknowledge the Aboriginal past on the ERH historical timeline and heal the future by remaining focused upon strengthening cultural respect and safety. Discussion ERH was not immune to the Commonwealth Segregation Policy that spanned sixty years. Preliminary steps toward cultural inclusion came from local self-determined Aboriginal people whom, in the face of cultural inequity, were able to achieve employment at the health service. Physically, a new health service exists today, built with a noteworthy level of collaboration with the local Aboriginal community. Multiple strategies have achieved significant progress toward a new vision of cultural respect, safety and inclusion. Conclusion Cultural healing is more than the responsibility of an individual, rather a collective commitment from the organisation in partnership with the community at large. Reconciling the past through acknowledging historical events and continually adapting through cultural learnings, demonstrates leadership and an opportunity to teach future generations that healing is possible. Culturally safe environments promote both healing and employment opportunities for Aboriginal people. Continued efforts that advance toward Aboriginal cultural inclusion may indeed mangan dunguludja ngatan (build strong employment). Recommendations Authors’ present study findings as valuable insight into the cultural significance of the past and how healing has emerged on a continuum to reconcile the history, to benefit the future. Recommendations have been proposed in the hope of informing success in mangan dunguludja ngatan (build strong employment) at ERH and a vision for reconciliation, cultural respect and safety. 1. Consider employing an Aboriginal Human Resources (HR) Coordinator to strengthen cultural relations with the community; 2. Commence recording Aboriginal status for all employees during the HR onboarding process, allowing rates to be monitored over time; 3. Consider the development of a formal mentoring program to strengthen cultural respect; 4. Consider formalising Cultural Competency Training (CCT) for Managers and key staff working alongside Aboriginal employees; 5. Develop an Aboriginal Staff Network to engender support and cultural safety within the workplace; 6. Consider including significant Aboriginal events on the ERH historical timeline; 7. Continue to develop partnership arrangements (with local training agencies and education providers) utilising skill matching based upon the needs identified in a workforce analysis across the community; 8. Foster opportunities for dual positions with ERH and local ACCHOs; 9. Build upon Aboriginal acknowledgement through promoting ERH as a culturally safe place (employee posters/biographies on ERH website); 10. Consider developing a Reconciliation Action Plan (RAP) or an updated AEP that reflects the Cultural Respect Framework to continue to strengthen the narrative around cultural safety; 11. Formally engage and celebrate culture with the Aboriginal community at every opportunity e.g. National Aborigines and Islander Day Observance Committee (NAIDOC) events.

BACKGROUND: In Australia people with a diagnosed chronic condition can be managed on unique funded care plans that allow the recruitment of a multidisciplinary team to assist in setting treatment goals and adequate follow up. In contrast to the World Health Organisation, the North American and European Medical Associations, the Australian Medical Association does not recognise obesity as a chronic condition, therefore excluding a diagnosis of obesity from qualifying for a structured and funded treatment plan. BODY: The Australian guidelines for management of Obesity in adults in Primary Care are structured around a five step process -the '5As': Ask & Assess, Advise, Assist and Arrange'. This article aims to identify the key challenges and successes associated with the '5As' approach, to better understand the reasons for the gap between the high Australian prevalence of overweight and obesity and an actual diagnosis and treatment plan for managing obesity. It argues that until the Australian health system follows the international lead and defines obesity as a chronic condition, the capacity for Australian doctors to diagnose and initiate structured treatment plans will remain limited and ineffective. CONCLUSION: Australian General Practitioners are limited in their ability manage obesity, as the current treatment guidelines only recognise obesity as a risk factor rather than a chronic condition.