Fine-mapping the HOXB region detects common variants tagging a rare coding allele : evidence for synthetic association in prostate cancer

The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.

Vascular endothelial growth factor receptor-3 directly interacts with phosphatidylinositol 3-kinase to regulate lymphangiogenesis

Background Dysfunctional lymphatic vessel formation has been implicated in a number of pathological conditions including cancer metastasis, lymphedema, and impaired wound healing. The vascular endothelial growth factor (VEGF) family is a major regulator of lymphatic endothelial cell (LEC) function and lymphangiogenesis. Indeed, dissemination of malignant cells into the regional lymph nodes, a common occurrence in many cancers, is stimulated by VEGF family members. This effect is generally considered to be mediated via VEGFR-2 and VEGFR-3. However, the role of specific receptors and their downstream signaling pathways is not well understood. Methods and Results Here we delineate the VEGF-C/VEGF receptor (VEGFR)-3 signaling pathway in LECs and show that VEGF-C induces activation of PI3K/Akt and MEK/Erk. Furthermore, activation of PI3K/Akt by VEGF-C/VEGFR-3 resulted in phosphorylation of P70S6K, eNOS, PLCc1, and Erk1/2. Importantly, a direct interaction between PI3K and VEGFR-3 in LECs was demonstrated both in vitro and in clinical cancer specimens. This interaction was strongly associated with the presence of lymph node metastases in primary small cell carcinoma of the lung in clinical specimens. Blocking PI3K activity abolished VEGF-C-stimulated LEC tube formation and migration. Conclusions Our findings demonstrate that specific VEGFR-3 signaling pathways are activated in LECs by VEGF-C. The importance of PI3K in VEGF-C/VEGFR-3-mediated lymphangiogenesis provides a potential therapeutic target for the inhibition of lymphatic metastasis.

Xenome--a tool for classifying reads from xenograft samples

Motivation Shotgun sequence read data derived from xenograft material contains a mixture of reads arising from the host and reads arising from the graft. Classifying the read mixture to separate the two allows for more precise analysis to be performed. Results We present a technique, with an associated tool Xenome, which performs fast, accurate and specific classification of xenograft-derived sequence read data. We have evaluated it on RNA-Seq data from human, mouse and human-in-mouse xenograft datasets.

Connecting the person with dementia and family : a feasibility study of a telepresence robot

Background Maintenance of communication is important for people with dementia living in long-term care. The purpose of this study was to assess the feasibility of using “Giraff”, a telepresence robot to enhance engagement between family and a person with dementia living in long-term care. Methods A mixed-methods approach involving semi-structured interviews, call records and video observational data was used. Five people with dementia and their family member participated in a discussion via the Giraff robot for a minimum of six times over a six-week period. A feasibility framework was used to assess feasibility and included video analysis of emotional response and engagement. Results Twenty-six calls with an average duration of 23 mins took place. Residents showed a general state of positive emotions across the calls with a high level of engagement and a minimal level of negative emotions. Participants enjoyed the experience and families reported that the Giraff robot offered the opportunity to reduce social isolation. A number of software and hardware challenges were encountered. Conclusions Participants perceived this novel approach to engage families and people with dementia as a feasible option. Participants were observed and also reported to enjoy the experience. The technical challenges identified have been improved in a newer version of the robot. Future research should include a feasibility trial of longer duration, with a larger sample and a cost analysis.

The quik fix study : a randomised controlled trial of brief interventions for young people with alcohol-related injuries and illnesses accessing emergency department and crisis support care

Background: Alcohol is a major preventable cause of injury, disability and death in young people. Large numbers of young people with alcohol-related injuries and medical conditions present to hospital emergency departments (EDs). Access to brief, efficacious, accessible and cost effective treatment is an international health priority within this age group. While there is growing evidence for the efficacy of brief motivational interviewing (MI) for reducing alcohol use in young people, there is significant scope to increase its impact, and determine if it is the most efficacious and cost effective type of brief intervention available. The efficacy of personality-targeted interventions (PIs) for alcohol misuse delivered individually to young people is yet to be determined or compared to MI, despite growing evidence for school-based PIs. This study protocol describes a randomized controlled trial comparing the efficacy and cost-effectiveness of telephone-delivered MI, PI and an Assessment Feedback/Information (AF/I) only control for reducing alcohol use and related harm in young people. Methods/design: Participants will be 390 young people aged 16 to 25 years presenting to a crisis support service or ED with alcohol-related injuries and illnesses (including severe alcohol intoxication). This single blinded superiority trial randomized young people to (i) 2 sessions of MI; (ii) 2 sessions of a new PI or (iii) a 1 session AF/I only control. Participants are reassessed at 1, 3, 6 and 12 months on the primary outcomes of alcohol use and related problems and secondary outcomes of mental health symptoms, functioning, severity of problematic alcohol use, alcohol injuries, alcohol-related knowledge, coping self-efficacy to resist using alcohol, and cost effectiveness. Discussion: This study will identify the most efficacious and cost-effective telephone-delivered brief intervention for reducing alcohol misuse and related problems in young people presenting to crisis support services or EDs. We expect efficacy will be greatest for PI, followed by MI, and then AF/I at 1, 3, 6 and 12 months on the primary and secondary outcome variables. Telephone-delivered brief interventions could provide a youth-friendly, accessible, efficacious, cost-effective and easily disseminated treatment for addressing the significant public health issue of alcohol misuse and related harm in young people. Trial registration: This trial is registered with the Australian and New Zealand Clinical Trials Registry ACTRN12613000108718.

Varenicline decreases ethanol intake and increases dopamine release via neuronal nicotinic acetylcholine receptors in the nucleus accumbens

BACKGROUND AND PURPOSE Varenicline, a neuronal nicotinic acetylcholine receptor (nAChR) modulator, decreases ethanol consumption in rodents and humans. The proposed mechanism of action for varenicline to reduce ethanol consumption has been through modulation of dopamine (DA) release in the nucleus accumbens (NAc) via α4*-containing nAChRs in the ventral tegmental area (VTA). However, presynaptic nAChRs on dopaminergic terminals in the NAc have been shown to directly modulate dopaminergic signalling independently of neuronal activity from the VTA. In this study, we determined whether nAChRs in the NAc play a role in varenicline’s effects on ethanol consumption. EXPERIMENTAL APPROACH Rats were trained to consume ethanol using the intermittent-access two-bottle choice protocol for 10 weeks. Ethanol intake was measured after varenicline or vehicle was microinfused into the NAc (core, shell or core-shell border) or the VTA (anterior or posterior). The effect of varenicline treatment on DA release in the NAc was measured using both in vivo microdialysis and in vitro fast-scan cyclic voltammetry (FSCV). KEY RESULTS Microinfusion of varenicline into the NAc core and core-shell border, but not into the NAc shell or VTA, reduced ethanol intake following long-term ethanol consumption. During microdialysis, a significant enhancement in accumbal DA release occurred following systemic administration of varenicline and FSCV showed that varenicline also altered the evoked release of DA in the NAc. CONCLUSION AND IMPLICATIONS Following long-term ethanol consumption, varenicline in the NAc reduces ethanol intake, suggesting that presynaptic nAChRs in the NAc are important for mediating varenicline’s effects on ethanol consumption.

The impact of cataract surgery on vision-related quality of life for bilateral cataract patients in Ho Chi Minh City, Vietnam : a prospective study

Background To determine the impact of cataract surgery on vision-related quality of life (VRQOL) and examine the association between objective visual measures and change in VRQOL after surgery among bilateral cataract patients in Ho Chi Minh City, Vietnam. Methods A cohort of older patients with bilateral cataract was assessed one week before and one to three months after first eye or both eye cataract surgery. Visual measures including visual acuity, contrast sensitivity and stereopsis were obtained. Vision-related quality of life was assessed using the NEI VFQ-25. Descriptive analyses and a generalized linear estimating equation (GEE) analysis were undertaken to measure change in VRQOL after surgery. Results Four hundred and thirteen patients were assessed before cataract surgery and 247 completed the follow-up assessment one to three months after first or both eye cataract surgery. Overall, VRQOL significantly improved after cataract surgery (p < 0.001) particularly after both eye surgeries. Binocular contrast sensitivity (p < 0.001) and stereopsis (p < 0.001) were also associated with change in VRQOL after cataract surgery. Visual acuity was not associated with VRQOL. Conclusions Cataract surgery significantly improved VRQOL among bilateral cataract patients in Vietnam. Contrast sensitivity as well as stereopsis, rather than visual acuity significantly affected VRQOL after cataract surgery.

Supporting residents’ expression of sexuality : the initial construction of a sexuality assessment tool for residential aged care facilities

Background: Sexuality is a key component of quality of life and well-being and a need to express one’s sexuality continues into old age. Staff and families in residential aged care facilities often find expressions of sexuality by residents, particularly those living with dementia, challenging and facilities often struggle to address individuals’ needs in this area. This paper describes the development of an assessment tool which enables residential aged care facilities to identify how supportive their organisation is of all residents’ expression of their sexuality, and thereby improve where required. Methods: Multi-phase design using qualitative methods and a Delphi technique. Tool items were derived from the literature and verified by qualitative interviews with aged care facility staff, residents and families. The final item pool was confirmed via a reactive Delphi process. Results: A final item pool of sixty-nine items grouped into seven key areas allows facilities to score their compliance with the areas identified as being supportive of older people’s expression of their sexuality in a residential aged care environment. Conclusions: The sexuality assessment tool (SexAT) guides practice to support the normalization of sexuality in aged care homes and assists facilities to identify where enhancements to the environment, policies, procedures and practices, information and education/training are required. The tool also enables facilities to monitor initiatives in these areas over time.

A comparison of Australian and Canadian informatics competencies for undergraduate nurses

Health information technologies (HIT) have changed healthcare delivery. Yet, there are few opportunities for student nurses in their undergraduate studies to develop nursing informatics competencies. More importantly, many countries around the world have not fully specified nursing informatics competencies that will be expected of student nurses prior to their graduation from undergraduate nursing programs. In this paper the authors compare and contrast the undergraduate nursing informatics competencies that were developed by two countries: Australia and Canada. They also identify some of the challenges and future research directions in the area.

Incidence of paediatric fatal and non-fatal low speed vehicle run over events in Queensland, Australia : eleven year analysis

Background The purpose of this study was to estimate the incidence of fatal and non-fatal Low Speed Vehicle Run Over (LSVRO) events among children aged 0–15 years in Queensland, Australia, at a population level. Methods Fatal and non-fatal LSVRO events that occurred in children resident in Queensland over eleven calendar years (1999-2009) were identified using ICD codes, text description, word searches and medical notes clarification, obtained from five health related data bases across the continuum of care (pre-hospital to fatality). Data were manually linked. Population data provided by the Australian Bureau of Statistics were used to calculate crude incidence rates for fatal and non-fatal LSVRO events. Results There were 1611 LSVROs between 1999–2009 (IR = 16.87/100,000/annum). Incidence of non-fatal events (IR = 16.60/100,000/annum) was 61.5 times higher than fatal events (IR = 0.27/100,000/annum). LSVRO events were more common in boys (IR = 20.97/100,000/annum) than girls (IR = 12.55/100,000/annum), and among younger children aged 0–4 years (IR = 21.45/100000/annum; 39% or all events) than older children (5–9 years: IR = 16.47/100,000/annum; 10–15 years IR = 13.59/100,000/annum). A total of 896 (56.8%) children were admitted to hospital for 24 hours of more following an LSVRO event (IR = 9.38/100,000/annum). Total LSVROs increased from 1999 (IR = 14.79/100,000) to 2009 (IR = 18.56/100,000), but not significantly. Over the 11 year period, there was a slight (non –significant) increase in fatalities (IR = 0.37-0.42/100,000/annum); a significant decrease in admissions (IR = 12.39–5.36/100,000/annum), and significant increase in non-admissions (IR = 2.02-12.77/100,000/annum). Trends over time differed by age, gender and severity. Conclusion This is the most comprehensive, population-based epidemiological study on fatal and non-fatal LSVRO events to date. Results from this study indicate that LSVROs incur a substantial burden. Further research is required on the characteristics and risk factors associated with these events, in order to adequately inform injury prevention. Strategies are urgently required in order to prevent these events, especially among young children aged 0-4 years.

Identification of eusynstyelamide B as a potent cell cycle inhibitor following the generation and screening of an ascidian-derived extract library using a real time cell analyzer

Ascidians are marine invertebrates that have been a source of numerous cytotoxic compounds. Of the first six marine-derived drugs that made anticancer clinical trials, three originated from ascidian specimens. In order to identify new anti-neoplastic compounds, an ascidian extract library (143 samples) was generated and screened in MDA-MB-231 breast cancer cells using a real-time cell analyzer (RTCA). This resulted in 143 time-dependent cell response profiles (TCRP), which are read-outs of changes to the growth rate, morphology, and adhesive characteristics of the cell culture. Twenty-one extracts affected the TCRP of MDA-MB-231 cells and were further investigated regarding toxicity and specificity, as well as their effects on cell morphology and cell cycle. The results of these studies were used to prioritize extracts for bioassay-guided fractionation, which led to the isolation of the previously identified marine natural product, eusynstyelamide B (1). This bis-indole alkaloid was shown to display an IC50 of 5 μM in MDA-MB-231 cells. Moreover, 1 caused a strong cell cycle arrest in G2/M and induced apoptosis after 72 h treatment, making this molecule an attractive candidate for further mechanism of action studies.

NT-ProBNP levels in saliva and its clinical relevance to heart failure

Background: Current blood based diagnostic assays to detect heart failure (HF) have large intra-individual and inter-individual variations which have made it difficult to determine whether the changes in the analyte levels reflect an actual change in disease activity. Human saliva mirrors the body's health and well being and similar to 20% of proteins that are present in blood are also found in saliva. Saliva has numerous advantages over blood as a diagnostic fluid which allows for a non-invasive, simple, and safe sample collection. The aim of our study was to develop an immunoassay to detect NT-proBNP in saliva and to determine if there is a correlation with blood levels. Methods: Saliva samples were collected from healthy volunteers (n = 40) who had no underlying heart conditions and HF patients (n = 45) at rest. Samples were stored at -80 degrees C until analysis. A customised homogeneous sandwich AlphaLISA((R)) immunoassay was used to quantify NT-proBNP levels in saliva. Results: Our NT-proBNP immunoassay was validated against a commercial Roche assay on plasma samples collected from HF patients (n = 37) and the correlation was r(2) = 0.78 (p<0.01, y = 1.705 x +1910.8). The median salivary NT-proBNP levels in the healthy and HF participants were <16 pg/mL and 76.8 pg/mL, respectively. The salivary NT-proBNP immunoassay showed a clinical sensitivity of 82.2% and specificity of 100%, positive predictive value of 100% and negative predictive value of 83.3%, with an overall diagnostic accuracy of 90.6%. Conclusion: We have firstly demonstrated that NT-proBNP can be detected in saliva and that the levels were higher in heart failure patients compared with healthy control subjects. Further studies will be needed to demonstrate the clinical relevance of salivary NT-proBNP in unselected, previously undiagnosed populations.

Tumor-suppressor gene promoter hypermethylation in saliva of head and neck cancer patients

Head and neck squamous cell carcinoma (HNSCC) accounts for a bulk of the oral and laryngeal cancers, the majority (70%) of which are associated with smoking and excessive drinking, major known risk factors for the development of HNSCC. In contrast to reports that suggest an inverse relationship between smoking and global DNA CpG methylation, hypermethylation of promoters of a number of genes was detected in saliva collected from patients with HNSCC. Using a sensitive methylation-specific polymerase chain reaction (MSP) assay to determine specific methylation events in the promoters of RASSF1A, DAPK1, and p16 genes, we demonstrate that we can detect tumor presence with an overall accuracy of 81% in the DNA isolated from saliva of patients with HNSCC (n = 143) when compared with the DNA isolated from the saliva of healthy nonsmoker controls (n = 31). The specificity for this MSP panel was 87% and the sensitivity was 80%(with a Fisher exact test P < .0001). In addition, the test panel performed extremely well in the detection of the early stages of HNSCCs, with a sensitivity of 94% and a specificity of 87%, and a high. concordance value of 0.8, indicating an excellent overall agreement between the presence of HNSCC and a positive MSP panel result. In conclusion, we demonstrate that the promoter methylation of RASSF1A, DAPK1, and p16 MSP panel is useful in detecting hypermethylation events in a noninvasive manner in patients with HNSCC.

What women want : qualitative analysis of consumer evaluations of maternity care in Queensland, Australia

Background Maternity care reform plans have been proposed at state and national levels in Australia, but the extent to which these respond to maternity care consumers’ expressed needs is unclear. This study examines open-text survey comments to identify women’s unmet needs and priorities for maternity care. It is then considered whether these needs and priorities are addressed in current reform plans. Methods Women who had a live single or multiple birth in Queensland, Australia, in 2010 (n 3,635) were invited to complete a retrospective self-report survey. In addition to questions about clinical and interpersonal maternity care experiences from pregnancy to postpartum, women were asked an open-ended question “Is there anything else you’d like to tell us about having your baby?” This paper describes a detailed thematic analysis of open-ended responses from a random selection of 150 women (10% of 1,510 who responded to the question). Results Four broad themes emerged relevant to improving women’s experiences of maternity care: quality of care (interpersonal and technical); access to choices and involvement in decision-making; unmet information needs; and dissatisfaction with the care environment. Some of these topics are reflected in current reform goals, while others provide evidence of the need for further reforms. Conclusions The findings reinforce the importance of some existing maternity reform objectives, and describe how these might best be met. Findings affirm the importance of information provision to enable informed choices; a goal of Queensland and national reform agendas. Improvement opportunities not currently specified in reform agendas were also identified, including the quality of interpersonal relationships between women and staff, particular unmet information needs (e.g., breastfeeding), and concerns regarding the care environment (e.g., crowding and long waiting times).

Creative occupations as knowledge practices : innovation and precarity in the creative economy

The ARC Centre of Excellence in Creative Industries and Innovation (herewith CCI) was established with two simple policy objectives. One was to assess anecdotal and boosterish claims about the growth rates of the creative industries, and hence, to measure the size of the creative industries contribution to gross domestic product (GDP). The other was to ascertain the contribution of the creative industries to employment. Preliminary research detailed in Cunningham and Higgs (2009) showed that the existing industrial classifications did not incorporate the terminology of the creative industries, nor did they disaggregate new categories of digital work such as video games. However, we discovered that occupational codes provide a much more fine-grained account of work that would enable us to disaggregate and track economic activity that corresponded to creative industries terminology. Thus was born one major centrepiece of CCI research – the tracking of national occupational codes in pursuit of measuring creative industries policy outcomes. This paper commences with some description of empirical work that investigates creative occupations; however, the real point is to suggest that this type of detailed, occupation-based empirical work has important theoretical potential that has not yet been fully expended (though see Cunningham 2013; Hearn and Bridgstock 2014; Bakhshi, Freeman and Higgs 2013; Hartley and Potts 2014).