miR-514a regulates the tumour suppressor NF1 and modulates BRAFi sensitivity in melanoma

To identify ‘melanoma-specific’ microRNAs (miRNAs) we used an unbiased microRNA profiling approach to comprehensively study cutaneous melanoma in relation to other solid malignancies, which revealed 233 differentially expressed (≥ 2 fold, p < 0.05) miRNAs. Among the top 20 most significantly different miRNAs was hsa-miR-514a-3p. miR-514a is a member of a cluster of miRNAs (miR-506-514) involved in initiating melanocyte transformation and promotion of melanoma growth. We found miR-514a was expressed in 38/55 (69%) melanoma cell lines but in only 1/34 (3%) other solid cancers. To identify miR-514a regulated targets we conducted a miR-514a-mRNA ‘pull-down’ experiment, which revealed hundreds of genes, including: CTNNB1, CDK2, MC1R, and NF1, previously associated with melanoma. NF1 was selected for functional validation because of its recent implication inacquired resistance to BRAFV600E-targeted therapy. Luciferase-reporter assays confirmed NF1 as a direct target of miR-514a and over-expression of miR-514a in melanoma cell lines inhibited NF1 expression, which correlated with increased survival of BRAFV600E cells treated with PLX4032. These data provide another mechanism for the dysregulation of the MAPK pathway which may contribute to the profound resistance associated with current RAF-targeted therapies.

Serum immunoreactive cationic trypsinogen: A useful indicator of severe exocrine dysfunction in the paediatric patient without cystic fibrosis

We evaluated serum cationic trypsinogen as a marker of exocrine pancreatic function in children without cystic fibrosis. The ability of this test to determine steatorrhoea of pancreatic origin, and its relationship to a wide range of exocrine pancreatic function were assessed. Serum trypsinogen was measured in 32 children with steatorrhoea, 10 with pancreatic and 22 with non-pancreatic causes. In patients with pancreatic steatorrhoea, serum cationic trypsinogen was 4·9±4·9 μg/l (mean ±SD), significantly below values in patients with non-pancreatic steatorrhoea (47·0±22·1 μg/l, p<0·001) and 50 control subjects (31·4±7·4 μg/l, p<0·001). Serum cationic trypsinogen values in patients with pancreatic steatorrhoea all fell below the lower limit of our control range and below all values for patients with non-pancreatic steatorrhoea. Serum cationic trypsinogen was also evaluated against pancreatic trypsin output in 47 patients (range 0·2-17·0 yr) who underwent a hormonal pancreatic stimulation test. In 17 patients, serum cationic trypsinogen was low (<-2SD or 16·6 μg/l), and associated with greatly impaired pancreatic trypsin output, ranging from 0-8% of mean normal trypsin output. Five of these 17 patients did not have steatorrhoea. In 30 patients with normal or raised serum cationic trypsinogen (≥16·6 μg/l), pancreatic trypsin output ranged from 15-183% of mean normal values. In conclusion, low serum cationic trypsinogen suggests severely impaired exocrine pancreatic function, with sensitivity extending above the steatorrhoeic threshold. In the presence of steatorrhoea, low serum cationic trypsinogen indicates a pancreatic aetiology. Normal serum cationic trypsinogen, however, does not exclude impaired pancreatic function, above the steatorrhoeic threshold.

Limitations of the manual supination resistance test

The aim of this study was to asses results obtained from a range of commonly performed lower extremity “open and closed” chain kinetic tests used for predicting foot function and correlate these test findings to data obtained from the Zebris WinFDM-T system®. When performed correctly these tests are thought to be indicators of lower extremity function. Podiatrists frequently perform examinations of joint and muscle structures to understand biomechanical function; however the relationship between these routine tests and forces generated during the gait cycle are not always well understood. This can introduce a degree of variability in clinical interpretation which creates conjecture regarding the value of these tests.

Guaiac versus immunochemical tests: Faecal occult blood test screening for colorectal cancer in a rural community

Objective: To describe patient participation and clinical performance in a colorectal cancer (CRC) screening program utilising faecal occult blood test (FOBT). Methods: A community-based intervention was conducted in a small, rural community in north Queensland, 2000/01. One of two FOBT kits – guaiac (Hemoccult-ll) or immunochemical (Inform) – was assigned by general practice and mailed to participants (3,358 patients aged 50–74 years listed with the local practices). Results: Overall participation in FOBT screening was 36.3%. Participation was higher with the immunochemical kit than the guaiac kit (OR=1.9, 95% Cl 1.6-2.2). Women were more likely to comply with testing than men (OR=1.4, 95% Cl 1.2-1.7), and people in their 60s were less likely to participate than those 70–74 years (OR=0.8, 95% Cl 0.6-0.9). The positivity rate was higher for the immunochemical (9.5%) than the guaiac (3.9%) test (χ2=9.2, p=0.002), with positive predictive values for cancer or adenoma of advanced pathology of 37.8% (95% Cl 28.1–48.6) for !nform and 40.0% (95% Cl 16.8–68.7) for Hemoccult-ll. Colonoscopy follow-up was 94.8% with a medical complication rate of 2–3%. Conclusions: An immunochemical FOBT enhanced participation. Higher positivity rates for this kit did not translate into higher false-positive rates, and both test types resulted in a high yield of neoplasia. Implications: In addition to type of FOBT, the ultimate success of a population-based screening program for CRC using FOBT will depend on appropriate education of health professionals and the public as well as significant investment in medical infrastructure for colonoscopy follow-up.

Evaluation of a Drunk Driving Warning System

The Drunk Driving Warning System is an alcohol interlock based on performance of the Critical Tracking Task (CTT). An evaluation was undertaken to determine CTT sensitivity to blood alcohol concentration (BAC), particularly at .05 g/100 ml. Subjects were 36 males in 3 age groups (18, 21 to 25, 35 years and above) divided into 2 alcohol consumption categories ("light" and "heavy"), and scored on 4 training and 2 test days (one alcohol and one placebo). The CTT performance declined as BAC increased and was significantly impaired at .05 BAC. However, performance was too variable for in-vehicle use. Age and alcohol consumption pattern were without effect.

Real-time wide-area loading margin sensitivity (WALMS) in power systems

Loading margin sensitivity (LMS) has been widely used in applications in the realm of voltage stability assessment and control. Typically, LMS is derived based on system equilibrium equations near bifurcation and therefore requires full detailed system model and significant computation effort. Availability of phasor measurement units (PMUs) due to the recent development of wide-area monitoring system (WAMS) provides an alternative computation-friendly approach for calculating LMS. With such motivation, this work proposes measurement-based wide-area loading margin sensitivity (WALMS) in bulk power systems. The proposed sensitivity, with its simplicity, has great potential to be embedded in real-time applications. Moreover, the calculation of the WALMS is not limited to low voltage near bifurcation point. A case study on IEEE 39-bus system verifies the proposed sensitivity. Finally, a voltage control scenario demonstrates the potential application of the WALMS.

A versatile gene-based test for genome-wide association studies

We have derived a versatile gene-based test for genome-wide association studies (GWAS). Our approach, called VEGAS (versatile gene-based association study), is applicable to all GWAS designs, including family-based GWAS, meta-analyses of GWAS on the basis of summary data, and DNA-pooling-based GWAS, where existing approaches based on permutation are not possible, as well as singleton data, where they are. The test incorporates information from a full set of markers (or a defined subset) within a gene and accounts for linkage disequilibrium between markers by using simulations from the multivariate normal distribution. We show that for an association study using singletons, our approach produces results equivalent to those obtained via permutation in a fraction of the computation time. We demonstrate proof-of-principle by using the gene-based test to replicate several genes known to be associated on the basis of results from a family-based GWAS for height in 11,536 individuals and a DNA-pooling-based GWAS for melanoma in approximately 1300 cases and controls. Our method has the potential to identify novel associated genes; provide a basis for selecting SNPs for replication; and be directly used in network (pathway) approaches that require per-gene association test statistics. We have implemented the approach in both an easy-to-use web interface, which only requires the uploading of markers with their association p-values, and a separate downloadable application.

A simple and fast two-locus quality control test to detect false positives due to batch effects in genome-wide association studies

The impact of erroneous genotypes having passed standard quality control (QC) can be severe in genome-wide association studies, genotype imputation, and estimation of heritability and prediction of genetic risk based on single nucleotide polymorphisms (SNP). To detect such genotyping errors, a simple two-locus QC method, based on the difference in test statistic of association between single SNPs and pairs of SNPs, was developed and applied. The proposed approach could detect many problematic SNPs with statistical significance even when standard single SNP QC analyses fail to detect them in real data. Depending on the data set used, the number of erroneous SNPs that were not filtered out by standard single SNP QC but detected by the proposed approach varied from a few hundred to thousands. Using simulated data, it was shown that the proposed method was powerful and performed better than other tested existing methods. The power of the proposed approach to detect erroneous genotypes was approximately 80% for a 3% error rate per SNP. This novel QC approach is easy to implement and computationally efficient, and can lead to a better quality of genotypes for subsequent genotype-phenotype investigations.

Stopover destination image: Using the repertory test to identify salient attributes

This paper reports a rare investigation of stopover destination image. Although the topic of destination image has been one of the most popular in the tourism literature since the 1970s, there has been a lack of research attention in relation to the context of stopover destinations for long haul international travellers. The purpose of this study was to identify attributes deemed salient to Australian consumers when considering stopover destinations for long haul travel to the United Kingdom and Europe. Underpinned by Personal Construct Theory (PCT), the study used the Repertory Test to identify 21 salient attributes, which could be used in the development of a survey instrument to measure the attractiveness of a competitive set of stopover destinations. While the list of attributes shared some commonality with general studies of destination image reported in the literature, the elicitation of a relatively large number of stopover context specific attributes highlights the potential benefit of engaging with consumers in qualitative research, such as using the Repertory Test, during the questionnaire development stage.

Prediction of masonry compressive behaviour using a damage mechanics inspired modelling method

Masonry under compression is affected by the properties of its constituents and their interfaces. In spite of extensive investigations of the behaviour of masonry under compression, the information in the literature cannot be regarded as comprehensive due to ongoing inventions of new generation products – for example, polymer modified thin layer mortared masonry and drystack masonry. As comprehensive experimental studies are very expensive, an analytical model inspired by damage mechanics is developed and applied to the prediction of the compressive behaviour of masonry in this paper. The model incorporates a parabolic progressively softening stress-strain curve for the units and a progressively stiffening stress-strain curve until a threshold strain for the combined mortar and the unit-mortar interfaces is reached. The model simulates the mutual constraints imposed by each of these constituents through their respective tensile and compressive behaviour and volumetric changes. The advantage of the model is that it requires only the properties of the constituents and considers masonry as a continuum and computes the average properties of the composite masonry prisms/wallettes; it does not require discretisation of prism or wallette similar to the finite element methods. The capability of the model in capturing the phenomenological behaviour of masonry with appropriate elastic response, stiffness degradation and post peak softening is presented through numerical examples. The fitting of the experimental data to the model parameters is demonstrated through calibration of some selected test data on units and mortar from the literature; the calibrated model is shown to predict the responses of the experimentally determined masonry built using the corresponding units and mortar quite well. Through a series of sensitivity studies, the model is also shown to predict the masonry strength appropriately for changes to the properties of the units and mortar, the mortar joint thickness and the ratio of the height of unit to mortar joint thickness. The unit strength is shown to affect the masonry strength significantly. Although the mortar strength has only a marginal effect, reduction in mortar joint thickness is shown to have a profound effect on the masonry strength. The results obtained from the model are compared with the various provisions in the Australian Masonry Structures Standard AS3700 (2011) and Eurocode 6.

Making decisions about antibiotic use in the Australian primary healthcare sector

Background Australia has one of the highest rates of antibiotic use amongst OECD countries. Data from the Australian primary healthcare sector suggests unnecessary antibiotics were prescribed for self-resolving conditions. We need to better understand what drives general practitioners (GPs) to prescribe antibiotics, consumers to seek antibiotics, and pharmacists to fill repeat antibiotic prescriptions. It is also not clear how these individuals trade-off between the possible benefits that antibiotics may provide in the immediate/short term, against the longer term societal risk of antimicrobial resistance. This project investigates what factors drive decisions to use antibiotics for GPs, pharmacists and consumers, and how these individuals discount the future. Methods Factors will be gleaned from published literature and from semi-structured interviews, to inform the development of Discrete Choice Experiments (DCEs). Three DCEs will be constructed – one for each group of interest – to allow investigation of which factors are more important in influencing (a) GPs to prescribe antibiotics, (b) consumers to seek antibiotics, and (c) pharmacists to fill legally valid but old or repeat prescriptions of antibiotics. Regression analysis will be conducted to understand the relative importance of these factors. A Time Trade Off exercise will be developed to investigate how these individuals discount the future. Results Findings from the DCEs will provide an insight into which factors are more important in driving decision making in antibiotic use for GPs, pharmacists and consumers. Findings from the Time Trade Off exercise will show what individuals are willing to trade for preserving the miracle of antibiotics. Conclusion Research findings will contribute to existing national programs to bring about a reduction in inappropriate use of antibiotic in Australia. Specifically, influencing how key messages and public health campaigns are crafted, and clinical education and empowerment of GPs and pharmacists to play a more responsive role as stewards of antibiotic use in the community.

What consumers think, do and say about antibiotic use

Objective The objectives of this study were to investigate (1) the attitudes and behaviours of Australian consumers in antibiotic use, and (2) their understanding of antibiotic resistance. Methods Semi-structured interviews were conducted with consumers in May/June 2015. Convenience sampling was used to recruit consumers between 18–54 years old. Thirty-two consumers were interviewed. Transcripts were analysed to identify themes. Lessons Learned Dominant themes for attitudes and behaviours regarding antibiotics were (a) avoidance of antibiotic use unless clinically warranted; (b) antibiotics were useful but “weakened the body”; and (c) use of complementary medicines as adjuncts to antibiotics or to strengthen the immune system. Key information needs were (a) unambiguous instructions from GPs when prescribed antibiotics, to avoid inappropriate medicine-taking behaviour; (b) rationale for antibiotic selection; and (c) treatment duration. Antibiotic resistance was conceptualised in three ways: as a property of the body (body becomes resistant to antibiotics); the medication (antibiotic no longer effective); and the bacteria (bacteria is resistant). Antibiotic resistance was perceived as an issue that would only affect the wider community in the future, although most recognised that it is a current challenge for hospitals. Personal good health and/or avoidance of antibiotics were perceived as insurance against being adversely affected by antibiotic resistance. Implications A structured survey (discrete choice experiment) will be developed from these findings to investigate how consumers trade-off on factors influencing antibiotic use. Public health campaigns promoting conservation of antibiotics can benefit from these findings.

Questionable antibiotic practices: Obtaining reliable estimates of consumer behaviours

Background: Significant recent attention has focussed on the role of antibiotic prescribing and usage with the aim of combating antibiotic resistance, a growing worldwide health concern. A significant gap in this literature concerns the consumption patterns and beliefs of consumers about antibiotics and their effects. We seek to remedy this gap by exploring a range of questionable antibiotic practices and obtaining reliable estimates of their prevalence as well as their normative status. Methods: We conducted an online survey of over 100 consumers. We used a new incentive compatible technique, the Bayesian Truth Serum (BTS), to elicit more truthful responding than standard self-report measures. We asked participants to indicate whether they engaged in a number of practices including whether they had: taken antibiotics when they are out of date and stored antibiotics at home for later use. We then sought estimates of the percentage of other patients (like them) who had engaged in each behaviour, as well as asking them among those patients who had, the percentage that would admit to having done so. We also asked about social acceptability and responsibility of the practices. Results: These results will show for each type of questionable practice how prevalent it is and whether consumers view it as both socially acceptable and socially responsible. We will gain the relative prevalence of each of these practices. Conclusion: These findings are of paramount importance in gaining a better understanding of consumers’ antibiotic consumption patterns. These will be vital for better targeting educational campaigns to lower inappropriate antibiotic consumption.

Benefits and challenges of antivirulence antimicrobials at the dawn of the post-antibiotic era

In April 2014, the World Health Organization announced the beginning of a post-antibiotic era and declared antimicrobial resistance (AMR) a public health priority demanding global action. If no action is taken, by 2050 AMR will kill more people each year than cancer, with 10 million estimated annual deaths at a cost of $100 trillion to the global economy. New therapies to tackle multidrug resistant bacterial pathogens are urgently needed. Unlike traditional antibiotics, antivirulence drugs inhibit bacterial virulence instead of growth promising to offer a new class of superior therapeutics that will be ‘evolution-proof’ and ‘tailored-spectrum’. This mini-review discusses the latest emerging evidence on the promised benefits of antivirulence drugs over conventional antibiotics, also highlighting the challenges in evaluating these properties for each of the diverse virulence targets that are currently under investigation. The author argues that overcoming such challenges early in the development process constitutes an important step towards successfully progressing each of the expanding number of antivirulence strategies into next-generation therapies for common human and animal infections that are becoming increasingly refractory to all available antibiotics.

The role of 25-hydroxyvitamin D deficiency in promoting insulin resistance and inflammation in patients with chronic kidney disease: A randomised controlled trial

BACKGROUND Approximately 50% of patients with stage 3 Chronic Kidney Disease are 25-hydroxyvitamin D insufficient, and this prevalence increases with falling glomerular filtration rate. Vitamin D is now recognised as having pleiotropic roles beyond bone and mineral homeostasis, with the vitamin D receptor and metabolising machinery identified in multiple tissues. Worryingly, recent observational data has highlighted an association between hypovitaminosis D and increased cardiovascular mortality, possibly mediated via vitamin D effects on insulin resistance and inflammation. The main hypothesis of this study is that oral Vitamin D supplementation will ameliorate insulin resistance in patients with Chronic Kidney Disease stage 3 when compared to placebo. Secondary hypotheses will test whether this is associated with decreased inflammation and bone/adipocyte-endocrine dysregulation. METHODS/DESIGN This study is a single-centre, double-blinded, randomised, placebo-controlled trial. Inclusion criteria include; estimated glomerular filtration rate 30-59 ml/min/1.73 m(2); aged >or=18 on entry to study; and serum 25-hydroxyvitamin D levels <75 nmol/L. Patients will be randomised 1:1 to receive either oral cholecalciferol 2000IU/day or placebo for 6 months. The primary outcome will be an improvement in insulin sensitivity, measured by hyperinsulinaemic euglycaemic clamp. Secondary outcome measures will include serum parathyroid hormone, cytokines (Interleukin-1beta, Interleukin-6, Tumour Necrosis Factor alpha), adiponectin (total and High Molecular Weight), osteocalcin (carboxylated and under-carboxylated), peripheral blood mononuclear cell Nuclear Factor Kappa-B p65 binding activity, brachial artery reactivity, aortic pulse wave velocity and waveform analysis, and indirect calorimetry. All outcome measures will be performed at baseline and end of study. DISCUSSION To date, no randomised controlled trial has been performed in pre-dialysis CKD patients to study the correlation between vitamin D status with supplementation, insulin resistance and markers of adverse cardiovascular risk. We remain hopeful that cholecalciferol may be a safe intervention, with health benefits beyond those related to bone-mineral homeostasis. TRIAL REGISTRATION Australian and New Zealand Clinical Trials Registry ACTRN12609000246280.