Canagliflozin : something new for type 2 diabetes, but is it safe and efficacious?

Evaluation of Inagaki N, Kondo K, Yoshinari T, et al. Efficacy and safety of canagliflozin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, 12-week study. Diabetes Obes Metab 2013. [Epub ahead of print] and Cefalu WT, Leiter LA, Yoon KH, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomized, double-blind, phase 3 non-inferiority trial. Lancet 2013;382:941-50 INTRODUCTION Inhibition of the sodium-glucose cotransporter 2 (SGLT2), to promote the excretion of glucose, is a new paradigm in the treatment of type 2 diabetes. AREAS COVERED Canagliflozin is an SGLT2 inhibitor, which has been the subject of two recent clinical trials, which are evaluated. EXPERT OPINION Studies with canagliflozin, in subjects with type 2 diabetes, have shown that its use is associated with reductions in HbA1c and body weight and small reductions in blood pressure and triglycerides, while increasing high-density lipoprotein cholesterol and low-density lipoprotein cholesterol. As monotherapy in Japanese subjects, or in comparison with glimepiride in CANTATA-SU (CANagliflozin Treatment and Trial Analysis versus SUlphonylurea), canagliflozin causes a low incidence of hypoglycemia, and this is an advantage over glimepiride. However, one of the disadvantages with canagliflozin, which was also highlighted in CANTATA-SU, is that canagliflozin can cause urogenital infections, which are not observed with other antidiabetic drugs. The Federal Drug Administration has recently approved canagliflozin for use in type 2 diabetes, while directing that a clinical outcome safety trial be undertaken. We are concerned that canagliflozin has been approved for use in type 2 diabetes prior to a clinical outcome study of efficacy being undertaken and without the outcome of further safety testing.

Bang and bust: almost everything you wanted to know about sex and the mining boom (but were afraid to ask)

Recent growth and expansion of the fly-in/fly-out (FIFO) model of mining in remote rural Australia has led to concerns about the health and well-being of those employed by the mines and those in the small rural communities where they are based. A particular concern has been the potential disruption to sexual norms in mining towns and increases in sexually transmitted infections (STIs) and HIV.

Introduction - There's crime out there, but not as we know it: Rural criminology - the last frontier

The idea that crime is a predominantly urban phenomenon has been pervasive in criminology, so much so that Australian criminology textbooks do not recognise rural crime as a distinct phenomenon worthy of scholarly attention (see Chappell & Wilson, 2000; Goldsmith et al, 2003; White & Haines, 2004; White & Habibis, 2005). There are no chapters or sections in Australian texts which specifically examine rural crime, despite the inclusion of a range of topics that appear to provide a broad coverage of crime in its many temporal and spatial dimensions. Nor is there so much as an index reference to "rural" issues in criminology textbooks. The standardised syllabus for crime texts provides coverage of topics such as violent crime, public crime, delinquency, race and crime, gender and crime, and crime and social class. This canon is mirrored in international texts, most of which also fail to address the issue of rural crime, but make abundant reference to crime in various urban contexts (see Carrabine et al, 2004; Conklin, 2004). This is not to suggest that Australian texts fail to localise their subject matter.

Plant diversity predicts beta but not alpha diversity of soil microbes across grasslands worldwide

Aboveground–belowground interactions exert critical controls on the composition and function of terrestrial ecosystems, yet the fundamental relationships between plant diversity and soil microbial diversity remain elusive. Theory predicts predominantly positive associations but tests within single sites have shown variable relationships, and associations between plant and microbial diversity across broad spatial scales remain largely unexplored. We compared the diversity of plant, bacterial, archaeal and fungal communities in one hundred and forty-five 1 m2 plots across 25 temperate grassland sites from four continents. Across sites, the plant alpha diversity patterns were poorly related to those observed for any soil microbial group. However, plant beta diversity (compositional dissimilarity between sites) was significantly correlated with the beta diversity of bacterial and fungal communities, even after controlling for environmental factors. Thus, across a global range of temperate grasslands, plant diversity can predict patterns in the composition of soil microbial communities, but not patterns in alpha diversity.

Cuelure but not zingerone make the sex pheromone of male Bactrocera tryoni (Tephritidae: Diptera) more attractive to females

In tephritid fruit flies of the genus Bactrocera Macquart, a group of plant derived compounds (sensu amplo ‘male lures') enhance the mating success of males that have consumed them. For flies responding to the male lure methyl eugenol, this is due to the accumulation of chemicals derived from the male lure in the male rectal gland (site of pheromone synthesis) and the subsequent release of an attractive pheromone. Cuelure, raspberry ketone and zingerone are a second, related group of male lures to which many Bactrocera species respond. Raspberry ketone and cuelure are both known to accumulate in the rectal gland of males as raspberry ketone, but it is not known if the emitted male pheromone is subsequently altered in complexity or is more attractive to females. Using Bactrocera tryoni as our test insect, and cuelure and zingerone as our test chemicals, we assess: (i) lure accumulation in the rectal gland; (ii) if the lures are released exclusively in association with the male pheromone; and (iii) if the pheromone of lure-fed males is more attractive to females than the pheromone of lure-unfed males. As previously documented, we found cuelure was stored in its hydroxyl form of raspberry ketone, while zingerone was stored largely in an unaltered state. Small but consistent amounts of raspberry ketone and β-(4-hydroxy-3-methoxyphenyl)-propionic acid were also detected in zingerone-fed flies. Males released the ingested lures or their analogues, along with endogenous pheromone chemicals, only during the dusk courtship period. More females responded to squashed rectal glands extracted from flies fed on cuelure than to glands from control flies, while more females responded to the pheromone of calling cuelure-fed males than to control males. The response to zingerone treatments in both cases was not different from the control. The results show that male B. tryoni release ingested lures as part of their pheromone blend and, at least for cuelure, this attracts more females.

Andrew Bolt isn't a racist, but ...

The Coalition's push to make changes to the Racial Discrimination Act was in part a response to a court ruling that Andrew Bolt had breached the Act over his comments about Aboriginal Australians. Here, Chelsea Bond revisits the newspaper columnist's treatment of Aboriginality, explaining that race is more than skin deep.

Now we can “see the forest and the trees too” but there are risks : Camera trapping and privacy law in Australia

The use of camera traps in wildlife management is an increasingly common practice. A phenomenon which is also becoming more common is for such camera traps to unintentionally film individuals engaged in a variety of activities, ranging from the innocent to the nefarious and including lewd or potentially embarrassing behaviour. It is therefore possible for the use of camera traps to accidentally encroach upon the privacy rights of persons who venture into the area of surveillance. In this chapter we describe the legal framework of privacy in Australia and discuss the potential risk of this sleeping tiger for users of camera traps. We also present the results of a survey of camera trap users to assess the frequency of such unintended captures and the nature of activity being filmed before discussing the practical implications of these laws for camera traps users in this country and make recommendations.

Not just what they want, but why they want it: Traditional market research to deep customer insights

Purpose This paper explores advantages and disadvantages of both traditional market research and deep customer insight methods in order to lay the platform for revealing how a relationship between these two domains could be optimised during firm-based innovation. Design/methodology/approach The paper reports on an empirical research study conducted with thirteen Australian based firms engaged in a design-led approach to innovation. Firms were facilitated through a design-led approach where the process of gathering deep customer insights was isolated and investigated further in comparison to traditional market research methods. Findings Results show that deep customer insight methods are able to provide fresh, non-obvious ways of understanding customer needs, problems and behaviours that can become the foundation of new business opportunities. Findings concluded that deep customer insights methods provide the critical layer to understand why customers do and don’t engage with businesses. Revealing why was not accessible in traditional market research methods. Research limitations/implications The theoretical outcome of this study is a complementary methods matrix, providing guidance on appropriate implementation of research methods in accordance with a project’s timeline to optimise the complementation of traditional market research methods with design-led customer engagement methods. Practical implications Deep customer insight methods provide fresh, non-obvious ways of understanding customer needs, problems and behaviours that can become the foundation of new business opportunities. It is hoped that those in a position of data collection are encouraged to experiment and use deep customer insight methods to connect with their customers on a meaningful level and translate these insights into value. Originality/value This paper provides original value to a new understanding how design techniques can be applied to compliment and strengthen existing market research strategies. This is crucial in an era where business competition hinges on a subtle and often intimate understanding of customer needs and behaviours.

But how do we know they watched it? Adapting to the flipped classroom conundrum

Those who teach film and media need to use screen content to illustrate their subjects. For example, students want illustrations to accompany lectures on film or television genres. Our experience has been that student access to the film and television screen content underpinning a study of genres is not only desirable but is, in fact, crucial for effective teaching and learning outcomes. Not so long ago, a screening during or at the completion of a lecture was the expected method by which educators delivered screen content to illustrate their teaching. Even if student attendance fluctuated from week to week a quick head count confirmed that a certain number of students were physically present. It was assumed that this physical attendance encouraged students to reflect upon and contextualize the material post lecture. While simply attending a lecture will not translate into actual student learning, it does demonstrate a willingness by students to engage with the course content by making a commitment to attend a scheduled and recurring lecture and screening program. However, as flipped classroom models gain acceptance in educational institutions, this traditional lecture-screening model is giving way to online, off-site, and student-controlled mechanisms for screen content delivery and viewing. Nevertheless, care should be taken when assessing how online delivery translates into student engagement and learning. As Junco (2012) points out, “it’s not the technology that generates learning, but the ways in which the technology are used.” Discussed, debated, and embraced to varying degrees by educators, there remains no definitive model for the flipped classroom – although many models involve ‘flipping’ content and knowledge acquisition (including viewing films and television shows) from scheduled on-campus classes to online material viewed by students in advance of an on-campus lecture or class. The classroom or tutorial room then becomes a space to problem-solve, engage in collaborate learning, and advance and explain concepts. From an institutional perspective, the flipped classroom model could deliver an additional benefit beyond immediate pedagogical concerns. Tucker (2012) suggests through the flipped classroom model “all aspects of instruction can be rethought to best maximize the scarcest learning resource — time.” The narrative most often associated with this shift is that the move to online content delivery of lecture and cinematic / televisual material may also provide educators with more time to do other work such as engage in research, plan strategies to empower students. Experimentation with the flipped classroom model is playing out in various educational institutions. Yet several core concerns remain — one of these concerns is the crucial question of whether an online/digital flipped approach is more effective for student engagement and learning than the traditional lecture-screening mode for screen content delivery. Some urge caution in this regard, arguing that “new technology isn’t always supported by change management and professional development to ensure that digital isn’t just a goal within itself, but actually helps to transform education” (Fleming cited in Blain 2014). The most fundamental concern remains how do lecturers, instructors, and tutors know students have watched the films and television shows associated with a subject? The remainder of this discussion deals with these concerns, and possible solutions offered, through an analysis of the Film, Television and Screen Genres subject at the Queensland University of Technology (QUT) in Brisbane, Queensland.

Nursing and medical perceptions of a hospital rapid response system: New process but same old game?

Perhaps no other patient safety intervention depends so acutely on effective interprofessional teamwork for patient survival than the hospital rapid response system (RRS). Yet little is known about nurse-physician relationships when rescuing at-risk patients. This study compared nursing and medical staff perceptions of a mature RRS at a large tertiary hospital. Findings indicate the RRS may be failing to address a hierarchical culture and systems-level barriers to early recognition and response to patient deterioration.

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10−14, odds ratio = 0.86, 95% confidence interval = 0.82–0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.

Antidepressants, but not antipsychotics, modulate GR function in human whole blood: An insight into molecular mechanisms

Clinical studies have demonstrated an impairment of glucocorticoid receptor (GR)-mediated negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis in patients with major depression (GR resistance), and its resolution by antidepressant treatment. Recently, we showed that this impairment is indeed due to a dysfunction of GR in depressed patients (Carvalho et al., 2009), and that the ability of the antidepressant clomipramine to decrease GR function in peripheral blood cells is impaired in patients with major depression who are clinically resistant to treatment (Carvalho et al. 2008). To further investigate the effect of antidepressants on GR function in humans, we have compared the effect of the antidepressants clomipramine, amytriptiline, sertraline, paroxetine and venlafaxine, and of the antipsychotics, haloperidol and risperidone, on GR function in peripheral blood cells from healthy volunteers (n=33). GR function was measured by glucocorticoid inhibition of lypopolysaccharide (LPS)-stimulated interleukin-6 (IL-6) levels. Compared to vehicle-treated cells, all antidepressants inhibited dexamethasone (DEX, 10-100nM) inhibition of LPS-stimulated IL-6 levels (p values ranging from 0.007 to 0.1). This effect was specific to antidepressants, as antipsychotics had no effect on DEX-inhibition of LPS-stimulated IL-6 levels. The phosphodiesterase (PDE) type 4 inhibitor, rolipram, potentiated the effect of antidepressants on GR function, while the GR antagonist, RU-486, inhibited the effect of antidepressants on GR function. These findings indicate that the effect of antidepressants on GR function are specific for this class of psychotropic drugs, and involve second messenger pathways relevant to GR function and inflammation. Furthermore, it also points towards a possible mechanism by which one maybe able to overcome treatment-resistant depression. Research in this field will lead to new insights into the pathophysiology and treatment of affective disorders.

Someone else's boom but always our bust: Australia as a derivative economy, implications for regions

This paper examines the socio-economic impact of mineral and agricultural resource extraction on local communities and explores policy options for addressing them. An emphasis on the marketisation of services together with tight fiscal control has reinforced decline in many country communities in Australia and elsewhere. However, the introduction by the European Union of Regional Policy which emphasises ‘smart specialisation’ can enhance greatly the capacity of local people to generate decent livelihoods. For this to have real effect, the innovative state has to enable partnerships between communities, researchers and industry. For countries like Australia, this would be a substantive policy shift.

Murine, but not human, ephrin-B2 can be efficiently cleaved by the serine protease kallikrein-4: Implications for xenograft models of human prostate cancer

Background Ephrin-B2 is the sole physiologically-relevant ligand of the receptor tyrosine kinase EphB4, which is over-expressed in many epithelial cancers, including 66% of prostate cancers, and contributes to cancer cell survival, invasion and migration. Crucially, however, the cancer-promoting EphB4 signalling pathways are independent of interaction with its ligand ephrin-B2, as activation of ligand-dependent signalling causes tumour suppression. Ephrin-B2, however, is often found on the surface of endothelial cells of the tumour vasculature, where it can regulate angiogenesis to support tumour growth. Proteolytic cleavage of endothelial cell ephrin-B2 has previously been suggested as one mechanism whereby the interaction between tumour cell-expressed EphB4 and endothelial cell ephrin-B2 is regulated to support both cancer promotion and angiogenesis. Methods An in silico approach was used to search accessible surfaces of 3D protein models for cleavage sites for the key prostate cancer serine protease, KLK4, and this identified murine ephrin-B2 as a potential KLK4 substrate. Mouse ephrin-B2 was then confirmed as a KLK4 substrate by in vitro incubation of recombinant mouse ephrin-B2 with active recombinant human KLK4. Cleavage products were visualised by SDS-PAGE, silver staining and Western blot and confirmed by N-terminal sequencing. Results At low molar ratios, KLK4 cleaved murine ephrin-B2 but other prostate-specific KLK family members (KLK2 and KLK3/PSA) were less efficient, suggesting cleavage was KLK4-selective. The primary KLK4 cleavage site in murine ephrin-B2 was verified and shown to correspond to one of the in silico predicted sites between extracellular domain residues arginine 178 and asparagine 179. Surprisingly, the highly homologous human ephrin-B2 was poorly cleaved by KLK4 at these low molar ratios, likely due to the 3 amino acid differences at this primary cleavage site. Conclusion These data suggest that in in vivo mouse xenograft models, endogenous mouse ephrin-B2, but not human tumour ephrin-B2, may be a downstream target of cancer cell secreted human KLK4. This is a critical consideration when interpreting data from murine explants of human EphB4+/KLK4+ cancer cells, such as prostate cancer cells, where differential effects may be seen in mouse models as opposed to human clinical situations.