Drink and drug driving in Australian young adult users and non-users of illicit stimulants

- Introduction There is limited understanding of how young adults’ driving behaviour varies according to long-term substance involvement. It is possible that regular users of amphetamine-type stimulants (i.e. ecstasy (MDMA) and methamphetamine) may have a greater predisposition to engage in drink/drug driving compared to non-users. We compare offence rates, and self-reported drink/drug driving rates, for stimulant users and non-users in Queensland, and examine contributing factors. - Methods The Natural History Study of Drug Use is a prospective longitudinal study using population screening to recruit a probabilistic sample of amphetamine-type stimulant users and non-users aged 19-23 years. At the 4 ½ year follow-up, consent was obtained to extract data from participants’ Queensland driver records (ATS users: n=217, non-users: n=135). Prediction models were developed of offence rates in stimulant users controlling for factors such as aggression and delinquency. - Results Stimulant users were more likely than non-users to have had a drink-driving offence (8.7% vs. 0.8%, p < 0.001). Further, about 26% of ATS users and 14% of non-users self-reported driving under the influence of alcohol during the last 12 months. Among stimulant users, drink-driving was independently associated with last month high-volume alcohol consumption (Incident Rate Ratio (IRR): 5.70, 95% CI: 2.24-14.52), depression (IRR: 1.28, 95% CI: 1.07-1.52), low income (IRR: 3.57, 95% CI: 1.12-11.38), and male gender (IRR: 5.40, 95% CI: 2.05-14.21). - Conclusions Amphetamine-type stimulant use is associated with increased long-term risk of drink-driving, due to a number of behavioural and social factors. Inter-sectoral approaches which target long-term behaviours may reduce offending rates.

Effect of an interactive therapeutic robotic animal on engagement, mood states, agitation and psychotropic drug use in people with dementia: A cluster-randomised controlled trial protocol

Introduction: Apathy, agitated behaviours, loneliness and depression are common consequences of dementia. This trial aims to evaluate the effect of a robotic animal on behavioural and psychological symptoms of dementia in people with dementia living in long-term aged care. Methods and analysis: A cluster-randomised controlled trial with three treatment groups: PARO (robotic animal), Plush-Toy (non-robotic PARO) or Usual Care (Control). The nursing home sites are Australian Government approved and accredited facilities of 60 or more beds. The sites are located in South-East Queensland, Australia. A sample of 380 adults with a diagnosis of dementia, aged 60 years or older living in one of the participating facilities will be recruited. The intervention consists of three individual 15 min non-facilitated sessions with PARO or Plush- Toy per week, for a period of 10 weeks. The primary outcomes of interest are improvement in agitation, mood states and engagement. Secondary outcomes include sleep duration, step count, change in psychotropic medication use, change in treatment costs, and staff and family perceptions of PARO or Plush-Toy. Video data will be analysed using Noldus XT Pocket Observer; descriptive statistics will be used for participants’ demographics and outcome measures; cluster and individual level analyses to test all hypotheses and Generalised Linear Models for cluster level and Generalised Estimation Equations and/or Multi-level Modeling for individual level data. Ethics and dissemination: The study participants or their proxy will provide written informed consent. The Griffith University Human Research Ethics Committee has approved the study (NRS/03/14/HREC). The results of the study will provide evidence of the efficacy of a robotic animal as a psychosocial treatment for the behavioural and psychological symptoms of dementia. Findings will be presented at local and international conference meetings and published in peer-reviewed journals.

Formulation and characterization of drug-loaded microparticles using distillers dried grain kafirin

Kafirin, a protein extracted from sorghum grain, has been formulated into microparticles and proposed for use as a delivery system owing to the resistance of kafirin to upper gastrointestinal digestion. However, extracting kafirin from sorghum distillers dried grains with solubles (DDGS) may be more efficient, because the carbohydrate component has been removed by fermentation. This study investigated the properties and use of kafirin extracted from DDGS to formulate microparticles. Prednisolone, an anti-inflammatory drug that could benefit from a delayed and targeted delivery system to the colon, was loaded into DDGS kafirin microparticles by phase separation with sodium chloride. Scanning electron micrographs revealed that the empty and prednisolone-loaded microparticles were round in shape and varied in size. Surface binding studies indicated prednisolone was loaded within the microparticles rather than being solely bound on the surface. These findings demonstrate DDGS kafirin can be formulated into microparticles and loaded with medication. Future studies could investigate the potential applications of DDGS kafirin microparticles as an orally administered targeted drug-delivery system.

There is 'hope for you yet': The female drug offender in sentencing discourse

Language and gender research has, in recent years, emphasised the importance of examining the context-specific ways in which people ‘do gender’ in different situations. In this paper, we explore how women involved in drug offences, specifically methamphetamine manufacture offences, are constructed within the language of the courts. Thirty-six sentencing transcripts from the New Zealand courts were examined to investigate how such offences, committed by women, are understood. In order to explore the representation of female offenders, a critical discourse analytic approach was adopted. Such an approach recognises that linguistic modes not only create and legitimise power inequalities but also embody a specific worldview. Three gendered discourses were identified in the sentencing texts: (i) the discourse of femininity, reinforcing the socially prescribed female role; (ii) the discourse of aberration, concerning women who breach traditional gender role expectations, and; (iii) the discourse of salvation, presenting aberrant women with an opportunity to become ‘good’ women once again. The findings illustrate the ways in which processes of gendering take place within a specific community of practice: the courtroom.

Age-related changes in hepatic function: An update on implications for drug therapy

The accumulation of deficits with increasing age results in a decline in the functional capacity of multiple organs and systems. These changes can have a significant influence on the pharmacokinetics and pharmacodynamics of prescribed drugs. Although alterations in body composition and worsening renal clearance are important considerations, for most drugs the liver has the greatest effect on metabolism. Age-related change in hepatic function thereby causes much of the variability in older people’s responses to medication. In this review, we propose that a decline in the ability of the liver to inactivate toxins may contribute to a proinflammatory state in which frailty can develop. Since inflammation also downregulates drug metabolism, medication prescribed to frail older people in accordance with disease-specific guidelines may undergo reduced systemic clearance, leading to adverse drug reactions, further functional decline and increasing polypharmacy, exacerbating rather than ameliorating frailty status. We also describe how increasing chronological age and frailty status impact liver size, blood flow and protein binding and enzymes of drug metabolism. This is used to contextualise our discussion of appropriate prescribing practices. For example, while the general axiom of ‘start low, go slow’ should underpin the initiation of medication (titrating to a defined therapeutic goal), it is important to consider whether drug clearance is flow or capacity-limited. By summarising the effect of age-related changes in hepatic function on medications commonly used in older people, we aim to provide a guide that will have high clinical utility for practising geriatricians.

The antihypertensive drug pindolol attenuates long-term but not short-term binge-like ethanol consumption in mice

Alcohol dependence is a debilitating disorder with current therapies displaying limited efficacy and/or compliance. Consequently, there is a critical need for improved pharmacotherapeutic strategies to manage alcohol use disorders (AUDs). Previous studies have shown that the development of alcohol dependence involves repeated cycles of binge-like ethanol intake and abstinence. Therefore, we used a model of binge-ethanol consumption (drinking-in-the-dark) in mice to test the effects of compounds known to modify the activity of neurotransmitters implicated in alcohol addiction. From this, we have identified the FDA-approved antihypertensive drug pindolol, as a potential candidate for the management of AUDs. We show that the efficacy of pindolol to reduce ethanol consumption is enhanced following long-term (12-weeks) binge-ethanol intake, compared to short-term (4-weeks) intake. Furthermore, pindolol had no effect on locomotor activity or consumption of the natural reward sucrose. Because pindolol acts as a dual beta-adrenergic antagonist and 5-HT1A/1B partial agonist, we examined its effect on spontaneous synaptic activity in the basolateral amygdala (BLA), a brain region densely innervated by serotonin- and norepinephrine-containing fibres. Pindolol increased spontaneous excitatory post-synaptic current frequency in BLA principal neurons from long-term ethanol consuming mice but not naïve mice. Additionally, this effect was blocked by the 5-HT1A/1B receptor antagonist methiothepin, suggesting that altered serotonergic activity in the BLA may contribute to the efficacy of pindolol to reduce ethanol intake following long-term exposure. Although further mechanistic investigations are required, this study demonstrates the potential of pindolol as a new treatment option for AUDs that can be fast-tracked into human clinical studies.

Evaluation of a workplace alcohol and other drug policy

BACKGROUND The current impetus for developing alcohol and/or other drugs (AODs) workplace policies in Australia is to reduce workplace AOD impairment, improve safety, and prevent AOD-related injury in the workplace. For these policies to be effective, they need to be informed by scientific evidence. Evidence to inform the development and implementation of effective workplace AOD policies is currently lacking. There does not currently appear to be conclusive evidence for the effectiveness of workplace AOD policies in reducing impairment and preventing AOD-related injury. There is also no apparent evidence regarding which factors facilitate or impede the success of an AOD policy, or whether, for example, unsuccessful policy outcomes were due to poor policy or merely poor implementation of the policy. It was the aim of this research to undertake a process, impact, and outcome evaluation of a workplace AOD policy, and to contribute to the body of knowledge on the development and implementation of effective workplace AOD policies. METHODS The research setting was a state-based power-generating industry in Australia between May 2008 and May 2010. Participants for the process evaluation study were individuals who were integral to either the development or the implementation of the workplace AOD policy, or both of these processes (key informants), and comprised the majority of individuals who were involved in the process of developing and/or implementing the workplace AOD policy. The sample represented the two main groups of interest—management and union delegates/employee representatives—from all three of the participating organisations. For the impact and outcome evaluation studies, the population included all employees from the three participating organisations, and participants were all employees who consented to participate in the study and who completed both the pre-and post-policy implementation questionnaires. Qualitative methods in the form of interviews with key stakeholders were used to evaluate the process of developing and implementing the workplace AOD policy. In order to evaluate the impact of the policy with regard to the risk factors for workplace AOD impairment, and the outcome of the policy in terms of reducing workplace AOD impairment, quantitative methods in the form of a non-randomised single group pre- and post-test design were used. Changes from Time 1 (pre) to Time 2 (post) in the risk factors for workplace AOD impairment, and changes in the behaviour of interest—(self-reported) workplace AOD impairment—were measured. An integration of the findings from the process, impact, and outcome evaluation studies was undertaken using a combination of qualitative and quantitative methods. RESULTS For the process evaluation study Study respondents indicated that their policy was developed in the context of comparable industries across Australia developing workplace AOD policies, and that this was mainly out of concern for the deleterious health and safety impacts of workplace AOD impairment. Results from the process evaluation study also indicated that in developing and implementing the workplace AOD policy, there were mainly ‗winners', in terms of health and safety in the workplace. While there were some components of the development and implementation of the policy that were better done than others, and the process was expensive and took a long time, there were, overall, few unanticipated consequences to implementing the policy and it was reported to be thorough and of a high standard. Findings also indicated that overall the policy was developed and implemented according to best-practice in that: consultation during the policy development phase (with all the main stakeholders) was extensive; the policy was comprehensive; there was universal application of the policy to all employees; changes in the workplace (with regard to the policy) were gradual; and, the policy was publicised appropriately. Furthermore, study participants' responses indicated that the role of an independent external expert, who was trusted by all stakeholders, was integral to the success of the policy. For the impact and outcome evaluation studies Notwithstanding the limitations of pre- and post-test study designs with regard to attributing cause to the intervention, the findings from the impact evaluation study indicated that following policy implementation, statistically significant positive changes with regard to workplace AOD impairment were recorded for the following variables (risk factors for workplace AOD impairment): Knowledge; Attitudes; Perceived Behavioural Control; Perceptions of the Certainty of being punished for coming to work impaired by AODs; Perceptions of the Swiftness of punishment for coming to work impaired by AODs; and Direct and Indirect Experience with Punishment Avoidance for workplace AOD impairment. There were, however, no statistically significant positive changes following policy implementation for Behavioural Intentions, Subjective Norms, and Perceptions of the Severity of punishment for workplace AOD impairment. With regard to the outcome evaluation, there was a statistically significant reduction in self-reported workplace AOD impairment following the implementation of the policy. As with the impact evaluation, these findings need to be interpreted in light of the limitations of the study design in being able to attribute cause to the intervention alone. The findings from the outcome evaluation study also showed that while a positive change in self-reported workplace AOD impairment following implementation of the policy did not appear to be related to gender, age group, or employment type, it did appear to be related to levels of employee general alcohol use, cannabis use, site type, and employment role. Integration of the process, impact, and outcome evaluation studies There appeared to be qualitative support for the relationship between the process of developing and implementing the policy, and the impact of the policy in changing the risk factors for workplace AOD impairment. That is, overall the workplace AOD policy was developed and implemented well and, following its implementation, there were positive changes in the majority of measured risk factors for workplace AOD impairment. Quantitative findings lend further support for a relationship between the process and impact of the policy, in that there was a statistically significant association between employee perceived fidelity of the policy (related to the process of the policy) and positive changes in some risk factors for workplace AOD impairment (representing the impact of the policy). Findings also indicated support for the relationship between the impact of the policy in changing the risk factors for workplace AOD impairment and the outcome of the policy in reducing workplace AOD impairment: positive changes in the risk factors for workplace AOD impairment (impact) were related to positive changes in self reported workplace AOD impairment (representing the main goal and outcome of the policy). CONCLUSIONS The findings from the research indicate support for the conclusion that the policy was appropriately implemented and that it achieved its objectives and main goal. The Doctoral research findings also addressed a number of gaps in the literature on workplace AOD impairment, namely: the likely effectiveness of AOD policies for reducing AOD impairment in the workplace, which factors in the development and implementation of a workplace AOD policy are likely to facilitate or impede the effectiveness of the policy to reduce workplace AOD impairment, and which employee groups are less likely to respond well to policies of this type. The findings from this research not only represent an example of translational, applied research—through the evaluation of the study industry's policy—but also add to the body of knowledge on workplace AOD policies and provide policy-makers with evidence which may be useful in the development and implementation of effective workplace AOD policies. Importantly, the findings espouse the importance of scientific evidence in the development, implementation, and evaluation of workplace AOD policies.

Drug discovery approaches utilizing three-dimensional cell culture

Historically, two-dimensional (2D) cell culture has been the preferred method of producing disease models in vitro. Recently, there has been a move away from 2D culture in favor of generating three-dimensional (3D) multicellular structures, which are thought to be more representative of the in vivo environment. This transition has brought with it an influx of technologies capable of producing these structures in various ways. However, it is becoming evident that many of these technologies do not perform well in automated in vitro drug discovery units. We believe that this is a result of their incompatibility with high-throughput screening (HTS). In this study, we review a number of technologies, which are currently available for producing in vitro 3D disease models. We assess their amenability with high-content screening and HTS and highlight our own work in attempting to address many of the practical problems that are hampering the successful deployment of 3D cell systems in mainstream research.

The gradual release of responsibility: A case study of teaching science inquiry skills

This thesis investigated how a year-4 teacher used a pedagogical approach referred to as the Gradual Release of Responsibility (GRR) model of instruction for teaching Science Inquiry Skills in a primary classroom. Through scaffolding her students' learning using the GRR, the teacher guided her students towards developing an understanding about Scientific Inquiry leading to the foundations of scientific literacy. A learning environment was established in which students engaged in rich conversations, designed and conducted experiments using fair testing procedures, analysed and offered justifications for results, and negotiated knowledge claims in ways similar to some of those in the scientific community.

Occupational release of engineered nanoparticles: A review

Characterising the release of different types of Engineered Nanoparticles (ENPs) from various processes is of critical importance for the assessment of human exposure, as well as understanding the possible health effects of these particles. Therefore, the main aim of this chapter is to present a comprehensive review of studies which report on the release of airborne ENPs in different nanotechnology workplaces. The chapter will cover topics of relevance to the occupational characterisation of ENP emissions, ranging from the identification of different particle release sources and scenarios, to measurement methods and working towards a more uniform approach to characterisation. Furthermore, a brief review of ENP exposure control strategies, together with the application of mathematical modelling as an effective tool for the characterisation of emissions at nanotechnology workplaces is included.

Computational analyses of the catalytic and heparin-binding sites and their interactions with glycosaminoglycans in glycoside hydrolase family 79 endo-d-glucuronidase (heparanase)

Mammalian heparanase is an endo-β-glucuronidase associated with cell invasion in cancer metastasis, angiogenesis and inflammation. Heparanase cleaves heparan sulfate proteoglycans in the extracellular matrix and basement membrane, releasing heparin/heparan sulfate oligosaccharides of appreciable size. This in turn causes the release of growth factors, which accelerate tumor growth and metastasis. Heparanase has two glycosaminoglycan-binding domains; however, no three-dimensional structure information is available for human heparanase that can provide insights into how the two domains interact to degrade heparin fragments. We have constructed a new homology model of heparanase that takes into account the most recent structural and bioinformatics data available. Heparin analogs and glycosaminoglycan mimetics were computationally docked into the active site with energetically stable ring conformations and their interaction energies were compared. The resulting docked structures were used to propose a model for substrates and conformer selectivity based on the dimensions of the active site. The docking of substrates and inhibitors indicates the existence of a large binding site extending at least two saccharide units beyond the cleavage site (toward the nonreducing end) and at least three saccharides toward the reducing end (toward heparin-binding site 2). The docking of substrates suggests that heparanase recognizes the N-sulfated and O-sulfated glucosamines at subsite +1 and glucuronic acid at the cleavage site, whereas in the absence of 6-O-sulfation in glucosamine, glucuronic acid is docked at subsite +2. These findings will help us to focus on the rational design of heparanase-inhibiting molecules for anticancer drug development by targeting the two heparin/heparan sulfate recognition domains.

Diverse populations of T cells with NK cell receptors accumulate in the human intestine in health and in colorectal cancer

T cells expressing NK cell receptors (NKR) display rapid MHC-unrestricted cytotoxicity and potent cytokine secretion and are thought to play roles in immunity against tumors. We have quantified and characterized NKR+ T cells freshly isolated from epithelial and lamina propria layers of duodenum and colon from 16 individuals with no evidence of gastrointestinal disease and from tumor and uninvolved tissue from 19 patients with colorectal cancer. NKR+ T cell subpopulations were differentially distributed in different intestinal compartments, and CD161+ T cells accounted for over one half of T cells at all locations tested. Most intestinal CD161+ T cells expressed alpha beta TCR and either CD4 or CD8. Significant proportions expressed HLA-DR,CD69 and Fas ligand. Upon stimulation in vitro, CD161+ T cells produced IFN-gamma and TNF-alpha but not IL-4. NKT cells expressing the Valpha24Vbeta11 TCR, which recognizes CD1d,were virtually absent from the intestine, but colonic cells produced IFN-gamma in response to the NKT cell agonist ligand alpha-galactosylceramide. NKR+ T cells were not expanded in colonic tumors compared to adjacent uninvolved tissue. The predominance, heterogeneity and differential distribution of NKR+ T cells at different intestinal locations suggests that they are central to intestinal immunity.

Effect of deletion of Ghrelin-O-Acyltransferase on the pulsatile release of growth hormone in mice

Ghrelin, a gut hormone originating from the post-translational cleavage of preproghrelin, is the endogenous ligand of growth hormone secretagogue receptor 1a (GHS-R1a). Within the growth hormone (GH) axis, the biological activity of ghrelin requires octanoylation by ghrelin-O-acyltransferase (GOAT), conferring selective binding to the GHS-R1a receptor via acylated ghrelin. Complete loss of preproghrelin-derived signalling (through deletion of the Ghrl gene) contributes to a decline in peak GH release; however, the selective contribution of endogenous acyl-ghrelin to pulsatile GH release remains to be established. We assessed the pulsatile release of GH in ad lib. fed male germline goat−/− mice, extending measures to include mRNA for key hypothalamic regulators of GH release, and peripheral factors that are modulated relative to GH release. The amount of GH released was reduced in young goat−/− mice compared to age-matched wild-type mice, whereas pulse frequency and irregularity increased. Altered GH release did not coincide with alterations in hypothalamic Ghrh, Srif, Npy or Ghsr mRNA expression, or pituitary GH content, suggesting that loss of Goat does not compromise canonical mechanisms that contribute to pituitary GH production and release. Although loss of Goat resulted in an irregular pattern of GH release (characterised by an increase in the number of GH pulses observed during extended secretory events), this did not contribute to a change in the expression of sexually dimorphic GH-dependent liver genes. Of interest, circulating levels of insulin-like growth factor (IGF)-1 were elevated in goat−/− mice. This rise in circulating levels of IGF-1 was correlated with an increase in GH pulse frequency, suggesting that sustained or increased IGF-1 release in goat−/− mice may occur in response to altered GH release patterning. Our observations demonstrate that germline loss of Goat alters GH release and patterning. Although the biological relevance of altered GH secretory patterning remains unclear, we propose that this may contribute to sustained IGF-1 release and growth in goat−/− mice.

Prostate cancer organoids: A potential new tool for testing drug sensitivity

Recent technical advances have enabled for the first time, reliable in vitro culture of prostate cancer samples as prostate cancer organoids. This breakthrough provides the significant possibility of high throughput drug screening covering the spectrum of prostate cancer phenotypes seen clinically. These advances will enable precision medicine to become a reality, allowing patient samples to be screened for effective therapeutics ex vivo, with tailoring of treatments specific to that individual. This will hopefully lead to enhanced clinical outcomes, avoid morbidity due to ineffective therapies and improve the quality of life in men with advanced prostate cancer.