Sortase A : an ideal target for anti-virulence drug development

Sortase A is a membrane enzyme responsible for the anchoring of surface-exposed proteins to the cell wall envelope of Gram-positive bacteria. As a well-studied member of the sortase subfamily catalysing the cell wall anchoring of important virulence factors to the surface of staphylococci, enterococci and streptococci, sortase A plays a critical role in Gram-positive bacterial pathogenesis. It is thus considered a promising target for the development of new anti-infective drugs that aim to interfere with important Gram-positive virulence mechanisms, such as adhesion to host tissues, evasion of host defences, and biofilm formation. The additional properties of sortase A as an enzyme that is not required for Gram-positive bacterial growth or viability and is conveniently located on the cell membrane making it more accessible to inhibitor targeting, constitute additional reasons reinforcing the view that sortase A is an ideal target for anti-virulence drug development. Many inhibitors of sortase A have been identified to date using high-throughput or in silico screening of compound libraries (synthetic or natural), and while many have proved useful tools for probing the action model of the enzyme, several are also promising candidates for the development into potent inhibitors. This review is focused on the most promising sortase A inhibitor compounds that are currently in development as leads towards a new class of anti-infective drugs that are urgently needed to help combat the alarming increase in antimicrobial resistance.

The perspectives of older drivers on the impact of feedback on their driving behaviours : a qualitative study

Self-regulation is a coping strategy that allows older drivers to drive safely for longer. Self-regulation depends largely on the ability of drivers to evaluate their own driving. Therefore the success of self-regulation, in terms of driving safety, is influenced by the ability of older drivers to have insight into their declining driving performance. In addition, previous studies suggest that providing feedback to older adults regarding their driving skills may lead them to change their driving behaviour. However, little is currently known about the impact of feedback on older drivers��� self-awareness and their subsequent driving regulatory behaviour. This study explored the process of self-regulation and driving cessation among older drivers using the PAPM as a framework. It also investigated older adults’ perceptions and opinions about receiving feedback in regards to their driving abilities. Qualitative focus groups with 27 participants aged 70 years or more were conducted. Thematic analysis resulted in the development of five main themes; the meaning of driving, changes in driving pattern, feedback, the planning process, and solutions. The analysis also resulted in an initial model of driving self-regulation among older drivers that is informed by the current research and the Precaution Adoption Process Model as the theoretical framework. It identifies a number of social, personal, and environmental factors that can either facilitate or hinder people’s transition between stages of change. The findings from this study suggest that further elaboration of the PAPM is needed to take into account the role of insight and feedback on the process of self-regulation among older drivers.

“I would have lost the respect of my friends and family if they knew I had bent the road rules” : parents, peers, and the perilous behaviour of young drivers

Young novice drivers are at considerable risk of injury on the road. Their behaviour appears vulnerable to the social influence of their parents and friends. The nature and mechanisms of parent and peer influence on young novice driver (16–25 years) behaviour was explored via small group interviews (n = 21) and two surveys (n1 = 1170, n2 = 390) to inform more effective young driver countermeasures. Parental and peer influence occurred in preLicence, Learner, and Provisional (intermediate) periods. Pre-Licence and unsupervised Learner drivers reported their parents were less likely to punish risky driving (e.g., speeding). These drivers were more likely to imitate their parents and reported their parents were also risky drivers. Young novice drivers who experienced or expected social punishments from peers, including ‘being told off’ for risky driving, reported less riskiness. Conversely drivers who experienced or expected social rewards such as being ‘cheered on’ by friends – who were also more risky drivers – reported more risky driving including crashes and offences. Interventions enhancing positive influence and curtailing negative influence may improve road safety outcomes not only for young novice drivers, but for all persons who share the road with them. Parent-specific interventions warrant further development and evaluation including: modelling safe driving behaviour by parents; active monitoring of driving during novice licensure; and sharing the family vehicle during the intermediate phase. Peer-targeted interventions including modelling of safe driving behaviour and attitudes; minimisation of social reinforcement and promotion of social sanctions for risky driving also need further development and evaluation.

The nature of errors made by drivers [Austroads Publication no: AP-R378-11]

It is important that we understand the factors and conditions that shape driver behaviour – those conditions within the road transport system that contribute to driver error and the situations where driver non-compliance to road regulations is likely. This report presents the findings derived from a program of research investigating the nature of errors made by drivers, involving a literature review and an on-road study. The review indicates that, despite significant investigation, the role of different error types in road traffic crashes remains unclear, as does the role of the wider road transport system failures in driver error causation.

Social and cultural drivers of incentive effectiveness in infrastructure projects

Formal incentives systems aim to encourage improved performance by offering a reward for the achievement of project-specific goals. Despite argued benefits of incentive systems on project delivery outcomes, there remains debate over how incentive systems can be designed to encourage the formation of strong project relationships within a complex social system such as an infrastructure project. This challenge is compounded by the increasing emphasis in construction management research on the important mediating influence of technical and organisational context on project performance. In light of this challenge, the research presented in this paper focuses on the design of incentive systems in four infrastructure projects: two road reconstructions in the Netherlands and two building constructions in Australia. Based on a motivational theory frame, a cross case analysis is conducted to examine differences and similarities across social and cultural drivers impacting on the effectiveness of the incentive systems in light of infrastructure project context. Despite significant differences in case project characteristics, results indicate the projects’ experience similar social drivers impacting on incentive effectiveness. Significant value across the projects was placed on: varied performance goals and multiple opportunities to across the project team to pursue incentive rewards; fair risk allocation across contract parties; value-driven tender selection; improved design-build integration; and promotion of future work opportunities. However, differences across the contexts were identified. Results suggest future work opportunities were a more powerful social driver in upholding reputation and establishing strong project relationships in the Australian context. On the other hand, the relationship initiatives in the Dutch context seemed to be more broadly embraced resulting in a greater willingness to collaboratively manage project risk. Although there are limitations with this research in drawing generalizations across two sets of case projects, the results provide a strong base to explore the social and cultural influences on incentive effectiveness across different geographical and contextual boundaries in future research.

Do we need a law to help people try experimental drugs?

People with life-threatening or incurable diseases may be willing to try experimental drugs and unproven treatments, but they face the risk of exploitation. Is the law the best avenue to ensure that they are protected while medical innovation is encouraged? Protection of vulnerable people is a thread running through many laws, in Australia and elsewhere. In medical law, for instance, children and people with impaired decision-making capacity warrant special attention. But what of the ordinary person diagnosed with a life-threatening disease? Such people are vulnerable to harm and potential exploitation when they seek access to innovative, experimental or unproven treatments that depart from the existing range of accepted medicine.

Antidepressant direct-to-consumer prescription drug advertising and public stigma of depression : the mediating role of perceived prevalence of depression

This study examines whether memory of antidepressant direct-to-consumer (DTC) prescription drug advertising is associated with the public stigma attached to depression. Results indicate that those who better remember antidepressant DTC ads tend to have a higher perceived prevalence of depression (i.e., more people suffer from depression). And, the perceived prevalence of depression is inversely associated with the public stigma toward depression. That is, those who have a higher perceived prevalence of depression report that they are more supportive of and comfortable with people who have depression. The results suggest that the perceived prevalence of depression is a mediating variable that accounts for the relationship between memory of antidepressant DTC ads and the public stigma toward depression. The implications and limitations of the study, as an exploratory investigation, are discussed.

Effect of mobile phone use and aggression on speed selection by young drivers : a driving simulator study

Aggressive driving has been associated with engagement in other risky driving behaviours, such as speeding; while drivers using their mobile phones have an increased crash risk, despite the tendency to reduce their speed. Research has amassed separately for mobile phone use and aggressive driving among younger drivers, however little is known about the extent to which these behaviours may function independently and in combination to influence speed selection behaviour. The main aim of the current study was to investigate the effect of driver aggression (measured by the Driving Anger Expression Inventory) and mobile phone use on speed selection by young drivers. The CARRS-Q advanced driving simulator was used to test the speed selection of drivers aged 18 to 26 years (N = 32) in a suburban (60kph zone) driving context. A 2 (level of driving anger expression: low, high) X 3 (mobile phone use condition: baseline, hands-free, hand-held) mixed factorial ANOVA was conducted with speed selection as the dependent variable. Results revealed a significant main effect for mobile phone use condition such that speed selection was lowest for the hand-held condition and highest for the baseline condition. Speed selection, however, was not significantly different across the levels of driving anger expression; nor was there a significant interaction effect between the mobile phone use and driving anger expression. As young drivers are over-represented in road crash statistics, future research should further investigate the combined impact of driver aggression and mobile phone use on speed selection.

Catching drink drivers in Queensland through Random Breath Testing : what does the last decade of data tell us

Background Random Breath Testing (RBT) has proven to be a cornerstone of enforcement attempts to deter (as well as apprehend) motorists from drink driving in Queensland (Australia) for decades. However, scant published research has examined the relationship between the frequency of implementing RBT activities and subsequent drink driving apprehension rates across time. Aim This study aimed to examine the prevalence of apprehending drink drivers in Queensland over a 12 year period. It was hypothesised that an increase in breath testing rates would result in a corresponding decrease in the frequency of drink driving apprehension rates over time, which would reflect general deterrent effects. Method The Queensland Police Service provided RBT data that was analysed. Results Between the 1st of January 2000 and 31st of December 2011, 35,082,386 random breath tests (both mobile and stationary) were conducted in Queensland, resulting in 248,173 individuals being apprehended for drink driving offences. A total of 342,801 offences were recorded during this period, representing an intercept rate of .96. Of these offences, 276,711 (80.72%) were recorded against males and 66,024 (19.28%) offences committed by females. The most common drink driving offence was between 0.05 and 0.08 BAC limit. The largest proportion of offences was detected on the weekends, with Saturdays (27.60%) proving to be the most common drink driving night followed by Sundays (21.41%). The prevalence of drink driving detection rates rose steadily across time, peaking in 2008 and 2009, before slightly declining. This decline was observed across all Queensland regions and any increase in annual figures was due to new offence types being developed. Discussion This paper will further outline the major findings of the study in regards to tailoring RBT operations to increase detection rates as well as improve the general deterrent effect of the initiative.

Using DNA as a drug - bioprocessing and delivery strategies

DNA may take a leading role in a future generation of blockbuster therapeutics. DNA has inherent advantages over other biomolecules such as protein, RNA and virus-like particles including safety, production simplicity and higher stability at ambient temperatures. Vaccination is the principal measure for preventing influenza and reducing the impact of pandemics; however, vaccines take up to 8-9 months to produce, and the global production capacity is woefully low. With production times as short as 2 weeks, improved safety and stability, bioprocess engineering developments, and the ability to perform numerous therapeutic roles, DNA has the potential to meet the demands of emerging and existing diseases. DNA is experiencing sharp growths in demand as indicated by its use in gene therapy trials and DNA vaccine related patents. Of particular interest for therapeutic use is plasmid DNA (pDNA), a form of non-genomic DNA that makes use of cellular machinery to express proteins or antigens. The production stages of fermentation and downstream purification are considered in this article. Forward looking approaches to purifying and delivering DNA are reported, including affinity chromatography and nasal inhalation. The place that pDNA may take in the preparation for and protection against pandemics is considered. If DNA therapeutics and vaccines prove to be effective, the ultimate scale of production will be huge which shall require associated bioprocess engineering research and development for purification of this large, unique biomolecule.

Using DNA as a drug : challenges and opportunities for process engineers

The maturing of the biotechnology industry and a focus on productivity has seen a shift from discovery science to small-scale bench-top research to higher productivity, large scale production. Health companies are aggressively expanding their biopharmaceutical interests, an expansion which is facilitated by biochemical and bioprocess engineering. An area of continuous growth is vaccines. Vaccination will be a key intervention in the case of an influenza pandemic. The global manufacturing capacity for fast turn around vaccines is currently woefully inadequate at around 300 million shots. As the prevention of epidemics requires > 80 % vaccination, in theory the world should currently be aiming for the ability to produce around 5.3 billion vaccines. Presented is a production method for the creation of a fast turn around DNA vaccine. A DNA vaccine could have a production time scale of as little as two weeks. This process has been harnessed into a pilot scale production system for the creation of a pre-clinical grade malaria vaccine in a collaborative project with the Coppel Lab, Department of Microbiology, Monash University. In particular, improvements to the fermentation, chromatography and delivery stages will be discussed. Consideration will then be given as to how the fermentation stage affects the mid and downstream processing stages.