Quantifying uncertainty in parameter estimates for stochastic models of collective cell spreading using approximate Bayesian computation

Wound healing and tumour growth involve collective cell spreading, which is driven by individual motility and proliferation events within a population of cells. Mathematical models are often used to interpret experimental data and to estimate the parameters so that predictions can be made. Existing methods for parameter estimation typically assume that these parameters are constants and often ignore any uncertainty in the estimated values. We use approximate Bayesian computation (ABC) to estimate the cell diffusivity, D, and the cell proliferation rate, λ, from a discrete model of collective cell spreading, and we quantify the uncertainty associated with these estimates using Bayesian inference. We use a detailed experimental data set describing the collective cell spreading of 3T3 fibroblast cells. The ABC analysis is conducted for different combinations of initial cell densities and experimental times in two separate scenarios: (i) where collective cell spreading is driven by cell motility alone, and (ii) where collective cell spreading is driven by combined cell motility and cell proliferation. We find that D can be estimated precisely, with a small coefficient of variation (CV) of 2–6%. Our results indicate that D appears to depend on the experimental time, which is a feature that has been previously overlooked. Assuming that the values of D are the same in both experimental scenarios, we use the information about D from the first experimental scenario to obtain reasonably precise estimates of λ, with a CV between 4 and 12%. Our estimates of D and λ are consistent with previously reported values; however, our method is based on a straightforward measurement of the position of the leading edge whereas previous approaches have involved expensive cell counting techniques. Additional insights gained using a fully Bayesian approach justify the computational cost, especially since it allows us to accommodate information from different experiments in a principled way.

Cultural safety, diversity and the servicer user and carer movement in mental health research

This study will be of interest to anyone concerned with a critical appraisal of mental health service users’ and carers’ participation in research collaboration and with the potential of the postcolonial paradigm of cultural safety to contribute to the service user research (SUR) movement. The history and nature of the mental health field and its relationship to colonial processes provokes a consideration of whether cultural safety could focus attention on diversity, power imbalance, cultural dominance and structural inequality, identified as barriers and tensions in SUR. We consider these issues in the context of state-driven approaches towards SUR in planning and evaluation and the concurrent rise of the SUR movement in the UK and Australia, societies with an intimate involvement in processes of colonisation. We consider the principles and motivations underlying cultural safety and SUR in the context of the policy agenda informing SUR. We conclude that while both cultural safety and SUR are underpinned by social constructionism constituting similarities in principles and intent, cultural safety has additional dimensions. Hence, we call on researchers to use the explicitly political and self-reflective process of cultural safety to think about and address issues of diversity, power and social justice in research collaboration.

Oncology service initiatives and research in regional Australia

Objective: This paper reflects on the recent growth of cancer research being conducted through some of Australia’s rural centres. It encompasses work being done across the fields of clinical, translational and health services research. Design: This is a collaborative piece with contributions from rural health researchers, clinical and cancer services staff from several different regions. Conclusion: The past decade has seen an expansion in cancer research in rural and regional Australia driven in part by the recognition that cancer patients in remote areas experience poorer outcomes than their metropolitan counterparts. This work has led to the development of more effective cancer networks and new models of care designed to meet the particular needs of the rural cancer patient. It is hoped that the growth of cancer research in regional centres will, in time, reduce the disparity between rural and urban communities and improve outcomes for cancer patients across both populations.

Modular design of profluorescent polymer sensors

A simple modular strategy for the synthesis of profluorescent nitroxide containing polymers is described. The incorporation of an epoxide as a pendant functionality on a polymer backbone synthesized using ATRP and subsequent nucleophilic ring-opening with sodium azide gave hydroxyl and azide functionality within a 3-bond radius. Orthogonal coupling chemistry then allowed the independent attachment of fluorophore and nitroxide groups in close proximity, giving rise to a profluorescent polymer. Validation of the viability of these materials as fluorescent sensors is demonstrated through efficient fluorescence switch-on observed when the materials are exposed to a model reductant or carbon-centred radical source.

Report to VicRoads: Vehicle based sanctions to address drink driving

Licence sanctions including suspension, disqualification, or revocation have been effective in reducing recidivism and crash rates among those convicted of driving while under the influence of alcohol and/or drugs. Nonetheless, studies have indicated that many offenders continue to drive while they are unlicensed. Consequently, more recent attention has been given to vehicle sanctions that separate the offender from their vehicle. Vehicle based interventions focus on incapacitating the vehicle or separating it from the offending driver rather than relying on the threat of further sanctions to encourage compliance. Following on from a previous review conducted by Dr. Ron Christie (2006) for VicRoads, which examined the effectiveness of vehicle based sanctions in deterring unlicensed driving, this report considers the effectiveness of the aforementioned vehicle based sanctions for addressing drink driving.

Teaching scenario analysis – An action learning pedagogy

In this paper we provide an introduction to our teaching of scenario analysis. Scenario analysis offers an excellent instructional vehicle for investigating ‘wicked problems’; issues that are complex and ambiguous and require trans-disciplinary inquiry. We outline the pedagogical underpinning based on action learning and provide a critical approach from the intuitive logics school of scenario analysis. We use this in our programme in which student groups engage in semi-structured, but divergent and inclusive analysis of a selected focal issue. They then develop a set of scenario storylines that outline the limits of possibility and plausibility for a selected time-horizon year. The scenarios are portrayed not as narratives, but as vehicles for exploration of the causes and outcomes of the interplay between forces in the contextual environment that drive the unfolding future in the context of the focal issue. In this way, we provide internally-generated challenges to both individual pre-conceptions and group-level thinking.

EVpedia: A community web portal for extracellular vesicles research

Motivation Extracellular vesicles (EVs) are spherical bilayered proteolipids, harboring various bioactive molecules. Due to the complexity of the vesicular nomenclatures and components, online searches for EV-related publications and vesicular components are currently challenging. Results We present an improved version of EVpedia, a public database for EVs research. This community web portal contains a database of publications and vesicular components, identification of orthologous vesicular components, bioinformatic tools and a personalized function. EVpedia includes 6879 publications, 172 080 vesicular components from 263 high-throughput datasets, and has been accessed more than 65 000 times from more than 750 cities. In addition, about 350 members from 73 international research groups have participated in developing EVpedia. This free web-based database might serve as a useful resource to stimulate the emerging field of EV research. Availability and implementation The web site was implemented in PHP, Java, MySQL and Apache, and is freely available at http://evpedia.info.

Business Ecosystems’ Evolution — An Ecosystem Clockspeed Perspective

There is a growing need for measures assessing technological changes in systemic contexts as business ecosystems replace standalone products. In these ecosystem contexts, organizations are required to manage their innovation processes in increasingly networked and complex environments. In this paper, we introduce the technology and ecosystem clockspeed measures that can be used to assess the temporal nature of technological changes in a business ecosystem. We analyze systemic changes in the personal computer (PC) ecosystem, explicitly focusing on subindustries central to the delivery of PC gaming value to the end user. Our results show that the time-based intensity of technological competition in intertwined subindustries of a business ecosystem may follow various trajectories during the evolution of the ecosystem. Hence, the technology and ecosystem clockspeed measures are able to pinpoint alternating dynamics in technological changes among the subindustries in the business ecosystem. We subsequently discuss organizational considerations and theoretical implications of the proposed measures.

Application of fragment-based screening to the design of inhibitors of Escherichia coli DsbA

The thiol-disulfide oxidoreductase enzyme DsbA catalyzes the formation of disulfide bonds in the periplasm of Gram-negative bacteria. DsbA substrates include proteins involved in bacterial virulence. In the absence of DsbA, many of these proteins do not fold correctly, which renders the bacteria avirulent. Thus DsbA is a critical mediator of virulence and inhibitors may act as antivirulence agents. Biophysical screening has been employed to identify fragments that bind to DsbA from Escherichia coli. Elaboration of one of these fragments produced compounds that inhibit DsbA activity in vitro. In cell-based assays, the compounds inhibit bacterial motility, but have no effect on growth in liquid culture, which is consistent with selective inhibition of DsbA. Crystal structures of inhibitors bound to DsbA indicate that they bind adjacent to the active site. Together, the data suggest that DsbA may be amenable to the development of novel antibacterial compounds that act by inhibiting bacterial virulence.

From ‘free’ to fee: Acceptability of airline ancillary fees and the effects on customer behavior

Businesses in various consumer service industries have begun to unbundle their service offerings by introducing numerous fees for products and services that were previously provided as “free.” Anecdotal evidence in the media indicates that these fees cause widespread public displeasure, frustration, and outrage. This paper develops a framework of fee acceptability, negative emotions, and dysfunctional customer behavior, which is tested using data from the airline industry. Findings identify the strongest effects on betrayal in the case of baggage fees, followed by charges for comfort. Also, betrayal has a direct effect on complaining, whereas anger mediates the relationship between betrayal and negative word of mouth.

A mercurial treaty: The Trans-Pacific Partnership (# TPP) and the United States

According to the United States Trade Representative (USTR), Ron Kirk, the Trans-Pacific Partnership is “an ambitious, next-generation, Asia-Pacific trade agreement that reflects U.S. priorities and values”.

New England Youth Speeding Project: A pilot study of young drivers and risky driving: Effective strategies for preventing speeding amongst young Australians aged 16-25 years in the New England Region

Young Australian drivers aged 17 – 25 years are overwhelmingly represented in road fatalities where speed is a factor. In the combined LGAs of Armidale Dumaresq, Guyra, Uralla and Walcha in the 5 years 1999-2003 inclusive, 43% of speeding related casualty crashes involved a young driver aged less than 25 years. This is despite the fact that the 17-25 age group account for only 25% of the driving population in this area. Young male drivers account for the majority of these crashes and also tend to have a higher number of driving offences and accrue more penalties for road traffic offences, especially speeding. By analysing data from questionnaires by male and female participants this research project has been able to evaluate road safety advertisements to determine which ones are most effective to young drivers, what features of these advertisements are effective, how males differ from females in their receptiveness and preferences for road safety advertisements and specifically how to target young people especially young men in conveying road safety messages. Finally this research project has identified factors that are important in the production of media road safety advertisements and has made recommendations for how best to convey effective road safety messages to young Australian drivers in rural areas.

Integration of Geospatial and Built Environment - National Data Policy

Digital technology offers enormous benefits (economic, quality of design and efficiency in use) if adopted to implement integrated ways of representing the physical world in a digital form. When applied across the full extent of the built and natural world, it is referred to as the Digital Built Environment (DBE) and encompasses a wide range of approaches and technology initiatives, all aimed at the same end goal: the development of a virtual world that sufficiently mirrors the real world to form the basis for the smart cities of the present and future, enable efficient infrastructure design and programmed maintenance, and create a new foundation for economic growth and social well-being through evidence-based analysis. The creation of a National Data Policy for the DBE will facilitate the creation of additional high technology industries in Australia; provide Governments, industries and citizens with greater knowledge of the environments they occupy and plan; and offer citizen-driven innovations for the future. Australia has slipped behind other nations in the adoption and execution of Building Information Modelling (BIM) and the principal concern is that the gap is widening. Data driven innovation added $67 billion to the Australian economy in 20131. Strong open data policy equates to $16 billion in new value2. Australian Government initiatives such as the Digital Earth inspired “National Map” offer a platform and pathway to embrace the concept of a “BIM Globe”, while also leveraging unprecedented growth in open source / open data collaboration. Australia must address the challenges by learning from international experiences—most notably the UK and NZ—and mandate the use of BIM across Government, extending the Framework for Spatial Data Foundation to include the Built Environment as a theme and engaging collaboration through a “BIM globe” metaphor. This proposed DBE strategy will modernise the Australian urban planning and the construction industry. It will change the way we develop our cities by fundamentally altering the dynamics and behaviours of the supply chains and unlocking new and more efficient ways of collaborating at all stages of the project life-cycle. There are currently two major modelling approaches that contribute to the challenge of delivering the DBE. Though these collectively encompass many (often competing) approaches or proprietary software systems, all can be categorised as either: a spatial modelling approach, where the focus is generally on representing the elements that make up the world within their geographic context; and a construction modelling approach, where the focus is on models that support the life cycle management of the built environment. These two approaches have tended to evolve independently, addressing two broad industry sectors: the one concerned with understanding and managing global and regional aspects of the world that we inhabit, including disciplines concerned with climate, earth sciences, land ownership, urban and regional planning and infrastructure management; the other is concerned with planning, design, construction and operation of built facilities and includes architectural and engineering design, product manufacturing, construction, facility management and related disciplines (a process/technology commonly known as Building Information Modelling, BIM). The spatial industries have a strong voice in the development of public policy in Australia, while the construction sector, which in 2014 accounted for around 8.5% of Australia’s GDP3, has no single voice and because of its diversity, is struggling to adapt to and take advantage of the opportunity presented by these digital technologies. The experience in the UK over the past few years has demonstrated that government leadership is very effective in stimulating industry adoption of digital technologies by, on the one hand, mandating the use of BIM on public procurement projects while at the same time, providing comparatively modest funding to address the common issues that confront the industry in adopting that way of working across the supply chain. The reported result has been savings of £840m in construction costs in 2013/14 according to UK Cabinet Office figures4. There is worldwide recognition of the value of bringing these two modelling technologies together. Australia has the expertise to exercise leadership in this work, but it requires a commitment by government to recognise the importance of BIM as a companion methodology to the spatial technologies so that these two disciplinary domains can cooperate in the development of data policies and information exchange standards to smooth out common workflows. buildingSMART Australasia, SIBA and their academic partners have initiated this dialogue in Australia and wish to work collaboratively, with government support and leadership, to explore the opportunities open to us as we develop an Australasian Digital Built Environment. As part of that programme, we must develop and implement a strategy to accelerate the adoption of BIM processes across the Australian construction sector while at the same time, developing an integrated approach in concert with the spatial sector that will position Australia at the forefront of international best practice in this area. Australia and New Zealand cannot afford to be on the back foot as we face the challenges of rapid urbanisation and change in the global environment. Although we can identify some exemplary initiatives in this area, particularly in New Zealand in response to the need for more resilient urban development in the face of earthquake threats, there is still much that needs to be done. We are well situated in the Asian region to take a lead in this challenge, but we are at imminent risk of losing the initiative if we do not take action now. Strategic collaboration between Governments, Industry and Academia will create new jobs and wealth, with the potential, for example, to save around 20% on the delivery costs of new built assets, based on recent UK estimates.

Use of observed within-person variation of cardiac troponin in emergency department patients for determination of biological variation and percentage and absolute reference change values

BACKGROUND Many patients presenting to the emergency department (ED) for assessment of possible acute coronary syndrome (ACS) have low cardiac troponin concentrations that change very little on repeat blood draw. It is unclear if a lack of change in cardiac troponin concentration can be used to identify acutely presenting patients at low risk of ACS. METHODS We used the hs-cTnI assay from Abbott Diagnostics, which can detect cTnI in the blood of nearly all people. We identified a population of ED patients being assessed for ACS with repeat cTnI measurement who ultimately were proven to have no acute cardiac disease at the time of presentation. We used data from the repeat sampling to calculate total within-person CV (CV(T)) and, knowing the assay analytical CV (CV(A)), we could calculate within-person biological variation (CV(i)), reference change values (RCVs), and absolute RCV delta cTnI concentrations. RESULTS We had data sets on 283 patients. Men and women had similar CV(i) values of approximately 14%, which was similar at all concentrations <40 ng/L. The biological variation was not dependent on the time interval between sample collections (t = 1.5-17 h). The absolute delta critical reference change value was similar no matter what the initial cTnI concentration was. More than 90% of subjects had a critical reference change value <5 ng/L, and 97% had values of <10 ng/L. CONCLUSIONS With this hs-cTnI assay, delta cTnI seems to be a useful tool for rapidly identifying ED patients at low risk for possible ACS.

Genome-wide association study to identify genetic determinants of severe asthma

Background: The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. Objective: To identify common genetic variants affecting susceptibility to severe asthma. Methods: A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. Results: An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10 (-8)following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10 (-8) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. Conclusions: The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.