A non-deformable crabbed impactor into a 1988 Ford Taurus 4-door sedan in support of CRASH3 damage algorithm reformulation. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

A 1988 Ford Taurus into a 50% left offset barrier in support of CRASH3 damage algorithm reformulation. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

A 1991 Chevrolet Silverado into a 50% left offset barrier in support of CRASH3 damage algorithm reformulation. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

A 1993 Honda Civic DX into heavy truck rigid rear underride guard in support of CRASH3 damage algorithm reformulation. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

A 1987 Ford Escort into a 50% left offset barrier in support of CRASH3 damage algorithm reformulation. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

Reformulation of a thermostable broadly protective recombinant vaccine against human papilloma virus

The causal relationship between Human Papilloma Virus (HPV) infection and cervical cancer has motivated the development, and further improvement, of prophylactic vaccines against this virus. 70% of cervical cancers, 80% of which in low-resources countries, are associated to HPV16 and HPV18 infection, with 13 additional HPV types, classified as high-risk, responsible for the remaining 30% of tumors. Current vaccines, Cervarix® (GlaxoSmithKline) and Gardasil®(Merk), are based on virus-like particles (VLP) obtained by self-assembly of the major capsid protein L1. Despite their undisputable immunogenicity and safety, the fact that protection afforded by these vaccines is largely limited to the cognate serotypes included in the vaccine (HPV 16 and 18, plus five additional viral types incorporated into a newly licensed nonavalent vaccine) along with high production costs and reduced thermal stability, are pushing the development of 2nd generation HPV vaccines based on minor capsid protein L2. The increase in protection broadness afforded by the use of L2 cross-neutralizing epitopes, plus a marked reduction of production costs due to bacterial expression of the antigens and a considerable increase in thermal stability could strongly enhance vaccine distribution and usage in low-resource countries. Previous studies from our group identified three tandem repeats of the L2 aa. 20-38 peptide as a strongly immunogenic epitope if exposed on the scaffold protein thioredoxin (Trx). The aim of this thesis work is the improvement of the Trx-L2 vaccine formulation with regard to cross-protection and thermostability, in order to identify an antigen suitable for a phase I clinical trial. By testing Trx from different microorganisms, we selected P. furiosus thioredoxin (PfTrx) as the optimal scaffold because of its sustained peptide epitope constraining capacity and striking thermal stability (24 hours at 100°C). Alternative production systems, such as secretory Trx-L2 expression in the yeast P. pastoris, have also been set-up and evaluated as possible means to further increase production yields, with a concomitant reduction of production costs. Limitations in immune-responsiveness caused by MHC class II polymorphisms –as observed, for example, in different mouse strains- have been overcome by introducing promiscuous T-helper (Th) epitopes, e.g., PADRE (Pan DR Epitope), at both ends of PfTrx. This allowed us to obtain fairly strong immune responses even in mice (C57BL/6) normally unresponsive to the basic Trx-L2 vaccine. Cross-protection was not increased, however. I thus designed, produced and tested a novel multi-epitope formulation consisting of 8 and 11 L2(20-38) epitopes derived from different HPV types, tandemly joined into a single thioredoxin molecule (“concatemers”). To try to further increase immunogenicity, I also fused our 8X and 11X PfTrx-L2 concatemers to the N-terminus of an engineered complement-binding protein (C4bp), capable to spontaneously assemble into ordered hepatmeric structures, previously validated as a molecular adjuvant. Fusion to C4bp indeed improved antigen presentation, with a fairly significant increase in both immunogenicity and cross-protection. Another important issue I addressed, is the reduction of vaccine doses/treatment, which can be achieved by increasing immunogenicity, while also allowing for a delayed release of the antigen. I obtained preliminary, yet quite encouraging results in this direction with the use of a novel, solid-phase vaccine formulation, consisting of the basic PfTrx-L2 vaccine and its C4bp fusion derivative adsorbed to mesoporus silica-rods (MSR).

Paediatric drug development:reformulation, in vitro, genomic and in vivo evaluation

Angiotensin converting enzyme (ACE) inhibitors lisinopril and ramipril were selected from EMA/480197/2010 and the potassium-sparing diuretic spironolactone was selected from the NHS specials list for November 2011 drug tariff with the view to produce oral liquid formulations providing dosage forms targeting paediatrics. Lisinopril, ramipril and spironolactone were chosen for their interaction with transporter proteins in the small intestine. Formulation limitations such as poor solubility or pH sensitivity needed consideration. Lisinopril was formulated without extensive development as drug and excipients were water soluble. Ramipril and spironolactone are both insoluble in water and strategies combating this were employed. Ramipril was successfully solubilised using low concentrations of acetic acid in a co-solvent system and also via complexation with hydroxypropyl-β-cyclodextrin. A ramipril suspension was produced to take formulation development in a third direction. Spironolactone dosages were too high for solubilisation techniques to be effective so suspensions were developed. A buffer controlled pH for the sensitive drug whilst a precisely balanced surfactant and suspending agent mix provided excellent physical stability. Characterisation, stability profiling and permeability assessment were performed following formulation development. The formulation process highlighted current shortcomings in techniques for taste assessment of pharmaceutical preparations resulting in early stage research into a novel in vitro cell based assay. The formulations developed in the initial phase of the research were used as model formulations investigating microarray application in an in vitro-in vivo correlation for carrier mediated drug absorption. Caco-2 cells were assessed following transport studies for changes in genetic expression of the ATP-binding cassette and solute carrier transporter superfamilies. Findings of which were compared to in vitro and in vivo permeability findings. It was not possible to ascertain a correlation between in vivo drug absorption and the expression of individual genes or even gene families, however there was a correlation (R2 = 0.9934) between the total number of genes with significantly changed expression levels and the predicted human absorption.

Paediatric drug development of ramipril:reformulation, in vitro and in vivo evaluation

Ramipril is used mainly for the treatment of hypertension and to reduce incidence of fatality following heart attacks in patients who develop indications of congestive heart failure. In the paediatric population it is used most commonly for the treatment of heart failure, hypertension in type 1 diabetes and diabetic nephropathy. Due to the lack of a suitable liquid formulation, the current study evaluates the development of a range of oral liquid formulations of ramipril along with their in vitro and in vivo absorption studies. Three different formulation development approaches were studied: solubilisation using acetic acid as a co-solvent, complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD) and suspension development using xanthan gum. Systematic optimisation of formulation parameters for the different strategies resulted in the development of products stable for twelve months at long term stability conditions. In vivo evaluation showed CMAX of 10.48 µg/mL for co-solvent, 13.04µg/ml for the suspension and 29.58µg/mL for the cyclodextrin based ramipril solution. Interestingly, both ramipril solution (co-solvent) and the suspension showed a TMAX of 2.5h, however, cyclodextrin based ramipril produced TMAX at 0.75h following administration. The results presented in this study provide translatable products for oral liquid ramipril which offer preferential paediatric use over existing alternatives.

Drug Reformulation Regulatory Gaming in Pharmaceuticals: Enforcement & Innovation Implications

This article examines drug reformulation regulatory gaming as a vehicle for analyzing the way in which European courts and the Commission are currently approaching innovation issues in the pharmaceutical sector. First, the economics literature regarding pharmaceutical innovation is briefly summarized. Next, the phenomenon of regulatory gaming is introduced, followed by an analysis of the two primary theories of harm being used to address drug reformulations as a competition concern. In comparing the recent General Court decision in AstraZeneca to earlier U.S. court cases addressing similar conduct, it is asserted that these approaches differ in significant ways with regards to preservation of innovation incentives as well as on the basis of institutional and evidentiary concerns. Finally, this discussion is then placed into the broader context of the ongoing debate regarding pharmaceutical innovation that first surfaced in the Syfait cases—in particular, the desirability of sector-specific competition law analysis of pharmaceutical innovation.

The Criminal Codes : Commentary and Materials

This edition has been substantially revised to increase overall clarity and to ensure a balanced examination of the criminal law in the 'Code' states, Queensland and Western Australia. The work has been brought up-to-date in all areas and provides valuable comment on the recent wide-reaching reforms to the law of homicide in Western Australia. Significant developments in both states discussed in this edition include: The abolition of wilful murder and infanticide, and the new definition of murder (WA); The introduction of the new offence of unlawful assault causing death (WA); The abolition of provocation to murder (WA), and whether this excuse still has a part to play (Qld); The reformulation of the excuse of self-defence, and the introduction of excessive self-defence (WA); The creation of offences for drink spiking (Qld and WA); and Current and proposed sentencing considerations (Qld and WA). Fundamental principles of the criminal law are illustrated throughout the book by selected extracts from the Codes and case law, while additional materials foster critical reflection on the law and the need for reform.

Identification of factors predicting clickthrough in Web searching using neural network analysis

In this research, we aim to identify factors that significantly affect the clickthrough of Web searchers. Our underlying goal is determine more efficient methods to optimize the clickthrough rate. We devise a clickthrough metric for measuring customer satisfaction of search engine results using the number of links visited, number of queries a user submits, and rank of clicked links. We use a neural network to detect the significant influence of searching characteristics on future user clickthrough. Our results show that high occurrences of query reformulation, lengthy searching duration, longer query length, and the higher ranking of prior clicked links correlate positively with future clickthrough. We provide recommendations for leveraging these findings for improving the performance of search engine retrieval and result ranking, along with implications for search engine marketing

Exploring young children's web searching and technoliteracy

Purpose – This paper aims to report findings from an exploratory study investigating the web interactions and technoliteracy of children in the early childhood years. Previous research has studied aspects of older children’s technoliteracy and web searching; however, few studies have analyzed web search data from children younger than six years of age. Design/methodology/approach – The study explored the Google web searching and technoliteracy of young children who are enrolled in a “preparatory classroom” or kindergarten (the year before young children begin compulsory schooling in Queensland, Australia). Young children were video- and audio-taped while conducting Google web searches in the classroom. The data were qualitatively analysed to understand the young children’s web search behaviour. Findings – The findings show that young children engage in complex web searches, including keyword searching and browsing, query formulation and reformulation, relevance judgments, successive searches, information multitasking and collaborative behaviours. The study results provide significant initial insights into young children’s web searching and technoliteracy. Practical implications – The use of web search engines by young children is an important research area with implications for educators and web technologies developers. Originality/value – This is the first study of young children’s interaction with a web search engine.

Governmentality and the reflection of legal educators : assessment practices as a case study

This paper presents a conceptual framework, informed by Foucault’s work on governmentality, which allows for new kinds of reflection on the practice of legal education. Put simply, this framework suggests that legal education can be understood as a form of government that relies on a specific rationalisation and programming of the activities of legal educators, students, and administrators, and is implemented by harnessing specific techniques and bodies of ‘know-how’. Applying this framework to assessment at three Australian law schools, this paper highlights how assessment practices are rationalised, programmed, and implemented, and points out how this government shapes students’ legal personae. In particular, this analysis focuses on the governmental effects of pedagogical discourses that are dominant within the design and scholarship of legal education. It demonstrates that the development of pedagogically-sound regimes of assessment has contributed to a reformulation of the terrain of government, by providing the conditions under which forms of legal personae may be more effectively shaped, and extending the power relations that achieve this. This analysis provides legal educators with an original way of reflecting on the power effects of teaching the law, and new opportunities for thinking about what is possible in legal education.