Decision-theoretic designs for dose-finding clinical trials with multiple outcomes

A decision-theoretic framework is proposed for designing sequential dose-finding trials with multiple outcomes. The optimal strategy is solvable theoretically via backward induction. However, for dose-finding studies involving k doses, the computational complexity is the same as the bandit problem with k-dependent arms, which is computationally prohibitive. We therefore provide two computationally compromised strategies, which is of practical interest as the computational complexity is greatly reduced: one is closely related to the continual reassessment method (CRM), and the other improves CRM and approximates to the optimal strategy better. In particular, we present the framework for phase I/II trials with multiple outcomes. Applications to a pediatric HIV trial and a cancer chemotherapy trial are given to illustrate the proposed approach. Simulation results for the two trials show that the computationally compromised strategy can perform well and appear to be ethical for allocating patients. The proposed framework can provide better approximation to the optimal strategy if more extensive computing is available.

Effective web service discovery using a combination of a semantic model and a data mining technique

With the advent of Service Oriented Architecture, Web Services have gained tremendous popularity. Due to the availability of a large number of Web services, finding an appropriate Web service according to the requirement of the user is a challenge. This warrants the need to establish an effective and reliable process of Web service discovery. A considerable body of research has emerged to develop methods to improve the accuracy of Web service discovery to match the best service. The process of Web service discovery results in suggesting many individual services that partially fulfil the user’s interest. By considering the semantic relationships of words used in describing the services as well as the use of input and output parameters can lead to accurate Web service discovery. Appropriate linking of individual matched services should fully satisfy the requirements which the user is looking for. This research proposes to integrate a semantic model and a data mining technique to enhance the accuracy of Web service discovery. A novel three-phase Web service discovery methodology has been proposed. The first phase performs match-making to find semantically similar Web services for a user query. In order to perform semantic analysis on the content present in the Web service description language document, the support-based latent semantic kernel is constructed using an innovative concept of binning and merging on the large quantity of text documents covering diverse areas of domain of knowledge. The use of a generic latent semantic kernel constructed with a large number of terms helps to find the hidden meaning of the query terms which otherwise could not be found. Sometimes a single Web service is unable to fully satisfy the requirement of the user. In such cases, a composition of multiple inter-related Web services is presented to the user. The task of checking the possibility of linking multiple Web services is done in the second phase. Once the feasibility of linking Web services is checked, the objective is to provide the user with the best composition of Web services. In the link analysis phase, the Web services are modelled as nodes of a graph and an allpair shortest-path algorithm is applied to find the optimum path at the minimum cost for traversal. The third phase which is the system integration, integrates the results from the preceding two phases by using an original fusion algorithm in the fusion engine. Finally, the recommendation engine which is an integral part of the system integration phase makes the final recommendations including individual and composite Web services to the user. In order to evaluate the performance of the proposed method, extensive experimentation has been performed. Results of the proposed support-based semantic kernel method of Web service discovery are compared with the results of the standard keyword-based information-retrieval method and a clustering-based machine-learning method of Web service discovery. The proposed method outperforms both information-retrieval and machine-learning based methods. Experimental results and statistical analysis also show that the best Web services compositions are obtained by considering 10 to 15 Web services that are found in phase-I for linking. Empirical results also ascertain that the fusion engine boosts the accuracy of Web service discovery by combining the inputs from both the semantic analysis (phase-I) and the link analysis (phase-II) in a systematic fashion. Overall, the accuracy of Web service discovery with the proposed method shows a significant improvement over traditional discovery methods.

Listening, sharing understanding and facilitating consumer, family and community empowerment through a priority driven partnership in Far North Queensland

Objectives: This paper provides an example of a mental health research partnership underpinned by empowerment principles that seeks to foster strength among community organizations to support better outcomes for consumers, families and communities. It aims to raise awareness among researchers and service providers that empowerment approaches to assist communities to address mental health problems are not too difficult to be practical but require long-term commitment and appropriate support. Methods: A collaborative research strategy that has become known as the Priority Driven Research (PDR) Partnership emerged through literature review,consultations, Family Wellbeing Program delivery with community groups and activities in two discrete Indigenous communities. Progress to date on three of the four components of the strategy is described. Results: The following key needs were identified in a pilot study and are now being addressed in a research-based implementation phase: (i) gaining two-way understanding of perspectives on mental health and promoting universal awareness; (ii) supporting the empowerment of carers, families, consumers and at-risk groups through existing community organizations to gain greater understanding and control of their situation; (iii) developing pathways of care at the primary health centre level to enable support of social and emotional wellbeing as well as more integrated mental health care; (iv) accessing data to enable an ongoing process of analysis/sharing/planning and monitoring to inform future activity. Conclusion: One of the key learnings to emerge in this project so far is that empowerment through partnership becomes possible when there is a concerted effort to strengthen grassroots community organizations. These include social health teams and men’s and women’s groups that can engage local people in an action orientation. Key words: Aboriginal, empowerment, Indigenous, mental health.

Immunogenicity and protective efficacy of an anti-Streptococcus pyogenes vaccine candidate in multiple animal species

Streptococcus pyogenes, also known as Group A Streptococcus (GAS) has been associated with a range of diseases from the mild pharyngitis and pyoderma to more severe invasive infections such as streptococcal toxic shock. GAS also causes a number of non-suppurative post-infectious diseases such as rheumatic fever, rheumatic heart disease and glomerulonephritis. The large extent of GAS disease burden necessitates the need for a prophylactic vaccine that could target the diverse GAS emm types circulating globally. Anti-GAS vaccine strategies have focused primarily on the GAS M-protein, an extracellular virulence factor anchored to GAS cell wall. As opposed to the hypervariable N-terminal region, the C-terminal portion of the protein is highly conserved among different GAS emm types and is the focus of a leading GAS vaccine candidate, J8-DT/alum. The vaccine candidate J8-DT/alum was shown to be immunogenic in mice, rabbits and the non-human primates, hamadryas baboons. Similar responses to J8-DT/alum were observed after subcutaneous and intramuscular immunization with J8-DT/alum, in mice and in rabbits. Further assessment of parameters that may influence the immunogenicity of J8-DT demonstrated that the immune responses were identical in male and female mice and the use of alum as an adjuvant in the vaccine formulation significantly increased its immunogenicity, resulting in a long-lived serum IgG response. Contrary to the previous findings, the data in this thesis indicates that a primary immunization with J8-DT/alum (50ƒÊg) followed by a single boost is sufficient to generate a robust immune response in mice. As expected, the IgG response to J8- DT/alum was a Th2 type response consisting predominantly of the isotype IgG1 accompanied by lower levels of IgG2a. Intramuscular vaccination of rabbits with J8-DT/alum demonstrated that an increase in the dose of J8-DT/alum up to 500ƒÊg does not have an impact on the serum IgG titers achieved. Similar to the immune response in mice, immunization with J8-DT/alum in baboons also established that a 60ƒÊg dose compared to either 30ƒÊg or 120ƒÊg was sufficient to generate a robust immune response. Interestingly, mucosal infection of naive baboons with a M1 GAS strain did not induce a J8-specific serum IgG response. As J8-DT/alum mediated protection has been previously reported to be due to the J8- specific antibody formed, the efficacy of J8-DT antibodies was determined in vitro and in vivo. In vitro opsonization and in vivo passive transfer confirmed the protective potential of J8-DT antibodies. A reduction in the bacterial burden after challenge with a bioluminescent M49 GAS strain in mice that were passively administered J8-DT IgG established that protection due to J8-DT was mediated by antibodies. The GAS burden in infected mice was monitored using bioluminescent imaging in addition to traditional CFU assays. Bioluminescent GAS strains including the ‘rheumatogenic’ M1 GAS could not be generated due to limitations with transformation of GAS, however, a M49 GAS strain was utilized during BLI. The M49 serotype is traditionally a ‘nephritogenic’ serotype associated with post-streptococcal glomerulonephritis. Anti- J8-DT antibodies now have been shown to be protective against multiple GAS strains such as M49 and M1. This study evaluated the immunogenicity of J8-DT/alum in different species of experimental animals in preparation for phase I human clinical trials and provided the ground work for the development of a rapid non-invasive assay for evaluation of vaccine candidates.

Designing ePortfolios for music postgraduate study : a practice-led inquiry

In this research I have examined how ePortfolios can be designed for Music postgraduate study through a practice led research enquiry. This process involved designing two Web 2.0 ePortfolio systems for a group of five post graduate music research students. The design process revolved around the application of an iterative methodology called Software Develop as Research (SoDaR) that seeks to simultaneously develop design and pedagogy. The approach to designing these ePortfolio systems applied four theoretical protocols to examine the use of digitised artefacts in ePortfolio systems to enable a dynamic and inclusive dialogue around representations of the students work. The research and design process involved an analysis of existing software and literature with a focus upon identifying the affordances of available Web 2.0 software and the applications of these ideas within 21st Century life. The five post graduate music students each posed different needs in relation to the management of digitised artefacts and the communication of their work amongst peers, supervisors and public display. An ePortfolio was developed for each of them that was flexible enough to address their needs within the university setting. However in this first SoDaR iteration data gathering phase I identified aspects of the university context that presented a negative case that impacted upon the design and usage of the ePortfolios and prevented uptake. Whilst the portfolio itself functioned effectively, the university policies and technical requirements prevented serious use. The negative case analysis of the case study found revealed that Access and Control and Implementation, Technical and Policy Constraints protocols where limiting user uptake. From the semistructured interviews carried out as part of this study participant feedback revealed that whilst the participants did not use the ePortfolio system I designed, each student was employing Web 2.0 social networking and storage processes in their lives and research. In the subsequent iterations I then designed a more ‘ideal’ system that could be applied outside of the University context that draws upon the employment of these resources. In conclusion I suggest recommendations about ePortfolio design that considers what the applications of the theoretical protocols reveal about creative arts settings. The transferability of these recommendations are of course dependent upon the reapplication of the theoretical protocols in a new context. To address the mobility of ePortfolio design between Institutions and wider settings I have also designed a prototype for a business card sized USB portal for the artists’ ePortfolio. This research project is not a static one; it stands as an evolving design for a Web 2.0 ePortfolio that seeks to refer to users needs, institutional and professional contexts and the development of software that can be incorporated within the design. What it potentially provides to creative artist is an opportunity to have a dialogue about art with artefacts of the artist products and processes in that discussion.

Development and evaluation of hydrocarbon sorbent materials with the aid of chemometrics

Hydrocarbon spills on roads are a major safety concern for the driving public and can have severe cost impacts both on pavement maintenance and to the economy through disruption to services. The time taken to clean-up spills and re-open roads in a safe driving condition is an issue of increasing concern given traffic levels on major urban arterials. Thus, the primary aim of the research was to develop a sorbent material that facilitates rapid clean-up of road spills. The methodology involved extensive research into a range of materials (organic, inorganic and synthetic sorbents), comprehensive testing in the laboratory, scale-up and field, and product design (i.e. concept to prototype). The study also applied chemometrics to provide consistent, comparative methods of sorbent evaluation and performance. In addition, sorbent materials at every stage were compared against a commercial benchmark. For the first time, the impact of diesel on asphalt pavement has been quantified and assessed in a systematic way. Contrary to conventional thinking and anecdotal observations, the study determined that the action of diesel on asphalt was quite rapid (i.e. hours rather than weeks or months). This significant finding demonstrates the need to minimise the impact of hydrocarbon spills and the potential application of the sorbent option. To better understand the adsorption phenomenon, surface characterisation techniques were applied to selected sorbent materials (i.e. sand, organo-clay and cotton fibre). Brunauer Emmett Teller (BET) and thermal analysis indicated that the main adsorption mechanism for the sorbents occurred on the external surface of the material in the diffusion region (sand and organo-clay) and/or capillaries (cotton fibre). Using environmental scanning electron microscopy (ESEM), it was observed that adsorption by the interfibre capillaries contributed to the high uptake of hydrocarbons by the cotton fibre. Understanding the adsorption mechanism for these sorbents provided some guidance and scientific basis for the selection of materials. The study determined that non-woven cotton mats were ideal sorbent materials for clean-up of hydrocarbon spills. The prototype sorbent was found to perform significantly better than the commercial benchmark, displaying the following key properties: • superior hydrocarbon pick-up from the road pavement; • high hydrocarbon retention capacity under an applied load; • adequate field skid resistance post treatment; • functional and easy to use in the field (e.g. routine handling, transportation, application and recovery); • relatively inexpensive to produce due to the use of raw cotton fibre and simple production process; • environmentally friendly (e.g. renewable materials, non-toxic to environment and operators, and biodegradable); and • rapid response time (e.g. two minutes total clean-up time compared with thirty minutes for reference sorbents). The major outcomes of the research project include: a) development of a specifically designed sorbent material suitable for cleaning up hydrocarbon spills on roads; b) submission of patent application (serial number AU2005905850) for the prototype product; and c) preparation of Commercialisation Strategy to advance the sorbent product to the next phase (i.e. R&D to product commercialisation).

Integrating information literacy into higher education curricula : an IL curricular integration model

This study investigates a way to systematically integrate information literacy (IL) into an undergraduate academic programme and develops a model for integrating information literacy across higher education curricula. Curricular integration of information literacy in this study means weaving information literacy into an academic curriculum. In the associated literature, it is also referred to as the information literacy embedding approach or the intra-curricular approach. The key findings identified from this study are presented in 4 categories: the characteristics of IL integration; the key stakeholders in IL integration; IL curricular design strategies; and the process of IL curricular integration. Three key characteristics of the curricular integration of IL are identified: collaboration and negotiation, contextualisation and ongoing interaction with information. The key stakeholders in the curricular integration of IL are recognised as the librarians, the course coordinators and lecturers, the heads of faculties or departments, and the students. Some strategies for IL curricular design include: the use of IL policies and standards in IL curricular design; the combination of face to face and online teaching as an emerging trend; the use of IL assessment tools which play an important role in IL integration. IL can be integrated into the intended curriculum (what an institution expects its students to learn), the offered curriculum (what the teachers teach) and the received curriculum (what students actually learn). IL integration is a process of negotiation, collaboration and the implementation of the intended curriculum. IL can be integrated at different levels of curricula such as: institutional, faculty, departmental, course and class curriculum levels. Based on these key findings, an IL curricular integration model is developed. The model integrates curriculum, pedagogy and learning theories, IL theories, IL guidelines and the collaboration of multiple partners. The model provides a practical approach to integrating IL into multiple courses across an academic degree. The development of the model was based on the IL integration experiences of various disciplines in three universities and the implementation experience of an engineering programme at another university; thus it may be of interest to other disciplines. The model has the potential to enhance IL teaching and learning, curricular development and to implement graduate attributes in higher education. Sociocultural theories are applied to the research process and IL curricular design of this study. Sociocultural theories describe learning as being embedded within social events and occurring as learners interact with other people, objects, and events in a collaborative environment. Sociocultural theories are applied to explore how academic staff and librarians experience the curricular integration of IL; they also support collaboration in the curricular integration of IL and the development of an IL integration model. This study consists of two phases. Phase I (2007) was the interview phase where both academic staff and librarians at three IL active universities were interviewed. During this phase, attention was paid specifically to the practical process of curricular integration of IL and IL activity design. Phase II, the development phase (2007-2008), was conducted at a fourth university. This phase explores the systematic integration of IL into an engineering degree from Year 1 to Year 4. Learning theories such as sociocultural theories, Bloom’s Taxonomy and IL theories are used in IL curricular development. Based on the findings from both phases, an IL integration model was developed. The findings and the model contribute to IL education, research and curricular development in higher education. The sociocultural approach adopted in this study also extends the application of sociocultural theories to the IL integration process and curricular design in higher education.

Sentencing and public confidence : results from a national Australian survey on public opinions towards sentencing

This paper examines the critical issue of public confidence in sentencing, and presents findings from Phase I of an Australia-wide sentencing and public confidence project. Phase I comprised a nationally representative telephone survey of 6005 participants. The majority of respondents expressed high levels of punitiveness and were dissatisfied with sentences imposed by the courts. Despite this, many were strongly supportive of the use of alternatives to imprisonment for a range of offences. These nuanced views raise questions regarding the efficacy of gauging public opinion using opinion poll style questions; indeed the expected outcome from this first phase of the four phase sentencing and public confidence project. The following phases of this project, reported on elsewhere, examined the effects of various interventions on the robustness and nature of these views initially expressed in a standard ‘top of the head’ opinion poll.

Plant-made vaccines for humans and animals

Summary: The concept of using plants to produce high-value pharmaceuticals such as vaccines is 20 years old this year and is only now on the brink of realisation as an established technology. The original reliance on transgenic plants has largely given way to transient expression; proofs of concept for human and animal vaccines and of efficacy for animal vaccines have been established; several plant-produced vaccines have been through Phase I clinical trials in humans and more are scheduled; regulatory requirements are more clear than ever, and more facilities exist for manufacture of clinic-grade materials. The original concept of cheap edible vaccines has given way to a realisation that formulated products are required, which may well be injectable. The technology has proven its worth as a means of cheap, easily scalable production of materials: it now needs to find its niche in competition with established technologies. The realised achievements in the field as well as promising new developments will be reviewed, such as rapid-response vaccines for emerging viruses with pandemic potential and bioterror agents. © 2010 The Author. Journal compilation © 2010 Blackwell Publishing Ltd.

Nucleation experiments in a microgravity environment

A simple experimental apparatus is described in which a wide variety of vapor phase nucleation studies of refractory materials could be performed aboard NASA's KC-135 Research Aircraft. The chief advantage of a microgravity environment for these studies is the expected absence of thermally driven convective motions in the gas. The absence of convection leads to much more accurate knowledge of both the temperature distribution in the system and the time evolution of the refractory vapor concentration as a function of distance from the crucible.The evolution of the apparatus will be described as more experience is gained with the microgravity environment. Such experiments will be used to prepare for similar ones carried out aboard either the shuttle or Space Station where considerably longer duration experiments are possible.

Contemporaneous correlations within individuals in an automated web-based walking program (Walk@Work) over a six week period (three phases) of time

Introduction: Participants may respond to phases of a workplace walking program at different rates. This study evaluated the factors that contribute to the number of steps through phases of the program. The intervention was automated through a web-based program designed to increase workday walking. Methods: The study reviewed independent variable influences throughout phases I–III. A convenience sample of university workers (n=56; 43.6±1.7 years; BMI 27.44±.2.15 kg/m2; 48 female) were recruited at worksites in Australia. These workers were given a pedometer (Yamax SW 200) and access to the website program. For analyses, step counts entered by workers into the website were downloaded and mean workday steps were compared using a seemingly unrelated regression. This model was employed to capture the contemporaneous correlation within individuals in the study across observed time periods. Results: The model predicts that the 36 subjects with complete information took an average 7460 steps in the baseline two week period. After phase I, statistically significance increases in steps (from baseline) were explained by age, working status (full or part time), occupation (academic or professional), and self reported public transport (PT) use (marginally significant). Full time workers walked more than part time workers by about 440 steps, professionals walked about 300 steps more than academics, and PT users walked about 400 steps more than non-PT users. The ability to differentiate steps after two weeks among participants suggests a differential affect of the program after only two weeks. On average participants increased steps from week two to four by about 525 steps, but regular auto users had nearly 750 steps less than non-auto users at week four. The effect of age was diminished in the 4th week of observation and accounted for 34 steps per year of age. In phase III, discriminating between participants became more difficult, with only age effects differentiating their increase over baseline. The marginal effect of age by phase III compared to phase I, increased from 36 to 50, suggesting a 14 step per year increase from the 2nd to 6th week. Discussion: The findings suggest that participants responded to the program at different rates, with uniformity of effect achieved by the 6th week. Participants increased steps, however a tapering off occurred over time. Age played the most consistent role in predicting steps over the program. PT use was associated with increased step counts, while Auto use was associated with decreased step counts.

Development of a rapid and validated method for investigating the metabolism of scoparone in rat using ultra-performance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry

Scoparone (6,7-dimethoxycoumarin) is known to have a wide range of pharmacological properties. In this study, a rapid and validated ultra-performance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry (UPLC/ESI-QTof-MS) method was developed to investigate the metabolism of scoparone in rat for the first time. The new method reduced the sample handling and analytical time by three- to six-fold, and the detection limit by five- to 1000-fold, compared to published methods. Far more metabolites were detected and identified compared to published data, which were preliminarily identified as scopoletin, isoscopoletin, isofraxidin, and fraxidin, respectively, when subjected to tandem mass spectrometry analyses. It is found that the metabolic trajectory of scoparone in rat focused on phase I metabolism which is obviously different from published results, and revealed a wide range of pharmacological properties of scoparone partly attributed to the bioactivities of its metabolites.

Preparation of metal-TCNQ charge-transfer complexes on conducting and insulating surfaces by photocrystallization

A generic method for the synthesis of metal-7,7,8,8-tetracyanoquinodimethane (TCNQ) charge-transfer complexes on both conducting and nonconducting substrates is achieved by photoexcitation of TCNQ in acetonitrile in the presence of a sacrificial electron donor and the relevant metal cation. The photochemical reaction leads to reduction of TCNQ to the TCNQ- monoanion. In the presence of Mx+(MeCN), reaction with TCNQ-(MeCN) leads to deposition of Mx+[TCNQ]x crystals onto a solid substrate with morphologies that are dependent on the metal cation. Thus, CuTCNQ phase I photocrystallizes as uniform microrods, KTCNQ as microrods with a random size distribution, AgTCNQ as very long nanowires up to 30 μm in length and with diameters of less than 180 nm, and Co[TCNQ]2(H2O)2 as nanorods and wires. The described charge-transfer complexes have been characterized by optical and scanning electron microscopy and IR and Raman spectroscopy. The CuTCNQ and AgTCNQ complexes are of particular interest for use in memory storage and switching devices. In principle, this simple technique can be employed to generate all classes of metal−TCNQ complexes and opens up the possibility to pattern them in a controlled manner on any type of substrate.

Platinum-based chemotherapy in metastatic breast cancer : current status

Cisplatin and carboplatin are active in previously untreated patients with metastatic breast cancer (MBC) with mean response rates (RRs) of 50 and 32%, respectively. In pretreated patients the RR to cisplatin/carboplatin monotherapy declines markedly to <10%. Cisplatin and carboplatin have been combined with many other cytotoxics. In first-line setting high activity has been observed in combination with taxanes or vinorelbine (RRs consistently ∼60%). It appears that these newer combinations are superior to older regimens with etoposide (RRs 30 to 50%) or 5-fluorouracil (RRs 40 to 60%). Cisplatin-/carboplatin-based regimens with infusional 5-FU and epirubicin/paclitaxel/vinorelbine achieve high RRs of around 60 to 80%. However these regimens are difficult to administer in all patients because they require central venous access for continuous 5-FU infusion. In pretreated MBC the combinations of cisplatin-taxane/vinorelbine/gemcitabine or carboplatin-docetaxel/vinorelbine yield RRs of 40 to 50%, which are higher than those achieved with platinum-etoposide/5-FU. In locally advanced disease cisplatin-based regimens achieve very high RRs (>80%). This would suggest that in chemotherapy-naïve patients platinum-based therapy might have an important role to play. Additionally the synergy demonstrated between platinum compounds, taxanes and herceptin, in preclinical and clinical studies is of immense importance and the results of the two ongoing Breast Cancer International Research Group randomized phase III studies are eagerly awaited. These studies may help clarify the role of platinum compounds in the treatment of metastatic and possibly early breast cancer. © 2003 Elsevier Ltd. All rights reserved.