Telcagepant is a new oral treatment for migraine

Background : Migraine is a common cause of disability. Many subjects (30 – 40%) do not respond to the 5-HT 1B/1D agonists (the triptans) commonly used in the treatment of migraine attacks. Calcitonin gene-related protein (CGRP) receptor antagonism is a new approach to the treatment of migraine attacks. Objectives/methods : This evaluation is of a Phase III clinical trial comparing telcagepant, an orally active CGRP receptor antagonist, with zolmitriptan in subjects during an attack of migraine. Results : Telcagepant 300 mg has a similar efficacy to zolmitriptan in relieving pain, phonophobia, photophobia, and nausea. Telcagepant was better tolerated than zolmitriptan. Conclusions : The initial Phase III clinical trial results with telcagepant are promising but several further clinical trials are needed to determine the place of telcagepant in the treatment of migraine attacks

Tesofensine : a novel potent weight loss medicine

Background: The incidence of obesity is increasing; this is of major concern, as obesity is associated with cardiovascular disease, stroke, type 2 diabetes, respiratory tract disease, and cancer. Objectives/methods: This evaluation is of a Phase II clinical trial with tesofensine in obese subjects. Results: After 26 weeks, tesofensine caused a significant weight loss, and may have a higher maximal ability to reduce weight than the presently available anti-obesity agents. However, tesofensine also increased blood pressure and heart rate, and may increase psychiatric disorders. Conclusions: It is encouraging that tesofensine 0.5 mg may cause almost double the weight loss observed with sibutramine or rimonabant. As tesofensine and sibutramine have similar pharmacological profiles, it would be of interest to compare the weight loss with tesofensine in a head-to-head clinical trial with sibutramine, to properly assess their comparative potency. Also, as teso fensine 0.5 mg increases heart rate, as well as increasing the incidence of adverse effects such as nausea, drug mouth, flatulence, insomnia, and depressed mode, its tolerability needs to be further evaluated in large Phase III clinical trials.

Clinical efficacy and safety of zoledronic acid in osteoporosis and Paget's disease

Osteoporosis and Paget’s bone disease are the most common diseases of the bone. In addition to glucocorticoid treatment, there are many other secondary causes of osteoporosis. Bisphosphonates are used to treat these bone conditions. Zoledronic acid is the most potent bisphosphonate at inhibiting bone resorption. In osteoporosis, zoledronic acid increases bone mineral density for at least 1 year following a single intravenous administration. The efficacy and safety of zoledronic acid in the treatment of osteoporosis and Paget’s bone disease are reviewed. This article also covers the studies of the effects of zoledronic acid in the bone loss associated with the secondary osteoporosis.

Anti-cancer activity of zoledronic acid in breast cancer

Background: Zoledronic acid is used to prevent the bone loss associated with antioestrogen treatments in subjects with breast cancer. Preclinical studies suggest that zoledronic acid may have anticancer activity in its own right. This anticancer possibility with zoledronic acid has not been investigated extensively in clinical trials. Objectives/methods: This evaluation is of a large clinical trial that investigated the effect of zoledronic acid on cancer outcomes in premenopausal women with breast cancer. Results: The trial showed that after 4 years, 94.0% of subjects who were treated with zoledronic acid were disease-free compared with 90.8% of those not treated with zoledronic acid. Recurrence survival was a secondary end point; this occurred in 94.0% with, and 90.9% without, zoledronic acid treatment. Conclusions: Zoledronic acid does have anticancer activity in premenopausal women with cancer.

Is liraglutide or exenatide better in type 2 diabetes?

Background: Subjects with type 2 diabetes have high circulating levels of glucose. Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that has a major role in glucose homeostasis. Exenatide and liraglutide are both agonists at the GLP-1 receptor, and are effective at reducing circulating glucose levels (measured as HbA1c levels), but they have not been compared. Objectives/methods: This evaluation is of a clinical trial comparing liraglutide once a day with exenatide twice a day in subjects with type 2 diabetes. Results: In the Liraglutide Effect and Action in Diabetes (LEAD)-6 trial, subcutaneous liraglutide 1.8 mg once a day was compared with exenatide 10 μg twice a day. The primary efficacy outcome was change in HbA1c levels, and this was significantly greater with liraglutide (1.12%) than with exenatide (0.79%). Liraglutide and exenatide had similar small abilities to reduce body weight, blood pressure and LDL-cholesterol. Conclusions: Liraglutide was more effective than exenatide for overall glycaemic control in subjects with type 2 diabetes. However, this is only true for the preparations and doses tested, that is liraglutide 1.8 mg once weekly and exenatide 10 μg b.i.d., and may not apply when the comparison is undertaken with the new longer-lasting preparation of exenatide once weekly.

Clinical efficacy and safety of zoledronic acid in prostate and breast cancer

The anti-estrogen treatment for hormone-sensitive breast cancer and the androgen deprivation therapy for prostate cancer can lead to the development of osteoporosis and bone fractures. Metastases associated with prostate and breast cancer can also occur in bone. Bisphosphonates are used in these types of bone dysfunction. Zoledronic acid is the most potent bisphosphonate. In osteoporosis, zoledronic acid inhibits bone reabsorption and increases bone mineral density for at least a year after intravenous administration. The efficacy and safety of zoledronic acid in osteoporosis secondary to hormone-sensitive cancers (prostate and breast), and in the bone metastases associated with these cancers are reviewed.

Good clinical endpoints with denosumab in osteoporosis and cancer

Background: Bone loss associated with low oestrogen levels in postmenopausal women, and with androgen deprivation therapy in men with hormone-sensitive prostate cancer, result in an increased incidence of fractures. Denosumab has been shown to increase bone mineral density in these two conditions. Objectives/methods: The objective of this evaluation is to review the clinical trials that have studied clinical endpoints in these conditions. Results: FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) was an International Phase III clinical trial that measured the clinical endpoints with denosumab in postmenopausal women with osteoporosis. At 36 months, new vertebral fractures had occurred in 7.2% of subjects in the placebo group and this was lowered to 2.3% of subjects treated with denosumab. HALT (Denosumab Hormone Ablation Bone Loss Trial) studied the clinical endpoints in men with non-metastatic prostate cancer receiving androgen-deprivation therapy. The incidence of vertebral fractures was significantly lower in the denosumab group (1.5%) than in the placebo group (3.9%). The incidence of adverse effects with denosumab in both clinical trials was low. Conclusions: Denosumab reduces the incidence of fractures in postmenopausal women with osteoporosis and in men with non-metastatic prostate cancer receiving androgen-deprivation therapy. Denosumab is well tolerated.

Hypercapitalism : an investigation into the relationship between language, new media, and social perceptions of value

Overall, this thesis purports to make two significant contributions to knowledge. The first is a foundational critique of political economy in the context of an emergent global knowledge economy. The second is a method for analysing evaluations in language. The relationships that give coherence to those two contributions are as follows. The widely-heralded emergence of a knowledge economy indicates that more intimate aspects of human activity have become exposed to commodification on a massive scale, specifically, activities associated with thought and language. Correspondingly, more abstract forms of value have developed as the products of thought and language have become dominant commodity forms. Historical investigation shows that value has moved from an objective category in political economy, pertaining to such substances as precious metals and land, to become situated today predominantly in “expert” expressions of language, or more precisely, their institutional contexts of production. These are now propagated and circulated on a global scale. Legal, political, and technological developments are key in the development of new, more abstract forms of labour and value, although the relationships connecting these are neither simple nor direct. They are, however, inseparably related in the trajectories that this thesis describes. Consequently they are dealt with inseparably throughout.

Recommending best answer in a collaborative question answering system

The World Wide Web has become a medium for people to share information. People use Web-based collaborative tools such as question answering (QA) portals, blogs/forums, email and instant messaging to acquire information and to form online-based communities. In an online QA portal, a user asks a question and other users can provide answers based on their knowledge, with the question usually being answered by many users. It can become overwhelming and/or time/resource consuming for a user to read all of the answers provided for a given question. Thus, there exists a need for a mechanism to rank the provided answers so users can focus on only reading good quality answers. The majority of online QA systems use user feedback to rank users’ answers and the user who asked the question can decide on the best answer. Other users who didn’t participate in answering the question can also vote to determine the best answer. However, ranking the best answer via this collaborative method is time consuming and requires an ongoing continuous involvement of users to provide the needed feedback. The objective of this research is to discover a way to recommend the best answer as part of a ranked list of answers for a posted question automatically, without the need for user feedback. The proposed approach combines both a non-content-based reputation method and a content-based method to solve the problem of recommending the best answer to the user who posted the question. The non-content method assigns a score to each user which reflects the users’ reputation level in using the QA portal system. Each user is assigned two types of non-content-based reputations cores: a local reputation score and a global reputation score. The local reputation score plays an important role in deciding the reputation level of a user for the category in which the question is asked. The global reputation score indicates the prestige of a user across all of the categories in the QA system. Due to the possibility of user cheating, such as awarding the best answer to a friend regardless of the answer quality, a content-based method for determining the quality of a given answer is proposed, alongside the non-content-based reputation method. Answers for a question from different users are compared with an ideal (or expert) answer using traditional Information Retrieval and Natural Language Processing techniques. Each answer provided for a question is assigned a content score according to how well it matched the ideal answer. To evaluate the performance of the proposed methods, each recommended best answer is compared with the best answer determined by one of the most popular link analysis methods, Hyperlink-Induced Topic Search (HITS). The proposed methods are able to yield high accuracy, as shown by correlation scores: Kendall correlation and Spearman correlation. The reputation method outperforms the HITS method in terms of recommending the best answer. The inclusion of the reputation score with the content score improves the overall performance, which is measured through the use of Top-n match scores.

Towards a reference model for SOA governance (extended version)

Although the lack of elaborate governance mechanisms is often seen as the main reason for failures of SOA projects, SOA governance is still very low in maturity. In this paper, we follow a design science approach to address this drawback by presenting a framework that can guide organisations in implementing a governance approach for SOA more successfully. We have reviewed the highly advanced IT governance frameworks Cobit and ITIL and mapped them to the SOA domain. The resulting blueprint for an SOA governance framework was refined based on a detailed literature review, expert interviews and a practical application in a government organisation. The proposed framework stresses the need for business representatives to get involved in SOA decisions and to define benefits ownership for services.

The development and evaluation of an innovative nursing practice model to improve undergraduate nursing students' competence in paediatric physical assessment

Introduction The purpose of this study was to develop, implement and evaluate the impact of an educational intervention, comprising an innovative model of clinical decisionmaking and educational delivery strategy for facilitating nursing students‘ learning and development of competence in paediatric physical assessment practices. Background of the study Nursing students have an undergraduate education that aims to produce graduates of a generalist nature who demonstrate entry level competence for providing nursing care in a variety of health settings. Consistent with population morbidity and health care roles, paediatric nursing concepts typically form a comparatively small part of undergraduate curricula and students‘ exposure to paediatric physical assessment concepts and principles are brief. However, the nursing shortage has changed traditional nursing employment patterns and new graduates form the majority of the recruitment pool for paediatric nursing speciality staff. Paediatric nursing is a popular career choice for graduates and anecdotal evidence suggests that nursing students who select a clinical placement in their final year intend to seek employment in paediatrics upon graduation. Although concepts of paediatric nursing are included within undergraduate curriculum, students‘ ability to develop the required habits of mind to practice in what is still regarded as a speciality area of practice is somewhat limited. One of the areas of practice where this particularly impacts is in paediatric nursing physical assessment. Physical assessment is a fundamental component of nursing practice and competence in this area of practice is central to nursing students‘ development of clinical capability for practice as a registered nurse. Timely recognition of physiologic deterioration of patients is a key outcome of nurses‘ competent use of physical assessment strategies, regardless of the practice context. In paediatric nursing contexts children‘s physical assessment practices must specifically accommodate the child‘s different physiological composition, function and pattern of clinical deterioration (Hockenberry & Barrera, 2007). Thus, to effectively manage physical assessment of patients within the paediatric practice setting nursing students need to integrate paediatric nursing theory into their practice. This requires significant information processing and it is in this process where students are frequently challenged. The provision of rules or models can guide practice and assist novice-level nurses to develop their capabilities (Benner, 1984; Benner, Hooper-Kyriakidis & Stannard, 1999). Nursing practice models are cognitive tools that represent simplified patterns of expert analysis employing concepts that suit the limited reasoning of the inexperienced, and can represent the =rules‘ referred to by Benner (1984). Without a practice model of physical assessment students are likely to be uncertain about how to proceed with data collection, the interpretation of paediatric clinical findings and the appraisal of findings. These circumstances can result in ad hoc and unreliable nursing physical assessment that forms a poor basis for nursing decisions. The educational intervention developed as part of this study sought to resolve this problem and support nursing students‘ development of competence in paediatric physical assessment. Methods This study utilised the Context Input Process Product (CIPP) Model by Stufflebeam (2004) as the theoretical framework that underpinned the research design and evaluation methodology. Each of the four elements in the CIPP model were utilised to guide discrete stages of this study. The Context element informed design of the clinical decision-making process, the Paediatric Nursing Physical Assessment model. The Input element was utilised in appraising relevant literature, identifying an appropriate instructional methodology to facilitate learning and educational intervention delivery to undergraduate nursing students, and development of program content (the CD-ROM kit). Study One employed the Process element and used expert panel approaches to review and refine instructional methods, identifying potential barriers to obtaining an effective evaluation outcome. The Product element guided design and implementation of Study Two, which was conducted in two phases. Phase One employed a quasiexperimental between-subjects methodology to evaluate the impact of the educational intervention on nursing students‘ clinical performance and selfappraisal of practices in paediatric physical assessment. Phase Two employed a thematic analysis and explored the experiences and perspectives of a sample subgroup of nursing students who used the PNPA CD-ROM kit as preparation for paediatric clinical placement. Results Results from the Process review in Study One indicated that the prototype CDROM kit containing the PNPA model met the predetermined benchmarks for face validity and the impact evaluation instrumentation had adequate content validity in comparison with predetermined benchmarks. In the first phase of Study Two the educational intervention did not result in statistically significant differences in measures of student performance or self-appraisal of practice. However, in Phase Two qualitative commentary from students, and from the expert panel who reviewed the prototype CD-ROM kit (Study One, Phase One), strongly endorsed the quality of the intervention and its potential for supporting learning. This raises questions regarding transfer of learning and it is likely that, within this study, several factors have influenced students‘ transfer of learning from the educational intervention to the clinical practice environment, where outcomes were measured. Conclusion In summary, the educational intervention employed in this study provides insights into the potential e-learning approaches offer for delivering authentic learning experiences to undergraduate nursing students. Findings in this study raise important questions regarding possible pedagogical influences on learning outcomes, issues within the transfer of theory to practice and factors that may have influenced findings within the context of this study. This study makes a unique contribution to nursing education, specifically with respect to progressing an understanding of the challenges faced in employing instructive methods to impact upon nursing students‘ development of competence. The important contribution transfer of learning processes make to students‘ transition into the professional practice context and to their development of competence within the context of speciality practice is also highlighted. This study contributes to a greater awareness of the complexity of translating theoretical learning at undergraduate level into clinical practice, particularly within speciality contexts.

Estimating interactive coefficients for analysing interactive failures

Engineering assets are often complex systems. In a complex system, components often have failure interactions which lead to interactive failures. A system with interactive failures may lead to an increased failure probability. Hence, one may have to take the interactive failures into account when designing and maintaining complex engineering systems. To address this issue, Sun et al have developed an analytical model for the interactive failures. In this model, the degree of interaction between two components is represented by interactive coefficients. To use this model for failure analysis, the related interactive coefficients must be estimated. However, methods for estimating the interactive coefficients have not been reported. To fill this gap, this paper presents five methods to estimate the interactive coefficients including probabilistic method; failure data based analysis method; laboratory experimental method; failure interaction mechanism based method; and expert estimation method. Examples are given to demonstrate the applications of the proposed methods. Comparisons among these methods are also presented.

Multi-objective mission flight planning in civil unmanned aerial systems

Unmanned Aerial Vehicles (UAVs) are emerging as an ideal platform for a wide range of civil applications such as disaster monitoring, atmospheric observation and outback delivery. However, the operation of UAVs is currently restricted to specially segregated regions of airspace outside of the National Airspace System (NAS). Mission Flight Planning (MFP) is an integral part of UAV operation that addresses some of the requirements (such as safety and the rules of the air) of integrating UAVs in the NAS. Automated MFP is a key enabler for a number of UAV operating scenarios as it aids in increasing the level of onboard autonomy. For example, onboard MFP is required to ensure continued conformance with the NAS integration requirements when there is an outage in the communications link. MFP is a motion planning task concerned with finding a path between a designated start waypoint and goal waypoint. This path is described with a sequence of 4 Dimensional (4D) waypoints (three spatial and one time dimension) or equivalently with a sequence of trajectory segments (or tracks). It is necessary to consider the time dimension as the UAV operates in a dynamic environment. Existing methods for generic motion planning, UAV motion planning and general vehicle motion planning cannot adequately address the requirements of MFP. The flight plan needs to optimise for multiple decision objectives including mission safety objectives, the rules of the air and mission efficiency objectives. Online (in-flight) replanning capability is needed as the UAV operates in a large, dynamic and uncertain outdoor environment. This thesis derives a multi-objective 4D search algorithm entitled Multi- Step A* (MSA*) based on the seminal A* search algorithm. MSA* is proven to find the optimal (least cost) path given a variable successor operator (which enables arbitrary track angle and track velocity resolution). Furthermore, it is shown to be of comparable complexity to multi-objective, vector neighbourhood based A* (Vector A*, an extension of A*). A variable successor operator enables the imposition of a multi-resolution lattice structure on the search space (which results in fewer search nodes). Unlike cell decomposition based methods, soundness is guaranteed with multi-resolution MSA*. MSA* is demonstrated through Monte Carlo simulations to be computationally efficient. It is shown that multi-resolution, lattice based MSA* finds paths of equivalent cost (less than 0.5% difference) to Vector A* (the benchmark) in a third of the computation time (on average). This is the first contribution of the research. The second contribution is the discovery of the additive consistency property for planning with multiple decision objectives. Additive consistency ensures that the planner is not biased (which results in a suboptimal path) by ensuring that the cost of traversing a track using one step equals that of traversing the same track using multiple steps. MSA* mitigates uncertainty through online replanning, Multi-Criteria Decision Making (MCDM) and tolerance. Each trajectory segment is modeled with a cell sequence that completely encloses the trajectory segment. The tolerance, measured as the minimum distance between the track and cell boundaries, is the third major contribution. Even though MSA* is demonstrated for UAV MFP, it is extensible to other 4D vehicle motion planning applications. Finally, the research proposes a self-scheduling replanning architecture for MFP. This architecture replicates the decision strategies of human experts to meet the time constraints of online replanning. Based on a feedback loop, the proposed architecture switches between fast, near-optimal planning and optimal planning to minimise the need for hold manoeuvres. The derived MFP framework is original and shown, through extensive verification and validation, to satisfy the requirements of UAV MFP. As MFP is an enabling factor for operation of UAVs in the NAS, the presented work is both original and significant.