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.

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.

Continuous infusion of ticarcillin-clavulanate for home treatment of serious infections : clinical efficacy, safety, pharmacokinetics and pharmacodynamics

Continuous infusion (CI) ticarcillin–clavulanate is a potential therapeutic improvement over conventional intermittent dosing because the major pharmacodynamic (PD) predictor of efficacy of β-lactams is the time that free drug levels exceed the MIC. This study incorporated a 6-year retrospective arm evaluating efficacy and safety of CI ticarcillin–clavulanate in the home treatment of serious infections and a prospective arm additionally evaluating pharmacokinetics (PK) and PD. In the prospective arm, steady-state serum ticarcillin and clavulanate levels and MIC testing of significant pathogens were performed. One hundred and twelve patients (median age, 56 years) were treated with a CI dose of 9.3–12.4 g/day and mean CI duration of 18.0 days. Infections treated included osteomyelitis (50 patients), septic arthritis (6), cellulitis (17), pulmonary infections (12), febrile neutropenia (7), vascular infections (7), intra-abdominal infections (2), and Gram-negative endocarditis (2); 91/112 (81%) of patients were cured, 14 (13%) had partial response and 7 (6%) failed therapy. Nine patients had PICC line complications and five patients had drug adverse events. Eighteen patients had prospective PK/PD assessment although only four patients had sufficient data for a full PK/PD evaluation (both serum steady-state drug levels and ticarcillin and clavulanate MICs from a bacteriological isolate), as this was difficult to obtain in home-based patients, particularly as serum clavulanate levels were found to deteriorate rapidly on storage. Three of four patients with matched PK/PD assessment had free drug levels exceeding the MIC of the pathogen. Home CI of ticarcillin–clavulanate is a safe, effective, convenient and practical therapy and is a therapeutic advance over traditional intermittent dosing when used in the home setting.

Adherence to medicines in the older-aged with chronic conditions : does an intervention concerning adherence by an allied health professional help?

Adherence to medicines is a major determinant of the effectiveness of medicines. However, estimates of non-adherence in the older-aged with chronic conditions vary from 40 to 75%. The problems caused by non-adherence in the older-aged include residential care and hospital admissions, progression of the disease, and increased costs to society. The reasons for non-adherence in the older-aged include items related to the medicine (e.g. cost, number of medicines, adverse effects) and those related to person (e.g. cognition, vision, depression). It is also known that there are many ways adherence can be increased (e.g. use of blister packs, cues). It is assumed that interventions by allied health professions, including a discussion of adherence, will improve adherence to medicines in the older aged but the evidence for this has not been reviewed. There is some evidence that telephone counselling about adherence by a nurse or pharmacist does improve adherence, short- and long-term. However, face-to-face intervention counselling at the pharmacy, or during a home visit by a pharmacist, has shown variable results with some studies showing improved adherence and some not. Education programs during hospital stays have not been shown to improve adherence on discharge, but education programs for subjects with hypertension have been shown to improve adherence. In combination with an education program, both counselling and a medicine review program have been shown to improve adherence short-term in the older-aged. Thus, there are many unanswered questions about the most effective interventions to promote adherence. More studies are needed to determine the most appropriate interventions by allied health professions, and these need to consider the disease state, demographics, and socio-economic status of the older-aged subject, and the intensity and duration of intervention needed.

Good results for early treatment of clinically isolated syndrome prior to multiple sclerosis with interferon beta-1b and glatiramer

Background: The first sign of developing multiple sclerosis is a clinically isolated syndrome that resembles a multiple sclerosis relapse. Objective/methods: The objective was to review the clinical trials of two medicines in clinically isolated syndromes (interferon β and glatiramer acetate) to determine whether they prevent progression to definite multiple sclerosis. Results: In the BENEFIT trial, after 2 years, 45% of subjects in the placebo group developed clinically definite multiple sclerosis, and the rate was lower in the interferon β-1b group. Then all subjects were offered interferon β-1b, and the original interferon β-1b group became the early treatment group, and the placebo group became the delayed treatment group. After 5 years, the number of subjects with clinical definite multiple sclerosis remained lower in the early treatment than late treatment group. In the PreCISe trial, after 2 years, the time for 25% of the subjects to convert to definite multiple sclerosis was prolonged in the glatiramer group. Conclusions: Interferon β-1b and glatiramer acetate slow the progression of clinically isolated syndromes to definite multiple sclerosis. However, it is not known whether this early treatment slows the progression to the physical disabilities experienced in multiple sclerosis.

The low-affinity site of the β1-adrenoceptor and its relevance to cardiovascular pharmacology

β-Adrenoceptor blocking agents (β-blockers) that at low concentrations antagonize cardiostimulant effects of catecholamines, but at high concentrations also cause cardiostimulation, have been appearing since the late 1960s. These cardiostimulant β-blockers, coined non-conventional partial agonists, antagonize the effects of catecholamines through a high-affinity site (β1HAR), but cause cardiostimulation mainly through a low-affinity site (β1LAR) of the myocardial β1-adrenoceptor. The experimental non-conventional partial agonist (−)-CGP12177 increases cardiac L-type Ca2+ current density and Ca2+ transients, shortens action potential duration but augments action potential plateau, increases heart rate and force, as well as causes arrhythmic Ca2+ transients and arrhythmic cardiocyte contractions. Other β-blockers, which do not cause cardiostimulation, consistently have lower affinity for β1LAR than β1HAR. These sites were verified and the cardiac pharmacology of non-conventional partial agonists confirmed on recombinant β1-adrenoceptors and on β1-adrenoceptors overexpressed into the heart. A targeted mutation of Asp138 to Glu138 virtually abolished the pharmacology of β1HAR but left intact the pharmacology of β1LAR. Non-conventional partial agonists may be beneficial for the treatment of peripheral autonomic neuropathy but probably due to their arrhythmic propensities, may be harmful for the treatment of chronic heart failure.

An analysis of the nature and effectiveness of corporate governance in smaller listed Australian companies

The objective of this thesis is to investigate the corporate governance attributes of smaller listed Australian firms. This study is motivated by evidence that these firms are associated with more regulatory concerns, the introduction of ASX Corporate Governance Recommendations in 2004, and a paucity of research to guide regulators and stakeholders of smaller firms. While there is an extensive body of literature examining the effectiveness of corporate governance, the literature principally focuses on larger companies, resulting in a deficiency in the understanding of the nature and effectiveness of corporate governance in smaller firms. Based on a review of agency theory literature, a theoretical model is developed that posits that agency costs are mitigated by internal governance mechanisms and transparency. The model includes external governance factors but in many smaller firms these factors are potentially absent, increasing the reliance on the internal governance mechanisms of the firm. Based on the model, the observed greater regulatory intervention in smaller companies may be due to sub-optimal internal governance practices. Accordingly, this study addresses four broad research questions (RQs). First, what is the extent and nature of the ASX Recommendations that have been adopted by smaller firms (RQ1)? Second, what firm characteristics explain differences in the recommendations adopted by smaller listed firms (RQ2), and third, what firm characteristics explain changes in the governance of smaller firms over time (RQ3)? Fourth, how effective are the corporate governance attributes of smaller firms (RQ4)? Six hypotheses are developed to address the RQs. The first two hypotheses explore the extent and nature of corporate governance, while the remaining hypotheses evaluate its effectiveness. A time-series, cross-sectional approach is used to evaluate the effectiveness of governance. Three models, based on individual governance attributes, an index of six items derived from the literature, and an index based on the full list of ASX Recommendations, are developed and tested using a sample of 298 smaller firms with annual observations over a five-year period (2002-2006) before and after the introduction of the ASX Recommendations in 2004. With respect to (RQ1) the results reveal that the overall adoption of the recommendations increased from 66 per cent in 2004 to 74 per cent in 2006. Interestingly, the adoption rate for recommendations regarding the structure of the board and formation of committees is significantly lower than the rates for other categories of recommendations. With respect to (RQ2) the results reveal that variations in rates of adoption are explained by key firm differences including, firm size, profitability, board size, audit quality, and ownership dispersion, while the results for (RQ3) were inconclusive. With respect to (RQ4), the results provide support for the association between better governance and superior accounting-based performance. In particular, the results highlight the importance of the independence of both the board and audit committee chairs, and of greater accounting-based expertise on the audit committee. In contrast, while there is little evidence that a majority independent board is associated with superior outcomes, there is evidence linking board independence with adverse audit opinion outcomes. These results suggest that board and chair independence are substitutes; in the presence of an independent chair a majority independent board may be an unnecessary and costly investment for smaller firms. The findings make several important contributions. First, the findings contribute to the literature by providing evidence on the extent, nature and effectiveness of governance in smaller firms. The findings also contribute to the policy debate regarding future development of Australia’s corporate governance code. The findings regarding board and chair independence, and audit committee characteristics, suggest that policy-makers could consider providing additional guidance for smaller companies. In general, the findings offer support for the “if not, why not?” approach of the ASX, rather than a prescriptive rules-based approach.

Corporate governance and misappropriation

This study examines the occurrence of misappropriation-type fraud within Australian listed firms and the relation between the incidence of this type of fraud and a firm's governance strength. We measure governance strength using factors relating to traditional corporate governance, such as board composition, CEO duality, and audit committee composition, as well as factors relating to information technology governance. In our study, we use actual dollar amount of fraud reported by listed companies responding to the 2004 KPMG Fraud Survey as one of three different misappropriation measures and publicly available firm-specific data to measure the other variables in the model. Our study found that where the chief executive officer (CEO) also holds the position of chairperson of the board of directors, the likelihood of fraud increases. We also find that the greater the number of independent directors on the audit committee, the lower the level of fraud. Taken together, these results are particularly encouraging as they provide support for regulatory bodies such as the Australian Stock Exchange (ASX) and the Australian Securities and Investment Commission (ASIC), which place considerable emphasis on the importance of establishing good corporate governance practices. The study provides empirical evidence that employing good corporate governance reduces the risk of the misappropriation of assets.

Pragmatics, perceptions and strategies in Chinese college English learning

This study investigated Chinese College English students. perceptions of pragmatics, their pragmatic competence in selected speech acts, strategies they employed in acquiring pragmatic knowledge, as well as their general approach to learning English as a foreign language. The research was triggered by a national curriculum initiative that prioritizes the need for College English students to enhance their ability to use English effectively in different social interactions (Chinese College English Education and Supervisory Committee, 2007). The traditional "grammar-translation" and "examination-oriented" method is believed to have reduced Chinese College English students to what is dubbed "mute" and "deaf" language learners (Zhang, 2008; Zhao, 2009). Many students lack pragmatic knowledge on how to interpret discourse by relating utterances to their meanings, understanding the intention of language users, and how language is used in specific settings (Bachman & Palmer, 1996, 2010). There is an increasing body of literature on awareness-raising of the importance of pragmatic knowledge and strategies for classroom instruction. However, to date, researchers have tended to focus largely on the teaching of pragmatics, rather than on how students acquire pragmatic competence (Bardovi-Harlig & Dornyei, 1998; Du, 2004; Hou, 2007; Ruan, 2007; Schauer, 2009). It is this gap in the research that this study fills, with a focus on different types of pragmatic knowledge, learner perceptions of such knowledge, and learning strategies that College English students employ in the process of learning English in general, and pragmatics in particular. Three strands of theories of second language acquisition (Ellis, 1985, 1994): pragmatics (Levinson, 1983; Mey, 2001; Yule, 1996), intercultural communications (Kramsch, 1998; Samovar & Porter, 1997; Samovar, Porter & McDaniel, 2009) and English as a lingua franca (ELF) (Canagarajah, 2006; Firth, 1996; Pennycook, 2010) were employed to establish a conceptual framework for data collection and analyses. Key constructs derived from the three related theories helped to form a typology for a detailed examination and theorization of the empirical evidence gathered from different sources. Four research instruments: a questionnaire (N=237), Discourse Completion Tasks (DCTs) (N=55), focus group interviews (N=18), and a textbook tasks analysis were employed to collect data for this systematic inquiry. Data collected by different instruments were analyzed and compared by way of a triangulation to enhance its validity and reliability. Major findings derived from different sources highlighted that, although College English students were grammatically advanced language learners, they displayed limited pragmatic knowledge and a highly restricted repertoire of language learning strategies. The majority of the respondents, however, believed that pragmatic knowledge was as important as linguistic knowledge in the process of developing communicative competence for interaction in different contexts. It was argued that a combination of a less than sufficient English proficiency, limited knowledge of pragmatics, inadequate language materials and tasks, and a small stock of language learning strategies, were a major hindrance to effective learning and communication, resulting in pragmatic failures in many intercultural communication situations. As the first systematic study of how Chinese College English students learned pragmatics, the research provided a solid empirical base for developing a tentative model for the learning of pragmatics in a College English classroom in China and similar educational contexts. The model was strengthened by a unique combination of theories of pragmatics, intercultural communication and ELF. Findings from this research provided insights into how Chinese College English students perceived pragmatics in the English as foreign language (EFL) curriculum, the processes of learning, as well as strategies they utilized in developing linguistic and pragmatic knowledge and competence.

Improved treatment of nicotine addiction and emerging pulmonary drug delivery

Nicotine addiction remains the leading cause of death and disease in developed and developing nations and a major cause of mortality around the world. Currently, nicotine replacement therapies (NRTs), bupropion, and varenicline are approved by the regulatory agencies as first-line treatments for nicotine addiction. Emerging evidence indicates that varenicline and bupropion have some therapeutic limitations for treating nicotine addiction with oral route of administration. Thus, continued investigation of innovative drug delivery for nicotine addiction remains a critical priority. This review will discuss some novel strategies and future directions for pulmonary drug delivery, an emerging route of administration for smoking cessation. It is anticipated that the advancement of knowledge on pulmonary drug delivery will provide better management for nicotine addiction and other addictive disorders.

The committee on public information : a transmedia war propaganda campaign

This thesis develops an understanding of how propaganda entered the realm of journalism and popular culture in the United States during World War I through an examination of materials created by the Committee on Public Information (CPI). The CPI was a US governmental propaganda organisation created during World War I to persuade the nation to mobilise for war. Three of its divisions were chosen for this study: the Division of News (DoN), the Division of Four Minute Men (FMM) and the Division of Pictorial Publicity (DPP). Chapter 1 provides a general context for the thesis, outlines the research questions and details previous research on the CPI. Chapter 2 outlines the methods of analysis for interpreting the case study chapters and provides contextual information. The case studies are presented in Chapters 3, 4 and 5. These chapters are structured in the order of context, medium and content, and contain historical contextual information about each particular division, medialogical aspects of its propagated form and thematic groupings created from close reading of CPI materials. A semiotic analysis in the Peircian tradition is also performed on visual forms of propaganda in Chapter 5. Chapter 6 discusses how the expectations of persuasion, truth and amusement relate to each other when mediated in culture, using Lotman’s concept of the semiosphere. This further develops an understanding of propaganda as a cultural system in relation to other cultural systems – in this case, journalism and popular culture. Chapter 7 provides conclusions about the study, outlines relative strengths and weaknesses regarding the selection and deployment of methods, makes recommendations for future research, and summarises the key contributions of the thesis.

Striving to achieve best practice in heart failure disease management

Based on a national audit of chronic heart failure (CHF) management programmes (CHF-MPs) conducted in 2006, Driscoll et al identified a disproportionate distribution ranging from 0 to 4.2 programmes/million population in the various states of Australia with many programmes not following best practice.1 We welcome their proposal to develop national benchmarks for CHF management and acknowledge the contributions of the Heart Foundation and health professionals in finalising these recommendations.2 We would like to share the Queensland experience in striving towards best practice with the number of CHF-MPs increasing from four (at the time of the 2006 survey) to 23, equating to 5.0 programmes/million population. Queensland now has a state-wide heart failure service steering committee with a focus on the development of CHF-MPs supported by a central coordinator...

Strategies for gaining and maintaining academic support for the institutional open access repository

The impact of research can be measured by use or citation count. The more widely available that research outputs are; the more likely they are to be used, and the higher the impact. Making the author-manuscript version of research outputs freely available via the institutional repository greatly increases the availability of research outputs and can increase the impact. QUT ePrints, the open access institutional repository of research outputs at Queensland University of Technology (QUT), Australia, was established in 2003 and is managed by the QUT Library. The repository now contains over 39,000 records. More than 21,000 of these records have full-text copies attached as result of continuous effort to maintain momentum and encourage academic engagement. The full-text deposit rate has continued to increase over time and, in 2012 (August, at the time of writing), 88% of the records for works published in 2012 provide access to a full-text copy. Achieving success has required a long term approach to collaboration, open access advocacy, repository promotion, support for the deposit process, and ongoing system development. This paper discusses the various approaches adopted by QUT Library, in collaboration with other areas of the University, to achieve success. Approaches include mainstreaming the repository via having it report to the University Research and Innovation Committee; regular provision of deposit rate data to faculties; championing key academic supporters; and holding promotional competitions and events such as during Open Access Week. Support and training is provided via regular deposit workshops with academics and faculty research support groups and via the provision of online self-help information. Recent system developments have included the integration of citation data (from Scopus and Web of Science) and the development of a statistical reporting system which incentivise engagement.