Dalcetrapib restoring belief in modulating CETP as a beneficial mechanism in cardiovascular disease

Abstract Background: As low HDL cholesterol levels are a risk factor for cardiovascular disease, raising HDL cholesterol substantially by inhibiting or modulating cholesteryl ester transfer protein (CETP) may be useful in coronary artery disease. The first CETP inhibitor that went into clinical trial, torcetrapib, was shown to increase the levels of HDL cholesterol, but it also increased cardiovascular outcomes, probably due to an increase in blood pressure and aldosterone secretion, by an off-target mechanism/s. Objective/methods: Dalcetrapib is a new CETP modulator that increases the levels of HDL cholesterol, but does not increase blood pressure or aldosterone secretion. The objective was to evaluate a paper describing the effects of dalcetrapib on carotid and aortic wall thickness in subjects with, or at high risk, of coronary artery disease; the dal-PLAQUE study. Results: dal-PLAQUE showed that dalcetrapib reduced the progression of atherosclerosis and may also reduce the vascular inflammation associated with this, in subjects with, or with high risk of, coronary heart disease, who were already taking statins. Conclusions: These results suggest that modulating CETP with dalcetrapib may be a beneficial mechanism in cardiovascular disease. The results of the dal-HEART series, which includes dal-PLAQUE 1 and 2, and dal-OUTCOMES, when complete, will provide more definitive information about the benefit, or not, of dalcetrapib in coronary artery disease.

PALLAS : limiting indications for dronedarone treatment of atrial fibrillation.

Atrial fibrillation increases the risk of stroke. Dronedarone has been shown to reduce the composite of hospitalizations due to cardiovascular events or death, in subjects with intermittent atrial fibrillation or flutter. Recently, dronedarone has been tested in subjects with permanent atrial fibrillation in the PALLAS (permanent atrial fibrillation outcome study using dronedarone on top of standard therapy) trial, and this clinical trial is evaluated in this paper. PALLAS was stopped early as there was an increased incidence of cardiovascular events in the dronedarone group. Dronedarone also increased the rate of hospitalizations in PALLAS. As a result of PALLAS, dronedarone has been contraindicated in permanent atrial fibrillation. The outcomes of PALLAS highlight a discontinuity between dronedarone actions in permanent and intermittent atrial fibrillation. The mechanism(s) underlying the detrimental effects of dronedarone in permanent atrial fibrillation are unknown at present and need to be investigated.

More light at the end of the tunnel – apixaban in atrial fibrillation

Introduction: Subjects with atrial fibrillation are at risk of thromboembolic events. The vitamin K antagonists (e.g., warfarin) are useful at preventing coagulation in atrial fibrillation, but are difficult to use. One of the FXa inhibitors, oral apixaban, has been tested as an anticoagulant in atrial fibrillation. Areas covered: In ARISTOTLE (Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation) apixaban was compared to warfarin in subjects with atrial fibrillation, and shown to cause a lower rate of stroke or systemic embolism and of major bleeding, than warfarin. In the AVERROES (Apixaban versus acetylsalicylic acid [ASA] to prevent stroke in atrial fibrillations patients who have failed or are unsuitable for vitamin K antagonist treatment) trial, stroke or systemic embolism occurred less often with apixaban than aspirin, whereas the occurrence of major bleeding was similar in the groups. Expert opinion: Apixaban is much easier for subjects with atrial fibrillation to use than warfarin, as it does not require regular monitoring by a health professional, with dosage adjustment. In addition to replacing warfarin in subjects with atrial fibrillation who are unable or not prepared to use warfarin, apixaban has the potential to replace warfarin more widely in the prevention of thromboembolism in subjects with atrial fibrillation.

Evaluation of the cost-effectiveness of strategies claiming to reduce the risk of surgical site infections following primary total hip arthroplasty

Background Total hip arthroplasty (THA) is a commonly performed procedure and numbers are increasing with ageing populations. One of the most serious complications in THA are surgical site infections (SSIs), caused by pathogens entering the wound during the procedure. SSIs are associated with a substantial burden for health services, increased mortality and reduced functional outcomes in patients. Numerous approaches to preventing these infections exist but there is no gold standard in practice and the cost-effectiveness of alternate strategies is largely unknown. Objectives The aim of this project was to evaluate the cost-effectiveness of strategies claiming to reduce deep surgical site infections following total hip arthroplasty in Australia. The objectives were: 1. Identification of competing strategies or combinations of strategies that are clinically relevant to the control of SSI related to hip arthroplasty 2. Evidence synthesis and pooling of results to assess the volume and quality of evidence claiming to reduce the risk of SSI following total hip arthroplasty 3. Construction of an economic decision model incorporating cost and health outcomes for each of the identified strategies 4. Quantification of the effect of uncertainty in the model 5. Assessment of the value of perfect information among model parameters to inform future data collection Methods The literature relating to SSI in THA was reviewed, in particular to establish definitions of these concepts, understand mechanisms of aetiology and microbiology, risk factors, diagnosis and consequences as well as to give an overview of existing infection prevention measures. Published economic evaluations on this topic were also reviewed and limitations for Australian decision-makers identified. A Markov state-transition model was developed for the Australian context and subsequently validated by clinicians. The model was designed to capture key events related to deep SSI occurring within the first 12 months following primary THA. Relevant infection prevention measures were selected by reviewing clinical guideline recommendations combined with expert elicitation. Strategies selected for evaluation were the routine use of pre-operative antibiotic prophylaxis (AP) versus no use of antibiotic prophylaxis (No AP) or in combination with antibiotic-impregnated cement (AP & ABC) or laminar air operating rooms (AP & LOR). The best available evidence for clinical effect size and utility parameters was harvested from the medical literature using reproducible methods. Queensland hospital data were extracted to inform patients’ transitions between model health states and related costs captured in assigned treatment codes. Costs related to infection prevention were derived from reliable hospital records and expert opinion. Uncertainty of model input parameters was explored in probabilistic sensitivity analyses and scenario analyses and the value of perfect information was estimated. Results The cost-effectiveness analysis was performed from a health services perspective using a hypothetical cohort of 30,000 THA patients aged 65 years. The baseline rate of deep SSI was 0.96% within one year of a primary THA. The routine use of antibiotic prophylaxis (AP) was highly cost-effective and resulted in cost savings of over $1.6m whilst generating an extra 163 QALYs (without consideration of uncertainty). Deterministic and probabilistic analysis (considering uncertainty) identified antibiotic prophylaxis combined with antibiotic-impregnated cement (AP & ABC) to be the most cost-effective strategy. Using AP & ABC generated the highest net monetary benefit (NMB) and an incremental $3.1m NMB compared to only using antibiotic prophylaxis. There was a very low error probability that this strategy might not have the largest NMB (<5%). Not using antibiotic prophylaxis (No AP) or using both antibiotic prophylaxis combined with laminar air operating rooms (AP & LOR) resulted in worse health outcomes and higher costs. Sensitivity analyses showed that the model was sensitive to the initial cohort starting age and the additional costs of ABC but the best strategy did not change, even for extreme values. The cost-effectiveness improved for a higher proportion of cemented primary THAs and higher baseline rates of deep SSI. The value of perfect information indicated that no additional research is required to support the model conclusions. Conclusions Preventing deep SSI with antibiotic prophylaxis and antibiotic-impregnated cement has shown to improve health outcomes among hospitalised patients, save lives and enhance resource allocation. By implementing a more beneficial infection control strategy, scarce health care resources can be used more efficiently to the benefit of all members of society. The results of this project provide Australian policy makers with key information about how to efficiently manage risks of infection in THA.

How should Australia regulate voluntary euthanasia and assisted suicide?

The purpose of this paper is to provide a basis from which to start an informed and rational dialogue in Australia about voluntary euthanasia (VE) and assisted suicide (AS). It does this by seeking to chart the broad landscape of issues that can be raised as relevant to how this conduct should be regulated by the law. It is not our purpose to persuade. Rather, we have attempted to address the issues as neutrally as possible and to canvass both sides of the argument in an even-handed manner. We hope that this exercise places the reader in a position to consider the question posed by this paper: How should Australia regulate voluntary euthanasia and assisted suicide? In line with the approach taken in the paper, this question does not take sides in the debate. It simply asks how VE and AS should be regulated, acknowledging that both prohibition and legalisation of such conduct involve regulation. We begin by considering the wider legal framework that governs end of life decision-making. Decisions to withhold or withdraw life-sustaining treatment that result in a person’s death can be lawful. This could be because, for example, a competent adult refuses such treatment. Alternatively, stopping or not providing treatment can be lawful when it is no longer in a person’s best interests to receive it. The law also recognises that appropriate palliative care should not attract criminal responsibility. By contrast, VE and AS are unlawful in Australia and could lead to prosecution for crimes such as murder, manslaughter or aiding and abetting suicide. But this is not to say that such conduct does not occur in practice. Indeed, there is a body of evidence that VE and AS occur in Australia, despite them being unlawful. There have been repeated efforts to change the law in this country, mainly by the minor political parties. However, apart from a brief period when VE and AS was lawful in the Northern Territory, these attempts to reform the law have been unsuccessful. The position is different in a small but increasing number of jurisdictions overseas where such conduct is lawful. The most well known is the Netherlands but there are also statutory regimes that regulate VE and/or AS in Belgium and Luxembourg in Europe, and Oregon and Washington in the United States. A feature of these legislative models is that they incorporate review or oversight processes that enable the collection of data about how the law is being used. As a result, there is a significant body of evidence that is available for consideration to assess the operation of the law in these jurisdictions and some of this is considered briefly here. Assisting a suicide, if done for selfless motives, is also legal in Switzerland, and this has resulted in what has been referred to as ‘euthanasia tourism’. This model is also considered. The paper also identifies the major arguments in favour of, and against, legalisation of VE and AS. Arguments often advanced in favour of law reform include respect for autonomy, that public opinion favours reform, and that the current law is incoherent and discriminatory. Key arguments against legalising VE and AS point to the sanctity of life, concerns about the adequacy and effectiveness of safeguards, and a ‘slippery slope’ that will allow euthanasia to occur for minors or for adults where it is not voluntary. We have also attempted to step beyond these well trodden and often rehearsed cases ‘for and against’. To this end, we have identified some ethical values that might span both sides of the debate and perhaps be the subject of wider consensus. We then outline a framework for considering the issue of how Australia should regulate VE and AS. We begin by asking whether such conduct should be criminal acts (as they presently are). If VE and AS should continue to attract criminal responsibility, the next step is to enquire whether the law should punish such conduct more or less than is presently the case, or whether the law should stay the same. If a change is favoured as to how the criminal law punishes VE and AS, options considered include sentencing reform, creating context-specific offences or developing prosecutorial guidelines for how the criminal justice system deals with these issues. If VE and AS should not be criminal acts, then questions arise as to how and when they should be permitted and regulated. Possible elements of any reform model include: ensuring decision-making is competent and voluntary; ascertaining a person’s eligibility to utilise the regime, for example, whether it depends on him or her having a terminal illness or experiencing pain and suffering; and setting out processes for how any decision must be made and evidenced. Options to bring about decriminalisation include challenging the validity of laws that make VE and AS unlawful, recognising a defence to criminal prosecution, or creating a statutory framework to regulate the practice. We conclude the paper where we started: with a call for rational and informed consideration of a difficult and sensitive issue. How should Australia regulate voluntary euthanasia and assisted suicide?

Interactive conference voting

We describe and analyze opinion polling results from interactive voting procedures undertaken before and after presentations during the Outcome Measures in Rheumatoid Arthritis Clinical Trials Conference (OMERACT II) in Ottawa, Canada, June 30-July 2, 1994. The scoring procedure was a matched voting design; when a participant used the same keypad at the beginning and end of voting, change within a participant could be estimated. Participants, experienced in the rheumatic diseases included clinicians, researchers, methodologists, regulators, and representatives of the pharmaceutical industry. Patients under consideration were those with any rheumatic diseases. Questions were constructed to evaluate the change in voting behavior expected from the content of the presentation. Statistically significant and substantively important changes were evident in most questions.

A chance for diversity? Australian online journalism

Australia’s mainstream media landscape has long been recognised as highly limited – media ownership in the country has traditionally been concentrated in the hands of a very few, and (except for Sydney and Melbourne) it is common for major Australian cities to be served by only one local newspaper, usually produced by Rupert Murdoch’s News Ltd. This can be seen also to affect the quality and diversity of Australian journalism; additionally, the global decline of newspaper publishers’ revenues and overall adverse economic conditions exert further pressure on journalistic operations in the country. At the same time, and possibly in response to the increasing stresses on industrial journalism in the country and the implications they have for the quality of journalistic products, a vibrant and dynamic ecosystem of Australian industrial and citizen journalism publications has emerged online. Existing media organisations have built strong news brands online, while citizen journalists and political bloggers have given voice to issues, concerns, and opinions hitherto underrepresented in Australian mainstream journalism; of particular interest, however, is the increasing level of engagement and interaction between the two. While such interaction has been characterised by deep animosity at times (especially also in the context of the Australian federal election in November 2007), Australia has also seen the emergence and establishment of a number of new, intermediary online publications which act as spaces for public debate and analysis – from the public intellectualism of Online Opinion through the muckraking of Crikey to the progressive politics of New Matilda. The rise of social media as spaces for the discussion of news and politics further changes the media environment, potentially leading both to renewed conflict between professional and citizen journalists and to a greater level of engagement between journalists and audiences. Overall, then, such online developments offer a chance for a greater diversity of opinion and representation in Australian journalism, but also remain under a cloud from uncertain long-term business models and funding arrangements. This chapter outlines current trends in Australian online journalism, and speculates about their effect on the Australian news media landscape.

Learning personalized tag ontology from user tagging information

The cross-sections of the Social Web and the Semantic Web has put folksonomy in the spot light for its potential in overcoming knowledge acquisition bottleneck and providing insight for "wisdom of the crowds". Folksonomy which comes as the results of collaborative tagging activities has provided insight into user's understanding about Web resources which might be useful for searching and organizing purposes. However, collaborative tagging vocabulary poses some challenges since tags are freely chosen by users and may exhibit synonymy and polysemy problem. In order to overcome these challenges and boost the potential of folksonomy as emergence semantics we propose to consolidate the diverse vocabulary into a consolidated entities and concepts. We propose to extract a tag ontology by ontology learning process to represent the semantics of a tagging community. This paper presents a novel approach to learn the ontology based on the widely used lexical database WordNet. We present personalization strategies to disambiguate the semantics of tags by combining the opinion of WordNet lexicographers and users’ tagging behavior together. We provide empirical evaluations by using the semantic information contained in the ontology in a tag recommendation experiment. The results show that by using the semantic relationships on the ontology the accuracy of the tag recommender has been improved.

Personalization in tag ontology learning for recommendation making

Due to the explosive growth of the Web, the domain of Web personalization has gained great momentum both in the research and commercial areas. One of the most popular web personalization systems is recommender systems. In recommender systems choosing user information that can be used to profile users is very crucial for user profiling. In Web 2.0, one facility that can help users organize Web resources of their interest is user tagging systems. Exploring user tagging behavior provides a promising way for understanding users’ information needs since tags are given directly by users. However, free and relatively uncontrolled vocabulary makes the user self-defined tags lack of standardization and semantic ambiguity. Also, the relationships among tags need to be explored since there are rich relationships among tags which could provide valuable information for us to better understand users. In this paper, we propose a novel approach for learning tag ontology based on the widely used lexical database WordNet for capturing the semantics and the structural relationships of tags. We present personalization strategies to disambiguate the semantics of tags by combining the opinion of WordNet lexicographers and users’ tagging behavior together. To personalize further, clustering of users is performed to generate a more accurate ontology for a particular group of users. In order to evaluate the usefulness of the tag ontology, we use the tag ontology in a pilot tag recommendation experiment for improving the recommendation performance by exploiting the semantic information in the tag ontology. The initial result shows that the personalized information has improved the accuracy of the tag recommendation.

The social mechanism of political deliberation and citizen participation in Guangdong China

Many studies have focused on why deliberative institutions should be established in order to develop Chinese people’s citizenry skills; however few focus on the social conditions and public sentiments that shape the development of deliberative mechanisms. Skills and awareness of citizenry is not only brought into being by deliberative institutions that are set up by the government, but evolve through interplays between technologies and social changes. As a test-bed for economic reform Guangdong is increasingly identified by translocality and hybrid culture. This is framed by identity conflict and unrests, much of which is due to soaring wealth polarisation, high volumes of population movement, cultural collisions and ongoing linguistic contestations. These unrests show the region’s transformation goes beyond the economic front. Profound changes are occurring at what anthropologists and philosophers call the changing social conciseness or moral landscape (Ci, 1994; Yan, 2010). The changing social moralities are a reflection of the awareness of individuals’ rights and responsibilities, and their interdependencies from dominant ideologies. This paper discusses Guangdong’s social and cultural characteristics, and questions how existing social conditions allow the staging of political deliberation by facilitating political engagement and the formation of public opinion. The paper will investigate the tragedy of Xiao Yueyue in Foshan, Guangdong, where ‘right’ and ‘responsibility’, ‘self’ and ‘other’ define the public sentiments of deliberation and participation.

Are we keeping the bastards honest? Perceptions of corruption, integrity and influence on politics

The words of the late Don Chipp, the founder of the Australian Democrats, have a perennial relevance to politics. When Chipp talked about ‘keeping the bastards honest’, it related to a minor political party playing a role of keeping the major political parties true to their word (Warhurst 1997). Yet it is also a democratic role that citizens play on an ongoing basis, particularly through the mechanism of elections. At the ballot box, governments that are widely perceived to have acted with a lack of integrity are roundly punished. This chapter explores public opinion on issues of integrity, corruption, influence and trust in politics and politicians in Australia. The evidence paints a differentiated picture of a public which sees little sign of overtly corrupt political practices but on the other hand does not feel terribly influential and is not always confident of fair treatment from public officials...

Child rearing Inc : On the perils of political paralysis Down Under

In his 2007 PESA keynote address, Paul Smeyers discussed the increasing regulation of child-rearing through government intervention and the generation of “experts,” citing particular examples from Europe where cases of childhood obesity and parental neglect have stirred public opinion and political debate. In his paper (this issue), Smeyers touches on a number of tensions before concluding that child rearing qualifies as a practice in which liberal governments should be reluctant to intervene. In response, I draw on recent experiences in Australia and argue that certain tragic events of late are the result of an ethical, moral and social vacuum in which these tensions coalesce. While I agree with Smeyers that governments should be reluctant to “intervene” in the private domain of the family, I argue that there is a difference between intervention and support. In concluding, I maintain that if certain Western liberal democracies did a more comprehensive job of supporting children and their families through active social investment in primary school education, then both families and schools would be better equipped to deal with the challenges they now face.

Update on complex nonpharmacological interventions for breathlessness

Purpose of review: The study provides a review of current evidence about the role of complex nonpharmacological strategies in managing the multidimensional components of the breathlessness experience for individuals with life-limiting conditions. Recent findings: Evidence continues to demonstrate the significant impact of breathlessness on patients’ quality of life, day-to-day activity, and physical and psychosocial functioning. Recent evidence also confirms that patients draw on a number of self-initiated actions to cope with breathlessness, although many do not use strategies that are supported by a growing body of evidence from randomized controlled trials. Current literature supports the use of multicomponent, nonpharmacological interventions comprising strategies to improve breathing efficiency and reducing psychological distress to manage breathlessness. However trials of these approaches have mostly been conducted among patients with chronic obstructive pulmonary disease (COPD) or lung cancer, and few studies have investigated the benefits of nonpharmacological for patients in later stages of disease. Further investigation of interventions is required across a broader range of chronic life-limiting conditions. Addressing breathlessness and its co-occurring symptoms (symptom clusters) is also an area for future enquiry. Summary: The experience of breathlessness and strategies adopted by patients to manage the experience highlight the importance of multidimensional approaches to improve outcomes for patients with life-limiting conditions. There is good evidence to support the role of multicomponent, nonpharmacological interventions in reducing breathlessness for patients with COPD and lung cancer, although further studies are required to understand the particular clinical contexts in which such interventions are appropriate.

Avoiding uninformed responses in destination image questionnaires

Since the first destination image studies were published in the early 1970s, the field has become one of the most popular in the tourism literature. While reviews of the destination image literature show no commonly agreed conceptualisation of the construct, researchers have predominantly used structured questionnaires for measurement. There has been criticism that the way some of these scales have been selected means a greater likelihood of attributes being irrelevant to participants. This opens up the risk of stimulating uninformed responses. The issue of uninformed response was first raised as a source of error 60 years ago. However, there has been little, if any, discussion in relation to destination image measurement, studies of which often require participants to provide opinion-driven rather than fact-based responses. This paper reports the trial of a ‘don’t know’ (DK) non-response option for participants in two destination image questionnaires. It is suggested the use of a DK option provides participants with an alternative to i) skipping the question, ii) using the scale midpoint to denote neutrality, or iii) providing an uninformed response. High levels of DK usage by participants can then alert the marketer of the need to improve awareness of destination performance for potential salient attributes.