Bariatric surgery or medicine for type 2 diabetes?

Diet and medical treatment are the standard treatment for type 2 diabetes. In obese subjects with type 2 diabetes, bariatric surgery is effective in resolving diabetes. Two clinical trials comparing bariatric surgery to medical treatment were evaluated. Both the Surgical Treatment And Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial (laparoscopic Roux-En Y gastric bypass and sleeve gastrectomy) and the DIet and medical therapy versus BAriatric SurgerY in type 2 diabetes (DIBASY) trial (laparoscopic gastric bypass and biliopancreatic-diversion) showed that surgery was more effective than medical care in resolving or managing type 2 diabetes. Larger studies, or a compilation of studies, are needed to determine whether one of these procedures is better, or if they are all similarly effective, and this should also be weighed against the risk of the operations.

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.

A pharmacogenomic evaluation of migraine therapy

Migraine is a common idiopathic primary headache disorder with significant mental, physical and social health implications. Accompanying an intense unilateral pulsating head pain other characteristic migraine symptoms include nausea, emesis, phonophobia, photophobia and in approximately 20-30% of migraine cases, neurologic disturbances associated with the aura phase. Although selective serotonin (5-HT) receptor agonists (i.e., 5-HT(1B/1D)) are successful in alleviating migrainous symptoms in < or = 70% of known sufferers, for the remaining 30%, additional migraine abortive medications remain unsuccessful, not tested or yet to be identified. Genetic characterization of the migrainous disorder is making steady progress with an increasing number of genomic susceptibility loci now identified on chromosomes 1q, 4q, 5q, 6p, 11q, 14q, 15q, 17p, 18q, 19p and Xq. The 4q, 5q, 17p and 18q loci involve endophenotypic susceptibility regions for various migrainous symptoms. In an effort to develop individualized pharmacotherapeutics, the identification of these migraine endophenotypic loci may well be the catalyst needed to aid in this goal. In this review the authors discuss the present treatment of migraine, known genomic susceptibility regions and results from migraine (genetic) association studies. The authors also discuss pharmacogenomic considerations for more individualized migraine prophylactic treatments.

Academics and activists in the policy process : engagement with Australian media inquiries 2011-13

After its narrow re-election in June 2010, the Australian Labor government undertook a series of public inquiries into reform of Australian media, communications and copyright laws. One important driver of policy reform was the government’s commitment to building a National Broadband Network (NBN), and the implications this had for existing broadcasting and telecommunications policy, as it would constitute a major driver of convergence of media and communications access devices and content platforms. These inquiries included: the Convergence Review of media and communications legislation; the Australian Law Reform Commission (ALRC) review of the National Classification Scheme; the Independent Media Inquiry (Finkelstein Review) into Media and Media Regulation; and the ALRC review of Copyright and the Digital Economy. One unusual feature of this review process, discussed in the paper, was the degree to which academics were involved in the process, not simply as providers of expert opinion, but as review chairs seconded from their universities. This paper considers the role played by activist groups in all of these inquiries and their relationship to the various participants in the inquiries, as well as the implications of academics being engaged in such inquiries, not simply as activist-scholars, but as those primarily responsible for delivering policy review outcomes. The latter brings to the forefront issues arising in from direct engagement with governments and state agencies themselves, which challenges traditional understandings of the academic community as “critical outsiders” towards such policy processes.

A Bayesian network approach to modelling temporal behaviour of Lyngbya majuscula bloom initiation

Lyngbya majuscula is a cyanobacterium (blue-green algae) occurring naturally in tropical and subtropical coastal areas worldwide. Deception Bay, in Northern Moreton Bay, Queensland, has a history of Lyngbya blooms, and forms a case study for this investigation. The South East Queensland (SEQ) Healthy Waterways Partnership, collaboration between government, industry, research and the community, was formed to address issues affecting the health of the river catchments and waterways of South East Queensland. The Partnership coordinated the Lyngbya Research and Management Program (2005-2007) which culminated in a Coastal Algal Blooms (CAB) Action Plan for harmful and nuisance algal blooms, such as Lyngbya majuscula. This first phase of the project was predominantly of a scientific nature and also facilitated the collection of additional data to better understand Lyngbya blooms. The second phase of this project, SEQ Healthy Waterways Strategy 2007-2012, is now underway to implement the CAB Action Plan and as such is more management focussed. As part of the first phase of the project, a Science model for the initiation of a Lyngbya bloom was built using Bayesian Networks (BN). The structure of the Science Bayesian Network was built by the Lyngbya Science Working Group (LSWG) which was drawn from diverse disciplines. The BN was then quantified with annual data and expert knowledge. Scenario testing confirmed the expected temporal nature of bloom initiation and it was recommended that the next version of the BN be extended to take this into account. Elicitation for this BN thus occurred at three levels: design, quantification and verification. The first level involved construction of the conceptual model itself, definition of the nodes within the model and identification of sources of information to quantify the nodes. The second level included elicitation of expert opinion and representation of this information in a form suitable for inclusion in the BN. The third and final level concerned the specification of scenarios used to verify the model. The second phase of the project provides the opportunity to update the network with the newly collected detailed data obtained during the previous phase of the project. Specifically the temporal nature of Lyngbya blooms is of interest. Management efforts need to be directed to the most vulnerable periods to bloom initiation in the Bay. To model the temporal aspects of Lyngbya we are using Object Oriented Bayesian networks (OOBN) to create ‘time slices’ for each of the periods of interest during the summer. OOBNs provide a framework to simplify knowledge representation and facilitate reuse of nodes and network fragments. An OOBN is more hierarchical than a traditional BN with any sub-network able to contain other sub-networks. Connectivity between OOBNs is an important feature and allows information flow between the time slices. This study demonstrates more sophisticated use of expert information within Bayesian networks, which combine expert knowledge with data (categorized using expert-defined thresholds) within an expert-defined model structure. Based on the results from the verification process the experts are able to target areas requiring greater precision and those exhibiting temporal behaviour. The time slices incorporate the data for that time period for each of the temporal nodes (instead of using the annual data from the previous static Science BN) and include lag effects to allow the effect from one time slice to flow to the next time slice. We demonstrate a concurrent steady increase in the probability of initiation of a Lyngbya bloom and conclude that the inclusion of temporal aspects in the BN model is consistent with the perceptions of Lyngbya behaviour held by the stakeholders. This extended model provides a more accurate representation of the increased risk of algal blooms in the summer months and show that the opinions elicited to inform a static BN can be readily extended to a dynamic OOBN, providing more comprehensive information for decision makers.

Targeting oxidative stress in cancer

Importance of the field: Reactive oxygen species (ROS) occur as natural by-products of oxygen metabolism and have important cellular functions. Normally, the cell is able to maintain an adequate balance between the formation and removal of ROS either via anti-oxidants or through the use specific enzymatic pathways. However, if this balance is disturbed, oxidative stress may occur in the cell, a situation linked to the pathogenesis of many diseases, including cancer. Areas covered in this review: HDACs are important regulators of many oxidative stress pathways including those involved with both sensing and coordinating the cellular response to oxidative stress. In particular aberrant regulation of these pathways by histone deacetylases may play critical roles in cancer progression. What the reader will gain: In this review we discuss the notion that targeting HDACs may be a useful therapeutic avenue in the treatment of oxidative stress in cancer, using chronic obstructive pulmonary disease (COPD), NSCLC and hepatocellular carcinoma (HCC) as examples to illustrate this possibility. Take home message: Epigenetic mechanisms may be an important new therapeutic avenue for targeting oxidative stress in cancer. © 2010 Informa UK, Ltd.

Cardiac safety concerns for ondansetron, an antiemetic commonly used for nausea linked to cancer treatment and following anaesthesia

Introduction: Ondansetron is a 5-HT3 receptor antagonist commonly used as an anti-emetic to prevent the nausea and vomiting associated with anti-cancer drugs, cancer radiotherapy, or postoperatively. Recently, the US Food and Drug Administration (FDA) issued a warning for ondansetron due to a potential for prolongation of the QT interval of the electrocardiogram (ECG), a phenomenon that is associated with an increased risk of the potentially fatal arrhythmia torsade de pointes. Areas covered: We undertook a review of the cardiac safety of ondansetron. Our primary sources of information were PubMed (with downloading of full articles), and the internet. Expert opinion: The dose of ondansetron that the FDA has concerns about is 32 mg iv (or several doses that are equivalent to this), which is only used in preventing nausea and vomiting associated with cancer chemotherapy. This suggests that ondansetron may be safe in the lower doses used to prevent the nausea and vomiting in radiation treatment or postoperatively. However, as there is a report that a lower dose of ondansetron prolonged the QT interval in healthy volunteers, this needs to be clarified by the FDA. More research needs to be undertaken of the relationship between QT prolongation and torsades in order that the FDA can produce clear-cut evidence of pro-arrhythmic risk when introducing warnings for this.