Deconstructing antiobesity compound action : requirement of serotonin 5-HT2B receptors for dexfenfluramine anorectic effects

The now-banned anorectic molecule, dexfenfluramine, promotes serotonin release through a serotonin transporter-dependent mechanism, and it has been widely prescribed for the treatment of obesity. Previous studies have identified that 5-HT(2B) receptors have important roles in dexfenfluramine side effects, that is, pulmonary hypertension, plasma serotonin level regulation, and valvulopathy. We thus investigated a putative contribution of 5-HT(2B) receptors in dexfenfluramine-dependent feeding behavior in mice. Interestingly, the hypophagic response to dexfenfluramine (3-10 mg/kg) observed in wild-type mice (1-4 h) was eliminated in mice lacking 5-HT(2B) receptors (5-HT(2B)(-/-)). These findings were further validated by the lack of hypophagic response to dexfenfluramine in wild-type mice treated with RS127445, a highly selective and potent antagonist (pKi=8.22 ± 0.24). Using microdialysis, we observed that in 5-HT(2B)(-/-) awake mice, the dexfenfluramine-induced hypothalamic peak of serotonin release (1 h) was strongly reduced (fourfold) compared with wild type. Moreover, using hypothalamic synaptosomes, we established the serotonergic neuron autonomous properties of this effect: a strong serotonin release was observed upon dexfenfluramine stimulation of synaptosome preparation from wild type but not from mice lacking active 5-HT(2B) receptors. These findings strongly suggest that activation of presynaptic 5-HT(2B) receptors is a limiting step in the serotonin transporter dependent-releasing effect of dexfenfluramine, whereas other serotonin receptors act downstream with respect to feeding behavior.

Improving the outcomes of foot and ankle surgery through the audit cycle : a case study

The direct costs of managing adverse outcomes from Australian health care are estimated to be $2 billion. The audit cycle is considered an important tool to assist in the preventive management of adverse outcomes.Australian guidelines for audit cycle design allow for comparison of data sets derived from similar surgical specialities. However a lack of data set standardisation inhibits meaningful comparisons of foot and ankle surgical audits. This research will assist development of a best practice model for auditing foot and ankle surgery. Data derived from this model will improve the safety and quality of foot and ankle surgery. The preliminary phase of this process is to identify and understand the attitudes and behaviours of how and why surgeons participate in the audit cycle. A descriptive embedded multiple case study research design is planned to provide an intense focus on a single phenomenon (the audit cycle) within its real life context (clinical governance). The measures to be included in the case study have been identified by the Balanced Patient Safety Measurement Framework. These include: audit and peer review activity, provider attitudes to patient safety, safety learning, action and performance. A purposive sample of 6 to 8 surgeons (units of analysis) from 3 to 4 specialities (cases) will undergo semi-structured interview. This will investigate: current audit tools and processes; attitudes; and behaviours of surgeons to the audit cycle. Similarities in and differences between the units of analysis will indicate which identified measures function as barriers or enablers of the audit cycle. Reliability and validity (external and construct) will be assessed using established methods for case studies. The descriptive embedded multiple case study will reveal how and why foot and ankle surgeons participate in the audit cycle. This will inform further research to improve the outcomes of foot and ankle surgery through development of an audit tool.

An analytical framework for quantifying aquifer response time scales associated with transient boundary conditions

A major challenge in studying coupled groundwater and surface-water interactions arises from the considerable difference in the response time scales of groundwater and surface-water systems affected by external forcings. Although coupled models representing the interaction of groundwater and surface-water systems have been studied for over a century, most have focused on groundwater quantity or quality issues rather than response time. In this study, we present an analytical framework, based on the concept of mean action time (MAT), to estimate the time scale required for groundwater systems to respond to changes in surface-water conditions. MAT can be used to estimate the transient response time scale by analyzing the governing mathematical model. This framework does not require any form of transient solution (either numerical or analytical) to the governing equation, yet it provides a closed form mathematical relationship for the response time as a function of the aquifer geometry, boundary conditions, and flow parameters. Our analysis indicates that aquifer systems have three fundamental time scales: (i) a time scale that depends on the intrinsic properties of the aquifer; (ii) a time scale that depends on the intrinsic properties of the boundary condition, and; (iii) a time scale that depends on the properties of the entire system. We discuss two practical scenarios where MAT estimates provide useful insights and we test the MAT predictions using new laboratory-scale experimental data sets.

Technical Action Research

This entry into the SAGE Encyclopedia of Action Research outlines the history, purpose and orientation of what has been termed 'technical action research'. The primary purpose of technical action research (commonly referred to as TAR) is improving the outcomes of a practice or intervention, with the focus of the inquiry process typically determined by parties external to those directly involved in the practice.

Model choice problems using approximate Bayesian computation with applications to pathogen transmission data sets

Analytically or computationally intractable likelihood functions can arise in complex statistical inferential problems making them inaccessible to standard Bayesian inferential methods. Approximate Bayesian computation (ABC) methods address such inferential problems by replacing direct likelihood evaluations with repeated sampling from the model. ABC methods have been predominantly applied to parameter estimation problems and less to model choice problems due to the added difficulty of handling multiple model spaces. The ABC algorithm proposed here addresses model choice problems by extending Fearnhead and Prangle (2012, Journal of the Royal Statistical Society, Series B 74, 1–28) where the posterior mean of the model parameters estimated through regression formed the summary statistics used in the discrepancy measure. An additional stepwise multinomial logistic regression is performed on the model indicator variable in the regression step and the estimated model probabilities are incorporated into the set of summary statistics for model choice purposes. A reversible jump Markov chain Monte Carlo step is also included in the algorithm to increase model diversity for thorough exploration of the model space. This algorithm was applied to a validating example to demonstrate the robustness of the algorithm across a wide range of true model probabilities. Its subsequent use in three pathogen transmission examples of varying complexity illustrates the utility of the algorithm in inferring preference of particular transmission models for the pathogens.

Conceptual and statistical framework for a water quality component of the integrated report card for the Great Barrier Reef catchments

This report presents the final deliverable from the project titled Conceptual and statistical framework for a water quality component of an integrated report card’ funded by the Marine and Tropical Sciences Research Facility (MTSRF; Project 3.7.7). The key management driver of this, and a number of other MTSRF projects concerned with indicator development, is the requirement for state and federal government authorities and other stakeholders to provide robust assessments of the present ‘state’ or ‘health’ of regional ecosystems in the Great Barrier Reef (GBR) catchments and adjacent marine waters. An integrated report card format, that encompasses both biophysical and socioeconomic factors, is an appropriate framework through which to deliver these assessments and meet a variety of reporting requirements. It is now well recognised that a ‘report card’ format for environmental reporting is very effective for community and stakeholder communication and engagement, and can be a key driver in galvanising community and political commitment and action. Although a report card it needs to be understandable by all levels of the community, it also needs to be underpinned by sound, quality-assured science. In this regard this project was to develop approaches to address the statistical issues that arise from amalgamation or integration of sets of discrete indicators into a final score or assessment of the state of the system. In brief, the two main issues are (1) selecting, measuring and interpreting specific indicators that vary both in space and time, and (2) integrating a range of indicators in such a way as to provide a succinct but robust overview of the state of the system. Although there is considerable research and knowledge of the use of indicators to inform the management of ecological, social and economic systems, methods on how to best to integrate multiple disparate indicators remain poorly developed. Therefore the objective of this project was to (i) focus on statistical approaches aimed at ensuring that estimates of individual indicators are as robust as possible, and (ii) present methods that can be used to report on the overall state of the system by integrating estimates of individual indicators. It was agreed at the outset, that this project was to focus on developing methods for a water quality report card. This was driven largely by the requirements of Reef Water Quality Protection Plan (RWQPP) and led to strong partner engagement with the Reef Water Quality Partnership.

Identifying influential users of micro-blogging services : a dynamic action-based network approach

In this paper, we present a dynamic model to identify influential users of micro-blogging services. Micro-blogging services, such as Twitter, allow their users (twitterers) to publish tweets and choose to follow other users to receive tweets. Previous work on user influence on Twitter, concerns more on following link structure and the contents user published, seldom emphasizes the importance of interactions among users. We argue that, by emphasizing on user actions in micro-blogging platform, user influence could be measured more accurately. Since micro-blogging is a powerful social media and communication platform, identifying influential users according to user interactions has more practical meanings, e.g., advertisers may concern how many actions – buying, in this scenario – the influential users could initiate rather than how many advertisements they spread. By introducing the idea of PageRank algorithm, innovatively, we propose our model using action-based network which could capture the ability of influential users when they interacting with micro-blogging platform. Taking the evolving prosperity of micro-blogging into consideration, we extend our actionbaseduser influence model into a dynamic one, which could distinguish influential users in different time periods. Simulation results demonstrate that our models could support and give reasonable explanations for the scenarios that we considered.

Reduced motor facilitation during action observation in schizophrenia : a mirror neuron deficit?

Impairments in social cognitive functioning are well documented in schizophrenia, however the neural basis of these deficits is unclear. A recent explanatory model of social cognition centers upon the activity of mirror neurons, which are cortical brain cells that become active during both the performance and observation of behavior. Here, we test for the first time whether mirror neuron functioning is reduced in schizophrenia. Fifteen individuals with schizophrenia or schizoaffective disorder and fifteen healthy controls completed a transcranial magnetic stimulation (TMS) experiment designed to assess mirror neuron activation. While patients demonstrated no abnormalities in cortical excitability, motor facilitation during action observation, putatively reflecting mirror neuron activity, was reduced in schizophrenia. Dysfunction within the mirror neuron system may contribute to the pathophysiology of schizophrenia.

Learning about and taking action for the environment : child and teacher experiences in a preschool water education program

Water education and conservation programs have grown exponentially in Australian primary and secondary schools and, although early childhood services have been slower to respond to the challenges of sustainability, they are catching up fast. One early program targeted at preschools was the Water Aware Centre Program in northern New South Wales developed by the local water supply authority. This paper reports on a qualitative study of children’s and teachers’ experiences of the program in three preschools. The study’s aim was to identify program attributes and pedagogies that supported learning and action taking for water conservation, and to investigate if and how the program influenced children’s and teachers’practices. Data were collected through an interview with the program designer, conversations with child participants of the program, and a qualitative survey with early childhood staff. A three-step thematic analysis was conducted on the children’s and teachers’ data. Findings revealed that the program expanded children and teachers’ ideas about water conservation and increased their water conservation practices. The children were found to influence the water conservation practices of the adults around them, thus changing practices at school and at home.

A clarion call for action based on refined DALY estimates for South Africa

Initial estimates of the burden of disease in South Africa in 20001 have been revised on the basis of additional data to estimate the disability-adjusted life-years (DALYs) for single causes for the first time in South Africa. The findings highlight the fact that despite uncertainty in the estimates, they provide important information to guide public health responses to improve the health of the nation...

Developing and evaluating interventions that are applicable and relevant to inpatients and those who care for them; a multiphase, pragmatic action research approach

Background Randomised controlled trials may be of limited use to evaluate the multidisciplinary and multimodal interventions required to effectively treat complex patients in routine clinical practice; pragmatic action research approaches may provide a suitable alternative. Methods A multiphase, pragmatic, action research based approach was developed to identify and overcome barriers to nutritional care in patients admitted to a metropolitan hospital hip-fracture unit. Results Four sequential action research cycles built upon baseline data including 614 acute hip-fracture inpatients and 30 purposefully sampled clinicians. Reports from Phase I identified barriers to nutrition screening and assessment. Phase II reported post-fracture protein-energy intakes and intake barriers. Phase III built on earlier results; an explanatory mixed-methods study expanded and explored additional barriers and facilitators to nutritional care. Subsequent changes to routine clinical practice were developed and implemented by the treating team between Phase III and IV. These were implemented as a new multidisciplinary, multimodal nutritional model of care. A quasi-experimental controlled, ‘before-and-after’ study was then used to compare the new model of care with an individualised nutritional care model. Engagement of the multidisciplinary team in a multiphase, pragmatic action research intervention doubled energy and protein intakes, tripled return home discharge rates, and effected a 75% reduction in nutritional deterioration during admission in a reflective cohort of hip-fracture inpatients. Conclusions This approach allowed research to be conducted as part of routine clinical practice, captured a more representative patient cohort than previously reported studies, and facilitated exploration of barriers and engagement of the multidisciplinary healthcare workers to identify and implement practical solutions. This study demonstrates substantially different findings to those previously reported, and is the first to demonstrate that multidisciplinary, multimodal nutrition care reduces intake barriers, delivers a higher proportional increase in protein and energy intake compared with baseline than other published intervention studies, and improves patient outcomes when compared with individualised nutrition care. The findings are considered highly relevant to clinical practice and have high translation validity. The authors strongly encourage the development of similar study designs to investigate complex health problems in elderly, multi-morbid patient populations as a way to evaluate and change clinical practice.