Brette Blakely

Wnt5a regulates midbrain dopaminergic axon growth and guidance.

During development, precise temporal and spatial gradients are responsible for guiding axons to their appropriate targets. Within the developing ventral midbrain (VM) the cues that guide dopaminergic (DA) axons to their forebrain targets remain to be fully elucidated. Wnts are morphogens that have been identified as axon guidance molecules. Several Wnts are expressed in the VM where they regulate the birth of DA neurons. Here, we describe that a precise temporo-spatial expression of Wnt5a accompanies the development of nigrostriatal projections by VM DA neurons. In mice at E11.5, Wnt5a is expressed in the VM where it was found to promote DA neurite and axonal growth in VM primary cultures. By E14.5, when DA axons are approaching their striatal target, Wnt5a causes DA neurite retraction in primary cultures. Co-culture of VM explants with Wnt5a-overexpressing cell aggregates revealed that Wnt5a is capable of repelling DA neurites. Antagonism experiments revealed that the effects of Wnt5a are mediated by the Frizzled receptors and by the small GTPase, Rac1 (a component of the non-canonical Wnt planar cell polarity pathway). Moreover, the effects were specific as they could be blocked by Wnt5a antibody, sFRPs and RYK-Fc. The importance of Wnt5a in DA axon morphogenesis was further verified in Wnt5a −/− mice, where fasciculation of the medial forebrain bundle (MFB) as well as the density of DA neurites in the MFB and striatal terminals were disrupted. Thus, our results identify a novel role of Wnt5a in DA axon growth and guidance.

Ryk, a Receptor Regulating Wnt5a-Mediated Neurogenesis and Axon Morphogenesis of Ventral Midbrain Dopaminergic Neurons

Ryk is an atypical transmembrane receptor tyrosine kinase that has been shown to play multiple roles in development through the modulation of Wnt signaling. Within the developing ventral midbrain (VM), Wnts have been shown to contribute to the proliferation, differentiation, and connectivity of dopamine (DA) neurons; however, the Wnt-related receptors regulating these events remain less well described. In light of the established roles of Wnt5a in dopaminergic development (regulating DA differentiation as well as axonal growth and repulsion), and its interaction with Ryk elsewhere within the central nervous system, we investigated the potential role of Ryk in VM development. Here we show temporal and spatial expression of Ryk within the VM, suggestive of a role in DA neurogenesis and axonal plasticity. In VM primary cultures, we show that the effects of Wnt5a on VM progenitor proliferation, DA differentiation, and DA axonal connectivity can be inhibited using an Ryk-blocking antibody. In support, Ryk knockout mice showed reduced VM progenitors and DA precursor populations, resulting in a significant decrease in DA cells. However, Ryk(-/-) mice displayed no defects in DA axonal growth, guidance, or fasciculation of the MFB, suggesting other receptors may be involved and/or compensate for the loss of this receptor. These findings identify for the first time Ryk as an important receptor for midbrain DA development.

Health system frameworks and performance indicators in eight countries: A comparative international analysis:

Objectives: Performance indicators are a popular mechanism for measuring the quality of healthcare to facilitate both quality improvement and systems management. Few studies make comparative assessments of different countries’ performance indicator frameworks. This study identifies and compares frameworks and performance indicators used in selected Organisation for Economic Co-operation and Development health systems to measure and report on the performance of healthcare organisations and local health systems. Countries involved are Australia, Canada, Denmark, England, the Netherlands, New Zealand, Scotland and the United States. Methods: Identification of comparable international indicators and analyses of their characteristics and of their broader national frameworks and contexts were undertaken. Two dimensions of indicators – that they are nationally consistent (used across the country rather than just regionally) and locally relevant (measured and reported publicly at a local level, for example, a health service) – were deemed important. Results: The most commonly used domains in performance frameworks were safety, effectiveness and access. The search found 401 indicators that fulfilled the ‘nationally consistent and locally relevant’ criteria. Of these, 45 indicators are reported in more than one country. Cardiovascular, surgery and mental health were the most frequently reported disease groups. Conclusion: These comparative data inform researchers and policymakers internationally when designing health performance frameworks and indicator sets.

The basis of clinical tribalism, hierarchy and stereotyping: a laboratory-controlled teamwork experiment

Objectives To examine the basis of multidisciplinary teamwork. In real-world healthcare settings, clinicians often cluster in profession-based tribal silos, form hierarchies and exhibit stereotypical behaviours. It is not clear whether these social structures are more a product of inherent characteristics of the individuals or groups comprising the professions, or attributable to a greater extent to workplace factors. Setting Controlled laboratory environment with well-appointed, quiet rooms and video and audio equipment. Participants Clinical professionals (n=133) divided into 35 groups of doctors, nurses and allied health professions, or mixed professions. Interventions Participants engaged in one of three team tasks, and their performance was video-recorded and assessed. Primary and secondary measures Primary: teamwork performance. Secondary, pre-experimental: a bank of personality questionnaires designed to assess participants’ individual differences. Postexperimental: the 16-item Mayo High Performance Teamwork Scale (MHPTS) to measure teamwork skills; this was self-assessed by participants and also by external raters. In addition, external, arms length blinded observations of the videotapes were conducted. Results At baseline, there were few significant differences between the professions in collective orientation, most of the personality factors, Machiavellianism and conservatism. Teams generally functioned well, with effective relationships, and exhibited little by way of discernible tribal or hierarchical behaviours, and no obvious differences between groups (F (3, 31)=0.94, p=0.43). Conclusions Once clinicians are taken out of the workplace and put in controlled settings, tribalism, hierarchical and stereotype behaviours largely dissolve. It is unwise therefore to attribute these factors to fundamental sociological or psychological differences between individuals in the professions, or aggregated group differences. Workplace cultures are more likely to be influential in shaping such behaviours. The results underscore the importance of culture and context in improvement activities. Future initiatives should factor in culture and context as well as individuals’ or professions’ characteristics as the basis for inducing more lateral teamwork or better interprofessional collaboration.

Macquarie Surgical Innovation Identification Tool (MSIIT): a study protocol for a usability and pilot test

Introduction Medicine relies on innovation to continually improve. However, innovation is potentially risky, and not all innovations are successful. Therefore, it is important to identify innovations prospectively and provide support, to make innovation as safe and effective as possible. The Macquarie Surgical Innovation Identification Tool (MSIIT) is a simple checklist designed as a practical tool for hospitals to identify planned surgical innovations. This project aims to test the usability and pilot the use of the MSIIT in a surgical setting. Methods and analysis The project will run in two phases at two Australian hospitals, one public and one private. Phase I will involve interviews, focus groups and a survey of hospital administrators and surgical teams to assess the usability and system requirements for the use of the MSIIT. Current practice regarding surgical innovation within participating hospitals will be mapped, and the best implementation strategy for MSIIT completion will be established. Phase II will involve trialling the MSIIT for each surgery within the trial period by various surgical personnel. Follow-up interviews, focus groups and a survey will be conducted with trial participants to collect feedback on their experience of using the MSIIT during the trial period. Comparative data on rates of surgical innovation during the trial period will also be gathered from existing hospital systems and compared to the rates identified by the MSIIT. Ethics and dissemination Ethical approval has been obtained. The results of this study will be presented to interested health services and other stakeholders, presented at conferences and published in a peer-reviewed MEDLINE-indexed journal.

Device representatives in hospitals: are commercial imperatives driving clinical decision-making?

Despite concerns about the relationships between health professionals and the medical device industry, the issue has received relatively little attention. Prevalence data are lacking; however, qualitative and survey research suggest device industry representatives, who are commonly present in clinical settings, play a key role in these relationships. Representatives, who are technical product specialists and not necessarily medically trained, may attend surgeries on a daily basis and be available to health professionals 24 hours a day, 7 days a week, to provide advice. However, device representatives have a dual role: functioning as commissioned sales representatives at the same time as providing advice on approaches to treatment. This duality raises the concern that clinical decision-making may be unduly influenced by commercial imperatives. In this paper, we identify three key ethical concerns raised by the relationship between device representatives and health professionals: (1) impacts on healthcare costs, (2) the outsourcing of expertise and (3) issues of accountability and informed consent. These ethical concerns can be addressed in part through clarifying the boundary between the support and sales aspects of the roles of device representatives and developing clear guidelines for device representatives providing support in clinical spaces. We suggest several policy options including hospital provision of expert support, formalising clinician conduct to eschew receipt of meals and payments from industry and establishing device registries.

Association between the expression of vascular endothelial growth factors and metabolic syndrome or its components: a systematic review and meta-analysis

BackgroundSeveral studies have linked vascular endothelial growth factors (VEGFs) with metabolic syndrome or its components. However, there has been no systematic appraisal of the findings of these studies to date. The current systematic review and meta-analysis was conducted to explore this association.MethodsPubMed, EMBASE, the Cochrane library, and clinical trials registries were used to retrieve peer-reviewed clinical studies that had evaluated the association of VEGFs with metabolic syndrome or its components without applying language and date restrictions. The final search was performed on 29 September 2017.ResultsWe included 32 studies in this systematic review and meta-analysis, of which 16 studies (19 study arms) were included in the meta-analysis and remaining studies were qualitatively assessed. Overall, VEGF-A, VEGF-B and VEGF-C were strongly associated with metabolic syndrome or its components. The components of metabolic syndrome varied in their association. Obesity was not correlated with increased VEGF-A expression (p = 0.12), whereas VEGF-B and VEGF-C expression was significantly higher in those with obesity. In contrast, hyperglycemia in type 1 diabetes was strongly associated with increased VEGF-A levels (p < 0.00001), as was type 2 diabetes (p = 0.0006). The studies included in the qualitative analysis similarly showed an increase in VEGF family expression in people with metabolic syndrome, and with its components.ConclusionThe increased concentrations of vascular endothelial growth factors are variably associated with metabolic syndrome or its components. Each VEGF protein has a unique set of associations with the disease state.

Conflicts of interest in Australia’s IVF industry: an empirical analysis and call for action

Abstract In Australia, the growing assisted reproductive technologies (ART) industry has recently received some public criticism. Much of this criticism centres on the concern that doctors are increasingly motivated by profit, rather than patient interests. These concerns appear to suggest that the growing business of ART generates conflicts of interest (COI) for clinicians. While media reports may be rhetorically compelling, claims that ART practice is distorted by COI must be supported by empirical evidence. This preliminary study sought to engage with people involved with the ART industry and map out their concerns related to COI in ART. A small convenience sample of eight professionals was interviewed. Here, we present the major themes uncovered, including a richer understanding of the ‘interests’ of various parties involved in Australian ART. We then propose a strategy for how this topic could be constructively explored.

On the fragility of medical virtue in a neoliberal context: the case of commercial conflicts of interest in reproductive medicine

Social, political, and economic environments play an active role in nurturing professional virtue. Yet, these environments can also lead to the erosion of virtue. As such, professional virtue is fragile and vulnerable to environmental shifts. While physicians are often considered to be among the most virtuous of professional groups, concern has also always existed about the impact of commercial arrangements on physicians’ willingness and capacity to enact their professional virtues. This article examines the ways in which commercial arrangements have been negotiated to secure medical virtue from real or perceived threats of erosion. In particular, we focus on the concern surrounding conflicts of interest arising from commercial arrangements that have developed as a result of neoliberal economic and social policies. The deregulation of medical markets and privatization of services have produced new commercial relationships that are often misunderstood by patients, publics, and physicians themselves. ‘Conflicts of interest’ policies have been introduced in an attempt to safeguard ethical conduct and medical practice. However, a number of virtue ethicists have critiqued these policies as inadequate for securing virtue. We examine the ways in which commercial arrangements have been seen to impact upon medical virtue, both historically and in the context of modern medicine (using the example of fertility services in Australia). We then describe and critique current efforts to restore clinical virtue through both conflict of interest policies and through virtue ethics. Finally, we suggest some possible ways of addressing the corrosive effects of neoliberalism on medical virtue.