An In Vivo Study of a Rat Fluid-Percussion-Induced Traumatic Brain Injury Model with [11C]PBR28 and [18F]flumazenil PET Imaging.

Traumatic brain injury (TBI) modelled by lateral fluid percussion-induction (LFPI) in rats is a widely used experimental rodent model to explore and understand the underlying cellular and molecular alterations in the brain caused by TBI in humans. Current improvements in imaging with positron emission tomography (PET) have made it possible to map certain features of TBI-induced cellular and molecular changes equally in humans and animals. The PET imaging technique is an apt supplement to nanotheranostic-based treatment alternatives that are emerging to tackle TBI. The present study aims to investigate whether the two radioligands, [11C]PBR28 and [18F]flumazenil, are able to accurately quantify in vivo molecular-cellular changes in a rodent TBI-model for two different biochemical targets of the processes. In addition, it serves to observe any palpable variations associated with primary and secondary injury sites, and in the affected versus the contralateral hemispheres. As [11C]PBR28 is a radioligand of the 18 kD translocator protein, the up-regulation of which is coupled to the level of neuroinflammation in the brain, and [18F]flumazenil is a radioligand for GABAA-benzodiazepine receptors, whose level mirrors interneuronal activity and eventually cell death, the use of the two radioligands may reveal two critical features of TBI. An up-regulation in the [11C]PBR28 uptake triggered by the LFP in the injured (right) hemisphere was noted on day 14, while the uptake of [18F]flumazenil was down-regulated on day 14. When comparing the left (contralateral) and right (LFPI) hemispheres, the differences between the two in neuroinflammation were obvious. Our results demonstrate a potential way to measure the molecular alterations in a rodent-based TBI model using PET imaging with [11C]PBR28 and [18F]flumazenil. These radioligands are promising options that can be eventually used in exploring the complex in vivo pharmacokinetics and delivery mechanisms of nanoparticles in TBI treatment.

Digital Education in Health Professions: The Need for Overarching Evidence Synthesis.

Synthesizing evidence from randomized controlled trials of digital health education poses some challenges. These include a lack of clear categorization of digital health education in the literature; constantly evolving concepts, pedagogies, or theories; and a multitude of methods, features, technologies, or delivery settings. The Digital Health Education Collaboration was established to evaluate the evidence on digital education in health professions; inform policymakers, educators, and students; and ultimately, change the way in which these professionals learn and are taught. The aim of this paper is to present the overarching methodology that we use to synthesize evidence across our digital health education reviews and to discuss challenges related to the process. For our research, we followed Cochrane recommendations for the conduct of systematic reviews; all reviews are reported according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidance. This included assembling experts in various digital health education fields; identifying gaps in the evidence base; formulating focused research questions, aims, and outcome measures; choosing appropriate search terms and databases; defining inclusion and exclusion criteria; running the searches jointly with librarians and information specialists; managing abstracts; retrieving full-text versions of papers; extracting and storing large datasets, critically appraising the quality of studies; analyzing data; discussing findings; drawing meaningful conclusions; and drafting research papers. The approach used for synthesizing evidence from digital health education trials is commonly regarded as the most rigorous benchmark for conducting systematic reviews. Although we acknowledge the presence of certain biases ingrained in the process, we have clearly highlighted and minimized those biases by strictly adhering to scientific rigor, methodological integrity, and standard operating procedures. This paper will be a valuable asset for researchers and methodologists undertaking systematic reviews in digital health education.

Virtual Patient Simulations in Health Professions Education: Systematic Review and Meta-Analysis by the Digital Health Education Collaboration.

BACKGROUND: Virtual patients are interactive digital simulations of clinical scenarios for the purpose of health professions education. There is no current collated evidence on the effectiveness of this form of education. OBJECTIVE: The goal of this study was to evaluate the effectiveness of virtual patients compared with traditional education, blended with traditional education, compared with other types of digital education, and design variants of virtual patients in health professions education. The outcomes of interest were knowledge, skills, attitudes, and satisfaction. METHODS: We performed a systematic review on the effectiveness of virtual patient simulations in pre- and postregistration health professions education following Cochrane methodology. We searched 7 databases from the year 1990 up to September 2018. No language restrictions were applied. We included randomized controlled trials and cluster randomized trials. We independently selected studies, extracted data, and assessed risk of bias and then compared the information in pairs. We contacted study authors for additional information if necessary. All pooled analyses were based on random-effects models. RESULTS: A total of 51 trials involving 4696 participants met our inclusion criteria. Furthermore, 25 studies compared virtual patients with traditional education, 11 studies investigated virtual patients as blended learning, 5 studies compared virtual patients with different forms of digital education, and 10 studies compared different design variants. The pooled analysis of studies comparing the effect of virtual patients to traditional education showed similar results for knowledge (standardized mean difference [SMD]=0.11, 95% CI -0.17 to 0.39, I2=74%, n=927) and favored virtual patients for skills (SMD=0.90, 95% CI 0.49 to 1.32, I2=88%, n=897). Studies measuring attitudes and satisfaction predominantly used surveys with item-by-item comparison. Trials comparing virtual patients with different forms of digital education and design variants were not numerous enough to give clear recommendations. Several methodological limitations in the included studies and heterogeneity contributed to a generally low quality of evidence. CONCLUSIONS: Low to modest and mixed evidence suggests that when compared with traditional education, virtual patients can more effectively improve skills, and at least as effectively improve knowledge. The skills that improved were clinical reasoning, procedural skills, and a mix of procedural and team skills. We found evidence of effectiveness in both high-income and low- and middle-income countries, demonstrating the global applicability of virtual patients. Further research should explore the utility of different design variants of virtual patients.

Strengthening health professions regulation in Cambodia: a rapid assessment.

BACKGROUND: This paper describes a rapid assessment of Cambodia's current system for regulating its health professions. The assessment forms part of a co-design process to set strategic priorities for strengthening health profession regulation to improve the quality and safety of health services. A health system approach for strengthening health professions' regulation is underway and aims to support the Government of Cambodia's plans for scaling up its health workforce, improving health services' safety and quality, and meeting its Association of South East Asian Nations (ASEAN) obligations to facilitate trade in health care services. METHODS: The assessment used a mixed methods approach including: A desktop review of key laws, plans, reports and other documents relating to the regulation of the health professions in Cambodia (medicine, dentistry, midwifery, nursing and pharmacy); Key informant interviews with stakeholders in Cambodia (The term "stakeholders" refers to government officials, people working on health professional regulation, people working for the various health worker training institutions and health workers at the national and provincial level); Surveys and questionnaires to assess Cambodian stakeholder knowledge of regulation; Self-assessments by members of the five Cambodian regulatory councils regarding key capacities and activities of high-performing regulatory bodies; and A rapid literature review to identify: The key functions of health professional regulation; The key issues affecting the Cambodian health sector (including relevant developments in the wider ASEAN region); and "Smart" health profession regulation practices of possible relevance to Cambodia. RESULTS: We found that the current regulatory system only partially meets Cambodia's needs. A number of key regulatory functions are being performed, but overall, the current system was not designed with Cambodia's specific needs in mind. The existing system is also overly complex, with considerable duplication and overlap between governance and regulatory arrangements for the five regulated professions. CONCLUSIONS: There is considerable scope for reform to the current regulatory system to better align the system to Cambodia's: Current needs and circumstances; Health system strategic priorities; and International obligations. Cambodia is also well placed to base its reformed regulatory system on recent developments of "smart regulatory practices" for health professionals.

Re-visiting scholarly community engagement in the contemporary research assessment environments of Australasian universities.

Restructuring of university environments to meet funding requirements based on research performance presents challenges internationally to nursing and other allied health groups. These funding models generate more emphasis on the scholarship of discovery than on the scholarship of integration, the scholarship of application, and the scholarship of sharing knowledge. Yet achievement of health advances by these disciplines is unlikely to emerge through laboratory-based research. They are more likely to emerge through scholarly research activities which involve partnerships between universities and communities. Current emphases on research assessment and quantum measurements are particularly associated with the scholarship of discovery, and thus raise concerns that such pressures may lead universities and other organisations away from community engagement. In response to these issues, the importance of linking scholarship and communities, furthering mechanisms to legitimise scholarly community engagement, and reducing barriers to this in the context of the contemporary university research environments are argued. Boyer's model of scholarship (that the work of universities centres around four areas of scholarship: discovery, integration, application and sharing knowledge) highlights these tensions. It is suggested that by revisiting Boyer's model and considering the ways in which it may generate possibilities for scholarly community engagement, university schools of nursing in the contemporary research assessment environment could find ways to balance the forms of scholarship by which social good can be advanced.

The expectations of two New Zealand health services of the role of Clinical Chairs in Nursing and Midwifery.

Clinical Professoriate positions within nursing or midwifery in New Zealand are a relatively recent development. One New Zealand University worked collaboratively to establish two joint clinical Professorial appointments with different District Health Boards. Each position had unique mandates around research platforms, and differing operational responsibilities. This paper reports on the qualitative component of a larger study that aimed to examine the research culture, and the role of Clinical Chairs, within the two District Health Boards. This phase of the research involved semi-structured interviews with senior staff from the DHB to explore their experiences of working with the Clinical Professor. Themes that emerged revolved around expectations of the role during its development, and the subsequent perceived outcomes. The need for objective measures of the roles' impact on clinical outcomes emerged as a key impression from the participants. Future research that focuses on measurements of outcomes attributable to the roles will ensure their sustainability over time.

Senior nurses as patients: narratives of special and meagre care.

Like the general population, nurses become patients within the health care services available to them. They write anecdotal accounts of their experience and research the experience of their colleagues. This paper reports a small descriptive study of how the positions of senior nurses who experienced a life threatening condition influenced their illness trajectories. Eleven nurses in both New Zealand and Australia told stories of their experiences which focussed on intercessions/intervention by themselves, their family and the health care team. Themes identified were: looking after our own, the gaze of family and friends in advocacy and intercession, stereotypes of nurses as patients, senior nurses as vulnerable patients - existential healing through the small things, and senior nurses as knowledgeable people. Within these themes were narratives of special and meagre care. The authors conclude that all senior nurses should receive care that is regardful of who they are as senior nurses and vulnerable patients.

Locating nursing classification schemes within health information strategies for New Zealand.

The potential to use classification schemes to describe and measure nursing in a country that has previously not used them as a part of practice is fraught with issues. Such is the case for New Zealand. Without nursing specific classification scheme use in the information systems of day to day function, nursing cannot validate what it does and the difference it makes to health outcomes for New Zealanders. The local use of valid and reliable classification schemes as tools to capture locally generated data that is able to be used as quality data needs to be considered alongside the national use of reliable clinical reference tools that are consistent with international standards. This may make the difference to the potential for significant contribution of nursing practice specific data to health information collections in preference to a 'one fits all' approach to user interface nursing classification scheme adoption at a local level. Tensions between a top-down approach and a locally based bottoms-up practice based approach and associated issues provide the core to this paper.

Designing an effective evaluation plan: a tool for understanding and planning evaluations for complex nursing contexts.

With the increasing emphasis on the development of nursing, evidence based practice, practice development and new and extended nursing roles, nurses are faced with the challenge of developing effective evaluation practices in an increasingly complex health care environment. This complexity has seen a number of evaluation methodologies and methods used in health care and nurses in clinical settings may find it difficult to know what approach or approaches best apply to their context. Given that evaluation of nursing innovations and interventions can have political, practical and fiscal consequences it is important that nurses have a broad understanding of evaluation, why it is important, the various types of evaluation methods and methodologies as well as some way of working through this complexity in order to develop evaluation plans and practices that best meet their needs. This paper explores a number of common types of evaluation methodologies and aims to assist nurses to better understand the 'why' and the 'how' of evaluation. In addition the paper describes the development of an evaluation tool which aims to assist nurses to develop effective evaluation plans that will best meet their evaluation needs.

Toward standardising nursing language in New Zealand.

Historically nursing in New Zealand has not used any standardised means to classify practice. In a rapidly developing health information technology (IT) sector this raises serious questions about documentation processes, information management and knowledge development nursing. Recently the Nursing Council of New Zealand has redefined nursing practice, included documentation skills and information management as core competencies within the Registered Nurse and Nurse Practitioner Scopes of Practice (2004) and included information technology as core curricula content within pre-registration nursing programmes. This opinion paper will argue that continued lack of description and analysis of nursing practice in this country will enhance nursing vulnerability. It will background the extent of this issue and outline a project that aims to explore the contextual issues, test a language embedded with a clinical information system and develop a procedural framework to guide the implementation of automated means to describe, compare, examine and analyse nursing practices and processes within New Zealand. The framework will take into account the uniqueness of New Zealand nursing located within international positions and will be a first step toward using a standardised professional language embedded in clinical information systems.

Identification of a novel glucocorticoid receptor mutation in budesonide-resistant human bronchial epithelial cells.

We developed a molecular genetic model to investigate glucocorticoid receptor (GR) signaling in human bronchial epithelial cells in response to the therapeutic steroid budesonide. Based on a genetic selection scheme using the human Chago K1 cell line and integrated copies of a glucocorticoid-responsive herpes simplex virus thymidine kinase gene and a green fluorescent protein gene, we isolated five Chago K1 variants that grew in media containing budesonide and ganciclovir. Three spontaneous budesonide-resistant subclones were found to express low levels of GR, whereas two mutants isolated from ethylmethane sulfonate-treated cultures contained normal levels of GR protein. Analysis of the GR coding sequence in the budesonide-resistant subclone Ch-BdE5 identified a novel Val to Met mutation at amino acid position 575 (GRV575M) which caused an 80% decrease in transcriptional regulatory functions with only a minimal effect on ligand binding activity. Homology modeling of the GR structure in this region of the hormone binding domain and molecular dynamic simulations suggested that the GRV575M mutation would have a decreased affinity for the LXXLL motif of p160 coactivators. To test this prediction, we performed transactivation and glutathione-S-transferase pull-down assays using the p160 coactivator glucocorticoid interacting protein 1 (GRIP1)/transcriptional intermediary factor 2 and found that GRV575M transcriptional activity was not enhanced by GRIP1 in transfected cells nor was it able to bind GRIP1 in vitro. Identification of the novel GRV575M variant in human bronchial epithelial cells using a molecular genetic selection scheme suggests that functional assays performed in relevant cell types could identify subtle defects in GR signaling that contribute to reduced steroid sensitivities in vivo.

Involvement of multidrug resistance proteins (MDR) in the modulation of glucocorticoid response.

Glucocorticoid resistance is a problem in the treatment of many diseases. One possible factor involved in the modulation of a glucocorticoid response is the export of glucocorticoids out of the cell. It has been shown that multidrug resistance protein 1 (MDR1, ABCB1), a member of the ABC family, is capable of transporting some glucocorticoids. This paper uses a mouse cell line, LMCAT in which the glucocorticoid response can be modulated by inhibitors of multidrug resistance proteins. Glucocorticoids fall into three categories. Firstly, those that are transported by an Abcb1a/Abcb1b transporter and whose transport can be inhibited by inhibitors of ABCB1 activity. Functional Abcb1a/Abcb1b was detected by inhibition of rhodamine efflux by these drugs and mRNA for Abcb1a and Abcb1b were detected in these cells. Secondly, those that are not transported. Finally, those that are transported by an Abcc1a transporter. Calcein transport out of these cells was blocked by treatment with probenecid indicating a functional Abcc1a transporter. Abcc1a mRNA was also detected in these cells. Thus, this paper provides insight into the mechanisms of glucocorticoid transport in cells and demonstrates a diversity of two independent mechanisms of transport of glucocorticoids by Abcb1a/Abcb1b and Abcc1a with individual patterns of steroid specificity.

Risks of malignant and non-malignant tumours in tall women treated with high-dose oestrogen during adolescence.

BACKGROUND/AIM: High-dose oestrogen treatment has been used to reduce growth in tall adolescent girls. The long-term safety with regard to cancer has not been clarified. Our aim was to study if this growth reduction therapy affects cancer risk later in life. METHODS: A cohort study of 369 (172 treated, 197 untreated) Swedish women who in 1973-1993 were assessed for tall adolescent stature was designed. Data were collected from university hospital records, patient questionnaires, and the Swedish Cancer Register. RESULTS: Risks are presented as odds ratios (ORs) with 95% confidence intervals comparing treated to untreated subjects. In treated subjects, the overall OR for having a tumour (malignant or non-malignant) was 1.7 (0.8-3.8). The ORs were 2.3 (0.4-12.8) for breast tumours, 0.8 (0.2-2.6) for gynaecological tumours, and 6.1 (1.04-∞) for melanoma. When limiting to malignant tumours, the crude ORs were of similar magnitude. CONCLUSION: The OR for any melanoma was higher in treated than in untreated women, suggesting an increased risk of melanoma associated with high-dose oestrogen treatment during adolescence. Although the risk estimates were increased for overall tumours, breast tumours, malignant gynaecological tumours, and malignant melanoma, these associations were not statistically significant. Our results need to be verified in a larger cohort.

The three-dimensional structures of antagonistic and agonistic forms of the glucocorticoid receptor ligand-binding domain: RU-486 induces a transconformation that leads to active antagonism.

Here we describe the three-dimensional crystal structures of human glucocorticoid receptor ligand-binding domain (GR-LBD) in complex with the antagonist RU-486 at 2.3 A resolution and with the agonist dexamethasone ligand together with a coactivator peptide at 2.8 A. The RU-486 structure was solved in several different crystal forms, two with helix 12 intact (GR1 and GR3) and one with a protease-digested C terminus (GR2). In GR1, part of helix 12 is in a position that covers the co-activator pocket, whereas in the GR3, domain swapping is seen between the crystallographically identical subunits in the GR dimer. An arm consisting of the end of helix 11 and beyond stretches out from one molecule, and helix 12 binds to the other LBD, partly blocking the coactivator pocket of that molecule. This type of GR-LBD dimer has not been described before but might be an artifact from crystallization. Furthermore, the subunits of the GR3 dimers are covalently connected via a disulfide bond between the Cys-736 residues in the two molecules. All three RU-486 GR-LBD structures show that GR has a very flexible region between the end of helix 11 and the end of helix 12.