Strain variation amongst clinical and potable water isolates of M.kansasii using automated repetitive unit PCR

Mycobacterium kansasii is a pulmonary pathogen that has been grown readily from municipal water, but rarely isolated from natural waters. A definitive link between water exposure and disease has not been demonstrated and the environmental niche for this organism is poorly understood. Strain typing of clinical isolates has revealed seven subtypes with Type 1 being highly clonal and responsible for most infections worldwide. The prevalence of other subtypes varies geographically. In this study 49 water isolates are compared with 72 patient isolates from the same geographical area (Brisbane, Australia), using automated repetitive unit PCR (Diversilab) and ITS RFLP. The clonality of the dominant clinical strain type is again demonstrated but with rep-PCR, strain variation within this group is evident comparable with other reported methods. There is significant heterogeneity of water isolates and very few are similar or related to the clinical isolates. This suggests that if water or aerosol transmission is the mode of infection, then point source contamination likely occurs from an alternative environmental source.

Incorporating adverse event relatedness into dose-finding clinical trial designs

Dose-finding designs estimate the dose level of a drug based on observed adverse events. Relatedness of the adverse event to the drug has been generally ignored in all proposed design methodologies. These designs assume that the adverse events observed during a trial are definitely related to the drug, which can lead to flawed dose-level estimation. We incorporate adverse event relatedness into the so-called continual reassessment method. Adverse events that have ‘doubtful’ or ‘possible’ relationships to the drug are modelled using a two-parameter logistic model with an additive probability mass. Adverse events ‘probably’ or ‘definitely’ related to the drug are modelled using a cumulative logistic model. To search for the maximum tolerated dose, we use the maximum estimated toxicity probability of these two adverse event relatedness categories. We conduct a simulation study that illustrates the characteristics of the design under various scenarios. This article demonstrates that adverse event relatedness is important for improved dose estimation. It opens up further research pathways into continual reassessment design methodologies.

Good practice report : clinical teaching

Clinical experience, or experience in the ‘real world’ of practice, is a fundamental component of many health professional courses. It often involves students undertaking practical experience in clinical workplace settings, typically referred to as clinical placements, under the supervision of health professionals. Broadly speaking, the role of clinical supervisors, or teachers, is aimed at assisting students to integrate the theoretical and skills based components of the curriculum within the context of patient/client care (Erstzen et al 2009). Clinical experience also provides students with the opportunity to assimilate the attitudes, values and skills which they require to become appropriately skilled professionals in the environments in which they will eventually practise. However, clinical settings are particularly challenging learning environments for students. Unlike classroom learning, students in the clinical setting frequently find themselves involved in unplanned and often complex activities with patients and other health care providers, being supervised by a variety of clinical staff who have very different methods and styles of teaching, and negotiating bureaucratic or hierarchical structures in busy clinical workplaces where they may only be spending a limited amount of time. Kilminster et al (2007) also draw attention to tensions that may exist between the learning needs of students and the provision of quality care or need to prevent harm to the patient (e.g. Elkind et al 2007). All of these factors complicate the realisation of clinical education goals and underscore the need for effective clinical teaching practices that maximise student learning in clinical environments. This report provides a summary of work that has been achieved in relation to ALTC projects and fellowships associated with clinical teaching, and a review of scholarly publications relevant to this field. The report also makes recommendations based on issues identified and/or where further work is indicated. The projects and fellowships reviewed cover a range of discipline areas including Biology, Paramedic Practice, Clinical Exercise Physiology, Occupational Therapy, Speech Pathology, Physiotherapy, Pharmacy, Nursing and Veterinary Science. The main areas of focus cover issues related to curriculum, particularly in relation to industry expectations of ‘work-ready’ graduates and the implications for theoretical and practical, or clinical preparation; development of competency assessment tools that are nationally applicable across discipline-specific courses; and improvement of clinical learning through strategies targeting the clinical learning environment, building the teaching capacity of clinical supervisors and/or enhancing the clinical learning/teaching process.

Enhancing student learning in the workplace through developing the leadership capabilities of clinical supervisors in the nursing discipline

The purpose of this project was to build the leadership capacity of clinical supervisors in the nursing discipline by developing, implementing and systematically embedding a leadership model into the structure and practice of student supervision. The University worked in partnership with three major metropolitan hospitals in Queensland to develop a framework and professional development program incorporating leadership and clinical supervision. The Leadership and Clinical Education (LaCE) program consisted of two structured workshops complemented by individual personal development projects undertaken by participants. Participants were supported in these activities with a purpose-built website that provides access to a wide variety of information and other learning resources. Quantitative and qualitative evaluations indicated that the approach was highly valued by participants, as it promoted useful peer dialogue, sharing of experiences and personal development in relation to assisting leadership development and student learning in the workplace. The LaCE program provides an ideal springboard for introducing the development of welltrained leaders into the clinical workplace. The resources developed have the potential to provide ongoing support for clinical supervisors to improve the learning of undergraduate nursing student. The challenge will be to achieve continued innovation within clinical education through sustainable leadership programs.

Registration of clinical trials: Challenges for global regulation

In 2004 the International Committee of Medical Journal Editors (ICMJE) issued a statement indicating that from 1 July 2005 registration in a publicly accessible trials registry would be a condition of publication in an ICMJE member journal. The World Health Organisation is coordinating the International Clinical Trials Registry Platform (ICTRP) as a means of providing a standardised framework for registration. This article considers the practical challenges and opportunities that arise from these developments and considers the relevance of trial registration for women and minorities and for developing countries.

Tailored interventions based on sputum eosinophils versus clinical symptoms for asthma in children and adults

BACKGROUND Asthma severity and control can be measured both subjectively and objectively. Sputum analysis for evaluation of percentage of sputum eosinophilia directly measures airway inflammation, and is one method of objectively monitoring asthma. Interventions for asthma therapies have been traditionally based on symptoms and spirometry. OBJECTIVES To evaluate the efficacy of tailoring asthma interventions based on sputum analysis in comparison to clinical symptoms (with or without spirometry/peak flow) for asthma related outcomes in children and adults. SEARCH STRATEGY We searched the Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and reference lists of articles. The last search was on 31 October 2006. SELECTION CRITERIA All randomised controlled comparisons of adjustment of asthma therapy based on sputum eosinophils compared to traditional methods (primarily clinical symptoms and spirometry/peak flow). DATA COLLECTION AND ANALYSIS Results of searches were reviewed against pre-determined criteria for inclusion. Three sets of reviewers selected relevant studies.Two review authors independently assessed trial quality extracted data. Authors were contacted for further information but none were received. Data was analysed as "treatment received" and sensitivity analyses performed. MAIN RESULTS Three adult studies were included; these studies were clinically and methodologically heterogenous (use of medications, cut off for percentage of sputum eosinophils and definition of asthma exacerbation). There were no eligible paediatric studies. Of 246 participants randomised, 221 completed the trials. In the meta-analysis, a significant reduction in number of participants who had one or more asthma exacerbations occurred when treatment was based on sputum eosinophils in comparison to clinical symptoms; pooled odds ratio (OR) was 0.49 (95% CI 0.28 to 0.87); number needed to treat to benefit (NNTB) was 6 (95% CI 4 to 32).There were also differences between groups in the rate of exacerbation (any exacerbation per year) and severity of exacerbations defined by requirement for use of oral corticosteroids but the reduction in hospitalisations was not statistically significant. Data for clinical symptoms, quality of life and spirometry were not significantly different between groups. The mean dose of inhaled corticosteroids per day was similar in both groups and no adverse events were reported. However sputum induction was not always possible. AUTHORS' CONCLUSIONS Tailored asthma interventions based on sputum eosinophils is beneficial in reducing the frequency of asthma exacerbations in adults with asthma. This review supports the use of sputum eosinophils to tailor asthma therapy for adults with frequent exacerbations and severe asthma. Further studies need to be undertaken to strengthen these results and no conclusion can be drawn for children with asthma.

Tailored interventions based on exhaled nitric oxide versus clinical symptoms for asthma in children and adults

Background The measurement of severity and control of asthma in both children and adults can be based on subjective or objective measures. It has been advocated that fractional exhaled nitric oxide (FeNO) can be used to monitor airway inflammation as it correlates with some markers of asthma. Interventions for asthma therapies have been traditionally based on symptoms and/or spirometry. Objectives To evaluate the efficacy of tailoring asthma interventions based on exhaled nitric oxide in comparison to clinical symptoms (with or without spirometry/peak flow) for asthma related outcomes in children and adults. Search methods We searched the Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and reference lists of articles. The last search was completed in February 2009. Selection criteria All randomised controlled comparisons of adjustment of asthma therapy based on exhaled nitric oxide compared to traditional methods (primarily clinical symptoms and spirometry/peak flow). Data collection and analysis Results of searches were reviewed against pre-determined criteria for inclusion. Relevant studies were independently selected in duplicate. Two authors independently assessed trial quality and extracted data. Authors were contacted for further information with response from one. Main results Two studies have been added for this update, which now includes six (2 adults and 4 children/adolescent) studies; these studies differed in a variety of ways including definition of asthma exacerbations, FeNO cut off levels, the way in which FeNO was used to adjust therapy and duration of study. Of 1053 participants randomised, 1010 completed the trials. In the meta-analysis, there was no significant difference between groups for the primary outcome of asthma exacerbations or for other outcomes (clinical symptoms, FeNO level and spirometry). In post-hoc analysis, a significant reduction in mean final daily dose inhaled corticosteroid per adult was found in the group where treatment was based on FeNO in comparison to clinical symptoms, (mean difference -450 mcg; 95% CI -677 to -223 mcg budesonide equivalent/day). However, the total amount of inhaled corticosteroid used in one of the adult studies was 11% greater in the FeNO arm. In contrast, in the paediatric studies, there was a significant increase in inhaled corticosteroid dose in the FeNO strategy arm (mean difference of 140 mcg; 95% CI 29 to 251, mcg budesonide equivalent/day). Authors' conclusions Tailoring the dose of inhaled corticosteroids based on exhaled nitric oxide in comparison to clinical symptoms was carried out in different ways in the six studies and found only modest benefit at best and potentially higher doses of inhaled corticosteroids in children. The role of utilising exhaled nitric oxide to tailor the dose of inhaled corticosteroids cannot be routinely recommended for clinical practice at this stage and remains uncertain.

Clinical dyslipidaemia is associated with changes in the lipid composition and inflammatory properties of apolipoprotein-B-containing lipoproteins from women with type 2 diabetes

The aim of this study was to use lipidomics to determine if the lipid composition of apolipoprotein-B-containing lipoproteins is modified by dyslipidaemia in type 2 diabetes and if any of the identified changes potentially have biological relevance in the pathophysiology of type 2 diabetes. VLDL and LDL from normolipidaemic and dyslipidaemic type 2 diabetic women and controls were isolated and quantified with HPLC and mass spectrometry. A detailed molecular characterisation of VLDL triacylglycerols (TAG) was also performed using the novel ozone-induced dissociation method, which allowed us to distinguish vaccenic acid (C18:1 n-7) from oleic acid (C18:1 n-9) in specific TAG species. Lipid class composition was very similar in VLDL and LDL from normolipidaemic type 2 diabetic and control participants. By contrast, dyslipidaemia was associated with significant changes in both lipid classes (e.g. increased diacylglycerols) and lipid species (e.g. increased C16:1 and C20:3 in phosphatidylcholine and cholesteryl ester and increased C16:0 [palmitic acid] and vaccenic acid in TAG). Levels of palmitic acid in VLDL and LDL TAG correlated with insulin resistance, and VLDL TAG enriched in palmitic acid promoted increased secretion of proinflammatory mediators from human smooth muscle cells. We showed that dyslipidaemia is associated with major changes in both lipid class and lipid species composition in VLDL and LDL from women with type 2 diabetes. In addition, we identified specific molecular lipid species that both correlate with clinical variables and are proinflammatory. Our study thus shows the potential of advanced lipidomic methods to further understand the pathophysiology of type 2 diabetes.

Three-dimensional dose verification for clinical treatments of small intracranial tumours

Cancers of the brain and central nervous system account for 1.6% of new cancers and 1.8% of cancer deaths globally. The highest rates of all developed nations are observed in Australia and New Zealand. There are known complexities associated with dose measurement of very small radiation fields. Here, 3D dosimetric verification of treatments for small intracranial tumours using gel dosimetry was investigated.

Clinical use of objective measures of physical activity

With measurement of physical activity becoming more common in clinical practice, it is imperative that healthcare professionals become more knowledgeable about the different methods available to objectively measure physical activity behaviour. Objective measures do not rely on information provided by the patient, but instead measure and record the biomechanical or physiological consequences of performing physical activity, often in real time. As such, objective measures are not subject to the reporting bias or recall problems associated with self-report methods. The purpose of this article was to provide an overview of the different methods used to objectively measure physical activity in clinical practice. The review was delimited to heart rate monitoring, accelerometers and pedometers since their small size, low participant burden and relatively low cost make these objective measures appropriate for use in clinical practice settings. For each measure, strengths and weakness were discussed; and whenever possible, literature-based examples of implementation were provided.

EMT and MET in carcinoma : clinical observations, regulatory pathways and new models

The articles collected here in this special edition Epithelial-Mesenchymal (EMT) and Mesenchymal-Epithelial Transitions (MET) in Cancer provide a snapshot of the very rapidly progressing cinemascope of the involvement of these transitions in carcinoma progression. Pubmed analysis of EMT and cancer shows an exponential increase in the last few years in the number of papers and reviews published under these terms (Fig. 1). The last few years have seen these articles appearing in high calibre journals including Nature, Nature Cell Biology, Cancer Cell, PNAS, JNCI, JCI, and Cell, signaling the acceptance and quality of work in this field.

Understanding negation and family history to improve clinical information retrieval

We present a study to understand the effect that negated terms (e.g., "no fever") and family history (e.g., "family history of diabetes") have on searching clinical records. Our analysis is aimed at devising the most effective means of handling negation and family history. In doing so, we explicitly represent a clinical record according to its different content types: negated, family history and normal content; the retrieval model weights each of these separately. Empirical evaluation shows that overall the presence of negation harms retrieval effectiveness while family history has little effect. We show negation is best handled by weighting negated content (rather than the common practise of removing or replacing it). However, we also show that many queries benefit from the inclusion of negated content and that negation is optimally handled on a per-query basis. Additional evaluation shows that adaptive handing of negated and family history content can have significant benefits.

Role of intratumoural heterogeneity in cancer drug resistance : molecular and clinical perspectives

Drug resistance continues to be a major barrier to the delivery of curative therapies in cancer. Historically, drug resistance has been associated with over-expression of drug transporters, changes in drug kinetics or amplification of drug targets. However, the emergence of resistance in patients treated with new-targeted therapies has provided new insight into the complexities underlying cancer drug resistance. Recent data now implicate intratumoural heterogeneity as a major driver of drug resistance. Single cell sequencing studies that identified multiple genetically distinct variants within human tumours clearly demonstrate the heterogeneous nature of human tumours. The major contributors to intratumoural heterogeneity are (i) genetic variation, (ii) stochastic processes, (iii) the microenvironment and (iv) cell and tissue plasticity. Each of these factors impacts on drug sensitivity. To deliver curative therapies to patients, modification of current therapeutic strategies to include methods that estimate intratumoural heterogeneity and plasticity will be essential.

An exploratory study for the development of emergency nurse practitioner specialist clinical practice standards

This thesis presents a mixed methods study to develop specialty specific clinical practice standards for Emergency Nurse Practitioners. This is the first time in Australia that Nurse Practitioners standards have been developed for a clinical specialty. These standards will guide educational preparation for the role and ongoing Continuous Professional Development for endorsed Emergency Nurse Practitioners.