ASAP ECMO : antibiotic, sedative and analgesic pharmacokinetics during extracorporeal membrane oxygenation : a multi-centre study to optimise drug therapy during ECMO

BACKGROUND: Given the expanding scope of extracorporeal membrane oxygenation (ECMO) and its variable impact on drug pharmacokinetics as observed in neonatal studies, it is imperative that the effects of the device on the drugs commonly prescribed in the intensive care unit (ICU) are further investigated. Currently, there are no data to confirm the appropriateness of standard drug dosing in adult patients on ECMO. Ineffective drug regimens in these critically ill patients can seriously worsen patient outcomes. This study was designed to describe the pharmacokinetics of the commonly used antibiotic, analgesic and sedative drugs in adult patients receiving ECMO. METHODS: This is a multi-centre, open-label, descriptive pharmacokinetic (PK) study. Eligible patients will be adults treated with ECMO for severe cardiac and/or respiratory failure at five Intensive Care Units in Australia and New Zealand. Patients will receive the study drugs as part of their routine management. Blood samples will be taken from indwelling catheters to investigate plasma concentrations of several antibiotics (ceftriaxone, meropenem, vancomycin, ciprofloxacin, gentamicin, piperacillin-tazobactum, ticarcillin-clavulunate, linezolid, fluconazole, voriconazole, caspofungin, oseltamivir), sedatives and analgesics (midazolam, morphine, fentanyl, propofol, dexmedetomidine, thiopentone). The PK of each drug will be characterised to determine the variability of PK in these patients and to develop dosing guidelines for prescription during ECMO. DISCUSSION: The evidence-based dosing algorithms generated from this analysis can be evaluated in later clinical studies. This knowledge is vitally important for optimising pharmacotherapy in these most severely ill patients to maximise the opportunity for therapeutic success and minimise the risk of therapeutic failure

Does the addition of integrated cognitive behaviour therapy and motivational interviewing improve the outcomes of standard care for young people with comorbid depression and substance misuse?

Background: The high rates of comorbid depression and substance use in young people have been associated with a range of adverse outcomes. Yet, few treatment studies have been conducted with this population. Objective: To determine if the addition of Motivational Interviewing and Cognitive Behaviour Therapy (MI/CBT) to standard alcohol and other drug (AOD) care improves the outcomes of young people with comorbid depression and substance use. Participants and Setting: Participants comprised 88 young people with comorbid depression (Kessler 10 score of > 17) and substance use (mainly alcohol/cannabis) seeking treatment at two youth AOD services in Melbourne, Australia. Sixty young people received MI/CBT in addition to standard care (SC) and 28 received SC alone. Outcomes Measures: Primary outcome measures were depressive symptoms and drug and alcohol use in the past month. Assessments were conducted at baseline, 3 and 6 months follow up. Results and Conclusions: The addition of MI/CBT to SC was associated with a significantly greater rate of change in depression, cannabis use, motivation to change substance use and social contact in the first 3 months. However, those who received SC had achieved similar improvements on these variables by 6 months follow up. All young people achieved significant improvements in functioning and quality of life variables over time, regardless of the treatment group. No changes in alcohol or other drug use were found in either group. The delivery of MI/CBT in addition to standard AOD care may offer accelerated treatment gains in the short-term.

Signal transduction mechanisms underlying growth hormone receptor action

Our understanding of the mechanisms of action of GH and its receptor, the GHR, has advanced significantly in the last decade and has provided some important surprises. It is now clear that the GH-GHR axis activates a number of inter-related signalling pathways, not all of which are dependent on the intracellular tyrosine kinase, JAK2 as originally postulated. JAK2-independent pathways, mediated via the Src family kinases, together with a number of negative regulators of GH signalling and emerging cross-talk mechanisms with other growth factor receptors, provide a complex array of mechanisms that are capable of fine-tuning responses to GH in a cell context dependent manner. Additionally, it is also now clear that GH and the GHR can translocate to the nucleus of target cells and initiate, as yet not well defined, nuclear responses. Continued emphasis on elucidation of these complex mechanisms is critical to provide further insights into the diverse physiological and pathophysiological effects of GH.

Cloning of a novel insulin-regulated ghrelin transcript in prostate cancer

Ghrelin is a multifunctional hormone, with roles in stimulating appetite and regulating energy balance, insulin secretion and glucose homeostasis. The ghrelin gene locus (GHRL) is highly complex and gives rise to a range of novel transcripts derived from alternative first exons and internally spliced exons. The wild-type transcript encodes a 117 amino acid preprohormone that is processed to yield the 28 amino acid peptide ghrelin. Here, we identified insulin-responsive transcription corresponding to cryptic exons in intron 2 of the human ghrelin gene. A transcript, termed in2c-ghrelin (intron 2-cryptic), was cloned from the testis and the LNCaP prostate cancer cell line. This transcript may encode an 83 AA preproghrelin isoform that codes for the ghrelin, but not obestatin. It is expressed in a limited number of normal tissues and in tumours of the prostate, testis, breast and ovary. Finally, we confirmed that in2c-ghrelin transcript expression, as well as the recently described in1-ghrelin transcript, is significantly upregulated by insulin in cultured prostate cancer cells. Metabolic syndrome and hyperinsulinaemia has been associated with prostate cancer risk and progression. This may be particularly significant after androgen deprivation therapy for prostate cancer, which induces hyperinsulinaemia, and this could contribute to castrate resistant prostate cancer growth. We have previously demonstrated that ghrelin stimulates prostate cancer cell line proliferation in vitro. This study is the first description of insulin regulation of a ghrelin transcript in cancer, and should provide further impetus for studies into the expression, regulation and function of ghrelin gene products.

Metacognitive therapy for alcohol abuse and dependence

While the consumption of alcohol has been part of the collective psyche of Australians since colonisation, the overconsumption of alcohol has been and continues to be a significant problem for the Australian community. Currently motivational interviewing and cognitive behaviour therapy are seen as the two standard psychological interventions for alcohol abuse and dependence. While these two approaches have shown significant impact on reducing alcohol abuse and dependence, they are not without their limitations. As such there is a need to continue to explore the application of newer developments in psychotherapy to the treatment problematic drinking behaviours. In this chapter we propose that Metacognitive Therapy is one such psychotherapy that is likely to provide a promising new approach to the treatment of alcohol abuse and dependence. In this chapter we will first briefly outline the history and significance of problematic drinking behaviours in Australia. Following this, we will quickly summarise the literature regarding motivational interviewing and cognitive behaviour therapy. Next we will provide an outline of the theoretical framework of Metacognitive Therapy and then describe two brief case studies illustrating the application of Metacognitive Therapy to the treatment of alcohol abuse and dependence. From this discussion we propose that the combination of Motivational Interviewing and Metacognitive Therapy is a promising new approach that can provide great assistance for the treatment of alcohol abuse or dependence.

Response to “Topical agent therapy for prevention and treatment of radiodermatitis : a meta-analysis”

To the Editor; It was with interest that I read the recent article by Zhang et al. published in Supportive Care in Cancer [1]. This paper highlighted the importance of radiodermatitis (RD) being an unresolved and distressing clinical issue in patients with cancer undergoing radiation therapy. However, I am concerned with a number of clinical and methodological issues within this paper: (i) the clinical and operational definition of prophylaxis and treatment of RD; (ii) the accuracy of the identification of trials; and (iii) the appropriateness of the conduct of the meta-analyses...

Selective cleavage of human sex hormone-binding globulin by kallikrein-related peptidases and effects on androgen action in LNCaP prostate cancer cells

Stimulation of the androgen receptor via bioavailable androgens, including testosterone and testosterone metabolites, is a key driver of prostate development and the early stages of prostate cancer. Androgens are hydrophobic and as such require carrier proteins, including sex hormone-binding globulin (SHBG), to enable efficient distribution from sites of biosynthesis to target tissues. The similarly hydrophobic corticosteroids also require a carrier protein whose affinity for steroid is modulated by proteolysis. However, proteolytic mechanisms regulating the SHBG/androgen complex have not been reported. Here, we show that the cancer-associated serine proteases, kallikrein-related peptidase (KLK)4 and KLK14, bind strongly to SHBG in glutathione S-transferase interaction analyses. Further, we demonstrate that active KLK4 and KLK14 cleave human SHBG at unique sites and in an androgen-dependent manner. KLK4 separated androgen-free SHBG into its two laminin G-like (LG) domains that were subsequently proteolytically stable even after prolonged digestion, whereas a catalytically equivalent amount of KLK14 reduced SHBG to small peptide fragments over the same period. Conversely, proteolysis of 5α-dihydrotestosterone (DHT)-bound SHBG was similar for both KLKs and left the steroid binding LG4 domain intact. Characterization of this proteolysis fragment by [(3)H]-labeled DHT binding assays revealed that it retained identical affinity for androgen compared with full-length SHBG (dissociation constant = 1.92 nM). Consistent with this, both full-length SHBG and SHBG-LG4 significantly increased DHT-mediated transcriptional activity of the androgen receptor compared with DHT delivered without carrier protein. Collectively, these data provide the first evidence that SHBG is a target for proteolysis and demonstrate that a stable fragment derived from proteolysis of steroid-bound SHBG retains binding function in vitro.

Compression therapy : getting it right

Teaching basic principles of colonisation, contamination and infection has revolutionised approaches to wound care. Wound colonisation is classified as the existence of bacteria with no obvious host reaction (Carville 2005). The act of wound contamination is recognised as introducing micro-organisms into the wound (Ellis 2004). Wound infection is an invasion and multiplication of micro-organisms causing localised and systemic effects (Baranoski and Ayello 2004). Through clinical practice, nurses inadvertently engage in wound contamination thus setting the environment for wound infection.

Psychology students’ beliefs about integrating Complementary and Alternative Therapy (CAT) into their future psychology practice

We investigated whether belief-based differences exist between students who have strong and weak intentions to integrate complementary and alternative therapy (CAT) into future psychology practice by recommending CAT or specific CAT practitioners to clients. A cross-sectional methodology was used. Psychology undergraduate students (N = 106) participated in a paper-based questionnaire design to explore their underlying beliefs related to CAT integration. The study was undertaken at a major university in Queensland, Australia. The theory of planned behaviour belief-based framework guided the study. Multivariate analyses of variance examined the influence of behavioural, normative, and control beliefs on the strong and weak intention groups. A multiple regression analysis investigated the relative importance of these belief sets for predicting intentions. We found that clear differences emerged between strong and weak intenders on behavioural and normative beliefs, but not control beliefs. Strong intenders perceived the positive outcomes of integrating CAT, such as being able to offer clients a more holistic practice and having confidence in the practitioners/practices, as more likely to occur than weak intenders, and perceived the negative outcome of compromising my professional practice as less likely. Strong in-tenders were more likely than weak intenders to perceive that a range of important referents (e.g., clients) would think they should integrate CAT. Results of the regression analysis revealed the same pattern of results in that behavioural and normative beliefs, but not control beliefs, significantly predicted intentions. The findings from this study can be used to inform policy and educational initiatives that aim to encourage CAT use in psychology practice.

Starter packs : a good start to therapy?

Samples of drugs are often given to doctors by pharmaceutical representatives as part of a marketing strategy. Despite the well described advantages of drug samples, little has been published on the potential adverse outcomes. A series of consumer calls to the Adverse Medicine Events Line has highlighted concerns regarding the quality use of medicines associated with drug samples. The most commonly reported problems were drug samples being supplied to patients with inadequate information regarding dosage, administration, storage and possible adverse effects. In addition, some patients were given excessive quantities of a drug. To reduce such adverse outcomes, the drug industry, health professionals and consumers should be aware of the potential problems associated with starter packs.

A snapshot of radiation therapy techniques and technology in Queensland : an aid to mapping undergraduate curriculum

Introduction: Undergraduate students studying the Bachelor of Radiation Therapy at Queensland University of Technology (QUT) attend clinical placements in a number of department sites across Queensland. To ensure that the curriculum prepares students for the most common treatments and current techniques in use in these departments, a curriculum matching exercise was performed. Methods: A cross-sectional census was performed on a pre-determined “Snapshot” date in 2012. This was undertaken by the clinical education staff in each department who used a standardized proforma to count the number of patients as well as prescription, equipment, and technique data for a list of tumour site categories. This information was combined into aggregate anonymized data. Results: All 12 Queensland radiation therapy clinical sites participated in the Snapshot data collection exercise to produce a comprehensive overview of clinical practice on the chosen day. A total of 59 different tumour sites were treated on the chosen day and as expected the most common treatment sites were prostate and breast, comprising 46% of patients treated. Data analysis also indicated that intensity-modulated radiotherapy (IMRT) use is relatively high with 19.6% of patients receiving IMRT treatment on the chosen day. Both IMRT and image-guided radiotherapy (IGRT) indications matched recommendations from the evidence. Conclusion: The Snapshot method proved to be a feasible and efficient method of gathering useful

Standardising radiation therapy undergraduate competency levels

QUT Bachelor of Radiation Therapy students progress from first visiting a radiation therapy department to graduation and progression into the NPDP over a span of three years. Although there are clear guidelines as to expected competency level post-NPDP, there is still a variety of perceived levels prior to this. Staff and students feedback both suggest that different centres and within centres different staff have differing opinions of these levels. Indeed, many staff members object to the use of the word “competency” for a pre-NPODP undergraduate, preferring the term “achievement”. While it is acknowledged that students progress at different rates, it is vitally important for equity that staff expectations of students at different academic levels are identical. Provision of guidelines for different stages of progression are essential for equitable assessment and most assessments, including the NRTAT are complemented by statements to enable level to be determined. For the University-specific competency assessments some level of consensus between clinical staff is required, especially where students are placed at a large number of different placement sites. Aims The main aim of this initial study is to gauge staff opinions of levels of student progression in order to judge cross-centres consistency. A secondary objective is to evaluate the degree of correlation between staff seniority and perception of student levels. Informal feedback suggests that staff at or just post NPDP level have a different perception of student competency expectations than more senior staff. If these perceptions change with level it will make agreement of guidelines statements more challenging. Study Methods A standard evaluation questionnaire was provided to RT staff participating in ongoing updates to clinical assessment. As part of curriculum development staff were asked to provide anonymous and optional answers to further questions in order to audit current practice. This involved assigning level of student progression to different statements relating to tasks or competencies. After data collation, scores were assigned to level and totals used to rank statements according to perceived student level. Descriptive statistical analysis was used to identify which statements were easier to assign to student level and which were more ambiguous. Further sub-analysis was performed for each category of staff seniority to judge differences in perception. Strength of correlation between seniority and expectation was calculated to confirm or contradict the informal feedback. Results By collating different staff perceptions of competencies for different student levels commonly agreed statements can be used to define achievement level. This presentation outlines the results of the audit including statements that most staff perceived as relevant to a specific student group and statements that staff found to be harder to attribute. Strength of correlation between staff perception and seniority will be outlined where statistically significant.

Managing the therapeutic relationship in online cognitive behavioural therapy for depression: Therapists' treatment of clients' contributions

This article examines how therapists and clients manage the therapeutic relationship in online psychotherapy. Our study focuses on early sessions of therapy involving 22 therapist-client pairs participating in online Cognitive Behavioural Therapy (CBT) for depression. Using Conversation Analysis (CA), we examine how therapists can orient to clients’ contributions, while also retaining control of the therapeutic trajectory. We report two practices that therapists can use, at their discretion, following clients’ responses to requests for information. The first, thanking, accepts clients’ responses, orienting to the neutral affective valence of those responses. The second, commiseration, orients to the negative affective valence of clients’ responses. We argue that both practices are a means by which therapists can simultaneously manage developing rapport, while also retaining control of the therapeutic process.

Interobserver variability of radiation therapists aligning to fiducial markers for prostate radiation therapy

As the use of fiducial markers (FMs) for the localisation of the prostate during external beam radiation therapy (EBRT) has become part of routine practice, radiation therapists (RTs) have become increasingly responsible for online image interpretation. The aim of this investigation was to quantify the limits of agreement (LoA) between RTs when localising to FMs with orthogonal kilovoltage (kV) imaging. Methods Six patients receiving prostate EBRT utilising FMs were included in this study. Treatment localisation was performed using kV imaging prior to each fraction. Online stereoscopic assessment of FMs, performed by the treating RTs, was compared with the offline assessment by three RTs. Observer agreement was determined by pairwise Bland-Altman analysis. Results Stereoscopic analysis of 225 image pairs was performed online at the time of treatment, and offline by three RT observers. Eighteen pairwise Bland-Altman analyses were completed to assess the level of agreement between observers. Localisation by RTs was found to be within clinically acceptable 95% LoAs. Conclusions Small differences between RTs, in both the online and offline setting, were found to be within clinically acceptable limits. RTs were able to make consistent and reliable judgements when matching FMs on planar kV imaging.