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Objective: To compare the clinical appropriateness of the prescribing and monitoring of gentamicin. Method: A retrospective study was undertaken at two tertiary teaching hospitals in Australia. 161 adult patients administered gentamicin and who had at least one serum concentration taken whilst an inpatient were eligible for analysis. The main outcome measures were adherence to local and national guidelines for dosing and monitoring of gentamicin, and percentage of the recommended measure of adequate gentamicin exposure (Area-Under the concentration-time Curve (AUC)) using a nomogram and a Bayesian calculation. Results: Results were similar in both hospitals. Initial dosing: Adherence to local and national dosing guidelines was poor - approximately 50% of initial doses using less than local and 88% less than national recommendations. Monitoring: Approximately 20% of all gentamicin concentrations were collected outside the required sampling window. Sampling was particularly problematic after the initial dose. Here up with to half of the samples were taken outside the recommended time frame for sampling, therefore making interpretation of the nomogram difficult. Dose adjustment: 15% of doses were adjusted without monitoring and approximately half of all dose adjustments were based on inadequate information or inaccurate nomogram interpretation. Dose evaluation: Approximately half of the AUCs were below the therapeutic range. Conclusion: A large number of issues around appropriate use and monitoring of gentamicin were seen. This is particularly concerning considering both hospitals are large tertiary hospitals with expert clinical pharmacy support. We believe it is time for a randomised controlled trial to be undertaken, comparing Bayesian modelling techniques with standard nomogram, powered for clinical endpoints

There is currently a looming world-wide problem in antimicrobial resistance. Methods to make antimicrobial prescribing more appropriate and incorporate quality use of medicines guidelines have clearly been ineffective. Further there is a dearth of ‘new’ antimicrobials in the pharmaceutical industry pipeline. The optimal use of older, effective drugs are therefore of clinical relevance. Gentamicin is an antibiotic that is inexpensive and has proven efficacy. However, its use is becoming restricted, due to toxicity concerns. Research to improve knowledge in this area is thus urgently needed.

Introduction: CIN/FN is a major dose-limiting toxicity of many cancer chemotherapy (CTX) regimens. CIN/FN may require hospitalization, increase monitoring requirements and diagnostic and treatment costs, and reduce patient quality of life. Myeloid growth factors such as filgrastim or pegfilgrastim have been shown to reduce the incidence and severity of neutropenic complications. International guidelines recommend that pegfilgrastim be administered once per cycle 24-72 hours after chemotherapy, though recent NCCN guidelines mention the option of same-day administration. From the patients' perspective, the time lag is potentially cumbersome because of the need for additional visits. Several studies varying in design and outcomes have evaluated same-day administration of pegfilgrastim compared to standard (next-day) administration 24-72 hours after completion of the CTX cycle. Purpose: To conduct a meta-analysis of studies of same-day vs. next-day pegfilgrastim administration in terms of the incidence of (1) Grade 4 CIN during cycle 1 of CTX and (2) CTX dose reduction in subsequent CTX cycles. Methods: We performed a search for same-day administration of pegfilgrastim using PubMed search engines to complement investigators' familiarity with the literature. Considering heterogeneity (I2) across studies, random-effects meta-analyses were used to quantify pooled estimates of relative risk (RR), taking into account both within- (standard error) and between-study variance (τ2) using the DerSimonian and Laird method. Z-scores (weighted mean divided by the standard error of the weighted mean) and associated p-values (testing against the null hypothesis of RR = 1.0) quantified the precision of pooled RRs across studies. All analyses were performed using StataMP 14 (College Station, Texas, USA). Results: There were8 comparative studies with data on Grade 4 neutropenia that included a total of 446 patients treated the same day and 697 patients treated next day (Figure 1). Patients treated with pegfilgrastim on the same day after the first cycle of chemotherapy were equally likely to develop Grade 4 neutropenia as those treated the next day (RR = 1.13, 95% CI 0.87-1.47, p =0.371; I2 =54.1%, p=0.033). There were 8 comparative studies with data on chemotherapy dose reduction that included a total of 414 patients treated the same day and 428 patients treated next day (Figure 2). Patients treated with pegfilgrastim on the same day were equally likely to require a reduction in chemotherapy dose compared with those treated the next day (RR = 0.97, 95% CI 0.68-1.39, p =0.863; I2 =62.7%, p=0.009). Conclusion: The incidence of Grade 4 neutropenia and CTX dose reduction in patients receiving same-day pegfilgrastim were equal to those undergoing standard administration. To be confirmed through controlled studies, same-day administration of pegfilgrastim can be considered in the prophylaxis of CIN/FN in patients receiving myelotoxic CTX. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures McBride: Janssen Scientific Affairs, LLC: Consultancy. Persky:Gilead Sciences, Inc: Speakers Bureau.

Background: The number of young volunteers in international social projects has increased significantly with governmental and non-governmental project support. This paper investigates the hypothesis that the preventative medical advice currently given prior to departure is inadequate because the risk profile of young persons (

Accurate knowledge of the glomerular filtration rate (GFR) is imperative in the intensive care unit (ICU) as renal status is important for medical decisions, including drug dosing.Recently, an estimation of GFR (eGFR) was suggested as a method of estimating GFR. How well this formula predicts GFR in unwell patients with normal initial serum creatinine concentrations has not been examined.The accuracy of the eGFR (before and after adjustment for actual body surface area (BSA)) was compared with measured and with estimated creatinine clearance using the Cockcroft Gault (CG) formula adjusted for total and lean body weight.A total of 237 observations was recorded in 47 subjects. These were initially analysed independently, and then using the first observation only. Overall the mean difference between measured creatinine clearance and eGFR was -12 mL/min (95% confidence interval (CI) -20 to -3), between measured creatinine clearance and CG +17 mL/min (95% CI 9-24), between measured creatinine clearance and CG adjusted for ideal body weight +12 mL/min (95% CI 4-21) and between measured creatinine clearance and eGFR 'unadjusted' for BSA 5 mL/min (95% CI -2-13).Using either eGFR or CG formulae to estimate renal function in ICU subjects with normal serum creatinine concentrations is inaccurate. Although correcting for BSA improves the eGFR, this requirement to measure height and weight removes a major attraction for its use. We suggest that eGFR should not be automatically calculated in the ICU setting.

The increasing burden of harm resulting from the use of multiple drugs in older patient populations represents a major health problem in developed countries. Approximately 1 in 4 older patients admitted to hospitals are prescribed at least 1 inappropriate medication, and up to 20% of all inpatient deaths are attributable to potentially preventable adverse drug reactions. To minimize this drug-related iatrogenesis, we propose a quality use of medicine framework that comprises 10 sequential steps: 1) ascertain all current medications; 2) identify patients at high risk of or experiencing adverse drug reactions; 3) estimate life expectancy in high-risk patients; 4) define overall care goals in the context of life expectancy; 5) define and confirm current indications for ongoing treatment; 6) determine the time until benefit for disease-modifying medications; 7) estimate the magnitude of benefit versus harm in relation to each medication; 8) review the relative utility of different drugs; 9) identify drugs that may be discontinued; and 10) implement and monitor a drug minimization plan with ongoing reappraisal of drug utility and patient adherence by a single nominated clinician. The framework aims to reduce drug use in older patients to the minimum number of essential drugs, and its utility is demonstrated in reference to a hypothetic case study. Further studies are warranted in validating this framework as a means for assisting clinicians to make more appropriate prescribing decisions in at-risk older patients.

Nutrapharmacology, or the use of bioactive food compounds at pharmacological doses is emerging as a therapeutic approach to target the complex metabolic dysregulations in ageing and obesity-related chronic disease. Resveratrol, a polyphenol found in the skin of grapes, and other edible plants and related food products, has received extensive attention through the link with the French paradox, and later with its chemopreventive activity demonstrated in vitro and in animal cancer models. A plethora of laboratory investigations has provided evidence for the multi-faceted properties of resveratrol and suggests that resveratrol may target ageing and obesity-related chronic disease by regulating inflammation and oxidative stress. A number of obstacles stand in the path to clinical usage however, not least the lack of clinical evidence to date, and the myriad of doses and formulations available. Further, data on the effects of resveratrol consumption in a capsule vs. food form is conflicting, and there are uncertain effects of long term dosing. The review will summarize the human pharmacokinetic and pharmacodynamic published data, and the topics for research if resveratrol is to become a multi-target therapeutic agent addressing chronic disease.

This article describes the creation and implementation of focus groups to evaluate the effectiveness of a health sciences library's liaison program of the College of Pharmacy faculty and to better understand the faculty's information needs in order to design new and improved library services. The liaison services support the teaching and research needs of faculty and students through literature research, classroom teaching, and an extensive library collection of pharmacy literature. Focus group results demonstrated a high level of satisfaction with library liaison services and collections. Opportunities exist for expanded interaction with graduate students and greater marketing of library services to increase faculty awareness of specific library programs.

The issue of planning the timing and dosing of insulin in relation to food is one of the most difficult issues confronting people with diabetes. Recent focus on improving quality of life in this area has focused on developing different modes of administration of insulin thereby avoiding subcutaneous injections and developing new analoguesof insulin. Both inhalational and buccal administration technologies have been developed, and have essentially overcome some of the difficult pharmacokinetic issues regarding large peptide molecules, however there remain some clinical problems. Advances in the practicalities of treating insulin have occurred, such as more accurate and less expensive glucometers, new administration alternatives such as implantable pumps, with further developments in the pipeline including islet and gene replacement for Type I disease. However all of these newer options havelimitations and currently subcutaneous administration is the only real option for most people. Insulin analogues have so far been relatively disappointing in terms of improvement in mortality and morbidity although for some patients the ability to alter the dosage of insulin depending on the planned meal size or reduction of between meal snacks has been helpful. Furthermore there is a yet unknown question around long term safety. This review will discuss the major clinical issues surrounding the new insulin analogues as they relate to efficacy and side effects.

Assessment of glomerular filtration rate (GFR) is essential for calculating safe dosages of renally cleared drugs. Formulae for estimating reliable GFRs assume that plasma creatinine concentrations are stable. This study evaluates the variability of plasma creatinine (PCr) concentrations in patients admitted acutely to hospital. From 2,293 newly admitted patients, those in whom a subsequent clinically significant change (>20%) in PCr had occurred were identified. Median age was 81.1 years. Median baseline PCr was 90 umol/l (eGFR 60 ml/min). In total, 46.3% of the patients had a PCr that varied >20% from baseline three to seven days following admission. A 10-year increase in age increased the odds of a rise in PCr over the next week by 11.1% (odds ratio = 1.11, 95% confidence interval = 1.03, 1.20; p = 0.007). Overall, baseline creatinine was a poor predictor of subsequent variation in PCr. GFR formulae for calculating renally-cleared drug dosages should be used with caution in elderly patients admitted acutely to hospital.

Patients with type 2 diabetes mellitus (T2DM) might have subclinical myocardial dysfunction identified at rest or unmasked during exercise. We examined the correlates of the myocardial exercise response in patients with T2DM. Myocardial dysfunction was sought during at rest and exercise echocardiography in 167 healthy patients with T2DM (97 men, 55 ± 10 years). Myocardial ischemia was excluded using stress echocardiography. Standard echocardiography and color tissue Doppler imaging measures (early diastolic tissue velocity [Em], strain, and strain rate) were acquired at baseline and peak stress. The calibrated integrated backscatter was calculated from the at rest parasternal long-axis view. The longitudinal diastolic functional reserve index after exercise was defined as ΔEm [1 - (1/Em(base))]. The clinical, anthropometric, and metabolic data were collected at rest and stress. Subclinical myocardial dysfunction at baseline (n = 24) was independently associated with weight (odds ratio [OR] 1.02, p = 0.04) and hemoglobin A1c (OR 1.36, p = 0.03). This group displayed an impaired exercise response that was independently associated with a reduced exercise capacity (OR 0.84, p = 0.034) and longitudinal diastolic functional reserve index (OR 0.69, p = 0.001). Inducible myocardial dysfunction (stress Em

The measurement of drug concentrations, for clinical purposes, occurs in many diagnostic laboratories throughout Australia and New Zealand. However, the provision of a comprehensive therapeutic drug monitoring (TDM) service requires the additional elements of pre- and postanalytical advice to ensure that concentrations reported are meaningful, interpretable, and clinically applicable to the individual patient. The aim of this project was to assess the status of TDM services in Australia and New Zealand. A range of professions involved in key aspects of TDM was surveyed by questionnaire in late 2007. Information gathered included: the list of drugs assayed; analytical methods used; interpretation services offered; interpretative methods used; and further monitoring advice provided. Fifty-seven responses were received, of which 42% were from hospitals (public and/or private); 11% a hospital (public and/or private) and pathology provider; and 47% a pathology provider only (public and/or private). Results showed that TDM is applied to a large number of different drugs. Poorly performing assay methods were used in some cases, even when published guidelines recommended alternative practices. Although there was a wide array of assays available, the evidence suggested a need for better selection of assay methods. In addition, only limited advice and/or interpretation of results was offered. Of concern, less than 50% of those providing advice on aminoglycoside dosing in adults used pharmacokinetic tools with six of 37 (16.2%) respondents using Bayesian pharmacokinetic tools, the method recommended in the Australian Therapeutic Guidelines: Antibiotic. In conclusion, the survey highlighted deficiencies in the provision of TDM services, in particular assay method selection and both quality and quantity of postanalytical advice. A range of recommendations, some of which may have international implications, are discussed. There is a need to include measures of impact on clinical decision-making when assessing assay methodologies. Best practice guidelines and professional standards of practice in TDM are needed, supported by an active program of professional development to ensure the benefits of TDM are realized. This will require significant partnerships between the various professions involved.

Context: Postprandial dysmetabolism is emerging as an important cardiovascular risk factor. Augmentation index (AIx) is a measure of systemic arterial stiffness and independently predicts cardiovascular outcome. Objective: The objective of this study was to assess the effect of a standardized high-fat meal on metabolic parameters and AIx in 1) lean, 2) obese nondiabetic, and 3) subjects with type 2 diabetes mellitus (T2DM). Design and Setting: Male subjects (lean, n = 8; obese, n = 10; and T2DM, n = 10) were studied for 6 h after a high-fat meal and water control. Glucose, insulin, triglycerides, and AIx (radial applanation tonometry) were measured serially to determine the incremental area under the curve (iAUC). Results: AIx decreased in all three groups after a high-fat meal. A greater overall postprandial reduction in AIx was seen in lean and T2DM compared with obese subjects (iAUC, 2251 ± 1204, 2764 ± 1102, and 1187 ± 429% · min, respectively; P < 0.05). The time to return to baseline AIx was significantly delayed in subjects with T2DM (297 ± 68 min) compared with lean subjects (161 ± 88 min; P < 0.05). There was a significant correlation between iAUC AIx and iAUC triglycerides (r = 0.50; P < 0.05). Conclusions: Obesity is associated with an attenuated overall postprandial decrease in AIx. Subjects with T2DM have a preserved, but significantly prolonged, reduction in AIx after a high-fat meal. The correlation between AIx and triglycerides suggests that postprandial dysmetabolism may impact on vascular dynamics. The markedly different response observed in the obese subjects compared with those with T2DM was unexpected and warrants additional evaluation.

Obesity is a risk factor for the development of new cases of breast cancer and also affects survival in women who have already been diagnosed with breast cancer. Early studies of obesity and breast cancer survival have been summarised in two meta-analyses, but the latest of these only included studies that recruited women diagnosed as recently as 1991. The primary aim of this study was to conduct a meta-analysis that included the more recent studies. A systematic search of MEDLINE, EMBASE and CINAHL was conducted to identify original data evaluating the effects of obesity on survival in newly diagnosed breast cancer patients. Adjusted hazard ratios (HR) from individual studies were pooled using a random effects model. A series of pre-specified sensitivity analyses were conducted on factors such as overall versus breast cancer survival and treatment versus observational cohort. The meta-analysis included 43 studies that enrolled women diagnosed with breast cancer between 1963 and 2005. Sample size ranged from 100 to 424168 (median 1192). The meta-analysis showed poorer survival among obese compared with non-obese women with breast cancer, which was similar for overall (HR = 1.33; 95% confidence interval (CI): 1.21, 1.47) and breast cancer specific survival (HR = 1.33; 95% CI: 1.19, 1.50). The survival differential varied only slightly, depending on whether body mass index (1.33; 1.21, 1.47) or waist-hip ratio (1.31; 1.08, 1.58) was used as the measure of obesity. There were larger differences by whether the woman was pre-menopausal (1.47) or post-menopausal (1.22); whether the cohort included women diagnosed before (1.31) or after 1995 (1.49); or whether the women were in a treatment (1.22) or observational cohort (1.36), but none of the differences were statistically significant. Women with breast cancer, who are obese, have poorer survival than women with breast cancer, who are not obese. However, no study has elucidated the causal mechanism and there is currently no evidence that weight loss after diagnosis improves survival. Consequently, there is currently no reason to place the additional burden of weight loss on women already burdened with a diagnosis of cancer. Further research should concentrate on assessing whether factors such as diabetes or type of chemotherapy modify the obesity effect and on understanding the causal mechanism, in particular the role of relative under-dosing.

Diabetes is one of the major causes of morbidity and mortality in the Western world and it currently affects 35 million people in the US alone. Cardiovascular and renal complications of diabetes, Type I and II, account for much of this morbidity, and are now known to be the end result of a complex interplay of pathophysiological processes. These include haemodynamic and metabolic abnormalities such as endothelial dysfunction, inflammation, vasoconstriction, oxidation and fibrosis. For some time it has been difficult to elucidate whether these processes and subsequent dysfunction in organs such as the heart and kidney is due to processes that often coexist with diabetes, such as hypertension. However, it is now clear that there is a distinct pro-inflammatory and pro-fibrotic state in diabetes, which may in addition be complicated by synergistic disease processes. The use of statins in diabetes has been of interest for a while due to the known effect of statins on inflammatory and fibrotic pathways. This review covers the clinical evidence for the use of statins in diabetes, the major known pathophysiological processes that occur in diabetic organ disease and discusses the known and putative effects of statins on these pathways. It concludes with a brief discussion of some early and yet unpublished work regarding the addition of statin therapy to angiotensin inhibition therapy in diabetic disease.

In recent years, there has been significant growth in consumption of commodities in virtual social worlds, such as Second Life, and in the economies that arise from this practice. While these economic systems have been acknowledged and studied, there remains relatively little understanding of the reasons why individuals choose to purchase such goods, despite the fact that reasons for consumption are strong enough to drive a virtual goods industry with annual profits in the millions of dollars. Virtual goods, the author argues, meet no immediate needs for avatars or individuals and, as such, are purchased based exclusively on their exchange- and symbolic-values. Due to the graphical nature of Second Life and the consequent visibility of commodities within the environment, these reasons for purchasing virtual goods are explored in terms of their roles for users, and especially in terms of their potential for expressing wealth, power, status, individuality, and belonging. As such, this paper considers the roles of consumption in a way that relies on and further illuminates theories of consumption and value with respect to virtual environments and commodities.

Despite many post hoc analyses of cardiovascular databases in recent years suggesting a benefit of statins in the prevention and treatment of congestive heart failure (HF), a prospective study of statin therapy on two clinically relevant end points--HF morbidity and survival--had not been reported until 2007. However, a large-scale prospective trial, Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA), has just reported its primary results. These results somewhat surprisingly show no survival benefit in a group of patients with ischemic systolic HF given low-dose rosuvastatin. In addition to this uncertainty generated by the results of CORONA, there remains additional uncertainty in the existing, predominantly retrospective data on statins because of the potential bias in study designs, use of post hoc subgroup analyses, and lack of mechanistic data. This review critically evaluates the recent literature in this area.

Effect of HMGCoA Reductase Inhibitors on Cardiac Remodelling and Mortality in Rats. Following Hyperglycemia and Myocardial Infarction.The presence of diabetes mellitus (DM) in patients with myocardial infarction (MI) increases mortality, due in part to the presence of known cardiovascular risk factors. However little is known about the impact of DM on cardiac remodelling and on clinical outcomes. We aimed to investigate whether hyperglycaemia may adversely and additionally affect LV remodelling post-MI, and whether the addition of a statin, known to reduce mortality both post MI and in humans with DM, has an effect on these outcomes.Eight week old Sprague-Dawley rats were allocated to 5 groups--control (non-DM)/sham, control-MI, DM-sham, DM-MI and DM-MI with statin gavage (DM-MI/ATV). Echocardiogram and invasive pressure volume analysis were performed prior to sacrifice for estimation of cardiac function. Tissue was analysed for total cardiac collagen, collagen I and III.Hyperglycaemia in the remodelling period significantly increased mortality (70% survival in the C-MI group vs 27% in the DM-MI group), worsened cardiac function and increased fibrosis. All of these variables were attenuated by the addition of a statin.Hyperglycaemia increased mortality in MI and exacerbated LV remodeling, and this was attenuated with statin use. This study confirms the importance of early and intensive treatment of hyperglycaemia in patients with MI and suggests that in humans with both DM and MI the addition of a statin may be beneficial.

To investigate the quality of drug interaction decision support in selected prescribing and dispensing software systems, and to compare this information with that found in a range of reference sources.A comparative study, conducted between June 2006 and February 2007, of the support provided for making decisions about 20 major and 20 minor drug interactions in six prescribing and three dispensing software systems used in primary care in Australia. Five electronic reference sources were evaluated for comparison.Sensitivity, specificity and quality of information; for major interactions: whether information on clinical effects, timeframe and pharmacological mechanism was included, whether management advice was helpful, and succinctness.Six of the nine software systems had a sensitivity rateor = 90%, detecting most of the major interactions. Only 3/9 systems had a specificity rate ofor = 80%, with other systems providing inappropriate or unhelpful alerts for many minor interactions. Only 2/9 systems provided adequate information about clinical effects for more than half the major drug interactions, and 1/9 provided useful management advice for more than half of these. The reference sources had high sensitivity and in general provided more comprehensive clinical information than the software systems.Drug interaction decision support in commonly used prescribing and dispensing software has significant shortcomings.

Inappropriate polypharmacy, especially in older people, imposes a substantial burden of adverse drug events, ill health, disability, hospitalization, and even death. The single most important predictor of inappropriate prescribing and risk of adverse drug events in older patients is the number of prescribed drugs. Deprescribing is the process of tapering or stopping drugs, aimed at minimizing polypharmacy and improving patient outcomes. Evidence of efficacy for deprescribing is emerging from randomized trials and observational studies. A deprescribing protocol is proposed comprising 5 steps: (1) ascertain all drugs the patient is currently taking and the reasons for each one; (2) consider overall risk of drug-induced harm in individual patients in determining the required intensity of deprescribing intervention; (3) assess each drug in regard to its current or future benefit potential compared with current or future harm or burden potential; (4) prioritize drugs for discontinuation that have the lowest benefit-harm ratio and lowest likelihood of adverse withdrawal reactions or disease rebound syndromes; and (5) implement a discontinuation regimen and monitor patients closely for improvement in outcomes or onset of adverse effects. Whereas patient and prescriber barriers to deprescribing exist, resources and strategies are available that facilitate deliberate yet judicious deprescribing and deserve wider application. Refereed/Peer-reviewed

Parasite infection is increasingly recognised as a factor shaping the population dynamics, life history and behaviour of hosts. However, before the impacts of parasites on wildlife hosts can be investigated, seasonal patterns in host exposure to parasitic agents must be determined. We examined infection patterns at three sites in Victoria, and combined field experiments and observations to construct a generalised life cycle of the helminth community in eastern grey kangaroos (Macropus giganteus). Kangaroo populations in Victoria had very similar helminth communities, with 20–25 species detected at each site. Despite examining relatively few hosts in this study, at least 87% of all gastrointestinal helminths were recovered according to bootstrap estimates. The prepatent period of infection in eastern grey kangaroo nematodes was at least 3 months, and faecal egg output showed a distinct seasonal pattern, with a peak in egg counts from October through to January each year. Data from one site indicated that faecal egg counts were influenced predominantly by the abundance of a single nematode species (Pharyngostrongylus kappa), despite adults accounting for only 7% of the total nematode burden. This highlights the problems associated with using faecal egg counts to estimate nematode burdens in this host. Contamination of pasture plots showed that nematode eggs take ~14 days to larvate once deposited, and that autumn rains likely triggered emergence from faecal pellets. The abundance of infective larvae in the environment therefore appears to be closely tied to environmental conditions, with a peak in infection of hosts in the winter months.

Background & Aims Nonalcoholic fatty liver disease (NAFLD), characterized by accumulation of hepatic triglycerides (steatosis), is associated with abdominal obesity, insulin resistance, and inflammation. Although weight loss via calorie restriction reduces features of NAFLD, there is no pharmacologic therapy. Resveratrol is a polyphenol that prevents high-energy diet-induced steatosis and insulin resistance in animals by up-regulating pathways that regulate energy metabolism. We performed a placebo-controlled trial to assess the effects of resveratrol in patients with NAFLD. Methods Overweight or obese men diagnosed with NAFLD were recruited from hepatology outpatient clinics in Brisbane, Australia from 2011 through 2012. They were randomly assigned to groups given 3000 mg resveratrol (n = 10) or placebo (n = 10) daily for 8 weeks. Outcomes included insulin resistance (assessed by the euglycemic-hyperinsulinemic clamp), hepatic steatosis, and abdominal fat distribution (assessed by magnetic resonance spectroscopy and imaging). Plasma markers of inflammation, as well as metabolic, hepatic, and antioxidant function, were measured; transcription of target genes was measured in peripheral blood mononuclear cells. Resveratrol pharmacokinetics and safety were assessed. Results Eight-week administration of resveratrol did not reduce insulin resistance, steatosis, or abdominal fat distribution when compared with baseline. No change was observed in plasma lipids or antioxidant activity. Levels of alanine and aspartate aminotransferases increased significantly among patients in the resveratrol group until week 6 when compared with the placebo group. Resveratrol did not significantly alter transcription of NQO1 , PTP1B , IL6 , or HO1 in peripheral blood mononuclear cells. Resveratrol was well-tolerated. Conclusions Eight weeks administration of resveratrol did not significantly improve any features of NAFLD, compared with placebo, but it increased hepatic stress, based on observed increases in levels of liver enzymes. Further studies are needed to determine whether agents that are purported to mimic calorie restriction, such as resveratrol, are safe and effective for complications of obesity. Clinical trials registration no: ACTRN12612001135808.

We report a case of khat-associated hepatitis in a 32-year-old Somali man living in Australia. This is the first case of hepatoxicity related to khat ingestion reported in Australia.

Modification of milk fat both by partially replacing saturated FA with oleic acid (18:1) and by increasing calcium intake independently reduces plasma cholesterol. Whether modification of both factors together would synergistically reduce plasma cholesterol is unknown. Seventy-two male golden Syrian hamsters were separated into four diet treatment groups (n = 18/group) and fed ad libitum for 7 wk. Diets contained either modified milk fat (MMF) or regular milk fat (RMF) with either 0.5% (MMF and RMF) or 1.3% calcium (w/w) (MMFC and RMFC). All diets contained 11% test fat, 4% soybean oil, and 0.15% cholesterol (w/w). During the last week, feces were collected for three consecutive days for analysis of fecal FA, cholesterol, and calcium excretion. Overnight-fasted animals were sacrificed, and plasma and livers were collected for lipid analysis. Neither MMF nor additional calcium significantly affected plasma lipids. However, significant interactions existed between MMF and additional calcium for the ratio of LDL cholesterol to HDL cholesterol (LDL/HDL), indicating that increased calcium intake reduced this ratio only in RMF animals. In addition, MMF reduced LDL/HDL relative to RMF. MMF significantly increased hepatic total and esterified cholesterol. Additional calcium significantly increased fecal calcium and saturated FA (SFA) excretion, whereas MMF significantly reduced SFA excretion. RMFC induced the highest excretion of 16:0 among all groups. Replacement of SFA with 18:1 in the MMF reduced the impact of high calcium on LDL/HDL. Additional calcium reduced LDL/HDL only in the presence of RMF, which may be achieved through an increased excretion of 16:0.

Objective : The pathological accumulation of extracellular matrix is a characteristic feature of diabetic cardiomyopathy that is directly related to a loss of function. Tranilast ( n -[3,4-anthranilic acid), used for the treatment of fibrotic skin diseases, has also been shown to inhibit transforming growth factor-β (TGF-β)-induced matrix production in kidney epithelial cells. Methods : To investigate the effects of tranilast in the diabetic heart, we examined its effects in cultured cardiac fibroblasts and then assessed its effects in (mRen-2)27 diabetic rats with established disease (8 weeks after streptozotocin). Results : In vitro studies demonstrated a 58% reduction in TGF-β1-induced 3[H]-hydroxyproline incorporation with tranilast 30 μM ( p

The present review outlines the clinical relevance of pharmacokinetic drug interactions within the HMG-CoA reductase inhibitor class. These interactions can result in markedly increased or decreased plasma concentrations of some drugs within this class. However, the relationship between altered plasma concentrations and adverse effects or toxicity may not be linear. It is likely that other variables affect this concentration-effect relationship including: rapid changes in the concentration, concomitant lipid-lowering therapy or host genetic factors that code for different forms or amounts of metabolising enzymes and drug receptors. It is not currently possible to predict which patients will manifest clinically important drug-drug interactions, nor what concentration of an HMG-CoA reductase inhibitor will cause rhabdomyolysis. Thus, until prescribers have better scientific information from which to develop a 'therapeutic range' for each agent, caution should be exercised. In particular, patients taking a CYP3A4-metabolised agent, e.g. atorvastatin, simvastatin and lovastatin, should not be started on a CYP3A4 inhibitor or inducer without close monitoring.

Australia's efforts to prevent, diagnose and treat cancer are not as successful for Aboriginal and Torres Strait Islander people as they are for other Australians. There is a need for a nationally coordinated, collaborative, priority-driven research effort to better understand what works, and we need to implement that knowledge. All aspects of the process must involve genuine Indigenous leadership and participation.

Background and Aim Carbohydrate deficient transferrin (CDT) is the most specific serum biomarker of heavy alcohol consumption, defined as ≥ 350–420 g alcohol/week. Despite introduction of a standardized reference measurement technique, widespread use of CDT remains limited due to low sensitivity. The aim of this study was to determine the factors that affect diagnostic sensitivity in patients with sustained heavy alcohol intake. Methods Patients with a self-reported history of sustained heavy alcohol consumption were recruited from the hepatology outpatient department or medical wards. Each patient was interviewed with a validated structured questionnaire of alcohol consumption and CDT analysis using the standardized reference measurement technique with high performance liquid chromatography was performed on serum collected at time of interview. Results 52 patients were recruited: 19 from the hepatology outpatient department and 33 from general medical wards. Median alcohol intake was 1013 (range 366–5880) g/week over the preceding two week period. 26 patients had a diagnostic CDT based on a threshold value of %CDT > 1.7 indicating heavy alcohol consumption, yielding a sensitivity of 50%. Overweight/obesity (defined as body mass index (BMI) ≥ 25 kg/m2 in Caucasians and ≥ 23.0 kg/m2 in Asians), female gender and presence of cirrhosis were independently associated with non-diagnostic %CDT (≤ 1.7). Conclusions CDT has limited sensitivity as a biomarker of heavy alcohol consumption. Caution should be applied when ordering and interpreting %CDT results, particularly in women, patients with cirrhosis and those with an elevated BMI.

Objective To implement and evaluate strategies for improving access to emergency department (ED) care in a tertiary hospital. Methods A retrospective pre–post intervention study using routinely collected data involving all patients presenting acutely to the ED of a major tertiary hospital over a 2-year period. Main outcome measures were changes in: the percentage of patients exiting the ED (all patients, patients discharged directly from the ED, patients admitted to inpatient wards); mean patient transit times in the ED; inpatient mortality rates; rates of ED ‘did not wait’ and re-presentations within 48 h of ED discharge; and selected safety indicators. Qualitative data on staff perceptions of interventions were also gathered. Results Working groups focused on ED internal processes, ED–inpatient unit interface, hospital-wide discharge processes and performance monitoring and feedback. Twenty-five different reforms were enacted over a 9-month period from April to December 2012. Comparing the baseline period (January–March 2012) with the post-reform period (January–March 2013), the percentage of patients exiting the ED within 4 h rose for all patients presenting to the ED (from 32% to 62%), for patients discharged directly from the ED (from 41% to 75%) and for admitted patients (from 12% to 32%; P

Purpose: Interstitial fibrosis is believed to be one of several contributors to diabeticcardiomyopathy (DCM), manifesting as myocardial dysfunction in the absenceof ischemic heart disease in subjects with type 2 diabetes (T2DM). Myocardialultrasound reflectivity is proportionate to fibrosis, but use of the pericardiumas a frame of reference (calibrated integrated backscatter, cIB) may be limitedby signal saturation. Recently, diffuse fibrosis has been shown to be inverselyproportionate to T1 time on post-contrast T1 mapping using cardiac magneticresonance imaging. We sought to compare the association of cIB and T1 timewith DCM.Methods: Demographic, anthropometric, hemodynamic and biochemical datawere measured in 107 apparently healthy, asymptomatic subjects with T2DM (65men, 60±9 years). LV dysfunction (LVD) was sought on resting echo (early diastolictissue velocity [Em] < 1SD from mean for age). Ischemia was excludedby exercise echo. Standard 2D and color TDI measures (tissue velocity, strainand strain rate) were acquired in apical long axis views. Calibrated integratedbackscatter (cIB) was calculated from a parasternal long axis view. Tonometricaortic pulse wave velocity (APWV) was used to determine arterial stiffness. T1mapping was performed in those with LVD and matched controls.Results: LVD was identified in 23 subjects (28%) who also demonstrated significantlypoorer diabetic control (HbA1c 8.2±2.0 vs 7.3±1.4 mmol/L) but no relationshipwith cIB. T1 mapping was performed in 26 subjects (17 men, 60±10years) comprising 20 with LVD and 6 controls. Em was independently associatedwith age (β=-0.76 p

Background: Amiodarone-induced hyperthyroidism has been extensively reported in the Australian and international literature. However, amiodarone-induced hypothyroidism, although much less common, is also seen in clinical practice.Aim: To describe a case of rapidly progressive severe amiodarone-induced hypothyroidism complicated by myxoedema, cognitive decline and peripheral neuropathy in an elderly female.Clinical Details: An elderly female presented with a 3 to 6 month history of fatigue, cold intolerance and constipation. Her medical history was significant for type 2 diabetes, ischaemic heart disease and moderate mitral regurgitation complicated by severe left atrial dilatation and chronic atrial fibrillation.Outcomes: Her amiodarone was stopped and thyroxine commenced at 25 microgram daily. One week after admission her energy levels had improved to the point where she could safely manage at home. 6 months after amiodarone cessation she was euthyroid on thyroxine replacement and remained in rate controlled atrial fibrillation. Conclusion: Prescribers are reminded of the risk of serious thyroid morbidity associated with amiodarone use. Current recommendations include evaluation of risk against benefit with prolonged amiodarone therapy and periodic screening for early toxicity.

In wildlife research, our ability to GPS track sufficient numbers of individuals is always limited by cost, which restricts inference of species–habitat relationships. Here, we describe the modification and use of a relatively new and inexpensive off-the-shelf GPS device, to provide detailed and accurate information on the movement patterns of individuals (mountain brushtail possums, Trichosurus cunninghami), including how movement varies through time, and how individuals interact with each other. Our results demonstrated that this technology has enormous potential to contribute to an improved understanding of the movement patterns and habitat preferences of wildlife at a fraction of the cost of traditional GPS technology.

culated, and two novel indices of ventricular compliance; LV circumferential (CRI) and longitudinal (LRI) relaxation indices. Results: LV EF was significantly lower in ICM (32± 2 vs 65± 2, p< 0.001) and hyperdynamic in HCM (72± 2 vs 65± 2, p= 0.03) when compared to VOL. SV was similar in all groups. ICM LV EDV was 1.8× greater than VOL (p< 0.001) and 2.2× greater than HCM (p< 0.001). CRI was impaired in ICM patients (19% lower than VOL, p< 0.001) and preserved in HCM. LRI was significantly lower in ICM (72% lower, p< 0.001) and HCM patients (50% lower, p< 0.001) when compared to VOL. Atrial EF was significantly lower in both ICM (22.6± 10.2) andHCM (28.8± 10.5) than VOL (49.1± 9.1, p< 0.001). Conclusions: This work demonstrates cMRI is capable of producing measures of diastolic function, which are at least comparable with current techniques in echocardiography. Using novel LR and CR indices, we have shown that impairment of diastolic function is primarily due to abnormal relaxation of LV longitudinal fibers and that this maybe compensated for byhyperdynamic circumferential fibers in order to maintain SV. doi:10.1016/j.hlc.2011.05.452

Therapeutic drug concentrations are measured in many diagnostic laboratories;however, providing a comprehensive therapeutic drug monitoring (TDM) service requires the additional elements of pre- and post-analytical advice to ensure that concentrations reported are meaningful and clinically interpretable. The aim of this project was to assess the status of such TDM services in Australasia. Laboratories were surveyed by questionnaire in late 2007. The results included responses from 57 laboratories of which 42% were from hospital laboratories, 11% hospital pathology providers, 47% as pathology providers. Questions included tests offered, methods adopted, interpretation and further monitoring advice provided. Whilst there was wide array of tests available and support for analytical aspects, there was only limited advice/interpretation of results offered. For example, In conclusion, the survey reinforces that provision of quality TDM services requires more than issuing just drug concentrations and suggested the need to define appropriate professional practice standards that could potentially be accredited.

Detailed knowledge of how individuals use space when active and while sheltering is crucial to understanding the habitat requirements of a species. I present the first home-range estimates for bobucks, Trichosurus cunninghami, that are based on both nocturnal and diurnal radio-tracking fixes. I tracked 37 individuals (14 adult females, 14 adult males, three subadult females and six subadult males) between mid-1999 and late 2003 in a forest patch in the Strathbogie Ranges, south-eastern Australia. I collected a total of 9562 diurnal fixes (mean 309 fixes per adult) and 5211 nocturnal fixes (mean 169 fixes per adult). All individuals used multiple den-trees; adults used a mean of 7.2 den-trees per individual. Adult bobucks of both sexes had a mean home-range size of 6.0 ha. There were no significant differences in the mean number of den-trees used or in the mean home-range size of adult males and females. Subadults used significantly fewer den-trees and had significantly smaller home ranges than adults. This study demonstrates the importance of large and long-term datasets in accurately determining the habitat requirements of a population.

Background Optimal peri-operative corticosteroid dosing to avoid excess or deficiency for patients taking chronic prednisone (c-PRED) is unknown. Methods In a randomized double-blind trial, traditional doses of IV hydrocortisone (HC) were compared to lower doses matched to patients' c-PRED dose. Patients taking ≥G5mg c-PRED for ≥G2 wks within 15 mg/day) preoperatively then q8h X24h (LD). Low dose (1 mcg) co-syntropin stimulation test assessed adrenal function. Results Among 70 subjects (mean c-PRED exposure 1,870 mg/6 months), inflammatory bowel diseases (39%) and connective tissue disorders (36%) commonly led to abdominal (43%) and joint replacement (30%) procedures, respectively. Co-primary outcome measures, adrenal insufficiency and corticosteroids excess scales, did not meaningfully differ between LD and TD, although AIS trends favored TD. Blood pressure was lower following surgery in LD: 109/63 vs TD: 120/69 (SBP: p=0.01; DBP: p=0.04) and hypotension was more common in LD (58% vs TD: 29%; p=0.01). Post-operative infections and wound healing did not differ. Conclusions Lower doses of peri-operative HC may lead to more hypotension in the post-operative period. However, only 1–2 higher HC doses may be required. Larger trials are needed to assess impact on post-operative wound healing and infections. Clinical Pharmacology & Therapeutics (2004) 75, P76–P76; doi: 10.1016/j.clpt.2003.11.287