Navigating uncertainty in Australia : fostering informed citizenship through teaching controversial issues with pre-service teachers

Australia is a multicultural immigrant society created by public policy and direct state action over a period of two hundred years. It is now one of the world’s most diverse societies. However, like many nations, Australia faces challenges to managing ‘unauthorized arrivals’ who claim to be refugees. The issue of how to deal with unauthorized arrivals is controversial and highly emotive as it challenges public policy and government capacity to manage the multicultural ‘mix’ of Australia’s population. It also raises questions about border security. Given that it is impossible to discern beforehand who is a ‘proper’ refugee and who is not, claims to refugee status by unauthorised arrivals in Australia need to be tested against international convention criteria devised by the United Nations High Commissioner for Refugees (UNHCR). There are no simple solutions to controversial questions such as how and where should unauthorised arrivals, and the children accompanying them, be housed whilst their claims are investigated? Moreover, as this issue continues to prompt division and heated debate in Australian society, teachers new to the profession are often reluctant to explore it in the classroom. However, there are opportunities in national and state curriculum documents for the values dimensions of curriculum inquiries into controversial issues such as this to be addressed. For example, the most recent national statement on the goals for schooling in Australia, the Melbourne Declaration (MCEETYA, 2008), makes clear that Australian students need to be prepared for the challenges of the 21st century and to develop the capacity for innovation and complex problem-solving. The Melbourne Declaration informs the first national curriculum to be implemented in the Australian states and territories, and all other national and state initiatives. Its focus on developing active and informed citizens who can contribute to a socially cohesive society implies a capacity to deal with a range of issues associated with cultural diversity, This chapter explores the ways in which pre-service and early career teachers in one Australian state reflect upon curriculum opportunities to address controversial issues in the social sciences and history classroom. As part of their pre-service education, all the participants in this study completed a final year social science curriculum method unit that embedded a range of controversial issues, including the placement of children in Australian Immigration Detention Centres (IDCs), for investigation. By drawing from interviews and focus groups conducted with different cohorts of pre-service teachers in their final year of university study and beginning years of teaching, this chapter analyses the range of perceptions about how controversial issues can be examined in the secondary classroom as part of fostering informed citizenship. The discussion and analysis of the qualitative data in this study makes no claims for the representativeness of its findings, rather, a range of beginner teacher insights into a complex and important facet of teaching in a period of change and uncertainty is offered.

A randomised controlled trial of an online theory-based intervention to improve adult Australians' sun-protective behaviours

Objective. To evaluate the effectiveness of a single-session online theory of planned behaviour (TPB)-based intervention to improve sun-protective attitudes and behaviour among Australian adults. Methods. Australian adults (N = 534; 38.7% males; Mage = 39.3 years) from major cities (80.9%), regional (17.6%) and remote areas (1.5%)were recruited and randomly allocated to an intervention (N=265) and information only group (N = 267). The online intervention focused on fostering positive attitudes, perceptions of normative support, and control perceptions for sun protection. Participants completed questionnaires assessing standard TPB measures (attitude, subjective norm, perceived behavioural control, intention, behaviour) and extended TPB constructs of group norm (friends, family), personal norm, and image norm, pre-intervention (Time 1) and one week (Time 2) and one month post-intervention (Time 3). Repeated Measures Multivariate Analysis of Variance tested intervention effects across time. Results. Intervention participants reported more positive attitudes towards sun protection and used sunprotective measures more often in the subsequent month than participants receiving information only. The intervention effects on control perceptions and norms were non-significant. Conclusions. A theory-based online intervention fostering more favourable attitudes towards sun safety can increase sun protection attitudes and self-reported behaviour among Australian adults in the short term.

Implementation of individualised medication administration guides for patients with dysphagia: Results from a pilot controlled trial

Introduction Patients with dysphagia (PWDs) have been shown to be four times more likely to suffer medication administration errors (MAEs).1 2 Individualised medication administration guides (I-MAGs) which outline how each formulation should be administered, have been developed to standardise medication administration by nurses on the ward and reduce the likelihood of errors. This pilot study aimed to determine the recruitment rates, estimate effect on errors and develop the intervention to design a future full scale randomised controlled trial to determine the costs and effects of I-MAG implementation. Ethical approval was granted by local ethics committee. Method Software was developed to enable I-MAG production (based on current best practice)3 4 for all PWDs on two care of the older person wards admitted during a six month period from January to July 2011. I-MAGs were attached to the medication administration record charts to be utilised by nurses when administering medicines. Staff training was provided for all staff on the intervention wards. Two care of the older person wards in the same hospital were used for control purposes. All patients with dysphagia were recruited for follow up purposes at discharge. Four ward rounds at each intervention and control ward were observed pre and post I-MAG implementation to determine the level of medication administration errors. NHS ethical approval for the study was obtained. Results 164 I-MAGs were provided for 75 patients with dysphagia (PWDs) in the two intervention wards. At discharge, 23 patients in the intervention wards and 7 patients in the control wards were approached for recruitment of which 17 (74%) & 5 (71.5%) respectively consented. Discussion Recruitment rates were low on discharge due to the dysphagia remitting during hospitalisation. The introduction of the I-MAG demonstrated no effect on the quality of administration on the intervention ward and interestingly practice improved on the control ward. The observation of medication rounds at least one month post I-MAG removal may have identified a reversal to normal practice and ideally observations should have been undertaken with I-MAGs in place. Identification of the reason for the improvement in the control ward is warranted.

Effects of compression on lymphoedema during resistance exercise in women with breast cancer-related lymphoedema: A randomised, cross-over trial

Background The use of compression garments during exercise is recommended for women with breast cancer-related lymphoedema, but the evidence behind this clinical recommendation is unclear. The aim of this randomised, cross-over trial was to compare the acute effects of wearing versus not wearing compression during a single bout of moderate-load resistance exercise on lymphoedema status and its associated symptoms in women with breast cancer-related lymphoedema. Methods Twenty-five women with clinically diagnosed, stable unilateral breast cancer-related lymphoedema completed two resistance exercise sessions, one with compression and one without, in a randomised order separated by a 14 day wash-out period. The resistance exercise session consisted of six upper-body exercises, with each exercise performed for three sets at a moderate-load (10-12 repetition maximum). Primary outcome was lymphoedema, assessed using bioimpedance spectroscopy (L-Dex score). Secondary outcomes were lymphoedema as assessed by arm circumferences (percent inter-limb difference and sum-of-circumferences), and symptom severity for pain, heaviness and tightness, measured using visual analogue scales. Measurements were taken pre-, immediately post- and 24 hours post-exercise. Results There was no difference in lymphoedema status (i.e., L-Dex scores) pre- and post-exercise sessions or between the compression and non-compression condition [Mean (SD) for compression pre-, immediately post- and 24 hours post-exercise: 17.7 (21.5), 12.7 (16.2) and 14.1 (16.7), respectively; no compression: 15.3 (18.3), 15.3 (17.8), and 13.4 (16.1), respectively]. Circumference values and symptom severity were stable across time and treatment condition. Conclusions An acute bout of moderate-load, upper-body resistance exercise performed in the absence of compression does not exacerbate lymphoedema in women with breast cancer-related lymphoedema.

EVERSUN: A phase 2 trial of alternating sunitinib and everolimus as first-line therapy for advanced renal cell carcinoma

Background We hypothesised that alternating inhibitors of the vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin pathways would delay the development of resistance in advanced renal cell carcinoma (aRCC). Patients and methods A single-arm, two-stage, multicentre, phase 2 trial to determine the activity, feasibility, and safety of 12-week cycles of sunitinib 50 mg daily 4 weeks on / 2 weeks off, alternating with everolimus 10 mg daily for 5 weeks on / 1 week off, until disease progression or prohibitive toxicity in favourable or intermediate-risk aRCC. The primary end point was proportion alive and progression-free at 6 months (PFS6m). The secondary end points were feasibility, tumour response, overall survival (OS), and adverse events (AEs). The correlative objective was to assess biomarkers and correlate with clinical outcome. Results We recruited 55 eligible participants from September 2010 to August 2012. Demographics: mean age 61, 71% male, favourable risk 16%, intermediate risk 84%. Cycle 2 commenced within 14 weeks for 80% of participants; 64% received ≥22 weeks of alternating therapy; 78% received ≥22 weeks of any treatment. PFS6m was 29/55 (53%; 95% confidence interval [CI] 40% to 66%). Tumour response rate was 7/55 (13%; 95% CI 4% to 22%, all partial responses). After median follow-up of 20 months, 47 of 55 (86%) had progressed with a median progression-free survival of 8 months (95% CI 5–10), and 30 of 55 (55%) had died with a median OS of 17 months (95% CI 12–undefined). AEs were consistent with those expected for each single agent. No convincing prognostic biomarkers were identified. Conclusions The EVERSUN regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. This supports the current approach of continuing anti-VEGF therapy until progression or prohibitive toxicity before changing treatment.

Pre-release evaluation of the efficacy of the leaf-sucking bug Carvalhotingis visenda (Heteroptera: Tingidae) as a biological control agent for cat's claw creeper Macfadyena unguis-cati (Bignoniaceae)

In classical weed biological control, assessing weed response to simulated herbivory is one option to assist in the prioritization of available agents and prediction of their potential efficacy. Previously reported simulated herbivory studies suggested that a specialist herbivore in the leaf-feeding guild is desirable as an effective biological control agent for cat's claw creeper Macfadyena unguis-cati (Bignoniaceae), an environmental weed that is currently a target for biological control. In this study, we tested (i) whether the results from glasshouse-based simulated herbivory can be used to prioritise potential biological control agents by evaluating the impact of a leaf-sucking tingid bug Carvalhotingis visenda (Drake & Hambleton) (Hemiptera: Tingidae) in quarantine; and (ii) the likely effectiveness of low- and high-densities of the leaf-sucking tingid after its release in the field. The results suggest that a single generation of C. visenda has the potential to reduce leaf chlorophyll content significantly, resulting in reduced plant height and leaf biomass. However, the impact of one generation of tingid herbivory on below-ground plant components, including the roots and tuber size and biomass, were not significant. These findings are consistent with results obtained from a simulated herbivory trial, highlighting the potential role of simulated herbivory studies in agent prioritisation.

Cluster randomised-control trial for an Australian child protection education program: Study protocol for the Learn to be safe with Emmy and friends™

Background Child maltreatment has severe short-and long-term consequences for children’s health, development, and wellbeing. Despite the provision of child protection education programs in many countries, few have been rigorously evaluated to determine their effectiveness. We describe the design of a multi-site gold standard evaluation of an Australian school-based child protection education program. The intervention has been developed by a not-for-profit agency and comprises 5 1-h sessions delivered to first grade students (aged 5–6 years) in their regular classrooms. It incorporates common attributes of effective programs identified in the literature, and aligns with the Australian education curriculum. Methods/Design A three-site cluster randomised controlled trial (RCT) of Learn to be safe with Emmy and friends™ will be conducted with children in approximately 72 first grade classrooms in 24 Queensland primary (elementary) schools from three state regions, over a period of 2 years. Entire schools will be randomised, using a computer generated list of random numbers, to intervention and wait-list control conditions, to prevent contamination effects across students and classes. Data will be collected at baseline (pre-assessment), immediately after the intervention (post-assessment), and at 6-, 12-, and 18-months (follow-up assessments). Outcome assessors will be blinded to group membership. Primary outcomes assessed are children’s knowledge of program concepts; intentions to use program knowledge, skills, and help-seeking strategies; actual use of program material in a simulated situation; and anxiety arising from program participation. Secondary outcomes include a parent discussion monitor, parent observations of their children’s use of program materials, satisfaction with the program, and parental stress. A process evaluation will be conducted concurrently to assess program performance. Discussion This RCT addresses shortcomings in previous studies and methodologically extends research in this area by randomising at school-level to prevent cross-learning between conditions; providing longer-term outcome assessment than any previous study; examining the degree to which parents/guardians discuss intervention content with children at home; assessing potential moderating/mediating effects of family and child demographic variables; testing an in-vivo measure to assess children’s ability to discriminate safe/unsafe situations and disclose to trusted adults; and testing enhancements to existing measures to establish greater internal consistency.

The role of 25-hydroxyvitamin D deficiency in promoting insulin resistance and inflammation in patients with chronic kidney disease: A randomised controlled trial

BACKGROUND Approximately 50% of patients with stage 3 Chronic Kidney Disease are 25-hydroxyvitamin D insufficient, and this prevalence increases with falling glomerular filtration rate. Vitamin D is now recognised as having pleiotropic roles beyond bone and mineral homeostasis, with the vitamin D receptor and metabolising machinery identified in multiple tissues. Worryingly, recent observational data has highlighted an association between hypovitaminosis D and increased cardiovascular mortality, possibly mediated via vitamin D effects on insulin resistance and inflammation. The main hypothesis of this study is that oral Vitamin D supplementation will ameliorate insulin resistance in patients with Chronic Kidney Disease stage 3 when compared to placebo. Secondary hypotheses will test whether this is associated with decreased inflammation and bone/adipocyte-endocrine dysregulation. METHODS/DESIGN This study is a single-centre, double-blinded, randomised, placebo-controlled trial. Inclusion criteria include; estimated glomerular filtration rate 30-59 ml/min/1.73 m(2); aged >or=18 on entry to study; and serum 25-hydroxyvitamin D levels <75 nmol/L. Patients will be randomised 1:1 to receive either oral cholecalciferol 2000IU/day or placebo for 6 months. The primary outcome will be an improvement in insulin sensitivity, measured by hyperinsulinaemic euglycaemic clamp. Secondary outcome measures will include serum parathyroid hormone, cytokines (Interleukin-1beta, Interleukin-6, Tumour Necrosis Factor alpha), adiponectin (total and High Molecular Weight), osteocalcin (carboxylated and under-carboxylated), peripheral blood mononuclear cell Nuclear Factor Kappa-B p65 binding activity, brachial artery reactivity, aortic pulse wave velocity and waveform analysis, and indirect calorimetry. All outcome measures will be performed at baseline and end of study. DISCUSSION To date, no randomised controlled trial has been performed in pre-dialysis CKD patients to study the correlation between vitamin D status with supplementation, insulin resistance and markers of adverse cardiovascular risk. We remain hopeful that cholecalciferol may be a safe intervention, with health benefits beyond those related to bone-mineral homeostasis. TRIAL REGISTRATION Australian and New Zealand Clinical Trials Registry ACTRN12609000246280.

An EORTC-IDBBC phase I study of gemcitabine and continuous infusion 5-fluorouracil in patients with metastatic breast cancer resistant to anthracyclines or pre-treated with both anthracyclines and taxanes.

The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and potential activity of combined gemcitabine and continuous infusion 5-fluorouracil (5-FU) in metastatic breast cancer (MBC) patients that are resistant to anthracyclines or have been pretreated with both anthracyclines and taxanes. 15 patients with MBC were studied at three European Organization for Research and Treatment of Cancer centres. 13 patients had received both anthracylines and taxanes. Gemcitabine was given intravenously (i.v.) on days 1 and 8, and 5-FU as a continuous i.v. infusion on days 1 through to 14, both drugs given in a 21-day schedule at four different dose levels. Both were given at doses commonly used for the single agents for the last dose level (dose level 4). One of 6 patients at level 4 (gemcitabine 1200 mg/m2 and 5-FU 250 mg/m2/day) had a DLT, a grade 3 stomatitis and skin toxicity. One DLT, a grade 3 transaminase rise and thrombosis, occurred in a patient at level 2 (gemcitabine 1000 mg/m2 and 5-FU 200 mg/m2/day). Thus, the MTD was not reached. One partial response and four disease stabilisations were observed. Only 1 patient withdrew from the treatment due to toxicity. The MTD was not reached in the phase I study. The combination of gemcitabine and 5-FU is well tolerated at doses up to 1200 mg/m2 given on days 1 and 8 and 250 mg/m2/day given on days 1 through to 14, respectively, every 21 days. The clinical benefit rate (responses plus no change of at least 6 months) was 33% with one partial response, suggesting that MBC patients with prior anthracycline and taxane therapy may derive significant benefit from this combination with minimal toxicity.

A randomized clinical trial of a coping improvement group intervention for HIV-infected older adults.

This research tested if a 12-session coping improvement group intervention (n = 104) reduced depressive symptoms in HIV-infected older adults compared to an interpersonal support group intervention (n = 105) and an individual therapy upon request (ITUR) control condition (n = 86). Participants were 295 HIV-infected men and women 50-plus years of age living in New York City, Cincinnati, OH, and Columbus, OH. Using A-CASI assessment methodology, participants provided data on their depressive symptoms using the Geriatric Depression Screening Scale (GDS) at pre-intervention, post-intervention, and 4- and 8-month follow-up. Whether conducted with all participants (N = 295) or only a subset of participants diagnosed with mild, moderate, or severe depressive symptoms (N = 171), mixed models analyses of repeated measures found that both coping improvement and interpersonal support group intervention participants reported fewer depressive symptoms than ITUR controls at post-intervention, 4-month follow-up, and 8-month follow-up. The effect sizes of the differences between the two active interventions and the control group were greater when outcome analyses were limited to those participants with mild, moderate, or severe depressive symptoms. At no assessment period did coping improvement and interpersonal support group intervention participants differ in depressive symptoms.

Randomised controlled trial of effects of Helicobacter pylori infection and its eradication on heartburn and gastro-oesophageal reflux: the bristol helicobacter project

Objectives To investigate the effects of Helicobacter pylori infection and its eradication on heartburn and gastro-oesophageal reflux. Design Cross sectional study, followed by a randomised placebo controlled trial. Setting Seven general practices in Bristol, England. Participants 10 537 people, aged 20-59 years, with and without H pylori infection (determined by the 13C-urea breath test). Main outcome measures Prevalence of heartburn and gastro-oesophageal acid reflux at baseline and two years after treatment to eradicate H pylori infection. Results At baseline, H pylori infection was associated with increased prevalence of heartburn (odds ratio 1.14, 95% confidence interval 1.05 to 1.23) but not reflux (1.05, 0.97 to 1.14). In participants with H pylori infection, active treatment had no effect on the overall prevalence of heartburn (0.99, 0.88 to 1.12) or reflux (1.04, 0.91 to 1.19) and did not improve pre-existing symptoms of heartburn or reflux. Conclusions H pylori infection is associated with a slightly increased prevalence of heartburn but not reflux. Treatment to eradicate H pylori has no net benefit in patients with heartburn or gastro-oesophageal reflux

Molecular detection of exercise-induced free radicals following ascorbate prophylaxis in type 1 diabetes mellitus: a randomised controlled trial

Aims/hypothesis: Patients with type 1 diabetes mellitus are more susceptible than healthy individuals to exercise-induced oxidative stress and vascular endothelial dysfunction, which has important implications for the progression of disease. Thus, in the present study, we designed a randomised double-blind, placebo-controlled trial to test the original hypothesis that oral prophylaxis with vitamin C attenuates rest and exercise-induced free radical-mediated lipid peroxidation in type 1 diabetes mellitus. Methods: All data were collected from hospitalised diabetic patients. The electron paramagnetic resonance spectroscopic detection of spin-trapped a-phenyl-tert-butylnitrone (PBN) adducts was combined with the use of supporting markers of lipid peroxidation and non-enzymatic antioxidants to assess exercise-induced oxidative stress in male patients with type 1 diabetes (HbA1c 7.9±1%, n=12) and healthy controls (HbA1c 4.6±0.5%, n=14). Following participant randomisation using numbers in a sealed envelope, venous blood samples were obtained at rest, after a maximal exercise challenge and before and 2 h after oral ingestion of 1 g ascorbate or placebo. Participants and lead investigators were blinded to the administration of either placebo or ascorbate treatments. Primary outcome was the difference in changes in free radicals following ascorbate ingestion. Resuts: Six diabetic patients and seven healthy control participants were randomised to each of the placebo and ascorbate groups. Diabetic patients (n=12) exhibited an elevated concentration of PBN adducts (p<0.05 vs healthy, n=14), which were confirmed as secondary, lipid-derived oxygen-centred alkoxyl (RO•) radicals (a nitrogen=1.37 mT and aßhydrogen=0.18 mT). Lipid hydroperoxides were also selectively elevated and associated with a depression of retinol and lycopene (p<0.05 vs healthy). Vitamin C supplementation increased plasma vitamin C concentration to a similar degree in both groups (p<0.05 vs pre-supplementation) and attenuated the exercise-induced oxidative stress response (p<0.05 vs healthy). There were no selective treatment differences between groups in the primary outcome variable. Conclusions/ interpretation: These findings are the first to suggest that oral vitamin C supplementation provides an effective prophylaxis against exercise-induced free radical-mediated lipid peroxidation in human diabetic blood.

Computer simulating a trial of a load-bearing implant: example of an intramedullary prosthesis

Computational modelling is becoming ever more important for obtaining regulatory approval for new medical devices. An accepted approach is to infer performance in a population from an analysis conducted for an idealised or ‘average’ patient; we present here a method for predicting the performance of an orthopaedic implant when released into a population—effectively simulating a clinical trial. Specifically we hypothesise that an analysis based on a method for predicting the performance in a population will lead to different conclusions than an analysis based on an idealised or ‘average’ patient. To test this hypothesis we use a finite element model of an intramedullary implant in a bone whose size and remodelling activity is different for each individual in the population. We compare the performance of a low Young’s modulus implant (View the MathML source) to one with a higher Young’s modulus (200 GPa). Cyclic loading is applied and failure is assumed when the migration of the implant relative to the bone exceeds a threshold magnitude. The analysis for an idealised of ‘average’ patient predicts that the lower modulus device survives longer whereas the analysis simulating a clinical trial predicts no statistically-significant tendency (p=0.77) for the low modulus device to perform better. It is concluded that population-based simulations of implant performance–simulating a clinical trial–present a very valuable opportunity for more realistic computational pre-clinical testing of medical devices.

Efficacy of a powered wheelchair simulator for school aged children: A randomised controlled trial.

Purpose: To determine the efficacy of a custom made wheelchair simulation in training children to use a powered wheelchair (PWC). Design: Randomised controlled trial employing the 4C/ID-model of learning. Twenty-eight typically developing children (13M, 15F; mean age 6 years, SD 6 months) were assessed on their operation of a PWC using a functional evaluation rating scale. Participants were randomly assigned to intervention (8x 30minute training sessions using a joystick operated wheelchair simulation) or control conditions (no task), and were re-assessed on their PWC use following the intervention phase. Additional data from the simulation on completion times, errors and total scores were recorded for the intervention group. Results: Analysis of variance showed a main effect of time, with planned comparisons revealing a statistically significant change in PWC use for the intervention (p = 0.022) but not the control condition. Whilst the intervention group showed greater improvement than the controls this did not reach statistical significance. Multiple regression analyses showed that gender was predictive of pre-test (p = 0.005) functional ability. Implications: A simulated wheelchair task appears to be effective in helping children learn to operate a PWC. Greater attention should be given to female learners who underperformed when compared to their male counterparts. This low cost intervention could be easily employed at home to reduce PWC training times in children with motor disorders.

Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial: study protocol for a randomized controlled trial

Background: Acute lung injury (ALI) is a common devastating clinical syndrome characterized by life-threatening respiratory failure requiring mechanical ventilation and multiple organ failure. There are in vitro, animal studies and pre-clinical data suggesting that statins may be beneficial in ALI. The Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial is a multicenter, prospective, randomized, allocation concealed, double-blind, placebo-controlled clinical trial which aims to test the hypothesis that treatment with simvastatin will improve clinical outcomes in patients with ALI.

Methods/Design: Patients fulfilling the American-European Consensus Conference Definition of ALI will be randomized in a 1: 1 ratio to receive enteral simvastatin 80 mg or placebo once daily for a maximum of 28 days. Allocation to randomized groups will be stratified with respect to hospital of recruitment and vasopressor requirement. Data will be recorded by participating ICUs until hospital discharge, and surviving patients will be followed up by post at 3, 6 and 12 months post randomization. The primary outcome is number of ventilator-free days to day 28. Secondary outcomes are: change in oxygenation index and sequential organ failure assessment score up to day 28, number of non pulmonary organ failure free days to day 28, critical care unit mortality; hospital mortality; 28 day post randomization mortality and 12 month post randomization mortality; health related quality of life at discharge, 3, 6 and 12 months post randomization; length of critical care unit and hospital stay; health service use up to 12 months post-randomization; and safety. A total of 540 patients will be recruited from approximately 35 ICUs in the UK and Ireland. An economic evaluation will be conducted alongside the trial. Plasma and urine samples will be taken up to day 28 to investigate potential mechanisms by which simvastatin might act to improve clinical outcomes.