Characterising in situ activation and degradation of hindered amine light stabilisers using liquid extraction surface analysis-mass spectrometry

Changes in the molecular structure of polymer antioxidants such as hindered amine light stabilisers (HALS) is central to their efficacy in retarding polymer degradation and therefore requires careful monitoring during their in-service lifetime. The HALS, bis-(1-octyloxy-2,2,6,6-tetramethyl-4-piperidinyl) sebacate (TIN123) and bis-(1,2,2,6,6-pentamethyl-4-piperidinyl) sebacate (TIN292), were formulated in different polymer systems and then exposed to various curing and ageing treatments to simulate in-service use. Samples of these coatings were then analysed directly using liquid extraction surface analysis (LESA) coupled with a triple quadrupole mass spectrometer. Analysis of TIN123 formulated in a cross-linked polyester revealed that the polymer matrix protected TIN123 from undergoing extensive thermal degradation that would normally occur at 292 degrees C, specifically, changes at the 1- and 4-positions of the piperidine groups. The effect of thermal versus photo-oxidative degradation was also compared for TIN292 formulated in polyacrylate films by monitoring the in situ conversion of N-CH3 substituted piperidines to N-H. The analysis confirmed that UV light was required for the conversion of N-CH3 moieties to N-H - a major pathway in the antioxidant protection of polymers - whereas this conversion was not observed with thermal degradation. The use of tandem mass spectrometric techniques, including precursor-ion scanning, is shown to be highly sensitive and specific for detecting molecular-level changes in HALS compounds and, when coupled with LESA, able to monitor these changes in situ with speed and reproducibility. (C) 2013 Elsevier B. V. All rights reserved.

A comparison of surface doses for very small field size x-ray beams : Monte Carlo calculations and radiochromic film measurements

Stereotactic radiosurgery treatments involve the delivery of very high doses for a small number of fractions. To date, there is limited data in terms of the skin dose for the very small field sizes used in these treatments. In this work, we determine relative surface doses for small size circular collimators as used in stereotactic radiosurgery treatments. Monte Carlo calculations were performed using the BEAMnrc code with a model of the Novalis 15 Trilogy linear accelerator and the BrainLab circular collimators. The surface doses were calculated at the ICRU skin dose depth of 70 m all using the 6 MV SRS x-ray beam. The calculated surface doses varied between 15 – 12% with decreasing values as the field size increased from 4 to 30 mm. In comparison, surface doses were measured using Gafchromic EBT3 film positioned at the surface of a Virtual Water phantom. The absolute agreement between calculated and measured surface doses was better than 2.5% which is well within the 20 uncertainties of the Monte Carlo calculations and the film measurements. Based on these results, we have shown that the Gafchromic EBT3 film is suitable for surface dose estimates in very small size fields as used in SRS.

Predicting the likelihood of QA failure using treatment plan accuracy metrics

This study used automated data processing techniques to calculate a set of novel treatment plan accuracy metrics, and investigate their usefulness as predictors of quality assurance (QA) success and failure. 151 beams from 23 prostate and cranial IMRT treatment plans were used in this study. These plans had been evaluated before treatment using measurements with a diode array system. The TADA software suite was adapted to allow automatic batch calculation of several proposed plan accuracy metrics, including mean field area, small-aperture, off-axis and closed-leaf factors. All of these results were compared the gamma pass rates from the QA measurements and correlations were investigated. The mean field area factor provided a threshold field size (5 cm2, equivalent to a 2.2 x 2.2 cm2 square field), below which all beams failed the QA tests. The small aperture score provided a useful predictor of plan failure, when averaged over all beams, despite being weakly correlated with gamma pass rates for individual beams. By contrast, the closed leaf and off-axis factors provided information about the geometric arrangement of the beam segments but were not useful for distinguishing between plans that passed and failed QA. This study has provided some simple tests for plan accuracy, which may help minimise time spent on QA assessments of treatments that are unlikely to pass.

Retrospective evaluation of dosimetric quality for prostate carcinomas treated with 3D conformal, intensity-modulated and volumetric-modulated arc radiotherapy

Introduction This study examines and compares the dosimetric quality of radiotherapy treatment plans for prostate carcinoma across a cohort of 163 patients treated across 5 centres: 83 treated with three-dimensional conformal radiotherapy (3DCRT), 33 treated with intensity-modulated radiotherapy (IMRT) and 47 treated with volumetric-modulated arc therapy (VMAT). Methods Treatment plan quality was evaluated in terms of target dose homogeneity and organ-at-risk sparing, through the use of a set of dose metrics. These included the mean, maximum and minimum doses; the homogeneity and conformity indices for the target volumes; and a selection of dose coverage values that were relevant to each organ-at-risk. Statistical significance was evaluated using two-tailed Welch’s T-tests. The Monte Carlo DICOM ToolKit software was adapted to permit the evaluation of dose metrics from DICOM data exported from a commercial radiotherapy treatment planning system. Results The 3DCRT treatment plans offered greater planning target volume dose homogeneity than the other two treatment modalities. The IMRT and VMAT plans offered greater dose reduction in the organs-at-risk: with increased compliance with recommended organ-at-risk dose constraints, compared to conventional 3DCRT treatments. When compared to each other, IMRT and VMAT did not provide significantly different treatment plan quality for like-sized tumour volumes. Conclusions This study indicates that IMRT and VMAT have provided similar dosimetric quality, which is superior to the dosimetric quality achieved with 3DCRT.

Influence of different nitrogen rates and DMPP nitrification inhibitor on annual N2O emissions from a subtropical wheat–maize cropping system

Global cereal production will need to increase by 50% to 70% to feed a world population of about 9 billion by 2050. This intensification is forecast to occur mostly in subtropical regions, where warm and humid conditions can promote high N2O losses from cropped soils. To secure high crop production without exacerbating N2O emissions, new nitrogen (N) fertiliser management strategies are necessary. This one-year study evaluated the efficacy of a nitrification inhibitor (3,4-dimethylpyrazole phosphate—DMPP) and different N fertiliser rates to reduce N2O emissions in a wheat–maize rotation in subtropical Australia. Annual N2O emissions were monitored using a fully automated greenhouse gas measuring system. Four treatments were fertilized with different rates of urea, including a control (40 kg-N ha−1 year−1), a conventional N fertiliser rate adjusted on estimated residual soil N (120 kg-N ha−1 year−1), a conventional N fertiliser rate (240 kg-N ha−1 year−1) and a conventional N fertiliser rate (240 kg-N ha−1 year−1) with nitrification inhibitor (DMPP) applied at top dressing. The maize season was by far the main contributor to annual N2O emissions due to the high soil moisture and temperature conditions, as well as the elevated N rates applied. Annual N2O emissions in the four treatments amounted to 0.49, 0.84, 2.02 and 0.74 kg N2O–N ha−1 year−1, respectively, and corresponded to emission factors of 0.29%, 0.39%, 0.69% and 0.16% of total N applied. Halving the annual conventional N fertiliser rate in the adjusted N treatment led to N2O emissions comparable to the DMPP treatment but extensively penalised maize yield. The application of DMPP produced a significant reduction in N2O emissions only in the maize season. The use of DMPP with urea at the conventional N rate reduced annual N2O emissions by more than 60% but did not affect crop yields. The results of this study indicate that: (i) future strategies aimed at securing subtropical cereal production without increasing N2O emissions should focus on the fertilisation of the summer crop; (ii) adjusting conventional N fertiliser rates on estimated residual soil N is an effective practice to reduce N2O emissions but can lead to substantial yield losses if the residual soil N is not assessed correctly; (iii) the application of DMPP is a feasible strategy to reduce annual N2O emissions from sub-tropical wheat–maize rotations. However, at the N rates tested in this study DMPP urea did not increase crop yields, making it impossible to recoup extra costs associated with this fertiliser. The findings of this study will support farmers and policy makers to define effective fertilisation strategies to reduce N2O emissions from subtropical cereal cropping systems while maintaining high crop productivity. More research is needed to assess the use of DMPP urea in terms of reducing conventional N fertiliser rates and subsequently enable a decrease of fertilisation costs and a further abatement of fertiliser-induced N2O emissions.

Translational approaches to medication development

Alcohol accounts for major disability worldwide and available treatments are insufficient. A massive growth in the area of addiction neuroscience over the last several decades has not resulted in a corresponding expansion of treatment options available to patients. In this chapter, we describe our experience with building translational research programs aimed at developing novel pharmacotherapies for alcoholism. The narrative is based on experience and considerations made in the course of building these programs, and work on four mechanisms targeted by our libraries: cholinergic nicotine receptors, receptors for corticotropin-releasing hormone (CRH), neurokinin 1 (NK1) receptors for substance P (SP) and hypocretin/orexin receptors. Around this experience, we discuss issues we believe to be critical for successful translation of basic addiction neuroscience into treatments, and complementarities between academic and other actors that in our assessment need to be harnessed in order to bring treatments to the clinic.

Social ecological influences on preferences for care provided at the end of life amongst Taiwanese city-dwelling adults

Social and cultural elements are an essential part of the contexts within which people understand their word and make end-of-life decisions. A developmental social ecological model was used in this thesis to provide a comprehensive framework for examining influences on end-of-life preferences. The findings support claims made by social ecologists that individual's health-related choices can be influenced by cultural, social contextual and environmental factors over the course of life. The results of this study have implications for health professionals and the practices they can adopt to enhance end-of-life care.

Use of simple pharmacokinetic modeling to characterize exposure of Australians to perfluorooctanoic acid and perfluorooctane sulfonic acid

Perflurooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) have been used for a variety of applications including fluoropolymer processing, fire-fighting foams and surface treatments since the 1950s. Both PFOS and PFOA are polyfluoroalkyl chemicals (PFCs), man-made compounds that are persistent in the environment and humans; some PFCs have shown adverse effects in laboratory animals. Here we describe the application of a simple one compartment pharmacokinetic model to estimate total intakes of PFOA and PFOS for the general population of urban areas on the east coast of Australia. Key parameters for this model include the elimination rate constants and the volume of distribution within the body. A volume of distribution was calibrated for PFOA to a value of 170ml/kgbw using data from two communities in the United States where the residents' serum concentrations could be assumed to result primarily from a known and characterized source, drinking water contaminated with PFOA by a single fluoropolymer manufacturing facility. For PFOS, a value of 230ml/kgbw was used, based on adjustment of the PFOA value. Applying measured Australian serum data to the model gave mean+/-standard deviation intake estimates of PFOA of 1.6+/-0.3ng/kgbw/day for males and females >12years of age combined based on samples collected in 2002-2003 and 1.3+/-0.2ng/kg bw/day based on samples collected in 2006-2007. Mean intakes of PFOS were 2.7+/-0.5ng/kgbw/day for males and females >12years of age combined based on samples collected in 2002-2003, and 2.4+/-0.5ng/kgbw/day for the 2006-2007 samples. ANOVA analysis was run for PFOA intake and demonstrated significant differences by age group (p=0.03), sex (p=0.001) and date of collection (p<0.001). Estimated intake rates were highest in those aged >60years, higher in males compared to females, and higher in 2002-2003 compared to 2006-2007. The same results were seen for PFOS intake with significant differences by age group (p<0.001), sex (p=0.001) and date of collection (p=0.016).

Polycaprolactone scaffold and reduced rhBMP-7 dose for the regeneration of critical-sized defects in sheep tibiae

The transplantation of autologous bone graft as a treatment for large bone defects has the limitation of harvesting co-morbidity and limited availability. This drives the orthopaedic research community to develop bone graft substitutes. Routinely, supra-physiological doses of bone morphogenetic proteins (BMPs) are applied perpetuating concerns over undesired side effects and cost of BMPs. We therefore aimed to design a composite scaffold that allows maintenance of protein bioactivity and enhances growth factor retention at the implantation site. Critical-sized defects in sheep tibiae were treated with the autograft and with two dosages of rhBMP-7, 3.5 mg and 1.75 mg, embedded in a slowly degradable medical grade poly(ε-caprolactone) (PCL) scaffold with β-tricalcium phosphate microparticles (mPCL-TCP). Specimens were characterised by biomechanical testing, microcomputed tomography and histology. Bridging was observed within 3 months for the autograft and both rhBMP-7 treatments. No significant difference was observed between the low and high rhBMP-7 dosages or between any of the rhBMP-7 groups and autograft implantation. Scaffolds alone did not induce comparable levels of bone formation compared to the autograft and rhBMP-7 groups. In summary, the mPCL-TCP scaffold with the lower rhBMP-7 dose led to equivalent results to autograft transplantation or the high BMP dosage. Our data suggest a promising clinical future for BMP application in scaffold-based bone tissue engineering, lowering and optimising the amount of required BMP.

Lumbar epidural steroids are not cost effective in sciatica

Background Lumbar Epidural Steroids Injections (ESI’s) have previously been shown to provide some degree of pain relief in sciatica. Number Needed To Treat (NNT) to achieve 50% pain relief has been estimated at 7 from the results of randomised controlled trials. Pain relief is temporary. They remain one of the most commonly provided procedures in the UK. It is unknown whether this pain relief represents good value for money. Methods 228 patients were randomised into a multi-centre Double Blind Randomised Controlled Trial. Subjects received up to 3 ESI’s or intra-spinous saline depending on response and fall off with the first injection. All other treatments were permitted. All received a review of analgesia, education and physical therapy. Quality of life was assessed using the SF36 at 6 points and compared using independent sample t-tests. Follow up was up to 1 yr. Missing data was imputed using last observation carried forward (LOCF). QALY’s (Quality of Life Years) were derived from preference based heath values (summary health utility score). SF-6D health state classification was derived from SF-36 raw score data. Standard gambles (SG) were calculated using Model 10. SG scores were calculated on trial results. LOCF was not used for this. Instead average SG were derived for a subset of patients with observations for all visits up to week 12. Incremental QALY’s were derived as the difference in the area between the SG curve for the active group and placebo group. Results SF36 domains showed a significant improvement in pain at week 3 but this was not sustained (mean 54 Active vs 61 Placebo P<0.05). Other domains did not show any significant gains compared with placebo. For derivation of SG the number in the sample in each period differed. In week 12, average SG scores for active and placebo converged. In other words, the health gain for the active group as measured by SG was achieved by the placebo group by week 12. The incremental QALY gained for a patient under the trial protocol compared with the standard care package was 0.0059350. This is equivalent to an additional 2.2 days of full health. The cost per QALY gained to the provider from a patient management strategy administering one epidural as suggested by results was £25 745.68. This result was derived assuming that the gain in QALY data calculated for patients under the trial protocol would approximate that under a patient management strategy based on the trial results (one ESI). This is above the threshold suggested by some as a cost effective treatment. Conclusions The transient benefit in pain relief afforded by ESI’s does not appear to be cost-effective. Further work is needed to develop more cost-effective conservative treatments for sciatica.

Review: "Controversies in Health Law" by In Freckelton and Kerry Peterson

During the past couple of decades health law has been transformed. Within that period we have been confronted with advances in medical science, particularly in genetics, reproductive technology and life-sustaining treatments. Health care has become more expensive, more consumer oriented and more litigious. In addition, the ethical implications of these developments, and the role for law, both as a regulator of health care and in its responses to emerging challenges, have occupied policy-makers, law reformers, health professionals, ethicists and the broader community in Australia and overseas. While many issues have emerged from these developments, there have been few easy solutions...

A systematic review and meta-analysis : tailoring asthma treatment on eosinophilic markers (exhaled nitric oxide or sputum eosinophils)

Asthma severity and control can be measured both subjectively and objectively. Traditionally asthma treatments have been individualised using symptoms and spirometry/peak flow. Increasingly treatment tailored in accordance with inflammatory markers (sputum eosinophil counts or fractional exhaled nitric oxide (FeNO) data) is advocated as an alternative strategy. The objective of this review was to evaluate the efficacy of tailoring asthma interventions based on inflammatory markers (sputum analysis and FeNO) in comparison with clinical symptoms (with or without spirometry/peak flow) for asthma-related outcomes in children and adults. Cochrane Airways Group Specialised Register of Trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and reference lists of articles were searched. The last searches were in February 2009. All randomised controlled comparisons of adjustment of asthma treatment based on sputum analysis or FeNO compared with traditional methods (primarily clinical symptoms and spirometry/peak flow) were selected. Results of searches were reviewed against predetermined criteria for inclusion. Relevant studies were selected, assessed and data extracted independently by at least two people. The trial authors were contacted for further information. Data were analysed as 'intervention received' and sensitivity analyses performed. Six (2 adults and 4 children/adolescent) studies utilising FeNO and three adult studies utilising sputum eosinophils were included. These studies had a degree of clinical heterogeneity including definition of asthma exacerbations, duration of study and variations in cut-off levels for percentage of sputum eosinophils and FeNO to alter management in each study. Adults who had treatment adjusted according to sputum eosinophils had a reduced number of exacerbations compared with the control group (52 vs. 77 patients with >=1 exacerbation in the study period; p=0.0006). There was no significant difference in exacerbations between groups for FeNO compared with controls. The daily dose of inhaled corticosteroids at the end of the study was decreased in adults whose treatment was based on FeNO in comparison with the control group (mean difference -450.03 mug, 95% CI -676.73 to -223.34; p<0.0001). However, children who had treatment adjusted according to FeNO had an increase in their mean daily dose of inhaled corticosteroids (mean difference 140.18 mug, 95% CI 28.94 to 251.42; p=0.014). It was concluded that tailoring of asthma treatment based on sputum eosinophils is effective in decreasing asthma exacerbations. However, tailoring of asthma treatment based on FeNO levels has not been shown to be effective in improving asthma outcomes in children and adults. At present, there is insufficient justification to advocate the routine use of either sputum analysis (due to technical expertise required) or FeNO in everyday clinical practice.

Review : "Genetic Privacy: A challenge to Medico-Legal Norms" by Laurie, G

The discovery by Watson and Crick of the structure of DNA is one of the great scientific discoveries. In the period since that discovery new areas of genetic research have opened up which hold out the hope of developing treatments or cures for many illnesses and diseases. Yet with these discoveries have also come an array of ethical and legal dilemmas about the use of genetic information and concerns about the potential for those with genetic diseases or conditions to be stigmatised and discriminated against. The discussion about the developments in genetic science has become increasingly, a debate about the use of genetic information within our society. Graeme Laurie’s book, Genetic Privacy: A Challenge to Medico-Legal Norms, guides the reader through the complexities of these debates by considering what we mean by privacy and asking whether our existing concepts are adequate to meet the challenges posed by the new genetics.

Model-driven service engineering in home telecare

Health care systems are highly dynamic not just due to developments and innovations in diagnosis and treatments, but also by virtue of emerging management techniques supported by modern information and communication technology. A multitude of stakeholders such as patients, nurses, general practitioners or social carers can be integrated by modeling complex interactions necessary for managing the provision and consumption of health care services. Furthermore, it is the availability of Service-oriented Architecture (SOA) that supports those integration efforts by enabling the flexible and reusable composition of autonomous, loosely-coupled and web-enabled software components. However, there is still the gap between SOA and predominantly business-oriented perspectives (e.g. business process models). The alignment of both views is crucial not just for the guided development of SOA but also for the sustainable evolution of holistic enterprise architectures. In this paper, we combine the Semantic Object Model (SOM) and the Business Process Modelling Notation (BPMN) towards a model-driven approach to service engineering. By addressing a business system in Home Telecare and deriving a business process model, which can eventually be controlled and executed by machines; in particular by composed web services, the full potential of a process-centric SOA is exploited.

Treatment plan complexity metrics for predicting IMRT pre-treatment quality assurance results

The planning of IMRT treatments requires a compromise between dose conformity (complexity) and deliverability. This study investigates established and novel treatment complexity metrics for 122 IMRT beams from prostate treatment plans. The Treatment and Dose Assessor software was used to extract the necessary data from exported treatment plan files and calculate the metrics. For most of the metrics, there was strong overlap between the calculated values for plans that passed and failed their quality assurance (QA) tests. However, statistically significant variation between plans that passed and failed QA measurements was found for the established modulation index and for a novel metric describing the proportion of small apertures in each beam. The ‘small aperture score’ provided threshold values which successfully distinguished deliverable treatment plans from plans that did not pass QA, with a low false negative rate.