Neuroimaging techniques are likely to continue to improve our understanding of the brain in health and disease, but studies tend to be small, based in one imaging centre and of uncertain generalisability. Multicentre imaging studies therefore have great appeal but it is not yet clear under which circumstances data from different scanners can be combined. The successful harmonisation of multiple Magnetic Resonance Imaging (MRI) machines will increase study power, flexibility and generalisability. I have conducted a detailed study of the performance of three research MRI scanners in Scotland under the name CaliBrain, with the aims of developing reliable, valid image acquisition and analysis techniques that will facilitate multicentre MRI studies in Scotland and beyond. Fourteen healthy volunteers had two brain scans on each of three 1.5T MRI research machines in Aberdeen, Edinburgh and Glasgow. The scans usually took place 2-3 weeks apart. Each scan was performed using an identical scanning protocol consisting of a detailed structural MRI (sMRI) and a range of functional MRI (fMRI) paradigms. The quality assurance (QA) of scanner performance was monitored in all three sites over the duration of the study using a three-part protocol comprising a baseline assessment, regular measures and session specific measures. The analyses have demonstrated that the data are comparable but also that within- and between-scanner variances are evident and that harmonisation work could enhance the level of agreement. The QA data suggest that scanner performance was similar between and within machines over the course of the study. For the structural MRI scans an optimised methodology was utilised to minimise variation in brain geometry between scanners and fit all the scanned brains into a common stereotactic space, such that repeated measures analyses yielded no significant differences over time for any of the three scanners. I examined the reproducibility of the fMRI motor task within and between the three sites. Similar results were obtained in all analyses; areas consistently activated by the task include the premotor, primary motor and supplementary motor areas, the striatum and the cerebellum. Reproducibility of statistical parametric maps was evaluated within and between sites comparing the activation extent and spatial agreement of maps at both the subject and the group level. The results were within the range reported by studies examining the reproducibility of similar tasks on one scanner and reproducibility was found to be comparable within and between sites, with between site comparisons often exceeding the within site measures. A components of variance analysis showed a relatively small contribution of the factor site with subject being the main source of variation. Similar results were obtained for the working memory task. The analysis of the emotional face processing task showed poor reproducibility both within and between sites. These findings suggest that multicentre structural and functional MRI studies are feasible, at least on similar machines, when a consistent protocol is followed in all participating scanning sites, a suitable fMRI task is employed and appropriate analysis methods are used.

Meta-analysis is now commonly used in medical research. However there are statistical issues relating to the subject that require investigation and some are considered here, from both a methodological and a practical perspective. Each of the fixed effect and the random effects models for meta-analysis are based on certain assumptions and the validity of these is investigated. A formal test of the homogeneity assumption made in the fixed effect model may be performed. Since the test has low power, simulation was used to investigate the power under various conditions. The random effects model incorporates a between-study component of variance into the model. A likelihood based method was used to obtain a confidence interval for this variance and also to provide an interval for the overall treatment effect which takes into account the fact that the between-study variance is estimated, rather than assuming it to be known. In order to obtain confidence intervals for the treatment effect for both the fixed effect and the random effects models, distributional assumptions of normality are usually made. Such assumptions may be checked using q-q plots of the residuals obtained for each trial in the meta-analysis. In both meta-analysis models it is assumed that the weight allocated to each study is known, when in fact it must be estimated from the data. The effect of estimating the weights on the overall treatment effect estimate, its confidence intervals, the between-study variance estimate and the test statistic for homogeneity, is investigated by both analytic and simulation methods. It is shown how meta-analysis methods may be used to analyse multicentre trials of a paired cluster randomised design. Meta-analysis techniques are found to be preferable to previously published methods specifically developed for the analysis of such designs, which produce biased and potentially misleading results when a large treatment effect is present.

Masters Research - Masters of Philosophy / INTRODUCTION: Level III dosimetric intercomparison studies test the entire radiotherapy patient treatment chain from diagnostic imaging to treatment delivery and verification imaging at multiple radiotherapy centres. The anthropomorphic phantom employed in an intercomparison needs to meet specific criteria including portability, tissue equivalence and accommodation of radiation detectors to ensure clinical relevance and dosimetric accuracy. The proposition that a purpose-built phantom can encompass all the attributes necessary for precise Level III dosimetric intercomparisons for prostate cancer is the premise of this body of work. METHODS: Organ outlines were generated from a human computed tomography image set and incorporated into the phantom design to replicate human anatomy as closely as possible. Twenty-five points of interest were located throughout the dataset to identify where point-dose values could be measured with thermoluminescence dosimeters. The centre of the prostate was identified as the location for measurement with a small-volume ionization chamber. The materials used in this phantom were tested against water to determine relative attenuation, density and Hounsfield Units. Three materials were chosen to mimic bone, organs, and a backfill material and the phantom was manufactured using modern prototyping techniques into five separate coronal slices. Time lines and resource requirements for the phantom design and manufacture were recorded. The ability of the phantom to mimic the entire treatment chain was tested at the Calvary Mater Newcastle Hospital. RESULTS: The phantom CT images indicated the densities and organ geometries were comparable to the original patient. The phantom proved simple to load for dosimetry and rapid to assemble. Measurements indicated the reproducibility to be in the order of 1% for the ionization chamber measurement and within 3% for thermoluminescence dosimeters. Due to heat release during manufacture, small airgaps were present throughout the phantom producing artifacts on lateral images. The overall cost for production of the prototype phantom was comparable to other commercial anthropomorphic phantoms ($AU45,000). The phantom was shown to be suitable for use as a “patient” to mimic the entire treatment chain for typical external beam radiotherapy for prostate and rectal cancer. Outlining of relevant structures by a radiation oncologist was uncomplicated and the computerised treatment plan compared well with the dose measured using ionisation chambers and thermoluminescence dosimeters. DISCUSSION & CONCLUSIONS: The phantom constructed for the present study incorporates all characteristics necessary for accurate Level III intercomparison studies and will be an effective tool for an intercomparison of pelvic treatments in Australasia. These results may benefit analysis of outcomes for prostate cancer treatments, especially in the clinical trial environment. It will be of significant interest in the future to use the phantom to assess advanced radiotherapy delivery techniques such as Intensity Modulated Radiation Therapy (IMRT).

Imaging based muscle density (MD) is associated with poor lower extremity performance, the development of mobility impairments, frailty, and hip fracture. These associations are all related to falls, yet no studies have investigated MD in community dwelling fallers. The primary objective of this study was to determine whether lower leg MD differed between community dwelling elderly women who do and do not report falls. The secondary objective was to determine if lower leg muscle cross sectional area (MCSA), timed up & go (TUG) test, and relative grip strength (RGS; as a ratio to body mass) differed between fallers and non-fallers. Women (N = 135), 60 years or older (mean age 74.1, SD 7.6) were recruited from a random sample of Saskatoon residents. Fallers (n = 36) and Non-fallers (n = 99) were grouped based on 12-month retrospective falls survey response. A peripheral quantitative computed tomography (pQCT) scan of the non-dominant lower leg was acquired to determine MD and MCSA. Participant age, height, weight, TUG test result and RGS were recorded. Between-group differences in mean age, body mass index (BMI), MD, MCSA, TUG and RGS were compared using independent t-tests (P < 0.05). MD and TUG results were transformed to meet the assumption of normality for parametric analysis. Age, BMI, MCSA and RGS did not differ (P > 0.5). Fallers had 3.2% lower MD (P = 0.01) and 15.1% slower TUG scores (P = 0.02), than non-fallers. Muscle density may serve as a physiological marker for the assessment of muscular health and fall risk in community dwelling elderly women.

Imaging based muscle density (MD) is associated with poor lower extremity performance, the development of mobility impairments, frailty, and hip fracture. These associations are all related to falls, yet no studies have investigated MD in community dwelling fallers. The primary objective of this study was to determine whether lower leg MD differed between community dwelling elderly women who do and do not report falls. The secondary objective was to determine if lower leg muscle cross sectional area (MCSA), timed up & go (TUG) test, and relative grip strength (RGS; as a ratio to body mass) differed between fallers and non-fallers. Women (N = 135), 60 years or older (mean age 74.1, SD 7.6) were recruited from a random sample of Saskatoon residents. Fallers (n = 36) and Non-fallers (n = 99) were grouped based on 12-month retrospective falls survey response. A peripheral quantitative computed tomography (pQCT) scan of the non-dominant lower leg was acquired to determine MD and MCSA. Participant age, height, weight, TUG test result and RGS were recorded. Between-group differences in mean age, body mass index (BMI), MD, MCSA, TUG and RGS were compared using independent t-tests (P < 0.05). MD and TUG results were transformed to meet the assumption of normality for parametric analysis. Age, BMI, MCSA and RGS did not differ (P > 0.5). Fallers had 3.2% lower MD (P = 0.01) and 15.1% slower TUG scores (P = 0.02), than non-fallers. Muscle density may serve as a physiological marker for the assessment of muscular health and fall risk in community dwelling elderly women.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24492号 / 医博第4934号 / 新制||医||1063(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 今中 雄一, 教授 川上 浩司, 教授 妹尾 浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(社会健康医学) / 甲第24094号 / 社医博第125号 / 新制||社医||12(附属図書館) / 京都大学大学院医学研究科社会健康医学系専攻 / (主査)教授 佐藤 俊哉, 教授 中山 健夫, 教授 松田 秀一 / 学位規則第4条第1項該当 / Doctor of Public Health / Kyoto University / DFAM

Pour enrayer la progression des résistances bactériennes aux antibiotiques (AB), liée, en partie, à un mésusage de ces médicaments, l’Union européenne (UE) s’est mobilisée en adoptant, en 2001, une recommandation prônant un usage prudent des AB. En 2008, sous l’égide de la Commission européenne, nous avons évalué la mise en œuvre de cette recommandation et son impact dans les Etats membres, et nous avons réalisé une analyse du cadre juridique développé dans 12 de ces Etats. De plus, une étude a été conduite entre 2005 et 2009 sur 74 établissements de santé (ES) volontaires du Sud-Ouest de la France pour identifier l’impact du cadre juridique sur l’évolution des consommations d’AB. Les Etats de l’UE ont engagé un grand nombre d’actions pour rationaliser l’utilisation des AB, mais des progrès dans le champ de l’évaluation demeurent nécessaires. Il ressort de l’analyse sur 12 Etats qu’un cadre juridique plus important semble associé à une plus grande sensibilisation de la population générale et à une meilleure maîtrise de la consommation de fluoroquinolones. Dans les ES du Sud-Ouest, les politiques locales de bon usage des AB ont progressé. Une combinaison de mesures telles que la présence d’un référent « AB », l’organisation de formations et le recours à des prescriptions à durée limitée, était associée à une réduction significative de la consommation des fluoroquinolones. L’amélioration de l’utilisation des AB implique de préciser les conditions d’efficacité optimale des actions et de renforcer l’encadrement juridique dans les Etats de l’UE, notamment en matière de surveillance, d’évaluation, de moyens d’incitation, en l’adaptant aux caractéristiques nationales. / Antimicrobial resistance (AMR) is a public health problem worldwide. As antibiotic (AB) use is one of the drivers of AMR, the Council of the European Union adopted in 2001 a recommendation on the prudent use of antimicrobial agents. To analyze the way Member States (MS) had implemented this recommendation and to approach its efficacy, we performed a survey under the auspices of the European Commission in 2008, completed by a thorough analysis of the legal framework in twelve Member States. In addition, relationships between AB stewardship programmes (ABS) and trends in AB consumption were studied from 2005 to 2009 in 74 voluntary hospitals in Southwestern France. MS had implemented a broad range of activities to improve AB use, but differences were seen namely in evaluation systems. Further analysis in 12 MS highlighted discrepancies regarding the scope of the legal framework, incentives for its enforcement, and means of evaluation. A legal framework regarding surveillance and national organisation seemed in favor of higher citizens’ knowledge and awareness and appeared to be associated with lower increase in fluoroquinolone (FQ) use. In French hospitals, ABS had sharply improved and AB consumption remained stable when adjusted on activity. The presence of an antibiotic advisor combined with provision of training and use of prescriptions with stop-orders was associated with a significant decrease in FQ use. Progress in the use of AB could be achieved by sharing experience on best practices and by enforcing legal framework, tailored to MS organisation and epidemiology, targeting activities such as surveillance and evaluation

Work deals with methods of calibration of multi-center study of magnetic resonance imaging. Magnetic resonance is the phenomenon of the substance in a magnetic field of induction B0 delivers energy in the form of RF pulse with the Larmor frequency and thus to excite particles to higher energy levels. Calibration can be performed using the distinctive and homogeneous RF phantoms. Furthermore, we can perform calibration using image registration. To calibrate the images by registering the work described in the classical linear (affine) and nonlinear. Listed below are the simulators, which are also useful for modeling various artifacts.

Strategies on informed consent process and capacity monitoring for mild dementia research are at developing state. We reflected on our experience and found that the successful collection of informed consent and full participation of PwD required the involvement of familiar healthcare professionals/care workers/staff at the recruitment and data collection stages and this needs to occur in an active support environment. Time is another important factor affecting the success of the study.