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Activation of mitogen/extracellular-signal-regulated kinase kinase 5/extracellular signal-regulated kinase-5 (MEK5/ERK5) growth signalling is coupled to increased cell proliferation in prostate cancer (PCa). Dysregulation of the DNA replication licensing pathway, a critical step in growth control downstream of transduction signalling pathways, is associated with development of PCa. In this study we have investigated linkages between the MEK5/ERK5 pathway and DNA replication licensing during prostate carcinogenesis. The effects of increased MEK5/ERK5 signalling on the expression of replication licensing factors Mcm2 and geminin and the proliferation marker Ki67 were studied in an ecdysone-inducible system expressing a constitutively activated mutant of MEK5 in EcR293 cells and in stable ERK5 over-expressing PC3 clones. In parallel, expression of these biomarkers in PCa biopsy specimens (n=58) was studied and compared to clinicopathological parameters. In both in vitro systems induction of MEK5 expression resulted in increased levels of phosphorylated ERK5 and Mcm2, geminin and Ki67 proteins. In PCa specimens average Mcm2 expression was greater than Ki67 and geminin expression (median labelling index (LI) 36.7, 18.1, and 3.4% respectively), consistent with their differential expression according to growth status (P<0.0001). Mcm2, geminin and Ki67 expression were significantly associated with Gleason grade (P=0.0002, P=0.0003, P=0.004); however there was no link with T or M stage. There was a significant relationship between increasing ERK5 expression and increasing Mcm2 (P=0.003) and Ki67 (P=0.009) expression, with non-significant trends seen with increasing MEK5 expression. There were significant associations between Gleason grade and the number of cells traversing G1 phase (Ki67LI-gemininLI; (P=0.001)), with high ERK5 levels associated with both an increase in replication licensed but non-cycling cells (Mcm2LI-Ki67LI; (P=0.01)) and accelerated cell cycle progression (gemininLI/ Ki67LI; (P= 0.005)), all indicative of a shift towards increasing proliferative potential. While Mcm2 and Ki67 were both prognostic factors on univariate analysis, only Mcm2 remained an independent prognostic marker on multivariate analysis. Taken together, our data show that induction of MEK5/ERK5 signalling is linked to activation of the DNA replication licensing pathway in PCa, and that the strong prognostic value of MCM proteins may result from their function as relay stations coupling growth regulatory pathways to genome duplication. \u00a9 2007 Cancer Research.
\n \n\n \n \nBackground: Declining physical activity is associated with a rising burden of global disease. Efforts to reverse this trend have not been successful. We aimed to assess the efficacy of a facilitated behavioural intervention to increase the physical activity of sedentary individuals at familial risk of diabetes. Methods: We enrolled 365 sedentary adults who had a parental history of type 2 diabetes. They were recruited from either diabetes or family history registers at 20 general practice clinics in the UK. Eligible participants were randomly assigned to one of two intervention groups, or to a comparison group. All participants were posted a brief advice leaflet. One intervention group was offered a 1-year behaviour-change programme, to be delivered by trained facilitators in participants' homes, and the other the same programme by telephone. The programme was designed to alter behavioural determinants, as defined by the theory of planned behaviour, and to teach behaviour-change strategies. The principal outcome at 1 year was daytime physical activity, which was objectively measured as a ratio to resting energy expenditure. Analysis was by intention to treat. This study is registered as ISRCTN61323766. Findings: Of 365 patients, we analysed primary endpoints for 321 (88%) for whom we had data after 1 year of follow-up. At 1 year, the physical-activity ratio of participants who received the intervention, by either delivery route, did not differ from the ratio in those who were given a brief advice leaflet. The mean difference in daytime physical-activity ratio, adjusted for baseline, was -0\u00b704 (95% CI -0\u00b716 to 0\u00b708). The physical-activity ratio did not differ between participants who were delivered the intervention face-to-face or by telephone (mean difference -0\u00b705; 95% CI -0\u00b719 to 0\u00b710). Interpretation: A facilitated theory-based behavioural intervention was no more effective than an advice leaflet for promotion of physical activity in an at-risk group; therefore health-care providers should remain cautious about commissioning behavioural programmes into individual preventive health-care services. \u00a9 2008 Elsevier Ltd. All rights reserved.
\n \n\n \n \nPurpose: The origin licensing factors minichromosome maintenance 2 (Mcm2) and Geminin have recently been identified as critical regulators of growth and differentiation. Here we have investigated the regulation of these licensing factors together with Ki67 to further elucidate the cell cycle kinetics of renal cell carcinoma (RCC). Furthermore, we have examined the role of Ki67, Mcm2, and Geminin in disease-free survival after nephrectomy in patients with localized RCC. Experimental Design: Tissue sections from 176 radical nephrectomy specimens were immunohistochemically stained with Mcm2, Geminin, and Ki67 antibodies. Labeling indices (LI) for these markers were compared with clinicopathologic parameters (median follow-up 44 months). Results: In RCC, Mcm2 is expressed at much higher levels than Ki-67 and Geminin, respectively [medians 41.6%, 7.3%, and 3.5% (P < 0.001)] and was most closely linked to tumor grade (P < 0.001). For each marker, Kaplan-Meier survival curves provided strong evidence that increased expression is associated with reduced disease-free survival time (P < 0.001). Additionally, an Mcm2 - Ki67 LI identified a unique licensed but nonproliferating population of tumor cells that increased significantly with tumor grade (P = 0.004) and was also of prognostic value (P = 0.01). On multivariate analysis, grade, vascular invasion, capsular invasion, Ki67 LI >12%, and age were found to be independent prognostic markers. Conclusions: Although Ki67 is identified as an independent prognostic marker, semiquantitative assessment is difficult due to the very low proliferative fraction identified by this marker. In contrast, Mcm2 identifies an increased growth fraction that is closely linked to grade, provides prognostic information, and is amenable to semiquantitative analysis in routine pathologic assessment. \u00a9 2005 American Association for Cancer Research.
\n \n\n \n \nTom Fanshawe looks at the statistical theory that judges the winner of disciplines that combine several separate elements. \u00a9 2012 The Royal Statistical Society.
\n \n\n \n \nWe present a comprehensive review of multivariate geostatistical models, focusing on the bivariate case. We compare in detail three approaches, the linear model of coregionalisation, the common component model and the kernel convolution approach, and discuss similarities between them. We demonstrate the merits of the common component class of models as a flexible means for modelling bivariate geostatistical data of the type that frequently arises in environmental applications. In particular, we show how kernel convolution can be used to approximate the common component model, and demonstrate the method using a data-set of calcium and magnesium concentrations in soil samples. We then apply the model to a study of domestic radon concentrations in the city of Winnipeg, Canada, in which exposure was measured at two sites (bedroom and basement) in each residential location. Our analysis demonstrates that in this study the correlation between the two sites within each house dominates the short-range spatial correlation typical of the distribution of radon. \u00a9 2011 Springer Science+Business Media, LLC.
\n \n\n \n \nGreat disasters can bring forth great courage. Tom Fanshawe finds that the bravery and self-sacrifice of the men, women and children in a small Derbyshire village 350 years ago have helped to trace the way that epidemics spread and fade. \u00a9 2012 The Royal Statistical Society.
\n \n\n \n \nStandard analyses of spatial data assume that measurement and prediction locations are measured precisely. In this paper we consider how appropriate methods of estimation and prediction change when this assumption is relaxed and the locations are subject to positional error. We describe basic models for positional error and assess their impact on spatial prediction. Using both simulated data and lead concentration pollution data from Galicia, Spain, we show how the predictive distributions of quantities of interest change after allowing for the positional error, and describe scenarios in which positional errors may affect the qualitative conclusions of an analysis. The subject of positional error is of particular relevance in assessing the exposure of an individual to an environmental pollutant when the position of the individual is tracked using imperfect measurement technology. \u00a9 2010 John Wiley & Sons, Ltd..
\n \n\n \n \nAims and method: To systematically review the published literature with respect to formulating a dose-response curve for flupentixol decanoate. A systematic literature search using the Cochrane Database was performed for studies that published both dosage information and data on relapse rates. Results: The data showed modest effects of dose on survival rates. Increasing dose may be associated with increased survival rates up to around 50-60 mg of flupentixol decanoate every 4 weeks. There was no evidence of increased survival rates at higher doses and higher doses may be associated with lower rates of survival. There is considerable uncertainty as to the true effects of dose of flupentixol decanoate on relapse rates. Clinical implications: There is no evidence that survival rates improve for doses above 50-60 mg every 4 weeks. These doses are much lower than doses commonly prescribed. Clinicians may wish to consider these data when prescribing flupentixol decanoate. Declaration of interest: None.
\n \n\n \n \nDeveloping more effective behavioural interventions requires an understanding of the mechanisms of behaviour change, and methods to rigorously test their theoretical basis. The delivery and theoretical basis of an intervention protocol were assessed in ProActive, a UK trial of an intervention to increase the physical activity of those at risk of Type 2 diabetes (N = 365). In 108 intervention sessions, behaviours of facilitators were mapped to four theories that informed intervention development and behaviours of participants were mapped to 17 theoretical components of these four theories. The theory base of the intervention specified by the protocol was different than that delivered by facilitators, and that received by participants. Of the intervention techniques delivered, 25% were associated with theory of planned behaviour (TPB), 42% with self-regulation theory (SRT), 24% with operant learning theory (OLT) and 9% with relapse prevention theory (RPT). The theoretical classification of participant talk showed a different pattern, with twice the proportion associated with OLT (48%), 21% associated with TPB, 31% with SRT and no talk associated with RPT. This study demonstrates one approach to assessing the extent to which the theories used to guide intervention development account for any changes observed.
\n \n\n \n \nAssessing fidelity of behavioural interventions is important, but demanding and rarely done. This study assessed adherence to behaviour change techniques used in an intervention to increase physical activity among sedentary adults (ProActive; N = 365). Transcripts of 108 sessions with a sub-sample of 27 participants were assessed. An independent assessor coded adherence of four 'facilitators' who delivered the intervention to 208 protocol-specified facilitator behaviours (e.g. 'elicit perceived advantages of becoming more active') in four key sessions. Four raters classified the 208 behaviours under 14 techniques (e.g., goal setting, use of rewards) to enable calculation of adherence to techniques. Observed adherence to techniques across participants was modest (median 44%, IQR 35-62%), and lower than that reported by facilitators. Adherence differed between facilitators (range: 26-63%) and decreased across the four sessions (mean drop 9% per session, 95% confidence interval 7-11%). In this small sample facilitator adherence was unrelated to (change in) participants' physical activity or its cognitive predictors: Attitudes, subjective norm, perceived behavioural control and intention. Future research should investigate causal pathways between fidelity indicators and outcomes in larger samples and develop and test less intensive measures of fidelity.
\n \n\n \n \nStudies investigating associations between air pollution exposure and health outcomes benefit from the estimation of exposures at the individual level, but explicit consideration of the spatio-temporal variation in exposure is relatively new in air pollution epidemiology. We address the problem of estimating spatially and temporally varying particulate matter concentrations (black smoke = BS = PM4) using data routinely collected from 20 monitoring stations in Newcastle-upon-Tyne between 1961 and 1992. We propose a two-stage strategy for modelling BS levels. In the first stage, we use a dynamic linear model to describe the long-term trend and seasonal variation in area-wide average BS levels. In the second stage, we account for the spatio-temporal variation between monitors around the area-wide average in a linear model that incorporates a range of spatio-temporal covariates available throughout the study area, and test for evidence of residual spatio-temporal correlation. We then use the model to assign time-aggregated predictions of BS exposure, with associated prediction variances, to each singleton pregnancy that occurred in the study area during this period, guided by dates of conception and birth and mothers' residential locations. In work to be reported separately, these exposure estimates will be used to investigate relationships between maternal exposure to BS during pregnancy and a range of birth outcomes. Our analysis demonstrates how suitable covariates can be used to explain residual spatio-temporal variation in individual-level exposure, thereby reducing the need to model the residual spatio-temporal correlation explicitly. Copyright \u00a9 2007 John Wiley & Sons, Ltd.
\n \n\n \n \nObjectives: To measure the reliability of tooth length measurements taken using dental pantomograms (DPT), long cone periapical radiographs (PR), and cone beam computed tomography (CBCT) and to compare their effective radiation dose. Subjects and methods: A model containing sixteen anterior teeth was used to simulate a patient undergoing fixed appliance treatment. PRs were taken at standardized vertical angulations to the occlusal plane (0, 5, 10, 15, and 20\u00b0) using conventional and digital techniques. DPT and CBCT images were also taken. Measurements of radiation dosages were used to estimate a risk benefit analysis for each of the techniques. Results: DPT consistently overestimated tooth lengths by 2 mm or more [mean: 2.34 mm; 95% confidence interval (CI): 1.4-3.3 mm]. CBCT consistently underestimated tooth length (mean: 20.89 mm; 95% CI: 20.44 to 21.33 mm). PRs taken at 90\u00b0 angulation closely resembled the actual tooth length (mean: 20.14 mm; 95% CI: 20.64 to 0.37 mm), but overestimation occurred with increasing PR film angulation. The radiation dosages ranged widely: DPT plus eight PRs that would be necessary to assess all teeth and root length of the upper and lower labial segments amounted to 23 \u03bcSv. Radiation dose from CBCT ranged from 17.8 to 60 \u03bcSv, depending on equipment and settings. \u00a9 2013 British Orthodontic Society.
\n \n\n \n \nBackground: Osteoarthritis of the first metatarsophalangeal joint (hallux rigidus) leads to pain and poor function and mobility. Arthrodesis is the gold standard treatment for end-stage disease. Total joint arthroplasties have been attempted, but early loosening has been attributed to dorsally directed shear forces on the metatarsal component. Metallic proximal phalangeal hemiarthroplasty theoretically avoids this. Whilst early results are promising, no comparative trials exist comparing this to arthrodesis.Methods/Design: The primary objectives are to determine the range of outcome scores between the two treatment arms (to inform a power calculation). Outcome measures will include the MOXFQ, AOFAS-Hallux and EuroQol EQ-5D-5 L. Secondary objectives are to determine the accrual rate, dropout rate and trial acceptability to both patients and surgeons. These data will allow the development of a larger trial with longer follow-up.This is a prospective randomised controlled single-centre study comparing proximal phalanx hemiarthroplasty (AnaToemic, Arthrex Ltd., Sheffield, UK) with arthrodesis (15 patients in each arm). Randomisation will be performed using a 1:1 allocation ratio in blocks of six.Patients meeting the eligibility criteria will be recruited from three foot and ankle consultant surgeon's clinics (East Lancashire Hospitals NHS Trust). If agreeable, informed consent will be obtained before patients are randomised.The outcome measure scores will be completed pre-operatively and repeated at 6 weeks, 3 months and 12 months. A radiological review will be performed at 6 weeks and 12 months to determine rates of loosening (hemiarthroplasty) and union (arthrodesis). Data on length of stay, return to work, complications and re-operation rates will also be collected.The analysis will compare the change in outcome scores between treatment groups at all follow-up time points. Scores will be compared using a Student t-test, adjusting for scores at baseline.This study will be conducted in accordance with the current revision of the Declaration of Helsinki (1996) and the ICH-GCP Guideline (International Conference on Harmonisation, Good Clinical Practice, E6(R1), 1996). This study has been approved by the sponsor, the Trust Research & Development office. Ethical approval has been received from the National Research Ethics Service (North East: 12/NE/0385 for protocol version 5.3 dated 3 June 2013).Trial registration: Current Controlled Trials ISRCTN88273654. \u00a9 2014 Divecha et al.; licensee BioMed Central Ltd.
\n \n\n \n \nObjective: Eye tracking in three dimensions is novel, but established descriptors derived from two-dimensional (2D) studies are not transferable. We aimed to develop metrics suitable for statistical comparison of eye-tracking data obtained from readers of three-dimensional (3D) \"virtual\" medical imaging, using CT colonography (CTC) as a typical example.
\n \n\n \n \nPurpose: To identify and compare key stages of the visual process in experienced and inexperienced readers and to examine how these processes are used to search a moving threedimensional (3D) image and their relationship to falsenegative errors.
\n \n\n \n \nMany cases of giardiasis in the UK are undiagnosed and among other things, diagnosis is dependent upon the readiness of GPs to request a specimen. The aim of this study is to assess the rate of specimens requested per GP practice in Central Lancashire, to examine the differences between GP practices and to estimate the pattern of unexplained spatial variation in the practice rate of specimens after adjustment for deprivation. To achieve this, we fitted a set of binomial and Poisson regression models, with random effects for GP practice. Our analysis suggests that there were differences in the rate of specimens by GP practices (P < 0\u00b7001) for a single year, but no difference in the proportion of positive tests per specimen submitted or in the rate of positive specimens per practice population. There was a difference in the cumulative rate of positive specimens per practice population over a 9-year period (P < 0\u00b7001). Neither the specimen rate per practice for a single year nor the cumulative rate of positive specimens over multiple years demonstrated significant spatial correlation. Hence, spatial variation in the incidence of giardiasis is unlikely to be confounded by variation in GP rate of specimens.
\n \n\n \n \nObjective: We aimed to identify the effect of computer-aided detection (CAD) on visual search and performance in CT Colonography (CTC) of inexperienced and experienced readers. Methods: Fifteen endoluminal CTC examinations were recorded, each with one polyp, and two videos were generated, one with and one without a CAD mark. Forty-two readers (17 experienced, 25 inexperienced) interpreted the videos during infrared visual search recording. CAD markers and polyps were treated as regions of interest in data processing. This multi-reader, multi-case study was analysed using multilevel modelling. Results: CAD drew readers\u2019 attention to polyps faster, accelerating identification times: median \u2018time to first pursuit\u2019 was 0.48\u00a0s (IQR 0.27 to 0.87\u00a0s) with CAD, versus 0.58\u00a0s (IQR 0.35 to 1.06\u00a0s) without. For inexperienced readers, CAD also held visual attention for longer. All visual search metrics used to assess visual gaze behaviour demonstrated statistically significant differences when \u201cwith\u201d and \u201cwithout\u201d CAD were compared. A significant increase in the number of correct polyp identifications across all readers was seen with CAD (74\u00a0% without CAD, 87\u00a0% with CAD; p < 0.001). Conclusions: CAD significantly alters visual search and polyp identification in readers viewing three-dimensional endoluminal CTC. For polyp and CAD marker pursuit times, CAD generally exerted a larger effect on inexperienced readers. Key Points: \u2022 Visual gaze is attracted by computer-assisted detection (CAD) marks on polyps \u2022 Inexperienced readers\u2019 gaze is affected more by CAD than experienced readers. \u2022 CAD marks could mean that the unannotated endoluminal surface is relatively neglected. \u2022 Correct polyp identification is increased significantly by CAD.
\n \n\n \n \nMany cases of giardiasis in the UK are undiagnosed and among other things, diagnosis is dependent upon the readiness of GPs to request a specimen. The aim of this study is to assess the rate of specimens requested per GP practice in Central Lancashire, to examine the differences between GP practices and to estimate the pattern of unexplained spatial variation in the practice rate of specimens after adjustment for deprivation. To achieve this, we fitted a set of binomial and Poisson regression models, with random effects for GP practice. Our analysis suggests that there were differences in the rate of specimens by GP practices (P < 0\u00b7001) for a single year, but no difference in the proportion of positive tests per specimen submitted or in the rate of positive specimens per practice population. There was a difference in the cumulative rate of positive specimens per practice population over a 9-year period (P < 0\u00b7001). Neither the specimen rate per practice for a single year nor the cumulative rate of positive specimens over multiple years demonstrated significant spatial correlation. Hence, spatial variation in the incidence of giardiasis is unlikely to be confounded by variation in GP rate of specimens.
\n \n\n \n \nThere are many examples from the scientific literature of visual search tasks in which the length, scope and success rate of the search have been shown to vary according to the searcher's expectations of whether the search target is likely to be present. This phenomenon has major practical implications, for instance in cancer screening, when the prevalence of the condition is low and the consequences of a missed disease diagnosis are severe. We consider this problem from an empirical Bayesian perspective to explain how the effect of a low prior probability, subjectively assessed by the searcher, might impact on the extent of the search. We show how the searcher\u2019s posterior probability that the target is present depends on the prior probability and the proportion of possible target locations already searched, and also consider the implications of imperfect search, when the probability of false-positive and false-negative decisions is non-zero. The theoretical results are applied to two studies of radiologists\u2019 visual assessment of pulmonary lesions on chest radiographs. Further application areas in diagnostic medicine and airport security are also discussed.
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