Sorting out measures and definitions of screening participation to improve comparability: The example of colorectal cancer.

Participation is a key indicator of the potential effectiveness of any population-based intervention. Defining, measuring and reporting participation in cancer screening programmes has become more heterogeneous as the number and diversity of interventions have increased, and the purposes of this benchmarking parameter have broadened. This study, centred on colorectal cancer, addresses current issues that affect the increasingly complex task of comparing screening participation across settings. Reports from programmes with a defined target population and active invitation scheme, published between 2005 and 2012, were reviewed. Differences in defining and measuring participation were identified and quantified, and participation indicators were grouped by aims of measure and temporal dimensions. We found that consistent terminology, clear and complete reporting of participation definition and systematic documentation of coverage by invitation were lacking. Further, adherence to definitions proposed in the 2010 European Guidelines for Quality Assurance in Colorectal Cancer Screening was suboptimal. Ineligible individuals represented 1% to 15% of invitations, and variable criteria for ineligibility yielded differences in participation estimates that could obscure the interpretation of colorectal cancer screening participation internationally. Excluding ineligible individuals from the reference population enhances comparability of participation measures. Standardised measures of cumulative participation to compare screening protocols with different intervals and inclusion of time since invitation in definitions are urgently needed to improve international comparability of colorectal cancer screening participation. Recommendations to improve comparability of participation indicators in cancer screening interventions are made.

Investigation of Postmortem Gases: A Forensic Imaging and Analytical Chemistry Approach

Background: Distinguishing postmortem gas accumulations in the body due to natural decomposition and other phenomena such as gas embolism can prove a difficult task using purely Multi-Detector Computed Tomography (MDCT). The Radiological Alteration Index (RAI) was created with the intention to be able to identify bodies undergoing the putrefaction process based on the quantity of gas detected within the body. The flaw in this approach is the inability to absolutely determine putrefaction as the origin of gas volumes in cases of moderate alteration. The aim of the current study is to identify percentage compositions of O2, N2, CO2 and the presence of gases such as H2 and H2S within these sampling sites in order to resolve this complication. Materials and methods: All cases investigated in our University Center of Legal Medicine are undergoing a Post-Mortem Computed Tomography (PMCT)-scan before external examination or autopsy as a routine investigation. In the obtained images, areas of gas were characterized as 0, I, II or III based on the amount of gas present according to the RAI (1). The criteria for these characterizations were dependent of the site of gas, for example thoracic and abdominal cavities were graded as I (1 - 3cm gas), II (3 - 5cm gas) and III (>5cm gas). Cases showing gaseous sites with grade II or III were selected for this study. The sampling was performed under CT-guidance to target the regions to be punctured. Luer-lock PTFE syringes equipped with a three-way valve and needles were used to sample the gas directly (2). Gaseous samples were then analysed using gas chromatography coupled to a thermal conductivity detector (GC-TCD). The components present in the samples were expressed as a percentage of the overall gas present. Results: Up to now, we have investigated more than 40 cases using our standardized procedure for sampling and analysis of gas. O2, N2 and CO2 were present in most samples. The following distributions were found to correlate to gas origins of gas embolism/scuba diving accidents, trauma and putrefaction: ? Putrefaction → O2 = 1 - 5%; CO2 > 15%; N2 = 10 - 70%; H2 / H2S / CH4 variable presence ? Gas embolism/Scuba diving accidents → O2 and N2= varying percentages; CO2 > 20% ? Trauma → O2 = small percentage; CO2 < 15%; N2 > 65% H2 and H2S indicated levels of putrefaction along with methane which can also gauge environmental conditions or conditions of body storage/burial. Many cases showing large RAI values (advanced alteration) did reveal a radiological diagnosis which was in concordance with the interpretation of the gas composition. However, in certain cases (gas embolism, scuba divers) radiological interpretation was not possible and only chemical gas analysis was found to lead to the correct diagnosis, meaning that it provided complementary information to the radiological diagnosis. Conclusion: Investigation of postmortem gases is a useful tool to determine origin of gas generation which can aid the diagnosis of the cause of death. Levels of gas can provide information on stage of putrefaction and help to perform essential medico-legal diagnosis such as vital gas embolism.

Pharmacokinetic (PK)-based dosage individualization of imatinib: evaluation of efficiency and clinical usefulness

Background: Retrospective analyses suggest that personalized PK-based dosage might be useful for imatinib, as treatment response correlates with trough concentrations (Cmin) in cancer patients. Our objectives were to improve the interpretation of randomly measured concentrations and to confirm its efficiency before evaluating the clinical usefulness of systematic PK-based dosage in chronic myeloid leukemia patients. Methods and Results: A Bayesian method was validated for the prediction of individual Cmin on the basis of a single random observation, and was applied in a prospective multicenter randomized controlled clinical trial. 28 out of 56 patients were enrolled in the systematic dosage individualization arm and had 44 follow-up visits (their clinical follow-up is ongoing). PK-dose-adjustments were proposed in 39% having predicted Cmin significantly away from the target (1000 ng/ml). Recommendations were taken up by physicians in 57%, patients were considered non-compliant in 27%. Median Cmin at study inclusion was 754 ng/ml and differed significantly from the target (p=0.02, Wilcoxon test). On follow-up, Cmin was 984 ng/ml (p=0.82) in the compliant group. CV decreased from 46% to 27% (p=0.02, F-test). Conclusion: PK-based (Bayesian) dosage adjustment is able to bring individual drug exposure closer to a given therapeutic target. Its influence on therapeutic response remains to be evaluated.

Simulation-based systematic review of imatinib population pharmacokinetics and PK-PD relationships in chronic myeloid leukemia (CML) patients

Objectives: Several population pharmacokinetic (PPK) and pharmacokinetic-pharmacodynamic (PK-PD) analyses have been performed with the anticancer drug imatinib. Inspired by the approach of meta-analysis, we aimed to compare and combine results from published studies in a useful way - in particular for improving the clinical interpretation of imatinib concentration measurements in the scope of therapeutic drug monitoring (TDM). Methods: Original PPK analyses and PK-PD studies (PK surrogate: trough concentration Cmin; PD outcomes: optimal early response and specific adverse events) were searched systematically on MEDLINE. From each identified PPK model, a predicted concentration distribution under standard dosage was derived through 1000 simulations (NONMEM), after standardizing model parameters to common covariates. A "reference range" was calculated from pooled simulated concentrations in a semi-quantitative approach (without specific weighting) over the whole dosing interval. Meta-regression summarized relationships between Cmin and optimal/suboptimal early treatment response. Results: 9 PPK models and 6 relevant PK-PD reports in CML patients were identified. Model-based predicted median Cmin ranged from 555 to 1388 ng/ml (grand median: 870 ng/ml and inter-quartile range: 520-1390 ng/ml). The probability to achieve optimal early response was predicted to increase from 60 to 85% from 520 to 1390 ng/ml across PK-PD studies (odds ratio for doubling Cmin: 2.7). Reporting of specific adverse events was too heterogeneous to perform a regression analysis. The general frequency of anemia, rash and fluid retention increased however consistently with Cmin, but less than response probability. Conclusions: Predicted drug exposure may differ substantially between various PPK analyses. In this review, heterogeneity was mainly attributed to 2 "outlying" models. The established reference range seems to cover the range where both good efficacy and acceptable tolerance are expected for most patients. TDM guided dose adjustment appears therefore justified for imatinib in CML patients. Its usefulness remains now to be prospectively validated in a randomized trial.

Techniques for analytical testing of unconventional samples.

Forensic scientists have long detected the presence of drugs and their metabolites in biological materials using body fluids such as urine, blood and/or other biological liquids or tissues. For doping analysis, only urine has so far been collected. In recent years, remarkable advances in sensitive analytical techniques have encouraged the analysis of drugs in unconventional biological samples such as hair, saliva and sweat. These samples are easily collected, although drug levels are often lower than the corresponding levels in urine or blood. This chapter reviews recent studies in the detection of doping agents in hair, saliva and sweat. Sampling, analytical procedures and interpretation of the results are discussed in comparison with those obtained from urine and blood samples.

Análisis de una iniciativa estudiantil de investigación surgida en Criptogamia, una asignatura optativa de segundo ciclo de Biología = Analysis of a students’ research initiative originating in Cryptogamy, an elective course in the last two years of the Biology degree

Presentamos una experiencia exitosa de aprendizaje que partió de Criptogamia (asignatura optativa de segundo ciclo de Biología), que dio lugar a un proyecto de investigación gestionado por los propios alumnos. La iniciativa se consolidó estableciendo una Asociación de Estudiantes centrada en investigación y divulgación. En poco tiempo, los participantes han presentado comunicaciones científicas, y organizado actividades dirigidas a diversos públicos, dentro y fuera de la comunidad universitaria. Actualmente se plantea una colaboración multidisciplinar con otros organismos de investigación y la extensión de su ámbito de estudio. Abordamos su incidencia en el aprendizaje en varios aspectos: científico (técnicas específicas, rigor, búsqueda de información e interpretación de resultados), comunicativo (estructuración y presentación de la información obtenida, para diversos públicos), y organizativo, incluyendo el trabajo en equipo. Aunque de carácter espontáneo, esta experiencia muestra rasgos evaluables en cuanto a sus posibilidades para otras asignaturas. Analizamos las características y planteamiento de esta optativa, el perfil de sus alumnos, y el contexto universitario que la acoge. Detectamos como factores principales los aspectos participativos de la asignatura, la cohesión del grupo, el carácter voluntario de la implicación, los beneficios percibidos por los estudiantes, y la disponibilidad de recursos humanos (supervisión) y materiales (equipamiento y subvenciones).

On problems of calculating energy expenditure and substrate utilization from respiratory exchange data.

Indirect calorimetry based on respiratory exchange measurement has been successfully used from the beginning of the century to obtain an estimate of heat production (energy expenditure) in human subjects and animals. The errors inherent to this classical technique can stem from various sources: 1) model of calculation and assumptions, 2) calorimetric factors used, 3) technical factors and 4) human factors. The physiological and biochemical factors influencing the interpretation of calorimetric data include a change in the size of the bicarbonate and urea pools and the accumulation or loss (via breath, urine or sweat) of intermediary metabolites (gluconeogenesis, ketogenesis). More recently, respiratory gas exchange data have been used to estimate substrate utilization rates in various physiological and metabolic situations (fasting, post-prandial state, etc.). It should be recalled that indirect calorimetry provides an index of overall substrate disappearance rates. This is incorrectly assumed to be equivalent to substrate "oxidation" rates. Unfortunately, there is no adequate golden standard to validate whole body substrate "oxidation" rates, and this contrasts to the "validation" of heat production by indirect calorimetry, through use of direct calorimetry under strict thermal equilibrium conditions. Tracer techniques using stable (or radioactive) isotopes, represent an independent way of assessing substrate utilization rates. When carbohydrate metabolism is measured with both techniques, indirect calorimetry generally provides consistent glucose "oxidation" rates as compared to isotopic tracers, but only when certain metabolic processes (such as gluconeogenesis and lipogenesis) are minimal or / and when the respiratory quotients are not at the extreme of the physiological range. However, it is believed that the tracer techniques underestimate true glucose "oxidation" rates due to the failure to account for glycogenolysis in the tissue storing glucose, since this escapes the systemic circulation. A major advantage of isotopic techniques is that they are able to estimate (given certain assumptions) various metabolic processes (such as gluconeogenesis) in a noninvasive way. Furthermore when, in addition to the 3 macronutrients, a fourth substrate is administered (such as ethanol), isotopic quantification of substrate "oxidation" allows one to eliminate the inherent assumptions made by indirect calorimetry. In conclusion, isotopic tracers techniques and indirect calorimetry should be considered as complementary techniques, in particular since the tracer techniques require the measurement of carbon dioxide production obtained by indirect calorimetry. However, it should be kept in mind that the assessment of substrate oxidation by indirect calorimetry may involve large errors in particular over a short period of time. By indirect calorimetry, energy expenditure (heat production) is calculated with substantially less error than substrate oxidation rates.

Clinical and genetic findings in a large cohort of patients with congenital myopathies due to mutations in the skeletal muscle ryanodine receptor (RYR1) gene

RYR1 mutations are the most common cause of structural congenital myopathies and may exhibit both dominant and recessive inheritance. Histopathological findings are variable and include central cores, multi-minicores, type 1 predominance/ uniformity, fibre type disproportion, increased internal nucleation and fatty and connective tissue. Until recently, diagnostic RYR1 sequencing was limited to mutational hotspots due to the large size of the gene. Since the introduction of full RYR1 sequencing in 2007 we have detected pathogenic mutations in 77 families: 39 had dominant inheritance and 38 recessive inheritance. In some cases with presumably recessive inheritance, only one heterozygous mutation inherited from an asymptomatic parent was identified. Of 28 dominant mutations, 6 were novel; 37 of the 59 recessive mutations were also novel. Dominant mutations were more frequently in recognized hotspot regions, while recessive mutations were distributed throughout the coding sequence. Dominant mutations were predominantly missense, whereas recessive mutations included many nonsense and splice mutations expected to result in reduced RyR1 protein. There was wide clinical variability in patients with both dominant and recessive inheritance. As a group, those with dominant mutations were generally more mildly affected than those with recessive inheritance, who had earlier onset and were weaker with more functional limitations. Extraocular muscle involvement was almost exclusively observed in the recessive group. Bulbar involvement was also more prominent in this group, resulting in a larger number requiring gastrostomy insertion. In conclusion, genomic sequencing of the entire RYR1 leads to the detection of many novel mutations, but may miss large genetic rearrangements in some cases. Assigning pathogenicity to novel mutations is often difficult and interpretation of genetic results in the context of clinical, histological and, increasingly, muscle MRI findings is essential.

Preferential binding of the methyl-CpG binding domain protein 2 at methylated transcriptional start site regions.

Methyl-CpG Binding Domain (MBD) proteins are thought to be key molecules in the interpretation of DNA methylation signals leading to gene silencing through recruitment of chromatin remodeling complexes. In cancer, the MBD-family member, MBD2, may be primarily involved in the repression of genes exhibiting methylated CpG at their 5' end. Here we ask whether MBD2 randomly associates methylated sequences, producing chance effects on transcription, or exhibits a more specific recognition of some methylated regions. Using chromatin and DNA immunoprecipitation, we analyzed MBD2 and RNA polymerase II deposition and DNA methylation in HeLa cells on arrays representing 25,500 promoter regions. This first whole-genome mapping revealed the preferential localization of MBD2 near transcription start sites (TSSs), within the region analyzed, 7.5 kb upstream through 2.45 kb downstream of 5' transcription start sites. Probe by probe analysis correlated MBD2 deposition and DNA methylation. Motif analysis did not reveal specific sequence motifs; however, CCG and CGC sequences seem to be overrepresented. Nonrandom association (multiple correspondence analysis, p < 0.0001) between silent genes, DNA methylation and MBD2 binding was observed. The association between MBD2 binding and transcriptional repression weakened as the distance between binding site and TSS increased, suggesting that MBD2 represses transcriptional initiation. This hypothesis may represent a functional explanation for the preferential binding of MBD2 at methyl-CpG in TSS regions.

Molecular Epidemiologic Typing Systems of Bacterial Pathogens: Current Issues and Perpectives

The epidemiologic typing of bacterial pathogens can be applied to answer a number of different questions: in case of outbreak, what is the extent and mode of transmission of epidemic clone(s )? In case of long-term surveillance, what is the prevalence over time and the geographic spread of epidemic and endemic clones in the population? A number of molecular typing methods can be used to classify bacteria based on genomic diversity into groups of closely-related isolates (presumed to arise from a common ancestor in the same chain of transmission) and divergent, epidemiologically-unrelated isolates (arising from independent sources of infection). Ribotyping, IS-RFLP fingerprinting, macrorestriction analysis of chromosomal DNA and PCR-fingerprinting using arbitrary sequence or repeat element primers are useful methods for outbreak investigations and regional surveillance. Library typing systems based on multilocus sequence-based analysis and strain-specific probe hybridization schemes are in development for the international surveillance of major pathogens like Mycobacterium tuberculosis. Accurate epidemiological interpretation of data obtained with molecular typing systems still requires additional research on the evolution rate of polymorphic loci in bacterial pathogens.

Youth of the Eighties, Parents of 2000, Sociological Observations

(Résumé de l'ouvrage) This book is meant to honour the Belgian religious educationalist Herman Lombaerts reflecting on his legacy. He is internationally renowned as a scholar with a strong commitment to and a conceptual analysis of the social and cultural context in which people live and learn. This series of essays is build upon a thought provoking, streamlined design on the relationship between theology and education, relying on Lombaerts' societal and cultural analysis of contemporary religious education. Three key elements are at stake: the self-agency of the learner, the hermeneutic and communitive interpretation of religious traditions in the teaching of religion, and the radical re-imagination of Christian theology relying on this new model of religious educational praxis. For Lombaerts, the search processes of religious people have their own dynamic and dignity. Practical theology should listen carefully and empathetically to this quest. But he is also convinced of the need of solid fundamental research to understand critically its ambiguities and perspectives. Scholars from Europe, the United States and Australia lead the way in this process of "conceptual stretching". Issues such as happiness of children, identity formation of youth, educational and religious insecurity of parents, multi-faith education, tradition crisis of churches, theological education of lay ministers, narrativity and modern art in religious education, etc. are examined from a practical theological point of view, with a strong commitment to the philosophical, psychological, sociological, educational and political dimensions of three issues. With this book the editors hope to commemorate Lombaerts' international radiation, by building a collegial bridge between the different theoretical approaches in the German, Dutch, French, Italian and Anglo-Saxon religious educational research.

Atlas iconographique tomodensitométrique des pathologies bénignes de l'amiante [Computed tomographic atlas of benign asbestos related pathology].

The demonstration by computed tomography of abnormalities related to asbestos is essential for the recognition of industrial disease, the compensation of which has considerable economic consequences. The use of compute tomography, the most reliable technique for the detection of pleuro-parenchymatous abnormalities related to asbestos exposure, has increased considerably in France since the publication of the results of a consensus conference in Paris in 1999. Since that time, developments in technology have noticeably modified the protocols of investigation and increased the sensitivity of the detection of pleural and interstitial parenchymatous abnormalities and of nodules. The technical recommendations and those for the interpretation of pleural and parenchymatous abnormalities need to be well known. They are presented in the form of an atlas that gives detailed criteria for asbestosis, pleural plaques and pleural fibrosis. The diagnosis of pleural plaques depends on the combination of clear limits at the pleural and pulmonary interface, typical topography and multiple, bilateral localization. In the context of asbestos exposure the plaques are characteristic of this exposure, unlike diffuse pleural thickening, crow's feet images, parenchymatous bands and entrapped atalectasis. The writing of the radiological report would be most appropriate on this basis.

Analysis of genetic diversity of Trypanosoma cruzi: an application of riboprinting and gradient gel electrophoresis methods

Analysis of restriction fragment length polymorphism (RFLP) profiles derived from digestion of polymerase chain reaction (PCR) products of the ribosomal 18S from Trypanosoma cruzi yields a typical `riboprint' profile that can vary intraspecifically. A selection of 21 stocks of T. cruzi and three outgroup taxa: T. rangeli, T. conorhini and Leishmania braziliensis were analysed by riboprinting to assess divergence within and between taxa. T. rangeli, T. conorhini and L. braziliensis could be easily differentiated from each other and from T. cruzi. Phenetic analysis of PCR-RFLP profiles indicated that, with one or two exceptions, stocks of T. cruzi could be broadly partitioned into two groups that formally corresponded to T. cruzi I and T. cruzi II respectively. To test if ribosomal 18S sequences were homogeneous within each taxon, gradient gel electrophoresis methods were employed utilising either chemical or temperature gradients. Upon interpretation of the melting profiles of riboprints and a section of the 18S independently amplified by PCR, there would appear to be at least two divergent 18S types present within T. cruzi. Heterogeneity within copies of the ribosomal 18S within a single genome has therefore been demonstrated and interestingly, this dimorphic arrangement was also present in the outgroup taxa. Presumably the ancestral duplicative event that led to the divergent 18S types preceded that of speciation within this group. These divergent 18S paralogues may have, or had, different functional pressures or rates of molecular evolution. Whether or not these divergent types are equally transcriptionally active throughout the life cycle, remain to be assessed.

The First Christian Historian. Writing the "Acts of the Apostles"

As the first historian of Christianity, Luke's reliability is vigorously disputed among scholars. The author of the Acts is often accused of being a biased, imprecise, and anti-Jewish historian who created a distorted portrait of Paul. Daniel Marguerat tries to avoid being caught in this true/false quagmire when examining Luke's interpretation of history. Instead he combines different tools - reflection upon historiography, the rules of ancient historians and narrative criticism - to analyse the Acts and gauge the historiographical aims of their author. Marguerat examines the construction of the narrative, the framing of the plot and the characterization, and places his evaluation firmly in the framework of ancient historiography, where history reflects tradition and not documentation. This is a fresh and original approach to the classic themes of Lucan theology: Christianity between Jerusalem and Rome, the image of God, the work of the Spirit, the unity of Luke and the Acts.

New perspectives in the use of ink evidence in forensic science

Resume : L'utilisation de l'encre comme indice en sciences forensiques est décrite et encadrée par une littérature abondante, comprenant entre autres deux standards de l'American Society for Testing and Materials (ASTM). La grande majorité de cette littérature se préoccupe de l'analyse des caractéristiques physiques ou chimiques des encres. Les standards ASTM proposent quelques principes de base qui concernent la comparaison et l'interprétation de la valeur d'indice des encres en sciences forensiques. L'étude de cette littérature et plus particulièrement des standards ASTM, en ayant a l'esprit les développements intervenus dans le domaine de l'interprétation de l'indice forensique, montre qu'il existe un potentiel certain pour l'amélioration de l'utilisation de l'indice encre et de son impact dans l'enquête criminelle. Cette thèse propose d'interpréter l'indice encre en se basant sur le cadre défini par le théorème de Bayes. Cette proposition a nécessité le développement d'un système d'assurance qualité pour l'analyse et la comparaison d'échantillons d'encre. Ce système d'assurance qualité tire parti d'un cadre théorique nouvellement défini. La méthodologie qui est proposée dans ce travail a été testée de manière compréhensive, en tirant parti d'un set de données spécialement créer pour l'occasion et d'outils importés de la biométrie. Cette recherche répond de manière convaincante à un problème concret généralement rencontré en sciences forensiques. L'information fournie par le criminaliste, lors de l'examen de traces, est souvent bridée, car celui-ci essaie de répondre à la mauvaise question. L'utilisation d'un cadre théorique explicite qui définit et formalise le goal de l'examen criminaliste, permet de déterminer les besoins technologiques et en matière de données. Le développement de cette technologie et la collection des données pertinentes peut être justifiées économiquement et achevée de manière scientifique. Abstract : The contribution of ink evidence to forensic science is described and supported by an abundant literature and by two standards from the American Society for Testing and Materials (ASTM). The vast majority of the available literature is concerned with the physical and chemical analysis of ink evidence. The relevant ASTM standards mention some principles regarding the comparison of pairs of ink samples and the evaluation of their evidential value. The review of this literature and, more specifically, of the ASTM standards in the light of recent developments in the interpretation of forensic evidence has shown some potential improvements, which would maximise the benefits of the use of ink evidence in forensic science. This thesis proposes to interpret ink evidence using the widely accepted and recommended Bayesian theorem. This proposition has required the development of a new quality assurance process for the analysis and comparison of ink samples, as well as of the definition of a theoretical framework for ink evidence. The proposed technology has been extensively tested using a large dataset of ink samples and state of the art tools, commonly used in biometry. Overall, this research successfully answers to a concrete problem generally encountered in forensic science, where scientists tend to self-limit the usefulness of the information that is present in various types of evidence, by trying to answer to the wrong questions. The declaration of an explicit framework, which defines and formalises their goals and expected contributions to the criminal and civil justice system, enables the determination of their needs in terms of technology and data. The development of this technology and the collection of the data is then justified economically, structured scientifically and can be proceeded efficiently.