An empirical hierarchical Bayesian unification of occupational exposure assessment methods.

In occupational exposure assessment of airborne contaminants, exposure levels can either be estimated through repeated measurements of the pollutant concentration in air, expert judgment or through exposure models that use information on the conditions of exposure as input. In this report, we propose an empirical hierarchical Bayesian model to unify these approaches. Prior to any measurement, the hygienist conducts an assessment to generate prior distributions of exposure determinants. Monte-Carlo samples from these distributions feed two level-2 models: a physical, two-compartment model, and a non-parametric, neural network model trained with existing exposure data. The outputs of these two models are weighted according to the expert's assessment of their relevance to yield predictive distributions of the long-term geometric mean and geometric standard deviation of the worker's exposure profile (level-1 model). Bayesian inferences are then drawn iteratively from subsequent measurements of worker exposure. Any traditional decision strategy based on a comparison with occupational exposure limits (e.g. mean exposure, exceedance strategies) can then be applied. Data on 82 workers exposed to 18 contaminants in 14 companies were used to validate the model with cross-validation techniques. A user-friendly program running the model is available upon request.

The attractiveness of nations in global competition : an empirical assessment of the effects of country attractiveness on the success of strategy for hosting international sports events, 1990-2012

This dissertation aims to investigate empirical evidence on the importance and influence of attractiveness of nations in global competition. The notion of country attractiveness, which has been widely developed in the research areas of international business, tourism and migration, is a multi-dimensional construct to measure a country's characteristics with regard to its market or destination that attract international investors, tourists and migrants. This analytical concept provides an account of the mechanism as to how potential stakeholders evaluate more attractive countries based on certain criteria. Thus, in the field of international sport-event bidding, do international sport event owners also have specific country attractiveness for their sport event hosts? The dissertation attempts to address this research question by statistically assessing the effects of country attractiveness on the success of strategy for hosting international sports events. Based on theories of signaling and soft power, country attractiveness is defined and measured as the three dimensions of sustainable development: economic, social, and environmental attractiveness. This thesis proceeds to examine the concept of sport-event-hosting strategy and explore multi-level factors affecting the success in international sport-event bidding. By exploring past history of the Olympic Movement from theoretical perspectives, the thesis proposes and tests the hypotheses that economic, social and environmental attractiveness of a country may be correlated with its bid wins or the success of sport-event-hosting strategy. Quantitative analytical methods with various robustness checks are employed with using collected data on bidding results of major events in Olympic sports during the period from 1990 to 2012. The analysis results reveal that event owners of international Olympic sports are likely to prefer countries that have higher economic, social, and environmental attractiveness. The empirical assessment of this thesis suggests that high country attractiveness can be an essential element of prerequisites for a city/country to secure in order to bid with an increased chance of success.

Which European Public Sphere? Normative Standards and Empirical Insights from Multilingual Switzerland

Since the beginning of the 1990s, the EU has been increasingly criticised for its democratic deficit, which is intrinsically linked to the absence of a public sphere at the European level. Whereas scholars consider the emergence of such a public sphere as a necessary requirement for the democratisation of the EU, they disagree on the conceptualisation and normative requirements for a meaningful public sphere at the European level. This article takes an empirical perspective and draws on the nation-state context of multilingual Switzerland to get insights into what a European public sphere might realistically look like. Based on a content analysis of the leading quality paper from each German- and French-speaking Switzerland by means of political claims analysis, it shows that three of the most often cited criteria for a European public sphere - horizontal openness and interconnectedness, shared meaning structures, and inclusiveness - are hardly met in the Swiss context. On this basis, it concludes that the normative barrier for finding a European public sphere might be unrealistically high and should be reconsidered.

Antibiotic-dependent correlation between drug-induced killing and loss of luminescence in Streptococcus gordonii expressing luciferase.

Measuring antibiotic-induced killing relies on time-consuming biological tests. The firefly luciferase gene (luc) was successfully used as a reporter gene to assess antibiotic efficacy rapidly in slow-growing Mycobacterium tuberculosis. We tested whether luc expression could also provide a rapid evaluation of bactericidal drugs in Streptococcus gordonii. The suicide vectors pFW5luc and a modified version of pJDC9 carrying a promoterless luc gene were used to construct transcriptional-fusion mutants. One mutant susceptible to penicillin-induced killing (LMI2) and three penicillin-tolerant derivatives (LMI103, LMI104, and LMI105) producing luciferase under independent streptococcal promoters were tested. The correlation between antibiotic-induced killing and luminescence was determined with mechanistically unrelated drugs. Chloramphenicol (20 times the MIC) inhibited bacterial growth. In parallel, luciferase stopped increasing and remained stable, as determined by luminescence and Western blots. Ciprofloxacin (200 times the MIC) rapidly killed 1.5 log10 CFU/ml in 2-4 hr. Luminescence decreased simultaneously by 10-fold. In contrast, penicillin (200 times the MIC) gave discordant results. Although killing was slow (< or = 0.5 log10 CFU/ml in 2 hr), luminescence dropped abruptly by 50-100-times in the same time. Inactivating penicillin with penicillinase restored luminescence, irrespective of viable counts. This was not due to altered luciferase expression or stability, suggesting some kind of post-translational modification. Luciferase shares homology with aminoacyl-tRNA synthetase and acyl-CoA ligase, which might be regulated by macromolecule synthesis and hence affected in penicillin-inhibited cells. Because of resemblance, luciferase might be down-regulated simultaneously. Luminescence cannot be universally used to predict antibiotic-induced killing. Thus, introducing reporter enzymes sharing mechanistic similarities with normal metabolic reactions might reveal other effects than those expected.

Telomerase activity and human telomerase reverse transcriptase mRNA expression in soft tissue tumors: correlation with grade, histology, and proliferative activity.

Telomerase activity (TA) is detected in most human cancers but, with few exceptions, not in normal somatic cells. Little is known about TA in soft tissue tumors. We have examined a series of benign and malignant soft tissue tumors for TA using the telomerase repeat amplification protocol assay. Analysis of the expression of the human telomerase reverse transcriptase was also carried out using RT-PCR. TA was undetectable in benign lesions (15 of 15) and low-grade sarcomas (6 of 6) and was detectable in 50% (19 of 38) of intermediate-/high-grade sarcomas. Although the presence of TA in soft tissue tumors is synonymous with malignancy, it is neither a reliable method in making the distinction between reactive/benign and malignant (especially low-grade) lesions nor a reliable marker of tumor aggressiveness. Leiomyosarcomas and storiform/pleomorphic malignant fibrous histiocytomas rarely showed TA, irrespective of their grade. A strong correlation between human telomerase reverse transcriptase mRNA expression and TA was observed, supporting the close relationship between both parameters. No significant relationship was observed between proliferative activity (as assessed by MIB-1 immunolabeling) and TA. We verified that the absence of telomerase expression was not due to the presence of telomerase inhibitors and therefore alternative mechanism(s) for cell immortalization, yet to be determined, seem to be involved in the development and/or maintenance of some soft tissue sarcomas.

CD30 in PTCLS: correlation between RNA and protein levels in a large european series from the LYSA

Introduction: CD22 is expressed on most B-non-Hodgkin lymphomas (NHL); inotuzumab ozogamicin (INO) is an anti-CD22 antibody conjugated to calicheamicin. This study evaluated the safety and tolerability of INO plus R-CVP in patients (pts) with relapsed/refractory CD22+ B-NHL. Efficacy data were also collected. Methods: Part 1 of this open-label study identified a maximum tolerated dose (MTD) of INO 0.8mg/m,2 on day 2 plus R-CVP (rituximab 375mg/m,2 cyclophosphamide 750mg/m,2 and vincristine 1.4mg/m,2 on day 1; prednisone 40mg/m,2 on days 1-5) every 21 days. Subsequently, pts were enrolled in the MTD confirmation cohort (part 2, n = 10), which required a dose-limiting toxicity rate of <33% in cycle 1 and <4 pts discontinuing prior to cycle 3 due to an adverse event (AE) in the MTD expansion cohort (part 3, n = 22), which explored preliminary activity. Results: Parts 2 and 3 enrolled 32 pts: 16 pts with diffuse large B-cell lymphoma, 15 with follicular lymphoma and one with mantle cell lymphoma. Median age was 64.5 years (range 44-81 years); 34% of pts had 1 prior regimen, 34% had 2, 28% had ≥3 and 3% had none (median 2; range 0-6).Median treatment duration was five cycles (range 1-6). Part 2 confirmed the MTD as standard dose R-CVP plus INO 0.8mg/m,2; 2/10 pts had a dose-limiting toxicity (grade 3 increased ALT/AST, grade 4 neutropenia requiring G-CSF). One pt discontinued because of an AE prior to cycle 3. Common treatment-related AEs were thrombocytopenia (78%), neutropenia (66%), fatigue (50%), leukopenia (50%), nausea (41%) and lymphopenia (38%); common grade 3/4 AEs were neutropenia (63%), thrombocytopenia (53%), leukopenia (38%) and lymphopenia (31%). There was one case of treatment-related fatal pneumonia with grade 4 neutropenia. Ten pts discontinued treatment due to AEs; thrombocytopenia/delayed platelet recovery was the leading cause (grade 1/2, n = 6; grade 3/4, n = 3). Objective response rate (ORR) was 77% (n = 24/31 evaluable pts), including 26% (n=8/31) with complete response (CR); three pts had stable disease. Of the pts with follicular lymphoma, ORR was 100% (n = 15/15), including seven pts with CR. Of the pts with diffuse large B-cell lymphoma, ORR was 60% (n = 9/16), including one pt with CR. Conclusions: Results suggest that INOplus R-CVP has acceptable toxicity and promising activity in relapsed/refractory CD22+ B-NHL. The most common grade 3/4 AEs were hematologic. Follow-up for progression-free and overall survival is ongoing.

Measuring an effect size from dichotomized data : contrasted results whether using a correlation or an odds-ratio

It is well known that dichotomizing continuous data has the effect to decrease statistical power when the goal is to test for a statistical association between two variables. Modern researchers however are focusing not only on statistical significance but also on an estimation of the "effect size" (i.e., the strength of association between the variables) to judge whether a significant association is also clinically relevant. In this article, we are interested in the consequences of dichotomizing continuous data on the value of an effect size in some classical settings. It turns out that the conclusions will not be the same whether using a correlation or an odds ratio to summarize the strength of association between the variables: Whereas the value of a correlation is typically decreased by a factor pi/2 after each dichotomization, the value of an odds ratio is at the same time raised to the power 2. From a descriptive statistical point of view, it is thus not clear whether dichotomizing continuous data leads to a decrease or to an increase in the effect size, as illustrated using a data set to investigate the relationship between motor and intellectual functions in children and adolescents

Trypanosoma cruzi: blood parasitism kinetics and their correlation with heart parasitism intensity during long-term infection of Beagle dogs

The goals of the present study were to evaluate the kinetics of blood parasitism by examination of fresh blood, blood culture (BC) and PCR assays and their correlation with heart parasitism during two years of infection in Beagle dogs inoculated with the Be-78, Y and ABC Trypanosoma cruzi strains. Our results showed that the parasite or its kDNA is easily detected during the acute phase in all infected animals. On the other hand, a reduced number of positive tests were verified during the chronic phase of the infection. The frequency of positive tests was correlated with T. cruzi strain. The percentage of positive BC and blood PCR performed in samples from animals inoculated with Be-78 and ABC strains were similar and significantly larger in relation to animals infected with the Y strain.Comparison of the positivity of PCR tests performed using blood and heart tissue samples obtained two years after infection showed two different patterns associated with the inoculated T. cruzi strain: (1) high PCR positivity for both blood and tissue was observed in animals infected with Be-78 or ABC strains; (2) lower and higher PCR positivity for the blood and tissue, respectively, was detected in animals infected with Y strains. These data suggest that the sensitivity of BC and blood PCR was T. cruzi strain dependent and, in contrast, the heart tissue PCR revealed higher sensitivity regardless of the parasite stock.

Statistical treatment of grain-size curves and empirical distributions: densities as compositions?

The preceding two editions of CoDaWork included talks on the possible considerationof densities as infinite compositions: Egozcue and D´ıaz-Barrero (2003) extended theEuclidean structure of the simplex to a Hilbert space structure of the set of densitieswithin a bounded interval, and van den Boogaart (2005) generalized this to the setof densities bounded by an arbitrary reference density. From the many variations ofthe Hilbert structures available, we work with three cases. For bounded variables, abasis derived from Legendre polynomials is used. For variables with a lower bound, westandardize them with respect to an exponential distribution and express their densitiesas coordinates in a basis derived from Laguerre polynomials. Finally, for unboundedvariables, a normal distribution is used as reference, and coordinates are obtained withrespect to a Hermite-polynomials-based basis.To get the coordinates, several approaches can be considered. A numerical accuracyproblem occurs if one estimates the coordinates directly by using discretized scalarproducts. Thus we propose to use a weighted linear regression approach, where all k-order polynomials are used as predictand variables and weights are proportional to thereference density. Finally, for the case of 2-order Hermite polinomials (normal reference)and 1-order Laguerre polinomials (exponential), one can also derive the coordinatesfrom their relationships to the classical mean and variance.Apart of these theoretical issues, this contribution focuses on the application of thistheory to two main problems in sedimentary geology: the comparison of several grainsize distributions, and the comparison among different rocks of the empirical distribution of a property measured on a batch of individual grains from the same rock orsediment, like their composition

Early and late skin reactions to radiotherapy for breast cancer and their correlation with radiation-induced DNA damage in lymphocytes

INTRODUCTION Radiotherapy outcomes might be further improved by a greater understanding of the individual variations in normal tissue reactions that determine tolerance. Most published studies on radiation toxicity have been performed retrospectively. Our prospective study was launched in 1996 to measure the in vitro radiosensitivity of peripheral blood lymphocytes before treatment with radical radiotherapy in patients with breast cancer, and to assess the early and the late radiation skin side effects in the same group of patients. We prospectively recruited consecutive breast cancer patients receiving radiation therapy after breast surgery. To evaluate whether early and late side effects of radiotherapy can be predicted by the assay, a study was conducted of the association between the results of in vitro radiosensitivity tests and acute and late adverse radiation effects. METHODS Intrinsic molecular radiosensitivity was measured by using an initial radiation-induced DNA damage assay on lymphocytes obtained from breast cancer patients before radiotherapy. Acute reactions were assessed in 108 of these patients on the last treatment day. Late morbidity was assessed after 7 years of follow-up in some of these patients. The Radiation Therapy Oncology Group (RTOG) morbidity score system was used for both assessments. RESULTS Radiosensitivity values obtained using the in vitro test showed no relation with the acute or late adverse skin reactions observed. There was no evidence of a relation between acute and late normal tissue reactions assessed in the same patients. A positive relation was found between the treatment volume and both early and late side effects. CONCLUSION After radiation treatment, a number of cells containing major changes can have a long survival and disappear very slowly, becoming a chronic focus of immunological system stimulation. This stimulation can produce, in a stochastic manner, late radiation-related adverse effects of varying severity. Further research is warranted to identify the major determinants of normal tissue radiation response to make it possible to individualize treatments and improve the outcome of radiotherapy in cancer patients.

Correlation of biological serum markers with the degree of hepatic fibrosis and necroinflammatory activity in hepatitis C and schistosomiasis patients

Liver biopsy is the gold-standard method to stage fibrosis; however, it is an invasive procedure and is potentially dangerous. The main objective of this study was to evaluate biological markers, such as cytokines IL-13, IFN-γ, TNF-α and TGF-β, platelets, bilirubins (Bil), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), total proteins, γ-glutamil transferase (γ-GT) and alkaline phosphatase (AP), that could be used to predict the severity of hepatic fibrosis in schistosomiasis and hepatitis C (HC) as isolated diseases or co-infections. The following patient groups were selected: HC (n = 39), HC/hepatosplenic schistosomiasis (HSS) (n = 19), HSS (n = 22) and a control group (n = 13). ANOVA and ROC curves were used for statistical analysis. P < 0.05 was considered significant. With HC patients we showed that TNF-α (p = 0.020) and AP (p = 0.005) could differentiate mild and severe fibrosis. With regard to necroinflammatory activity, AST (p = 0.002), γ-GT (p = 0.034) and AP (p = 0.001) were the best markers to differentiate mild and severe activity. In HC + HSS patients, total Bil (p = 0.008) was capable of differentiating between mild and severe fibrosis. In conclusion, our study was able to suggest biological markers that are non-invasive candidates to evaluate fibrosis and necroinflammatory activity in HC and HC + HSS.

Patterns of Subject Mix in Higher Education Institutions : A First Empirical Analysis Using the AQUAMETH Database

Teaching and research are organised differently between subject domains: attempts to construct typologies of higher education institutions, however, often do not include quantitative indicators concerning subject mix which would allow systematic comparisons of large numbers of higher education institutions among different countries, as the availability of data for such indicators is limited. In this paper, we present an exploratory approach for the construction of such indicators. The database constructed in the AQUAMETH project, which includes also data disaggregated at the disciplinary level, is explored with the aim of understanding patterns of subject mix. For six European countries, an exploratory and descriptive analysis of staff composition divided in four large domains (medical sciences, engineering and technology, natural sciences and social sciences and humanities) is performed, which leads to a classification distinguishing between specialist and generalist institutions. Among the latter, a further distinction is made based on the presence or absence of a medical department. Preliminary exploration of this classification and its comparison with other indicators show the influence of long term dynamics on the subject mix of individual higher education institutions, but also underline disciplinary differences, for example regarding student to staff ratios, as well as national patterns, for example regarding the number of PhD degrees per 100 undergraduate students. Despite its many limitations, this exploratory approach allows defining a classification of higher education institutions that accounts for a large share of differences between the analysed higher education institutions.

Epileptogenic zone, electrode location and clinical outcome in hippocampal electrical stimulation for mesial temporal lobe epilepsy : a correlation study

Objectif : Etudier les résultats cliniques du traitement de patients atteints pai- une épilepsie mésiale du lobe temporal (MTLE) réfractaire, par stimulation cérébrale profonde (DBS) de l'hippocampe, en fonction de l'emplacement de l'électrode. Méthodes : Huit patients atteints de MTLE implantés dans l'hippocampe et stimulés par DBS à haute fréquence ont été inclus dans cette étude. Cinq ont subi des enregistrements invasifs avec des électrodes profondes dans le but d'estimer la localisation du foyer ictal avant de procéder à une DBS chronique. La position des contacts actifs de l'électrode a été mesurée en utilisant une imagerie post-opératoire. Les distances par rapport au foyer ictal ont été calculées, et les structures hippocampiques influencées par la stimulation ont été identifiées au moyen d'un atlas neuro-anatomique. Ces deux paramètres ont été corrélés avec la réduction de la fréquence d'apparition des crises. Résultats : Les distances entre la localisation estimée des contacts actifs de l'électrode et le foyer ictal étaient respectivement 11.0 +/- 4.3 ou 9.1 +/- 2.3 mm pour les patients présentant une réduction de > 50% ou < 50% de la fréquence des crises. Chez les patients (N = 6) montrant une réduction de > 50% de la fréquence des crises, 100% avaient des contacts actifs situés à < 3 mm du subiculum (p < 0,05). Les 2 patients ne répondant pas au traitement étaient stimulés par des contacts situés à > 3mm du subiculum. Conclusion : La diminution de l'activité épileptogène induite par DBS sur l'hippocampe dans les cas de MTLE réfractaires : 1) ne semble pas directement liée à la proximité des contacts actifs de l'électrode au foyer ictal déterminé par les enregistrements invasifs ; 2) pourrait être obtenue par une neuro-modulation du subiculum.

European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on Infections in Leukemia.

Owing to increasing resistance and the limited arsenal of new antibiotics, especially against Gram-negative pathogens, carefully designed antibiotic regimens are obligatory for febrile neutropenic patients, along with effective infection control. The Expert Group of the 4(th) European Conference on Infections in Leukemia has developed guidelines for initial empirical therapy in febrile neutropenic patients, based on: i) the local resistance epidemiology; and ii) the patient's risk factors for resistant bacteria and for a complicated clinical course. An 'escalation' approach, avoiding empirical carbapenems and combinations, should be employed in patients without particular risk factors. A 'de-escalation' approach, with initial broad-spectrum antibiotics or combinations, should be used only in those patients with: i) known prior colonization or infection with resistant pathogens; or ii) complicated presentation; or iii) in centers where resistant pathogens are prevalent at the onset of febrile neutropenia. In the latter case, infection control and antibiotic stewardship also need urgent review. Modification of the initial regimen at 72-96 h should be based on the patient's clinical course and the microbiological results. Discontinuation of antibiotics after 72 h or later should be considered in neutropenic patients with fever of unknown origin who are hemodynamically stable since presentation and afebrile for at least 48 h, irrespective of neutrophil count and expected duration of neutropenia. This strategy aims to minimize the collateral damage associated with antibiotic overuse, and the further selection of resistance.