Response Prediction in Chronic Hepatitis C by Assessment of IP-10 and IL28B-Related Single Nucleotide Polymorphisms.

BACKGROUND: High baseline levels of IP-10 predict a slower first phase decline in HCV RNA and a poor outcome following interferon/ribavirin therapy in patients with chronic hepatitis C. Several recent studies report that single nucleotide polymorphisms (SNPs) adjacent to IL28B predict spontaneous resolution of HCV infection and outcome of treatment among HCV genotype 1 infected patients. METHODS AND FINDINGS: In the present study, we correlated the occurrence of variants at three such SNPs (rs12979860, rs12980275, and rs8099917) with pretreatment plasma IP-10 and HCV RNA throughout therapy within a phase III treatment trial (HCV-DITTO) involving 253 Caucasian patients. The favorable SNP variants (CC, AA, and TT, respectively) were associated with lower baseline IP-10 (P = 0.02, P = 0.01, P = 0.04) and were less common among HCV genotype 1 infected patients than genotype 2/3 (P<0.0001, P<0.0001, and P = 0.01). Patients carrying favorable SNP genotypes had higher baseline viral load than those carrying unfavorable variants (P = 0.0013, P = 0.029, P = 0.0004 respectively). Among HCV genotype 1 infected carriers of the favorable C, A, or T alleles, IP-10 below 150 pg/mL significantly predicted a more pronounced reduction of HCV RNA from day 0 to 4 (first phase decline), which translated into increased rates of RVR (62%, 53%, and 39%) and SVR (85%, 76%, and 75% respectively) among homozygous carriers with baseline IP-10 below 150 pg/mL. In multivariate analyses of genotype 1-infected patients, baseline IP-10 and C genotype at rs12979860 independently predicted the first phase viral decline and RVR, which in turn independently predicted SVR. CONCLUSIONS: Concomitant assessment of pretreatment IP-10 and IL28B-related SNPs augments the prediction of the first phase decline in HCV RNA, RVR, and final therapeutic outcome.

BME-based uncertainty assessment of the Chernobyl fallout

The vast territories that have been radioactively contaminated during the 1986 Chernobyl accident provide a substantial data set of radioactive monitoring data, which can be used for the verification and testing of the different spatial estimation (prediction) methods involved in risk assessment studies. Using the Chernobyl data set for such a purpose is motivated by its heterogeneous spatial structure (the data are characterized by large-scale correlations, short-scale variability, spotty features, etc.). The present work is concerned with the application of the Bayesian Maximum Entropy (BME) method to estimate the extent and the magnitude of the radioactive soil contamination by 137Cs due to the Chernobyl fallout. The powerful BME method allows rigorous incorporation of a wide variety of knowledge bases into the spatial estimation procedure leading to informative contamination maps. Exact measurements (?hard? data) are combined with secondary information on local uncertainties (treated as ?soft? data) to generate science-based uncertainty assessment of soil contamination estimates at unsampled locations. BME describes uncertainty in terms of the posterior probability distributions generated across space, whereas no assumption about the underlying distribution is made and non-linear estimators are automatically incorporated. Traditional estimation variances based on the assumption of an underlying Gaussian distribution (analogous, e.g., to the kriging variance) can be derived as a special case of the BME uncertainty analysis. The BME estimates obtained using hard and soft data are compared with the BME estimates obtained using only hard data. The comparison involves both the accuracy of the estimation maps using the exact data and the assessment of the associated uncertainty using repeated measurements. Furthermore, a comparison of the spatial estimation accuracy obtained by the two methods was carried out using a validation data set of hard data. Finally, a separate uncertainty analysis was conducted that evaluated the ability of the posterior probabilities to reproduce the distribution of the raw repeated measurements available in certain populated sites. The analysis provides an illustration of the improvement in mapping accuracy obtained by adding soft data to the existing hard data and, in general, demonstrates that the BME method performs well both in terms of estimation accuracy as well as in terms estimation error assessment, which are both useful features for the Chernobyl fallout study.

Assessment of diesel exhaust particulate exposure and surface characteristics in association with levels of oxidative stress biomarkers

Exposure to PM10 and PM2.5 (particulate matter with aerodynamic diameter smaller than 10 μm and 2.5 μm, respectively) is associated with a range of adverse health effects, including cancer, pulmonary and cardiovascular diseases. Surface characteristics (chemical reactivity, surface area) are considered of prime importance to understand the mechanisms which lead to harmful effects. A hypothetical mechanism to explain these adverse effects is the ability of components (organics, metal ions) adsorbed on these particles to generate Reactive Oxygen Species (ROS), and thereby to cause oxidative stress in biological systems (Donaldson et al., 2003). ROS can attack almost any cellular structure, like DNA or cellular membrane, leading to the formation of a wide variety of degradation products which can be used as a biomarker of oxidative stress. The aim of the present research project is to test whether there is a correlation between the exposure to Diesel Exhaust Particulate (DEP) and the oxidative stress status. For that purpose, a survey has been conducted in real occupational situations where workers were exposed to DEP (bus depots). Different exposure variables have been considered: - particulate number, size distribution and surface area (SMPS); - particulate mass - PM2.5 and PM4 (gravimetry); - elemental and organic carbon (coulometry); - total adsorbed heavy metals - iron, copper, manganese (atomic adsorption); - surface functional groups present on aerosols (Knudsen flow reactor). (Demirdjian et al., 2005). Several biomarkers of oxidative stress (8-hydroxy-2'-deoxyguanosine and several aldehydes) have been determined either in urine or serum of volunteers. Results obtained during the sampling campaign in several bus depots indicated that the occupational exposure to particulates in these places was rather low (40-50 μg/m3 for PM4). Size distributions indicated that particles are within the nanometric range. Surface characteristics of sampled particles varied strongly, depending on the bus depot. They were usually characterized by high carbonyl and low acidic sites content. Among the different biomarkers which have been analyzed within the framework of this study, mean levels of 8- hydroxy-2'-deoxyguanosine and several aldehydes (hexanal, heptanal, octanal, nonanal) increased during two consecutive days of exposure for non-smokers. In order to bring some insight into the relation between the particulate characteristics and the formation of ROS by-products, biomarkers levels will be discussed in relation with exposure variables.

Who is at low risk for cardiovascular disease? An assessment of different definitions

Background: There is little information regarding the determinants and trends of the prevalence of low cardiovascular risk factor (RF) profile in the general population. The aim of this study was to assess the prevalence and trends of low RF profile in the Swiss population according to different definitions. Methods: Population-based cross-sectional studies conducted in 1984-6 (N=3300), 1988-9 (N=3331), 1992-3 (N=3133) and 2003-6 (N=6170) and restricted to age group 35-75 years. Seven different definitions of low RF profile were used to assess determinants, while two definitions were used to assess trends. Results: Prevalence of low RF profile varied between 6.5% (95% confidence interval: 5.9-7.1) and 9.7% (9.0-10.5) depending on the definition used. This prevalence was higher than in other countries. Irrespective of the definition used, the prevalence of low RF profile was higher in women and in physically active participants, and decreased with increasing age or in the presence of a family history of cardiovascular disease. Using one definition, the prevalence of low RF profile increased from 3.8% (3.1-4.5) in 1984-6 to 6.7% (6.1-7.3) in 2003-6; using another definition, the results were 5.9% (5.1-6.8) and 9.7% (9.0-10.5), respectively. Conclusion: Switzerland is characterized by a high and increasing prevalence of low RF profile within the age group 35 to 75, irrespective of the criteria used. This high prevalence might partly e

Toward a Statistically Robust Assessment of Social and Solidarity Economy Actors. Conceptual Development and Empirical Validation

Many definitions and debates exist about the core characteristics of social and solidarity economy (SSE) and its actors. Among others, legal forms, profit, geographical scope, and size as criteria for identifying SSE actors often reveal dissents among SSE scholars. Instead of using a dichotomous, either-in-or-out definition of SSE actors, this paper presents an assessment tool that takes into account multiple dimensions to offer a more comprehensive and nuanced view of the field. We first define the core dimensions of the assessment tool by synthesizing the multiple indicators found in the literature. We then empirically test these dimensions and their interrelatedness and seek to identify potential clusters of actors. Finally we discuss the practical implications of our model.

What kind of relationships between the evolution of pain, beliefs and bio-psycho-social complexity after a locomotor traumatism?

Introduction: Pain and beliefs have an influence on the patient's course in rehabilitation, pain causes fears and fears influence pain perception. The aim of this study is to understand pain and beliefs evolutions during rehabilitation taking into account of bio-psycho-social complexity.Patients and methods: 631 consecutive patients admitted in rehabilitation after a musculoskeletal traumatism were included and assessed at admission and at discharge. Pain was measured by VAS (Visual Analogical Scale), bio-psycho-social complexity by Intermed scale, and beliefs by judgement on Lickert scales. Four kinds of beliefs were evaluated: fear of a severe origin of pain, fear of movement, fear of pain and feeling of distress (loss of control). The association between the changes in pain and beliefs during the hospitalization was assessed by linear regressions.Results: After adjustment for gender, age, education and native language, patients with a decrease in pain during rehabilitation have higher probability of decreasing their fears. For the distress feeling, this relationship is weaker among bio-psycho-socially complex patients (odds-ratio 1.22 for each decreasing of 10mm/100 VAS) than among non-complex patients (OR 1.47). Patients with a pain decrease of 30% or more during hospitalization have higher probability of seeing their fears decrease, this relationship being stronger in complex patient for fear of a severe origin of pain.Discussion: The relationships between evolution of pain and beliefs move in the same direction. The higher a patient feels pain, the less they could be able to modify their dysfunctional beliefs. When the pain diminishes of 30% or more, the probability to challenge the beliefs is increased. The prognostic with regard to feeling of distress and fear of a severe origin of pain, is worse among bio-psycho-socially complex patients.

In vitro assessment of the pulmonary toxicity and gastric availability of lead-rich particles from a lead recycling plant

Epidemiological studies in urban areas have linked increasing respiratory and cardiovascular pathologies with atmospheric particulate matter (PM) from anthropic activities. However, the biological fate of metal-rich PM industrial emissions in urban areas of developed countries remains understudied. Lead toxicity and bioaccessibility assessments were therefore performed on emissions from a lead recycling plant, using complementary chemical acellular tests and toxicological assays, as a function of PM size (PM(10-2.5), PM(2.5-1) and PM(1)) and origin (furnace, refining and channeled emissions). Process PM displayed differences in metal content, granulometry, and percentage of inhalable fraction as a function of their origin. Lead gastric bioaccessibility was relatively low (maximum 25%) versus previous studies; although, because of high total lead concentrations, significant metal quantities were solubilized in simulated gastrointestinal fluids. Regardless of origin, the finest PM(1) particles induced the most significant pro-inflammatory response in human bronchial epithelial cells. Moreover, this biological response correlated with pro-oxidant potential assay results, suggesting some biological predictive value for acellular tests. Pulmonary effects from lead-rich PM could be driven by thiol complexation with either lead ions or directly on the particulate surface. Finally, health concern of PM was discussed on the basis of pro-inflammatory effects, accellular test results, and PM size distribution.

Assessment of needs, health-related quality of life, and satisfaction with care in breast cancer patients to better target supportive care.

BACKGROUND: This study assessed whether breast cancer (BC) patients express similar levels of needs for equivalent severity of symptoms, functioning difficulties, or degrees of satisfaction with care aspects. BC patients who did (or not) report needs in spite of similar difficulties were identified among their sociodemographic or clinical characteristics. PATIENTS AND METHODS: Three hundred and eighty-four (73% response rate) BC patients recruited in ambulatory or surgery hospital services completed the European Organisation for Research and Treatment of Cancer Quality of Life questionnaire (EORTC QLQ)-C30 quality of life [health-related quality of life (HRQOL)], the EORTC IN-PATSAT32 (in-patient) or OUT-PATSAT35 (out-patient) satisfaction with care, and the supportive care needs survey short form 34-item (SCNS-SF34) measures. RESULTS: HRQOL or satisfaction with care scale scores explained 41%, 45%, 40% and 22% of variance in, respectively, psychological, physical/daily living needs, information/health system, and care/support needs (P < 0.001). BC patients' education level, having children, hospital service attendance, and anxiety/depression levels significantly predicted differences in psychological needs relative to corresponding difficulties (adjusted R(2) = 0.11). Medical history and anxiety/depression levels significantly predicted differences in information/health system needs relative to degrees of satisfaction with doctors, nurses, or radiotherapy technicians and general satisfaction (adjusted R(2) = 0.12). Unmet needs were most prevalent in the psychological domains across hospital services. CONCLUSIONS: Assessment of needs, HRQOL, and satisfaction with care highlights the subgroups of BC patients requiring better supportive care targeting.

Assessment of a new MRI classification of spinal stenosis based on cross-sectional morphology of the dural sac : FM2

Introduction: Quantitative measures of degree of lumbar spinal stenosis (LSS) such as antero-posterior diameter of the canal or dural sac cross sectional area vary widely and do not correlate with clinical symptoms or results of surgical decompression. In an effort to improve quantification of stenosis we have developed a grading system based on the morphology of the dural sac and its contents as seen on T2 axial images. The grading comprises seven categories ranging form normal to the most severe stenosis and takes into account the ratio of rootlet/CSF content. Material and methods: Fifty T2 axial MRI images taken at disc level from twenty seven symptomatic lumbar spinal stenosis patients who underwent decompressive surgery were classified into seven categories by five observers and reclassified 2 weeks later by the same investigators. Intra- and inter-observer reliability of the classification were assessed using Cohen's and Fleiss' kappa statistics, respectively. Results: Generally, the morphology grading system itself was well adopted by the observers. Its success in application is strongly influenced by the identification of the dural sac. The average intraobserver Cohen's kappa was 0.53 ± 0.2. The inter-observer Fleiss' kappa was 0.38 ± 0.02 in the first rating and 0.3 ± 0.03 in the second rating repeated after two weeks. Discussion: In this attempt, the teaching of the observers was limited to an introduction to the general idea of the morphology grading system and one example MRI image per category. The identification of the dimension of the dural sac may be a difficult issue in absence of complete T1 T2 MRI image series as it was the case here. The similarity of the CSF to possibly present fat on T2 images was the main reason of mismatch in the assignment of the cases to a category. The Fleiss correlation factors of the five observers are fair and the proposed morphology grading system is promising.

Assessment of human skin penetration of two irritant herbicides

Two common herbicides; isoproturon and bentazon, are strong skin irritants and cross the skin barrier easily. Assessment of percutaneous absorption of these substances is a very important step in the evaluation of any dermal or transdermal dose, especially among agricultural workers who frequently have dermal exposures during crop treatment. The aims of the study were to determine the permeation rate of human skin for both herbicides in vitro, and histologically evaluate skin damage due to irritation at different concentrations. Skin penetration was assessed using a dynamic flow-through in vitro penetration system and analysis were performed with ion trap LC-MS (acidified water: acetronitile, C18 column). Two concentrations of bentazon (75 and 150 μg/mL) and isoproturon (125 and 250 μg/mL) in saline solution were applied on excised human skin from several donors. Saline water was used as receptor fluid. Collection times were: 4, 8, and 24 hours. After the experiments, the skin was removed and examined by histopathology for apoptosis, acanthosis, acantholysis and epidermolysis. The skin permeation rate, J, was calculated from the slope of the cumulative amount permeated as a function of time. The lag time, tL, was assigned from the time-axis intercept of the extrapolation of this linearity. Our results showed that tL for bentazon and isoproturon for both concentrations tested were similar; 2, 1.5 hours, respectively. Bentazon had a lowerer J compared to isoproturon; 350, 600 ng/cm2/h, respectively. Some acanthosis was observed after 8 hours of exposure to either of the two substances. In conclusion, our in vitro experiments demonstrate that bentazon and isoproturon cross the skin barrier within 2 hours even at very low concentrations, and showed some signs of skin damage. Future tests involve concentrations found in commercial products.

Visualization and quality assessment of de novo genome assemblies.

Recent technological progress has greatly facilitated de novo genome sequencing. However, de novo assemblies consist in many pieces of contiguous sequence (contigs) arranged in thousands of scaffolds instead of small numbers of chromosomes. Confirming and improving the quality of such assemblies is critical for subsequent analysis. We present a method to evaluate genome scaffolding by aligning independently obtained transcriptome sequences to the genome and visually summarizing the alignments using the Cytoscape software. Applying this method to the genome of the red fire ant Solenopsis invicta allowed us to identify inconsistencies in 7%, confirm contig order in 20% and extend 16% of scaffolds.Scripts that generate tables for visualization in Cytoscape from FASTA sequence and scaffolding information files are publicly available at https://github.com/ksanao/TGNet.

Systematic Assessment of Factors Influencing Preferences of Crohn's Disease Patients in Selecting an Anti-TNF agent (CHOOSE TNF TRIAL)

Background a nd A ims: I nfliximab (IFX), adalimumab (ADA)and certolizumab pegol (CZP) have similar efficacy for inductionand maintenance of clinical response and remission in Crohn'sdisease (CD). Given the comparable nature of t hese drugs,patients' p references m ay i nfluence the choice o f the product.Goal: to identify factors contributing to CD patients' decision inselecting one anti-TNF agent over the others.Methods: A p rospectdive s urvey was performed a mong a nti-TNF-naïve CD patients. Prior to completion of a questionnaire,patients were provided with a description of the three anti-TNFagents f ocusing on indications, route of administration, s ideeffects, and scientific evidence of efficacy and safety.Results: One hundred patients (47f/53m, mean age 45±16yrs)completed the questionnaire. Disease location was ileal, colonicand ileocolonic in 33%, 40% and 27% of patients, respectively.Thirty-six percent preferred ADA as medication of choice, while28% and 2 5% p referred CZP and IFX; 11% were u ndecided.Patients' decision in selecting an anti-TNF drug was influencedby t he following f actors: side effects ( 76%), p hysician'srecommendation (66%), route of administration (54%), efficacydata (52%), time required for therapy administration (27%),recommendations by other CD patients (21%) and interactionswith other medications (12%).Conclusions: T he majority of p atients p referred anti-TNFmedications t hat were a dministered by s ubcutaneous i njectionrather t han b y intravenous i nfusion. Side effect profile andphysicians' r ecommendation are t wo m ajor factors influencingthe patients' s election of a specific anti-TNF d rug. Patients'concerns about safety and lifestyle habits should be taken intoaccount when prescribing anti-TNF drugs.