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Contains fulltext : 293456.pdf (Publisher’s version ) (Open Access) Imatinib plasma trough concentrations are associated with efficacy for patients treated for advanced or metastatic KIT-positive gastrointestinal stromal tumours (GISTs). This relationship has not been studied for patients treated in the neoadjuvant setting, let alone its correlation with tumour drug concentrations. In this exploratory study we aimed to determine the correlation between plasma and tumour imatinib concentrations in the neoadjuvant setting, investigate tumour imatinib distribution patterns within GISTs, and analyse its correlation with pathological response. Imatinib concentrations were measured in both plasma and in three regions of the resected primary tumour: the core, middle part, and periphery. Twenty-four tumour samples derived from the primary tumours of eight patients were included in the analyses. Imatinib tumour concentrations were higher compared to plasma concentrations. No correlation was observed between plasma and tumour concentrations. Interpatient variability in tumour concentrations was high compared to interindividual variability in plasma concentrations. Although imatinib accumulates in tumour tissue, no distribution pattern of imatinib in tumour tissue could be identified. There was no correlation between imatinib concentrations in tumour tissue and pathological treatment response.

INTRODUCTION The distinction between epidermal necrolysis [EN; including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and overlap syndrome] and erythema multiforme major (EMM) in children is confusing. We aimed to better describe and compare these entities. MATERIALS AND METHODS This French retrospective multicentre study included children ≤18 years old referred for EN or EMM between 1 January 2008 and 1 March 2019. According to pictures, children were reclassified into TEN/overlap, SJS or EMM/unclassified (SJS/EMM) groups and compared for epidemiological and clinical data, triggers, histology and follow-up. RESULTS We included 62 children [43 boys, median age 10 years (range 3-18)]: 16 with TEN/overlap, 11 SJS and 35 EMM. The main aetiologies were drugs in EN and infections (especially Mycoplasma pneumoniae) in EMM (P

Resume Introduction Avec les progres effectues en reanimation pediatrique ces dernieres annees et l’augmentation de la survie des grands prematures, les consequences de la prematurite sont de plus en plus documentees. Au niveau ophtalmologique, la retinopathie du premature est bien connue, mais la papille presente, elle aussi, des particularites. L’objectif de cette etude est de comparer les nerfs optiques des enfants prematures en fonction du terme de naissance avec une population temoin du meme âge. Materiel et methodes Notre etude etait une etude cas-temoins avec l’appariement d’un enfant ne a terme pour chaque enfant ne premature. Les criteres d’inclusions pour les cas etaient : tout enfant premature, âge de 5 a 10 ans, separe en trois sous-groupes en fonction du degre de prematurite. Les criteres de comparaison etaient : le rapport cup/disc, la biometrie oculaire, la pression intraoculaire, l’epaisseur des fibres optiques RNFL. Resultats Trente-sept enfants nes prematures et 37 temoins ont ete inclus dans l’etude. L’âge moyen des enfants nes prematures etait de 7,05 ans, au moment de l’inclusion, et 7,19 pour les temoins. Au niveau de la longueur axiale et de l’equivalent spherique, il n’y avait pas de difference significative avec respectivement p = 0,31, et p = 0,98. Concernant la pachymetrie et la pression intraoculaire, il n’y avait pas non plus de difference significative avec respectivement p = 0,28 et p = 0,22. On retrouve cependant une difference significative concernant le rapport cup/disc avec p Conclusions La reduction du nombre de fibres au RNFL est un phenomene qui depend essentiellement du stade de la prematurite chez les enfants etudies, âges de 5 a 10 ans. Il serait utile de suivre au long cours ces populations d’anciens prematures et de pouvoir les comparer a des temoins dans le temps et ainsi en tirer des resultats fonctionnels.

Objectives To describe the cumulative incidences of adverse drug reactions (ADRs) associated with disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients from real-world data (RWD), using the DREAM-RA registry, and to compare these with incidence frequencies mentioned in the Summary of Product Characteristics (SmPC). Methods All ADRs in patients with recorded use of adalimumab, etanercept, hydroxychloroquine, leflunomide, oral and subcutaneous methotrexate, and sulfasalazine from a single center participating in the DREAM-RA registry (n = 1,098 patients) that were directly sent to the Netherlands Pharmacovigilance Center Lareb were assessed. Cumulative incidences were calculated, described and compared to the most recently revised SmPCs. Results In total, 14 ADRs (>= 5 case reports) associated with the use of one of the included DMARDs were reported with a higher estimated cumulative incidence compared to the SmPC. For hydroxychloroquine and sulfasalazine, 5 ADRs (>= 5 case reports) mentioned with an 'unknown' incidence in the SmPC were reported as 'common' in this study. Conclusions Although ADR data in the DREAM-RA registry were partly comparable with data in the SmPCs, RWD from this patient registry provided an added value to the currently available information on the incidences of ADRs associated with DMARDs in RA patients as described in SmPCs.

The human auditory system is not equally reactive to all frequencies of the audible spectrum. Emotional and behavioral reactions to loud or aversive acoustic features can vary from one individual to another, to the point that some exhibit exaggerated or even pathological responses to certain sounds. The neural mechanisms underlying these interindividual differences remain unclear. Whether distinct aversion profiles map onto neural excitability at the individual level needs to be tested. Here, we measured behavioral and EEG responses to click trains (from 10 to 250 Hz, spanning the roughness and pitch perceptual ranges) to test the hypothesis that interindividual variability in aversion to rough sounds is reflected in neural response differences between participants. Linking subjective aversion to 40 Hz steady-state EEG responses, we demonstrate that participants experiencing enhanced aversion to roughness also show stronger neural responses to this attribute. Interestingly, this pattern also correlates with inter-individual anxiety levels, suggesting that this personality trait might interact with subjective sensitivity and neural excitability to these sounds. These results support the idea that 40 Hz sounds can probe the excitability of non-canonical auditory systems involved in exogenous salience processing and aversive responses at the individual level. By linking subjective aversion to neural excitability, 40 Hz sounds provide neuromarkers relevant to a variety of pathological conditions, such as those featuring enhanced emotional sensitivity (hyperacusis, anxiety) or aberrant neural responses at 40 Hz (autism, schizophrenia).

The antipsychotic drug clozapine is associated with weight gain. The proposed mechanisms include blocking of serotonin (5-HT2a/2c ), dopamine (D2 ) and histamine (H1 ) receptors. Clozapine is metabolized by cytochrome P450 1A2 (CYP1A2) to norclozapine, a metabolite with more 5-HT2c -receptor and less H1 blocking capacity. We hypothesized that norclozapine serum levels correlate with body mass index (BMI), waist circumference and other parameters of the metabolic syndrome. We performed a retrospective cross-sectional study in 39 patients (female n = 8 (20.5%), smokers n = 18 (46.2%), average age 45.8 ± 9.9 years) of a clozapine outpatient clinic in the Netherlands between 1 January 2017 and 1 July 2020. Norclozapine concentrations correlated with waist circumference (r = 0.354, P = .03) and hemoglobin A1c (HbA1c) (r = 0.34, P = .03). In smokers (smoking induces CYP1A2), norclozapine concentrations correlated with waist circumference (r = 0.723, P = .001), HbA1c (r = 0.49, P = .04) and BMI (r = 0.63, P = .004). Elucidating the relationship between norclozapine and adverse effects of clozapine use offers perspectives for interventions and treatment options.

The diagnosis of exercise-induced laryngeal obstruction (EILO) should be suspected when exercise triggers inspiratory stridor. EILO is common in adolescent populations and has a significant impact on sports. Identification of laryngeal obstruction during continuous laryngoscopy during exercise (CLE) is the gold standard diagnostic tool for this disorder, which is not widely known in France. The challenge faced by otolaryngologists is to identify, among patients referred by pulmonologists or sports physicians, those with exercise-induced inspiratory symptoms or poorly controlled exercise-induced asthma, in whom a diagnosis of EILO is strongly suspected. Laryngoscopy at rest may reveal a laryngeal, glottic or supraglottic abnormality predictive of obstruction at increased inspiratory airflow. When pulmonary function tests are normal or in the case of failure of treatment of exercise-induced asthma, the otolaryngologist must complete the examination by a CLE test to confirm the diagnosis of EILO and identify the site of obstruction. This examination is well tolerated, minimally invasive and allows identification of the site of airflow obstruction, allowing specific conservative or surgical treatment. This technical note describes in detail clinical examination and CLE testing in patients with suspected EILO.

Introduction Inflammatory bowel disease (IBD) frequently requires chronic immunosuppressive treatment and active involvement from patients during treatment decision making. Information about the risk of developing adverse drug reactions (ADRs) to IBD therapies is required in this process. Objective The aim of this study was to describe the ADRs reported in IBD patients from real-world data, using the Dutch nationwide IBDREAM registry, and compare the occurrence and cumulative incidences with the Summary of Product Characteristics (SmPC) of the associated drugs. Methods In this retrospective multicentre study, ADRs related to IBD medication were assessed. Only reports associated with the use of drugs used for the maintenance treatment of IBD were included. All ADRs were verified by healthcare professionals and coded by trained pharmacovigilance assessors. Results In total, 3080 ADRs were reported in 1179 patients. Twenty-three new drug–ADR associations related to the use of azathioprine, mercaptopurine, infliximab, oral mesalamine and thioguanine were reported in the IBDREAM registry that were not mentioned in the corresponding SmPCs. The most frequently reported new association was pyrexia for azathioprine (3.1%) and mercaptopurine (4.9%). In addition, there were seven ADRs with a higher cumulative incidence in IBDREAM compared with the SmPC, and included, among others, arthralgia during mercaptopurine use (2.5%), and diarrhoea (1.4%), alopecia (1.2%) and infections (1.6%) during azathioprine use. Conclusions Based on real-world data, ADR reporting demonstrated new ADRs and higher incidences of ADRs to IBD therapies. This information will contribute to drug safety by updating the SmPCs, allowing better risk assessment and communication towards patients. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01045-3.

Propylthiouracil (PTU) is a synthetic antithyroid drug that can induce ANCA-associated vasculitis.A 27-year-old woman diagnosed with Graves' disease was on PTU for the past 10 years. She developed purpuric lesions of the legs and on the tip of the nose diagnosed as vasculitis. ANCAs were positive, with anti-MPO and anti-PR3 on blood ELISA. After discontinuation of PTU, she was able to fully recover.All synthetic antithyroid drugs can induce ANCA-associated vasculitis, more often PTU. In most cases, antibodies are directed against MPO. Dual anti-MPO and anti-PR3 positivity is possible, but rare. The mechanism could be through an accumulation of PTU in neutrophils, altering the structure of MPO and making it immunogenic. PTU can also induce ANCA-free or lupus vasculitis, maculopapular rashes or urticaria. Many other drugs can induce ANCA-associated vasculitis.

Caudal vena cava (CVC) diameter and collapsibility index (CVCThis retrospective study included 79 dogs with DMVD presented to the cardiology department between January 2017 and 2019. Subxiphoid views were used to obtain CVC cineloops. By visual inspection, CVC was subjectively scored as flat, normal or fat. Maximal and minimal CVCSubjective assessment was associated with American College of Veterinary Internal Medicine (ACVIM) stages (P 0.001). The proportion of fat CVC was greater in stages C and D. In stage D, CVCIn dogs with DMVD without clinically important right heart disease, CVC variables differ across ACVIM stage. Subjective and objective CVC variables may be used to predict hypervolemia.

Thanks to the progress made in the past few years in pediatric intensive care as well as the increased survival of preterm infants, the consequences of premature birth are increasingly well documented. With regard to ophthalmologic complications, retinopathy of prematurity is well described, but the optic nerve may also be affected. The goal of this study is to compare the optic nerves of preterm infants as a function of their gestational period with a control group of the same age.We conducted a case-control study pairing a full-term infant with each preterm infant. Inclusion criteria were: any child from 5- to 10-years-old, separated into three sub-groups according to their degree of prematurity. Variables were: cup/disc ratio, ocular biometry, intraocular pressure and RNFL thickness.Thirty-seven preterm infants and 37 controls were included in the study. The mean age at the time of inclusion was 7.05 years for the preterm group and 7.19 years for the control group. No significant difference was observed in axial length or spherical equivalent (P=0.31 and P=0.98, respectively). No significant difference was observed in pachymetry or intraocular pressure (P=0.28 and P=0.22, respectively). We observed a significant increase of 0.1 in the cup/disc ratio of the preterm group compared to the control group (P0.05). The preterm group cup/disc ratio was 0.36 versus 0.27 for the control group. No significant difference was observed in the 7 quadrants of RNFL between the two groups. However, when comparing infants born before 28 weeks gestation with the control group, we observed a mean decrease of 14.5 microns in the superior temporal sector (P=0.04), a 9 micron decrease in the global thickness G (P=0.03) and a 12.7 micron decrease in the nasal sector (P=0.01).In the case of the studied children (aged 5 to 10), the reduced RNFL fiber thickness is a phenomenon dependent essentially on the stage of prematurity. It would be useful to follow these preterm populations over the long term and to compare them to a matched control group to be able to obtain functional results.

Introduction Les vascularites medicamenteuses sont rares. Nous rapportons le cas d’une vascularite cutanee a ANCA induite par le propylthiouracil (PTU) chez une patiente suivie pour maladie de Basedow. Observations Une femme de 27 ans, traitee par PTU depuis 10 ans pour maladie de Basedow, avait des papules urticariennes des jambes evoluant par poussees depuis 3 ans. Depuis 3 semaines, le tableau s’etait complete de nouvelles lesions, motivant la consultation. L’examen revelait des maculo-papules purpuriques douloureuses, necrotiques ou pustuleuses, des membres inferieurs et de la pointe du nez. On notait des arthralgies inflammatoires et une dyspnee recente. Une vascularite systemique a ANCA etait suspectee. Le bilan immunologique trouvait des ANCA positifs a 1/400, de fluorescence cytoplasmique et peri-nucleaire, des anti-MPO et anti-PR3 positifs en Elisa, des anticorps antinucleaires negatifs, un anticoagulant circulant lupique douteux et des IgM anticardiolipides et anti-β2GP1 faiblement positifs. Le bilan systemique (ECG, TDM thoracique, EFR, proteinurie, TDM des sinus et examen ORL) etait normal. Le bilan thyroidien sous PTU trouvait une euthyroidie avec des TRAK positifs (anticorps antirecepteurs de la TSH). La biopsie cutanee trouvait un aspect de vascularite leucocytoclasique associee a des thromboses superficielles dermiques ; l’IFD des amas granuleux de C3 et IgM sur les vaisseaux. Le diagnostic de vascularite cutanee au PTU etait pose. Apres arret de celui-ci, un autre antithyroidien ne pouvant etre instaure, la maladie thyroidienne etait traitee par iode radioactif encadre d’une corticotherapie generale sur 2 mois afin d’eviter l’aggravation de l’orbitopathie. A 2 mois, il n’y avait plus aucune lesion clinique, le titre d’ANCA avait baisse a 1/100 et les anticardiolipides avaient disparu. Discussion Tous les antithyroidiens de synthese, plus souvent le PTU que le carbimazole ou le thiamazole, peuvent, rarement, induire des vascularites a ANCA (0,47 a 0,71/10 000 patients traites). Le mecanisme pourrait passer par une accumulation du PTU dans les neutrophiles, se liant et alterant la MPO. Le delai d’induction peut etre long (jusqu’a 20 ans). Outre la peau (purpura, urticaire), les atteintes renales sont frequentes (58 %). L’histologie peut etre atypique avec aspect de vascularite thrombosante. Le bilan immunologique revele des anti-MPO (les plus frequents) et, rarement, des anti-PR3. Les anticardiolipides ne sont pas typiques. Le traitement repose sur l’arret du PTU, associe ou non a une corticotherapie generale. L’evolution est le plus souvent favorable, mais 5 patients sont decedes. Pour le traitement de la thyroide, le risque lie a l’effet de classe doit etre pris en compte. En conclusion, les vascularites a ANCA au PTU, et plus generalement aux antithyroidiens de synthese, sont trompeuses mais doivent etre connues des dermatologues.

Introduction La necrolyse epidermique (NE, syndrome de Lyell, chevauchement et Stevens–Johnson [SJS]) et l’erytheme polymorphe majeur (EPM) de l’enfant sont mal individualises dans la litterature, avec des donnees descriptives confuses. L’objectif principal de notre etude etait de mieux decrire et comparer ces deux entites chez l’enfant. Materiel et methodes Cette etude retrospective, multicentrique a inclus les enfants avec NE ou EPM (hospitalises > 3 jours) entre 01/2008 et 03/2019. Les dossiers, issus du PMSI et/ou des fichiers de service (items Lyell, SJS, EPM), ont ete analyses avec recueil des donnees demographiques, cliniques, paracliniques, les traitements et complications. Les photographies disponibles ont ete revues. Trois groupes (selon conclusions des dossiers) ont ete individualises et compares : Lyell/chevauchement, SJS, EPM/inclassable (c.-a-d. SJS/EPM). Resultats Soixante-dix-neuf patients (51 garcons, âge moyen 9,4 ans) ont ete inclus : 19 Lyell/chevauchement,13 SJS et 47 EPM dont 3 inclassables ( Tableau 1 ). Il existait dans les 3 groupes une survenue majoritaire en automne/hiver (60 %). Un asthme etait note chez 23 % des EPM vs 5–15 % des NE (p = 0,14). L’etiologie majoritaire etait medicamenteuse pour les NE et infectieuse pour les EPM (p Tableau 2 ) mais 38 % des cas etaient idiopathiques (Lyell 47 %, SJS 23 %, EPM 38 %). Les cocardes typiques etaient plus frequentes dans les EPM (p = 0,0065), la topographie plus souvent le tronc dans la NE (p Discussion Dans cette serie de NE et EPM pediatriques, les aspects cliniques des NE et EPM sont assez tranches, les formes de transition semiologiques peu frequentes. Le MP (1/3 des cas) est le plus souvent associe a un tableau d’EPM typique. L’asthme pourrait en etre un facteur favorisant. Des virus sont parfois retrouves, de causalite difficile a affirmer. Les formes idiopathiques sont frequentes, notamment pour les NE (53 %). Les EPM exposent a des sequelles tout comme les NE. Conclusion Les tableaux de NE et EPM de l’enfant sont le plus souvent bien distincts. Le bilan infectieux doit etre complet mais les cas idiopathiques sont frequents. Le depistage des complications doit etre precoce.

Introduction La dermatose a IgA lineaire (DIGAL), dermatose bulleuse auto-immune (DBAI) la plus frequente chez l’enfant, est rare avant l’âge de 5 ans. Nous discutons les causes d’une DIGAL de survenue neonatale. Observations Un nouveau-ne de 5 jours presentait une eruption bulleuse apparue a deux jours de vie. La grossesse etait de deroulement normal et l’accouchement, par voie basse, sans complication. L’enfant etait apyretique et en bon etat general. Des bulles tendues sur peau saine etaient disposees de maniere symetrique autour de la bouche, sur les quatre membres et le siege. Les paumes, les plantes et les muqueuses etaient respectees. L’histoire familiale etait negative. En per partum, une fievre maternelle a 38,5 °C avait justifie un traitement intraveineux par amoxicilline. Les prelevements vaginaux etaient negatifs. Malgre des prelevements microbiologiques negatifs et l’absence de syndrome inflammatoire, l’enfant etait traite par amoxicilline – acide clavulanique (Augmentin®) pendant 7 jours. Le cytodiagnostic de Tzanck trouvait des polynucleaires eosinophiles. La biopsie cutanee d’une bulle montrait un decollement a la jonction dermo-epidermique (JDE) avec un toit intact, un infiltrat inflammatoire majoritairement a polynucleaires eosinophiles et neutrophiles, des depots lineaires d’IgA le long de la JDE en immunofluorescence directe (IFD). La recherche d’anticorps, par immunofluorescence indirecte et ELISA, etait negative chez l’enfant et sa mere ; l’IFD maternelle egalement. L’immunoblot de l’enfant etait negatif pour les IgG, en cours pour les IgA. Le diagnostic de DIGAL etait retenu. Cette unique poussee, guerissait spontanement, avec un recul sans recidive de 6 mois ( Fig. 1 et 2 ). Discussion Six observations de DIGAL neonatales ont ete rapportees. Les meres etaient, cliniquement et immunologiquement, indemnes de DBAI (n = 3), ou leur statut etait inconnu (n = 3). Leur evolution a ete rapidement favorable sans traitement systemique. Les formes de DIGAL neonatales avec atteinte muqueuse ont necessite un traitement systemique (dapsone, corticotherapie, immunoglobulines). Conclusion En l’absence d’histoire maternelle de DBAI, le role d’un agent infectieux et/ou d’un facteur medicamenteux peut etre discute ici. Cependant l’exposition fœtale courte, huit heures, a l’amoxicilline, et la guerison sous Augmentin® apres la naissance semblent ecarter le role de l’antibiotique et faire privilegier l’hypothese d’un facteur declenchant infectieux.

It is well known that the convergence of the conjugate gradient method for solving symmetric positive definite linear systems depends to a large extent on the eigenvalue distribution. In many cases, it is observed that "removing" the extreme eigenvalues can greatly improve the convergence. Several preconditioning techniques based on approximate eigenelements have been proposed in the past few years that attempt to tackle this problem. The proposed approaches can be split into two main families, depending on whether the extreme eigenvalues are moved exactly to one or are shifted to close to one. The first technique is often referred to as the deflation approach, while the latter is referred to as a coarse grid preconditioner by analogy to techniques first used in domain decomposition methods. Many variants exist in the two families that reduce to the same preconditioners if the exact eigenelements are used. In this paper we investigate the behavior of some of these techniques when the eigenelements are known only approximately. We use the first-order perturbation theory for eigenvalues and eigenvectors to investigate the behavior of the spectrum of the preconditioned systems using first-order approximation. We illustrate the sharpness of the first-order approximation and show the effect of the inexactness of the eigenelements on the behavior of the resulting preconditioner when applied to accelerating the conjugate gradient method.

Does willingness to pay a premium for local specialty food products differ between consumers in Maine, New Hampshire, and Vermont? Two food categories are investigated: low-end ($5) and high-end ($20) products. Premia estimates are compared across states and across base prices within states using dichotomous choice contingent valuation methods. Results suggest that the three states of northern New England have many similarities, including comparable price premia for the lower-priced good. However, there is some evidence that the premium for the higher-priced good is greater for the pooled Vermont and Maine treatment than for the New Hampshire treatment. Vermont and New Hampshire residents are willing to pay a higher premium for a $20 than for a $5 food item, while the evidence suggests that Maine residents are not.

This paper presents a simple computational method for measuring the difference of independent empirical distributions estimated by bootstrapping or other resampling approaches. Using data from a field test of external scope in contingent valuation, this complete combinatorial method is compared with other methods (empirical convolutions, repeated sampling, normality, nonoverlapping confidence intervals) that have been suggested in the literature. Tradeoffs between methods are discussed in terms of programming complexity, time and computer resources required, bias, and the precision of the estimate. Copyright 2005, Oxford University Press.

This paper examines willingness to pay for an endangered species protection program across geographically embedded samples. The samples range from the boroughs that contain critical habitat for the Steller sea lion to the state that contains these boroughs to the entire United States. The analysis is done using the contingent valuation method and comparing mean willingness to pay estimates using the Method of Convolution. When comparing willingness-to-pay estimates among paired samples, results indicate significantly different values across geographic samples, which may lead to dramatically different policy implications. Respondent motivating factors also vary from sample to sample, which may be of interest to the management agencies, especially federal agencies and those with a national scope.

This study represents the first comprehensive survey of German sport fishing anglers in Alaska. Utilizing an approach previously developed in the literature, differentiating anglers on a continuum from occasional anglers to specialists, the current study adapts this typology to a travel context and shows these distinctions are useful in developing a tourism marketing strategy to attract the international angling tourist.

This paper examines willingness to pay (WTP) for an endangered species across geographically nested samples using the Contingent Valuation Method (CVM). The three samples range from (1) the boroughs that contain critical habitat for the Steller sea lion to (2) the state that contains these boroughs to and (3) the entire United States. Depending on the assumptions of the model, WTP varies tremendously from sample to sample. WTP for the United States is the highest and it is the lowest for the boroughs. The null hypotheses that mean WTP estimates are greater then zero were rejected for the boroughs and the state but were not rejected for the United States based on the 95% confidence intervals.

The authors describe a renewable resource allocation game designed to stimulate students' interest in and understanding of market failure associated with open-access types of resource use. They also use the game to discuss the advantages and disadvantages of various property rights and regulation schemes. Because this exercise demonstrates the power of unregulated and regulated economic incentives, many types of students may benefit from this game, including undergraduates enrolled in the standard introductory and in more advanced microeconomics classes, as well as courses in environmental economics and natural resource economics. This game was specifically designed so that noneconomics majors in natural resource management and environmental courses could also benefit.

To exploit the possibilities of parallel computers, we designed a large-scale bidimensional atmospheric transport model named Pangolin. As the basis for a future chemistry-transport model, a finite-volume approach was chosen both for mass preservation and to ease parallelization. To overcome the pole restriction on time-steps for a regular latitude-longitude grid, Pangolin uses a quasi-area-preserving reduced latitude-longitude grid. The features of the regular grid are exploited to improve parallel performances and a custom domain decomposition algorithm is presented. To assess the validity of the transport scheme, its results are compared with state-of-the-art models on analytical test cases. Finally, parallel performances are shown in terms of strong scaling and confirm the efficient scalability up to a few hundred of cores.

Referendum style willingness to pay questions have been used to estimatepassive use values. This referendum question format method may beproblematic for many reasons, including the statistical techniques used toestimate willingness to pay from discrete responses. This paper comparesa number of parametric, semi-nonparametric and nonparametric estimationtechniques using data collected from US households regarding Federalprotection of endangered fish species.The advantages and disadvantagesof the various statistical models used are explored. A hypothesis test forstatistical equality among estimation techniques is performed using ajackknife bootstrapping method. When the equality test is applied, themodeling techniques do show significant differences in some possiblecomparisons, but only those that are nonparamentric. This can lead toconflicting interpretations of what the data show. Resource managers andpolicy analysts need to use caution when interpreting results until anindustry standard can be developed for estimating willingness to pay fromclosed ended questions.

Economic theory suggests that willingness to pay for two goods independently offered should remain unchanged when the survey instrument changes slightly. Four survey treatments consisting of comprehensive good and a subset of that good were used. The surveys alternated in the question ordering and in the embedded good which accompanied the comprehensive good. We tested for sequencing and instrument context effects using both a combined and split sample designs. In the combined sample case we found some evidence to sequencing effects in the data containing the first subset good. Likelihood ratio tests indicated that sequencing did not effect scale or location of parameters. In the test for instrument context effects, evidence was found indicating context does effect willingness to pay estimates.

Economic theory suggests willingness-to-pay (WTP) should be significantly higher for a comprehensive good than for a subset of that good. We tested this using both a split sample design (external scope test) and paired responses (internal scope test) for WTP for several endangered fish and wildlife species in the US. In the paired response case we corrected for correlation of willingness-to-pay responses using a bivariate probit model. Surprisingly, the independent split samples passed the scope test but the paired samples did not. As the results contradict each other, questions of validity for policy implications are raised. However, using either approach, the benefit of maintaining critical habitat for these species exceeds the costs.

We present two new variants of Schur complement domain decomposition preconditioners suitable for 2D anisotropic problems. These variants are based on adaptations of the probing idea, described by Chan et al (1992 Fifth Int. Symp. on Domain Decomposition Methods for Partial Differential Equations, Philadelphia: SIAM, pp 236-249), used in conjunction with a coarse grid approximation as introduced by Bramble et al (1986 Math. Comput. 47, 103-134). The new methods are specifically designed for situations where the coupling between neighbouring interfaces is stronger than the coupling within an interface. Taking into account this strong coupling, one variant uses a multicolour probing technique to avoid distortion in the probe approximations that appear when using the method proposed by Chan et al. The second technique uses additional probe matrices to approximate not only the coupling within the interfaces but also the coupling between interface points across the subdomains. This latter procedure looks somewhat like an alternating line relaxation procedure and was motivated by the success of line relaxation within the multigrid method for anisotropic problems, see Brandt (1977 Math. Comput. 31, 333-390). To assess the relevance of the new preconditioners, we compare their numerical behaviour with well-known robust preconditioners such as the balanced Neumann-Neumann method proposed by Mandel (1993 Commun. Numer, Methods Eng. 9, 233-241).

In this letter, we show that an eleven-velocity two-dimensional lattice Boltzmann model using several relaxation times obeys a Jeffreys viscoelastic constitutive law with full isotropic behavior. The connection between the free parameters of the model and the Jeffreys transport coefficients is made with the help of a modified Chapman-Enskog expansion taking into account large relaxation time effects. Numerical simulation of a pulsed Couette flow is performed leading to an excellent agreement with predictions.

We present a parallel domain decomposition method based on a hybrid direct-iterative solver for 3D frequency-domain modelling of visco-acoustic waves. Frequency-domain seismic modelling reduces to the solution of a large and sparse system of linear equations for each frequency. The hybrid directiterative approach aims to overcome the memory requirement and the limited scalability of direct-solver approaches, on the one hand, and to iteratively solve better-conditioned system than in global iterative approaches on the other hand. The domain decomposition is based upon the algebraic Schur complement method. The reduced Schur complement system is solved with the global minimum residual method (GMRES) and is preconditioned by an algebraic additive Schwarz preconditioner. The MUMPS direct solver is used to factorize local impedance matrices defined on each subdomain. Simulations in the salt models for frequencies up to 12.5 Hz show that the number of iterations increases linearly with frequencies when the grid interval is matched to the frequency and the size of the subdomains is kept constant over frequencies. This makes the time complexity of the hybrid approach similar to that of global iterative solvers. Possible improvements of the method for multi-source simulation involve the use of block iterative solver and two levels of parallelism.

Large-scale scientific simulations are nowadays fully integrated in many scientific and industrial applications. Many of these simulations rely on modelisations based on PDEs that lead to the solution of huge linear or nonlinear systems of equations involving millions of unknowns. In that context, the use of large high performance computers in conjunction with advanced fully parallel and scalable numerical techniques is mandatory to efficiently tackle these problems. In this paper, we consider a parallel linear solver based on a domain decomposition approach. Its implementation naturally exploits two levels of parallelism, that offers the flexibility to combine the numerical and the parallel implementation scalabilities. The combination of the two levels of parallelism enables an optimal usage of the computing resource while preserving attractive numerical performance. Consequently, such a numerical technique appears as a promising candidate for intensive simulations on massively parallel platforms. The robustness and parallel numerical performance of the solver is investigated on large challenging linear systems arising from the finite element discretization in structural mechanics applications.

International audience; Chitosan, the deacetylated derivative of chitin, is a natural D-glucosamine polymer that can be extracted from the shells of seafood such as prawns crabs and lobsters. It can be used as a flocculent, plant disease resistant promoter, anti-cancer agent, wound healing promotion agent and antimicrobial agent. The aim of this paper is the study of the interaction between chitosan powder and various kinds of pathogen microorganisms potentially present in water. First of all, physico-chemical characterisations of chitin and chitosan powder were performed. The deacetylation yields were 35 %, 60 % and 80 +/- 10 %. The experimental studies focused on the measurements of the mortality constant rate for various bacterial strains, Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis and Staphylococcus saprophyticus. An explanation of the antibacterial mechanisms is proposed involving the cell wall disruption due to free amino groups present in chitosan.

The aim of this work was to formulate a powder for inhalation with fusafungine, a drug substance initially highly cohesive. The classical approach based on micronization by jet milling to prepare respirable drug particles and then blending with a carrier was first applied. A fractional factorial experimental design was implemented to screen six formulation parameters. The effect of drug/lactose co-micronization on aerosolization was then evaluated. In vitro deposition studies were performed with the twin stage glass impinger and the inhaler Spinhaler. Micronization did not induce DSC-detectable amorphization and gave a highly cohesive, poor flowable powder with a theoretical aerodynamic diameter of 5 microm. The powder was then blended with coarse lactose and optionally fine lactose. Unfortunately, the respirable fraction could not be optimized and remained below 10%. On the other hand, a co-micronized powder drug/fine lactose 50:50 gave a respirable fraction of 16%. Following blending with a carrier, the respirable fraction and the emitted dose fraction reached 23% and 69%, respectively. The use of a fine lactose grade for co-micronization was essential. In conclusion, this study demonstrated that co-micronization with a fine lactose is an efficient and simple strategy to formulate a powder for inhalation with enhanced aerosolization properties, especially for highly cohesive drug substance.