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Objectives Respiratory viral infections lead to bronchial inflammation in cystic fibrosis patients, especially during pulmonary exacerbations. The aim of the present study was to determine the impact of viral associated pulmonary exacerbations in children with cystic fibrosis and failure to improve force expiratory volume in 1 second (FEV1) levels after an appropriate treatment. Methods Children with a diagnosis of cystic fibrosis were longitudinally evaluated three times: at baseline (Visit 1), at the diagnosis of pulmonary exacerbation (Visit 2) and after exacerbation treatment (Visit 3). Nasal and bronchial swabs were analyzed at each visit with multiplex viral respiratory PCR panel. Pulmonary function tests were recorded at each visit, in order to highlight a possible failure to improve them after treatment. Lack of improvement was defined by an increase of FEV1 less than 5% between Visit 2 and Visit 3. Results 18 children were included in the study. 10 patients failed to show an improvement of more than 5% in their FEV1 between Visit 2 and Visit 3. Rhinovirus infection at Visit 2 or Visit 3 was the only risk factor significantly associated with such a failure, both in univariate (OR 12, p Conclusion Rhinovirus infection seems to play a role in the FEV1 recovery after pulmonary exacerbation treatment in children with cystic fibrosis. Such an association needs to be confirmed by a large-scale study, since this finding may have important implication on pulmonary exacerbation management.

Background Club cell secretory protein (CCSP) is an endogenous anti-inflammatory product supposed to have an important protective role in the respiratory tract. Genome-wide association study and disease severity and susceptibility studies identified the A38G polymorphism in this gene as a candidate single-nucleotide polymorphism (SNP). Impaired airway homeostasis in chronic bronchial diseases (bronchiolitis obliterans syndrome, chronic obstructive pulmonary disease and asthma) might be related to CCSP defect but the SNP-transcription relationship is not established. This study was conducted to examine the influence of ccsp A38G polymorphism on CCSP expression at rest and to identify potentially modulating transcription factors. Methods Vectors constructions (proximal promoter: 229bp; and distal promoter: 926bp) containing -38G wild type or the -38A variant were designed. Human bronchial BEAS-2B cells were transfected with these proximal or distal promoters bearing wild type or mutant constructions. Dual luciferase assay system reflected CCSP transcription levels. In parallel, dual transfections with candidate modulating transcription factors identified by in silico analysis using ConSite and TFSEARCH were conducted. Results Transiently transfected BEAS-2B cells with the -38A 926bp variant vector induced less CCSP transcripts than the -38G and -38A 226bp vectors ( P -values 0.0256 and 0.0360, respectively). Cotransfection with Nkx2.1 (a candidate transcription factor overexpressed in most lung diseases with several binding sites identified by the in silico analysis within the CCSP gene promoter) significantly increased CCSP transcription. Interestingly, with proximal promoter only, -38A variant gene response to Nkx2.1 was higher than -38G wild type response. In depth-in silico analyzes identified two novel candidate transcription factors that could specifically bind to the A38G locus: Thing1E47 and p53. Further experiments will be done to check whether A38G polymorphism will differently affect CCSP production with these transcription factors. Conclusion Our data indicate that the distal promoter is the site bearing regulatory elements required for A38G polymorphism to affect CCSP expression. Also, -38A variant CCSP gene modulation induced by Nkx2.1 is significant. Finding transcription factors that could restore normal levels of CCSP expression is of interest.

International audience; This paper describes an R package, named SPATCLUS, that implements a method recently proposed for spatial cluster detection of case event data. This method is based on a data transformation. This transformation is achieved by the definition of a trajectory which allows to attribute to each point a selection order and the distance to its nearest neighbour. The nearest point is searched among the points which have not yet been selected in the trajectory. Due to the trajectory effects, the distance is weighted by the expected distance under the uniform distribution hypothesis. Potential clusters are located by using multiple structural change models and a dynamic programming algorithm. The double maximum test allows to select the best model. The significativity of potential clusters is determined by Monte Carlo simulations. This method makes it possible the detection of multiple clusters of any shape.

International audience; Understanding how management practices apply selective pressures that shape adaptive traits in forage grass is essential for managing genetic resources and breeding improved cultivars. The defoliation regime, for instance, induces a genotypic differentiation in plant height and heading. To explore these changes, plant height, heading date, and their relationship were studied in a nursery experiment among populations of perennial ryegrass (Lolium perenne L.) that had experienced different selection pressures: the cultivar ‘Clerpin’ from the original seed lot and its derived population from a pasture intensively grazed, 23 commercial cultivars, and 86 families coming from a divergent and recurrent mass selection for leaf length. A controlled experiment was performed on two populations contrasted on both plant height and heading date to compare their phyllochron, leaf elongation rate, leaf elongation duration, tiller number, and biomass per plant. Dissections were performed to monitor apex development and stem elongation. Genetic differentiations in plant height and heading date were found as a result of grazing pressure, commercial breeding, and selection for leaf length. Heading date was negatively correlated to plant height. Delayed flowering and reduction in plant stature resulted from a reduction in both leaf and stem elongation rate and were associated with a delay in the production of double ridge at the apex level. Selecting for a short plant resulted in an overall decrease in both vegetative and reproductive plant growth. Genetic differentiation in heading date in response to defoliation regime could be interpreted as an indirect effect of an adaptive differentiation in plant height.

To detect temporal case clustering in patients with pityriasis rosea in different geographic locations.Regression analysis of dates on which 1379 patients were diagnosed as having pityriasis rosea in 3 different geographic locations. The control data consisted of dates of diagnosis of patients with psoriasis in the same settings.Dermatology clinics in Kuwait, Minnesota, and Diyarbakir, Turkey.Patients Patients with pityriasis rosea and psoriasis seeking care in the clinics.Three significant positive clusters (P = .005, P =.001, and P =.01, respectively) and 1 significant negative cluster (P.001) were detected in these series of patients. No cluster was detected in 2 corresponding series of patients with psoriasis in Kuwait and Turkey.Temporal case clustering exists in pityriasis rosea.

International audience; GeneSys models the effects of regional cropping systems on gene flow between cropped and volunteer rape plants. Its sensitivity to field patterns and cropping system input variables was analysed using Monte Carlo simulations of which the output was analysed by regression trees and linear regressions. The studied simulated output variable was the harvest contamination of conventional crops by genetically modified seeds. The study showed that field characteristics (areas, shapes, distances and orientation) have little effect compared with cropping systems. Gene flow increased with the area of the pollen- and seed-producing field and decreased with the area of the gene-receiving field; it increased for elongated vs. square fields and decreased with the distance between fields. The sensitivity analysis identified the distance and time during which cropping systems influence harvest contamination in various field plants. The harvest purity of a cluster of fields was influenced by the cropping history of the fields located less than 200 to 400 m around the cluster, and of three past years in addition to the ongoing analysed year for major variables such as crop succession or sowing date. The analysis of these major variables pointed to strategies for reducing gene flow, such as increasing the time between successive rape varieties; avoiding high-risk crops such as genetically modified (GM) rape and set-aside in the neighbouring fields for the year preceding the cultivation of a non-GM crop as well as the year during which the non-GM rape is grown; delaying the sowing of non-GM rape.

Fur Patienten auf der Intensivstation ist die morgendliche Prozedur mit wiederholtem Lagerungswechsel fur Waschen, Wechsel von Kleidung und Bettbezug etc. meist schmerzhaft und mit Stress verbunden. In einer franzosischen Studie pruften Kollegen, welche Vorteile ein spezielles Analgesie-Qualitatsmanagement fur diese Pflegemasnahmen bietet.

Background Mutations in the GJB2 gene have been established as a major cause of inherited non syndromic deafness in different populations. A high number of sequence variations have been described in the GJB2 gene and the associated pathogenic effects are not always clearly established. The prevalence of a number of mutations is known to be population specific, and therefore population specific testing should be a prerequisite step when molecular diagnosis is offered. Moreover, population studies are needed to determine the contribution of GJB2 variants to deafness. We present our findings from the molecular diagnostic screening of the GJB2 and GJB6 genes over a three year period, together with a population-based study of GJB2 variants. Methods and results Molecular studies were performed using denaturing High Performance Liquid Chromatograghy (DHPLC) and sequencing of the GJB2 gene. Over the last 3 years we have studied 159 families presenting sensorineural hearing loss, including 84 with non syndromic, stable, bilateral deafness. Thirty families were genotyped with causative mutations. In parallel, we have performed a molecular epidemiology study on more than 3000 dried blood spots and established the frequency of the GJB2 variants in our population. Finally, we have compared the prevalence of the variants in the hearing impaired population with the general population. Conclusion Although a high heterogeneity of sequence variation was observed in patients and controls, the 35delG mutation remains the most common pathogenic mutation in our population. Genetic counseling is dependent on the knowledge of the pathogenicity of the mutations and remains difficult in a number of cases. By comparing the sequence variations observed in hearing impaired patients with those sequence variants observed in general population, from the same ethnic background, we show that the M34T, V37I and R127H variants can not be responsible for profound or severe deafness.

Objectives To investigate the epidemiology of pityriasis rosea in primary care settings in Hong Kong and to analyze for temporal clustering. Design Retrospective epidemiologic study. Setting Six primary care teaching practices affiliated with a university. Patients Forty-one patients with pityriasis rosea, 564 patients with atopic dermatitis (negative control condition), and 35 patients with scabies (positive control condition). Methods We retrieved all records of patients with pityriasis rosea, atopic dermatitis, or scabies diagnosed in 3 years. We analyzed temporal clustering by a method based on a regression model. Results The monthly incidence of pityriasis rosea is negatively but insignificantly correlated with mean air temperature (γ s = −0.41, P = .19) and mean total rainfall (γ s = −0.34, P = .27). Three statistically significant clusters with 7, 6, and 7 cases were identified ( P = .03), occurring in the second coldest month in the year (February), the second hottest month (July), and a temperate month (April), respectively. For atopic dermatitis (negative control condition), the nonclustering regression model was selected by Akaike information criteria. For scabies (positive control condition), 1 cluster of 20 cases was detected ( P = .03). Conclusions Significant temporal clustering independent of seasonal variation occurred in our series of patients with pityriasis rosea. This may be indicative of an infectious cause.

Summary. This article proposes a simple method to determine single or multiple temporal clustering on a variable size population. By a transformation of the data set, the method based on a regression model allows consideration of a variable population size during the time of study. A model selection procedure and a resampling method are used to select the number of clusters. The results have applications in epidemiological studies of rare diseases.

Using a B-spline representation for splines, knots seen as free variables, the approximation to data by splines improve greatly. The damage due to the presence of a lot of local optima is very important in the univariate regression context, and things are getting worse in multivariate additive modeling. We present a new algorithm to select knots submitted to constraints for computing least squares spline approximations.

Objectif Le referentiel sur le depistage du diabete gestationnel (DG) a ete publie en decembre 2010 avec modification des seuils (HGPO 75g : T0 35 ans, IMC>25, ATCD 1 er degre de diabete, ATCD de DG ou macrosomie) mais aussi sur la prevalence du diabete gestationnel apres les modifications des seuils. Materiels et methodes Nous avons analyses 150 dossiers tires au sort 6 mois avant (G1) et 6 mois apres (G2) la publication en decembre 2010. 150 dossiers de 2009 ont permis d'etudier la prevalence du DG (Carpenter Coustan) avant toute modification. Resultats Le depistage du diabete gestationnel est passe de 92 % a 68 %. La prevalence de femmes avec FR etait stable (58,7 % vs 60,7 %). L'utilisation de HGPO 75 g de glucose sur 3 temps etait stable dans les 2 groupes (81,9 % et 94,1 %) prouvant que les medecins n'ont pas attendu le referentiel national pour changer leur pratique. De meme la glycemie a jeun en debut de grossesse etait frequemment pratiquee (58 % G1 vs 65 % G2). Dans G2, elle etait rarement anormale (10,7 %). Dans 75 % des DG, l'IMC etait>25. Du fait de l'anticipation des medecins la prevalence du DG variait peu entre G1 et G2 (16,7 % vs 19,6 %), alors qu'elle etait a 6 %. en 2009. Conclusion Malgre le depistage cible la prevalence du depistage du DG varie peu, cependant la prevalence du DG s'est majoree de facon importante (19,6 %) necessitant une reflexion sur les moyens de sa prise en charge.

Introduction: The causative role of new hydroxyethyl starch (HES 130/0.4) in renal dysfunction frequency (a > 50% increase in serum creatinine or need for renal replacement therapy (RRT)) remains debated. Using the database of a multicenter study focusing on patients with severe sepsis and septic shock, the present study aimed at identifying factors associated with the occurrence of renal dysfunction. Methods: Among the 435 patients in a multicenter study of patients with severe sepsis and septic shock in 15 Southern French ICUs, 388 patients surviving after 24 hour, without a history of renal failure were included. Factors associated with renal dysfunction and RRT were isolated using a multivariate analysis with logistic regression. Results: Renal dysfunction was reported in 117 (33%) patients. Ninety patients required RRT. Among study participants, 379 (98%) were administered fluids in the first 24 hours of management: HES 130/0.4 only (n = 39), crystalloids only (n = 63), or both HES 130/0.4 and crystalloids (n = 276). RRT was independently associated with the need for vasopressors and the baseline value of serum creatinine in the first 24 hours. Multivariate analysis indicated that male gender, SAPS II score, being a surgical patient, lack of decrease in SOFA score during the first 24 hours, and the interventional period of the study were independently associated with renal dysfunction. Mortality increased in the presence of renal dysfunction (48% versus 24%, P < 0.01). Conclusions: Despite being used in more than 80% of patients with severe sepsis and/or septic shock, the administration of HES 130/0.4 in the first 24 hours of management was not associated with the occurrence of renal dysfunction.

Familial Mediterranean fever (FMF) and Behcet's disease (BD), both inflammatory diseases, are highly prevalent in the Middle Eastern and Mediterranean populations. FMF is a Mendelian autosomic recessive disease linked to MEFV, a gene of unknown function. BD in contrast is a polyfactorial disease associated with the major histocompatibility complex. Because FMF and BD have epidemiological similarities, we asked whether the FMF gene was implicated in BD. We screened for the common MEFV mutations a cohort of 114 chromosomes from definite BD patients [meeting the criteria of the International study group] and probable cases [meeting at least two of these criteria]. We screened in parallel an ethnically matched cohort of FMF and control chromosomes. The M694V, V726A and E148Q mutations tended to be more frequent in definite BD (2.6%, 2.6%, and 5.2%, respectively) than in controls (0%, 0%, and 2.2%). The P706 polymorphism was found in 10.5% of the probable BD chromosomes, but in only 1.6% of the controls (p=0.01). Because some MEFV mutations were more frequent in BD than in controls, we suggest that they may act as additional susceptibility factors in BD.

Objectif Mettre au point une methode de classification des courbes d’evolution de la charge virale au sein d’une cohorte de patients infectes pas le VIH. Patients et methodes Pour n = 110 patients seropositifs pour le VIH suivis au sein d’une cohorte, nous disposions des valeurs de la charge virale a plus de 30 dates de mesure differentes. Les observations etaient donc les courbes CV1 a CV110 de l’evolution de la charge virale de ces patients au cours du temps. Afin d’obtenir des groupes de patients ayant une evolution comparable (classification non supervisee), chaque courbe a ete ajustee par une fonction spline (polynome par morceaux) et la methode des moindres carres ordinaires. Les coefficients de la fonction de regression obtenue ont alors ete classes par la procedure des k-means. Les 110 courbes ont ete regroupees en 3 groupes homogenes d’evolution de la charge virale. La methode de classification de courbes a permis la prise en compte de la structure temporelle des donnees et ainsi la dependance entre chaque observation. Resultats La courbe « resumee » de chacun des groupes rend possible l’interpretation des resultats. Le premier groupe represente les patients gardant une charge virale elevee, le second ceux ayant rapidement une charge virale faible et la conservant, enfin le dernier groupe rassemble les patients dont la charge virale oscille. Discussion Les variables cliniques et biologiques mesurees chez les patients peuvent alors etre utilisees comme variables explicatives de l’appartenance aux differents groupes de classification. Ainsi, les effets du sexe, de l’âge, de la date de debut de la maladie, de la date de debut du traitement, de la consommation de tabac, d’alcool, de la toxicomanie IV et des pathologies associees pourront etre recherches.

Hypothesis: Lung cancer remains the leading cause of cancer-related mortality worldwide. Currently known serum markers do not efficiently diagnose lung cancer at early stage. Methods: In the present study, we developed a serum proteomic fingerprinting approach Coupled with a three-step classification method to address two important clinical questions: (i) to determine whether or not proteomic profiling differs between lung cancer and benign lung diseases in a population of smokers and (ii) to assess the prognostic impact of this profiling in lung cancer. Proteomic spectra were obtained from 170 pathologically confirmed lung cancer or smoking patients with benign chronic lung disease serum samples. Results: Among the 228 protein peaks differentially expressed in the whole Population, 88 differed significantly between lung cancer patients and benign lung disease. with area under the curve diagnostic values ranging from 0.63 to 0.84. Multiprotein classifiers based on differentially expressed peaks allowed the classification of lung cancer and benign disease with an area under the curve ranging from 0.991 to 0.994. Using a cross-validation methodology, diagnostic accuracy was 93.1% (sensitivity 94.3%, specificity 85.9%), and more than 90% of the stage I/II lung cancers were correctly classified. Finally, in the prognosis part of the Study, a 4628 Da protein was found to be significantly and independently associated with prognosis in advanced stage non-small cell lung cancer patients (p = 0.0005). Conclusions: The potential markers that we identified through proteomic fingerprinting Could accurately classify lung cancers ill a high-risk population and predict survival in a non-small cell lung cancer population.

In this manuscript, we compared serum profiles obtained with two related technologies, SELDI-TOF and Clinprot, using a single bioinformatic algorithm. These two approaches rely on mass spectrometry to detect proteins and peptides initially selected by binding to various chromatographic matrices. They are proposed by two different companies, and they are competing for being the reference in high throughput serum profiling for clinical proteomics. This independent evaluation of these two technologies put the light on some of their differences, suggests that they address different proteome fractions and, thus, could be complementary. Taken together, our data could contribute to the parameters relevant for the choice of one technology or the other.

International audience; Background: The majority of caries lesions in adults occur on the proximal tooth surfaces of the posterior teeth. A comprehensive study of the composition of the oral microbiota is fundamental for a better understanding of the etiology of interdental caries.Methods: Twenty-five caries-free subjects (20–35 years old) were enrolled in the study. The interden- tal biofilm of four interdental sites were collected. The real-time polymerase chain reaction (PCR) methodology were used to quantify (i) the following bacteria: Streptococcus spp., Streptococcus mutans, Lactobacillus spp., Enterococcus spp., and Enterococcus faecalis; (ii) the fungus Candida albicans; and (iii) total bacteria.Results: Streptococcus spp. was the most abundant species, followed by Lactobacillus spp. and Enterococcus spp. Streptococcus spp. and Lactobacillus spp. were detected at all tested sites and Enterococcus spp. at 99% of sites. S. mutans was detected at only 28% of the tested sites and C. albicans was detected at 11% of sites. E. faecalis was never detected. In 54.5% of the biofilm inhabited by C. albicans, S. mutans was present. Moreover, 28% of the ID sites co-expressed S. mutans and Lactobacillus spp. The studied pathogens were organized into two correlated groups of species. Strikingly, the fungus C. albicans and the bacteria Enterococcus spp. cluster together, whereas Streptococcus spp., S. mutans and Lactobacillus spp. form one distinct cluster.Conclusion: The interdental biofilm of young caries-free adults is comprised of pathogens that are able to induce interproximal caries. That several of these pathogens are implicated in heart disease or other systemic diseases is an argument for the disruption of interdental biofilms using daily oral hygiene.

Skeletal muscle atrophy is a major systemic impairment in chronic diseases. Yet its determinants have been hard to identify because a clear research definition has not been agreed upon. The reduction in muscle fiber cross-sectional area (CSA) is a widely acknowledged marker of muscle atrophy, but no reference values for the muscle fiber CSA at the age of the onset of chronic disease have ever been published. Thus, we aimed to systematically review the studies providing data on fiber CSA and fiber type proportion in the vastus lateralis of the quadriceps of healthy subjects (age >40 yr) and then to pool and analyze the data from the selected studies to determine reference values for fiber CSA. We followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and identified 19 studies, including 423 subjects that matched the inclusion criteria. On the basis of fiber type and gender, the mean fiber CSA and the lower limits of normal (LLNs) were (%type I*60) + 1,743 μm2 and (%type I*60) − 718 μm2, respectively, for men; and (%type I*70) + 139 μm2 and (%type I*70) − 1,485 μm2, respectively, for women. There was no significant heterogeneity among subgroups of fiber type and gender. The pooled type I fiber proportion was 50.3% (LLN = 32.9%). In multivariate analysis, fiber CSA was significantly correlated with V̇o2 peak ( r = 190.92; P = 0.03), and type I fiber proportion was correlated with age ( r = −0.024; P = 0.005), body mass index ( r = 0.096; P = 0.005), and V̇o2 peak ( r = −0.053; P = 0.005). Our metaanalysis of a homogeneous set of studies is the first to provide valuable LLNs for fiber CSA according to fiber type and gender. This analysis will be improved by prospective assessment in well-characterized healthy subjects.

International audience; Introduction: Procalcitonin (PCT) biomarker is suggested to tailor antibiotic therapy in the medical intensive care unit (ICU) but studies in perioperative medicine are scarce. The aim of this study was to determine whether PCT reported thresholds are associated with the initial treatment response in perioperative septic shock secondary to intra-abdominal infection. Methods: This single ICU, observational study included patients with perioperative septic shocks secondary to intra-abdominal infection. Demographics, PCT at days 0, 1, 3, 5, treatment response and outcome were collected. Treatment failure included death related to the initial infection, second source control treatment or a new onset intra-abdominal infection. The primary endpoint was to assess whether PCT thresholds (0.5 ng/ml or a drop from the peak of at least 80%) predict the initial treatment response. Results: We included 101 consecutive cases. Initial treatment failed in 36 patients with a subsequent mortality of 75%. Upon admission, PCT was doubled when treatment ultimately failed (21.7 ng/ml +/- 38.7 vs. 41.7 ng/ml +/- 75.7; P = 0.04). Although 95% of the patients in whom PCT dropped down below 0.5 ng/ml responded to treatment, 50% of the patients in whom PCT remained above 0.5 ng/ml also responded successfully to treatment. Moreover, despite a PCT drop of at least 80%, 40% of patients had treatment failure. Conclusions: In perioperative intra-abdominal infections with shock, PCT decrease to 0.5 ng/ml lacked sensitivity to predict treatment response and its decrease of at least 80% from its peak failed to accurately predict treatment response. Studies in perioperative severe infections are needed before using PCT to tailor antibiotic use in this population.

International audience; INTRODUCTION: To investigate whether respiratory variation of inferior vena cava diameter (cIVC) predict fluid responsiveness in spontaneously breathing patients with acute circulatory failure (ACF). METHODS: Forty patients with ACF and spontaneous breathing were included. Response to fluid challenge was defined as a 15% increase of subaortic velocity time index (VTI) measured by transthoracic echocardiography. Inferior vena cava diameters were recorded by a subcostal view using M Mode. The cIVC was calculated as follows: (Dmax - Dmin/Dmax) × 100 and then receiver operating characteristic (ROC) curves were generated for cIVC, baseline VTI, E wave velocity, E/A and E/Ea ratios. RESULTS: Among 40 included patients, 20 (50%) were responders (R). The causes of ACF were sepsis (n = 24), haemorrhage (n = 11), and dehydration (n = 5). The area under the ROC curve for cIVC was 0.77 (95% CI: 0.60-0.88). The best cutoff value was 40% (Se = 70%, Sp = 80%). The AUC of the ROC curves for baseline E wave velocity, VTI, E/A ratio, E/Ea ratio were 0.83 (95% CI: 0.68-0.93), 0.78 (95% CI: 0.61-0.88), 0.76 (95% CI: 0.59-0.89), 0.58 (95% CI: 0.41-0.75), respectively. The differences between AUC the ROC curves for cIVC and baseline E wave velocity, baseline VTI, baseline E/A ratio, and baseline E/Ea ratio were not statistically different (p = 0.46, p = 0.99, p = 1.00, p = 0.26, respectively). CONCLUSION: In spontaneously breathing patients with ACF, high cIVC values (>40%) are usually associated with fluid responsiveness while low values (< 40%) do not exclude fluid responsiveness.

As the different subtypes of juvenile idiopathic arthritis (JIA) do not have the same severity and prognosis, they do not require the same therapeutic modalities. The goal is to obtain clinical remission with steroid-sparing strategy and identify prognosis …

In chronic obstructive lung diseases, mainly represented by asthma, chronic obstructive pulmonary disease (COPD) and non-CF bronchiectasis , excessive mucus production is the cause of acute and/or chronic airway obstruction and represents a marker of exacerbation of these pathologies. Based on this observation, we have structured our project around the following axes:I) To study the biological determinants of the variation of sputum rheology in chronic bronchial diseases. Through a study sponsored by the University Hospital of Montpellier, we collected sputum samples from patients with asthma, COPD and non-CF bronchiectasis, and studied their microbiological (cytobacteriological examination), biophysical (rheology) and biochemical (determination of protein components, ions, etc...) characteristics. The "rheology" part of the study was based on a bench-top device (Rheomuco© - Rheonova Grenoble) allowing a rapid analysis of sputum on site within the hour. This first part allowed us to establish links between eosinophilia in sputum and some rheological variables, but also between the concentration of mucins evaluated by mass spectrometry and these same rheological variables. II) To assess the impact of AZITHROMYCIN prescribed according to the biophysical characteristics (rheology) of patients' sputum on the prevention of COPD exacerbationsFirstly, in order to ensure the reproducibility of the rheological sputum analysis device, we conducted several intra- and inter-operator reproducibility analyses in different centres (Bordeaux, Grenoble and Montpellier), on different samples with "extreme rheological values". This step allowed us to confirm the reliability of the measurement methodSecondly, in a desire to make the link between the bench and the clinic, we have developed a protocol that is part of the PHRC GIRCI/SOHO 2018. The aim of this protocol will be to explore the impact of a therapeutic strategy based not on standard clinical assessment, but on the biophysical properties of sputum and in particular of mucus from COPD patients. This study will also allow us to collect biological samples (blood, sputum) on which secondary analyses are planned in order to finely determine the endotypes of the patients included., Dans les bronchopathies chroniques, représentées majoritairement par l’asthme, la bronchopneumopathie chronique obstructive (BPCO) et la dilatation de bronches (non mucoviscidose), la production excessive de mucus est à l’origine d’une obstruction aigue et/ou chronique des voies aériennes et représente un marqueur d’exacerbation de ces pathologies. Partant de ce constat, nous avons articulé notre projet autour des axes suivants :I)Etudier les déterminants biologiques de la variation de la rhéologie des expectorations dans les bronchopathies chroniques. Via une étude dont le promoteur est le CHU de Montpellier, nous avons recueilli des échantillons d’expectorations chez des patients atteints d’asthme, de BPCO et de dilatation de bronches (non mucoviscidosiques), et en avons étudié les caractéristiques microbiologiques (examen cytobactériologique), biophysiques (rhéologie) et biochimiques (dosage des constituants protéïques, ions, etc…). La partie "rhéologie" de l'étude s'est appuyée sur un dispositif de paillasse (Rhéomuco© - Rhéonova Grenoble) permettant de réaliser une analyse rapide dans l'heure, sur site, de l'expectoration. Cette première partie nous a permis d'établir des liens entre l'éosinophilie dans l'expectoration et certaines variables rhéologiques , mais aussi entre la concentration de mucines évaluée en spectrométrie de masse et ces mêmes variables rhéologiques. II)Evaluer l’impact de l’AZITHROMYCINE prescrite en fonction des caractéristiques biophysiques (rhéologie) des expectorations des patients, sur la prévention des exacerbations de BPCO Premièrement, afin de s'assurer de la reproductibilité du dispositif d'analyse rhéologique des expectorations, nous avons conduit dans différents centres (Bordeaux, Grenoble et Montpellier) plusieurs analyses de reproductibilité intra- et -inter opérateur, sur différents échantillons aux valeurs rhéologiques extrêmes". Cette étape nous a permis de confirmer la fiabilité de la méthode de mesure Deuxièmement, dans une volonté de faire le lien entre la paillasse et la clinique, nous avons élaboré un protocole qui s’inscrit dans le cadre du PHRC GIRCI/SOHO 2018. Celui- ci aura pour objectif d’explorer l’impact d’une stratégie thérapeutique basée non pas sur l’évaluation clinique standard, mais sur les propriétés biophysiques de l’expectoration et en particulier du mucus des patients atteints de BPCO. Cette étude nous permettra également de réaliser une collecte d’échantillons biologiques (sang, expectorations) sur lesquels sont prévus des analyses secondaires afin de déterminer finement les endotypes des patients inclus.

Background Zoonotic visceral leishmaniasis (VL) is endemic in the Mediterranean basin. However, large-scale comparative analyses of the commercial kits for the serological diagnosis of this neglected disease are lacking. This study compared the performances of four enzyme-linked immunosorbent assays (ELISA) and two immunochromatographic tests (ICT) as screening tests for the serodiagnosis of human VL in the Mediterranean region. Methodology/Principal findings Serum samples from 319 patients living in France, Tunisia or Morocco were tested using two ICT (IT LEISH and TruQuick LEISH IgG/IgM Meridian) and four ELISA reagents (NovaLisa Leishmania infantum IgG, Bordier Leishmania infantum, Ridascreen Leishmania IgG, and Vircell Leishmania). The population with proven VL (n = 181) included 65 immunocompromised patients. Significantly higher percentages of false-negative results were obtained with all assays in immunocompromised patients, compared with the immunocompetent population. In the whole population, sensitivity and specificity ranged from 80.7% to 93.9% and from 95.7% to 100%, respectively. The maximum accuracy was observed with the Bordier and Vircell ELISA kits (96.2%), and the lowest accuracy with Ridascreen reagent (88.7%). New thresholds of positivity are proposed for the Bordier, Vircell and NovaLisa ELISA kits to achieve 95% sensitivity with the highest possible specificity. Western blot (WB), used as a confirmation method, showed 100% sensitivity and identified 10.1% of asymptomatic carriers among the control population from the South of France. Conclusions/Significance This is the first study that compared commercially available kits for VL serodiagnosis in the endemic region of the Mediterranean basin. It provides specific information about the tests’ performance to help clinicians and biologists to select the right assay for VL screening., Author summary Human visceral leishmaniasis (VL) is a neglected disease endemic in the Mediterranean region, caused by Leishmania infantum. Accurate VL diagnosis is critical for rapid and correct patient management. Various serological tests are used, including commercial kits that require qualifications with specific information about their performance. In this study, we compared the performance of six commercial kits, two immunochromatographic tests (ICT; IT LEISH and TruQuick LEISH IgG/IgM Meridian) and four enzyme-linked immunosorbent assays (ELISA; NovaLisa Leishmania infantum IgG, Bordier Leishmania infantum, Ridascreen Leishmania IgG, and Vircell Leishmania), available in France and used as screening tests. The Bordier and Vircell ELISA reagents displayed the highest analytic performance compared with all the other kits. However, no test displayed 95% sensitivity at the thresholds recommended by the manufacturers. To reach this sensitivity value with the highest possible specificity, new thresholds are proposed for the Bordier, Vircell and NovaLisa ELISA reagents. Positive and negative results obtained with the six screening tests were confirmed by Western blot (100% sensitivity). Overall, this study presents a comparative analysis of commercially available kits for the serodiagnosis of human VL and provides additional information on the prevalence of asymptomatic carriers in the Mediterranean basin.

Sleep Apnea syndrome (SAS) is a common sleep disorder with a prevalence ranging from 5.9% to 79.2% in European general populations over 35 years of age old but remains under diagnosed. Continuous positive airway Pressure (CPAP) remains the treatment reference for moderate to severe forms of SAS in 2019. CPAP benefits depend on sufficient patient adherence, which is conditioned by multiple factors, including interface related side effects (leakage and their consequences, among others).In this thesis, we demonstrate the feasibility of OSA screening with Jawac® signaling in the general population. The analysis of the long-term CPAP-treated patient results in the interface-vent cohort highlighted that side-effects reported by these patients (some associated with leakage) are associated with compliance and sleepiness, while machine data (residual apnea/hypopnea index and machine leakage) are not.This lack of association between machine data (that could be monitored as proposed in the ATS 2013 algorithm) and patient compliance was confirmed for the patient subgroup of the cohort respecting the machine criteria and interface equipment of the ATS 2013 algorithm.Collaborative work has also made it possible to address the issue of leaks reported by the machine under two other aspects. First of all, it has been shown that the auto- or constant mode of the CPAP has no effect on the level of the leak reported by the machine (while the oro-nasal interface and the pressure level machine have an impact). By studying determinants of leaks during a night of polygraphic recording, the heterogeneity of unintentional leak determinants at the individual was demonstrated. Finding a consensus for how to quantify leak patterns remains a challenge in the field.; Le SAHOS présente une prévalence de 5.9% à 79% dans la population générale de plus de 35 ans mais reste sous diagnostiqué. Le traitement de référence des formes modérées à sévère reste en 2019 la Pressions Positive Continue (PPC). Le bénéfice à la PPC implique une observance suffisante du patient, cette observance étant conditionnée par de multiples facteurs dont les effets secondaires liés à l’interface (fuite entre autres et conséquences de ces fuites). Au cours de cette thèse, nous démontrons la faisabilité du dépistage du SAOS par signal Jawac® dans la population générale.L’analyse des résultats des patients de la cohorte Interface-vent traités par PPC au long cours, souligne que les effets secondaires tels que rapportés par ces patients (dont certains associés aux fuites) sont associés à l’observance et à la somnolence alors que les données machines (index d’apnée hypopnée résiduel et fuites machines) ne le sont pas. Cette absence d’association entre données machine pouvant faire l’objet d’un télésuivi (tel que proposé dans l’algorithme ATS 2013) et observance du patient a été confirmé pour le sous-groupe de patient de la cohorte respectant les critères d’appareillage machine et d’interface de l’algorithme ATS 2013.Les travaux de collaborations ont par ailleurs permis d’aborder la thématique des fuites rapportées par la machine sous deux autres aspects. Tout d’abord, il a été démontré que le mode auto-piloté ou constant de la PPC n’a aucun effet sur le niveau de la fuite rapportée par la machine (alors que l’interface faciale et le niveau de pression machine ont un impact). L’étude des déterminants des fuites au cours d’une nuit d’enregistrement polygraphique a permis de souligner l’hétérogénéité des déterminants de ces fuites non intentionnelles au niveau individuel et la difficulté pour certains patterns de fuites à trouver un consensus de traitement de la fuite.

This thesis presents a solution for comparing and identifying air trapping profiles among asthmatic patients. Asthma is defined as a narrowing of the airways following irritation. The mechanical reactions associated with irritation affect the expiratory flow by reducing the bronchial lumen, and thus causing exacerbation. This air flow reduction leads to the non-evacuation of air from certain regions of the lung upon expiration, a phenomenon named air trapping. Though triggers are well known, the mechanisms underlying the irritation are complex and poorly understood, the lung being a complex internal organ. This work is primarily intended to detect and describe different trapping profiles which correspond to specific sensitivities of the bronchial tree between patients. We also sought to associate a clinical data with trapping profiles. This work is based on data from patient scans collected during a bronchial reactivity test designed to capture the evolution of airway obstruction. The statistical models consists of comparing trapping profiles in a standardized way. Such profiles are derived by isolating pulmonary parenchyma on CT images, then generating a data space with mathematical properties enabling analysis. In this space, trapping profiles are characterized by the distribution of their nearest neighbors. This makes it possible to obtain for each image a local representation of the trapping distribution. The estimator of this distribution is standardized by a theoretical uniform distribution, which further renders between-patient comparisons possible. Finally, a B-spline classification of standardized distribution profiles using Ward's unsupervised method was performed. These grouped profiles were then compared to clinical observations.; Cette thèse a pour but de présenter une solution permettant d’identifier et de comparer différents profils de piégeage aérique chez des patients asthmatiques. L’asthme se décrit comme l’atteinte des voies aériennes en réponse à une irritation. Les réactions mécaniques associées à cette stimulation affectent le flux expiratoire en réduisant la lumière des bronches, et engendrent une exacerbation. La réduction du flux d’air entraine, lors de l’expiration, l’apparition de régions d’air piégé non expiré, phénomène appelé trappage aérien. Les facteurs déclencheurs ou d’aggravation sont bien connus, mais les mécanismes sous-jacents à l’irritation sont complexes et méconnus, le poumon étant un organe complexe et interne. Le travail présenté ici a pour but premier de rechercher l’existence de profils de trappage différents, correspondant à des sensibilités spécifiques de l’arbre bronchique entre patients. Nous avons également cherché à associer une dimension clinique aux profils de trappage. Pour cela, le travail se base sur des données de scanners de patients recueillis au cours d’un test de réactivité bronchique, permettant de capturer l’évolution de l’obstruction des voies respiratoires. Le modèle statistique mis en place consiste à comparer le profil normalisé de trappage de chaque patient. Ce profil est issu d’un parenchyme pulmonaire segmenté, complété dans un espace aux propriétés mathématiques permettant une analyse. Dans cet espace, les profils de trappage sont caractérisés par la distribution de leurs proches voisins. Cela permet d’obtenir pour chaque image une représentation locale de la distribution du trappage. L’estimateur de cette distribution est normalisé par une distribution théorique sous condition d’uniformité, permettant une comparaison entre les patients. Pour finir, une classification en B-splines des profils de distribution normalisée et faite par la méthode non supervisée de Ward, permettant d’obtenir des profils similaires de trappage. Ces profils sont ensuite comparés aux observations cliniques.

Understanding how patients choose hospitals is of utmost importance for both hospitals administrators and healthcare decision makers; the formers for patients incoming tide and the laters for regulations.In this thesis, we present different methods of modelling patients admission data in order to forecast patients incoming tide and compare hospitals attractiveness.The two first method use counting data models with possible spatial dependancy. Illustration is done on patients admission data in Languedoc-Roussillon.The third method uses discrete choice models (RUMs). Due to some limitations of these models according to our goal, we introduce a new approach where we released the assumption of utility maximization for an utility-threshold ; that is to say that an agent (patient) can choose an alternative (hospital) since he thinks that he can obtain a certain level of satisfaction of doing so, according to some aspects. Illustration of the approach is done on 2009 asthma admission data in Hérault.; Savoir comment les patients choisissent les hôpitaux est d'une importance majeure non seulement pour les gestionnaires des hôpitaux mais aussi pour les décideurs. Il s'agit entre autres pour les premiers, de la gestion des flux et l'offre des soins et pour les seconds, l'implémentation des reformes dans le système de santé.Nous proposons dans cette thèse différentes modélisations des données d'admission de patients en fonction de la distance par rapport à un hôpital afin de prévoir le flux des patients et de comparer son attractivité par rapport à d'autres hôpitaux. Par exemple, nous avons utilisé des modèles bayésiens hiérarchiques pour des données de comptage avec possible dépendance spatiale. Des applications on été faites sur des données d'admission de patients dans la région de Languedoc-Roussillon.Nous avons aussi utilisé des modèles de choix discrets tels que les RUMs. Mais vu certaines limites qu'ils présentent pour notre objectif, nous avons relâché l'hypothèse de maximisation d'utilité pour une plus souple et selon laquelle un agent (patient) peut choisir un produit (donc hôpital) dès lors que l'utilité que lui procure ce produit a atteint un certain seuil de satisfaction, en considérant certains aspects. Une illustration de cette approche est faite sur trois hôpitaux de l'Hérault pour les séjours dus à l'asthme en 2009 pour calculer l'envergure territorial d'un hôpital donné .

Understanding how patients choose hospitals is of utmost importance for both hospitals administrators and healthcare decision makers; the formers for patients incoming tide and the laters for regulations.In this thesis, we present different methods of modelling patients admission data in order to forecast patients incoming tide and compare hospitals attractiveness.The two first method use counting data models with possible spatial dependancy. Illustration is done on patients admission data in Languedoc-Roussillon.The third method uses discrete choice models (RUMs). Due to some limitations of these models according to our goal, we introduce a new approach where we released the assumption of utility maximization for an utility-threshold ; that is to say that an agent (patient) can choose an alternative (hospital) since he thinks that he can obtain a certain level of satisfaction of doing so, according to some aspects. Illustration of the approach is done on 2009 asthma admission data in Hérault.; Savoir comment les patients choisissent les hôpitaux est d'une importance majeure non seulement pour les gestionnaires des hôpitaux mais aussi pour les décideurs. Il s'agit entre autres pour les premiers, de la gestion des flux et l'offre des soins et pour les seconds, l'implémentation des reformes dans le système de santé.Nous proposons dans cette thèse différentes modélisations des données d'admission de patients en fonction de la distance par rapport à un hôpital afin de prévoir le flux des patients et de comparer son attractivité par rapport à d'autres hôpitaux. Par exemple, nous avons utilisé des modèles bayésiens hiérarchiques pour des données de comptage avec possible dépendance spatiale. Des applications on été faites sur des données d'admission de patients dans la région de Languedoc-Roussillon.Nous avons aussi utilisé des modèles de choix discrets tels que les RUMs. Mais vu certaines limites qu'ils présentent pour notre objectif, nous avons relâché l'hypothèse de maximisation d'utilité pour une plus souple et selon laquelle un agent (patient) peut choisir un produit (donc hôpital) dès lors que l'utilité que lui procure ce produit a atteint un certain seuil de satisfaction, en considérant certains aspects. Une illustration de cette approche est faite sur trois hôpitaux de l'Hérault pour les séjours dus à l'asthme en 2009 pour calculer l'envergure territorial d'un hôpital donné .

This thesis is about the spatial analysis of public health issues in sub-Saharan Africa. In a first study, we analysed the spatial variations of HIV prevalence and the socio-behavioral determinants among people aged 15 to 49 in Burundi using 2010 Demographic and Health Survey (DHS) data. In a second study, we analysed the evolution of the spatial distribution of stunting prevalence among under-three children in Côte d’Ivoire using 1994, 1998-1999 and 2011-2012 DHS data. For both studies, we first predicted the prevalence levels of the public health issue under study in unsampled points by the kernel method or ordinary kriging. We then identified clusters using the Kulldorff’s method and zones of different risks using the oblique partitioning method of the study area. Finally, we used spatial modeling to identify associated risk factors. These spatial analysis techniques have not only many advantages but also many limitations that we emphasize.; Cette thèse porte sur l’analyse spatiale de problèmes de santé publique rencontrés en Afrique subsaharienne. Dans une première étude, nous avons analysé les variations spatiales de la prévalence du VIH au Burundi et les déterminants socio-comportementaux chez les personnes âgées de 15 à 49 ans à partir des données de l’Enquête Démographique et de Santé (EDS) de 2010. Dans une deuxième étude, nous avons analysé l’évolution de la répartition spatiale de la prévalence du retard de croissance chez les enfants âgés de moins de 3 ans en Côte d’Ivoire à partir des données des EDS de 1994, 1998-1999 et 2011-2012. Pour ces deux études, nous avons tout d’abord prédit en des points non échantillonnés les niveaux de prévalence du problème étudié, soit par la méthode des noyaux, soit par la méthode du krigeage ordinaire. Nous avons ensuite procédé à la détection des agrégats spatiaux ou clusters par la méthode de Kulldorff puis à l’identification de zones de différents risques par la méthode du partitionnement oblique du territoire. Finalement, nous avons utilisé la modélisation spatiale pour identifier les facteurs associés. Ces techniques d’analyse spatiale présentent de nombreux avantages mais également de nombreuses limites que nous soulignons.

This thesis is about the spatial analysis of public health issues in sub-Saharan Africa. In a first study, we analysed the spatial variations of HIV prevalence and the socio-behavioral determinants among people aged 15 to 49 in Burundi using 2010 Demographic and Health Survey (DHS) data. In a second study, we analysed the evolution of the spatial distribution of stunting prevalence among under-three children in Côte d’Ivoire using 1994, 1998-1999 and 2011-2012 DHS data. For both studies, we first predicted the prevalence levels of the public health issue under study in unsampled points by the kernel method or ordinary kriging. We then identified clusters using the Kulldorff’s method and zones of different risks using the oblique partitioning method of the study area. Finally, we used spatial modeling to identify associated risk factors. These spatial analysis techniques have not only many advantages but also many limitations that we emphasize.; Cette thèse porte sur l’analyse spatiale de problèmes de santé publique rencontrés en Afrique subsaharienne. Dans une première étude, nous avons analysé les variations spatiales de la prévalence du VIH au Burundi et les déterminants socio-comportementaux chez les personnes âgées de 15 à 49 ans à partir des données de l’Enquête Démographique et de Santé (EDS) de 2010. Dans une deuxième étude, nous avons analysé l’évolution de la répartition spatiale de la prévalence du retard de croissance chez les enfants âgés de moins de 3 ans en Côte d’Ivoire à partir des données des EDS de 1994, 1998-1999 et 2011-2012. Pour ces deux études, nous avons tout d’abord prédit en des points non échantillonnés les niveaux de prévalence du problème étudié, soit par la méthode des noyaux, soit par la méthode du krigeage ordinaire. Nous avons ensuite procédé à la détection des agrégats spatiaux ou clusters par la méthode de Kulldorff puis à l’identification de zones de différents risques par la méthode du partitionnement oblique du territoire. Finalement, nous avons utilisé la modélisation spatiale pour identifier les facteurs associés. Ces techniques d’analyse spatiale présentent de nombreux avantages mais également de nombreuses limites que nous soulignons.

The aim of this work is to propose new solutions in the field of health event cluster detection. This type of analysis is traditionally used in the survey of diseases of which the aetiology is unknown in order to locate and detect aggregates which have an abnormally high density in time and/or in space. The determination of these clusters generally represents a preliminary stage in search of risk factors.We propose a review of existing methods as well as our contribution in various directions. Two approaches are proposed in the temporal frame. The first allows to avoid the use of simulations. The second makes it possible to take into account data of which the temporal information is incomplete. We have also developped a method for the detection of arbitrarily shaped spatial clusters in order to be able to analyse data of which the exact geographic location is known. This approach has been applied on particular data, those obtained by functional Magnetic Resonance Imaging. The perspectives of spatio-temporal analysis are finally evoked.; L'objectif de ce travail est de proposer des solutions nouvelles dans le domaine de la détection de clusters d'évènements de santé. Ce type d'analyse est traditionnellement utilisé dans la surveillance de maladies dont l'étiologie est incertaine afin de localiser et mettre en évidence des agrégats ayant une densité anormalement élevée dans le temps et/ou dans l'espace. La détermination de ces clusters constitue généralement une étape préliminaire à la recherche de facteurs de risque.Nous proposons une revue des méthodes existantes ainsi que notre contribution dans différentes directions. Deux approches sont proposées dans le cadre temporel permettant pour l'une d'éviter l'utilisation de simulations et pour l'autre de prendre en compte les données dont l'information temporelle est incomplète. Nous avons également mis au point une méthode de détection de clusters spatiaux de forme arbitraire permettant d'analyser des données dont on connaît la localisation géographique exacte. Cette approche a été appliquée sur des données particulières, celles obtenues par Imagerie par Résonance Magnétique fonctionnelle. Les perspectives d'analyse spatio-temporelle sont finalement évoquées.

The aim of this work is to propose new solutions in the field of health event cluster detection. This type of analysis is traditionally used in the survey of diseases of which the aetiology is unknown in order to locate and detect aggregates which have an abnormally high density in time and/or in space. The determination of these clusters generally represents a preliminary stage in search of risk factors.We propose a review of existing methods as well as our contribution in various directions. Two approaches are proposed in the temporal frame. The first allows to avoid the use of simulations. The second makes it possible to take into account data of which the temporal information is incomplete. We have also developped a method for the detection of arbitrarily shaped spatial clusters in order to be able to analyse data of which the exact geographic location is known. This approach has been applied on particular data, those obtained by functional Magnetic Resonance Imaging. The perspectives of spatio-temporal analysis are finally evoked.; L'objectif de ce travail est de proposer des solutions nouvelles dans le domaine de la détection de clusters d'évènements de santé. Ce type d'analyse est traditionnellement utilisé dans la surveillance de maladies dont l'étiologie est incertaine afin de localiser et mettre en évidence des agrégats ayant une densité anormalement élevée dans le temps et/ou dans l'espace. La détermination de ces clusters constitue généralement une étape préliminaire à la recherche de facteurs de risque.Nous proposons une revue des méthodes existantes ainsi que notre contribution dans différentes directions. Deux approches sont proposées dans le cadre temporel permettant pour l'une d'éviter l'utilisation de simulations et pour l'autre de prendre en compte les données dont l'information temporelle est incomplète. Nous avons également mis au point une méthode de détection de clusters spatiaux de forme arbitraire permettant d'analyser des données dont on connaît la localisation géographique exacte. Cette approche a été appliquée sur des données particulières, celles obtenues par Imagerie par Résonance Magnétique fonctionnelle. Les perspectives d'analyse spatio-temporelle sont finalement évoquées.