New developments and applications in modelling occupational exposure to airborne contaminants

Résumé: L'évaluation de l'exposition aux nuisances professionnelles représente une étape importante dans l'analyse de poste de travail. Les mesures directes sont rarement utilisées sur les lieux même du travail et l'exposition est souvent estimée sur base de jugements d'experts. Il y a donc un besoin important de développer des outils simples et transparents, qui puissent aider les spécialistes en hygiène industrielle dans leur prise de décision quant aux niveaux d'exposition. L'objectif de cette recherche est de développer et d'améliorer les outils de modélisation destinés à prévoir l'exposition. Dans un premier temps, une enquête a été entreprise en Suisse parmi les hygiénistes du travail afin d'identifier les besoins (types des résultats, de modèles et de paramètres observables potentiels). Il a été constaté que les modèles d'exposition ne sont guère employés dans la pratique en Suisse, l'exposition étant principalement estimée sur la base de l'expérience de l'expert. De plus, l'émissions de polluants ainsi que leur dispersion autour de la source ont été considérés comme des paramètres fondamentaux. Pour tester la flexibilité et la précision des modèles d'exposition classiques, des expériences de modélisations ont été effectuées dans des situations concrètes. En particulier, des modèles prédictifs ont été utilisés pour évaluer l'exposition professionnelle au monoxyde de carbone et la comparer aux niveaux d'exposition répertoriés dans la littérature pour des situations similaires. De même, l'exposition aux sprays imperméabilisants a été appréciée dans le contexte d'une étude épidémiologique sur une cohorte suisse. Dans ce cas, certains expériences ont été entreprises pour caractériser le taux de d'émission des sprays imperméabilisants. Ensuite un modèle classique à deux-zone a été employé pour évaluer la dispersion d'aérosol dans le champ proche et lointain pendant l'activité de sprayage. D'autres expériences ont également été effectuées pour acquérir une meilleure compréhension des processus d'émission et de dispersion d'un traceur, en se concentrant sur la caractérisation de l'exposition du champ proche. Un design expérimental a été développé pour effectuer des mesures simultanées dans plusieurs points d'une cabine d'exposition, par des instruments à lecture directe. Il a été constaté que d'un point de vue statistique, la théorie basée sur les compartiments est sensée, bien que l'attribution à un compartiment donné ne pourrait pas se faire sur la base des simples considérations géométriques. Dans une étape suivante, des données expérimentales ont été collectées sur la base des observations faites dans environ 100 lieux de travail différents: des informations sur les déterminants observés ont été associées aux mesures d'exposition des informations sur les déterminants observés ont été associé. Ces différentes données ont été employées pour améliorer le modèle d'exposition à deux zones. Un outil a donc été développé pour inclure des déterminants spécifiques dans le choix du compartiment, renforçant ainsi la fiabilité des prévisions. Toutes ces investigations ont servi à améliorer notre compréhension des outils des modélisations ainsi que leurs limitations. L'intégration de déterminants mieux adaptés aux besoins des experts devrait les inciter à employer cet outil dans leur pratique. D'ailleurs, en augmentant la qualité des outils des modélisations, cette recherche permettra non seulement d'encourager leur utilisation systématique, mais elle pourra également améliorer l'évaluation de l'exposition basée sur les jugements d'experts et, par conséquent, la protection de la santé des travailleurs. Abstract Occupational exposure assessment is an important stage in the management of chemical exposures. Few direct measurements are carried out in workplaces, and exposures are often estimated based on expert judgements. There is therefore a major requirement for simple transparent tools to help occupational health specialists to define exposure levels. The aim of the present research is to develop and improve modelling tools in order to predict exposure levels. In a first step a survey was made among professionals to define their expectations about modelling tools (what types of results, models and potential observable parameters). It was found that models are rarely used in Switzerland and that exposures are mainly estimated from past experiences of the expert. Moreover chemical emissions and their dispersion near the source have also been considered as key parameters. Experimental and modelling studies were also performed in some specific cases in order to test the flexibility and drawbacks of existing tools. In particular, models were applied to assess professional exposure to CO for different situations and compared with the exposure levels found in the literature for similar situations. Further, exposure to waterproofing sprays was studied as part of an epidemiological study on a Swiss cohort. In this case, some laboratory investigation have been undertaken to characterize the waterproofing overspray emission rate. A classical two-zone model was used to assess the aerosol dispersion in the near and far field during spraying. Experiments were also carried out to better understand the processes of emission and dispersion for tracer compounds, focusing on the characterization of near field exposure. An experimental set-up has been developed to perform simultaneous measurements through direct reading instruments in several points. It was mainly found that from a statistical point of view, the compartmental theory makes sense but the attribution to a given compartment could ñó~be done by simple geometric consideration. In a further step the experimental data were completed by observations made in about 100 different workplaces, including exposure measurements and observation of predefined determinants. The various data obtained have been used to improve an existing twocompartment exposure model. A tool was developed to include specific determinants in the choice of the compartment, thus largely improving the reliability of the predictions. All these investigations helped improving our understanding of modelling tools and identify their limitations. The integration of more accessible determinants, which are in accordance with experts needs, may indeed enhance model application for field practice. Moreover, while increasing the quality of modelling tool, this research will not only encourage their systematic use, but might also improve the conditions in which the expert judgments take place, and therefore the workers `health protection.

A gene-rich, transcriptionally active environment and the pre-deposition of repressive marks are predictive of susceptibility to KRAB/KAP1-mediated silencing.

AbstractBACKGROUND: KRAB-ZFPs (Krüppel-associated box domain-zinc finger proteins) are vertebrate-restricted transcriptional repressors encoded in the hundreds by the mouse and human genomes. They act via an essential cofactor, KAP1, which recruits effectors responsible for the formation of facultative heterochromatin. We have recently shown that KRAB/KAP1 can mediate long-range transcriptional repression through heterochromatin spreading, but also demonstrated that this process is at times countered by endogenous influences.METHOD: To investigate this issue further we used an ectopic KRAB-based repressor. This system allowed us to tether KRAB/KAP1 to hundreds of euchromatic sites within genes, and to record its impact on gene expression. We then correlated this KRAB/KAP1-mediated transcriptional effect to pre-existing genomic and chromatin structures to identify specific characteristics making a gene susceptible to repression.RESULTS: We found that genes that were susceptible to KRAB/KAP1-mediated silencing carried higher levels of repressive histone marks both at the promoter and over the transcribed region than genes that were insensitive. In parallel, we found a high enrichment in euchromatic marks within both the close and more distant environment of these genes.CONCLUSION: Together, these data indicate that high levels of gene activity in the genomic environment and the pre-deposition of repressive histone marks within a gene increase its susceptibility to KRAB/KAP1-mediated repression.

High-resolution numerical modelling of flow-vegetation interactions

In this paper, we present and apply a new three-dimensional model for the prediction of canopy-flow and turbulence dynamics in open-channel flow. The approach uses a dynamic immersed boundary technique that is coupled in a sequentially staggered manner to a large eddy simulation. Two different biomechanical models are developed depending on whether the vegetation is dominated by bending or tensile forces. For bending plants, a model structured on the Euler-Bernoulli beam equation has been developed, whilst for tensile plants, an N-pendula model has been developed. Validation against flume data shows good agreement and demonstrates that for a given stem density, the models are able to simulate the extraction of energy from the mean flow at the stem-scale which leads to the drag discontinuity and associated mixing layer.

Population pharmacokinetic modelling and evaluation of different dosage regimens for darunavir and ritonavir in HIV-infected individuals.

OBJECTIVES: Darunavir is a protease inhibitor that is administered with low-dose ritonavir to enhance its bioavailability. It is prescribed at standard dosage regimens of 600/100 mg twice daily in treatment-experienced patients and 800/100 mg once daily in naive patients. A population pharmacokinetic approach was used to characterize the pharmacokinetics of both drugs and their interaction in a cohort of unselected patients and to compare darunavir exposure expected under alternative dosage regimens. METHODS: The study population included 105 HIV-infected individuals who provided darunavir and ritonavir plasma concentrations. Firstly, a population pharmacokinetic analysis for darunavir and ritonavir was conducted, with inclusion of patients' demographic, clinical and genetic characteristics as potential covariates (NONMEM(®)). Then, the interaction between darunavir and ritonavir was studied while incorporating levels of both drugs into different inhibitory models. Finally, model-based simulations were performed to compare trough concentrations (Cmin) between the recommended dosage regimen and alternative combinations of darunavir and ritonavir. RESULTS: A one-compartment model with first-order absorption adequately characterized darunavir and ritonavir pharmacokinetics. The between-subject variability in both compounds was important [coefficient of variation (CV%) 34% and 47% for darunavir and ritonavir clearance, respectively]. Lopinavir and ritonavir exposure (AUC) affected darunavir clearance, while body weight and darunavir AUC influenced ritonavir elimination. None of the tested genetic variants showed any influence on darunavir or ritonavir pharmacokinetics. The simulations predicted darunavir Cmin much higher than the IC50 thresholds for wild-type and protease inhibitor-resistant HIV-1 strains (55 and 550 ng/mL, respectively) under standard dosing in >98% of experienced and naive patients. Alternative regimens of darunavir/ritonavir 1200/100 or 1200/200 mg once daily also had predicted adequate Cmin (>550 ng/mL) in 84% and 93% of patients, respectively. Reduction of darunavir/ritonavir dosage to 600/50 mg twice daily led to a 23% reduction in average Cmin, still with only 3.8% of patients having concentrations below the IC50 for resistant strains. CONCLUSIONS: The important variability in darunavir and ritonavir pharmacokinetics is poorly explained by clinical covariates and genetic influences. In experienced patients, treatment simplification strategies guided by drug level measurements and adherence monitoring could be proposed.

La régression tumorale n'est pas un facteur de risque d'atteinte du ganglion sentinelle dans les mélanomes fins (indice de Breslow < or = 1 mm) [Tumour regression is not predictive for higher risk of sentinel node involvement in thin melanomas (Breslow thickness < or = 1 mm)]

Background: Thin melanomas (Breslow thickness <= 1 mm) are considered highly curable. The aim of this study was to evaluate the correlation between histological tumour regression and sentinel lymph node (SLN) involvement in thin melanomas. Patients and methods: This was a retrospective single-centre study of 34 patients with thin melanomas undergoing SLN biopsy between April 1998 and January 2005. Results: The study included 14 women and 20 men of mean age 56.3 years. Melanomas were located on the neck (n = 3), soles (n = 4), trunk (n = 13) and extremities (n = 14). Pathological examination showed 25 SSM, four acral lentiginous melanomas, three in situ melanomas, one nodular melanoma and one unclassified melanoma with a mean Breslow thickness of 0.57 mm. Histological tumour regression was observed in 26 over 34 cases and ulceration was found in one case. Clark levels were as follows: I (n = 3), II (n = 20), III (n = 9), IV (n = 2). Growth phase was available in 15 cases (seven radial and eight vertical). Mitotic rates, available in 24 cases, were: 0 (n = 9), 1 (n = 11), 2 (n = 2), 3 (n = 1), 6 (n = 1). One patient with histological tumour regression (2.9% of cases and 3.8% of cases with regressing tumours) had a metastatic SLN. One patient negative for SLN had a lung relapse and died of the disease. Mean follow-up was 26.2 months. Conclusion: The results of the present study and the analysis of the literature show that histological regression of the primary tumour does not seem predictive of higher risk of SLN involvement in thin melanomas. This suggests that screening for SLN is not indicated in thin melanomas, even those with histological regression.

Predictive models of syncope causes in an outpatient clinic

The investigation of unexplained syncope remains a challenging clinical problem. In the present study we sought to evaluate the diagnostic value of a standardized work-up focusing on non invasive tests in patients with unexplained syncope referred to a syncope clinic, and whether certain combinations of clinical parameters are characteristic of rhythmic and reflex causes of syncope. METHODS AND RESULTS: 317 consecutive patients underwent a standardized work-up including a 12-lead ECG, physical examination, detailed history with screening for syncope-related symptoms using a structured questionnaire followed by carotid sinus massage (CSM), and head-up tilt test. Invasive testings including an electrophysiological study and implantation of a loop recorder were only performed in those with structural heart disease or traumatic syncope. Our work-up identified an etiology in 81% of the patients. Importantly, three quarters of the causes were established non invasively combining head-up tilt test, CSM and hyperventilation testing. Invasive tests yielded an additional 7% of diagnoses. Logistic analysis identified age and number of significant prodromes as the only predictive factors of rhythmic syncope. The same two factors, in addition to the duration of the ECG P-wave, were also predictive of vasovagal and psychogenic syncope. These factors, optimally combined in predictive models, showed a high negative and a modest positive predictive value. CONCLUSION: A standardized work-up focusing on non invasive tests allows to establish more than three quarters of syncope causes. Predictive models based on simple clinical parameters may help to distinguish between rhythmic and other causes of syncope

Re: Cost effectiveness of strategies to combat cardiovascular disease, diabetes, and tobacco use in sub-Saharan Africa and South East Asia: mathematical modelling study.

Rapid response to: Ortegón M, Lim S, Chisholm D, Mendis S. Cost effectiveness of strategies to combat cardiovascular disease, diabetes, and tobacco use in sub-Saharan Africa and South East Asia: mathematical modelling study. BMJ. 2012 Mar 2;344:e607. doi: 10.1136/bmj.e607. PMID: 22389337.

Extreme Precipitation Modelling Using Geostatistics and Machine Learning Algorithms

The paper presents an approach for mapping of precipitation data. The main goal is to perform spatial predictions and simulations of precipitation fields using geostatistical methods (ordinary kriging, kriging with external drift) as well as machine learning algorithms (neural networks). More practically, the objective is to reproduce simultaneously both the spatial patterns and the extreme values. This objective is best reached by models integrating geostatistics and machine learning algorithms. To demonstrate how such models work, two case studies have been considered: first, a 2-day accumulation of heavy precipitation and second, a 6-day accumulation of extreme orographic precipitation. The first example is used to compare the performance of two optimization algorithms (conjugate gradients and Levenberg-Marquardt) of a neural network for the reproduction of extreme values. Hybrid models, which combine geostatistical and machine learning algorithms, are also treated in this context. The second dataset is used to analyze the contribution of radar Doppler imagery when used as external drift or as input in the models (kriging with external drift and neural networks). Model assessment is carried out by comparing independent validation errors as well as analyzing data patterns.

Persistence of a Gastrocutaneous Fistula after gastrostomy removal in children: Incidence and predictive factors

Background/Purpose: The aims of this study were to determine the incidence of persistent gastrocutaneous fistulas (GCF) after gastrostomy removal and to identify associated risk factors. Methods: This retrospective study included 75 children from the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland who had a gastrostomy performed between 1988 and 2010. The records of the children were reviewed for sex, age at the time of gastrostomy removal, underlying disease, type of gastrostomy placement and length of use, and then analyzed in order to find a correlation between the GCF and these parameters. Results: The gastrostomy orifice did not close spontaneously within the first month in 33 of the patients (44%), and 15 subsequently underwent surgical closure. The mean duration of gastrostomy use was significantly longer in children who developed a persistent GCF (30 vs. 19 months, P = 0.03). The other parameters studied did not show any significant association with the persistence of a GCF. Conclusions: The only predictive factor determining the persistence of a GCF was found to be the timespan between the placement and removal of the gastrostomy appliance. Elective surgical closure of the gastrostomy orifice should be considered after 1 month of persistent GCF.

Blood glucose level on postoperative day 1 is predictive of adverse outcomes after cardiovascular surgery

AIM: Hyperglycaemia is now a recognized predictive factor of morbidity and mortality after coronary artery bypass grafting (CABG). For this reason, we aimed to evaluate the postoperative management of glucose control in patients undergoing cardiovascular surgery, and to assess the impact of glucose levels on in-hospital mortality and morbidity. METHODS: This was a retrospective study investigating the association between postoperative blood glucose and outcomes, including death, post-surgical complications, and length of stay in the intensive care unit (ICU) and in hospital. RESULTS: A total of 642 consecutive patients were enrolled into the study after cardiovascular surgery (CABG, carotid endarterectomy and bypass in the lower limbs). Patients' mean age was 68+/-10 years, and 74% were male. In-hospital mortality was 5% in diabetic patients vs 2% in non-diabetic patients (OR: 1.66, P=0.076). Having blood glucose levels in the upper quartile range (> or =8.8 mmol/L) on postoperative day 1 was independently associated with death (OR: 10.16, P=0.0002), infectious complications (OR: 1.76, P=0.04) and prolonged ICU stay (OR: 3.10, P<0.0001). Patients presenting with three or more hypoglycaemic episodes (<4.1 mmol/L) had increased rates of mortality (OR: 9.08, P<0.0001) and complications (OR: 8.57, P<0.0001). CONCLUSION: Glucose levels greater than 8.8 mmol/L on postoperative day 1 and having three or more hypoglycaemic episodes in the postoperative period were predictive of mortality and morbidity among patients undergoing cardiovascular surgery. This suggests that a multidisciplinary approach may be able to achieve better postoperative blood glucose control. Conclusion: Objectif: L'hyperglycémie a été reconnue comme facteur prédictif de morbidité et mortalité après un pontage aortocoronaire. Notre étude avait pour objectif d'évaluer la prise en charge postopératoire des glycémies chez les patients qui avaient subi une intervention chirurgicale cardiovasculaire et d'évaluer l'impact de ces glycémies sur la mortalité et la morbidité intrahospitalières. Méthodes: Étude rétrospective recherchant une association entre la glycémie postopératoire et les complications postchirurgicales, la mortalité et la durée du séjour aux soins intensifs et à l'hôpital. Résultats: L'étude a été réalisée sur 642 patients qui avaient subi une intervention chirurgicale cardiovasculaire (ex. pontage aortocoronaire, endartérectomie de la carotide, pontage artériel des membres inférieurs). L'âge moyen est de 68 ± 10 ans et 74 % des patients étaient de sexe masculin. La mortalité intrahospitalière a été de 5 % parmi les patients diabétiques et 2 % chez les non-diabétiques (OR 1,66, p = 0,076). Les taux de glycémies situés dans le quartile supérieur (≥ 8,8 mmol/l) à j1 postopératoire sont associés de manière indépendante avec la mortalité (OR 10,16, 95 % CI 3,20-39,00, p = 0,0002), les complications infectieuses (OR 1,76, 95 % CI 1,02-3,00, p = 0,04) et la durée du séjour aux soins intensifs (OR 3,10, 95 % CI 1,83-5,38, p < 0,0001). Les patients qui avaient présenté trois hypoglycémies ou plus (< 4,1 mmol/l) ont présenté un taux augmenté de mortalité (OR 9,08, p ≤ 0,0001) et de complications (OR 8,57, p < 0,0001). Conclusion : Des glycémies supérieures à 8,8 mmol/l à j1 postopératoire et la présence de trois hypoglycémies ou plus en période postopératoire sont des facteurs prédictifs de mauvais pronostic chez les patients qui avaient subi une intervention chirurgicale cardiovasculaire. Ainsi, une approche multidisciplinaire devrait être proposée afin d'obtenir un meilleur contrôle postopératoire des glycémies.

Combining probabilistic land-use change and tree population dynamics modelling to simulate responses in mountain forests

Altitudinal tree lines are mainly constrained by temperature, but can also be influenced by factors such as human activity, particularly in the European Alps, where centuries of agricultural use have affected the tree-line. Over the last decades this trend has been reversed due to changing agricultural practices and land-abandonment. We aimed to combine a statistical land-abandonment model with a forest dynamics model, to take into account the combined effects of climate and human land-use on the Alpine tree-line in Switzerland. Land-abandonment probability was expressed by a logistic regression function of degree-day sum, distance from forest edge, soil stoniness, slope, proportion of employees in the secondary and tertiary sectors, proportion of commuters and proportion of full-time farms. This was implemented in the TreeMig spatio-temporal forest model. Distance from forest edge and degree-day sum vary through feed-back from the dynamics part of TreeMig and climate change scenarios, while the other variables remain constant for each grid cell over time. The new model, TreeMig-LAb, was tested on theoretical landscapes, where the variables in the land-abandonment model were varied one by one. This confirmed the strong influence of distance from forest and slope on the abandonment probability. Degree-day sum has a more complex role, with opposite influences on land-abandonment and forest growth. TreeMig-LAb was also applied to a case study area in the Upper Engadine (Swiss Alps), along with a model where abandonment probability was a constant. Two scenarios were used: natural succession only (100% probability) and a probability of abandonment based on past transition proportions in that area (2.1% per decade). The former showed new forest growing in all but the highest-altitude locations. The latter was more realistic as to numbers of newly forested cells, but their location was random and the resulting landscape heterogeneous. Using the logistic regression model gave results consistent with observed patterns of land-abandonment: existing forests expanded and gaps closed, leading to an increasingly homogeneous landscape.