Rapid bacterial genome sequencing: methods and applications in clinical microbiology.

The recent advances in sequencing technologies have given all microbiology laboratories access to whole genome sequencing. Providing that tools for the automated analysis of sequence data and databases for associated meta-data are developed, whole genome sequencing will become a routine tool for large clinical microbiology laboratories. Indeed, the continuing reduction in sequencing costs and the shortening of the 'time to result' makes it an attractive strategy in both research and diagnostics. Here, we review how high-throughput sequencing is revolutionizing clinical microbiology and the promise that it still holds. We discuss major applications, which include: (i) identification of target DNA sequences and antigens to rapidly develop diagnostic tools; (ii) precise strain identification for epidemiological typing and pathogen monitoring during outbreaks; and (iii) investigation of strain properties, such as the presence of antibiotic resistance or virulence factors. In addition, recent developments in comparative metagenomics and single-cell sequencing offer the prospect of a better understanding of complex microbial communities at the global and individual levels, providing a new perspective for understanding host-pathogen interactions. Being a high-resolution tool, high-throughput sequencing will increasingly influence diagnostics, epidemiology, risk management, and patient care.

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.

THE USE OF SIMULATIONS IN EVOLUTIONARY POPULATION GENETICS: APPLICATIONS ON HUMANS, OWLS AND VIRTUAL ORGANISMS

Summary (in English) Computer simulations provide a practical way to address scientific questions that would be otherwise intractable. In evolutionary biology, and in population genetics in particular, the investigation of evolutionary processes frequently involves the implementation of complex models, making simulations a particularly valuable tool in the area. In this thesis work, I explored three questions involving the geographical range expansion of populations, taking advantage of spatially explicit simulations coupled with approximate Bayesian computation. First, the neutral evolutionary history of the human spread around the world was investigated, leading to a surprisingly simple model: A straightforward diffusion process of migrations from east Africa throughout a world map with homogeneous landmasses replicated to very large extent the complex patterns observed in real human populations, suggesting a more continuous (as opposed to structured) view of the distribution of modern human genetic diversity, which may play a better role as a base model for further studies. Second, the postglacial evolution of the European barn owl, with the formation of a remarkable coat-color cline, was inspected with two rounds of simulations: (i) determine the demographic background history and (ii) test the probability of a phenotypic cline, like the one observed in the natural populations, to appear without natural selection. We verified that the modern barn owl population originated from a single Iberian refugium and that they formed their color cline, not due to neutral evolution, but with the necessary participation of selection. The third and last part of this thesis refers to a simulation-only study inspired by the barn owl case above. In this chapter, we showed that selection is, indeed, effective during range expansions and that it leaves a distinguished signature, which can then be used to detect and measure natural selection in range-expanding populations. Résumé (en français) Les simulations fournissent un moyen pratique pour répondre à des questions scientifiques qui seraient inabordable autrement. En génétique des populations, l'étude des processus évolutifs implique souvent la mise en oeuvre de modèles complexes, et les simulations sont un outil particulièrement précieux dans ce domaine. Dans cette thèse, j'ai exploré trois questions en utilisant des simulations spatialement explicites dans un cadre de calculs Bayésiens approximés (approximate Bayesian computation : ABC). Tout d'abord, l'histoire de la colonisation humaine mondiale et de l'évolution de parties neutres du génome a été étudiée grâce à un modèle étonnement simple. Un processus de diffusion des migrants de l'Afrique orientale à travers un monde avec des masses terrestres homogènes a reproduit, dans une très large mesure, les signatures génétiques complexes observées dans les populations humaines réelles. Un tel modèle continu (opposé à un modèle structuré en populations) pourrait être très utile comme modèle de base dans l'étude de génétique humaine à l'avenir. Deuxièmement, l'évolution postglaciaire d'un gradient de couleur chez l'Effraie des clocher (Tyto alba) Européenne, a été examiné avec deux séries de simulations pour : (i) déterminer l'histoire démographique de base et (ii) tester la probabilité qu'un gradient phénotypique, tel qu'observé dans les populations naturelles puisse apparaître sans sélection naturelle. Nous avons montré que la population actuelle des chouettes est sortie d'un unique refuge ibérique et que le gradient de couleur ne peux pas s'être formé de manière neutre (sans l'action de la sélection naturelle). La troisième partie de cette thèse se réfère à une étude par simulations inspirée par l'étude de l'Effraie. Dans ce dernier chapitre, nous avons montré que la sélection est, en effet, aussi efficace dans les cas d'expansion d'aire de distribution et qu'elle laisse une signature unique, qui peut être utilisée pour la détecter et estimer sa force.

Dermatologie esthétique et correctrice: applications cliniques et rôle social [Esthetic and corrective dermatology: clinical applications and social role].

Skin diseases may have severe aesthetic and psychological repercussions leading sometimes to discriminations and social isolation. Dermatologists have contributed to the development of many cosmetic procedures: peelings, botulinum toxin or hyaluronic acid injections, lasers, blepharoplasty, facelift, etc. Many of these treatments have interesting clinical applications and may help numerous patients with skin diseases to return to a normal social life.

Nonclassical measurement error with applications to labor and development issues

Zero correlation between measurement error and model error has been assumed in existing panel data models dealing specifically with measurement error. We extend this literature and propose a simple model where one regressor is mismeasured, allowing the measurement error to correlate with model error. Zero correlation between measurement error and model error is a special case in our model where correlated measurement error equals zero. We ask two research questions. First, we wonder if the correlated measurement error can be identified in the context of panel data. Second, we wonder if classical instrumental variables in panel data need to be adjusted when correlation between measurement error and model error cannot be ignored. Under some regularity conditions the answer is yes to both questions. We then propose a two-step estimation corresponding to the two questions. The first step estimates correlated measurement error from a reverse regression; and the second step estimates usual coefficients of interest using adjusted instruments.

Ambulatory measurement of ankle kinetics for clinical applications.

This study aimed to design and validate the measurement of ankle kinetics (force, moment, and power) during consecutive gait cycles and in the field using an ambulatory system. An ambulatory system consisting of plantar pressure insole and inertial sensors (3D gyroscopes and 3D accelerometers) on foot and shank was used. To test this system, 12 patients and 10 healthy elderly subjects wore shoes embedding this system and walked many times across a gait lab including a force-plate surrounded by seven cameras considered as the reference system. Then, the participants walked two 50-meter trials where only the ambulatory system was used. Ankle force components and sagittal moment of ankle measured by ambulatory system showed correlation coefficient (R) and normalized RMS error (NRMSE) of more than 0.94 and less than 13% in comparison with the references system for both patients and healthy subjects. Transverse moment of ankle and ankle power showed R>0.85 and NRMSE<23%. These parameters also showed high repeatability (CMC>0.7). In contrast, the ankle coronal moment of ankle demonstrated high error and lower repeatability. Except for ankle coronal moment, the kinetic features obtained by the ambulatory system could distinguish the patients with ankle osteoarthritis from healthy subjects when measured in 50-meter trials. The proposed ambulatory system can be easily accessible in most clinics and could assess main ankle kinetics quantities with acceptable error and repeatability for clinical evaluations. This system is therefore suggested for field measurement in clinical applications.

Proteomics of blood and derived products: what's next?

Proteomics has changed the way proteins are analyzed in living systems. This approach has been applied to blood products and protein profiling has evolved in parallel with the development of techniques. The identification of proteins belonging to red blood cell, platelets or plasma was achieved at the end of the last century. Then, the questions on the applications emerged. Hence, several studies have focused on problems related to blood banking and products, such as the aging of blood products, identification of biomarkers, related diseases and the protein-protein interactions. More recently, a mass spectrometry-based proteomics approach to quality control has been applied in order to offer solutions and improve the quality of blood products. The current challenge we face is developing a closer relationship between transfusion medicine and proteomics. In this article, these issues will be approached by focusing first on the proteome identification of blood products and then on the applications and future developments within the field of proteomics and blood products.

Do voting advice applications have an effect on electoral participation and voter turnout ? : Evidence from the 2007 Swiss Federal Elections

Voting Advice Applications (VAAs) render a valuable platform for tackling one of democracy's central challenges: low voter turnout. Studies indicate that lack of information and cost-benefit considerations cause voters to abstain from voting. VAAs are online voting assistance tools which match own political preferences with those of candidates and parties in elections. By assisting voters in their decision-making process prior to casting their votes, VAAs not only rebut rational choice reasoning against voting but also narrow existing information gaps. In this paper we examine the impact of VAAs on participation and voter turnout. Specifically, we present results on how the Swiss VAA smartvote affected voter turnout in the 2007 federal elections. Our analyses suggest that smartvote does have a mobilizing capacity, especially among young voters who are usually underrepresented at polls. Moreover, the study demonstrates how VAAs such as smartvote do affect citizen's propensity to deal with politics in general.

Phase Contrast X-Ray Tomographic Microscopy for Biological and Materials Science Applications

The application of two approaches for high-throughput, high-resolution X-ray phase contrast tomographic imaging being used at the tomographic microscopy and coherent radiology experiments (TOMCAT) beamline of the SLS is discussed and illustrated. Differential phase contrast (DPC) imaging, using a grating interferometer and a phase-stepping technique, is integrated into the beamline environment at TOMCAT in terms of the fast acquisition and reconstruction of data and the availability to scan samples within an aqueous environment. A second phase contrast method is a modified transfer of intensity approach that can yield the 3D distribution of the decrement of the refractive index of a weakly absorbing object from a single tomographic dataset. The two methods are complementary to one another: the DPC method is characterised by a higher sensitivity and by moderate resolution with larger samples; the modified transfer of intensity approach is particularly suited for small specimens when high resolution (around 1 mu m) is required. Both are being applied to investigations in the biological and materials science fields.

Gemcitabine, oxaliplatin and 5-FU in advanced bile duct and gallbladder carcinoma: two parallel, multicentre phase-II trials.

BACKGROUND: Gemcitabine, oxaliplatin and 5-fluorouracil (5-FU) are active in biliary tract cancer and have a potentially synergistic mode of action and non-overlapping toxicity. The objective of these trials was to determine response, survival and toxicity separately in patients with bile duct cancer (BDC) and gallbladder cancer (GBC) treated with gemcitabine/oxaliplatin/5-FU chemotherapy. METHODS: Eligible patients with histologically proven, advanced or metastatic BDC (n=37) or GBC (n=35) were treated with gemcitabine (900 mg m(-2) over 30 min), oxaliplatin (65 mg m(-2)) and 5-FU (1500 mg m(-2) over 24 h) on days 1 and 8 of a 21-day cycle. Tumour response was the primary outcome measure. RESULTS: Response rates were 19% (95% CI: 6-32%) and 23% (95% CI: 9-37%) for BDC and GBC, respectively. Median survivals were 10.0 months (95% CI: 8.6-12.4) and 9.9 months (95% CI: 7.5-12.2) for BDC and GBC, respectively, and 1- and 2-year survival rates were 40 and 23% in BDC and 34 and 6% in GBC (intention-to-treat analysis). Major grade III and IV adverse events were neutropenia, thrombocytopenia, elevated bilirubin and anorexia. CONCLUSION: Triple-drug chemotherapy achieves comparable results for response and survival to previously reported regimens, but with more toxicity.

'Bio-nano interactions: new tools, insights and impacts': summary of the Royal Society discussion meeting

Bio-nano interactions can be defined as the study of interactions between nanoscale entities and biological systems such as, but not limited to, peptides, proteins, lipids, DNA and other biomolecules, cells and cellular receptors and organisms including humans. Studying bio-nano interactions is particularly useful for understanding engineered materials that have at least one dimension in the nanoscale. Such materials may consist of discrete particles or nanostructured surfaces. Much of biology functions at the nanoscale; therefore, our ability to manipulate materials such that they are taken up at the nanoscale, and engage biological machinery in a designed and purposeful manner, opens new vistas for more efficient diagnostics, therapeutics (treatments) and tissue regeneration, so-called nanomedicine. Additionally, this ability of nanomaterials to interact with and be taken up by cells allows nanomaterials to be used as probes and tools to advance our understanding of cellular functioning. Yet, as a new technology, assessment of the safety of nanomaterials, and the applicability of existing regulatory frameworks for nanomaterials must be investigated in parallel with development of novel applications. The Royal Society meeting 'Bio-nano interactions: new tools, insights and impacts' provided an important platform for open dialogue on the current state of knowledge on these issues, bringing together scientists, industry, regulatory and legal experts to concretize existing discourse in science law and policy. This paper summarizes these discussions and the insights that emerged.

Unpacking the cognitive map: the parallel map theory of hippocampal function

In the parallel map theory, the hippocampus encodes space with 2 mapping systems. The bearing map is constructed primarily in the dentate gyrus from directional cues such as stimulus gradients. The sketch map is constructed within the hippocampus proper from positional cues. The integrated map emerges when data from the bearing and sketch maps are combined. Because the component maps work in parallel, the impairment of one can reveal residual learning by the other. Such parallel function may explain paradoxes of spatial learning, such as learning after partial hippocampal lesions, taxonomic and sex differences in spatial learning, and the function of hippocampal neurogenesis. By integrating evidence from physiology to phylogeny, the parallel map theory offers a unified explanation for hippocampal function.