Paper 5: Surveillance of multiple congenital anomalies: implementation of a computer algorithm in European registers for classification of cases.

BACKGROUND: Surveillance of multiple congenital anomalies is considered to be more sensitive for the detection of new teratogens than surveillance of all or isolated congenital anomalies. Current literature proposes the manual review of all cases for classification into isolated or multiple congenital anomalies. METHODS: Multiple anomalies were defined as two or more major congenital anomalies, excluding sequences and syndromes. A computer algorithm for classification of major congenital anomaly cases in the EUROCAT database according to International Classification of Diseases (ICD)v10 codes was programmed, further developed, and implemented for 1 year's data (2004) from 25 registries. The group of cases classified with potential multiple congenital anomalies were manually reviewed by three geneticists to reach a final agreement of classification as "multiple congenital anomaly" cases. RESULTS: A total of 17,733 cases with major congenital anomalies were reported giving an overall prevalence of major congenital anomalies at 2.17%. The computer algorithm classified 10.5% of all cases as "potentially multiple congenital anomalies". After manual review of these cases, 7% were agreed to have true multiple congenital anomalies. Furthermore, the algorithm classified 15% of all cases as having chromosomal anomalies, 2% as monogenic syndromes, and 76% as isolated congenital anomalies. The proportion of multiple anomalies varies by congenital anomaly subgroup with up to 35% of cases with bilateral renal agenesis. CONCLUSIONS: The implementation of the EUROCAT computer algorithm is a feasible, efficient, and transparent way to improve classification of congenital anomalies for surveillance and research.

Fuzzy logic algorithm to extract specific interaction forces from atomic force microscopy data

The atomic force microscope is not only a very convenient tool for studying the topography of different samples, but it can also be used to measure specific binding forces between molecules. For this purpose, one type of molecule is attached to the tip and the other one to the substrate. Approaching the tip to the substrate allows the molecules to bind together. Retracting the tip breaks the newly formed bond. The rupture of a specific bond appears in the force-distance curves as a spike from which the binding force can be deduced. In this article we present an algorithm to automatically process force-distance curves in order to obtain bond strength histograms. The algorithm is based on a fuzzy logic approach that permits an evaluation of "quality" for every event and makes the detection procedure much faster compared to a manual selection. In this article, the software has been applied to measure the binding strength between tubuline and microtubuline associated proteins.

The effect of mountain bike suspensions on vibrations and off-road uphill performance.

AIM: This study evaluates the effect of front suspension (FS) and dual suspension (DS) mountain-bike on performance and vibrations during off-road uphill riding. METHODS: Thirteen male cyclists (27+/-5 years, 70+/-6 kg, VO(2max)59+/-6 mL.kg(-1).min(-1), mean+/-SD) performed, in a random sequence, at their lactate threshold, an off-road uphill course (1.69 km, 212 m elevation gain) with both type of bicycles. Variable measured: a) VO(2) consumption (K4b2 analyzer, Cosmed), b) power output (SRM) c) gain in altitude and d) 3-D accelerations under the saddle and at the wheel (Physilog, EPFL, Switzerland). Power spectral analy- sis (Fourier) was performed from the vertical acceleration data. RESULTS: Respectively for the FS and DS mountain bike: speed amounted to 7.5+/-0.7 km.h(-1) and 7.4+/-0.8 km.h(-1), (NS), energy expenditure 1.39+/-0.16 kW and 1.38+/-0.18, (NS), gross efficiency 0.161+/-0.013 and 0.159+/-0.013, (NS), peak frequency of vibration under the saddle 4.78+/-2.85 Hz and 2.27+/-0.2 Hz (P<0.01) and median-frequency of vertical displacements of the saddle 9.41+/-1.47 Hz and 5.78+/-2.27 Hz (P<0.01). CONCLUSION: Vibrations at the saddle level of the DS bike are of low frequencies whereas those of the FS bike are mostly of high frequencies. In the DS bike, the torque produced by the cyclist at the pedal level may generate low frequency vibrations. We conclude that the DS bike absorbs more high frequency vibrations, is more comfortable and performs as well as the FS bicycle.

Diagnostic algorithm for a validated displacement grading of pediatric supracondylar fractures.

Background: The first AO comprehensive pediatric long bone fracture classification system has been established following a structured path of development and validation with experienced pediatric surgeons. Methods: A follow-up series of agreement studies was applied to specify and evaluate a grading system for displacement of pediatric supracondylar fractures. An iterative process comprising an international group of 5 experienced pediatric surgeons (Phase 1) followed by a pragmatic multicenter agreement study involving 26 raters (Phase 2) was used. The last evaluations were conducted on a consecutive collection of 154 supracondylar fractures documented by standard anteroposterior and lateral radiographs. Results: Fractures were classified according to 1 of 4 grades: I = incomplete fracture with no or minimal displacement; II = Incomplete fracture with continuity of the posterior (extension fracture) or anterior cortex (flexion fracture); III = lack of bone continuity (broken cortex), but still some contact between the fracture planes; IV = complete fracture with no bone continuity (broken cortex), and no contact between the fracture planes. A diagnostic algorithm to support the practical application of the grading system in a clinical setting, as well as an aid using a circle placed over the capitellum was proposed. The overall kappa coefficients were 0.68 and 0.61 in the Phase 1 and Phase 2 studies, respectively. In the Phase 1 study, fracture grades I, II, III, and IV were classified with median accuracies of 91%, 82%, 83%, and 99.5%, respectively. Similar median accuracies of 86% (Grade I), 73% (Grade II), 83%(Grade III), and 92% were reported for the Phase 2 study. Reliability was high in distinguishing complete, unstable fractures from stable injuries [ie, kappa coefficients of 0.84 (Phase 1) and 0.83 (Phase 2) were calculated]; in Phase 2, surgeons' accuracies in classifying complete fractures were all above 85%. Conclusions: With clear and unambiguous definition, this new grading system for supracondylar fracture displacement has proved to be sufficiently reliable and accurate when applied by pediatric surgeons in the framework of clinical routine as well as research.

Providing more informative projections of climate change impact on plant distribution in a mountain environment

Summary Due to their conic shape and the reduction of area with increasing elevation, mountain ecosystems were early identified as potentially very sensitive to global warming. Moreover, mountain systems may experience unprecedented rates of warming during the next century, two or three times higher than that records of the 20th century. In this context, species distribution models (SDM) have become important tools for rapid assessment of the impact of accelerated land use and climate change on the distribution plant species. In my study, I developed and tested new predictor variables for species distribution models (SDM), specific to current and future geographic projections of plant species in a mountain system, using the Western Swiss Alps as model region. Since meso- and micro-topography are relevant to explain geographic patterns of plant species in mountain environments, I assessed the effect of scale on predictor variables and geographic projections of SDM. I also developed a methodological framework of space-for-time evaluation to test the robustness of SDM when projected in a future changing climate. Finally, I used a cellular automaton to run dynamic simulations of plant migration under climate change in a mountain landscape, including realistic distance of seed dispersal. Results of future projections for the 21st century were also discussed in perspective of vegetation changes monitored during the 20th century. Overall, I showed in this study that, based on the most severe A1 climate change scenario and realistic dispersal simulations of plant dispersal, species extinctions in the Western Swiss Alps could affect nearly one third (28.5%) of the 284 species modeled by 2100. With the less severe 61 scenario, only 4.6% of species are predicted to become extinct. However, even with B1, 54% (153 species) may still loose more than 80% of their initial surface. Results of monitoring of past vegetation changes suggested that plant species can react quickly to the warmer conditions as far as competition is low However, in subalpine grasslands, competition of already present species is probably important and limit establishment of newly arrived species. Results from future simulations also showed that heavy extinctions of alpine plants may start already in 2040, but the latest in 2080. My study also highlighted the importance of fine scale and regional. assessments of climate change impact on mountain vegetation, using more direct predictor variables. Indeed, predictions at the continental scale may fail to predict local refugees or local extinctions, as well as loss of connectivity between local populations. On the other hand, migrations of low-elevation species to higher altitude may be difficult to predict at the local scale. Résumé La forme conique des montagnes ainsi que la diminution de surface dans les hautes altitudes sont reconnues pour exposer plus sensiblement les écosystèmes de montagne au réchauffement global. En outre, les systèmes de montagne seront sans doute soumis durant le 21ème siècle à un réchauffement deux à trois fois plus rapide que celui mesuré durant le 20ème siècle. Dans ce contexte, les modèles prédictifs de distribution géographique de la végétation se sont imposés comme des outils puissants pour de rapides évaluations de l'impact des changements climatiques et de la transformation du paysage par l'homme sur la végétation. Dans mon étude, j'ai développé de nouvelles variables prédictives pour les modèles de distribution, spécifiques à la projection géographique présente et future des plantes dans un système de montagne, en utilisant les Préalpes vaudoises comme zone d'échantillonnage. La méso- et la microtopographie étant particulièrement adaptées pour expliquer les patrons de distribution géographique des plantes dans un environnement montagneux, j'ai testé les effets d'échelle sur les variables prédictives et sur les projections des modèles de distribution. J'ai aussi développé un cadre méthodologique pour tester la robustesse potentielle des modèles lors de projections pour le futur. Finalement, j'ai utilisé un automate cellulaire pour simuler de manière dynamique la migration future des plantes dans le paysage et dans quatre scénarios de changement climatique pour le 21ème siècle. J'ai intégré dans ces simulations des mécanismes et des distances plus réalistes de dispersion de graines. J'ai pu montrer, avec les simulations les plus réalistes, que près du tiers des 284 espèces considérées (28.5%) pourraient être menacées d'extinction en 2100 dans le cas du plus sévère scénario de changement climatique A1. Pour le moins sévère des scénarios B1, seulement 4.6% des espèces sont menacées d'extinctions, mais 54% (153 espèces) risquent de perdre plus 80% de leur habitat initial. Les résultats de monitoring des changements de végétation dans le passé montrent que les plantes peuvent réagir rapidement au réchauffement climatique si la compétition est faible. Dans les prairies subalpines, les espèces déjà présentes limitent certainement l'arrivée de nouvelles espèces par effet de compétition. Les résultats de simulation pour le futur prédisent le début d'extinctions massives dans les Préalpes à partir de 2040, au plus tard en 2080. Mon travail démontre aussi l'importance d'études régionales à échelle fine pour évaluer l'impact des changements climatiques sur la végétation, en intégrant des variables plus directes. En effet, les études à échelle continentale ne tiennent pas compte des micro-refuges, des extinctions locales ni des pertes de connectivité entre populations locales. Malgré cela, la migration des plantes de basses altitudes reste difficile à prédire à l'échelle locale sans modélisation plus globale.

Typing less common ovarian tumors: A training tool based on a pattern-based algorithm applied to a set of 20 virtual slides.

Context: Ovarian tumors (OT) typing is a competency expected from pathologists, with significant clinical implications. OT however come in numerous different types, some rather rare, with the consequence of few opportunities for practice in some departments. Aim: Our aim was to design a tool for pathologists to train in less common OT typing. Method and Results: Representative slides of 20 less common OT were scanned (Nano Zoomer Digital Hamamatsu®) and the diagnostic algorithm proposed by Young and Scully applied to each case (Young RH and Scully RE, Seminars in Diagnostic Pathology 2001, 18: 161-235) to include: recognition of morphological pattern(s); shortlisting of differential diagnosis; proposition of relevant immunohistochemical markers. The next steps of this project will be: evaluation of the tool in several post-graduate training centers in Europe and Québec; improvement of its design based on evaluation results; diffusion to a larger public. Discussion: In clinical medicine, solving many cases is recognized as of utmost importance for a novice to become an expert. This project relies on the virtual slides technology to provide pathologists with a learning tool aimed at increasing their skills in OT typing. After due evaluation, this model might be extended to other uncommon tumors.

25 years of movement monitoring on the south peak of Turtle mountain: Understanding the hazard

En 1981, le gouvernement de l'Alberta a amélioré la surveillance de la pointe sud « South Peak » de la montagne Turtle, sur la frontière sud du glissement Frank de 1903. Le programme de surveillance vise à comprendre les taux de déformation des fissures larges et profondes sur « South Peak », et à prédire une seconde avalanche rocheuse sur la montagne. Le programme de surveillance consiste à installer un complément de points statiques et de stations suivies à distance, qui sont mesurés périodiquement. Des données climatiques, microsismiques et de déformation sont recueillies automatiquement à intervalles journaliers, et sont archivées. À la fin des années 1980, le financement pour le développement du programme de surveillance a cessé et quelques installations se sont détériorées. Entre mai 2004 et septembre 2006, des lectures sur les points de surveillance encore fonctionnels ont été compilées et interprétées. De plus, les lectures prélevées auparavant ont été réinterprétées à partir des connaissances récentes sur les modèles de mouvement à court terme et les influences climatiques. Ces observations ont été comparées à des récentes observations aériennes d'un modèle digital d'élévation, provenant de « light detection and ranging (LiDAR) », et des photos de terrain, afin d'estimer plus précisément les taux, l'étendue et la distribution des mouvements pour les derniers 25 ans.

Structural analysis of Turtle Mountain: Origin and influence of fractures in the development of rock slope failures

Large slope failures in fractured rocks are often controlled by the combination of pre-existing tectonic fracturing and brittle failure propagation in the intact rock mass during the pre-failure phase. This study focuses on the influence of fold-related fractures and of post-folding fractures on slope instabilities with emphasis on Turtle Mountain, located in SW Alberta (Canada). The structural features of Turtle Mountain, especially to the south of the 1903 Frank Slide, were investigated using a high-resolution digital elevation model combined with a detailed field survey. These investigations allowed the identification of six main discontinuity sets influencing the slope instability and surface morphology. According to the different deformation phases affecting the area, the potential origin of the detected fractures was assessed. Three discontinuity sets are correlated with the folding phase and the others with post-folding movements. In order to characterize the rock mass quality in the different portions of the Turtle Mountain anticline, the geological strength index (GSI) has been estimated. The GSI results show a decrease in rock mass quality approaching the fold hinge area due to higher fracture persistence and higher weathering. These observations allow us to propose a model for the potential failure mechanisms related to fold structures.

Ain't no mountain high enough: plant invasions reaching new elevations

Most studies of invasive species have been in highly modified, lowland environments, with comparatively little attention directed to less disturbed, high-elevation environments. However, increasing evidence indicates that plant invasions do occur in these environments, which often have high conservation value and provide important ecosystem services. Over a thousand non-native species have become established in natural areas at high elevations worldwide, and although many of these are not invasive, some may pose a considerable threat to native mountain ecosystems. Here, we discuss four main drivers that shape plant invasions into high-elevation habitats: (1) the (pre-)adaptation of non-native species to abiotic conditions, (2) natural and anthropogenic disturbances, (3) biotic resistance of the established communities, and (4) propagule pressure. We propose a comprehensive research agenda for tackling the problem of plant invasions into mountain ecosystems, including documentation of mountain invasion patterns at multiple scales, experimental studies, and an assessment of the impacts of non-native species in these systems. The threat posed to high-elevation biodiversity by invasive plant species is likely to increase because of globalization and climate change. However, the higher mountains harbor ecosystems where invasion by non-native species has scarcely begun, and where science and management have the opportunity to respond in time.

EADock : design of a new molecular docking algorithm and some of its applications

3 Summary 3. 1 English The pharmaceutical industry has been facing several challenges during the last years, and the optimization of their drug discovery pipeline is believed to be the only viable solution. High-throughput techniques do participate actively to this optimization, especially when complemented by computational approaches aiming at rationalizing the enormous amount of information that they can produce. In siiico techniques, such as virtual screening or rational drug design, are now routinely used to guide drug discovery. Both heavily rely on the prediction of the molecular interaction (docking) occurring between drug-like molecules and a therapeutically relevant target. Several softwares are available to this end, but despite the very promising picture drawn in most benchmarks, they still hold several hidden weaknesses. As pointed out in several recent reviews, the docking problem is far from being solved, and there is now a need for methods able to identify binding modes with a high accuracy, which is essential to reliably compute the binding free energy of the ligand. This quantity is directly linked to its affinity and can be related to its biological activity. Accurate docking algorithms are thus critical for both the discovery and the rational optimization of new drugs. In this thesis, a new docking software aiming at this goal is presented, EADock. It uses a hybrid evolutionary algorithm with two fitness functions, in combination with a sophisticated management of the diversity. EADock is interfaced with .the CHARMM package for energy calculations and coordinate handling. A validation was carried out on 37 crystallized protein-ligand complexes featuring 11 different proteins. The search space was defined as a sphere of 15 R around the center of mass of the ligand position in the crystal structure, and conversely to other benchmarks, our algorithms was fed with optimized ligand positions up to 10 A root mean square deviation 2MSD) from the crystal structure. This validation illustrates the efficiency of our sampling heuristic, as correct binding modes, defined by a RMSD to the crystal structure lower than 2 A, were identified and ranked first for 68% of the complexes. The success rate increases to 78% when considering the five best-ranked clusters, and 92% when all clusters present in the last generation are taken into account. Most failures in this benchmark could be explained by the presence of crystal contacts in the experimental structure. EADock has been used to understand molecular interactions involved in the regulation of the Na,K ATPase, and in the activation of the nuclear hormone peroxisome proliferatoractivated receptors a (PPARa). It also helped to understand the action of common pollutants (phthalates) on PPARy, and the impact of biotransformations of the anticancer drug Imatinib (Gleevec®) on its binding mode to the Bcr-Abl tyrosine kinase. Finally, a fragment-based rational drug design approach using EADock was developed, and led to the successful design of new peptidic ligands for the a5ß1 integrin, and for the human PPARa. In both cases, the designed peptides presented activities comparable to that of well-established ligands such as the anticancer drug Cilengitide and Wy14,643, respectively. 3.2 French Les récentes difficultés de l'industrie pharmaceutique ne semblent pouvoir se résoudre que par l'optimisation de leur processus de développement de médicaments. Cette dernière implique de plus en plus. de techniques dites "haut-débit", particulièrement efficaces lorsqu'elles sont couplées aux outils informatiques permettant de gérer la masse de données produite. Désormais, les approches in silico telles que le criblage virtuel ou la conception rationnelle de nouvelles molécules sont utilisées couramment. Toutes deux reposent sur la capacité à prédire les détails de l'interaction moléculaire entre une molécule ressemblant à un principe actif (PA) et une protéine cible ayant un intérêt thérapeutique. Les comparatifs de logiciels s'attaquant à cette prédiction sont flatteurs, mais plusieurs problèmes subsistent. La littérature récente tend à remettre en cause leur fiabilité, affirmant l'émergence .d'un besoin pour des approches plus précises du mode d'interaction. Cette précision est essentielle au calcul de l'énergie libre de liaison, qui est directement liée à l'affinité du PA potentiel pour la protéine cible, et indirectement liée à son activité biologique. Une prédiction précise est d'une importance toute particulière pour la découverte et l'optimisation de nouvelles molécules actives. Cette thèse présente un nouveau logiciel, EADock, mettant en avant une telle précision. Cet algorithme évolutionnaire hybride utilise deux pressions de sélections, combinées à une gestion de la diversité sophistiquée. EADock repose sur CHARMM pour les calculs d'énergie et la gestion des coordonnées atomiques. Sa validation a été effectuée sur 37 complexes protéine-ligand cristallisés, incluant 11 protéines différentes. L'espace de recherche a été étendu à une sphère de 151 de rayon autour du centre de masse du ligand cristallisé, et contrairement aux comparatifs habituels, l'algorithme est parti de solutions optimisées présentant un RMSD jusqu'à 10 R par rapport à la structure cristalline. Cette validation a permis de mettre en évidence l'efficacité de notre heuristique de recherche car des modes d'interactions présentant un RMSD inférieur à 2 R par rapport à la structure cristalline ont été classés premier pour 68% des complexes. Lorsque les cinq meilleures solutions sont prises en compte, le taux de succès grimpe à 78%, et 92% lorsque la totalité de la dernière génération est prise en compte. La plupart des erreurs de prédiction sont imputables à la présence de contacts cristallins. Depuis, EADock a été utilisé pour comprendre les mécanismes moléculaires impliqués dans la régulation de la Na,K ATPase et dans l'activation du peroxisome proliferatoractivated receptor a (PPARa). Il a également permis de décrire l'interaction de polluants couramment rencontrés sur PPARy, ainsi que l'influence de la métabolisation de l'Imatinib (PA anticancéreux) sur la fixation à la kinase Bcr-Abl. Une approche basée sur la prédiction des interactions de fragments moléculaires avec protéine cible est également proposée. Elle a permis la découverte de nouveaux ligands peptidiques de PPARa et de l'intégrine a5ß1. Dans les deux cas, l'activité de ces nouveaux peptides est comparable à celles de ligands bien établis, comme le Wy14,643 pour le premier, et le Cilengitide (PA anticancéreux) pour la seconde.

Combining digital elevation model analysis and run-out modeling to characterize hazard posed by a potentially unstable rock slope at Turtle Mountain, Alberta, Canada

Turtle Mountain in Alberta, Canada has become an important field laboratory for testing different techniques related to the characterization and monitoring of large slope mass movements as the stability of large portions of the eastern face of the mountain is still questionable. In order to better quantify the volumes potentially unstable and the most probable failure mechanisms and potential consequences, structural analysis and runout modeling were preformed. The structural features of the eastern face were investigated using a high resolution digital elevation model (HRDEM). According to displacement datasets and structural observations, potential failure mechanisms affecting different portions of the mountain have been assessed. The volumes of the different potentially unstable blocks have been calculated using the Sloping Local Base Level (SLBL) method. Based on the volume estimation, two and three dimensional dynamic runout analyses have been performed. Calibration of this analysis is based on the experience from the adjacent Frank Slide and other similar rock avalanches. The results will be used to improve the contingency plans within the hazard area.

Elemental (C/N ratios) and isotopic (δ15N(org), δ13C(org)) compositions of sedimentary organic matter from a high-altitude mountain lake (Meidsee, 2661 m a.s.l., Switzerland): Implications for Lateglacial and Holocene Alpine landscape evolution

The deposition of Late Pleistocene and Holocene sediments in the high-altitude lake Meidsee (located at an altitude of 2661 m a.s.l. in the Southwestern Alps) strikingly coincided with global ice-sheet and mountain-glacier decay in the Alpine forelands and the formation of perialpine lakes. Radiocarbon ages of bottom-core sediments point out (pre-) Holocene ice retreat below 2700 m a.s.l., at about 16, 13, 10, and 9 cal. kyr BP. The Meidsee sedimentary record therefore provides information about the high-altitude Alpine landscape evolution since the Late Pleistocene/Holocene deglaciation in the Swiss Southwestern Alps. Prior to 5 cal. kyr BP, the C/N ratio and the isotopic composition of sedimentary organic matter (delta N-15(org), delta C-13(org)) indicate the deposition of algal-derived organic matter with limited input of terrestrial organic matter. The early Holocene and the Holocene climatic optimum (between 7.0 and 5.5 cal. kyr BP) were characterized by low erosion (decreasing magnetic susceptibility, chi) and high content of organic matter (C-org > 13 wt.%), enriched in C-13(org) (>-18 parts per thousand) with a low C/N (similar to 10) ratio, typical of modern algal matter derived from in situ production. During the late Holocene, there was a long-term increasing contribution of terrestrial organic matter into the lake (C/N > 11), with maxima between 2.4 and 0.9 cal. kyr BP. A major environmental change took place 800 years ago, with an abrupt decrease in the relative contribution of terrestrial organic material into the lake compared with aquatic organic material which subsequently largely dominated (C/N drop from 16 to 10). Nonetheless, this event was marked by a rise in soil erosion (chi), in nutrients input (N and P contents) and in anthropogenic lead deposition, suggesting a human disturbance of Alpine ecosystems 800 years ago. Indeed, this time period coincided with the migration of the Walser Alemannic people in the region, who settled at relatively high altitude in the Southwestern Alps for farming and maintaining Alpine passes.