Computer-Aided Business Model Design

There is a lack of dedicated tools for business model design at a strategic level. However, in today's economic world the need to be able to quickly reinvent a company's business model is essential to stay competitive. This research focused on identifying the functionalities that are necessary in a computer-aided design (CAD) tool for the design of business models in a strategic context. Using design science research methodology a series of techniques and prototypes have been designed and evaluated to offer solutions to the problem. The work is a collection of articles which can be grouped into three parts: First establishing the context of how the Business Model Canvas (BMC) is used to design business models and explore the way in which CAD can contribute to the design activity. The second part extends on this by proposing new technics and tools which support elicitation, evaluation (assessment) and evolution of business models design with CAD. This includes features such as multi-color tagging to easily connect elements, rules to validate coherence of business models and features that are adapted to the correct business model proficiency level of its users. A new way to describe and visualize multiple versions of a business model and thereby help in addressing the business model as a dynamic object was also researched. The third part explores extensions to the business model canvas such as an intermediary model which helps IT alignment by connecting business model and enterprise architecture. And a business model pattern for privacy in a mobile environment, using privacy as a key value proposition. The prototyped techniques and proposition for using CAD tools in business model modeling will allow commercial CAD developers to create tools that are better suited to the needs of practitioners.

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.

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.

The Learning Affect Monitor (LAM) - A computer-based system integrating quantitative and qualitative assessment of affective states in daily life.

The Learning Affect Monitor (LAM) is a new computer-based assessment system integrating basic dimensional evaluation and discrete description of affective states in daily life, based on an autonomous adapting system. Subjects evaluate their affective states according to a tridimensional space (valence and activation circumplex as well as global intensity) and then qualify it using up to 30 adjective descriptors chosen from a list. The system gradually adapts to the user, enabling the affect descriptors it presents to be increasingly relevant. An initial study with 51 subjects, using a 1 week time-sampling with 8 to 10 randomized signals per day, produced n = 2,813 records with good reliability measures (e.g., response rate of 88.8%, mean split-half reliability of .86), user acceptance, and usability. Multilevel analyses show circadian and hebdomadal patterns, and significant individual and situational variance components of the basic dimension evaluations. Validity analyses indicate sound assignment of qualitative affect descriptors in the bidimensional semantic space according to the circumplex model of basic affect dimensions. The LAM assessment module can be implemented on different platforms (palm, desk, mobile phone) and provides very rapid and meaningful data collection, preserving complex and interindividually comparable information in the domain of emotion and well-being.

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.

Positron Emission Tomography and Computer Tomography (PET/CT) in Prostate, Bladder, and Testicular Cancers.

Positron emission computed tomography (PET) is a functional, noninvasive method for imaging regional metabolic processes that is nowadays most often combined to morphological imaging with computed tomography (CT). Its use is based on the well-founded assumption that metabolic changes occur earlier in tumors than morphologic changes, adding another dimension to imaging. This article will review the established and investigational indications and radiopharmaceuticals for PET/CT imaging for prostate cancer, bladder cancer and testicular cancer, before presenting upcoming applications in radiation therapy.

Computer Aided Detection and measurement of peripheral artery disease.

Computer-Aided Tomography Angiography (CTA) images are the standard for assessing Peripheral artery disease (PAD). This paper presents a Computer Aided Detection (CAD) and Computer Aided Measurement (CAM) system for PAD. The CAD stage detects the arterial network using a 3D region growing method and a fast 3D morphology operation. The CAM stage aims to accurately measure the artery diameters from the detected vessel centerline, compensating for the partial volume effect using Expectation Maximization (EM) and a Markov Random field (MRF). The system has been evaluated on phantom data and also applied to fifteen (15) CTA datasets, where the detection accuracy of stenosis was 88% and the measurement accuracy was with an 8% error.

A biophysical model of atrial fibrillation ablation: what can a surgeon learn from a computer model?

AIMS: Surgical ablation procedures for treating atrial fibrillation have been shown to be highly successful. However, the ideal ablation pattern still remains to be determined. This article reports on a systematic study of the effectiveness of the performance of different ablation line patterns. METHODS AND RESULTS: This study of ablation line patterns was performed in a biophysical model of human atria by combining basic lines: (i) in the right atrium: isthmus line, line between vena cavae and appendage line and (ii) in the left atrium: several versions of pulmonary vein isolation, connection of pulmonary veins, isthmus line, and appendage line. Success rates and the presence of residual atrial flutter were documented. Basic patterns yielded conversion rates of only 10-25 and 10-55% in the right and the left atria, respectively. The best result for pulmonary vein isolation was obtained when a single closed line encompassed all veins (55%). Combination of lines in the right/left atrium only led to a success rate of 65/80%. Higher rates, up to 90-100%, could be obtained if right and left lines were combined. The inclusion of a left isthmus line was found to be essential for avoiding uncommon left atrial flutter. CONCLUSION: Some patterns studied achieved a high conversion rate, although using a smaller number of lines than those of the Maze III procedure. The biophysical atrial model is shown to be effective in the search for promising alternative ablation strategies.

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.

Gadolinium-enhanced pulmonary magnetic resonance angiography in the diagnosis of acute pulmonary embolism: a prospective study on 48 patients.

OBJECTIVE: Gadolinium-enhanced pulmonary magnetic resonance angiography (MRA) can be an option in patients with a history of previous adverse reaction to iodinated contrast material and renal insufficiency. Radiation is also avoided. The aim of this study is to prospectively compare the diagnostic value of MRA with that of a diagnostic strategy, taking into account catheter angiography, computed tomography angiography (CTA), and lung scintigraphy [ventilation-perfusion (VQ)]. MATERIAL AND METHODS: Magnetic resonance angiography was done in 48 patients with clinically suspected pulmonary embolism (PE) using fast gradient echo coronal acquisition with gadolinium. Interpretation was done with native coronal images and multiplanar maximum intensity projection reconstructions. Results were compared to catheter angiography (n=15), CTA (n=34), VQ (n=45), as well as 6-12 months clinical follow-ups, according to a sequenced reference tree. RESULTS: The final diagnosis of PE was retained in 11 patients (23%). There were two false negatives and no false positive results with MRA. Computed tomography angiography resulted in no false negatives or false positives. Magnetic resonance angiography had a sensitivity of 82% and a specificity of 100%. CONCLUSION: In our study, pulmonary MRA had a sensitivity of 82% and a specificity of 100% for the diagnosis of PE, with slightly less sensitivity than CTA. In the diagnostic algorithm of PE, pulmonary MRA should be considered as an alternative to CTA when iodine contrast injection or radiation is a significant matter.

Study of OSEM with different subsets in grating-based X-ray differential phase-contrast imaging.

Impressive developments in X-ray imaging are associated with X-ray phase contrast computed tomography based on grating interferometry, a technique that provides increased contrast compared with conventional absorption-based imaging. A new "single-step" method capable of separating phase information from other contributions has been recently proposed. This approach not only simplifies data-acquisition procedures, but, compared with the existing phase step approach, significantly reduces the dose delivered to a sample. However, the image reconstruction procedure is more demanding than for traditional methods and new algorithms have to be developed to take advantage of the "single-step" method. In the work discussed in this paper, a fast iterative image reconstruction method named OSEM (ordered subsets expectation maximization) was applied to experimental data to evaluate its performance and range of applicability. The OSEM algorithm with different subsets was also characterized by comparison of reconstruction image quality and convergence speed. Computer simulations and experimental results confirm the reliability of this new algorithm for phase-contrast computed tomography applications. Compared with the traditional filtered back projection algorithm, in particular in the presence of a noisy acquisition, it furnishes better images at a higher spatial resolution and with lower noise. We emphasize that the method is highly compatible with future X-ray phase contrast imaging clinical applications.

Management of Pharyngeal Fistulas After Anterior Cervical Spine Surgery: A Treatment Algorithm for Severe Complications.

STUDY DESIGN:: Retrospective database- query to identify all anterior spinal approaches. OBJECTIVES:: To assess all patients with pharyngo-cutaneous fistulas after anterior cervical spine surgery. SUMMARY OF BACKGROUND DATA:: Patients treated in University of Heidelberg Spine Medical Center, Spinal Cord Injury Unit and Department of Otolaryngology (Germany), between 2005 and 2011 with the diagnosis of pharyngo-cutaneous fistulas. METHODS:: We conducted a retrospective study on 5 patients between 2005 and 2011 with PCF after ACSS, their therapy management and outcome according to radiologic data and patient charts. RESULTS:: Upon presentation 4 patients were paraplegic. 2 had PCF arising from one piriform sinus, two patients from the posterior pharyngeal wall and piriform sinus combined and one patient only from the posterior pharyngeal wall. 2 had previous unsuccessful surgical repair elsewhere and 1 had prior radiation therapy. In 3 patients speech and swallowing could be completely restored, 2 patients died. Both were paraplegic. The patients needed an average of 2-3 procedures for complete functional recovery consisting of primary closure with various vascularised regional flaps and refining laser procedures supplemented with negative pressure wound therapy where needed. CONCLUSION:: Based on our experience we are able to provide a treatment algorithm that indicates that chronic as opposed to acute fistulas require a primary surgical closure combined with a vascularised flap that should be accompanied by the immediate application of a negative pressure wound therapy. We also conclude that particularly in paraplegic patients suffering this complication the risk for a fatal outcome is substantial.

Safety of a new algorithm for the management of childhood illness (Almanach) to improve quality of care and rational use of drugs

Introduction New evidence from randomized controlled and etiology of fever studies, the availability of reliable RDT for malaria, and novel technologies call for revision of the IMCI strategy. We developed a new algorithm based on (i) a systematic review of published studies assessing the safety and appropriateness of RDT and antibiotic prescription, (ii) results from a clinical and microbiological investigation of febrile children aged <5 years, (iii) international expert IMCI opinions. The aim of this study was to assess the safety of the new algorithm among patients in urban and rural areas of Tanzania.Materials and Methods The design was a controlled noninferiority study. Enrolled children aged 2-59 months with any illness were managed either by a study clinician using the new Almanach algorithm (two intervention health facilities), or clinicians using standard practice, including RDT (two control HF). At day 7 and day 14, all patients were reassessed. Patients who were ill in between or not cured at day 14 were followed until recovery or death. Primary outcome was rate of complications, secondary outcome rate of antibiotic prescriptions.Results 1062 children were recruited. Main diagnoses were URTI 26%, pneumonia 19% and gastroenteritis (9.4%). 98% (531/541) were cured at D14 in the Almanach arm and 99.6% (519/521) in controls. Rate of secondary hospitalization was 0.2% in each. One death occurred in controls. None of the complications was due to withdrawal of antibiotics or antimalarials at day 0. Rate of antibiotic use was 19% in the Almanach arm and 84% in controls.Conclusion Evidence suggests that the new algorithm, primarily aimed at the rational use of drugs, is as safe as standard practice and leads to a drastic reduction of antibiotic use. The Almanach is currently being tested for clinician adherence to proposed procedures when used on paper or a mobile phone