Prediction of Infant Drug Exposure Through Breastfeeding: Population PK Modeling and Simulation of Fluoxetine Exposure.

The likelihood of significant exposure to drugs in infants through breast milk is poorly defined, given the difficulties of conducting pharmacokinetics (PK) studies. Using fluoxetine (FX) as an example, we conducted a proof-of-principle study applying population PK (popPK) modeling and simulation to estimate drug exposure in infants through breast milk. We simulated data for 1,000 mother-infant pairs, assuming conservatively that the FX clearance in an infant is 20% of the allometrically adjusted value in adults. The model-generated estimate of the milk-to-plasma ratio for FX (mean: 0.59) was consistent with those reported in other studies. The median infant-to-mother ratio of FX steady-state plasma concentrations predicted by the simulation was 8.5%. Although the disposition of the active metabolite, norfluoxetine, could not be modeled, popPK-informed simulation may be valid for other drugs, particularly those without active metabolites, thereby providing a practical alternative to conventional PK studies for exposure risk assessment in this population.

A Confluence of Risks: Control and Compliance in the World of Unstructured Data, Big Data and the Cloud

The emergence of powerful new technologies, the existence of large quantities of data, and increasing demands for the extraction of added value from these technologies and data have created a number of significant challenges for those charged with both corporate and information technology management. The possibilities are great, the expectations high, and the risks significant. Organisations seeking to employ cloud technologies and exploit the value of the data to which they have access, be this in the form of "Big Data" available from different external sources or data held within the organisation, in structured or unstructured formats, need to understand the risks involved in such activities. Data owners have responsibilities towards the subjects of the data and must also, frequently, demonstrate that they are in compliance with current standards, laws and regulations. This thesis sets out to explore the nature of the technologies that organisations might utilise, identify the most pertinent constraints and risks, and propose a framework for the management of data from discovery to external hosting that will allow the most significant risks to be managed through the definition, implementation, and performance of appropriate internal control activities.

Somewhere between illusion of control and powerlessness : trying to situate the pathological gambler's locus of control

It has been suggested that pathological gamblers develop illusory perceptions of control regarding the outcome of the games and should express higher Internal and Chance locus of control. A sample of 48 outpatients diagnosed with pathological gambling disorder who participated in this ex post facto study, completed the Internality, Powerful Others, and Chance scale, the South Oaks Gambling Screen questionnaire, and the Beck Depression Inventory. Results for the locus of control measure were compared with a reference group. Pathological gamblers scored higher than the reference group on the Chance locus of control, which increased with the severity of cases. Moreover, Internal locus of control did show a curvilinear relationship with the severity of cases. Pathological gamblers have specific locus of control scores that vary in function of the severity, in a linear fashion or a non-linear fashion according to the scale. This effect might be caused by competition between "illusion of control" and the tendency to attribute adverse consequence of gambling to external causes.

Selectome update: quality control and computational improvements to a database of positive selection.

Selectome (http://selectome.unil.ch/) is a database of positive selection, based on a branch-site likelihood test. This model estimates the number of nonsynonymous substitutions (dN) and synonymous substitutions (dS) to evaluate the variation in selective pressure (dN/dS ratio) over branches and over sites. Since the original release of Selectome, we have benchmarked and implemented a thorough quality control procedure on multiple sequence alignments, aiming to provide minimum false-positive results. We have also improved the computational efficiency of the branch-site test implementation, allowing larger data sets and more frequent updates. Release 6 of Selectome includes all gene trees from Ensembl for Primates and Glires, as well as a large set of vertebrate gene trees. A total of 6810 gene trees have some evidence of positive selection. Finally, the web interface has been improved to be more responsive and to facilitate searches and browsing.

Dosage optimization of treatments using population pharmacokinetic modeling and simulation.

Pharmacokinetic variability in drug levels represent for some drugs a major determinant of treatment success, since sub-therapeutic concentrations might lead to toxic reactions, treatment discontinuation or inefficacy. This is true for most antiretroviral drugs, which exhibit high inter-patient variability in their pharmacokinetics that has been partially explained by some genetic and non-genetic factors. The population pharmacokinetic approach represents a very useful tool for the description of the dose-concentration relationship, the quantification of variability in the target population of patients and the identification of influencing factors. It can thus be used to make predictions and dosage adjustment optimization based on Bayesian therapeutic drug monitoring (TDM). This approach has been used to characterize the pharmacokinetics of nevirapine (NVP) in 137 HIV-positive patients followed within the frame of a TDM program. Among tested covariates, body weight, co-administration of a cytochrome (CYP) 3A4 inducer or boosted atazanavir as well as elevated aspartate transaminases showed an effect on NVP elimination. In addition, genetic polymorphism in the CYP2B6 was associated with reduced NVP clearance. Altogether, these factors could explain 26% in NVP variability. Model-based simulations were used to compare the adequacy of different dosage regimens in relation to the therapeutic target associated with treatment efficacy. In conclusion, the population approach is very useful to characterize the pharmacokinetic profile of drugs in a population of interest. The quantification and the identification of the sources of variability is a rational approach to making optimal dosage decision for certain drugs administered chronically.

Reforms of the pre-graduate curriculum for medical students: the Bologna process and beyond.

For several years, all five medical faculties of Switzerland have embarked on a reform of their training curricula for two reasons: first, according to a new federal act issued in 2006 by the administration of the confederation, faculties needed to meet international standards in terms of content and pedagogic approaches; second, all Swiss universities and thus all medical faculties had to adapt the structure of their curriculum to the frame and principles which govern the Bologna process. This process is the result of the Bologna Declaration of June 1999 which proposes and requires a series of reforms to make European Higher Education more compatible and comparable, more competitive and more attractive for Europeans students. The present paper reviews some of the results achieved in the field, focusing on several issues such as the shortage of physicians and primary care practitioners, the importance of public health, community medicine and medical humanities, and the implementation of new training approaches including e-learning and simulation. In the future, faculties should work on several specific challenges such as: students' mobility, the improvement of students' autonomy and critical thinking as well as their generic and specific skills and finally a reflection on how to improve the attractiveness of the academic career, for physicians of both sexes.

Visual functions in the healthy and schizophrenic brain : from stimulus control to illusory perceptions using electrical neuroimaging

ABSTRACT (FRENCH)Ce travail de thèse basé sur le système visuel chez les sujets sains et chez les patients schizophrènes, s'articule autour de trois articles scientifiques publiés ou en cours de publication. Ces articles traitent des sujets suivants : le premier article présente une nouvelle méthode de traitement des composantes physiques des stimuli (luminance et fréquence spatiale). Le second article montre, à l'aide d'analyses de données EEG, un déficit de la voie magnocellulaire dans le traitement visuel des illusions chez les patients schizophrènes. Ceci est démontré par l'absence de modulation de la composante PI chez les patients schizophrènes contrairement aux sujets sains. Cette absence est induite par des stimuli de type illusion Kanizsa de différentes excentricités. Finalement, le troisième article, également à l'aide de méthodes de neuroimagerie électrique (EEG), montre que le traitement des contours illusoires se trouve dans le complexe latéro-occipital (LOC), à l'aide d'illusion « misaligned gratings ». De plus il révèle que les activités démontrées précédemment dans les aires visuelles primaires sont dues à des inférences « top- down ».Afin de permettre la compréhension de ces trois articles, l'introduction de ce manuscrit présente les concepts essentiels. De plus des méthodes d'analyses de temps-fréquence sont présentées. L'introduction est divisée en quatre parties : la première présente le système visuel depuis les cellules retino-corticales aux deux voix du traitement de l'information en passant par les régions composant le système visuel. La deuxième partie présente la schizophrénie par son diagnostic, ces déficits de bas niveau de traitement des stimuli visuel et ces déficits cognitifs. La troisième partie présente le traitement des contours illusoires et les trois modèles utilisés dans le dernier article. Finalement, les méthodes de traitement des données EEG seront explicitées, y compris les méthodes de temps-fréquences.Les résultats des trois articles sont présentés dans le chapitre éponyme (du même nom). De plus ce chapitre comprendra les résultats obtenus à l'aide des méthodes de temps-fréquenceFinalement, la discussion sera orientée selon trois axes : les méthodes de temps-fréquence ainsi qu'une proposition de traitement de ces données par une méthode statistique indépendante de la référence. La discussion du premier article en montrera la qualité du traitement de ces stimuli. La discussion des deux articles neurophysiologiques, proposera de nouvelles d'expériences afin d'affiner les résultats actuels sur les déficits des schizophrènes. Ceci pourrait permettre d'établir un marqueur biologique fiable de la schizophrénie.ABSTRACT (ENGLISH)This thesis focuses on the visual system in healthy subjects and schizophrenic patients. To address this research, advanced methods of analysis of electroencephalographic (EEG) data were used and developed. This manuscript is comprised of three scientific articles. The first article showed a novel method to control the physical features of visual stimuli (luminance and spatial frequencies). The second article showed, using electrical neuroimaging of EEG, a deficit in spatial processing associated with the dorsal pathway in chronic schizophrenic patients. This deficit was elicited by an absent modulation of the PI component in terms of response strength and topography as well as source estimations. This deficit was orthogonal to the preserved ability to process Kanizsa-type illusory contours. Finally, the third article resolved ongoing debates concerning the neural mechanism mediating illusory contour sensitivity by using electrical neuroimaging to show that the first differentiation of illusory contour presence vs. absence is localized within the lateral occipital complex. This effect was subsequent to modulations due to the orientation of misaligned grating stimuli. Collectively, these results support a model where effects in V1/V2 are mediated by "top-down" modulation from the LOC.To understand these three articles, the Introduction of this thesis presents the major concepts used in these articles. Additionally, a section is devoted to time-frequency analysis methods not presented in the articles themselves. The introduction is divided in four parts. The first part presents three aspects of the visual system: cellular, regional, and its functional interactions. The second part presents an overview of schizophrenia and its sensoiy-cognitive deficits. The third part presents an overview of illusory contour processing and the three models examined in the third article. Finally, advanced analysis methods for EEG are presented, including time- frequency methodology.The Introduction is followed by a synopsis of the main results in the articles as well as those obtained from the time-frequency analyses.Finally, the Discussion chapter is divided along three axes. The first axis discusses the time frequency analysis and proposes a novel statistical approach that is independent of the reference. The second axis contextualizes the first article and discusses the quality of the stimulus control and direction for further improvements. Finally, both neurophysiologic articles are contextualized by proposing future experiments and hypotheses that may serve to improve our understanding of schizophrenia on the one hand and visual functions more generally.

Introducing systematic dispatcher-assisted cardiopulmonary resuscitation (telephone-CPR) in a non-Advanced Medical Priority Dispatch System (AMPDS): implementation process and costs.

OBJECTIVE: In order to improve the quality of our Emergency Medical Services (EMS), to raise bystander cardiopulmonary resuscitation rates and thereby meet what is becoming a universal standard in terms of quality of emergency services, we decided to implement systematic dispatcher-assisted or telephone-CPR (T-CPR) in our medical dispatch center, a non-Advanced Medical Priority Dispatch System. The aim of this article is to describe the implementation process, costs and results following the introduction of this new "quality" procedure. METHODS: This was a prospective study. Over an 8-week period, our EMS dispatchers were given new procedures to provide T-CPR. We then collected data on all non-traumatic cardiac arrests within our state (Vaud, Switzerland) for the following 12months. For each event, the dispatchers had to record in writing the reason they either ruled out cardiac arrest (CA) or did not propose T-CPR in the event they did suspect CA. All emergency call recordings were reviewed by the medical director of the EMS. The analysis of the recordings and the dispatchers' written explanations were then compared. RESULTS: During the 12-month study period, a total of 497 patients (both adults and children) were identified as having a non-traumatic cardiac arrest. Out of this total, 203 cases were excluded and 294 cases were eligible for T-CPR. Out of these eligible cases, dispatchers proposed T-CPR on 202 occasions (or 69% of eligible cases). They also erroneously proposed T-CPR on 17 occasions when a CA was wrongly identified (false positive). This represents 7.8% of all T-CPR. No costs were incurred to implement our study protocol and procedures. CONCLUSIONS: This study demonstrates it is possible, using a brief campaign of sensitization but without any specific training, to implement systematic dispatcher-assisted cardiopulmonary resuscitation in a non-Advanced Medical Priority Dispatch System such as our EMS that had no prior experience with systematic T-CPR. The results in terms of T-CPR delivery rate and false positive are similar to those found in previous studies. We found our results satisfying the given short time frame of this study. Our results demonstrate that it is possible to improve the quality of emergency services at moderate or even no additional costs and this should be of interest to all EMS that do not presently benefit from using T-CPR procedures. EMS that currently do not offer T-CPR should consider implementing this technique as soon as possible, and we expect our experience may provide answers to those planning to incorporate T-CPR in their daily practice.