Enterprise Architecture Management Design: Towards Understanding Organizational Contingencies, Design Principles and Effectiveness

Despite the increasing popularity of enterprise architecture management (EAM) in practice, many EAM initiatives either do not fully meet the expected targets or fail. Several frameworks have been suggested as guidelines to EA implementation, but companies seldom follow prescriptive frameworks. Instead, they follow very diverse implementation approaches that depend on their organizational contingencies and the way of adopting and evolving EAM over time. This research strives for a broader understanding of EAM by exploring context-dependent EAM adoption approaches as well as identifying the main EA principles that affect EA effectiveness. Based on two studies, this dissertation aims to address two main questions: (1) EAM design: Which approaches do companies follow when adopting EAM? (2) EA principles and their impact: What impact does EA principles have on EA effectiveness/quality? By utilizing both qualitative and quantitative research methods, this research contributes to exploring different EAM designs in different organizational contingencies as well as using EA principles as an effective means to achieve principle-based EAM design. My research can help companies identify a suitable EAM design that fits their organizational settings and shape their EA through a set of principles.

Circulating insulin-like growth factor-I in pregnancy and maternal risk of breast cancer.

BACKGROUND: Elevated serum concentrations of insulin-like growth factor (IGF)-1 have been associated with increased risk of breast cancer. Previously, we reported a similar association in samples obtained during pregnancy. The current study was conducted to further characterize the association of IGF-1 during pregnancy with maternal breast cancer risk. METHODS: A case-control study was nested within the Finnish Maternity Cohort. The study was limited to primiparous women less than 40 years of age, who donated blood samples during early (median, 12 weeks) pregnancy and delivered a single child at term. Seven hundred and nineteen women with invasive breast cancer were eligible. Two controls (n = 1,434) were matched to each case on age and date at blood donation. Serum IGF-1 concentration was measured using an Immulite 2000 analyzer. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI).RESULTS: No significant associations were observed between serum IGF-1 concentrations and breast cancer risk in both the overall analysis (OR 1.08 (95% CI 0.80-1.47) and in analyses stratified by histological subtype, lag-time to cancer diagnosis, age at pregnancy or age at diagnosis.CONCLUSIONS: There was no association between IGF-1 and maternal breast cancer risk during early pregnancy in this large nested case-control study.Impact:Serum IGF-1 concentrations during early pregnancy may not be related to maternal risk of breast cancer.

Effectiveness of interventions targeting frequent users of emergency departments: a systematic review.

STUDY OBJECTIVE: Frequent users of emergency departments (EDs) are a relatively small group of vulnerable patients accounting for a disproportionally high number of ED visits. Our objective is to perform a systematic review of the type and effectiveness of interventions to reduce the number of ED visits by frequent users. METHODS: We searched MEDLINE, EMBASE, CINAHL, PsychINFO, the Cochrane Library, and ISI Web of Science for randomized controlled trials, nonrandomized controlled trials, interrupted time series, and controlled and noncontrolled before-and-after studies describing interventions targeting adult frequent users of EDs. Primary outcome of interest was the reduction in ED use. We also explored costs analyses and various clinical (alcohol and drug use, psychiatric symptoms, mortality) and social (homelessness, insurance status, social security support) outcomes. RESULTS: We included 11 studies (3 randomized controlled trials, 2 controlled and 6 noncontrolled before-and-after studies). Heterogeneity in both study designs and definitions of frequent users precluded meta-analyses of the results. The most studied intervention was case management (n=7). Only 1 of 3 randomized controlled trials showed a significant reduction in ED use compared with usual care. Six of the 8 before-and-after studies reported a significant reduction in ED use, and 1 study showed a significant increase. ED cost reductions were demonstrated in 3 studies. Social outcomes such as reduction of homelessness were favorable in 3 of 3 studies, and clinical outcomes trended toward positive results in 2 of 3 studies. CONCLUSION: Interventions targeting frequent users may reduce ED use. Case management, the most frequently described intervention, reduced ED costs and seemed to improve social and clinical outcomes. It appears to be beneficial to patients and justifiable for hospitals to implement case management for frequent users in the framework of a clear and consensual definition of frequent users and standardized outcome measures.

Disease in the dark: molecular characterization of Polychromophilus murinus in temperate zone bats revealed a worldwide distribution of this malaria-like disease.

For a better understanding of the complex coevolutionary processes between hosts and parasites, accurate identification of the actors involved in the interaction is of fundamental importance. Blood parasites of the Order Haemosporidia, responsible for malaria, have become the focus of a broad range of studies in evolutionary biology. Interestingly, molecular-based studies on avian malaria have revealed much higher species diversity than previously inferred with morphology. Meanwhile, studies on bat haemosporidian have been largely neglected. In Europe, only one genus (Polychromophilus) and two species have been morphologically described. To evaluate the presence of potential cryptic species and parasite prevalence, we undertook a molecular characterization of Polychromophilus in temperate zone bats. We used a nested-PCR approach on the cytochrome b mitochondrial gene to detect the presence of parasites in 237 bats belonging to four different species and in the dipteran bat fly Nycteribia kolenatii, previously described as being the vector of Polychromophilus. Polychromophilus murinus was found in the four bat species and in the insect vector with prevalence ranging from 4% for Myotis myotis to 51% for M. daubentoni. By sequencing 682 bp, we then investigated the phylogenetic relationships of Polychromophilus to other published malarial lineages. Seven haplotypes were found, all very closely related, suggesting the presence of a single species in our samples. These haplotypes formed a well-defined clade together with Haemosporidia of tropical bats, revealing a worldwide distribution of this parasite mostly neglected by malarial studies since the 1980s.

Adverse life events among community-dwelling persons aged 65-70 years: gender differences in occurrence and perceived psychological consequences.

OBJECTIVES: To describe the occurrence of selected adverse life events in young-old men and women, as well as their perceived psychological consequences. METHODS: In 2005, 1,422 participants in the Lausanne Cohort 65+ study, born in 1934-1938, self-reported whether they experienced any of 26 life events during the preceding year. Most participants (N = 1,309, 92%) completed the geriatric adverse life events scale during a face-to-face interview, by rating the level of stress associated with each event, as well as its impact on their psychological well-being. RESULTS: Overall, 72% of the participants experienced at least one of the 26 events in the preceding year (range 1-9). Disease affecting the respondent (N = 525) or a close relative (N = 276) was most frequent, as well as the death of a friend or non-close relative (N = 274). Women indicated a higher frequency of events (mean 2.1 vs. 1.7 events, P < 0.001), as well as a higher level of stress and a stronger negative impact on well-being than men. In multivariate analyses adjusting for self-rated health, depressive symptoms and comorbidity, female gender remained significantly associated with the level of stress and negative impact on psychological well-being. CONCLUSION: This exploratory study shows that several types of adverse life events frequently occur at age 65-70, with gender differences both in the frequency of reporting and consequences of these events. However, information on this topic is limited and studies based on different populations and designs are needed to better understand the impact of such events.

Searching for and positioning of contextualized learning objects

Learning object economies are marketplaces for the sharing and reuse of learning objects (LO). There are many motivations for stimulating the development of the LO economy. The main reason is the possibility of providing the right content, at the right time, to the right learner according to adequate quality standards in the context of a lifelong learning process; in fact, this is also the main objective of education. However, some barriers to the development of a LO economy, such as the granularity and editability of LO, must be overcome. Furthermore, some enablers, such as learning design generation and standards usage, must be promoted in order to enhance LO economy. For this article, we introduced the integration of distributed learning object repositories (DLOR) as sources of LO that could be placed in adaptive learning designs to assist teachers’ design work. Two main issues presented as a result: how to access distributed LO, and where to place the LO in the learning design. To address these issues, we introduced two processes: LORSE, a distributed LO searching process, and LOOK, a micro context-based positioning process, respectively. Using these processes, the teachers were able to reuse LO from different sources to semi-automatically generate an adaptive learning design without leaving their virtual environment. A layered evaluation yielded good results for the process of placing learning objects from controlled learning object repositories into a learning design, and permitting educators to define different open issues that must be covered when they use uncontrolled learning object repositories for this purpose. We verified the satisfaction users had with our solution

Plugg&Play&Green

Es tracta del concurs per reconvertir una antiga estació ferroviària en un centre cultura polifuncional

La implicació de les famílies immigrades en els processos educatius dels seus fills/es: estratègies davant l'èxit i el fracàs escolar

En el present projecte hem analitzat els determinants de les trajectòries educatives dels i les adolescents d'origen immigrant, centrant I'atenció en el paper de les seves famílies davant de I ‘èxit o fracàs escolar del seu fillla. Amb aquest objectiu, I'estudi combina tècniques quantitatives i qualitatives. Per una banda hem analitzat les dades longitudinals del Panel de Famílies i lnfancia, que ens permeten fer un seguiment de les trajectòries educatives i personals de 248 alumnes d'origen immigrant que al 2006 estudiaven I'ESO al llarg de la seva adolescència, i identificar els factors socials responsables de la seva diversificació. Els resultats indiquen que malgrat presentar actituds bastant favorables als estudis i I'assoliment educatiu, concentren diverses situacions de vulnerabilitat a la llar (dificultats socioeconòmiques, estructures familiars atípiques, i erosió de capital social), que incideixen negativament sobre els seus rendiments acadèmics. Per altra, hem realitzat 59 entrevistes semi-estructurades per a complementar i facilitar la interpretació dels resultats obtinguts a la recerca quantitativa i copsar les narratives dels propis protagonistes. Aquestes entrevistes s'han realitzat a: una submostra de les famílies d'aquests alumnes, seleccionades en funció de perfils d’èxit o fracàs educatiu de la trajectòria del menor (46), una submostra d'estudiants resilients (a), i una sèrie d'agents educatius i socials, que inclou membres d'equips directius de centres escolars, AMPA i entitats dedicades a I'atenció a la infància i les famílies (5). El projecte que presentem té una clara vocació de servei públic. L'objectiu és incrementar el coneixement de factors "extraescolars" que poden condicionar I ‘èxit escolar dels estudiants d'origen immigrant. Aquest coneixement constitueix la base per al disseny i orientació de programes d'acompanyament a les famílies dels infants en situació de risc. La nostra voluntat (que reflecteix el principal objectiu de I'lnstitut d’infància i Món Urbà, instituci6 que impulsa el projecte) és contribuir a la transferència de coneixement que pugui ser d'utilitat pels agents que treballen directament sobre les qüestions que estudiem.

Tools in pharmacovigilance in psychiatry: therapeutic drug monitoring, pharmacogenetic tests and drug-drug interactions databases

SUMMARYIn order to increase drug safety we must better understand how medication interacts with the body of our patients and this knowledge should be made easily available for the clinicians prescribing the medication. This thesis contributes to how the knowledge of some drug properties can increase and how to make information readily accessible for the medical professionals. Furthermore it investigates the use of Therapeutic drug monitoring, drug interaction databases and pharmacogenetic tests in pharmacovigilance.Two pharmacogenetic studies in the naturalistic setting of psychiatric in-patients clinics have been performed; one with the antidepressant mirtazapine, the other with the antipsychotic clozapine. Forty-five depressed patients have been treated with mirtazapine and were followed for 8 weeks. The therapeutic effect was as seen in other previous studies. Enantioselective analyses could confirm an influence of age, gender and smoking in the pharmacokinetics of mirtazapine; it showed a significant influence of the CYP2D6 genotype on the antidepressant effective S-enantiomer, and for the first time an influence of the CYP2B6 genotype on the plasma concentrations of the 8-OH metabolite was found. The CYP2B6*/*6 genotype was associated to better treatment response. A detailed hypothesis of the metabolic pathways of mirtazapine is proposed. In the second pharmacogenetic study, analyses of 75 schizophrenic patients treated with clozapine showed the influence of CYP450 and ABCB1 genotypes on its pharmacokinetics. For the first time we could demonstrate an in vivo effect of the CYP2C19 genotype and an influence of P-glycoprotein on the plasma concentrations of clozapine. Further we confirmed in vivo the prominent role of CYP1A2 in the metabolism of clozapine.Identifying risk factors for the occurrence of serious adverse drug reactions (SADR) would allow a more individualized and safer drug therapy. SADR are rare events and therefore difficult to study. We tested the feasibility of a nested matched case-control study to examine the influence of high drug plasma levels and CYP2D6 genotypes on the risk to experience an SADR. In our sample we compared 62 SADR cases with 82 controls; both groups were psychiatric patients from the in-patient clinic Königsfelden. Drug plasma levels of >120% of the upper recommended references could be identified as a risk factor with a statistically significant odds ratio of 3.5, a similar trend could be seen for CYP2D6 poor metaboliser. Although a matched case-control design seems a valid method, 100% matching is not easy to perform in a relative small cohort of one in-patient clinic. However, a nested case-control study is feasible.On the base of the experience gained in the AMSP+ study and the fact that we have today only sparse data indicating that routine drug plasma concentration monitoring and/or pharmacogenetic testing in psychiatry are justified to minimize the risk for ADR, we developed a test algorithm named "TDM plus" (TDM plus interaction checks plus pharmacogenetic testing).Pharmacovigilance programs such as the AMSP project (AMSP = Arzneimittelsicherheit in der Psychiatrie) survey psychiatric in-patients in order to collect SADR and to detect new safety signals. Case reports of such SADR are, although anecdotal, valuable to illustrate rare clinical events and sometimes confirm theoretical assumptions of e.g. drug interactions. Seven pharmacovigilance case reports are summarized in this thesis.To provide clinicians with meaningful information on the risk of drug combinations, during the course of this thesis the internet based drug interaction program mediQ.ch (in German) has been developed. Risk estimation is based on published clinical and pharmacological information of single drugs and alimentary products, including adverse drug reaction profiles. Information on risk factors such as renal and hepatic insufficiency and specific genotypes are given. More than 20'000 drug pairs have been described in detail. Over 2000 substances with their metabolic and transport pathways are included and all information is referenced with links to the published scientific literature or other information sources. Medical professionals of more than 100 hospitals and 300 individual practitioners do consult mediQ.ch regularly. Validations with comparisons to other drug interaction programs show good results.Finally, therapeutic drug monitoring, drug interaction programs and pharmacogenetic tests are helpful tools in pharmacovigilance and should, in absence of sufficient routine tests supporting data, be used as proposed in our TDM plus algorithm.RESUMEPour améliorer la sécurité d'emploi des médicaments il est important de mieux comprendre leurs interactions dans le corps des patients. Ensuite le clinicien qui prescrit une pharmacothérapie doit avoir un accès simple à ces informations. Entre autres, cette thèse contribue à mieux connaître les caractéristiques pharmacocinétiques de deux médicaments. Elle examine aussi l'utilisation de trois outils en pharmacovigilance : le monitorage thérapeutique des taux plasmatiques des médicaments (« therapeutic drug monitoring »), un programme informatisé d'estimation du risque de combinaisons médicamenteuses, et enfin des tests pharmacogénétiques.Deux études cliniques pharmacogénétiques ont été conduites dans le cadre habituel de clinique psychiatrique : l'une avec la mirtazapine (antidépresseur), l'autre avec la clozapine (antipsychotique). On a traité 45 patients dépressifs avec de la mirtazapine pendant 8 semaines. L'effet thérapeutique était semblable à celui des études précédentes. Nous avons confirmé l'influence de l'âge et du sexe sur la pharmacocinétique de la mirtazapine et la différence dans les concentrations plasmatiques entre fumeurs et non-fumeurs. Au moyen d'analyses énantiomères sélectives, nous avons pu montrer une influence significative du génotype CYP2D6 sur l'énantiomère S+, principalement responsable de l'effet antidépresseur. Pour la première fois, nous avons trouvé une influence du génotype CYP2B6 sur les taux plasmatiques de la 8-OH-mirtazapine. Par ailleurs, le génotype CYP2B6*6/*6 était associé à une meilleure réponse thérapeutique. Une hypothèse sur les voies métaboliques détaillées de la mirtazapine est proposée. Dans la deuxième étude, 75 patients schizophrènes traités avec de la clozapine ont été examinés pour étudier l'influence des génotypes des iso-enzymes CYP450 et de la protéine de transport ABCB1 sur la pharmacocinétique de cet antipsychotique. Pour la première fois, on a montré in vivo un effet des génotypes CYP2C19 et ABCB1 sur les taux plasmatiques de la clozapine. L'importance du CYP1A2 dans le métabolisme de la clozapine a été confirmée.L'identification de facteurs de risques dans la survenue d'effets secondaire graves permettrait une thérapie plus individualisée et plus sûre. Les effets secondaires graves sont rares. Dans une étude de faisabilité (« nested matched case-control design » = étude avec appariement) nous avons comparé des patients avec effets secondaires graves à des patients-contrôles prenant le même type de médicaments mais sans effets secondaires graves. Des taux plasmatiques supérieurs à 120% de la valeur de référence haute sont associés à un risque avec « odds ratio » significatif de 3.5. Une tendance similaire est apparue pour le génotype du CYP2D6. Le « nested matched case-control design » semble une méthode valide qui présente cependant une difficulté : trouver des patients-contrôles dans le cadre d'une seule clinique psychiatrique. Par contre la conduite d'une « nested case-control study » sans appariement est recommandable.Sur la base de notre expérience de l'étude AMSP+ et le fait que nous disposons que de peux de données justifiant des monitorings de taux plasmatiques et/ou de tests pharmacogénétiques de routine, nous avons développé un test algorithme nommé « TDMplus » (TDM + vérification d'interactions médicamenteuses + tests pharmacogénétique).Des programmes de pharmacovigilances comme celui de l'AMSP (Arzneimittelsicherheit in der Psychiatrie = pharmacovigilance en psychiatrie) collectent les effets secondaires graves chez les patients psychiatriques hospitalisés pour identifier des signaux d'alertes. La publication de certains de ces cas même anecdotiques est précieuse. Elle décrit des événements rares et quelques fois une hypothèse sur le potentiel d'une interaction médicamenteuse peut ainsi être confirmée. Sept publications de cas sont résumées ici.Dans le cadre de cette thèse, on a développé un programme informatisé sur internet (en allemand) - mediQ.ch - pour estimer le potentiel de risques d'une interaction médicamenteuse afin d'offrir en ligne ces informations utiles aux cliniciens. Les estimations de risques sont fondées sur des informations cliniques (y compris les profils d'effets secondaires) et pharmacologiques pour chaque médicament ou substance combinés. Le programme donne aussi des informations sur les facteurs de risques comme l'insuffisance rénale et hépatique et certains génotypes. Actuellement il décrit en détail les interactions potentielles de plus de 20'000 paires de médicaments, et celles de 2000 substances actives avec leurs voies de métabolisation et de transport. Chaque information mentionne sa source d'origine; un lien hypertexte permet d'y accéder. Le programme mediQ.ch est régulièrement consulté par les cliniciens de 100 hôpitaux et par 300 praticiens indépendants. Les premières validations et comparaisons avec d'autres programmes sur les interactions médicamenteuses montrent de bons résultats.En conclusion : le monitorage thérapeutique des médicaments, les programmes informatisés contenant l'information sur le potentiel d'interaction médicamenteuse et les tests pharmacogénétiques sont de précieux outils en pharmacovigilance. Nous proposons de les utiliser en respectant l'algorithme « TDM plus » que nous avons développé.

Prospective analysis of KRAS, BRAF, and PIK3CA mutations and EGFR copy number in patients (pts) with locally advanced rectal cancer: A translational substudy of a clinical trial (SAKK 41/07) evaluating the effect of neoadjuvant chemoradiation (CRT) with or without panitumumab

Background: Prognostic and predictive markers are of great importance for future study designs and essential for the interpretation of clinical trials incorporating an EGFR-inhibitor. The current study prospectively assessed and validated KRAS, BRAF and PIK3CA mutations in rectal cancer patients screened for the trial SAKK41/07 of concomitant preoperative radio-chemotherapy with or without panitumumab.Methods: Macrodissection was performed on pretreatment formalin fixed paraffin embedded biopsy tissue sections to arrive at a minimum of 50% of tumor cells. DNA was extracted with the Maxwell 16 FFPE Tissue LEV DNA purification kit. After PCR amplification, mutations were identified by pyrosequencing. We prospectively analysed pretreatment biopsy material from 149 rectal cancer pts biopsies for KRAS (exon 2 codon 12 [2-12] and 13 [2-13], exon 3 codon 59 [3-59]) and 61 [3-61], exon 4 codon 117 [4-117] and 146 [4-146]). Sixty-eight pts (KRASwt exon 2, 3 only) were further analysed for BRAF (exon 15 codon 600) and PIK3CA (exon 9 codon 542, 545 and 546, exon 20 codon 1043 [20-1043] and 1047 [20-1047]) mutations, and EGFR copy number by qPCR. For the calculation of the EGFR copy number, we used KRAS copy number as internal reference standard. The calculation was done on the basis of the two standard curves relative quantification method.Results: In 149 screened pts with rectal cancer, the prevalence of KRAS mutations was 36%. Among the 68 pts enrolled in SAKK 41/07 based on initially presumed KRASwt status (exon 2/codons 12+13), 18 pts (26%) had a total of 23 mutations in the RAS/PIK3CA-pathways upon validation analysis. Twelve pts had a KRAS mutation, 7 pts had a PIK3CA mutation, 3 pts had a NRAS mutation, 1 patient a BRAF mutation. Surprisingly, five of these pts had double- mutations, including 4 pts with KRAS plus PIK3CA mutations, and 1 pt with NRAS plus PIK3CA mutations. The median normalized EGFR copy number was 1. Neither mutations of KRAS, BRAF, and PIK3CA, nor EGFR copy number were statistically associated with the primary study endpoint pCR (pathological complete regression).Conclusions: The prevalence of KRAS mutations in rectal and in colon cancer appears to be similar. BRAF mutations are rare; PIK3CA mutations are more common (10%). EGFR copy number is not increased in rectal cancer. A considerable number or KRAS exon 2 wt tumors harbored KRAS exon 3+4 mutations. Further study is needed to determine if KRAS testing should include exons 2-4.

Genetics for clinicians: from candidate genes to whole genome scans (technological advances).

Human genetics has progressed at an unprecedented pace during the past 10 years. DNA microarrays currently allow screening of the entire human genome with high level of coverage and we are now entering the era of high-throughput sequencing. These remarkable technical advances are influencing the way medical research is conducted and have boosted our understanding of the structure of the human genome as well as of disease biology. In this context, it is crucial for clinicians to understand the main concepts and limitations of modern genetics. This review will describe key concepts in genetics, including the different types of genetic markers in the human genome, review current methods to detect DNA variation, describe major online public databases in genetics, explain key concepts in statistical genetics and finally present commonly used study designs in clinical and epidemiological research. This review will therefore concentrate on human genetic variation analysis.