'Do not attempt resuscitation' and 'cardiopulmonary resuscitation' in an inpatient setting: factors influencing physicians' decisions in Switzerland.

OBJECTIVE: To determine the prevalence of cardiopulmonary resuscitation (CPR) and do-not-attempt-resuscitation (DNAR) orders, to define factors associated with CPR/DNAR orders and to explore how physicians make and document these decisions. METHODS: We prospectively reviewed CPR/DNAR forms of 1,446 patients admitted to the General Internal Medicine Department of the Geneva University Hospitals, a tertiary-care teaching hospital in Switzerland. We additionally administered a face-to-face survey to residents in charge of 206 patients including DNAR and CPR orders, with or without patient inclusion. RESULTS: 21.2% of the patients had a DNAR order, 61.7% a CPR order and 17.1% had neither. The two main factors associated with DNAR orders were a worse prognosis and/or a worse quality of life. Others factors were an older age, cancer and psychiatric diagnoses, and the absence of decision-making capacity. Residents gave four major justifications for DNAR orders: important comorbid conditions (34%), the patients' or their family's resuscitation preferences (18%), the patients' age (14.2%), and the absence of decision-making capacity (8%). Residents who wrote DNAR orders were more experienced. In many of the DNAR or CPR forms (19.8 and 16%, respectively), the order was written using a variety of formulations. For 24% of the residents, the distinction between the resuscitation order and the care objective was not clear. 38% of the residents found the resuscitation form useful. CONCLUSION: Patients' prognosis and quality of life were the two main independent factors associated with CPR/DNAR orders. However, in the majority of cases, residents evaluated prognosis only intuitively, and quality of life without involving the patients. The distinction between CPR/DNAR orders and the care objectives was not always clear. Specific training regarding CPR/DNAR orders is necessary to improve the CPR/DNAR decision process used by physicians.

The persistence of lifestyles: rates and correlates of homicide in Western Europe from 1960 to 2010

This article analyses rates and correlates of homicide in 15 West European countries from 1960 to 2010. The results show that the levels of homicide in 2010 and the trends in homicide from 1960 to 2010 are not related to any of the traditional demographic and socioeconomic predictors of crime. Homicide victimization rates show an increase from the mid-1960s until the early 1990s, and a decrease since then. Victims of both genders and all group ages follow the same trend, except in the case of infanticide, which decreased during the whole period. These results do not support the hypothesis of a homicide trend driven by the evolution of victimization of young men in public space. The authors propose an explanation based on a lifestyle approach.

The role of the c-myc gene in pigment cell development and homeostasis

Résumé La dérégulation de c-Myc est un événement fréquent de la transformation cellulaire. Une régulation positive de cette oncoprotéine a été démontrée dans divers mélanomes cutanés primaires et métastatiques et est associée à un pronostic défavorable (Grover et al., 1996; Zhuang et al., 2008). c-Myc est considéré comme une molécule centrale impliquée dans plusieurs processus de l'homéostasie cellulaire. En raison de sa contribution importante dans la progression tumorale, la fonction de c-Myc a été étudiée intensément. Cependant nous connaissons peu le rôle de ce facteur de transcription dans l'embryogenèse et dans la spécification tissulaire. Un déficit total de c-Myc pendant l'embryogenèse conduit à la mort embryonnaire avant 10.5 jours de gestation. Cette mort est causée par de multiples imperfections du développement touchant la taille de l'embryon, le coeur, le péricarde, le tube neural et les cellules sanguines (Davis et al., 1993; Trumpp et al., 2001). Récemment, il a été montré que la plupart de ces anomalies sont secondaires et résultent d'une insuffisance du placenta dans les embryons c-myc-/- (Dubois et al., 2008). Sachant que c-Myc est important dans la maintenance des lignées de la crête neurale (Wei et al., 2007), nous nous sommes intéressés au rôle de c-Myc dans le développement des cellules pigmentaires et à leur homéostasie après la naissance. Un allèle floxé de c-myc (Trumpp et al., 2001) a été utilisé pour supprimer ce gène spécifiquement dans la lignée mélanocytaire à l'aide d'une souris transgénique Tyr::Cre (Delmas et al., 2003). L'ablation des deux allèles de c-myc dans les mélanocytes des souris c-myccKO conduit au phénotype de grisonnement des poils, observé directement après la naissance et associé à une diminution du nombre de mélanocytes dans le bulbe des follicules pileux. Les cellules pigmentaires restantes expriment les marqueurs mélanogéniques (Tyr, TRP-1, Dct and MITF) et semblent être fonctionnelles puisqu'elles peuvent produire et transférer la mélanine. De plus, la capacité de prolifération des mélanocytes déficients en c-Myc dans le bulbe des follicules pileux ne semble pas être affectée chez les nouveaux-nés. Les cellules souches mélanocytaires sont présentes, mais en nombre réduit, dans le bulge des follicules pileux à la fin de la morphogenèse chez les souris c-myccKO âgées de huit jours. Ces cellules sont maintenues sans changement durant le premier cycle pileux (vérifié à l'âge de trente jours), ce qui sous-entend que la fonction de c-Myc n'est pas nécessaire pour ce processus. Ceci explique pourquoi, en supposant que des cellules souches mélanocytaires fonctionnelles sont présentes dans la peau, nous n'observons pas de dilution de couleur de la robe liée à l'âge. Cependant, la présence de ces cellules souches mélanocytaires dans la peau c-myccKO ne suffit pas à assurer une quantité normale de mélanocytes différenciés dans le bulbe des follicules pileux. Cette population de cellules pigmentaires matures est sévèrement affectée par la suppression de c-Myc, ce qui contribue amplement au phénotype de grisonnement des poils. De plus, c-Myc paraît être important pour le développement des mélanocytes. Ainsi, le nombre de mélanoblastes diminue dans les embryons c-myccKO à partir du douzième jour de gestation. A treize jours de gestation, au stade où les mélanoblastes pénètrent dans l'épiderme et prolifèrent, les mélanoblastes déficients en c-Myc ne s'adaptent pas aux signaux de prolifération et se retrouvent en nombre réduit dans l'épiderme. Finalement, nous nous sommes intéressés, au rôle de N-Myc, un homologue proche de c-Myc, dans la lignée mélanocytaire. Nos expériences ont montré que. N-Myc était superflu pour le développement et l'homéostasie des mélanocytes, une seule copie du gène c-myc étant suffisante pour maintenir une pigmentation normale de la robe des souris c-mycc-myccKO/+~N_ myccKO/KO. Cependant, le rôle essentiel de N-Myc dans la maintenance des cellules mélanocytaires précurseurs apparaît lorsque c-Myc est absent, puisque la suppression simultanée des deux Myc résulte en une perte complète de la coloration de la robe. Ceci implique la présence d'un mécanisme compensatoire entre c- et N-Myc dans la lignée mélanocytaire, avec un rôle prédominant de c-Myc. Summary Deregulation of c-Myc is known to be a common event in cellular transformation. Upregulation of this oncoprotein was shown in a variety of primary and metastatic cutaneous melanomas and has been associated with a poor prognosis (Grover et al., 1996; Zhuang et al., 2008). c-myc is seen as a central molecule involved in many aspects of cellular homeostasis. c-Myc function has been intensively studied mostly because of its significant contribution to tumour progression. However little is known on the role of this transcription factor in embryogenesis and tissue specification. Complete loss of c-Myc during embryogenesis results in embryonic death before E10.5 due to multiple developmental defects including embryonic size, heart, pericardium, neural tube and blood cells (Davis et al., 1993; Trumpp et al., 2001). Recently it was discovered that most of these abnormalities are secondary and results of placental insufficiency in c-Myc-/- embryos (Dubois et al., 2008). Here, we focused on the role of c-Myc in pigment cell development and homeostasis after birth, knowing that c-Myc is important in the maintenance of neural crest lineages (Wei et al., 2007). A floxed allele of c-Myc (Trumpp et al., 2001) was used to specifically delete this gene in the melanocyte lineage using Tyr::Cre transgenic mice (Delmas et al., 2003). Removal of both c-Myc alleles in melanocytes of c-MyccKO mouse led to the grey hair phenotype which is seen directly after birth and was associated with a decrease in the melanocyte number in the bulb of the hair follicle. The remaining population of pigment cells express melanogenic markers (Tyr, TRP-1, Dct and MITF) and seem functionally normal since they can produce and transfer melanin. Furthermore proliferation capacity of c-Myc deficient melanocytes in the bulb of hair follicle seems not to be affected in newborn animals. Melanocyte stem cells (MSCs) are present but reduced in numbers in the bulge of the hair follicle at the end of morphogenesis in 8 days old c-MyccKO mice. These cells are maintained through the first hair cycle (as verified at P30) without any further changes, suggesting that c-Myc function is not required for this process. This explains why we did not detect any agerelated coat color dilution, assuming a presence of functional MSCs in the skin. Importantly, presence of MSCs in c-MyccKO skin was not sufficient for assuring a normal number of differentiated melanocytes in the bulb of the hair follicle. This population of mature pigmented cells is severely affected upon c-myc deletion thus largely contributing to the grey hair phenotype. Moreover, c-Myc appears to be important for melanocyte development. Thus, melanoblast number is affected in c-MyccKO embryos day 12 of gestation onwards. At E13.5, when melanoblasts enter the epidermis and proliferate, c-myc deficient melanoblasts failed to adapt to proliferation signals and are therefore reduced in number in the epidermis. Finally, we addressed the role of N-Myc, a closest homologue of c-Myc, in the melanocyte lineage. In these experiments, N-Myc was dispensable for melanocyte development and homeostasis, and even one copy of the c-myc gene was sufficient to maintain normal coat color pigmentation in c-mycc-mycCKO/+ ,N-myccKO/KO mice. However the crucial role of N-Myc in maintenance of melanocyte precursor cells became apparent when c-myc is eliminated since simultaneous deletion of both Myc results in complete loss of coat color pigmentation. This suggests compensatory mechanisms between c- and N-Myc with a predominant role of c-Myc in melanocyte lineage.

Determinants of the development of post-traumatic stress disorder, in the general population.

PURPOSE: To assess (1) the lifetime prevalence of exposure both to trauma and post-traumatic stress disorder (PTSD); (2) the risk of PTSD by type of trauma; and (3) the determinants of the development of PTSD in the community. METHODS: The Diagnostic Interview for Genetic Studies was administered to a random sample of an urban area (N = 3,691). RESULTS: (1) The lifetime prevalence estimates of exposure to trauma and PTSD were 21.0 and 5.0%; respectively, with a twice as high prevalence of PTSD in women compared to men despite a similar likelihood of exposure in the two sexes; (2) Sexual abuse was the trauma involving the highest risk of PTSD; (3) The risk of PTSD was most strongly associated with sexual abuse followed by preexisting bipolar disorder, alcohol dependence, antisocial personality, childhood separation anxiety disorder, being victim of crime, witnessing violence, Neuroticism and Problem-focused coping strategies. After adjustment for these characteristics, female sex was no longer found to be significantly associated with the risk of PTSD. CONCLUSIONS: The risk for the development of PTSD after exposure to traumatic events is associated with several factors including the type of exposure, preexisting psychopathology, personality features and coping strategies which independently contribute to the vulnerability to PTSD.

L'agrégation toxique des protéines: une forme de "delinquance moléculaire" activement combattue dans la cellule par les chaperones moléculaires et les protéases [The toxic aggregation of proteins: a kind of "molecular delinquency" actively fought in the cell by molecular chaperones and proteases]

Under various stresses, mutation-sensitised proteins may spontaneously convert into inactive, aggregation-prone structures, which may be cytotoxic and infectious. In the cell, this new kind of "molecular criminality" is actively fought against by a network of molecular chaperones that can specifically identify, isolate and unfold damaged (delinquent) proteins and favour their subsequent native refolding. Irreversibly damaged molecules unable to natively refold are preferentially "executed" and recycled by proteases. Failing that, they are "imprisoned" within compact amyloids, or "evicted" from the cell. Thus, striking parallels, although of questionable ethical value, exist between protein and human criminality, and between the cellular and social responses to these different types of criminality. Fundamental differences also exist. Whereas programmed death (apoptosis) is the preferred solution chosen by aged and aggregation-stressed cells, collective suicide is seldom an option chosen by lawless human societies. More significantly, there is no clear cellular equivalent for the role of the family and the education system, which are so essential to the proper shaping of functional individuals in the society, and give rise to humanism, that favours crime prevention, reeducation and reinsertion programs over capital punishment. To the cardiologist and transplantation surgeon, the interest of molecular chaperones, in particular of Hsp70, Hsp90 and Hsp27, lays in their ability to inhibit the signalling pathway of programmed cell death. Their induction before and during ischemia, by various treatments and drugs could significantly reduce damages from the post ischemic reperfusion of organs.

Development of pharmaceutical care services in nursing homes: practice and research in a Swiss canton.

OBJECTIVE: The aim of this study was to assess the implementation process and economic impact of a new pharmaceutical care service provided since 2002 by pharmacists in Swiss nursing homes. SETTING: The setting was 42 nursing homes located in the canton of Fribourg, Switzerland under the responsibility of 22 pharmacists. METHOD: We developed different facilitators, such as a monitoring system, a coaching program, and a research project, to help pharmacists change their practice and to improve implementation of this new service. We evaluated the implementation rate of the service delivered in nursing homes. We assessed the economic impact of the service since its start in 2002 using statistical evaluation (Chow test) with retrospective analysis of the annual drug costs per resident over an 8-year period (1998-2005). MAIN OUTCOME MEASURES: The description of the facilitators and their implications in implementation of the service; the economic impact of the service since its start in 2002. RESULTS: In 2005, after a 4-year implementation period supported by the introduction of facilitators of practice change, all 42 nursing homes (2,214 residents) had implemented the pharmaceutical care service. The annual drug costs per resident decreased by about 16.4% between 2002 and 2005; this change proved to be highly significant. The performance of the pharmacists continuously improved using a specific coaching program including an annual expert comparative report, working groups, interdisciplinary continuing education symposia, and individual feedback. This research project also determined priorities to develop practice guidelines to prevent drug-related problems in nursing homes, especially in relation to the use of psychotropic drugs. CONCLUSION: The pharmaceutical care service was fully and successfully implemented in Fribourg's nursing homes within a period of 4 years. These findings highlight the importance of facilitators designed to assist pharmacists in the implementation of practice changes. The economic impact was confirmed on a large scale, and priorities for clinical and pharmacoeconomic research were identified in order to continue to improve the quality of integrated care for the elderly.

Alleviating Working Poverty in Postindustrial Economies

In order to identify the main social policy tools that can efficiently combat working poverty, it is essential to identify its main driving factors. More importantly, this work shows that all poverty factors identified in the literature have a direct bearing on working households through three mechanisms, namely being badly paid, having a below-average workforce participation, and high needs. One of the main purposes of this work is to assess whether the policies put forward in the specialist literature as potentially efficient really work. This is done in two ways. A first empirical prong provides an evaluation of the employment and antipoverty effects of these instruments, based on a meta-analysis of four instruments: minimum wages, tax credits for working households, family cash benefits and childcare policies. The second prong relies on a broader framework based on welfare regimes. This work contributes to the identification of a typology of welfare regimes that is suitable for the analysis of working poverty, and four countries are chosen to exemplify each regime: the US, Sweden, Germany, and Spain. It then moves on to show that the weight of the three working poverty mechanisms varies widely from one welfare regime to the other. This second empirical contribution clearly shows that there is no "one-size-fits-all" approach to the fight against working poverty. But none of this is possible without having properly defined the phenomenon. Most of the literature is characterized by a "definitional chaos" that probably does more harm than good to social policy efforts. Hence, this book provides a conceptual reflection pleading for the use of a very encompassing definition of being in work. It shows that "the working poor" is too broad a category to be used for meaningful academic or policy discussion, and that a distinction must be operated between different categories of the working poor. Failing to acknowledge this prevents the design of an efficient policy mix.

Ruin and related quantities in some advanced insurance risk models

Risk theory has been a very active research area over the last decades. The main objectives of the theory are to find adequate stochastic processes which can model the surplus of a (non-life) insurance company and to analyze the risk related quantities such as ruin time, ruin probability, expected discounted penalty function and expected discounted dividend/tax payments. The study of these ruin related quantities provides crucial information for actuaries and decision makers. This thesis consists of the study of four different insurance risk models which are essentially related. The ruin and related quantities are investigated by using different techniques, resulting in explicit or asymptotic expressions for the ruin time, the ruin probability, the expected discounted penalty function and the expected discounted tax payments. - La recherche en théorie du risque a été très dynamique au cours des dernières décennies. D'un point de vue théorique, les principaux objectifs sont de trouver des processus stochastiques adéquats permettant de modéliser le surplus d'une compagnie d'assurance non vie et d'analyser les mesures de risque, notamment le temps de ruine, la probabilité de ruine, l'espérance de la valeur actuelle de la fonction de pénalité et l'espérance de la valeur actuelle des dividendes et taxes. L'étude de ces mesures associées à la ruine fournit des informations cruciales pour les actuaires et les décideurs. Cette thèse consiste en l'étude des quatre différents modèles de risque d'assurance qui sont essentiellement liés. La ruine et les mesures qui y sont associées sont examinées à l'aide de différentes techniques, ce qui permet d'induire des expressions explicites ou asymptotiques du temps de ruine, de la probabilité de ruine, de l'espérance de la valeur actuelle de la fonction de pénalité et l'espérance de la valeur actuelle des dividendes et taxes.

Das geplante "Datenschutz-Gesetz": eine Bedrohung der medizinisch-epidemiologischen Forschung in der Schweiz? [The proposed law on safeguarding of data: a threat to medical-epidemiologic research in Switzerland?].

The draft of the new law on the confidentiality of personal data severely curtails medical and epidemiological research. This might be detrimental and dangerous to public health. The project therefore has to be amended.

Binding free energy differences in a TCR-peptide-MHC complex induced by a peptide mutation: a simulation analysis.

Recognition by the T-cell receptor (TCR) of immunogenic peptides presented by class I major histocompatibility complexes (MHCs) is the determining event in the specific cellular immune response against virus-infected cells or tumor cells. It is of great interest, therefore, to elucidate the molecular principles upon which the selectivity of a TCR is based. These principles can in turn be used to design therapeutic approaches, such as peptide-based immunotherapies of cancer. In this study, free energy simulation methods are used to analyze the binding free energy difference of a particular TCR (A6) for a wild-type peptide (Tax) and a mutant peptide (Tax P6A), both presented in HLA A2. The computed free energy difference is 2.9 kcal/mol, in good agreement with the experimental value. This makes possible the use of the simulation results for obtaining an understanding of the origin of the free energy difference which was not available from the experimental results. A free energy component analysis makes possible the decomposition of the free energy difference between the binding of the wild-type and mutant peptide into its components. Of particular interest is the fact that better solvation of the mutant peptide when bound to the MHC molecule is an important contribution to the greater affinity of the TCR for the latter. The results make possible identification of the residues of the TCR which are important for the selectivity. This provides an understanding of the molecular principles that govern the recognition. The possibility of using free energy simulations in designing peptide derivatives for cancer immunotherapy is briefly discussed.

Violence in primary care: prevalence and follow-up of victims.

BACKGROUND: Primary care physicians underestimate the prevalence of domestic violence and community violence. Victims are therefore at risk of further episodes of violence, with psychological and physical consequences. We used an interview to assess the prevalence of domestic and community violence among Swiss natives and foreigners. In a follow-up study, we evaluated the consequences of the interview for the positive patients. METHODS: We evaluated the prevalence of violence by use of a questionnaire in an interview, in an academic general internal medicine clinic in Switzerland. In a follow-up, we evaluated the consequences of the interview for positive patients. The participants were 38 residents and 446 consecutive patients. Questionnaires were presented in the principal language spoken by our patients. They addressed sociodemographics, present and past violence, the security or lack of security felt by victims of violence, and the patients' own violence. Between 3 and 6 months after the first interview, we did a follow-up of all patients who had reported domestic violence in the last year. RESULTS: Of the 366 patients included in the study, 36 (9.8%) reported being victims of physical violence during the last year (physicians identified only 4 patients out of the 36), and 34/366 (9.3%) reported being victims of psychological violence. Domestic violence was responsible for 67.3% of the cases, and community violence for 21.8%. In 10.9% of the cases, both forms of violence were found. Of 29 patients who reported being victims of domestic violence, 22 were found in the follow-up. The frequency of violence had diminished (4/22) or the violence had ceased (17/22). CONCLUSION: The prevalence of violence is high; domestic violence is more frequent than community violence. There was no statistically significant difference between the Swiss and foreign patients' responses related to the rates of violence. Patients in a currently violent relationship stated that participating in the study helped them and that the violence decreased or ceased a few months later.

Three essays in dynamic corporate finance

The three essays constituting this thesis focus on financing and cash management policy. The first essay aims to shed light on why firms issue debt so conservatively. In particular, it examines the effects of shareholder and creditor protection on capital structure choices. It starts by building a contingent claims model where financing policy results from a trade-off between tax benefits, contracting costs and agency costs. In this setup, controlling shareholders can divert part of the firms' cash ows as private benefits at the expense of minority share- holders. In addition, shareholders as a class can behave strategically at the time of default leading to deviations from the absolute priority rule. The analysis demonstrates that investor protection is a first order determinant of firms' financing choices and that conflicts of interests between firm claimholders may help explain the level and cross-sectional variation of observed leverage ratios. The second essay focuses on the practical relevance of agency conflicts. De- spite the theoretical development of the literature on agency conflicts and firm policy choices, the magnitude of manager-shareholder conflicts is still an open question. This essay proposes a methodology for quantifying these agency conflicts. To do so, it examines the impact of managerial entrenchment on corporate financing decisions. It builds a dynamic contingent claims model in which managers do not act in the best interest of shareholders, but rather pursue private benefits at the expense of shareholders. Managers have discretion over financing and dividend policies. However, shareholders can remove the manager at a cost. The analysis demonstrates that entrenched managers restructure less frequently and issue less debt than optimal for shareholders. I take the model to the data and use observed financing choices to provide firm-specific estimates of the degree of managerial entrenchment. Using structural econometrics, I find costs of control challenges of 2-7% on average (.8-5% at median). The estimates of the agency costs vary with variables that one expects to determine managerial incentives. In addition, these costs are sufficient to resolve the low- and zero-leverage puzzles and explain the time series of observed leverage ratios. Finally, the analysis shows that governance mechanisms significantly affect the value of control and firms' financing decisions. The third essay is concerned with the documented time trend in corporate cash holdings by Bates, Kahle and Stulz (BKS,2003). BKS find that firms' cash holdings double from 10% to 20% over the 1980 to 2005 period. This essay provides an explanation of this phenomenon by examining the effects of product market competition on firms' cash holdings in the presence of financial constraints. It develops a real options model in which cash holdings may be used to cover unexpected operating losses and avoid inefficient closure. The model generates new predictions relating cash holdings to firm and industry characteristics such as the intensity of competition, cash flow volatility, or financing constraints. The empirical examination of the model shows strong support of model's predictions. In addition, it shows that the time trend in cash holdings documented by BKS can be at least partly attributed to a competition effect.