Premenopausal serum androgens and breast cancer risk: a nested case-control study.

ABSTRACT: INTRODUCTION: Prospective epidemiologic studies have consistently shown that levels of circulating androgens in postmenopausal women are positively associated with breast cancer risk. However, data in premenopausal women are limited. METHODS: A case-control study nested within the New York University Women's Health Study was conducted. A total of 356 cases (276 invasive and 80 in situ) and 683 individually-matched controls were included. Matching variables included age and date, phase, and day of menstrual cycle at blood donation. Testosterone, androstenedione, dehydroandrosterone sulfate (DHEAS) and sex hormone-binding globulin (SHBG) were measured using direct immunoassays. Free testosterone was calculated. RESULTS: Premenopausal serum testosterone and free testosterone concentrations were positively associated with breast cancer risk. In models adjusted for known risk factors of breast cancer, the odds ratios for increasing quintiles of testosterone were 1.0 (reference), 1.5 (95% confidence interval (CI), 0.9 to 2.3), 1.2 (95% CI, 0.7 to 1.9), 1.4 (95% CI, 0.9 to 2.3) and 1.8 (95% CI, 1.1 to 2.9; Ptrend = 0.04), and for free testosterone were 1.0 (reference), 1.2 (95% CI, 0.7 to 1.8), 1.5 (95% CI, 0.9 to 2.3), 1.5 (95% CI, 0.9 to 2.3), and 1.8 (95% CI, 1.1 to 2.8, Ptrend = 0.01). A marginally significant positive association was observed with androstenedione (P = 0.07), but no association with DHEAS or SHBG. Results were consistent in analyses stratified by tumor type (invasive, in situ), estrogen receptor status, age at blood donation, and menopausal status at diagnosis. Intra-class correlation coefficients for samples collected from 0.8 to 5.3 years apart (median 2 years) in 138 cases and 268 controls were greater than 0.7 for all biomarkers except for androstenedione (0.57 in controls). CONCLUSIONS: Premenopausal concentrations of testosterone and free testosterone are associated with breast cancer risk. Testosterone and free testosterone measurements are also highly reliable (that is, a single measurement is reflective of a woman's average level over time). Results from other prospective studies are consistent with our results. The impact of including testosterone or free testosterone in breast cancer risk prediction models for women between the ages of 40 and 50 years should be assessed. Improving risk prediction models for this age group could help decision making regarding both screening and chemoprevention of breast cancer.

Clinical chemistry variables in normal elderly and healthy ambulatory populations: comparison with reference values.

Laboratory values of the most commonly assayed clinical chemistry variables were determined in selected elderly and healthy ambulatory populations. The upper and lower limits (2.5 and 97.5 fractiles) were compared with the adult reference values in use in university hospitals of Switzerland. The results suggest that conventional adult reference values can be used for most variables in the elderly and that these values are also useful in an ambulatory population.

Multiple sclerosis decreases explicit counterfactual processing and risk taking in decision making.

INTRODUCTION: Deficits in decision making (DM) are commonly associated with prefrontal cortical damage, but may occur with multiple sclerosis (MS). There are no data concerning the impact of MS on tasks evaluating DM under explicit risk, where different emotional and cognitive components can be distinguished. METHODS: We assessed 72 relapsing-remitting MS (RRMS) patients with mild to moderate disease and 38 healthy controls in two DM tasks involving risk with explicit rules: (1) The Wheel of Fortune (WOF), which probes the anticipated affects of decisions outcomes on future choices; and (2) The Cambridge Gamble Task (CGT) which measures risk taking. Participants also underwent a neuropsychological and emotional assessment, and skin conductance responses (SCRs) were recorded. RESULTS: In the WOF, RRMS patients showed deficits in integrating positive counterfactual information (p<0.005) and greater risk aversion (p<0.001). They reported less negative affect than controls (disappointment: p = 0.007; regret: p = 0.01), although their implicit emotional reactions as measured by post-choice SCRs did not differ. In the CGT, RRMS patients differed from controls in quality of DM (p = 0.01) and deliberation time (p = 0.0002), the latter difference being correlated with attention scores. Such changes did not result in overall decreases in performance (total gains). CONCLUSIONS: The quality of DM under risk was modified by MS in both tasks. The reduction in the expression of disappointment coexisted with an increased risk aversion in the WOF and alexithymia features. These concomitant emotional alterations may have implications for better understanding the components of explicit DM and for the clinical support of MS patients.

Definition of key variables for the induction of optimal NY-ESO-1-specific T cells in HLA transgene mice.

An attractive treatment of cancer consists in inducing tumor-eradicating CD8(+) CTL specific for tumor-associated Ags, such as NY-ESO-1 (ESO), a strongly immunogenic cancer germ line gene-encoded tumor-associated Ag, widely expressed on diverse tumors. To establish optimal priming of ESO-specific CTL and to define critical vaccine variables and mechanisms, we used HLA-A2/DR1 H-2(-/-) transgenic mice and sequential immunization with immunodominant DR1- and A2-restricted ESO peptides. Immunization of mice first with the DR1-restricted ESO(123-137) peptide and subsequently with mature dendritic cells (DCs) presenting this and the A2-restriced ESO(157-165) epitope generated abundant, circulating, high-avidity primary and memory CD8(+) T cells that efficiently killed A2/ESO(157-165)(+) tumor cells. This prime boost regimen was superior to other vaccine regimes and required strong Th1 cell responses, copresentation of MHC class I and MHC class II peptides by the same DC, and resulted in upregulation of sphingosine 1-phosphate receptor 1, and thus egress of freshly primed CD8(+) T cells from the draining lymph nodes into circulation. This well-defined system allowed detailed mechanistic analysis, which revealed that 1) the Th1 cytokines IFN-gamma and IL-2 played key roles in CTL priming, namely by upregulating on naive CD8(+) T cells the chemokine receptor CCR5; 2) the inflammatory chemokines CCL4 (MIP-1beta) and CCL3 (MIP-1alpha) chemoattracted primed CD4(+) T cells to mature DCs and activated, naive CD8(+) T cells to DC-CD4 conjugates, respectively; and 3) blockade of these chemokines or their common receptor CCR5 ablated priming of CD8(+) T cells and upregulation of sphingosine 1-phosphate receptor 1. These findings provide new opportunities for improving T cell cancer vaccines.

Clinical and laboratory predictors of imported malaria in an outpatient setting: an aid to medical decision making in returning travellers with fever

Si le tableau clinique évoque une malaria et que le résultat des examens parasitologiques n?est pas disponible ou est négatif, le praticien n?a pas d?information basée sur l?évidence pour savoir s?il doit donner ou non un traitement présomptif. Afin d?identifier les facteurs cliniques et paracliniques prédictifs d?une parasitémie à Plasmodium, nous avons mené une étude prospective chez les voyageurs ou migrants en provenance d?une zone tropicale ou subtropicale et qui consultaient pour de la fièvre. Le questionnaire comprenait 49 items explorant les données démographiques, les caractéristiques du voyage, les éléments de l?anamnèse et de l?examen clinique ainsi que les résultats de laboratoire. 336 sujets avec données complètes ont été recrutés (97 patients atteints de malaria et 239 contrôles avec fièvre et examen parasitologique négatif). L?analyse de régression multivariée a permis d?identifier les facteurs prédictifs de maiaria suivants : prophylaxie inadéquate, sudations, absence de douleur abdominale, température )38"C, mauvais état général, splénomégalie, compte leucocytaire (1 O x 1 03/L, plaquettes ~ 1 5 0 x l 03/L, taux d?hémoglobine <12 g/dL et éosinophiles (5%. La présence d?une splénomégalie avait le coefficient de probabilité positif pour un diagnostic de malaria le plus élevé (1 3.6) ; venait ensuite la présence d?une thrombopénie (1 1 .O). Dans le contexte de la consultation ambulatoire de la Policlinique Médicale Universitaire (prévalence de malaria de 29%), la probabilité post- test d?avoir un examen parasitologique positif était de 85% pour la splénomégalie et de 82% pour la thrombopénie. Même si le seuil thérapeutique n?est pas absolument défini, il semble raisonnable d?envisager un traitement présomptif lorsque la probabilité post- test est >80%. Si le médecin est réticent à administrer un traitement sans documentation parasitologique, il devrait au moins se retenir d?entreprendre d?autres investigations coûteuses, et plutôt répéter l?examen parasitologique après 12-24 heures.

Determinació de l’estat de seguretat alimentària de dues zones d’Etiòpia i de les variables socioeconòmiques que les afecten

L’objectiu d’aquest estudi ha sigut generar dades especifiques locals de dos zones agroecològiques diferents d’Etiòpia ( el woreda Wukro i el woreda Abaya), mesurar l’estat de seguretat alimentària de la seva població, i els determinants socioeconòmics que els afecten, així com identificar els principals problemes metodològics, interpretatius que afecten a aquestes mesures i, en conseqüència, les intervencions que se’n poden derivar.

Technology selection and group decision support systems: Case studies on supporting strategic technology selection processes

The objective of the dissertation is to increase understanding and knowledge in the field where group decision support system (GDSS) and technology selection research overlap in the strategic sense. The purpose is to develop pragmatic, unique and competent management practices and processes for strategic technology assessment and selection from the whole company's point of view. The combination of the GDSS and technology selection is approached from the points of view of the core competence concept, the lead user -method, and different technology types. In this research the aim is to find out how the GDSS contributes to the technology selection process, what aspects should be considered when selecting technologies to be developed or acquired, and what advantages and restrictions the GDSS has in the selection processes. These research objectives are discussed on the basis of experiences and findings in real life selection meetings. The research has been mainly carried outwith constructive, case study research methods. The study contributes novel ideas to the present knowledge and prior literature on the GDSS and technology selection arena. Academic and pragmatic research has been conducted in four areas: 1) the potential benefits of the group support system with the lead user -method,where the need assessment process is positioned as information gathering for the selection of wireless technology development projects; 2) integrated technology selection and core competencies management processes both in theory and in practice; 3) potential benefits of the group decision support system in the technology selection processes of different technology types; and 4) linkages between technology selection and R&D project selection in innovative product development networks. New type of knowledge and understanding has been created on the practical utilization of the GDSS in technology selection decisions. The study demonstrates that technology selection requires close cooperation between differentdepartments, functions, and strategic business units in order to gather the best knowledge for the decision making. The GDSS is proved to be an effective way to promote communication and co-operation between the selectors. The constructs developed in this study have been tested in many industry fields, for example in information and communication, forest, telecommunication, metal, software, and miscellaneous industries, as well as in non-profit organizations. The pragmatic results in these organizations are some of the most relevant proofs that confirm the scientific contribution of the study, according to the principles of the constructive research approach.

Project Success through Effective Decisions: Case Studies on Project Goal Setting, Success Evaluation and Managerial Decision Making

The objective of the thesis is to structure and model the factors that contribute to and can be used in evaluating project success. The purpose of this thesis is to enhance the understanding of three research topics. The goal setting process, success evaluation and decision-making process are studied in the context of a project, business unitand its business environment. To achieve the objective three research questionsare posed. These are 1) how to set measurable project goals, 2) how to evaluateproject success and 3) how to affect project success with managerial decisions.The main theoretical contribution comes from deriving a synthesis of these research topics which have mostly been discussed apart from each other in prior research. The research strategy of the study has features from at least the constructive, nomothetical, and decision-oriented research approaches. This strategy guides the theoretical and empirical part of the study. Relevant concepts and a framework are composed on the basis of the prior research contributions within the problem area. A literature review is used to derive constructs of factors withinthe framework. They are related to project goal setting, success evaluation, and decision making. On the basis of this, the case study method is applied to complement the framework. The empirical data includes one product development program, three construction projects, as well as one organization development, hardware/software, and marketing project in their contexts. In two of the case studiesthe analytic hierarchy process is used to formulate a hierarchical model that returns a numerical evaluation of the degree of project success. It has its origin in the solution idea which in turn has its foundation in the notion of projectsuccess. The achieved results are condensed in the form of a process model thatintegrates project goal setting, success evaluation and decision making. The process of project goal setting is analysed as a part of an open system that includes a project, the business unit and its competitive environment. Four main constructs of factors are suggested. First, the project characteristics and requirements are clarified. The second and the third construct comprise the components of client/market segment attractiveness and sources of competitive advantage. Together they determine the competitive position of a business unit. Fourth, the relevant goals and the situation of a business unit are clarified to stress their contribution to the project goals. Empirical evidence is gained on the exploitation of increased knowledge and on the reaction to changes in the business environment during a project to ensure project success. The relevance of a successful project to a company or a business unit tends to increase the higher the reference level of project goals is set. However, normal performance or sometimes performance below this normal level is intentionally accepted. Success measures make project success quantifiable. There are result-oriented, process-oriented and resource-oriented success measures. The study also links result measurements to enablers that portray the key processes. The success measures can be classified into success domains determining the areas on which success is assessed. Empiricalevidence is gained on six success domains: strategy, project implementation, product, stakeholder relationships, learning situation and company functions. However, some project goals, like safety, can be assessed using success measures that belong to two success domains. For example a safety index is used for assessing occupational safety during a project, which is related to project implementation. Product safety requirements, in turn, are connected to the product characteristics and thus to the product-related success domain. Strategic success measures can be used to weave the project phases together. Empirical evidence on their static nature is gained. In order-oriented projects the project phases are oftencontractually divided into different suppliers or contractors. A project from the supplier's perspective can represent only a part of the ¿whole project¿ viewed from the client's perspective. Therefore static success measures are mostly used within the contractually agreed project scope and duration. Proof is also acquired on the dynamic use of operational success measures. They help to focus on the key issues during each project phase. Furthermore, it is shown that the original success domains and success measures, their weights and target values can change dynamically. New success measures can replace the old ones to correspond better with the emphasis of the particular project phase. This adjustment concentrates on the key decision milestones. As a conclusion, the study suggests a combination of static and dynamic success measures. Their linkage to an incentive system can make the project management proactive, enable fast feedback and enhancethe motivation of the personnel. It is argued that the sequence of effective decisions is closely linked to the dynamic control of project success. According to the used definition, effective decisions aim at adequate decision quality and decision implementation. The findings support that project managers construct and use a chain of key decision milestones to evaluate and affect success during aproject. These milestones can be seen as a part of the business processes. Different managers prioritise the key decision milestones to a varying degree. Divergent managerial perspectives, power, responsibilities and involvement during a project offer some explanation for this. Finally, the study introduces the use ofHard Gate and Soft Gate decision milestones. The managers may use the former milestones to provide decision support on result measurements and ad hoc critical conditions. In the latter milestones they may make intermediate success evaluation also on the basis of other types of success measures, like process and resource measures.

Stratification of the severity of critically ill patients with classification trees

Background: Development of three classification trees (CT) based on the CART (Classification and Regression Trees), CHAID (Chi-Square Automatic Interaction Detection) and C4.5 methodologies for the calculation of probability of hospital mortality; the comparison of the results with the APACHE II, SAPS II and MPM II-24 scores, and with a model based on multiple logistic regression (LR). Methods: Retrospective study of 2864 patients. Random partition (70:30) into a Development Set (DS) n = 1808 and Validation Set (VS) n = 808. Their properties of discrimination are compared with the ROC curve (AUC CI 95%), Percent of correct classification (PCC CI 95%); and the calibration with the Calibration Curve and the Standardized Mortality Ratio (SMR CI 95%). Results: CTs are produced with a different selection of variables and decision rules: CART (5 variables and 8 decision rules), CHAID (7 variables and 15 rules) and C4.5 (6 variables and 10 rules). The common variables were: inotropic therapy, Glasgow, age, (A-a)O2 gradient and antecedent of chronic illness. In VS: all the models achieved acceptable discrimination with AUC above 0.7. CT: CART (0.75(0.71-0.81)), CHAID (0.76(0.72-0.79)) and C4.5 (0.76(0.73-0.80)). PCC: CART (72(69- 75)), CHAID (72(69-75)) and C4.5 (76(73-79)). Calibration (SMR) better in the CT: CART (1.04(0.95-1.31)), CHAID (1.06(0.97-1.15) and C4.5 (1.08(0.98-1.16)). Conclusion: With different methodologies of CTs, trees are generated with different selection of variables and decision rules. The CTs are easy to interpret, and they stratify the risk of hospital mortality. The CTs should be taken into account for the classification of the prognosis of critically ill patients.