Combinations of prognostic tools for identification of high-risk normotensive patients with acute symptomatic pulmonary embolism.

Background: In haemodynamically stable patients with acute symptomatic pulmonary embolism (PE), studies have not evaluated the usefulness of combining the measurement of cardiac troponin, transthoracic echocardiogram (TTE), and lower extremity complete compression ultrasound (CCUS) testing for predicting the risk of PE-related death. Methods: The study assessed the ability of three diagnostic tests (cardiac troponin I (cTnI), echocardiogram, and CCUS) to prognosticate the primary outcome of PE-related mortality during 30 days of follow-up after a diagnosis of PE by objective testing. Results: Of 591 normotensive patients diagnosed with PE, the primary outcome occurred in 37 patients (6.3%; 95% CI 4.3% to 8.2%). Patients with right ventricular dysfunction (RVD) by TTE and concomitant deep vein thrombosis (DVT) by CCUS had a PE-related mortality of 19.6%, compared with 17.1% of patients with elevated cTnI and concomitant DVT and 15.2% of patients with elevated cTnI and RVD. The use of any two-test strategy had a higher specificity and positive predictive value compared with the use of any test by itself. A combined three-test strategy did not further improve prognostication. For a subgroup analysis of high-risk patients, according to the pulmonary embolism severity index (classes IV and V), positive predictive values of the two-test strategies for PE-related mortality were 25.0%, 24.4% and 20.7%, respectively. Conclusions: In haemodynamically stable patients with acute symptomatic PE, a combination of echocardiography (or troponin testing) and CCUS improved prognostication compared with the use of any test by itself for the identification of those at high risk of PE-related death.

Rapid transgene expression in multiple precursor cell types of adult rat subventricular zone mediated by adeno-associated type 1 vectors.

Abstract The adult rat brain subventricular zone (SVZ) contains proliferative precursors that migrate to the olfactory bulb (OB) and differentiate into mature neurons. Recruitment of precursors constitutes a potential avenue for brain repair. We have investigated the kinetics and cellular specificity of transgene expression mediated by AAV2/1 vectors (i.e., adeno-associated virus type 2 pseudotyped with AAV1 capsid) in the SVZ. Self-complementary (sc) and single-stranded (ss) AAV2/1 vectors mediated efficient GFP expression, respectively, at 17 and 24 hr postinjection. Transgene expression was efficient in all the rapidly proliferating cells types, that is, Mash1(+) precursors (30% of the GFP(+) cells), Dlx2(+) neuronal progenitors (55%), Olig2(+) oligodendrocyte progenitors (35%), and doublecortin-positive (Dcx(+)) migrating cells (40%), but not in the slowly proliferating glial fibrillary acidic protein-positive (GFAP(+)) neural stem cell pool (5%). Because cell cycle arrest by wild-type and recombinant AAV has been described in primary cultures, we examined SVZ proliferative activity after vector injection. Indeed, cell proliferation was reduced immediately after vector injection but was normal after 1 month. In contrast, migration and differentiation of GFP(+) precursors were unaltered. Indeed, the proportion of Dcx(+) cells was similar in the injected and contralateral hemispheres. Furthermore, 1 month after vector injection into the SVZ, GFP(+) cells, found, as expected, in the OB granular cell layer, were mature GABAergic neurons. In conclusion, the rapid and efficient transgene expression in SVZ neural precursors mediated by scAAV2/1 vectors underlines their potential usefulness for brain repair via recruitment of immature cells. The observed transient precursor proliferation inhibition, not affecting their migration and differentiation, will likely not compromise this strategy.

Three essays in financial economics: asset pricing, optimal portfolio selection and financial integration

Executive Summary The unifying theme of this thesis is the pursuit of a satisfactory ways to quantify the riskureward trade-off in financial economics. First in the context of a general asset pricing model, then across models and finally across country borders. The guiding principle in that pursuit was to seek innovative solutions by combining ideas from different fields in economics and broad scientific research. For example, in the first part of this thesis we sought a fruitful application of strong existence results in utility theory to topics in asset pricing. In the second part we implement an idea from the field of fuzzy set theory to the optimal portfolio selection problem, while the third part of this thesis is to the best of our knowledge, the first empirical application of some general results in asset pricing in incomplete markets to the important topic of measurement of financial integration. While the first two parts of this thesis effectively combine well-known ways to quantify the risk-reward trade-offs the third one can be viewed as an empirical verification of the usefulness of the so-called "good deal bounds" theory in designing risk-sensitive pricing bounds. Chapter 1 develops a discrete-time asset pricing model, based on a novel ordinally equivalent representation of recursive utility. To the best of our knowledge, we are the first to use a member of a novel class of recursive utility generators to construct a representative agent model to address some long-lasting issues in asset pricing. Applying strong representation results allows us to show that the model features countercyclical risk premia, for both consumption and financial risk, together with low and procyclical risk free rate. As the recursive utility used nests as a special case the well-known time-state separable utility, all results nest the corresponding ones from the standard model and thus shed light on its well-known shortcomings. The empirical investigation to support these theoretical results, however, showed that as long as one resorts to econometric methods based on approximating conditional moments with unconditional ones, it is not possible to distinguish the model we propose from the standard one. Chapter 2 is a join work with Sergei Sontchik. There we provide theoretical and empirical motivation for aggregation of performance measures. The main idea is that as it makes sense to apply several performance measures ex-post, it also makes sense to base optimal portfolio selection on ex-ante maximization of as many possible performance measures as desired. We thus offer a concrete algorithm for optimal portfolio selection via ex-ante optimization over different horizons of several risk-return trade-offs simultaneously. An empirical application of that algorithm, using seven popular performance measures, suggests that realized returns feature better distributional characteristics relative to those of realized returns from portfolio strategies optimal with respect to single performance measures. When comparing the distributions of realized returns we used two partial risk-reward orderings first and second order stochastic dominance. We first used the Kolmogorov Smirnov test to determine if the two distributions are indeed different, which combined with a visual inspection allowed us to demonstrate that the way we propose to aggregate performance measures leads to portfolio realized returns that first order stochastically dominate the ones that result from optimization only with respect to, for example, Treynor ratio and Jensen's alpha. We checked for second order stochastic dominance via point wise comparison of the so-called absolute Lorenz curve, or the sequence of expected shortfalls for a range of quantiles. As soon as the plot of the absolute Lorenz curve for the aggregated performance measures was above the one corresponding to each individual measure, we were tempted to conclude that the algorithm we propose leads to portfolio returns distribution that second order stochastically dominates virtually all performance measures considered. Chapter 3 proposes a measure of financial integration, based on recent advances in asset pricing in incomplete markets. Given a base market (a set of traded assets) and an index of another market, we propose to measure financial integration through time by the size of the spread between the pricing bounds of the market index, relative to the base market. The bigger the spread around country index A, viewed from market B, the less integrated markets A and B are. We investigate the presence of structural breaks in the size of the spread for EMU member country indices before and after the introduction of the Euro. We find evidence that both the level and the volatility of our financial integration measure increased after the introduction of the Euro. That counterintuitive result suggests the presence of an inherent weakness in the attempt to measure financial integration independently of economic fundamentals. Nevertheless, the results about the bounds on the risk free rate appear plausible from the view point of existing economic theory about the impact of integration on interest rates.

Spatial planning to the test of property rights in Switzerland : an innovative land management approach to coordinate spatial planning goals with property rights interests

In Switzerland, the land management regime is characterized by a liberal attitude towards the institution of property rights, which is guaranteed by the Constitution. Under the present Swiss constitutional arrangement, authorities (municipalities) are required to take into account landowners' interests when implementing their spatial planning policy. In other words, the institution of property rights cannot be restricted easily in order to implement zoning plans and planning projects. This situation causes many problems. One of them is the gap between the way land is really used by the landowners and the way land should be used based on zoning plans. In fact, zoning plans only describe how landowners should use their property. There is no sufficient provision for handling cases where the use is not in accordance with zoning plans. In particular, landowners may not be expropriated for a non-conforming use of the land. This situation often leads to the opening of new building areas in greenfields and urban sprawl, which is in contradiction with the goals set into the Federal Law on Spatial Planning. In order to identify legal strategies of intervention to solve the problem, our paper is structured into three main parts. Firstly, we make a short description of the Swiss land management regime. Then, we focus on an innovative land management approach designed to implement zoning plans in accordance with property rights. Finally, we present a case study that shows the usefulness of the presented land management approach in practice. We develop three main results. Firstly, the land management approach brings a mechanism to involve landowners in planning projects. Coordination principle between spatial planning goals and landowners' interests is the cornerstone of all the process. Secondly, the land use is improved both in terms of space and time. Finally, the institution of property rights is not challenged, since there is no expropriation and the market stays free.

Adaptive tracking of EEG oscillations.

Neuronal oscillations are an important aspect of EEG recordings. These oscillations are supposed to be involved in several cognitive mechanisms. For instance, oscillatory activity is considered a key component for the top-down control of perception. However, measuring this activity and its influence requires precise extraction of frequency components. This processing is not straightforward. Particularly, difficulties with extracting oscillations arise due to their time-varying characteristics. Moreover, when phase information is needed, it is of the utmost importance to extract narrow-band signals. This paper presents a novel method using adaptive filters for tracking and extracting these time-varying oscillations. This scheme is designed to maximize the oscillatory behavior at the output of the adaptive filter. It is then capable of tracking an oscillation and describing its temporal evolution even during low amplitude time segments. Moreover, this method can be extended in order to track several oscillations simultaneously and to use multiple signals. These two extensions are particularly relevant in the framework of EEG data processing, where oscillations are active at the same time in different frequency bands and signals are recorded with multiple sensors. The presented tracking scheme is first tested with synthetic signals in order to highlight its capabilities. Then it is applied to data recorded during a visual shape discrimination experiment for assessing its usefulness during EEG processing and in detecting functionally relevant changes. This method is an interesting additional processing step for providing alternative information compared to classical time-frequency analyses and for improving the detection and analysis of cross-frequency couplings.

A retrospective case-control study assessing the role of trabecular bone score in postmenopausal Caucasian women with osteopenia: analyzing the odds of vertebral fracture.

This case-control study assessed whether the trabecular bone score (TBS), determined from gray-level analysis of DXA images, might be of any diagnostic value, either alone or combined with bone mineral density (BMD), in the assessment of vertebral fracture risk among postmenopausal women with osteopenia. Of 243 postmenopausal Caucasian women, 50-80 years old, with BMD T-scores between -1.0 and -2.5, we identified 81 with osteoporosis-related vertebral fractures and compared them with 162 age-matched controls without fractures. Primary outcomes were BMD and TBS. For BMD, each incremental decrease in BMD was associated with an OR = 1.54 (95% CI = 1.17-2.03), and the AUC was 0.614 (0.550-0.676). For TBS, corresponding values were 2.53 (1.82-3.53) and 0.721 (0.660-0.777). The difference in the AUC for TBS vs. BMD was statistically significant (p = 0.020). The OR for (TBS + BMD) was 2.54 (1.86-3.47) and the AUC 0.732 (0.672-0.787). In conclusion, the TBS warrants a closer look to see whether it may be of clinical usefulness in the determination of fracture risk in postmenopausal osteopenic women.

Microbiota present in cystic fibrosis lungs as revealed by whole genome sequencing.

Determination of the precise composition and variation of microbiota in cystic fibrosis lungs is crucial since chronic inflammation due to microorganisms leads to lung damage and ultimately, death. However, this constitutes a major technical challenge. Culturing of microorganisms does not provide a complete representation of a microbiota, even when using culturomics (high-throughput culture). So far, only PCR-based metagenomics have been investigated. However, these methods are biased towards certain microbial groups, and suffer from uncertain quantification of the different microbial domains. We have explored whole genome sequencing (WGS) using the Illumina high-throughput technology applied directly to DNA extracted from sputa obtained from two cystic fibrosis patients. To detect all microorganism groups, we used four procedures for DNA extraction, each with a different lysis protocol. We avoided biases due to whole DNA amplification thanks to the high efficiency of current Illumina technology. Phylogenomic classification of the reads by three different methods produced similar results. Our results suggest that WGS provides, in a single analysis, a better qualitative and quantitative assessment of microbiota compositions than cultures and PCRs. WGS identified a high quantity of Haemophilus spp. (patient 1) or Staphylococcus spp. plus Streptococcus spp. (patient 2) together with low amounts of anaerobic (Veillonella, Prevotella, Fusobacterium) and aerobic bacteria (Gemella, Moraxella, Granulicatella). WGS suggested that fungal members represented very low proportions of the microbiota, which were detected by cultures and PCRs because of their selectivity. The future increase of reads' sizes and decrease in cost should ensure the usefulness of WGS for the characterisation of microbiota.

Imaging for trans-catheter pulmonary stent-valve implantation without angiography: role of intravascular ultrasound.

Patients with stenosed biologic pulmonary conduits require redo cardiac surgery to prevent severe right ventricular dysfunction. Following the latest trends, the trans-catheter pulmonary stent-valve implantation represents a new fascinating alternative carrying a lower operative risk, compared with the standard open-heart re-intervention. Traditionally, the pulmonary stent valve is positioned off pump, under fluoroscopic control, and requires angiographies. However, alternative tools not requiring contrast injections for the intra-operative cardiac imaging have to be also considered strongly. The usefulness of intravascular ultrasound for the positioning of aortic endoprosthesis has already been proven in previous reports and, following the same principle, we have started to routinely implant balloon-expandable stent valves (Edwards Sapien? THV) in stenosed pulmonary valve conduits using intravascular ultrasound for the stent-valve positioning without angiography. We describe the intra-operative intravascular imaging technique with technical details.

Effectiveness of a brief integrative multiple substance use intervention among young men with and without booster sessions.

Brief interventions (BI) commonly employ screening and target a single substance. Multi-substance interventions are a more adequate reflection of risk behaviors in adolescents and young adults. Systematic screening complicates BI in many settings. The effectiveness of a voluntary multi-substance intervention among 19-year-old men and the incremental impact of booster sessions were analyzed. Participants were enrolled during mandatory army conscription in Switzerland. Compared with 461 controls, 392 BI subjects showed reduced substance use on 10 of 12 measures (4 tobacco, 4 cannabis, and 2 alcohol measures). Between-group effects were small and non-significant (except for cannabis use prevalence). Three-month booster sessions were not effective and even contraindicated. The usefulness of targeting multi-substances during BIs without prior screening depends on the value of small effects. The addition of booster sessions was not effective and therefore is not recommended.

Combination of carbon isotope ratio with hydrogen isotope ratio determinations in sports drug testing.

Carbon isotope ratio (CIR) analysis has been routinely and successfully applied to doping control analysis for many years to uncover the misuse of endogenous steroids such as testosterone. Over the years, several challenges and limitations of this approach became apparent, e.g., the influence of inadequate chromatographic separation on CIR values or the emergence of steroid preparations comprising identical CIRs as endogenous steroids. While the latter has been addressed recently by the implementation of hydrogen isotope ratios (HIR), an improved sample preparation for CIR avoiding co-eluting compounds is presented herein together with newly established reference values of those endogenous steroids being relevant for doping controls. From the fraction of glucuronidated steroids 5β-pregnane-3α,20α-diol, 5α-androst-16-en-3α-ol, 3α-Hydroxy-5β-androstane-11,17-dione, 3α-hydroxy-5α-androstan-17-one (ANDRO), 3α-hydroxy-5β-androstan-17-one (ETIO), 3β-hydroxy-androst-5-en-17-one (DHEA), 5α- and 5β-androstane-3α,17β-diol (5aDIOL and 5bDIOL), 17β-hydroxy-androst-4-en-3-one and 17α-hydroxy-androst-4-en-3-one were included. In addition, sulfate conjugates of ANDRO, ETIO, DHEA, 3β-hydroxy-5α-androstan-17-one plus 17α- and androst-5-ene-3β,17β-diol were considered and analyzed after acidic solvolysis. The results obtained for the reference population encompassing n = 67 males and females confirmed earlier findings regarding factors influencing endogenous CIR. Variations in sample preparation influenced CIR measurements especially for 5aDIOL and 5bDIOL, the most valuable steroidal analytes for the detection of testosterone misuse. Earlier investigations on the HIR of the same reference population enabled the evaluation of combined measurements of CIR and HIR and its usefulness regarding both steroid metabolism studies and doping control analysis. The combination of both stable isotopes would allow for lower reference limits providing the same statistical power and certainty to distinguish between the endo- or exogenous origin of a urinary steroid.

Impact on assertivity of a social skills training with adolescents suffering from psychotic or anxiety/mood disorders: An exploratory study

During adolescence numerous of important social abilities are acquired within interactions with peers. Severe psychiatric disorders interfere with the acquisition of these social skills. For example, due to excessive shyness, adolescents with psychiatric disorders may not experiment positive social interactions. Social skills training (SKT) may help adolescents to remediate to these diffi culties. This exploratory study aims to assess the SKT's effect on assertivity, in a population of adolescents presenting psychiatric disorder and attending a day care unit for adolescents. The SKT, delivered in group, deals with different themes such as contact, conversation, problem solving, confl ict, fail, success, learning, effort, separation, breakdown, and project. In this context, 38 adolescents (19 suffering from anxiety / mood disorder and 19 suffering from psychotic disorder) rate their level of assertivity before and after a SKT with the Rathus assertivity scale. This scale allows to differentiate between inhibited, assertive and assertiveaggressive adolescents. Results showed a general improvement on assertivity after the SKT. More specifi cally, adolescents suffering from anxiety disorder and the 'inhibited' adolescents showed the higher benefi t from the SKT. Thus, two hours per week of SKT seems to enhance social abilities in a population with severe psychiatric disorders. More specifi - cally, adolescents with anxiety / mood disorders reported more benefi ts of the SKT on their assertivity. Nevertheless, adolescents with psychotic disorders did not report strong benefi ts from the SKT despite the improvement observed at a clinical level. This observation raises questions about the usefulness of self-reported questionnaire to measure such benefi t for adolescents with psychosis.

Age differences in biological monitoring of chemical exposure: a tentative description using a toxicokinetic model

AIM: Specific factors responsible for interindividual variability should be identified and their contribution quantified to improve the usefulness of biological monitoring. Among others, age is an easily identifiable determinant, which could play an important impact on biological variability. MATERIALS AND METHODS: A compartmental toxicokinetic model developed in previous studies for a series of metallic and organic compounds was applied to the description of age differences. Young male physiological and metabolic parameters, based on Reference Man information, were taken from preceding studies and were modified to take into account age based on available information about age differences. RESULTS: Numerical simulation using the kinetic model with the modified parameters indicates in some cases important differences due to age. The expected changes are mostly of the order of 10-20%, but differences up to 50% were observed in some cases. CONCLUSION: These differences appear to depend on the chemical and on the biological entity considered. Further work should be done to improve our estimates of these parameters, by considering for example uncertainty and variability in these parameters. [Authors]

First consumption ever of multiple substances: applying an expert-based taxonomy to a Swiss national sample of adolescents.

The use of multiple legal and illegal substances by adolescents is a growing concern in all countries, but since no consensus about a taxonomy did emerge yet, it is difficult to understand the different patterns of consumption and to implement tailored prevention and treatment programs directed towards specific subgroups of the adolescent population. Using data from a Swiss survey on adolescent health, we analyzed the age at which ten legal and illegal substances were consumed for the first time ever by applying a method combining the strength of both automatic clustering and use of substance experts. Results were then compared to 30 socio-economic factors to establish the usefulness of and to validate our taxonomy. We also analyzed the succession of substance first use for each group. The final taxonomy consists of eight groups ranging from non-consumers to heavy drug addicts. All but four socio-economic factors were significantly associated with the taxonomy, the strongest associations being observed with health, behavior, and sexuality factors. Numerous factors influence adolescents in their decision to first try substances or to use them on a regular basis, and no factor alone can be considered as an absolute marker of problematic behavior regarding substance use. Different processes of experimentation with substances are associated with different behaviors, therefore focusing on only one substance or only one factor is not efficient. Prevention and treatment programs can then be tailored to address specific issues related to different youth subgroups.

Allergic bronchopulmonary aspergillosis: the hunt for a diagnostic serological marker in cystic fibrosis patients.

The diagnosis of allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis patients remains challenging, mainly owing to overlapping symptoms of the underlying lung disease with clinical symptoms of ABPA. In addition, a varying mixture of diagnostic criteria, including clinical status, radiological findings and immunological measurements, has led to confusion and differing recommendations. In order to help simplify as well as standardize the diagnostic criteria for ABPA, different serological markers have been evaluated in the last 20 years and their usefulness has been assessed in many clinical studies. This review presents current diagnostic criteria of ABPA, with a special focus on serum markers supporting the diagnosis and explains why the hunt for a serological marker for ABPA is still ongoing.

Multiple Kernel Learning of Environmental Data. Case study: Analysis and Mapping of Wind Fields

The paper presents the Multiple Kernel Learning (MKL) approach as a modelling and data exploratory tool and applies it to the problem of wind speed mapping. Support Vector Regression (SVR) is used to predict spatial variations of the mean wind speed from terrain features (slopes, terrain curvature, directional derivatives) generated at different spatial scales. Multiple Kernel Learning is applied to learn kernels for individual features and thematic feature subsets, both in the context of feature selection and optimal parameters determination. An empirical study on real-life data confirms the usefulness of MKL as a tool that enhances the interpretability of data-driven models.