Estimation of reference curves for the urinary steroid metabolome in the first year of life in healthy children: tracing the complexity of human postnatal steroidogenesis

CONTEXT Complex steroid disorders such as P450 oxidoreductase deficiency or apparent cortisone reductase deficiency may be recognized by steroid profiling using chromatographic mass spectrometric methods. These methods are highly specific and sensitive, and provide a complete spectrum of steroid metabolites in a single measurement of one sample which makes them superior to immunoassays. The steroid metabolome during the fetal-neonatal transition is characterized by a) the metabolites of the fetal-placental unit at birth, b) the fetal adrenal androgens until its involution 3-6 months postnatally, and c) the steroid metabolites produced by the developing endocrine organs. All these developmental events change the steroid metabolome in an age- and sex-dependent manner during the first year of life. OBJECTIVE The aim of this study was to provide normative values for the urinary steroid metabolome of healthy newborns at short time intervals in the first year of life. METHODS We conducted a prospective, longitudinal study to measure 67 urinary steroid metabolites in 21 male and 22 female term healthy newborn infants at 13 time-points from week 1 to week 49 of life. Urine samples were collected from newborn infants before discharge from hospital and from healthy infants at home. Steroid metabolites were measured by gas chromatography-mass spectrometry (GC-MS) and steroid concentrations corrected for urinary creatinine excretion were calculated. RESULTS 61 steroids showed age and 15 steroids sex specificity. Highest urinary steroid concentrations were found in both sexes for progesterone derivatives, in particular 20α-DH-5α-DH-progesterone, and for highly polar 6α-hydroxylated glucocorticoids. The steroids peaked at week 3 and decreased by ∼80% at week 25 in both sexes. The decline of progestins, androgens and estrogens was more pronounced than of glucocorticoids whereas the excretion of corticosterone and its metabolites and of mineralocorticoids remained constant during the first year of life. CONCLUSION The urinary steroid profile changes dramatically during the first year of life and correlates with the physiologic developmental changes during the fetal-neonatal transition. Thus detailed normative data during this time period permit the use of steroid profiling as a powerful diagnostic tool.

Addressing Multilevel Program Complexity by Evaluation Design

In this paper, we present the evaluation design for a complex multilevel program recently introduced in Switzerland. The evaluation embraces the federal level, the cantonal program level, and the project level where target groups are directly addressed. We employ Pawson and Tilley’s realist evaluation approach, in order to do justice to the varying context factors that impact the cantonal programs leading to varying effectiveness of the implemented activities. The application of the model to the canton of Uri shows that the numerous vertical and horizontal relations play a crucial role for the program’s effectiveness. As a general learning for the evaluation of complex programs, we state that there is a need to consider all affected levels of a program and that no monocausal effects can be singled out in programs where multiple interventions address the same problem. Moreover, considering all affected levels of a program can mean going beyond the borders of the actual program organization and including factors that do not directly interfere with the policy delivery as such. In particular, we found that the relationship between the cantonal and the federal level was a crucial organizational factor influencing the effectiveness of the cantonal program.

Sensitivity of the WRF model to PBL parametrisations and nesting techniques: evaluation of wind storms over complex terrain

Simulating surface wind over complex terrain is a challenge in regional climate modelling. Therefore, this study aims at identifying a set-up of the Weather Research and Forecasting Model (WRF) model that minimises system- atic errors of surface winds in hindcast simulations. Major factors of the model configuration are tested to find a suitable set-up: the horizontal resolution, the planetary boundary layer (PBL) parameterisation scheme and the way the WRF is nested to the driving data set. Hence, a number of sensitivity simulations at a spatial resolution of 2 km are carried out and compared to observations. Given the importance of wind storms, the analysis is based on case studies of 24 historical wind storms that caused great economic damage in Switzerland. Each of these events is downscaled using eight different model set-ups, but sharing the same driving data set. The results show that the lack of representation of the unresolved topography leads to a general overestimation of wind speed in WRF. However, this bias can be substantially reduced by using a PBL scheme that explicitly considers the effects of non-resolved topography, which also improves the spatial structure of wind speed over Switzerland. The wind direction, although generally well reproduced, is not very sensitive to the PBL scheme. Further sensitivity tests include four types of nesting methods: nesting only at the boundaries of the outermost domain, analysis nudging, spectral nudging, and the so-called re-forecast method, where the simulation is frequently restarted. These simulations show that restricting the freedom of the model to develop large-scale disturbances slightly increases the temporal agreement with the observations, at the same time that it further reduces the overestimation of wind speed, especially for maximum wind peaks. The model performance is also evaluated in the outermost domains, where the resolution is coarser. The results demonstrate the important role of horizontal resolution, where the step from 6 to 2 km significantly improves model performance. In summary, the combination of a grid size of 2 km, the non-local PBL scheme modified to explicitly account for non-resolved orography, as well as analysis or spectral nudging, is a superior combination when dynamical downscaling is aimed at reproducing real wind fields.

A study of the time complexity of an Elitist Genetic Algorithm used for associating optical observations of MEO and GEO Space Debris

Currently several thousands of objects are being tracked in the MEO and GEO regions through optical means. The problem faced in this framework is that of Multiple Target Tracking (MTT). In this context both the correct associations among the observations, and the orbits of the objects have to be determined. The complexity of the MTT problem is defined by its dimension S. Where S stands for the number of ’fences’ used in the problem, each fence consists of a set of observations that all originate from dierent targets. For a dimension of S ˃ the MTT problem becomes NP-hard. As of now no algorithm exists that can solve an NP-hard problem in an optimal manner within a reasonable (polynomial) computation time. However, there are algorithms that can approximate the solution with a realistic computational e ort. To this end an Elitist Genetic Algorithm is implemented to approximately solve the S ˃ MTT problem in an e cient manner. Its complexity is studied and it is found that an approximate solution can be obtained in a polynomial time. With the advent of improved sensors and a heightened interest in the problem of space debris, it is expected that the number of tracked objects will grow by an order of magnitude in the near future. This research aims to provide a method that can treat the correlation and orbit determination problems simultaneously, and is able to e ciently process large data sets with minimal manual intervention.

An ice-rich flow origin for the banded terrain in the Hellas basin, Mars

The interior of Hellas Basin displays a complex landscape and a variety of geomorphological domains. One of these domains, the enigmatic banded terrain covers much of the northwestern part of the basin. We use high-resolution (CTX and HiRISE) Digital Terrain Models to show that most of the complex viscous flowing behavior exhibited by the banded terrain is controlled by topography and flow-like interactions between neighboring banded terrain. Furthermore, the interior of the basin hosts several landforms suggestive of the presence of near-surface ice, which include polygonal patterns with elongated pits, scalloped depressions, isolated mounds and collapse structures. We suggest that thermal contraction cracking and sublimation of near-surface ice are responsible for the formation and the development of most of the ice-related landforms documented in Hellas. The relatively pristine form, lack of superposed craters, and strong association with the banded terrain, suggest an Amazonian (<3 Ga) age of formation for these landforms. Finally, relatively high surface pressures (above the triple point of water) expected in Hellas and summer-time temperatures often exceeding the melting point of water ice suggest that the basin may have recorded relatively “temperate” climatic conditions compared to other places on Mars. Therefore, the potentially ice-rich banded terrain may have deformed with lower viscosity and stresses compared to other locations on Mars, which may account for its unique morphology.

Complex geomorphologic assemblage of terrains in association with the banded terrain in Hellas basin, Mars

Hellas basin acts as a major sink for the southern highlands of Mars and is likely to have recorded several episodes of sedimentation and erosion. The north-western part of the basin displays a potentially unique Amazonian landscape domain in the deepest part of Hellas, called “banded terrain”, which is a deposit characterized by an alternation of narrow band shapes and inter-bands displaying a sinuous and relatively smooth surface texture suggesting a viscous flow origin. Here we use high-resolution (HiRISE and CTX) images to assess the geomorphological interaction of the banded terrain with the surrounding geomorphologic domains in the NW interior of Hellas to gain a better understanding of the geological evolution of the region as a whole. Our analysis reveals that the banded terrain is associated with six geomorphologic domains: a central plateau named Alpheus Colles, plain deposits (P1 and P2), reticulate (RT1 and RT2) and honeycomb terrains. Based on the analysis of the geomorphology of these domains and their cross-cutting relationships, we show that no widespread deposition post-dates the formation of the banded terrain, which implies that this domain is the youngest and latest deposit of the interior of Hellas. Therefore, the level of geologic activity in the NW Hellas during the Amazonian appears to have been relatively low and restricted to modification of the landscape through mechanical weathering, aeolian and periglacial processes. Thermophysical data and cross-cutting relationships support hypotheses of modification of the honeycomb terrain via vertical rise of diapirs such as ice diapirism, and the formation of the plain deposits through deposition and remobilization of an ice-rich mantle deposit. Finally, the observed gradual transition between honeycomb and banded terrain suggests that the banded terrain may have covered a larger area of the NW interior of Hellas in the past than previously thought. This has implications on the understanding of the evolution of the deepest part of Hellas.

Comparative Effectiveness and Safety of New-Generation Versus Early-Generation Drug-Eluting Stents According to Complexity of Coronary Artery Disease: A Patient-Level Pooled Analysis of 6,081 Patients.

OBJECTIVES The purpose of this study was to compare the 2-year safety and effectiveness of new- versus early-generation drug-eluting stents (DES) according to the severity of coronary artery disease (CAD) as assessed by the SYNTAX (Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) score. BACKGROUND New-generation DES are considered the standard-of-care in patients with CAD undergoing percutaneous coronary intervention. However, there are few data investigating the effects of new- over early-generation DES according to the anatomic complexity of CAD. METHODS Patient-level data from 4 contemporary, all-comers trials were pooled. The primary device-oriented clinical endpoint was the composite of cardiac death, myocardial infarction, or ischemia-driven target-lesion revascularization (TLR). The principal effectiveness and safety endpoints were TLR and definite stent thrombosis (ST), respectively. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated at 2 years for overall comparisons, as well as stratified for patients with lower (SYNTAX score ≤11) and higher complexity (SYNTAX score >11). RESULTS A total of 6,081 patients were included in the study. New-generation DES (n = 4,554) compared with early-generation DES (n = 1,527) reduced the primary endpoint (HR: 0.75 [95% CI: 0.63 to 0.89]; p = 0.001) without interaction (p = 0.219) between patients with lower (HR: 0.86 [95% CI: 0.64 to 1.16]; p = 0.322) versus higher CAD complexity (HR: 0.68 [95% CI: 0.54 to 0.85]; p = 0.001). In patients with SYNTAX score >11, new-generation DES significantly reduced TLR (HR: 0.36 [95% CI: 0.26 to 0.51]; p < 0.001) and definite ST (HR: 0.28 [95% CI: 0.15 to 0.55]; p < 0.001) to a greater extent than in the low-complexity group (TLR pint = 0.059; ST pint = 0.013). New-generation DES decreased the risk of cardiac mortality in patients with SYNTAX score >11 (HR: 0.45 [95% CI: 0.27 to 0.76]; p = 0.003) but not in patients with SYNTAX score ≤11 (pint = 0.042). CONCLUSIONS New-generation DES improve clinical outcomes compared with early-generation DES, with a greater safety and effectiveness in patients with SYNTAX score >11.