Genetic variation in WNT9B increases relapse hazard in Multiple Sclerosis

Objective: Many multiple sclerosis (MS) genetic susceptibility variants have been identified, but understanding disease heterogeneity remains a key challenge. Relapses are a core feature of MS and a common primary outcome of clinical trials, with prevention of relapses benefiting patients immediately and potentially limiting long-term disability accrual. We aim to identify genetic variation associated with relapse hazard in MS by analyzing the largest study population to date.Methods: We performed a genomewide association study (GWAS) in a discovery cohort and investigated the genomewide significant variants in a replication cohort. Combining both cohorts, we captured a total of 2,231 relapses occurring before the start of any immunomodulatory treatment in 991 patients. For assessing time to relapse, we applied a survival analysis utilizing Cox proportional hazards models. We also investigated the association between MS genetic risk scores and relapse hazard and performed a gene ontology pathway analysis.Results: The low-frequency genetic variant rs11871306 within WNT9B reached genomewide significance in predicting relapse hazard and replicated (meta-analysis hazard ratio (HR) = 2.15, 95% confidence interval (CI) = 1.70-2.78, p = 2.07 × 10-10 ). A pathway analysis identified an association of the pathway "response to vitamin D" with relapse hazard (p = 4.33 × 10-6 ). The MS genetic risk scores, however, were not associated with relapse hazard.Interpretation: Genetic factors underlying disease heterogeneity differ from variants associated with MS susceptibility. Our findings imply that genetic variation within the Wnt signaling and vitamin D pathways contributes to differences in relapse occurrence. The present study highlights these cross-talking pathways as potential modulators of MS disease activity

Estimation of hydraulic conductivity and its uncertainty from grain-size data using GLUE and artificial neural networks

peer reviewedaudience: researcher, professionalVarious approaches exist to relate saturated hydraulic conductivity (Ks) to grain-size data. Most methods use a single grain-size parameter and hence omit the information encompassed by the entire grain-size distribution. This study compares two data-driven modelling methods, i.e.multiple linear regression and artificial neural networks, that use the entire grain-size distribution data as input for Ks prediction. Besides the predictive capacity of the methods, the uncertainty associated with the model predictions is also evaluated, since such information is important for stochastic groundwater flow and contaminant transport modelling. Artificial neural networks (ANNs) are combined with a generalized likelihood uncertainty estimation (GLUE) approach to predict Ks from grain-size data. The resulting GLUE-ANN hydraulic conductivity predictions and associated uncertainty estimates are compared with those obtained from the multiple linear regression models by a leave-one-out cross-validation. The GLUE-ANN ensemble prediction proved to be slightly better than multiple linear regression. The prediction uncertainty, however, was reduced by half an order of magnitude on average, and decreased at most by an order of magnitude. This demonstrates that the proposed method outperforms classical data-driven modelling techniques. Moreover, a comparison with methods from literature demonstrates the importance of site specific calibration. The dataset used for this purpose originates mainly from unconsolidated sandy sediments of the Neogene aquifer, northern Belgium. The proposed predictive models are developed for 173 grain-size -Ks pairs. Finally, an application with the optimized models is presented for a borehole lacking Ks data

Development and analysis of the Soil Water Infiltration Global database.

In this paper, we present and analyze a novel global database of soil infiltration measurements, the Soil Water Infiltration Global (SWIG) database. In total, 5023 infiltration curves were collected across all continents in the SWIG database. These data were either provided and quality checked by the scientists who performed the experiments or they were digitized from published articles. Data from 54 different countries were included in the database with major contributions from Iran, China, and the USA. In addition to its extensive geographical coverage, the collected infiltration curves cover research from 1976 to late 2017. Basic information on measurement location and method, soil properties, and land use was gathered along with the infiltration data, making the database valuable for the development of pedotransfer functions (PTFs) for estimating soil hydraulic properties, for the evaluation of infiltration measurement methods, and for developing and validating infiltration models. Soil textural information (clay, silt, and sand content) is available for 3842 out of 5023 infiltration measurements (~76%) covering nearly all soil USDA textural classes except for the sandy clay and silt classes. Information on land use is available for 76% of the experimental sites with agricultural land use as the dominant type (~40%). We are convinced that the SWIG database will allow for a better parameterization of the infiltration process in land surface models and for testing infiltration models. All collected data and related soil characteristics are provided online in *.xlsx and *.csv formats for reference, and we add a disclaimer that the database is for public domain use only and can be copied freely by referencing it. Supplementary data are available at https://doi.org/10.1594/PANGAEA.885492 (Rahmati et al., 2018). Data quality assessment is strongly advised prior to any use of this database. Finally, we would like to encourage scientists to extend and update the SWIG database by uploading new data to it

Derivation of flow and transport parameters from outcropping sediments of the Neogene aquifer, Belgium

Centimetre-scale saturated hydraulic conductivities (K) are derived from air permeability measurements on a selection of outcrops of the Neogene aquifer in the Campine area, Belgium. Outcrop sediments are of Miocene to Quaternary age and have a marine to continental origin. Grain size analyses for the same outcrops and corresponding K predictions using previously developed models are also presented. We discuss outcrop hydrogeological properties and quantify the heterogeneity within the outcrops in detail using geostatistical variography. Moreover, outcrop-scale K values, their anisotropy and dispersivities are numerically calculated as a means to upscale such small-scale measurements to a larger scale commensurate with the scale of flow and transport modelling. By studying the small-scale variability as observed in outcrops, we gain crucial understanding of the larger-scale behaviour of the corresponding hydrogeological units within the Neogene aquifer, the most important groundwater reservoir of Flanders. The results of this study will equally improve conceptual hydrogeological model building and parameterization

Air permeametry on outcrop analogues: a composite image of the Neogene aquifer, Belgium

Saturated hydraulic conductivity (Ks) is one of the most important parameters determining groundwater flow and contaminant transport in both unsaturated and saturated porous media. While several well-established laboratory methods exist for determining Ks, in-situ measurements of this parameter remain very complex. Since the 50’s, and increasingly from the late 80’s, air permeameters are being used effectively as an indirect method to determine Ks on outcrop sediments. In this paper, the heterogeneity within outcrop sediments that are analogues for the Neogene aquifer hydrostratigraphic units in northern Belgium is studied with a hand-held air permeameter. This aquifer, representing a major groundwater source, consists of several sandy geological units from Miocene to Pleistocene age with a marine to continental origin. Moreover, it plays an important role in the Belgian deep geological radwaste disposal studies, and is the subject of a safety assessment for a future low-level radwaste surface repository. To characterise the variability between and within the different lithostratigraphical aquifer units, 804 air permeability measurements at cm-scale were performed on several outcrops that are analogues for the sandy aquifer sediments and a highly heterogeneous aquitard. Equivalent meter-scale Ks tensors were calculated numerically through the law of flow conservation to obtain the vertical anisotropy factor. The off-diagonal tensor components were shown to be negligible. To validate the air permeametry data, 18 additional constant head permeameter tests on 100 cm3 cores and 27 grain size analyses based Ks assessments were performed on outcrop material. The comparison indicates that hand-held air permeameters are very effective and useful tools to characterise the magnitude of hydraulic conductivity, as well as it’s small-scale variability and anisotropy, on a broad range of sediment types. However, a comparison with data from a previous borehole campaign on similar though not identical aquifer sediments reveals that the Ks values predicted at the outcrops are systematically higher by at least a factor of 10 than the corresponding Ks distributions determined from the borehole cores. One explanation is the weathering state of several-cm thick clay lenses, i.e. much less weathered in the aquitard than in the analogous outcrop with correspondingly lower conductivities for the aquitard. This shows that transferring outcrop data to the subsurface should be done with care because of different degrees of compaction, weathering states, etc

Long-term evolution of the multi-layer cover: project near surface disposal of category a waste at Dessel

During the current project phase of the disposal of category A waste – short-lived low and intermediate level waste – ONDRAF/NIRAS must, following the governmental decision of 23 June 2006, develop a near surface disposal facility in Dessel, which is based on the near surface facility disposal design developed by the STOLA-Dessel partnership during the previous preliminary project phase. The present report is an integral part of the discussions between ONDRAF/NIRAS and the regulatory body FANC (Federal Agency for Nuclear Control) on the methodology and tools used for the long-term radiological safety assessments. These discussions aim in general at informing and asking the advice of the FANC about the long-term radiological safety assessment methodology, the general principles to be employed in the treatment of uncertainties, and the scenarios that will be considered in assessing the long-term safety of the near surface disposal system. Safety is the most important and driving requirement in planning and implementing such facilities. This report NIROND-TR 2010-03 describes the components of the multi-layer cover and their functioning and provides an estimate of their long-term evolution. Gradual degradation processes and major disruptive events are described. Examples of the latter are earthquakes and erosion. Long-term evolution of multi-layer cover performance is governed by two components: the earth cover - a series of natural materials including sand, gravel, clay - and (mainly) a fiber reinforced concrete slab which forms the structural basis of the earth cover. The multi-layer cover fulfills the safety function limitation of water infiltration through the prevention barriers (R2a). It is difficult to define an exact timing for failure of the multi-layer cover to fulfill the safety function limitation of water infiltration through the prevention barriers. Gradual degradation processes alone would not quickly deteriorate the effectiveness of the earth cover, certainly not the first few thousands of years. However, its behaviour – after release of nuclear regulatory control - will be mainly affected by arthquakes, as the earth cover is not designed to withstand design basis earthquakes (DBE). Available information on impact assessments for earthquakes indicates that disruption of top layers will happen within the next 1 000 years; performance may further deteriorate as a result of sequences of earthquakes in combination with extreme erosion events. These observations have led to the decision to conservatively put the performance of the earth cover to zero as concerns safety function R2a at the end of the nuclear regulatory control phase. Infiltration in the earth cover is assumed to increase to its maximum value, determined by the evapotranspiration of any remaining vegetation (i.e., net rainfall = total precipitation - evapotranspiration). Unlike the earth cover, the fiber reinforced concrete slab will resist design basis earthquakes, although it is not designed to resist beyond design basis earthquakes (BDBE). A BDBE with a return period of 20 000 years and a probability of non-exceedance of 4% at 816 y AP was considered. It is assumed that when the BDBE happens, i.e. at 816 years AP, the fiber reinforced concrete slab will no longer be effective in reducing infiltrating water. From then onwards, the overall multi-layer cover infiltration is maximal, determined by the net rainfall. For the multi-layer cover as a whole, a gradual increase in permeability (and hence infiltration) is assumed from the end of the nuclear regulatory control phase till the time of complete failure of R2a. This assumption will be imposed for safety and capacity calculations. For screening calculations, a much more conservative approach is taken: complete failure 40 years after start of cover placement

Upscaling a chemical screening approach to assess impacts of shale, tight and deep gas development on unconfined aquifers

Study region: Beetaloo Sub-basin (Northern Territory) and Cooper Basin (Queensland and South Australia), Australia. Study focus: A chemical screening approach was upscaled to regional scale to assess impacts of chemical spills on unconfined aquifers. Chemical dilution factors (DFs) were developed from hydrogeochemical modelling to predict the impact of hypothetical chemical spills as part of a hazard identification process from the potential development of shale, tight and deep gas in the Beetaloo Sub-basin and Cooper Basin. Advection and dispersion modelling (non-reactive HYDRUS 1-D) was used as a conservative screening approach to estimate DFs vertically through the unsaturated zone and laterally through the unconfined aquifers. The results were upscaled to basin scale, based on spatially distributed soil, groundwater and aquifer information, including the presence of karsts. The spatial approach successfully defined areas that required additional assessment prior to any future development. New hydrological insights for the region: For chemical concentrations from surface spills to not exceed ecotoxicological thresholds at the water table, a DF of > 1000 was required. Screening areas with a DF of > 1000 constrained the area of concern for aquifer contamination from spills to 0.3 % and 14 % of the Beetaloo and Cooper regions respectively. The likelihood for long term impacts from potential undetected chemical leaks on groundwater dependent ecosystems was assessed to < 0.1 % of the Cooper region due to dilution in lateral groundwater flow, but 18 % of the Beetaloo region