Exome Sequencing Identifies Susceptibility Loci for Sarcoidosis Prognosis

Many sarcoidosis-associating immunological genes have been shown to be shared between other immune-mediated diseases. In Finnish sarcoidosis patients, good prognosis subjects more commonly have HLA-DRB1*03:01 and/or HLA-DRB1*04:01-DPB1*04:01 haplotype, but no marker for persistent disease have been found. The objective was to further pinpoint genetic differences between prognosis subgroups in relation to the HLA markers. Whole-exome sequencing was conducted for 72 patients selected based on disease activity (resolved disease, n = 36; persistent disease, n = 36). Both groups were further divided by the HLA markers (one/both markers, n = 18; neither of the markers, n = 18). The Finnish exome data from the Genome Aggregation Database was used as a control population in the WES sample. Statistical analyses included single-variant analysis for common variants and gene level analysis for rare variants. We attempted to replicate associated variants in 181 Finnish sarcoidosis patients and 150 controls. An association was found in chromosome 1p36.21 (AADACL3 and C1orf158), which has recently been associated with sarcoidosis in another WES study. In our study, variations in these genes were associated with resolved disease (AADACL3, p = 0.0001 and p = 0.0003; C1orf158, p = 7.03E-05). Another interesting chromosomal region also peaked, Leucocyte Receptor Complex in 19q13.42, but the association diminished in the replication sample. In conclusion, this WES study supports the previously found association in the region 1p36.21. Furthermore, a novel to sarcoidosis region was found, but additional studies are warranted to verify this association.Peer reviewe

Disease marker combination enhances patient characterization in the Finnish sarcoidosis patients

Sarcoidosis is an inflammatory disease of unknown etiology and multiple clinical phenotypes. Clinical manifestations range from asymptomatic disease to severe loss-of-function leading to the hypothesis that sarcoidosis might not be just one disease, but consists of several distinct disease entities each with potentially distinct genetic associations. We have previously demonstrated that in our series HLADRB1* 03:01 and haplotype HLA-DRB1*04:01-DPB1*04:01 are associated with good prognosis sarcoidosis. In our recent work, we found a novel SNP (rs9905945) in the 50upstream region of the ACE gene to be associated with favorable disease prognosis as well. The main objective of this study was to expand the previous results and analyse combined influence of the found ACE SNP rs9905945 with the protective HLA markers HLADRB1*03:01 and HLA-DRB1*04:01-DPB1*04:01 in 188 Finnish sarcoidosis patients (resolved disease, n = 90; persistent disease, n = 98). When combining the frequencies of the rs9905945 and of the HLA markers, the strongest association was found for a combination of either/or both HLA markers and rs9905945 for good disease prognosis (37.1% in resolved vs. 11.3% in persistent, p <0.001, OR = 4.61, (95% CI 2.15-9.86)). In conclusion, we discovered that a combination of the ACE SNP rs9905945 and HLA markers enhance the accuracy for predicting disease course in Finnish sarcoidosis patients further characterizing genetic differences between Finnish sarcoidosis patients with different prognosis. (c) 2017 Elsevier Ltd. All rights reserved.Peer reviewe

Which fractures are imaged with Ground Penetrating Radar? Results from an experiment in the Äspö Hardrock Laboratory, Sweden

Identifying fractures in the subsurface is crucial for many geomechanical and hydrogeological applications. Here, we assess the ability of the Ground Penetrating Radar (GPR) method to image open fractures with sub-mm apertures in the context of future deep disposal of radioactive waste. GPR experiments were conducted in a tunnel located 410 m below sea level within the Äspö Hard Rock Laboratory (Sweden) using 3-D surface-based acquisitions (3.4 m × 19 m) with 160 MHz, 450 MHz and 750 MHz antennas. The nature of 17 identified GPR reflections was analyzed by means of three new boreholes (BH1-BH3; 9–9.5 m deep). Out of 21 injection and outflow tests in packed-off 1-m sections, only five provided responses above the detection threshold with the maximum transmissivity reaching 7.0 × 10−10 m2/s. Most GPR reflections are situated in these permeable regions and their characteristics agree well with core and Optical Televiewer data. A 3-D statistical fracture model deduced from fracture traces on neighboring tunnel walls show that the GPR data mainly identify fractures with dips between 0 and 25°. Since the GPR data are mostly sensitive to open fractures, we deduce that the surface GPR method can identify 80% of open sub-horizontal fractures. We also find that the scaling of GPR fractures in the range of 1–10 m2 agrees well with the statistical model distribution indicating that fracture lengths are preserved by the GPR imaging (no measurement bias). Our results suggests that surface-GPR carries the resolution needed to identify the most permeable sub-horizontal fractures even in very low-permeability formations, thereby, suggesting that surface-GPR could play an important role in geotechnical workflows, for instance, for industrial-scale siting of waste canisters below tunnel floors in nuclear waste repositories

Inhaler Competence and Patient Satisfaction with Easyhaler: Results of Two Real-Life Multicentre Studies in Asthma and COPD.

OBJECTIVE: The aim of this study was to investigate patients' inhaler competence and satisfaction with the Easyhaler(R) dry powder inhaler. DESIGN: Two open, uncontrolled, non-randomised studies. SETTING: Real life based on patients attending 56 respiratory clinics in Hungary. PARTICIPANTS: Patients with asthma or chronic obstructive pulmonary disease (COPD) (n = 1016). INTERVENTION: In a 3-month study, adult patients (age range 18-88 years; n = 797) received twice-daily inhalations of formoterol via Easyhaler(R), and in a consequential study (from one visit to another, with 3-12 months in-between) children and adolescents (age range 4-17 years; n = 219) received salbutamol via Easyhaler(R) as needed. MAIN OUTCOME MEASURES: Control of six Easyhaler(R) handling steps and patients' satisfaction with Easyhaler(R) based on questionnaires. RESULTS: Correct performances (minimum and maximum of the six steps) were noticed after one demonstration in 92-98 % of the adults, 87-99 % of the elderly, 81-96 % of the children and 83-99 % of the adolescents. These figures had markedly increased at the last visit. Repeat instructions were necessary in 26 % of the cases. Investigators found Easyhaler(R) easy to teach in 87 % of the patients and difficult in only 0.5 %. Patients found Easyhaler(R) easy to learn and use, and the patients' (and parents') satisfaction with the inhaler was very high. Lung function values [forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), peak expiratory flow (PEF)] improved statistically significantly during the studies, indicating good inhaler competence and treatment adherence. CONCLUSION: Investigators found Easyhaler(R) easy to teach and patients found it easy to use, and their satisfaction with the device was high

Data evaluation and numerical modeling of hydrological interactions between active layer, lake and talik in a permafrost catchment, Western Greenland

SummaryThis study investigates annual water balance conditions and their spatiotemporal variability under a wide variety of atmospheric driving conditions in the periglacial permafrost catchment of Two Boat Lake in Western Greenland. The study uses and combines a comprehensive hydrological multi-parameter dataset measured at the site with site conceptualization and numerical model development, application and testing. The model result reproduces measured lake and groundwater levels, as well as observations made by time-lapse cameras. The results highlights the importance of numerical modeling that takes into account and combines evapotranspiration with other surface and subsurface hydrological processes at various depths, in order to quantitatively understand and represent the dynamics and complexity of the interactions between meteorology, active layer hydrology, lakes, and unfrozen groundwater below permafrost in periglacial catchments. Regarding these interactions, the water flow between the studied lake and a through talik within and beneath it is found to be small compared to other water balance components. The modeling results show that recharge and discharge conditions in the talik can shift in time, while the lake and active layer conditions in the studied catchment are independent of catchment-external landscape features, such as the unfrozen groundwater system below the permafrost and the nearby continental-scale ice sheet

The Finnish experience to save asthma costs by improving care in 1987-2013

The Finnish National Asthma Program 1994-2004 markedly improved asthma care in the 1990s. We evaluated the changes in costs during 26 years from 1987 to 2013. Direct and indirect costs were calculated by using data from national registries. Costs from both the societal and patient perspectives were included. The costs were based on patients with persistent, physician-diagnosed asthma verified by lung function measurements. We constructed minimum and maximum scenarios to assess the effect of improved asthma care on total costs. The number of patients with persistent asthma in the national drug reimbursement register increased from 83,000 to 247,583. Improved asthma control reduced health care use and disability, resulting in major cost savings. Despite a 3-fold increase in patients, the total costs decreased by 14%, from (SIC)222 million to (SIC)191 million. Costs for medication and primary care visits increased, but overall annual costs per patient decreased by 72%, from (SIC)2656 to (SIC)749. The theoretical total cost savings for 2013, comparing actual with predicted costs, were between (SIC)120 and (SIC)475 million, depending on the scenario used. The Finnish Asthma Program resulted in significant cost savings at both the societal and patient levels during a 26-year period.Peer reviewe

Microtomography-based Inter-Granular Network for the simulation of radionuclide diffusion and sorption in a granitic rock

Field investigation studies, conducted in the context of safety analyses of deep geological repositories for nuclear waste, have pointed out that in fractured crystalline rocks sorbing radionuclides can diffuse surprisingly long distances deep into the intact rock matrix; i.e. much longer distances than those predicted by reactive transport models based on a homogeneous description of the properties of the rock matrix. Here, we focus on cesium diffusion and use detailed micro characterisation data, based on micro computed tomography, along with a grain-scale Inter-Granular Network model, to offer a plausible explanation for the anomalously long cesium penetration profiles observed in these in-situ experiments. The sparse distribution of chemically reactive grains (i.e. grains belonging to sorbing mineral phases) is shown to have a strong control on the diffusive patterns of sorbing radionuclides. The computed penetration profiles of cesium agree well with an analytical model based on two parallel diffusive pathways. This agreement, along with visual inspection of the spatial distribution of cesium concentration, indicates that for sorbing radionuclides the medium indeed behaves as a composite system, with most of the mass being retained close to the injection boundary and a non-negligible part diffusing faster along preferential diffusive pathways.Peer reviewe

Use of groundwater lifetime expectancy for the performance assessment of a deep geologic waste repository: 1. Theory, illustrations, and implications

Long-term solutions for the disposal of toxic wastes usually involve isolation of the wastes in a deep subsurface geologic environment. In the case of spent nuclear fuel, if radionuclide leakage occurs from the engineered barrier, the geological medium represents the ultimate barrier that is relied upon to ensure safety. Consequently, an evaluation of radionuclide travel times from a repository to the biosphere is critically important in a performance assessment analysis. In this study, we develop a travel time framework based on the concept of groundwater lifetime expectancy as a safety indicator. Lifetime expectancy characterizes the time that radionuclides will spend in the subsurface after their release from the repository and prior to discharging into the biosphere. The probability density function of lifetime expectancy is computed throughout the host rock by solving the backward-in-time solute transport adjoint equation subject to a properly posed set of boundary conditions. It can then be used to define optimal repository locations. The risk associated with selected sites can be evaluated by simulating an appropriate contaminant release history. The utility of the method is illustrated by means of analytical and numerical examples, which focus on the effect of fracture networks on the uncertainty of evaluated lifetime expectancy.Comment: 11 pages, 8 figures; Water Resources Research, Vol. 44, 200