Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

Background Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. Findings A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13×10– ¹⁵) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65×10– ²⁰) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69×10– ¹²; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baseline disease severity. Interpretation This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. Funding UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR

Jedna z możliwości kształtowania charakterystyki rozpraszania energii w konstrukcji samochodu

The importance of safety among all the factors that are taken into account by customers when planning to buy a car has been highlighted. The main factors concerning the shaping of passive safety of a motor vehicle have been described and guidelines on the assessment methods to be employed at the research work in this field have been given. The energy dissipation vs. vehicle body deformation curves that may be observed at frontal collisions have been discussed. The curve shapes that may represent favourable or adverse impact of the energy dissipation characteristics on vehicle occupants. chances to survive inside the vehicle body have been indicated. To obtain favourable energy dissipation characteristics, the authors have proposed their own engineering solution in the design of longitudinal vehicle bodywork beams. The energy dissipation process was improved by reinforcing the longitudinal beam models with special elements welded to beam walls. An assumption was simultaneously made that the shape of the energy dissipation curve might be controlled by the type and arrangement of individual welds. The beam models were actually made and used as specimens tested on a strengthtesting machine at a certified laboratory at the BOSMAL Automotive Research and Development Institute in Bielsko-Biała. Energy dissipation curves determined for test specimens without and with the reinforcements have been presented herein. The test results obtained have been compared with each other and assessed in both qualitative and quantitative terms. The publication has been based on a student.s graduation work done by Michał Szuberla under the supervision of Kazimierz M. Romaniszyn.W publikacji opisano jak ważną rolę w wyborze samochodu przez klienta stanowi czynnik bezpieczeństwa. Opisano również główne czynniki dotyczące kształtowania bezpieczeństwa biernego samochodu i wytyczne badawcze dotyczące metod tej oceny. Omówiono spotykane przebiegi rozpraszania energii w zależności od przebiegu zgniotu nadwozia przy uderzeniu czołowym. Wskazano na przebiegi o charakterze korzystnym i niekorzystnym dla przeżycia ludzi wewnątrz nadwozia. Dla ukształtowania korzystnej charakterystyki rozpraszania energii zaproponowano własne rozwiązanie konstrukcyjne belki podłużnej w konstrukcji nadwozia. Poprawę przebiegu rozpraszania energii uzyskano przez wzmocnienie wykonanych próbek podłużnic specjalnymi elementami przyspawanymi do ścianek podłużnic. Założono przy tym, że przez rodzaj spoiny można wpływać na krzywą rozpraszania energii. Wykonano próbki i poddano je badaniom na maszynie wytrzymałościowej w certyfikowanym laboratorium Instytutu Badań i Rozwoju Motoryzacji BOSMAL w Bielsku Białej. Zaprezentowano przebiegi rozpraszania energii dla próbki bez wzmocnień i ze wzmocnieniami. Porównano i oceniono uzyskane wyniki zarówno pod względem jakościowym i ilościowym. Publikacja powstała na bazie pracy dyplomowej studenta M. Szuberli, promotor; K.M. Romaniszyn

Combining Local and Remote Infrasound Recordings from the 2009 Redoubt Volcano Eruption

The explosive phase of the 2009 Redoubt Volcano eruption produced predominantly short duration, high-amplitude infrasound signals recorded up to 4500 km away. All 19 numbered explosive events were recorded at a local microphone (DFR, 12 km), as well as at an infrasound array in Fairbanks, Alaska (I53US, 547 km), most with high signal to noise ratios. The local microphone provides an estimate of the source parameters, and comparison between the two datasets allows the unique opportunity to evaluate acoustic source term estimation at a remote array. High waveform similarity between DFR and I53US occurs during much of the explosive phase due to strong stratospheric ducting, permitting accurate source constraints inferred from I53US data. Cross-correlation analysis after applying a Hilbert transform to the I53US data shows how the acoustic energy has passed through a single caustic, as predicted by ray theory. Similar to previous studies, significant low-frequency infrasound from Redoubt recorded at I53US is coincident with high-altitude ash emissions. The largest events also produced considerable energy at greater than 50 s periods, likely related to the initial oscillations of the volcanic plume or jet. Many of the explosive events have emergent onsets, somewhat unusual for explosive, short-duration eruptions. Comparison of the satellite-derived SO2 emissions with the relative amount of acoustic energy at I53US shows a very high, statistically significant correlation. This study reiterates the utility of using remote infrasound arrays for detection of hazardous emissions and characterization of large volcanic eruptions, and demonstrates how, under typical meteorological conditions, remote infrasound arrays can provide an accurate representation of the acoustic sourc

Interstation Pc3 coherence at cusp latitudes

Magnetic fluctuations in the 22-100 millihertz (Pc3) band are a consistent indicator of the presence of the cusp in the overhead ionosphere at high latitudes. Correlation of the signals from a variety of instruments have shown that the sources of these pulsations are local (ionospheric) rather than distant (magnetospheric) [Engebretson et al., 1990]. Modulated electron precipitation is presumed to be the source of the fluctuations through the modulations in ionospheric conductivity that they produce. Olson and Szuberla [1997] used data from a pair of cusp stations to deduce the scale size of the precipitating beams using a simple model in which the beams were assumed to have circular cross section. They obtained an upper bound for the coherence length of the order of 200 km. In this paper we extend the analysis of Olson and Szuberla by incorporating data from the Magnetometer Array for Cusp and Cleft Studies (MACCS) magnetometer array and the Australian ANARE antarctic sites to give a broader range of station separations. Using a statistical approach we computed the cumulative distribution function of the interstation coherence and from that distribution we established a measure of coherence, CL . The result of this analysis is a coherence that diminishes with inter-station distance as CL ≈ 1.4 exp(−S/250) where S is the station separation in km. When this result is interpreted in the context of the simple model mentioned above we find a coherence length of 140 - 180km

Infrasound Observations of the 2008 Explosive Eruptions of Okmok and Kasatochi Volcanoes, Alaska

The recent explosive eruptions of Okmok and Kasatochi volcanoes provide an opportunity to use seismic, local infrasound, distant infrasound array, and remote sensing data in concert to better monitor volcanoes in the Aleutian Arc and to better understand the source processes. The eruption of Okmok Volcano began on 12 July 2008 and included a seismically active phase that lasted continuously for about 10 h. In contrast, the eruption of Kasatochi which began on 7 August 2008 consisted of five explosive events that lasted from 26 to 68 min each and had a cumulative duration of 3.4 h. Given the event times by local seismic stations, the corresponding infrasound signals were found in the data recorded by local infrasound sensors and by distant infrasound arrays. Signals from the Okmok eruption were detected by three International Monitoring System (IMS) arrays as far away as 4400 km; signals from the Kasatochi eruption were detected at greater distances up to 5200 km away by seven infrasound arrays including the ones that detected the event at Okmok Volcano. Back azimuth propagation and a simple acoustic wave propagation model in unison with known event times were used to confirm that the planar, acoustic signals recorded at the arrays had originated from the eruptions. The infrasound array data reflected the differences in eruption styles between Okmok and Kasatochi as the signals from Kasatochi were of shorter duration, of greater amplitude, and detected over greater distances. The infrasound array data were also able to distinguish between two types of tremor episodes that occurred at Kasatochi Volcano based on atmospheric disturbance

Infrasound Observations of the 2008 Explosive Eruptions of Okmok and Kasatochi Volcanoes, Alaska

The recent explosive eruptions of Okmok and Kasatochi volcanoes provide an opportunity to use seismic, local infrasound, distant infrasound array, and remote sensing data in concert to better monitor volcanoes in the Aleutian Arc and to better understand the source processes. The eruption of Okmok Volcano began on 12 July 2008 and included a seismically active phase that lasted continuously for about 10 h. In contrast, the eruption of Kasatochi which began on 7 August 2008 consisted of five explosive events that lasted from 26 to 68 min each and had a cumulative duration of 3.4 h. Given the event times by local seismic stations, the corresponding infrasound signals were found in the data recorded by local infrasound sensors and by distant infrasound arrays. Signals from the Okmok eruption were detected by three International Monitoring System (IMS) arrays as far away as 4400 km; signals from the Kasatochi eruption were detected at greater distances up to 5200 km away by seven infrasound arrays including the ones that detected the event at Okmok Volcano. Back azimuth propagation and a simple acoustic wave propagation model in unison with known event times were used to confirm that the planar, acoustic signals recorded at the arrays had originated from the eruptions. The infrasound array data reflected the differences in eruption styles between Okmok and Kasatochi as the signals from Kasatochi were of shorter duration, of greater amplitude, and detected over greater distances. The infrasound array data were also able to distinguish between two types of tremor episodes that occurred at Kasatochi Volcano based on atmospheric disturbance