Pediatric severe asthma with fungal sensitization is mediated by steroid-resistant IL-33

Background: The mechanism underlying severe asthma with fungal sensitization (SAFS) is unknown. IL-33 is important in fungus-induced asthma exacerbations, but its role in fungal sensitization is unexplored. Objective: We sought to determine whether fungal sensitization in children with severe therapy-resistant asthma is mediated by IL-33. Methods: Eighty-two children (median age, 11.7 years; 63% male) with severe therapy-resistant asthma were included. SAFS (n= 38) was defined as specific IgE or skin prick test response positivity to Aspergillus fumigatus, Alternaria alternata, or Cladosporium herbarum. Clinical features and airway immunopathology were assessed. Chronic exposure to house dust mite and A alternata were compared in a neonatal mouse model. Results: Children with SAFS had earlier symptom onset (0.5 vs 1.5 years, P= .006), higher total IgE levels (637 vs 177 IU/mL, P= .002), and nonfungal inhalant allergen-specific IgE. Significantly more children with SAFS were prescribed maintenance oral steroids (42% vs 14%, P= .02). SAFS was associated with higher airway IL-33 levels. In neonatal mice A alternata exposure induced higher serum IgE levels, pulmonary IL-33 levels, and IL-13+ innate lymphoid cell (ILC) and TH2 cell numbers but similar airway hyperresponsiveness (AHR) compared with those after house dust mite exposure. Lung IL-33 levels, IL-13+ ILC numbers, TH2 cell numbers, IL-13 levels, and AHR remained increased with inhaled budesonide during A alternata exposure, but all features were significantly reduced in ST2-/- mice lacking a functional receptor for IL-33. Conclusion: Pediatric SAFS was associated with more oral steroid therapy and higher IL-33 levels. A alternata exposure resulted in increased IL-33-mediated ILC2 numbers, TH2 cell numbers, and steroid-resistant AHR. IL-33 might be a novel therapeutic target for SAFS

Predicting the effect of voids on mechanical properties of woven composites.

An accurate yet easy to use methodology for determining the effective mechanical properties of woven fabric reinforced composites is presented. The approach involves generating a representative unit cell geometry based on randomly selected 2D orthogonal slices from a 3D X-ray micro-tomographic scan. Thereafter, the finite element mesh is generated from this geometry. Analytical and statistical micromechanics equations are then used to calculate effective input material properties for the yarn and resin regions within the FE mesh. These analytical expressions account for the effect of resin volume fraction within the yarn (due to infiltration during curing) as well as the presence of voids within the composite. The unit cell model is then used to evaluate the effective properties of the composite.DelPHE 780 Project funded by UK Department of International Development (DFID), through British Council managed DelPHE scheme

3D geometric modelling of discontinuous fibre composites using a force-directed algorithm

A geometrical modelling scheme is presented to produce representative architectures for discontinuous fibre composites, enabling downstream modelling of mechanical properties. The model generates realistic random fibre architectures containing high filament count bundles (>3k) and high (~50%) fibre volume fractions. Fibre bundles are modelled as thin shells using a multi-dimension modelling strategy, in which fibre bundles are distributed and compacted to simulate pressure being applied from a matched mould tool. FE simulations are performed to benchmark the in-plane mechanical properties obtained from the numerical model against experimental data, with a detailed study presented to evaluate the tensile properties at various fibre volume fractions and specimen thicknesses. Tensile modulus predictions are in close agreement (less than 5% error) with experimental data at volume fractions below 45%. Ultimate tensile strength predictions are within 4.2% of the experimental data at volume fractions between 40%-55%. This is a significant improvement over existing 2D modelling approaches, as the current model offers increased levels of fidelity, capturing dominant failure mechanisms and the influence of out-of-plane fibres

Identification of new susceptibility loci for osteoarthritis (arcOGEN):a genome-wide association study

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.Osteoarthritis is the most common form of arthritis worldwide and is a major cause of pain and disability in elderly people. The health economic burden of osteoarthritis is increasing commensurate with obesity prevalence and longevity. Osteoarthritis has a strong genetic component but the success of previous genetic studies has been restricted due to insufficient sample sizes and phenotype heterogeneity. We undertook a large genome-wide association study (GWAS) in 7410 unrelated and retrospectively and prospectively selected patients with severe osteoarthritis in the arcOGEN study, 80% of whom had undergone total joint replacement, and 11,009 unrelated controls from the UK. We replicated the most promising signals in an independent set of up to 7473 cases and 42,938 controls, from studies in Iceland, Estonia, the Netherlands, and the UK. All patients and controls were of European descent. We identified five genome-wide significant loci (binomial test p≤5·0×10(-8)) for association with osteoarthritis and three loci just below this threshold. The strongest association was on chromosome 3 with rs6976 (odds ratio 1·12 [95% CI 1·08-1·16]; p=7·24×10(-11)), which is in perfect linkage disequilibrium with rs11177. This SNP encodes a missense polymorphism within the nucleostemin-encoding gene GNL3. Levels of nucleostemin were raised in chondrocytes from patients with osteoarthritis in functional studies. Other significant loci were on chromosome 9 close to ASTN2, chromosome 6 between FILIP1 and SENP6, chromosome 12 close to KLHDC5 and PTHLH, and in another region of chromosome 12 close to CHST11. One of the signals close to genome-wide significance was within the FTO gene, which is involved in regulation of bodyweight-a strong risk factor for osteoarthritis. All risk variants were common in frequency and exerted small effects. Our findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention.Arthritis Research UK 1803

Three-dimensional tomographic imaging of the Taranaki volcanoes, New Zealand

3-D models of the P-wave velocity (Vp), the ratio of P- to S-wave velocity (Vp/Vs), and the P-wave quality factor (Qp) are determined for the crust in Taranaki, New Zealand, using local tomography and data from a dense network (average spacing 5 km) of 68 three-component, broad-band seismographs. Vp and Vp/Vs models were determined by jointly inverting P traveltimes and S–P traveltime intervals, and a Qp model by inverting t* (t/Qp) observations derived from modelling the velocity amplitude spectrum of P wave arrivals. An approximately 5 km diameter region of high Vp and low Vp/Vs beneath the Taranaki volcanoes extends from the surface to a depth of about 10 km and images the roots of the volcanoes formed by successive magmatic intrusions. At Mt Taranaki this will probably be the path through which future magma intrusions will reach the surface. We are unable to image any magma storage within the upper 16 km of the crust as the volumes involved are probably smaller than the 5 km resolution of our models. The volcanoes sit in the Taranaki basin, a large sedimentary basin characterized by low Vp (c. 4 km s−1) and high Vp/Vs (≥1.9), attributed to unconsolidated, water-saturated sediments, and these are underlain by basement rocks with Vp≥ 5 km s−1 and Vp/Vs≤ 1.7 . There is a c. 20 per cent contrast in Vp across the Taranaki fault at the eastern boundary of the Taranaki basin, and a small, shallow, high Vp/Vs (≥2.0) anomaly above the seismically active Cape Egmont Fault Zone, west of the Taranaki volcanoes. Although the Qp model is of significantly lower resolution than the Vp and Vp/Vs models, it shows a low Qp anomaly (c. 100) between 4 and 10 km depth that corresponds to the deepest onshore part of the Taranaki basin

Earthquake Swarm Activity Beneath the Tokaanu-Waihi Geothermal System, Lake Taupo, New Zealand

The hypocenters of 4 earthquake swarms (total of 54 events), recorded with a local network between 1986 April and 1987 January, occur within upper crustal rocks of the deeper Tokaanu-Waihi geothermal reservoir; all the events had a magnitude M{sub L} {le} 3.2. Most foci are aligned along two NW-trending basement fault structures along which young rhyodacitic extrusions can be found. The swarm activity has been interpreted in terms of injections into basement fractures of magma from deeper chambers (dyke injection swarm activity)