Evidence for a persistent, major excess in all cause admissions to hospital in children with type-1 diabetes: results from a large Welsh national matched community cohort study

OBJECTIVES: To estimate the excess in admissions associated with type1 diabetes in childhood. DESIGN: Matched-cohort study using anonymously linked hospital admission data. SETTING: Brecon Group Register of new cases of childhood diabetes in Wales linked to hospital admissions data within the Secure Anonymised Information Linkage Databank. POPULATION: 1577 Welsh children (aged between 0 and 15 years) from the Brecon Group Register with newly-diagnosed type-1 diabetes between 1999–2009 and 7800 population controls matched on age, sex, county, and deprivation, randomly selected from the local population. MAIN OUTCOME MEASURES: Difference in all-cause hospital admission rates, 30-days post-diagnosis until 31 May 2012, between participants and controls. RESULTS: Children with type-1 diabetes were followed up for a total of 12 102 person years and were at 480% (incidence rate ratios, IRR 5.789, (95% CI 5.34 to 6.723), p<0.0001) increased risk of hospital admission in comparison to matched controls. The highest absolute excess of admission was in the age group of 0–5 years, with a 15.4% (IRR 0.846, (95% CI 0.744 to 0.965), p=0.0061) reduction in hospital admissions for every 5-year increase in age at diagnosis. A trend of increasing admission rates in lower socioeconomic status groups was also observed, but there was no evidence of a differential rate of admissions between men and women when adjusted for background risk. Those receiving outpatient care at large centres had a 16.1% (IRR 0.839, (95% CI 0.709 to 0.990), p=0.0189) reduction in hospital admissions compared with those treated at small centres. CONCLUSIONS: There is a large excess of hospital admissions in paediatric patients with type-1 diabetes. Rates are highest in the youngest children with low socioeconomic status. Factors influencing higher admission rates in smaller centres (eg, “out of hours resources”) need to be explored with the aim of targeting modifiable influences on admission rates

Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk.

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies

mVps34 is activated by an acute bout of resistance exercise

Resistance-exercise training results in a progressive increase in muscle mass and force production. Following an acute bout of resistance exercise, the rate of protein synthesis increases proportionally with the increase in protein degradation, correlating at 3 h in the starved state. Amino acids taken immediately before or immediately after exercise increase the post-exercise rate of protein synthesis. Therefore a protein that controls protein degradation and amino acid-sensitivity would be a potential candidate for controlling the activation of protein synthesis following resistance exercise. One such candidate is the class III PI3K (phosphoinositide 3-kinase) Vps34 (vacuolar protein sorting mutant 34). Vps34 controls both autophagy and amino acid signalling to mTOR (mammalian target of rapamycin) and its downstream target p70 S6K1 (S6 kinase 1). We have identified a significant increase in mVps34 (mammalian Vps34) activity 3 h after resistance exercise, continuing for at least 6 h, and propose a mechanism whereby mVps34 could act as an internal amino acid sensor to mTOR after resistance exercise

Quantifying damage, saturation and anisotropy in cracked rocks by inverting elastic wave velocities

Crack damage results in a decrease of elastic wave velocities and in the development of anisotropy. Using non-interactive crack effective medium theory as a fundamental tool, we calculate dry and wet elastic properties of cracked rocks in terms of a crack density tensor, average crack aspect ratio and mean crack fabric orientation from the solid grains and fluid elastic properties. Using this same tool, we show that both the anisotropy and shear-wave splitting of elastic waves can be derived. Two simple crack distributions are considered for which the predicted anisotropy depends strongly on the saturation, reaching up to 60% in the dry case. Comparison with experimental data on two granites, a basalt and a marble, shows that the range of validity of the non-interactive effective medium theory model extends to a total crack density of approximately 0.5, considering symmetries up to orthorhombic. In the isotropic case, Kachanov's (1994) non-interactive effective medium model was used in order to invert elastic wave velocities and infer both crack density and aspect ratio evolutions. Inversions are stable and give coherent results in terms of crack density and aperture evolution. Crack density variations can be interpreted in terms of crack growth and/or changes of the crack surface contact areas as cracks are being closed or opened respectively. More importantly, the recovered evolution of aspect ratio shows an exponentially decreasing aspect ratio (and therefore aperture) with pressure, which has broader geophysical implications, in particular on fluid flow. The recovered evolution of aspect ratio is also consistent with current mechanical theories of crack closure. In the anisotropic cases—both transverse isotropic and orthorhombic symmetries were considered—anisotropy and saturation patterns were well reproduced by the modelling, and mean crack fabric orientations we recovered are consistent with in situ geophysical imaging. Our results point out that: (1) It is possible to predict damage, anisotropy and saturation in terms of a crack density tensor and mean crack aspect ratio and orientation; (2) using well constrained wave velocity data, it is possible to extrapolate the contemporaneous evolution of crack density, anisotropy and saturation using wave velocity inversion as a tool; 3) using such an inversion tool opens the door in linking elastic properties, variations to permeability