We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

SummaryBackgroundOsteoarthritis 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.MethodsWe 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.FindingsWe 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.InterpretationOur findings provide insight into the genetics of arthritis and identify new pathways that might be amenable to future therapeutic intervention.FundingarcOGEN was funded by a special purpose grant from Arthritis Research UK.

The primary purpose of this study was to investigate the accuracy of theactivPAL physical activity monitor in measuring step number and cadence in older adults. Two pedometers (New-Lifestyles Digi-Walker SW-200 and New-Lifestyles NL-2000) used in clinical practice to count steps were simultaneously evaluated. Observation was the criterion measure. Twenty-one participants (65-87 yr old) recruited from community-based exercise classes walked on a treadmill at 5 speeds (0.67, 0.90, 1.12, 1.33, and 1.56 m/s) and outdoors at 3 self-selected speeds (slow, normal, and fast). The absolute percentage error of theactivPAL was <1% for all treadmill and outdoor conditions for measuring steps and cadence. With the exception of the slowest treadmill speed, the NL-2000 error was <2%. The SW-200 was the least accurate device, particularly at slower walking speeds. TheactivPAL monitor accurately recorded step number and cadence. Combined with its ability to identify primary postures, theactivPALmight be a useful and versatile device for measuring activity in older adults.

Progressive high-intensity quadriceps training in elderly proximal femoral fracture patients increased leg extensor power and reduced disability. This was accompanied by an increase in energy as measured by the Nottingham Health Profile. This intervention may provide a simple practical way of improving outcome in these patients.

ABSTRACT. In this paper we undertake a quantitative analysis of the dynamic process by which ice underneath a dry porous debris layer melts. We show that the incorporation of debris-layer airflow into a theoretical model of glacial melting can capture the empirically observed features of the so-called Østrem curve (a plot of the melt rate as a function of debris depth). Specifically, we show that the turning point in the Østrem curve can be caused by two distinct mechanisms: the increase in the proportion of ice that is debris-covered and/or a reduction in the evaporative heat flux as the debris layer thickens. This second effect causes an increased melt rate because the reduction in (latent) energy used for evaporation increases the amount of energy available for melting. Our model provides an explicit prediction for the melt rate and the temperature distribution within the debris layer, and provides insight into the relative importance of the two effects responsible for the maximum in the Østrem curve. We use the data of Nicholson and Benn (2006) to show that our model is consistent with existing empirical measurements.

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Abstract. The work in this paper concerns the study of conventional and refined heat balance integral methods for a number of phase change problems. These include standard test problems, both with one and two phase changes, which have exact solutions to enable us to test the accuracy of the approximate solutions. We also consider situations where no analytical solution is available and compare these to numerical solutions. It is popular to use a quadratic profile as an approximation of the temperature, but we show that a cubic profile, seldom considered in the literature, is far more accurate in most circumstances. In addition, the refined integral method can give greater improvement still and we develop a variation on this method which turns out to be optimal in some cases. We assess which integral method is better for various problems, showing that it is largely dependent on the specified boundary conditions.

ObjectivesThe genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis.MethodsThe authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44 449 individuals), and de novo in 14 534 independent samples, all of European descent.ResultsNone of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects.ConclusionsIdentifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity.