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Aims/hypothesis Among white European children developing type 1 diabetes, the otherwise common HLA haplotype DR15-DQ6 is rare, and highly protective. Adult-onset type 1 diabetes is now known to represent more overall cases than childhood onset, but it is not known whether DR15-DQ6 is protective in older-adult-onset type 1 diabetes. We sought to quantify DR15-DQ6 protection against type 1 diabetes as age of onset increased. Methods In two independent cohorts we assessed the proportion of type 1 diabetes cases presenting through the first 50 years of life with DR15-DQ6, compared with population controls. In the After Diabetes Diagnosis Research Support System-2 (ADDRESS-2) cohort (n = 1458) clinician-diagnosed type 1 diabetes was confirmed by positivity for one or more islet-specific autoantibodies. In UK Biobank (n = 2502), we estimated type 1 diabetes incidence rates relative to baseline HLA risk for each HLA group using Poisson regression. Analyses were restricted to white Europeans and were performed in three groups according to age at type 1 diabetes onset: 0–18 years, 19–30 years and 31–50 years. Results DR15-DQ6 was protective against type 1 diabetes through to age 50 years (OR p Conclusions/interpretation HLA DR15-DQ6 confers dominant protection from type 1 diabetes across the first five decades of life. Graphical abstract

Background Type 2 diabetes (T2D) is common and increasing in prevalence. It is possible to prevent or delay T2D using lifestyle intervention programmes. Entry to these programmes is usually determined by a measure of glycaemia in the ‘intermediate’ range. This paper investigated the relationship between HbA1c and future diabetes risk and determined the impact of varying thresholds to identify those at high risk of developing T2D. Methods We studied 4227 participants without diabetes aged ≥ 40 years recruited to the Exeter 10,000 population cohort in South West England. HbA1c was measured at study recruitment with repeat HbA1c available as part of usual care. Absolute risk of developing diabetes within 5 years, defined by HbA1c ≥ 48 mmol/mol (6.5%), according to baseline HbA1c, was assessed by a flexible parametric survival model. Results The overall absolute 5-year risk (95% CI) of developing T2D in the cohort was 4.2% (3.6, 4.8%). This rose to 7.1% (6.1, 8.2%) in the 56% (n = 2358/4224) of participants classified ‘high-risk’ with HbA1c ≥ 39 mmol/mol (5.7%; ADA criteria). Under IEC criteria, HbA1c ≥ 42 mmol/mol (6.0%), 22% (n = 929/4277) of the cohort was classified high-risk with 5-year risk 14.9% (12.6, 17.2%). Those with the highest HbA1c values (44–47 mmol/mol [6.2–6.4%]) had much higher 5-year risk, 26.4% (22.0, 30.5%) compared with 2.1% (1.5, 2.6%) for 39–41 mmol/mol (5.7–5.9%) and 7.0% (5.4, 8.6%) for 42–43 mmol/mol (6.0–6.1%). Changing the entry criterion to prevention programmes from 39 to 42 mmol/mol (5.7–6.0%) reduced the proportion classified high-risk by 61%, and increased the positive predictive value (PPV) from 5.8 to 12.4% with negligible impact on the negative predictive value (NPV), 99.6% to 99.1%. Increasing the threshold further, to 44 mmol/mol (6.2%), reduced those classified high-risk by 59%, and markedly increased the PPV from 12.4 to 23.2% and had little impact on the NPV (99.1% to 98.5%). Conclusions A large proportion of people are identified as high-risk using current thresholds. Increasing the risk threshold markedly reduces the number of people that would be classified as high-risk and entered into prevention programmes, although this must be balanced against cases missed. Raising the entry threshold would allow limited intervention opportunities to be focused on those most likely to develop T2D.

The current literature provides compelling evidence suggesting that an eddy-resolving (as opposed to eddy-permitting or eddy-parameterized) ocean component model will significantly impact the simulation of the large-scale climate, although this has not been fully tested to date in multi-decadal global coupled climate simulations. The purpose of this paper is to examine how resolved ocean fronts and eddies impact the simulation of large-scale climate. The model used for this study is the NCAR Community Climate System Model version 3.5 (CCSM3.5)—the forerunner to CCSM4. Two experiments are reported here. The control experiment is a 155-year present-day climate simulation using a 0.5° atmosphere component (zonal resolution 0.625 meridional resolution 0.5°; land surface component at the same resolution) coupled to ocean and sea-ice components with zonal resolution of 1.2° and meridional resolution varying from 0.27° at the equator to 0.54° in the mid-latitudes. The second simulation uses the same atmospheric and land-surface models coupled to eddy-resolving 0.1° ocean and sea-ice component models. The simulations are compared in terms of how the representation of smaller scale features in the time mean ocean circulation and ocean eddies impact the mean and variable climate. In terms of the global mean surface temperature, the enhanced ocean resolution leads to a ubiquitous surface warming with a global mean surface temperature increase of about 0.2 °C relative to the control. The warming is largest in the Arctic and regions of strong ocean fronts and ocean eddy activity (i.e., Southern Ocean, western boundary currents). The Arctic warming is associated with significant losses of sea-ice in the high-resolution simulation. The sea surface temperature gradients in the North Atlantic, in particular, are better resolved in the high-resolution model leading to significantly sharper temperature gradients and associated large-scale shifts in the rainfall. In the extra-tropics, the interannual temperature variability is increased with the resolved eddies, and a notable increases in the amplitude of the El Nino and the Southern Oscillation is also detected. Changes in global temperature anomaly teleconnections and local air-sea feedbacks are also documented and show large changes in ocean–atmosphere coupling. In particular, local air-sea feedbacks are significantly modified by the increased ocean resolution. In the high-resolution simulation in the extra-tropics there is compelling evidence of stronger forcing of the atmosphere by SST variability arising from ocean dynamics. This coupling is very weak or absent in the low-resolution model.