An age-dependent association between variation at the FTO locus and BMI in children has been suggested. We meta-analyzed associations between the FTO locus (rs9939609) and BMI in samples, aged from ...early infancy to 13 years, from 8 cohorts of European ancestry. We found a positive association between additional minor (A) alleles and BMI from 5.5 years onwards, but an inverse association below age 2.5 years. Modelling median BMI curves for each genotype using the LMS method, we found that carriers of minor alleles showed lower BMI in infancy, earlier adiposity rebound (AR), and higher BMI later in childhood. Differences by allele were consistent with two independent processes: earlier AR equivalent to accelerating developmental age by 2.37% (95% CI 1.87, 2.87, p = 10(-20)) per A allele and a positive age by genotype interaction such that BMI increased faster with age (p = 10(-23)). We also fitted a linear mixed effects model to relate genotype to the BMI curve inflection points adiposity peak (AP) in infancy and AR. Carriage of two minor alleles at rs9939609 was associated with lower BMI at AP (-0.40% (95% CI: -0.74, -0.06), p = 0.02), higher BMI at AR (0.93% (95% CI: 0.22, 1.64), p = 0.01), and earlier AR (-4.72% (-5.81, -3.63), p = 10(-17)), supporting cross-sectional results. Overall, we confirm the expected association between variation at rs9939609 and BMI in childhood, but only after an inverse association between the same variant and BMI in infancy. Patterns are consistent with a shift on the developmental scale, which is reflected in association with the timing of AR rather than just a global increase in BMI. Results provide important information about longitudinal gene effects and about the role of FTO in adiposity. The associated shifts in developmental timing have clinical importance with respect to known relationships between AR and both later-life BMI and metabolic disease risk.
Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor ...agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease.
REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952.
Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1–5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio HR 0·85, 95% CI 0·77–0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68–0·87; p<0·0001), with HRs of 0·89 (0·78–1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39–1·44; p=0·39) for chronic renal replacement therapy.
Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes.
Eli Lilly and Company.
Cavitation is a common damage mechanism in soft solids. Here, we study this using a phase separation technique in stretched, elastic solids to controllably nucleate and grow small cavities by several ...orders of magnitude. The ability to make stable cavities of different sizes, as well as the huge range of accessible strains, allows us to systematically study the early stages of cavity expansion. Cavities grow in a scale-free manner, accompanied by irreversible bond breakage that is distributed around the growing cavity rather than being localized to a crack tip. Furthermore, cavities appear to grow at constant driving pressure. This has strong analogies with the plasticity that occurs surrounding a growing void in ductile metals. In particular, we find that, although elastomers are normally considered as brittle materials, small-scale cavity expansion is more like a ductile process. Our results have broad implications for understanding and controlling failure in soft solids.
A global synthesis of the 13C/12C ratio of dissolved inorganic carbon (DIC) in the surface ocean is attempted by summarizing high‐precision data obtained from 1978 to 1997 in all major ocean basins. ...The data, mainly along transects but including three subtropical time series, are accompanied by simultaneous, precise measurements of DIC concentration and titration alkalinity. The reduced isotopic ratio, δ13C, in the surface ocean water is governed by a balance between biological and thermodynamic processes. These processes have strongly opposing tendencies, which result in a complex spatial pattern in δ13C with relatively little variability. The most distinctive feature in the spatial distribution of δ13C seen in our data is a maximum of δ13C near the subantarctic front with sharply falling values to the south. We attribute this feature to a combination of biological uptake of CO2 depleted in 13C (low δ13C) and air‐sea exchange near the front and upwelling further south of waters with low δ13C resulting from the remineralization of organic matter. Additional features are maxima in δ13C downstream of upwelling regions, reflecting biological uptake, and minima in the subtropical gyres caused by strongly temperature dependent thermodynamic isotopic fractionation. At the time series stations, two in the North Atlantic Ocean and one in the North Pacific, distinct seasonal cycles in δ13C are observed, the Pacific data exhibiting only about half the amplitude of the Atlantic. Secular decreases in δ13C caused by the invasion of isotopically light anthropogenic CO2 into the ocean (the 13C Suess effect) have been identified at these time series stations and also in data from repeated transects in the Indian Ocean and the tropical Pacific. A tentative global extrapolation of these secular decreases yields a surface oceanic 13C Suess effect of approximately −0.018‰ yr−1 from 1980 to 1995. This effect is nearly the same as the 13C Suess effect observed globally in the atmosphere over the same period. We attribute this response to a deceleration in the growth rate of anthropogenic CO2 emissions after 1979, which subsequently has reduced the atmospheric 13C Suess effect more than the surface ocean effect.
A potent series of inhibitors against the B-Raf super(V600E kinase have been developed that show excellent activity in cellular assays and good oral bioavailability in rats. The key structural ...features of the series are an arylsulfonamide headgroup, a thiazole core, and a fluorine ortho to the sulfonamide nitrogen.)
A potent series of inhibitors against the B-Raf
V600E kinase have been developed that show excellent activity in cellular assays and good oral bioavailability in rats. The key structural features of ...the series are an arylsulfonamide headgroup, a thiazole core, and a fluorine
ortho to the sulfonamide nitrogen.
Nature Communications 8: Article number: 14357 (2017); Published 27 February 2017; Updated 11 April 2017 The original version of the Supplementary Information attached to this Article did not include ...Supplementary Note 1 The HTML has now been updated to include a corrected version of the Supplementary Information.
This paper introduces micro‐optics fabrication on technical display glass. It improves display efficiency and enables innovative optical designs. Key value proposition is micro‐optics alignment with ...the display pixels. Technical data will be presented demonstrating the performance advantage of precision micro‐optics on technical glass compared to plastic substrate, and scalability to large‐size manufacturing.
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