New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Från projekt till process? : Försvarsmaktens doktrinutveckling i går, i dag, i morgon

Mycket talar för att den svenska doktrinutvecklingsprocessen inte fungerar. Frågan som dåinfinner sig är: Hur står det till med den svenska doktrinutvecklingen? Syftet med denna uppsats äratt undersöka, diskutera och värdera den svenska doktrinutvecklingsprocessens funktionssätt.Uppsatsen avsåg att undersöka den svenska doktrinutvecklingsprocessen genom att mäta gradenav institutionalisering och formalisering i den svenska doktrinutvecklingsprocessen. Därigenomerhölls slutsatser som kunde nyttjas för att utveckla doktrinutvecklingsprocessen. Graden avformaliseringen mättes genom en jämförelse mellan en ideal doktrinutvecklingsprocess och densvenska doktrinutvecklingsprocessen. Graden av institutionalisering i den svenskadoktrinutvecklingsprocessen mättes genom en jämförelse mot indikatorer som bör vara uppfyllda ien organisation som får anses vara väl institutionaliserad. Underlaget för jämförelsen erhöllsgenom skriftliga källor samt intervjuer med nyckelpersoner i den svenska doktrinutvecklingen.Uppsatsens resultat kan sammanfattas på följande sätt: Den svenska doktrinutvecklingsprocessenfår sägas ha en hög grad av formalisering, däremot får den sägas ha en låg grad avinstitutionalisering. Sammantaget talar detta för att den svenska doktrinutvecklingsprocessen kanliknas vid en projektbaserad doktrinutveckling, genomförd i linjeorganisationen, trots försök attskapa en integrerad och samordnad doktrinutvecklingsprocess i Försvarsmakten.The Swedish Armed Forces have decided to introduce a doctrine and a doctrine developmentprocess. There are indications that the Swedish doctrine development process does not function.The purpose of this essay was to examine, discuss and to evaluate the Swedish doctrinedevelopment process's operating methods.The essay examines the Swedish doctrine development process by measuring the degree offormalization and institutionalization in the Swedish doctrine development process. The degree offormalization was measured through a comparison between an ideal doctrine development processand the Swedish doctrine development process. The degree of institutionalization in the Swedishdoctrine development process was measured through a comparison against indicators that shouldbe met in an organisation considered to be well institutionalized. The basis for the comparison wasreceived from written sources and interviews with key persons in the Swedish doctrinedevelopment.The results of the essay can be summarized in the following ways: The Swedish doctrinedevelopment process has a high degree of formalization, but on the other hand, the Swedishdoctrine development process has a low degree of institutionalization. All in all, the SwedishArmed Forces’ doctrine development process can be compared to a project based doctrinedevelopment, implemented in the line organization. In spite of efforts to create one integrated andtimed doctrine development process.Avdelning: ALB - Slutet Mag 3 C-upps. Hylla: Upps. ChP 06-0

Genome-wide association study identifies novel breast cancer susceptibility loci

Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2 &gt; 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P &lt; 10(-7)). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P &lt; 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.<br/

Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI) : a phase 3, placebo-controlled, randomised trial

Background: Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor. Methods: The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria: a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population). Findings: Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58% of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3·3 years (IQR 2·8–3·8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7·3%] of 5558 vs 480 [8·6%] of 5596; HR 0·85 [95% CI 0·74–0·97], p=0·013). The same effect was not observed in patients without PCI (p=0·76, p interaction=0·16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3·1%] with ticagrelor vs 183 (3·3%) with placebo; HR 0·96 [95% CI 0·78–1·18], p=0·68), as well as all-cause death (282 [5·1%] vs 323 [5·8%]; 0·88 [0·75–1·03], p=0·11). TIMI major bleeding occurred in 111 (2·0%) of 5536 patients receiving ticagrelor and 62 (1·1%) of 5564 patients receiving placebo (HR 2·03 [95% CI 1·48–2·76], p<0·0001), and fatal bleeding in 6 (0·1%) of 5536 patients with ticagrelor and 6 (0·1%) of 5564 with placebo (1·13 [0·36–3·50], p=0·83). Intracranial haemorrhage occurred in 33 (0·6%) and 31 (0·6%) patients (1·21 [0·74–1·97], p=0·45). Ticagrelor improved net clinical benefit: 519/5558 (9·3%) versus 617/5596 (11·0%), HR=0·85, 95% CI 0·75–0·95, p=0·005, in contrast to patients without PCI where it did not, p interaction=0·012. Benefit was present irrespective of time from most recent PCI. Interpretation: In patients with diabetes, stable coronary artery disease, and previous PCI, ticagrelor added to aspirin reduced cardiovascular death, myocardial infarction, and stroke, although with increased major bleeding. In that large, easily identified population, ticagrelor provided a favourable net clinical benefit (more than in patients without history of PCI). This effect shows that long-term therapy with ticagrelor in addition to aspirin should be considered in patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischaemic risk, and low bleeding risk

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P &lt; 5 × 10 -8 ), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for &gt;20 % of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis

Genetic studies of body mass index yield new insights for obesity biology

Note: A full list of authors and affiliations appears at the end of the article. Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P 20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.</p