Evaluation of four novel genetic variants affecting hemoglobin A1c levels in a population-based type 2 diabetes cohort (the HUNT2 study)

<p>Abstract</p> <p>Background</p> <p>Chronic hyperglycemia confers increased risk for long-term diabetes-associated complications and repeated hemoglobin A1c (HbA1c) measures are a widely used marker for glycemic control in diabetes treatment and follow-up. A recent genome-wide association study revealed four genetic loci, which were associated with HbA1c levels in adults with type 1 diabetes. We aimed to evaluate the effect of these loci on glycemic control in type 2 diabetes.</p> <p>Methods</p> <p>We genotyped 1,486 subjects with type 2 diabetes from a Norwegian population-based cohort (HUNT2) for single-nucleotide polymorphisms (SNPs) located near the <it>BNC2</it>, <it>SORCS1</it>, <it>GSC </it>and <it>WDR72 </it>loci. Through regression models, we examined their effects on HbA1c and non-fasting glucose levels individually and in a combined genetic score model.</p> <p>Results</p> <p>No significant associations with HbA1c or glucose levels were found for the <it>SORCS1</it>, <it>BNC2</it>, <it>GSC </it>or <it>WDR72 </it>variants (all <it>P</it>-values > 0.05). Although the observed effects were non-significant and of much smaller magnitude than previously reported in type 1 diabetes, the <it>SORCS1 </it>risk variant showed a direction consistent with increased HbA1c and glucose levels, with an observed effect of 0.11% (<it>P </it>= 0.13) and 0.13 mmol/l (<it>P </it>= 0.43) increase per risk allele for HbA1c and glucose, respectively. In contrast, the <it>WDR72 </it>risk variant showed a borderline association with reduced HbA1c levels (<it>β </it>= -0.21, <it>P </it>= 0.06), and direction consistent with decreased glucose levels (<it>β </it>= -0.29, <it>P </it>= 0.29). The allele count model gave no evidence for a relationship between increasing number of risk alleles and increasing HbA1c levels (<it>β </it>= 0.04, <it>P </it>= 0.38).</p> <p>Conclusions</p> <p>The four recently reported SNPs affecting glycemic control in type 1 diabetes had no apparent effect on HbA1c in type 2 diabetes individually or by using a combined genetic score model. However, for the <it>SORCS1 </it>SNP, our findings do not rule out a possible relationship with HbA1c levels. Hence, further studies in other populations are needed to elucidate whether these novel sequence variants, especially rs1358030 near the <it>SORCS1 </it>locus, affect glycemic control in type 2 diabetes.</p

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

Modeling and Simulation of Ballistic Impact

Numerical simulations are increasingly becoming an important tool to obtain efficient designs of protective structures, and the existing literature shows that many phenomena can be accurately described by standard methods and models. This thesis, specifically, focuses on novel methods of modeling and simulating ballistic impact. Experiments are needed to validate such simulations, so numerous tests were conducted to investigate how projectile nose-shape, plate layering, target strength, ductility, and work hardening affect the penetration and perforation behavior of various structural configurations. Aluminum plates, steel plates, sand, and sand in combination with aluminum profiles were considered. These tests provide new information about the behavior of materials subjected to ballistic impact, and are valuable input for the evaluation of the numerical simulations. The novel node-splitting method, used to introduce fracture into a numerical model, and a newly implemented discrete particle method were particularly important in this work. The thesis consists of six individual parts. They are contextualized and linked together by a synopsis which includes a state-of-the-art of numerical modeling of ballistic impact and the objectives and scope of the thesis, along with summaries of the different parts, an overall conclusion and suggestions for further work. Part 1 considers low-velocity impact of layered thin steel plates. Two impactor nose shapes were used: blunt and ogival. The experimental setup is explained in detail and it was found that the resistance to perforation is highest for the blunt-nosed impactor. It was further seen that a monolithic configuration dissipates more energy than a layered configuration of the same thickness. The numerical model was able to predict the correct failure mechanisms and the trends from the experiments; however, a one-to-one relation between simulations and experiments was not obtained. In Part 2, microstructural modeling was used to determine the constitutive behavior of the base material and the heat affected zone (HAZ) of welded Al-Mg-Si aluminum alloy extrusions. Finite element simulations were conducted of impacts by 7.62 mm armor piercing bullets. The experimental validation showed that the purely numerical procedure to estimate the perforation capacity was accurate. Part 3 investigated the influence of target fragmentation on the capacity of plates subjected to ballistic impact. This was done by firing blunt and ogival-nosed projectiles at 20 mm thick plates made of four different tempers of aluminum alloy AA6070. It was shown that strength is not the only important parameter for the perforation resistance; ductility must be factored into the design as well. Node splitting, where new element faces are created at failure, was applied and evaluated in the numerical part. It was found to give as good, or better, results than conventional element erosion. In Part 4, node splitting was used to simulate ballistic impact on layered and surface-hardened steel plates. 7.62 mm armor piercing bullets struck 12 mm thick plate configurations (1x12 mm, 2x6 mm or 3x4 mm). Plate layering was found to be disadvantageous, especially for the surface-hardened plates. Numerical simulations adequately reproduced the experimental behavior. Part 5 and Part 6 looked at penetration and perforation of sand at both high and low impact velocities. A discrete particle method (DPM) where each individual sand grain is treated as a particle was used in the numerical parts of these studies. The DPM gave promising qualitative and quantitative results, and if we also consider results from other studies it becomes clear that the DPM has the potential to be used in a wide range of applications

Effects of Heat Treatment on the Ballistic Properties of AA6070 Aluminium Plates

The thesis includes a summary of important theory in the fields of impact engineering and plasticity theory, and a literature study is carried out on aluminium designations, alloying and heat treatment. The true stress-strain curves of aluminium alloy AA6070 in O-, T4-, T6-, and T7-configurations are identified by tensile tests where the behavior is continuously measured to fracture. The aluminium was delivered as 20 mm rolled plates; microstructural images and strain ratios are reported. Material constants are found by direct calibration and inverse modeling. Ballistic tests are done in a laboratory using 7.62 mm APM2 bullets, 20 mm blunt projectiles and 20 mm ogival projectiles (CRH = 3). From these tests the ballistic limit curves and the ballistic limit velocities are found for all temper/projectile combinations. In the material tests it was shown that the O-temper is the most ductile temper and consequently almost no fragmentation takes place in the ballistic tests for this temper. The T6-temper proved to be brittle, and fragmentation was commonly seen in the ballistic tests. The degree of fragmentation is found to be of vital importance for the ballistic performance. The Cockcroft-Latham fracture criterion is implemented by using the plastic work to fracture. Numerical analyses are performed with the IMPETUS Afea Solver and LS-DYNA, with 3D-models and 2D axisymmetric models, respectively. Ballistic limit curves and the ballistic limit velocities are calculated on the basis of the numerical results and then compared to the experimental values. Limited sensitivity studies are conducted on mesh size, heat-expansion dependency, strain-rate dependency, etc. Overall the results from 2D axisymmetric models are found to be consistent with previous studies, and the 3D-analyses carried out with the IMPETUS Afea Solver gave some good results. The IMPETUS Afea Solver proved to be a user-friendly finite element program with some powerful features. In addition to the numerical studies, a thorough derivation of the Cylindrical Cavity Expansion Theory (CCET) is given. Results from CCET are good for 7.62 mm APM2 bullets. A case-study where the ballistic performance is determined without conducting any experiments is also conducted. The results are promising, but less conservative than the original simulations, due to the inability to calibrate a fracture criterion. Some suggestions for further work within the field of impact engineering and the application of the finite element method are provided at the end of the thesis, followed by an appendix that includes graphical representations and photographs of the multiple material tests and program-codes written for use in the thesis

Discrete modeling of low-velocity penetration in sand

In this paper, a discrete particle method was evaluated and used in numerical simulations of low-velocity penetration in sand. Hemispherical, blunt, and ogival-nosed impactors were tested at striking velocities below 5 m/s. The tests were conducted in a dropped-object-rig where the resisting force from the sand was measured continuously during the experiments. This provided a basis for comparison for the simulations. The shapes of the force-penetration depth curves were different for the various impactors, but the ultimate penetration depths were similar in all tests that were done with the same impact velocity. Three-dimensional discrete particle simulations were generally capable of describing the behavior of the sand. However, the peak resisting force was underestimated, which led to a slight overestimation of the ultimate penetration depth. This discrete particle method has previously been evaluated at high impact velocities. The results presented in this study supplement past results and show that the method can also be used to describe the overall response of sand subjected to low-velocity penetration

Ballistic-Limit Velocities for 7.62 mm APM2 Bullets and Aluminum Alloy Armor Plates

In a previous paper, we presented a scaling law for the ballistic-limit velocity for the 7.62 mm APM2 bullet and aluminum armor plates. This scaling law predicts that the ballistic-limit velocity is proportional to the square root of the product of plate thickness and a material strength term. In this note, we present additional ballistic data from the US Army Research Laboratory (ARL) and the Norwegian University of Science and Technology (NTNU) to show that this scaling law is accurate for eight aluminum alloys, plate thicknesses from 10 to 60 mm, and yield strengths from 51 to 414 MPa

Influence of yield-surface shape in simulation of ballistic impact

A high-exponent yield criterion is applied in 3D nonlinear finite element simulations of ballistic impact. The computational models are based on a comprehensive experimental study including material tests of 12 mm thick high-strength Weldox 700 E steel plates and ballistic tests where the plates were struck by blunt-nosed and ogive-nosed projectiles with a diameter of 20 mm and a mass of approximately 200 g. We thoroughly describe the constitutive model and the numerical modeling procedure. The simulation results are discussed in light of the perforation mechanisms as well as the experimental results. Changing the shape of the yield surface in the deviatoric plane increases the residual velocity of the projectile and the effect was largest in simulations with the blunt-nosed projectile. Although the difference in residual velocity can be significant close to the ballistic limit velocity, the variation in predicted ballistic limit velocity itself was not more than 7%. To put this into context, the effect of the yield-surface shape was compared to the effects of changing the parameters controlling friction, rate sensitivity, adiabatic heating, and temperature softening. These results suggest that a high-exponent yield criterion is not essential for ordinary steels and aluminum alloys where moderate yield-surface exponents are expected

Experiments and simulations of empty and sand-filled aluminum alloy panels subjected to ballistic impact

In this study, we use a discrete particle method in combination with finite element analysis to describe the interaction between structures and granular media during ballistic impact. By applying a discrete particle method to model granular materials, issues like mesh distortion and element deletion can be avoided. This paper presents experiments and numerical simulations on the perforation of empty and sand-filled aluminum alloy panels subjected to impacts by small-arms bullets. The simulations of the sand-filled panels were conducted using a combined discrete particle–finite element approach that accounts for the coupling between structure and sand. The ballistic capacity of the sand-filled aluminum panels was more than 40% higher than that of the empty aluminum panels. Overall, the results from the numerical simulations describe the trends from the experiments. The predicted ballistic capacity of the empty panels was within 5% of the experimentally determined value and the critical velocity of the sand-filled panels was predicted within 11% of the experimentally determined critical velocity. The scatter in residual velocity was similar in simulations and experiments. However, in its current form the discrete particle method needs different calibrations for different velocity regimes to obtain accurate description of the sand behavior

Low-velocity impact on multi-layered dual-phase steel plates

In this paper an experimental program investigating the behavior of monolithic and multi-layered configurations of 0.8 mm and 1.8 mm medium-strength steel plates is presented. We have considered impacts by blunt-ended and ogival-ended impactors in the low-velocity regime (≤16 m/s). Experimental outputs include measurements of force and velocity, and deformation fields. Force and velocity readings were provided by a strain-gauge instrumented striker, while digital image correlation was used to obtain the displacement field from the rear side of the bottom plate. For the 0.8 mm plates a near linear relationship between the number of layers and the ballistic limit velocity was found. The plates' resistance against perforation was found to be higher for the blunt-ended impactor than for the ogival-ended impactor. This can be explained by the failure mechanisms. The monolithic plates have a higher capacity than layered plates with the same total thickness: this is particularly clear for plates struck by the ogival-ended impactor. The experiments provide ample data to validate the subsequent 3D numerical simulations. The analysis model is double-symmetric in simulations using the ogival-ended impactor, while only a 10° slice of the plate and impactor is needed in simulations using the blunt-ended impactor. A thermoelastic–thermoviscoplastic constitutive relation combined with the Cockcroft-Latham criterion for failure is implemented in IMPETUS Afea Solver, and used in all simulations. The simulations predict the failure modes fairly well, and the numerical results are within the range seen in previous publications. Sensitivity studies regarding friction, mesh refinement, thermal formulation and strain-rate dependence are conducted and discussed

Experimental tests and numerical simulations of ballistic impact on laminated glass

In this study, we investigate double-laminated glass plates under ballistic impact through experimental tests and numerical simulations. The experimental tests are used to determine the ballistic limit velocity and curve for the laminated glass targets, and to create a basis for comparison with numerical simulations. We tested two different glass pane configurations: (1) one double-laminated glass plate, and (2) two layers of double-laminated glass plates separated by an airgap. In the numerical study, we used finite element simulations that employed higher order elements and 3D node splitting to predict the residual velocities of the bullets in the experiments. Node splitting enabled modelling of fracture by element separation and was employed for the glass parts. The material and fracture models that we used for the glass and the PVB parts were simplified, but the numerical predictions proved to be in excellent agreement with the experimental results