Lack of Association of Type 2 Diabetes Susceptibility Genotypes and Body Weight on the Development of Islet Autoimmunity and Type 1 Diabetes

AIM: To investigate whether type 2 diabetes susceptibility genes and body weight influence the development of islet autoantibodies and the rate of progression to type 1 diabetes. METHODS: Genotyping for single nucleotide polymorphisms (SNP) of the type 2 diabetes susceptibility genes CDKAL1, CDKN2A/2B, FTO, HHEX-IDE, HMGA2, IGF2BP2, KCNJ11, KCNQ1, MTNR1B, PPARG, SLC30A8 and TCF7L2 was obtained in 1350 children from parents with type 1 diabetes participating in the BABYDIAB study. Children were prospectively followed from birth for islet autoantibodies and type 1 diabetes. Data on weight and height were obtained at 9 months, 2, 5, 8, 11, and 14 years of age. RESULTS: None of type 2 diabetes risk alleles at the CDKAL1, CDKN2A/2B, FTO, HHEX-IDE, HMGA2, IGF2BP2, KCNJ11, KCNQ1, MTNR1B, PPARG and SLC30A8 loci were associated with the development of islet autoantibodies or diabetes. The type 2 diabetes susceptible genotype of TCF7L2 was associated with a lower risk of islet autoantibodies (7% vs. 12% by age of 10 years, P = 0.015, P(corrected) = 0.18). Overweight children at seroconversion did not progress to diabetes faster than non-overweight children (HR: 1.08; 95% CI: 0.48-2.45, P>0.05). CONCLUSIONS: These findings do not support an association of type 2 diabetes risk factors with islet autoimmunity or acceleration of diabetes in children with a family history of type 1 diabetes

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Laboratory Evaluation and Construction of Fully Recycled Low-Temperature Asphalt for Low-Volume Roads

Growing economy and increasing pollution evoke the need for more environmentally friendly road construction techniques and the saving of natural resources. In this context, cold recycling plays an important role since, on the one hand, it allows to reduce CO2 emissions drastically and, on the other hand, it offers a variety of opportunities for high percentages of recycling. Inspired by experience in Sweden, the international project “Optimal Recycling of Reclaimed Asphalts for low-traffic Pavement” (ORRAP) for low-volume roads in the Upper Rhine region aims to develop and establish a new strategy for 100% reclaimed asphalt pavement (RAP) at ambient temperature (20°C) without adding virgin bituminous binders or rejuvenators. The still ongoing research project involves laboratory experiments as well as in situ test sections. The link between small-scale laboratory experiments and in situ testing is provided by medium-scale traffic simulation in the laboratory. This paper describes results from medium-scale compaction in the laboratory using different methods as well as traffic simulation with a medium-scale mobile traffic load simulator. The results show that compaction in the laboratory at ambient temperature (20°) is very difficult to achieve. Nevertheless, it was found that compaction at a temperature of 60°C appears possible and provides promising results regarding stability and rutting enabling the in situ construction. The in situ pavement construction at ambient temperature on a low-volume road in Switzerland resulted in a visibly well-compacted and stable base course which was covered by a hot mix asphalt surface course the day after. The test section will be monitored closely over the next 12 months

Effects of Moisture and Aging on Asphalt Binder Adhesion Failure Using Pull-Off Tension Test

Moisture damage is mainly characterized by the loss of adhesion between asphalt binder and aggregate and the loss of cohesion within the asphalt binder. The binder holds the aggregates firmly together and acts as a sealant against moisture ingress. Additives are added to enhance the performance-related properties of asphalt mixtures under different climatic and environmental conditions. In this study, warm mix additive was used to modify the asphalt binder PG-64. The asphalt binder modified with chemical surfactant based additive was tested against pull-off tension force using limestone aggregate substrates. The specimens were conditioned using accelerated laboratory vacuum saturator (ALVS). The results showed that the percent adhesion failure increased when specimens were subjected to moisture conditioning. Furthermore, adhesion failure also increased with binder aging and enhanced further when the binders were long term aged

Investigation into a Long-Term Interlayer Bonding of Asphalt Pavements

In recent years adhesion testing of pavement layers has gained more and more importance throughout Europe. In a lot of projects the bonding properties are determined after construction and many countries have developed standard requirements which the obtained bonding values have to fulfil.The paper focuses on the question of long-term behaviour of bonding properties and presents the results of an extensive Swiss study. The study compares the bonding properties determined with the Layer Parallel Direct Shear Test (LPDS) according to Leutner of 14 high volume roads from the years 1993–97 to the values for the same road sections determined 9–13 years later. In addition, a second study conducted on a circular track investigated the differences between the bonding properties in the wheel path and outside the wheel path. It could be shown that in most cases the bond improves due to compaction and settlement caused by the traffic. Problems arise, resulting in a reduction of shear forces, when the pavement shows distress phenomena. The difference between the bonding properties in the wheel path and outside it could be demonstrated in the circular track study, whereas the differences on the road depend on many factors and often seem to be eliminated over the years

Ageing and performance of warm mix asphalt pavements

This paper presents results from investigating the ageing behaviour and performance of different warm mix asphalt (WMA) pavement mixtures also called energy reduced pavements. The mixtures were either prepared in the laboratory or taken directly from a mixing plant. The study compared the rutting and fatigue behaviours of unaged material in comparison to long term laboratory aged material. In order to conduct the long term ageing, a special laboratory ageing protocol with different heating, cooling and watering cycles had been developed. The investigation revealed a quite controversial rutting behavior which could not be explained with the available data. While most aged energy reduced pavements showed increased rutting for other mixtures, lower rut depths could be found. As opposed to this finding, fatigue and stiffness of all aged energy reduced pavement samples compared to unaged samples improved significantly. The overall results led to the conclusion that the ageing of energy reduced pavement simulated in the laboratory is not very critical regarding their mechanical performance. Therefore, it was confirmed that the application of this type of pavement provides a good solution for saving on CO2 emissions. Another advantage is that by using energy reduced pavements the road construction season can be significantly prolonged

Recommendation of RILEM TC 241-MCD on Interface Debonding Testing in Pavements

International audienceThe following recommendations are based on the chapter III of a State of the Art review conducted by the Task Group 2 of the RILEM Technical Committee 241-MCD 'Mechanisms of cracking and debonding in asphalt and composite pavements' (Petit et al in Mechanisms of cracking and debonding in asphalt and composite pavements. Chapter III of the State-of-the-Art report of the RILEM technical committee 241-MCD series, vol 28. Springer, New York, pp 103-154. ISBN 978-3-319-76848-9 2018). The recommendations mostly concern 'pure' fracture mode test methods that are currently used worldwide and even standardized, while mixed mode test methods developed by few research teams have not received full attention. This paper intends to give guidance for the application and characterization of interlayer bond testing, looking at the appropriate test methods and the importance of influencing parameters

Interface debonding behaviour: Chapter III of the State-of-the-Art Report of RILEM Technical Committee 241-MCD Series

International audienceThe performance and durability of multi-layered pavements strongly depend on interlayer bonding between layers, especially for pavements with a thin or ultra-thin surface course. These pavements, comprised of several differing material layers, are often subjected to premature distresses (corrugation, peeling, slippage or fatigue cracking, etc.) caused by poor interface bonding. This chapter summarizes the different bond characterization tests available around the world (mostly in the laboratory) available to characterize the bond between pavement layers. Many of the tests can be performed on specimens prepared in the laboratory or on cores or slabs obtained from the pavement. Mostly, 'pure' fracture mode test methods (opening mode I or in-plane, shear mode II or out-of-plane, shear mode III) are currently used worldwide for determining the interlayer bond of pavement layers. Most of the mixed-mode test methods (mainly for the combination of Modes I and II) were developed by a few research teams and there are therefore no standard tests. Although tack coat type and content are the main parameters studied by researchers and engineers, surface roughness, moisture, freezing, and presence of dust or debris on the interface are additional parameters that may decrease bonding performance

Experimental and numerical modelling of shear bonding between asphalt layers

Interlayers in asphalt pavements are potential structural damage initiators. In order to better understand the quantitative role of interlayer parameters, such as surface roughness, binder type, binder content and loading type on interlayer shear strength, this paper focuses on the effects of particle interlock and contact conditions on interlayer strength through experimental and numerical modelling. Experimentally, interlayer shear box strength tests on a model material consisting of stiff binder blended with steel balls are performed with and without normal force confinement. A Discrete Element method model of the test is developed using measurements of the model material for calibrating the contact law and for validating the model. It is shown that this model captures adequately the measured force-displacement response of the specimens. It is thus a feasible starting point for numerically and experimentally studying the role of binder and tack coat regarding interlayer shear strength of real asphalt layers