African-American (AA) women have earlier menarche on average than women of European ancestry (EA), and earlier menarche is a risk factor for obesity and type 2 diabetes among other chronic diseases. ...Identification of common genetic variants associated with age at menarche has a potential value in pointing to the genetic pathways underlying chronic disease risk, yet comprehensive genome-wide studies of age at menarche are lacking for AA women. In this study, we tested the genome-wide association of self-reported age at menarche with common single-nucleotide polymorphisms (SNPs) in a total of 18 089 AA women in 15 studies using an additive genetic linear regression model, adjusting for year of birth and population stratification, followed by inverse-variance weighted meta-analysis (Stage 1). Top meta-analysis results were then tested in an independent sample of 2850 women (Stage 2). First, while no SNP passed the pre-specified P < 5 × 10(-8) threshold for significance in Stage 1, suggestive associations were found for variants near FLRT2 and PIK3R1, and conditional analysis identified two independent SNPs (rs339978 and rs980000) in or near RORA, strengthening the support for this suggestive locus identified in EA women. Secondly, an investigation of SNPs in 42 previously identified menarche loci in EA women demonstrated that 25 (60%) of them contained variants significantly associated with menarche in AA women. The findings provide the first evidence of cross-ethnic generalization of menarche loci identified to date, and suggest a number of novel biological links to menarche timing in AA women.
The Ki-67 staining index (Ki67-SI) has been associated with prostate cancer patient outcome; however, few studies have involved radiotherapy (RT) -treated patients. The association of Ki67-SI to ...local failure (LF), biochemical failure (BF), distant metastasis (DM), cause-specific death (CSD) and overall death (OD) was determined in men randomly assigned to short term androgen deprivation (STAD) + RT or long-term androgen deprivation (LTAD) + RT.
There were 537 patients (35.5%) on Radiation Therapy Oncology Group (RTOG) 92-02 who had sufficient tissue for Ki67-SI analysis. Median follow-up was 96.3 months. Ki67-SI cut points of 3.5% and 7.1% were previously found to be related to patient outcome and were examined here in a Cox proportional hazards multivariate analysis (MVA). Ki67-SI was also tested as a continuous variable. Covariates were dichotomized in accordance with stratification and randomization criteria.
Median Ki67-SI was 6.5% (range, 0% to 58.2%). There was no difference in the distribution of patients in the Ki-67 analysis cohort (n = 537) and the other patients in RTOG 92-02 (n = 977) by any of the covariates or end points tested. In MVAs, Ki67-SI (continuous) was associated with LF (P =.08), BF (P =.0445), DM (P <.0001), CSD (P <.0001), and OD (P =.0094). When categoric variables were used in MVAs, the 3.5% Ki67-SI cut point was not significant. The 7.1% cut point was related to BF (P =.09), DM (P =.0008), and CSD (P =.017). Ki67-SI was the most significant correlate of DM and CSD. A detailed analysis of the hazard rates for DM in all possible covariate combinations revealed subgroups of patients treated with STAD + RT that did not require LTAD.
Ki67-SI was the most significant determinant of DM and CSD and was also associated with OD. The Ki67-SI should be considered for the stratification of patients in future trials.
A new structure of cross-coupling controller for precise tracking in motion control is proposed in this paper. When compared with the conventional cross-coupling system, this new structure has the ...advantage that the compensators in CCC have a simpler design process than conventional ones and so does its stability analysis. The proposed compensator (or controller) is evaluated and compared experimentally with a traditional uncoupled controller on a microcomputer controlled dual-axis positioning system. The experimental results show that the new structure of cross-coupling controller remarkably reduces contour error. In addition, this new controller can be implemented easily on a majority of motion systems in use today via reprogramming the reference position command subroutine.
The European Commission asked EFSA for a scientific evaluation on the risks to human health related to the presence of perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) in food. ...Regarding PFOS and PFOA occurrence, the final data set available for dietary exposure assessment contained a total of 20,019 analytical results (PFOS n = 10,191 and PFOA n = 9,828). There were large differences between upper and lower bound exposure due to analytical methods with insufficient sensitivity. The CONTAM Panel considered the lower bound estimates to be closer to true exposure levels. Important contributors to the lower bound mean chronic exposure were ‘Fish and other seafood’, ‘Meat and meat products’ and ‘Eggs and egg products’, for PFOS, and ‘Milk and dairy products’, ‘Drinking water’ and ‘Fish and other seafood’ for PFOA. PFOS and PFOA are readily absorbed in the gastrointestinal tract, excreted in urine and faeces, and do not undergo metabolism. Estimated human half‐lives for PFOS and PFOA are about 5 years and 2–4 years, respectively. The derivation of a health‐based guidance value was based on human epidemiological studies. For PFOS, the increase in serum total cholesterol in adults, and the decrease in antibody response at vaccination in children were identified as the critical effects. For PFOA, the increase in serum total cholesterol was the critical effect. Also reduced birth weight (for both compounds) and increased prevalence of high serum levels of the liver enzyme alanine aminotransferase (ALT) (for PFOA) were considered. After benchmark modelling of serum levels of PFOS and PFOA, and estimating the corresponding daily intakes, the CONTAM Panel established a tolerable weekly intake (TWI) of 13 ng/kg body weight (bw) per week for PFOS and 6 ng/kg bw per week for PFOA. For both compounds, exposure of a considerable proportion of the population exceeds the proposed TWIs.
Artificial sensory disturbances (sound and light) can extend far beyond the physical footprint of human development. Nocturnal predators such as owls may be influenced by artificial sound and light, ...as they depend on aural and visual cues when hunting. Owl nocturnal movements may also be altered by physical changes to the landscape, as these can affect prey availability. The burrowing owl population in Canada has declined by 90% and was classified as endangered in 1995. We tracked adult male burrowing owls Athene cunicularia with GPS dataloggers, and used resource selection models to examine their night-time movement patterns in relation to human infrastructure and associated artificial light and sound. The amount of sound and light from compressor stations, oil wells, traffic, towns and buildings was calculated for each owl and random location. We found that owl night-time space use was better predicted by distance to infrastructure on the landscape than by intensity of sensory disturbance. Burrowing owls did not show a pronounced avoidance of artificial sound. Infrastructure best predicts owl space use, perhaps because associated changes to vegetation alter prey abundance and availability. While human infrastructure most influenced owl nocturnal space use, the extent to which ecosystems are impacted by artificial sound and light is becoming clearer and needs to be considered when assessing the total effect of human development on species.
Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that ...strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124A), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (−0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10−88). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio OR = 2.2, 95% confidence interval CI = 1.78–2.78, p = 1.26 × 10−12). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19–1.64, p = 2.63 × 10−5) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.
Esophageal adenocarcinoma (EAC) arises after normal squamous mucosa undergoes metaplasia to specialized columnar epithelium (intestinal metaplasia or Barrett's esophagus), which can then ultimately ...progress to dysplasia and subsequent malignancy. Epigenetic studies of this model have thus far been limited to the DNA methylation analysis of a few genes. In this study, we analyzed a panel of 20 genes using a quantitative, high-throughput methylation assay, METHYLIGHT: We used this broader approach to gain insight into concordant methylation behavior between genes and to generate epigenomic fingerprints for the different histological stages of EAC. Our study included a total of 104 tissue specimens from 51 patients with different stages of Barrett's esophagus and/or associated adenocarcinoma. We screened 84 of these samples with the full panel of 20 genes and found distinct classes of methylation patterns in the different types of tissue. The most informative genes were those with an intermediate frequency of significant hypermethylation ranging from 15% (CDKN2A) to 60% (MGMT) of the samples. This group could be further subdivided into three classes, according to the absence (CDKN2A, ESR1, and MYOD1) or presence (CALCA, MGMT, and TIMP3) of methylation in normal esophageal mucosa and stomach, or the infrequent methylation of normal esophageal mucosa accompanied by methylation in all normal stomach samples (APC). The other genes were less informative, because the frequency of hypermethylation was below 5% (ARF, CDH1, CDKN2B, GSTP1, MLH1, PTGS2, and THBS1), completely absent (CTNNB1, RB1, TGFBR2, and TYMS1), or ubiquitous (HIC1 and MTHFR), regardless of tissue type. Each class undergoes unique epigenetic changes at different steps of disease progression of EAC, suggesting a step-wise loss of multiple protective barriers against CpG island hypermethylation. The aberrant hypermethylation occurs at many different loci in the same tissues, suggestive of an overall deregulation of methylation control in EAC tumorigenesis. However, we did not find evidence for a distinct group of tumors with a CpG island methylator phenotype. Finally, we found that normal and metaplastic tissues from patients with evidence of associated dysplasia or cancer had a significantly higher incidence of hypermethylation than similar tissues from patients with no further progression of their disease. The fact that the samples from these two groups of patients were histologically indistinguishable, yet molecularly distinct, suggests that the occurrence of such hypermethylation may provide a clinical tool to identify patients with premalignant Barrett's who are at risk for further progression.
In the past few years the increased luminosity of the LHC, changes in the linux kernel and a move to a 64bit architecture have affected the ATLAS jobs memory usage and the ATLAS workload management ...system had to be adapted to be more flexible and pass memory parameters to the batch systems, which in the past wasn't a necessity. This paper describes the steps required to add the capability to better handle memory requirements, included the review of how each component definition and parametrization of the memory is mapped to the other components, and what changes had to be applied to make the submission chain work. These changes go from the definition of tasks and the way tasks memory requirements are set using scout jobs, through the new memory tool developed to do that, to how these values are used by the submission component of the system and how the jobs are treated by the sites through the CEs, batch systems and ultimately the kernel.
Sleep monitoring is an important issue and has drawn considerable attention in medicine and healthcare. Given that traditional approaches, such as polysomnography, are usually costly, and often ...require subjects to stay overnight at clinics, there has been a need for a low-cost system suitable for long-term sleep monitoring. In this paper, we propose a system using low-cost multimodality sensors such as video, passive infrared, and heart-rate sensors for sleep monitoring. We apply machine learning methods to automatically infer a person's sleep state, especially differentiating sleep and wake states. This is useful information for inferring sleep latency, efficiency, and duration that are important for long-term monitoring of sleep quality in healthy individuals and in those with a sleep-related disorder diagnosis. Our experiments show that the proposed approach offers reasonable performance compared to an existing standard approach (i.e., actigraphy), and that multimodality data fusion can improve the robustness and accuracy of sleep state detection.
Esophageal adenocarcinoma (EAC) is thought to develop through a multistage process in which Barrett's metaplasia progresses through low- and high-grade dysplasia to invasive cancer. Transcriptional ...silencing of tumor suppressor genes by promoter CpG island hypermethylation has been observed in many types of human cancer. Analysis of CpG island hypermethylation in EAC has thus far been limited to the CDKN2A (p16) gene. In this study, we extend the methylation analysis of EAC to include three other genes, APC, CDH1 (E-cadherin), and ESR1 (ER, estrogen receptor alpha), in addition to CDKN2A. Molecular analysis can provide insight into the complex relationships between tissues with different histologies in Barrett's esophagus and associated adenocarcinoma. Therefore, we have mapped the spatial distribution of methylation patterns in six esophagectomy cases in detail. Hypermethylation of the four CpG islands was analyzed by the MethyLight technique in 107 biopsies derived from these six patients for a total of 428 methylation analyses. Our results show that normal esophageal squamous epithelium is unmethylated at all four CpG islands. CDH1 is unmethylated in most other tissue types as well. Hypermethylation of ESR1 is seen at high frequency in inflammatory reflux esophagitis and at all subsequent stages, whereas APC and CDKN2A hypermethylation is found in Barrett's metaplasia, dysplasia, and EAC. When it occurs, hypermethylation of APC, CDKN2A, and ESR1 is usually found in a large contiguous field, suggesting either a concerted methylation change associated with metaplasia or a clonal expansion of cells with abnormal hypermethylation.
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