The depletion of disruptive variation caused by purifying natural selection (constraint) has been widely used to investigate protein-coding genes underlying human disorders
, but attempts to assess ...constraint for non-protein-coding regions have proved more difficult. Here we aggregate, process and release a dataset of 76,156 human genomes from the Genome Aggregation Database (gnomAD)-the largest public open-access human genome allele frequency reference dataset-and use it to build a genomic constraint map for the whole genome (genomic non-coding constraint of haploinsufficient variation (Gnocchi)). We present a refined mutational model that incorporates local sequence context and regional genomic features to detect depletions of variation. As expected, the average constraint for protein-coding sequences is stronger than that for non-coding regions. Within the non-coding genome, constrained regions are enriched for known regulatory elements and variants that are implicated in complex human diseases and traits, facilitating the triangulation of biological annotation, disease association and natural selection to non-coding DNA analysis. More constrained regulatory elements tend to regulate more constrained protein-coding genes, which in turn suggests that non-coding constraint can aid the identification of constrained genes that are as yet unrecognized by current gene constraint metrics. We demonstrate that this genome-wide constraint map improves the identification and interpretation of functional human genetic variation.
Background New endoscopic imaging techniques, such as autofluorescence imaging (AFI) and narrow-band imaging (NBI), have been developed to improve the detection of neoplastic lesions in Barrett's ...esophagus (BE). Objective To evaluate the clinical utility of AFI and magnification NBI to detect high-grade dysplasia (HGD) and early esophageal adenocarcinoma (EAC) and the interobserver agreement. Design Prospective tandem study of eligible patients. Setting Single, academic tertiary care center. Patients Forty-two patients with a history of confirmed BE were prospectively enrolled. Interventions The BE segment was examined under high-definition white-light endoscopy, and the presence of visible lesions was recorded. Subsequently, AFI and magnification NBI were performed in tandem on areas of the BE segment away from visible lesions; images obtained by these 2 systems were graded according to the color of reflected light and surface patterns, respectively. Biopsy specimens were obtained at the end of the procedure. Main Outcome Measurements The sensitivity, specificity, positive predictive value, and negative predictive value (NPV) of the AFI and NBI patterns for the detection of HGD/EAC and interobserver agreement. Results Of the 42 patients enrolled, 14 (33%) had HGD/EAC. On patient-based analysis, AFI alone had a sensitivity, specificity, and NPV of 50%, 61%, and 71%, respectively, and the overall accuracy for the detection of HGD/EAC patients was 57%. By using magnification NBI in tandem fashion, the sensitivity and NPV improved to 71% and 76%, respectively, with a decrease in specificity to 46% and in overall accuracy to 55%. The 2 techniques had moderate interobserver agreement for both the patterns and prediction of histology. Limitations Uncontrolled study performed at an academic center by expert endoscopists in a high-risk population. Conclusions By using a multimodality endoscope, both AFI and magnification NBI had limited clinical accuracy and moderate overall interobserver agreement. AFI does not appear to be useful as a broad-based technique for the detection of neoplasia in patients with BE.
Vitamin D deficiency in Europe: pandemic? Cashman, Kevin D; Dowling, Kirsten G; Škrabáková, Zuzana ...
The American journal of clinical nutrition,
04/2016, Letnik:
103, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Vitamin D deficiency has been described as being pandemic, but serum 25-hydroxyvitamin D 25(OH)D distribution data for the European Union are of very variable quality. The NIH-led international ...Vitamin D Standardization Program (VDSP) has developed protocols for standardizing existing 25(OH)D values from national health/nutrition surveys.
This study applied VDSP protocols to serum 25(OH)D data from representative childhood/teenage and adult/older adult European populations, representing a sizable geographical footprint, to better quantify the prevalence of vitamin D deficiency in Europe.
The VDSP protocols were applied in 14 population studies reanalysis of subsets of serum 25(OH)D in 11 studies and complete analysis of all samples from 3 studies that had not previously measured it by using certified liquid chromatography-tandem mass spectrometry on biobanked sera. These data were combined with standardized serum 25(OH)D data from 4 previously standardized studies (for a total n= 55,844). Prevalence estimates of vitamin D deficiency using various serum 25(OH)D thresholds were generated on the basis of standardized 25(OH)D data.
An overall pooled estimate, irrespective of age group, ethnic mix, and latitude of study populations, showed that 13.0% of the 55,844 European individuals had serum 25(OH)D concentrations <30 nmol/L on average in the year, with 17.7% and 8.3% in those sampled during the extended winter (October-March) and summer (April-November) periods, respectively. According to an alternate suggested definition of vitamin D deficiency (<50 nmol/L), the prevalence was 40.4%. Dark-skinned ethnic subgroups had much higher (3- to 71-fold) prevalence of serum 25(OH)D <30 nmol/L than did white populations.
Vitamin D deficiency is evident throughout the European population at prevalence rates that are concerning and that require action from a public health perspective. What direction these strategies take will depend on European policy but should aim to ensure vitamin D intakes that are protective against vitamin D deficiency in the majority of the European population.
BSCF5582 tubular oxygen separation membranes were prepared using the most cost effective slip casting techniques. The optimum slurry composition was identified and a dense, and crack free 60mm long ...BSCF5582 tubular membrane being successfully prepared after the programmed sintering process. The effects of the feed flow rate and the sweeping flow rate on the oxygen permeation flux of the tubular BSCF5582 membrane were investigated. The oxygen permeation flux increased with an increase of the oxygen chemical potential gradient to a maximum of 42.5cm3/min in an O2/N2 condition at 1223K for the 1.5mm thick, 60mm long BSCF tube, a value which corresponds to 1.42cm3/mincm2. The ionic conductivity of the oxygen was successfully calculated in the dominant electron conducting regime. The ionic conductivity was found to increase with an increase of the temperature to 900°C, indicating that it is a thermally activated process with an activation energy of 0.70±0.1eV in an air environment.
A new maximum power point tracker (MPPT) for a grid-connected photovoltaic system without solar array current sensor is proposed. The solar array current information is obtained from the sliding-mode ...observer and fed into the MPPT to generate the reference voltage. The parameter values such as capacitances can be changed up to 50% from their nominal values, and the linear observer cannot estimate the correct state values under the parameter variations and noisy environments. The structure of a sliding-mode observer is simple, but it shows the robust tracking property against modeling uncertainties and parameter variations. In this paper, the sliding-mode observer for the solar array current has been proposed to compensate for the parameter variations. The mathematical modeling and the experimental results verify the validity of the proposed method
We present the results of an optical spectroscopic monitoring program targeting NGC 5548 as part of a larger multiwavelength reverberation mapping campaign. The campaign spanned 6 months and achieved ...an almost daily cadence with observations from five ground-based telescopes. The Hβ and He ii λ4686 broad emission-line light curves lag that of the 5100 optical continuum by and , respectively. The Hβ lag relative to the 1158 ultraviolet continuum light curve measured by the Hubble Space Telescope is ∼50% longer than that measured against the optical continuum, and the lag difference is consistent with the observed lag between the optical and ultraviolet continua. This suggests that the characteristic radius of the broad-line region is ∼50% larger than the value inferred from optical data alone. We also measured velocity-resolved emission-line lags for Hβ and found a complex velocity-lag structure with shorter lags in the line wings, indicative of a broad-line region dominated by Keplerian motion. The responses of both the Hβ and He ii emission lines to the driving continuum changed significantly halfway through the campaign, a phenomenon also observed for C iv, Ly , He ii(+O iii), and Si iv(+O iv) during the same monitoring period. Finally, given the optical luminosity of NGC 5548 during our campaign, the measured Hβ lag is a factor of five shorter than the expected value implied by the RBLR-LAGN relation based on the past behavior of NGC 5548.
Background The Global Registry of Acute Coronary Events (GRACE) risk model provides a simple method for determining the probability of hospital death in acute coronary syndrome (ACS). The aim of this ...study was to explore the impact of modeling techniques on the risk model when generating predictions. Methods Patients with ACS (n = 48,023) with or without ST-segment elevation myocardial infarction (STEMI) were enrolled (123 hospitals, 14 countries) between April 1999 and June 2006. The original GRACE model did not include terms to account for possible differences in outcomes between patients with STEMI, non-STEMI, and unstable angina, nor did it account for changing risk across continuous measures. Results In this cohort, the influence on outcome of region of hospitalization and cardiac arrest at presentation changed over the 7-year study. Other interactions included previous percutaneous coronary intervention and age with type of ACS. However, these interactions were insufficient to affect the final risk score. The same variables as in the original score comprise the new score. Inclusion of nonlinearity and differential effects did little to change the model's discrimination but influenced predictions for patients at extremes of risk. Conclusions Irrespective of the inclusion of nonlinear and interaction terms, the updated GRACE risk model provides an excellent means to discriminate risk of death in patients with ACS and can be used as a simple nomogram to estimate risk in patients seen in clinical practice.
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