Barriers to enrollment in a randomized controlled trial of hydrocortisone for cardiovascular insufficiency in term and late preterm newborn infants.

ObjectiveTo analyze reasons for low enrollment in a randomized controlled trial (RCT) of the effect of hydrocortisone for cardiovascular insufficiency on survival without neurodevelopmental impairment (NDI) in term/late preterm newborns.Study designThe original study was a multicenter RCT. Eligibility: ⩾34 weeks' gestation, <72 h old, mechanically ventilated, receiving inotrope. Primary outcome was NDI at 2 years; infants with diagnoses at high risk for NDI were excluded. This paper presents an analysis of reasons for low patient enrollment.ResultsTwo hundred and fifty-seven of the 932 otherwise eligible infants received inotropes; however, 207 (81%) had exclusionary diagnoses. Only 12 infants were randomized over 10 months; therefore, the study was terminated. Contributing factors included few eligible infants after exclusions, open-label steroid therapy and a narrow enrollment window.ConclusionDespite an observational study to estimate the population, very few infants were enrolled. Successful RCTs of emergent therapy may require fewer exclusions, a short-term primary outcome, waiver of consent and/or other alternatives

Simultaneous Swift and REM monitoring of the blazar PKS0537-441 in 2005

The blazar PKS0537-441 has been observed by Swift between the end of 2004 and November 2005. The BAT monitored it recurrently for a total of 2.7 Ms, and the XRT and UVOT pointed it on seven occasions for a total of 67 ks, making it one of the AGNs best monitored by Swift. The automatic optical and infrared telescope REM has monitored simultaneously the source at all times. In January-February 2005 PKS0537-441 has been detected at its brightest in optical and X-rays: more than a factor of 2 brighter in X-rays and about a factor 60 brighter in the optical than observed in December 2004. The July 2005 observation recorded a fainter X-ray state. The simultaneous optical state, monitored by both Swift UVOT and REM, is high, and in the VRI bands it is comparable to what was recorded in early January 2005, before the outburst. In November 2005, the source subsided both in X-rays and optical to a quiescent state, having decreased by factors of ~4 and ~60 with respect to the January-February 2005 outburst, respectively. Our monitoring shows an overall well correlated optical and X-ray decay. On the shorter time scales (days or hours), there is no obvious correlation between X-ray and optical variations, but the former tend to be more pronounced, opposite to what is observed on monthly time scales. The widely different amplitude of the long term variability in optical and X-rays is very unusual and makes this observation a unique case study for blazar activity. The spectral energy distributions are interpreted in terms of the synchrotron and inverse Compton mechanisms within a jet where the plasma radiates via internal shocks and the dissipation depends on the distance of the emitting region from the central engine (abridged).Comment: 24 pages, 7 figures, 3 tables, in press in the Ap

Study of Gamma Ray Burst Binary Progenitors

Recently much work in studying Gamma-Ray Burst has been devoted to revealing the nature of outburst mechanism and studies of GRB afterglows. These issues have also been closely followed by the quest for identifying GRB progenitors. In this paper we consider the proposed binary star progenitors of GRBs: white dwarf neutron star binaries, white dwarf black hole binaries, helium core neutron star mergers, helium core black hole mergers, double neutron stars and neutron star black hole binaries. Using population synthesis methods we calculate merger rates of these binary progenitors and we compare them to the observed BATSE GRB rate. We also calculate the distribution of merger sites around host galaxies and compare them to the observed locations of GRB afterglows with respect to their hosts. We find that the rates of binary GRB progenitors in our standard model are lower than the observed GRB rates if GRBs are highly collimated. However, the uncertainty in the population synthesis results is too large to make this a firm conclusion. Although some observational signatures seem to point to collapsars as progenitors of long GRBs, we find that mergers of WD-NS, He-NS, He-BH, and NS-NS systems also trace the star formation regions of their host galaxies, as it is observed for long GRBs. We also speculate about possible progenitors of short-duration GRBs. For these, the most likely candidates are still mergers of compact objects. We find that the locations NS-NS and NS-BH mergers with respect to their hosts are significantly different. This may allow to distinguish between these two progenitor models, once current and near future missions, such as HETE-II or SWIFT, measure the locations of short GRBs.Comment: 26 pages, 12 figures, submitted to Ap

Discovery of a Be/X-ray Binary Consistent with the Position of GRO J2058+42

GRO J2058+42 is a 195 s transient X-ray pulsar discovered in 1995 with BATSE. In 1996, RXTE located GRO J2058+42 to a 90% confidence error circle with a 4' radius. On 20 February 2004, the region including the error circle was observed with Chandra ACIS-I. No X-ray sources were detected within the error circle, however, 2 faint sources were detected in the ACIS-I field-of-view. We obtained optical observations of the brightest object, CXOU J205847.5+414637, that had about 64 X-ray counts and was just 0.3' outside the error circle. The optical spectrum contained a strong H alpha line and corresponds to an infrared object in the 2MASS catalog, indicating a Be/X-ray binary system. Pulsations were not detected in the Chandra observations, but similar flux variations and distance estimates suggest that CXOU J205847.5+414637 and GRO J2058+42 are the same object. We present results from the Chandra observation, optical observations, new and previously unreported RXTE observations, and a reanalysis of a ROSAT observation.Comment: 18 pages, 6 figures, Accepted for publication in the Astrophysical Journa

Accelerated menopausal changes as human disease model 'FOCUM' for the development of osteoarthritis and other degenerative disorders:protocol for a prospective cohort study

INTRODUCTION: The incidence of degenerative disorders, including osteoarthritis (OA), increases rapidly in women after menopause. However, the influence of the menopause is still insufficiently investigated due to the slowness of menopausal transition. In this study, a novel human model is used in which it is expected that menopausal-related changes will occur faster. This is the Females discontinuing Oral Contraceptives Use at Menopausal age model. The ultimate aim is to link these changes to OA and other degenerative disorders, including cardiovascular diseases, diabetes, osteoporosis and tendinopathies. METHODS AND ANALYSIS: This is a pilot observational prospective cohort study with 2 years of follow-up. Fifty women aged 50–60 who use oral contraceptive (OC) and have the intention to stop are included. Measurements are performed once before stopping OC, and four times thereafter at 6 weeks, 6 months, 1 year and 2 years. At every time point, a questionnaire is filled in and a sample of blood is drawn. At the first and final time points, a physical examination, hand radiographs and a MRI scan of one knee are performed. The primary OA outcome is progression of the MRI Osteoarthritis Knee Score. Secondary OA outcomes are the development of clinical knee and hand OA, development of knee OA according to the MRI definition, and progression of radiographic features for hand OA. Principal component analysis will be used to assess which changes occur after stopping OC. Univariate and multivariate generalised estimating equation models will be used to test for associations between these components and OA. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee of the Erasmus MC University Medical Center Rotterdam (MEC-2019-0592). All participants must give informed consent before data collection. Results will be disseminated in national and international journals. TRIAL REGISTRATION NUMBER: NL70796.078.19

Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression

Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using Biobank-based Integrative Omics Study data (n = 2802). Of the total 21 significant DMRs, 14 DMRs were associated with gases/fumes and 7 with mineral dust. Three of these DMRs were associated with both exposures (RPLP1 and LINC02169 (2x)) and 11 DMRs were located within transcript start sites of gene expression regulating genes. We replicated two DMRs with gases/fumes (VTRNA2-1 and GNAS) and one with mineral dust (CCDC144NL). In addition, nine gases/fumes DMRs and six mineral dust DMRs significantly associated with gene expression levels. Our data suggest that occupational exposures may induce differential methylation of gene expression regulating genes and thereby may induce adverse health effects. Given the millions of workers that are exposed daily to occupational exposures, further studies on this epigenetic mechanism and health outcomes are warranted

The Hard X-ray Luminosity of OB Star Populations: Implications for the Contribution of Star Formation to the Cosmic X-ray Background

We present an empirical analysis of the integrated X-ray luminosity arising from populations of OB stars. In particular, we utilize results from the All-Sky Monitor on RXTE, along with archival data from previous missions, to assess the mean integrated output of X-rays in the 2-10 keV band from accreting early-type binaries within 3 kpc of the Sun. Using a recent OB star census of the Solar neighborhood, we then calculate the specific X-ray luminosity per O star from accretion-powered systems. We also assess the contribution to the total X-ray luminosity of an OB population from associated T Tauri stars, stellar winds, and supernovae. We repeat this exercise for the major Local Group galaxies, concluding that the total X-ray luminosity per O star spans a broad range from 2 to 20e34 erg/s. Contrary to previous results, we do not find a consistent trend with metallicity; in fact, the specific luminosities for M31 and the SMC are equal, despite having metallicities which differ by an order of magnitude. In light of these results, we assess the fraction of the observed 2-10 keV emission from starburst galaxies that arises directly from their OB star populations, concluding that, while binaries can explain most of the hard X-ray emission in many local starbursts, a significant additional component or components must be present in some systems. A discussion of the nature of this additional emission, along with its implications for the contribution of starbursts to the cosmic X-ray background, concludes our report.Comment: aastex, 30 pages including 2 tables and 1 figure. To appear in Ap

DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases

We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.