929 research outputs found
Safety of continuing mineralocorticoid receptor antagonist treatment in patients with heart failure with reduced ejection fraction and severe kidney disease: Data from Swedish Heart Failure Registry
AIMS
Mineralocorticoid receptor antagonists (MRAs) improve outcomes in heart failure with reduced ejection fraction (HFrEF) but remain underused and are often discontinued especially in patients with chronic kidney disease (CKD) due to concerns on renal safety. Therefore, in a real-world HFrEF population we investigated the safety of MRA use, in terms of risk of renal events, any mortality and any hospitalization, across the estimated glomerular filtration rate (eGFR) spectrum including severe CKD.
METHODS AND RESULTS
We analysed patients with HFrEF (ejection fraction <40%), not on dialysis, from the Swedish Heart Failure Registry. We performed multivariable logistic regression models to investigate patient characteristics independently associated with MRA use, and univariable and multivariable Cox regression models to assess the associations between MRA use and outcomes. Of 33 942 patients, 17 489 (51%) received MRA, 32%, 45%, 54%, 54% with eGFR <30, 30-44, 45-59 or ≥60 ml/min/1.73 m , respectively. An eGFR ≥60 ml/min/1.73 m and patient characteristics linked with more severe HF were independently associated with more likely MRA use. In multivariable analyses, MRA use was consistently not associated with a higher risk of renal events (i.e. composite of dialysis/renal death/hospitalization for renal failure or hyperkalaemia) (hazard ratio [HR] 1.04, 95% confidence interval [CI] 0.98-1.10), all-cause death (HR 1.02, 95% CI 0.97-1.08) as well as of all-cause hospitalization (HR 0.99, 95% CI 0.95-1.02) across the eGFR spectrum including also severe CKD.
CONCLUSIONS
The use of MRAs in patients with HFrEF decreased with worse renal function; however their safety profile was demonstrated to be consistent across the entire eGFR spectrum
Faeces as a novel material to estimate lyssavirus prevalence in bat populations
Rabies is caused by infection with a lyssavirus. Bat rabies is of concern for both public health and bat conservation. The current method for lyssavirus prevalence studies in bat populations is by oral swabbing, which is invasive for the bats, dangerous for handlers, time-consuming and expensive. In many situations, such sampling is not feasible, and hence, our understanding of epidemiology of bat rabies is limited. Faeces are usually easy to collect from bat colonies without disturbing the bats and thus could be a practical and feasible material for lyssavirus prevalence studies. To further explore this idea, we performed virological analysis on faecal pellets and oral swabs of seven serotine bats (Eptesicus serotinus) that were positive for European bat 1 lyssavirus in the brain. We also performed immunohistochemical and virological analyses on digestive tract samples of these bats to determine potential sources of lyssavirus in the faeces. We found that lyssavirus detection by RT-qPCR was nearly as sensitive in faecal pellets (6/7 bats positive, 86%) as in oral swabs (7/7 bats positive, 100%). The likely source of lyssavirus in the faeces was virus excreted into the oral cavity from the salivary glands (5/6 bats positive by immunohistochemistry and RT-qPCR) or tongue (3/4 bats positive by immunohistochemistry) and swallowed with saliva. Virus could not be isolated from any of the seven faecal pellets, suggesting the lyssavirus detected in faeces is not infectious. Lyssavirus detection in the majority of faecal pellets of infected bats shows that this novel material should be further explored for lyssavirus prevalence studies in bats
Multi-Messenger Gravitational Wave Searches with Pulsar Timing Arrays: Application to 3C66B Using the NANOGrav 11-year Data Set
When galaxies merge, the supermassive black holes in their centers may form
binaries and, during the process of merger, emit low-frequency gravitational
radiation in the process. In this paper we consider the galaxy 3C66B, which was
used as the target of the first multi-messenger search for gravitational waves.
Due to the observed periodicities present in the photometric and astrometric
data of the source of the source, it has been theorized to contain a
supermassive black hole binary. Its apparent 1.05-year orbital period would
place the gravitational wave emission directly in the pulsar timing band. Since
the first pulsar timing array study of 3C66B, revised models of the source have
been published, and timing array sensitivities and techniques have improved
dramatically. With these advances, we further constrain the chirp mass of the
potential supermassive black hole binary in 3C66B to less than using data from the NANOGrav 11-year data set. This
upper limit provides a factor of 1.6 improvement over previous limits, and a
factor of 4.3 over the first search done. Nevertheless, the most recent orbital
model for the source is still consistent with our limit from pulsar timing
array data. In addition, we are able to quantify the improvement made by the
inclusion of source properties gleaned from electromagnetic data to `blind'
pulsar timing array searches. With these methods, it is apparent that it is not
necessary to obtain exact a priori knowledge of the period of a binary to gain
meaningful astrophysical inferences.Comment: 14 pages, 6 figures. Accepted by Ap
Recurrent Coding Sequence Variation Explains only A Small Fraction of the Genetic Architecture of Colorectal Cancer
Whilst common genetic variation in many non-coding genomic regulatory regions are known to impart risk of colorectal cancer (CRC), much of the heritability of CRC remains unexplained. To examine the role of recurrent coding sequence variation in CRC aetiology, we genotyped 12,638 CRCs cases and 29,045 controls from six European populations. Single-variant analysis identified a coding variant (rs3184504) in SH2B3 (12q24) associated with CRC risk (OR = 1.08, P = 3.9 × 10-7), and novel damaging coding variants in 3 genes previously tagged by GWAS efforts; rs16888728 (8q24) in UTP23 (OR = 1.15, P = 1.4 × 10-7); rs6580742 and rs12303082 (12q13) in FAM186A (OR = 1.11, P = 1.2 × 10-
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.
The NANOGrav 11-Year Data Set: Arecibo Observatory Polarimetry And Pulse Microcomponents
We present the polarization pulse profiles for 28 pulsars observed with the
Arecibo Observatory by the North American Nanohertz Observatory for
Gravitational Waves (NANOGrav) timing project at 2.1 GHz, 1.4 GHz, and 430 MHz.
These profiles represent some of the most sensitive polarimetric millisecond
pulsar profiles to date, revealing the existence of microcomponents (that is,
pulse components with peak intensities much lower than the total pulse peak
intensity). Although microcomponents have been detected in some pulsars
previously, we present microcomponents for PSRs B1937+21, J1713+0747, and
J2234+0944 for the first time. These microcomponents can have an impact on
pulsar timing, geometry, and flux density determination. We present rotation
measures for all 28 pulsars, determined independently at different observation
frequencies and epochs, and find the Galactic magnetic fields derived from
these rotation measures to be consistent with current models. These
polarization profiles were made using measurement equation template matching,
which allows us to generate the polarimetric response of the Arecibo
Observatory on an epoch-by-epoch basis. We use this method to describe its time
variability, and find that the polarimetric responses of the Arecibo
Observatory's 1.4 and 2.1 GHz receivers vary significantly with time.Comment: 41 pages, 20 figure
The NANOGrav 11-year Data Set: High-precision Timing of 45 Millisecond Pulsars
We present high-precision timing data over time spans of up to 11 years for 45 millisecond pulsars observed as part of the North American Nanohertz Observatory for Gravitational Waves (NANOGrav) project, aimed at detecting and characterizing low-frequency gravitational waves. The pulsars were observed with the Arecibo Observatory and/or the Green Bank Telescope at frequencies ranging from 327 MHz to 2.3 GHz. Most pulsars were observed with approximately monthly cadence, and six high-timing-precision pulsars were observed weekly. All were observed at widely separated frequencies at each observing epoch in order to fit for time-variable dispersion delays. We describe our methods for data processing, time-of-arrival (TOA) calculation, and the implementation of a new, automated method for removing outlier TOAs. We fit a timing model for each pulsar that includes spin, astrometric, and (for binary pulsars) orbital parameters; time-variable dispersion delays; and parameters that quantify pulse-profile evolution with frequency. The timing solutions provide three new parallax measurements, two new Shapiro delay measurements, and two new measurements of significant orbital-period variations. We fit models that characterize sources of noise for each pulsar. We find that 11 pulsars show significant red noise, with generally smaller spectral indices than typically measured for non-recycled pulsars, possibly suggesting a different origin. A companion paper uses these data to constrain the strength of the gravitational-wave background
Bayesian Solar Wind Modeling with Pulsar Timing Arrays
Using Bayesian analyses we study the solar electron density with the NANOGrav
11-year pulsar timing array (PTA) dataset. Our model of the solar wind is
incorporated into a global fit starting from pulse times-of-arrival. We
introduce new tools developed for this global fit, including analytic
expressions for solar electron column densities and open source models for the
solar wind that port into existing PTA software. We perform an ab initio
recovery of various solar wind model parameters. We then demonstrate the
richness of information about the solar electron density, , that can be
gleaned from PTA data, including higher order corrections to the simple
model associated with a free-streaming wind (which are informative probes of
coronal acceleration physics), quarterly binned measurements of and a
continuous time-varying model for spanning approximately one solar cycle
period. Finally, we discuss the importance of our model for chromatic noise
mitigation in gravitational-wave analyses of pulsar timing data and the
potential of developing synergies between sophisticated PTA solar electron
density models and those developed by the solar physics community.Comment: 22 pages, 7 figures, Submitted to Ap
Removing critical gaps in chemical test methods by developing new assays for the identification of thyroid hormone system-disrupting chemicals—the athena project
The test methods that currently exist for the identification of thyroid hormone system-disrupting chemicals are woefully inadequate. There are currently no internationally validated in vitro assays, and test methods that can capture the consequences of diminished or enhanced thyroid hormone action on the developing brain are missing entirely. These gaps put the public at risk and risk assessors in a difficult position. Decisions about the status of chemicals as thyroid hormone system disruptors currently are based on inadequate toxicity data. The ATHENA project (Assays for the identification of Thyroid Hormone axis-disrupting chemicals: Elaborating Novel Assessment strategies) has been conceived to address these gaps. The project will develop new test methods for the disruption of thyroid hormone transport across biological barriers such as the blood–brain and blood–placenta barriers. It will also devise methods for the disruption of the downstream effects on the brain. ATHENA will deliver a testing strategy based on those elements of the thyroid hormone system that, when disrupted, could have the greatest impact on diminished or enhanced thyroid hormone action and therefore should be targeted through effective testing. To further enhance the impact of the ATHENA test method developments, the project will develop concepts for better international collaboration and development in the area of thyroid hormone system disruptor identification and regulation
Artemisinin-Naphthoquine versus Artemether-Lumefantrine for Uncomplicated Malaria in Papua New Guinean Children: An Open-Label Randomized Trial
© 2014 Laman et al. Artemisinin combination therapies (ACTs) with broad efficacy are needed where multiple Plasmodium species are transmitted, especially in children, who bear the brunt of infection in endemic areas. In Papua New Guinea (PNG), artemether-lumefantrine is the first-line treatment for uncomplicated malaria, but it has limited efficacy against P. vivax. Artemisinin-naphthoquine should have greater activity in vivax malaria because the elimination of naphthoquine is slower than that of lumefantrine. In this study, the efficacy, tolerability, and safety of these ACTs were assessed in PNG children aged 0.5–5 y.An open-label, randomized, parallel-group trial of artemether-lumefantrine (six doses over 3 d) and artemisinin-naphthoquine (three daily doses) was conducted between 28 March 2011 and 22 April 2013. Parasitologic outcomes were assessed without knowledge of treatment allocation. Primary endpoints were the 42-d P. falciparum PCR-corrected adequate clinical and parasitologic response (ACPR) and the P. vivax PCR-uncorrected 42-d ACPR. Non-inferiority and superiority designs were used for falciparum and vivax malaria, respectively. Because the artemisinin-naphthoquine regimen involved three doses rather than the manufacturer-specified single dose, the first 188 children underwent detailed safety monitoring. Of 2,542 febrile children screened, 267 were randomized, and 186 with falciparum and 47 with vivax malaria completed the 42-d follow-up. Both ACTs were safe and well tolerated. P. falciparum ACPRs were 97.8% and 100.0% in artemether-lumefantrine and artemisinin-naphthoquine-treated patients, respectively (difference 2.2% [95% CI -3.0% to 8.4%] versus -5.0% non-inferiority margin, p?=?0.24), and P. vivax ACPRs were 30.0% and 100.0%, respectively (difference 70.0% [95% CI 40.9%–87.2%], p<0.001). Limitations included the exclusion of 11% of randomized patients with sub-threshold parasitemias on confirmatory microscopy and direct observation of only morning artemether-lumefantrine dosing.Artemisinin-naphthoquine is non-inferior to artemether-lumefantrine in PNG children with falciparum malaria but has greater efficacy against vivax malaria, findings with implications in similar geo-epidemiologic settings within and beyond Oceania.Australian New Zealand Clinical Trials Registry ACTRN12610000913077.Please see later in the article for the Editors' Summary
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