The up-regulation of P-selectin in endothelial cells and platelets contributes to the cell-cell interactions that are involved in the pathogenesis of vaso-occlusion and sickle cell-related pain ...crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, were evaluated in patients with sickle cell disease.
In this double-blind, randomized, placebo-controlled, phase 2 trial, we assigned patients to receive low-dose crizanlizumab (2.5 mg per kilogram of body weight), high-dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell-related pain crises with high-dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism) and the acute chest syndrome, and patient-reported outcomes were also assessed.
A total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high-dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high-dose crizanlizumab, P=0.01). The median time to the first crisis was significantly longer with high-dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02). The median rate of uncomplicated crises per year was 1.08 with high-dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high-dose crizanlizumab, P=0.02). Adverse events that occurred in 10% or more of the patients in either active-treatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain.
In patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell-related pain crises than placebo and was associated with a low incidence of adverse events. (Funded by Selexys Pharmaceuticals and others; SUSTAIN ClinicalTrials.gov number, NCT01895361 .).
This catalog summarizes 117 high-confidence > or =0.1 GeV gamma-ray pulsar detections using three years of data acquired by the Large Area Telescope (LAT) on the Fermi satellite. Half are neutron ...stars discovered using LAT data through periodicity searches in gamma-ray and radio data around LAT unassociated source positions. The 117 pulsars are evenly divided into three groups: millisecond pulsars, young radio-loud pulsars, and young radio-quiet pulsars. We characterize the pulse profiles and energy spectra and derive luminosities when distance information exists. Spectral analysis of the off-peak phase intervals indicates probable pulsar wind nebula emission for four pulsars, and off-peak magnetospheric emission for several young and millisecond pulsars. We compare the gamma-ray properties with those in the radio, optical, and X-ray bands. We provide flux limits for pulsars with no observed gamma-ray emission, highlighting a small number of gamma-faint, radio-loud pulsars. The large, varied gamma-ray pulsar sample constrains emission models. Fermi's selection biases complement those of radio surveys, enhancing comparisons with predicted population distributions.
Although most children with Hirschsprung disease ultimately do well, many experience a variety of ongoing problems after pull-through surgery. The most common include obstructive symptoms, soiling, ...enterocolitis and failure to thrive. The purpose of this guideline is to present a rational approach to the management of postoperative obstructive symptoms in children with Hirschsprung disease. The American Pediatric Surgical Association Board of Governors established a Hirschsprung Disease Interest Group. Group discussions, literature review and expert consensus were then used to summarize the current state of knowledge regarding causes, methods of diagnosis, and treatment approaches to children with obstructive symptoms following pull-through for Hirschsprung disease. Causes of obstructive symptoms post-pull-through include mechanical obstruction; persistent or acquired aganglionosis, hypoganglionosis, or transition zone pull-through; internal sphincter achalasia; disordered motility in the proximal intestine that contains ganglion cells; or functional megacolon caused by stool-holding behavior. An algorithm for the diagnosis and management of obstructive symptoms after a pull-through for Hirschsprung disease is presented. A stepwise, logical approach to the diagnosis and management of patients experiencing obstructive symptoms following pull-through for Hirschsprung disease can facilitate treatment.
Level of evidence
V.
Abstract
We investigate the importance of the shielding of chemical photorates by molecular hydrogen photodissociation lines and the carbon photoionization continuum deep within models of ...photon-dominated regions (PDRs). In particular, the photodissociation of N2 and CN is significantly shielded by the H2 photodissociation line spectrum. We model this by switching off the photodissociation channels for these species behind the H i→H2 transition. We also model the shielding effect of the carbon photoionization continuum as an attenuation of the incident radiation field shortwards of 1102 Å. Using recent line and continuum cross-section data, we present calculations of the direct and cosmic-ray-induced photorates for a range of species, as well as optically thick shielding factors for the carbon continuum. Applying these to a time-dependent PDR model we see enrichments in the abundances of N2, N2H+, NH3 and CN by factors of ∼3-100 in the extinction band A
v = 2.0-4.0 for a range of environments. While the precise quantitative results of this study are limited by the simplicity of our model, they highlight the importance of these mutual shielding effects, neither of which has been discussed in recent models.
An overview of research on green fluorescent protein (GFP) and its use in fungal biology is presented. Recent advances in GFP molecule engineering, fluorescence detection, and imaging analysis are ...occurring at a time in which scientists are poised to gain considerable information about fungal genomes.
Novae are thermonuclear explosions on a white dwarf surface fueled by mass accreted from a companion star. Current physical models posit that shocked expanding gas from the nova shell can produce ...x-ray emission, but emission at higher energies has not been widely expected. Here, we report the Fermi Large Area Telescope detection of variable γ-ray emission (0.1 to 10 billion electron volts) from the recently detected optical nova of the symbiotic star V407 Cygni. We propose that the material of the nova shell interacts with the dense ambient medium of the red giant primary and that particles can be accelerated effectively to produce π° decay γ-rays from proton-proton interactions. Emission involving inverse Compton scattering of the red giant radiation is also considered and is not ruled out.
Stratospheric aerosols (SAs) are a variable component of the Earth's albedo that may be intentionally enhanced in the future to offset greenhouse gases (geoengineering). The role of ...tropospheric‐sourced sulfur dioxide (SO2) in maintaining background SAs has been debated for decades without in situ measurements of SO2 at the tropical tropopause to inform this issue. Here we clarify the role of SO2 in maintaining SAs by using new in situ SO2 measurements to evaluate climate models and satellite retrievals. We then use the observed tropical tropopause SO2 mixing ratios to estimate the global flux of SO2 across the tropical tropopause. These analyses show that the tropopause background SO2 is about 5 times smaller than reported by the average satellite observations that have been used recently to test atmospheric models. This shifts the view of SO2 as a dominant source of SAs to a near‐negligible one, possibly revealing a significant gap in the SA budget.
Key Points
First in situ measurements of SO2 in the tropical UT/LS
Typical SO2 at the tropical tropopause is near 5‐10 pptv
Flux of SO2 across the tropopause is a minor source of stratospheric aerosol
ABSTRACT
We develop a novel data-driven method for generating synthetic optical observations of galaxy clusters. In cluster weak lensing, the interplay between analysis choices and systematic effects ...related to source galaxy selection, shape measurement, and photometric redshift estimation can be best characterized in end-to-end tests going from mock observations to recovered cluster masses. To create such test scenarios, we measure and model the photometric properties of galaxy clusters and their sky environments from the Dark Energy Survey Year 3 (DES Y3) data in two bins of cluster richness $\lambda \in 30; 45)$, $\lambda \in 45; 60)$ and three bins in cluster redshift ($z\in 0.3; 0.35)$, $z\in 0.45; 0.5)$ and $z\in 0.6; 0.65)$. Using deep-field imaging data, we extrapolate galaxy populations beyond the limiting magnitude of DES Y3 and calculate the properties of cluster member galaxies via statistical background subtraction. We construct mock galaxy clusters as random draws from a distribution function, and render mock clusters and line-of-sight catalogues into synthetic images in the same format as actual survey observations. Synthetic galaxy clusters are generated from real observational data, and thus are independent from the assumptions inherent to cosmological simulations. The recipe can be straightforwardly modified to incorporate extra information, and correct for survey incompleteness. New realizations of synthetic clusters can be created at minimal cost, which will allow future analyses to generate the large number of images needed to characterize systematic uncertainties in cluster mass measurements.
The efficiency of dehydration in the tropical tropopause layer (TTL) determines how closely water vapor will be reduced to the lowest saturation mixing ratio encountered along a trajectory to the ...stratosphere, thereby strongly influencing stratospheric humidity. The NASA Airborne Tropical Tropopause Experiment (ATTREX) provided an unprecedented number and quality of in situ observations to constrain the key mechanisms controlling this dehydration. Statistical analyses of the ATTREX data show that nucleation, growth, and sedimentation each result in TTL dehydration becoming increasingly inefficient at temperatures below 200 K. Because of these inefficiencies, models that ignore these mechanisms likely underestimate water vapor at the stratospheric entry point by ~10–20% at the lowest temperatures.
Key Points
New data set of TTL water and cirrus microphysical observations
Ice nucleation, growth, and sedimentation are important limiting factors in dehydration
Dehydration efficiency decreases with temperature below 200 K
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