1,731 research outputs found
Influence of enrollment sequence effect on observed outcomes in the ADDRESS and PROWESS studies of drotrecogin alfa (activated) in patients with severe sepsis
INTRODUCTION: We performed a study to determine whether an enrollment sequence effect noted in the PROWESS (recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis) trial exists in the ADDRESS (Administration of Drotrecogin Alfa [Activated] [DrotAA] in Early Stage Severe Sepsis) trial. METHODS: We evaluated prospectively defined subgroups from two large phase 3 clinical trials: ADDRESS, which included 516 sites in 34 countries, and PROWESS, which included 164 sites in 11 countries. ADDRESS consisted of patients with severe sepsis at low risk of death not indicated for treatment with DrotAA. PROWESS consisted of patients with severe sepsis with one or more organ dysfunctions. DrotAA (24 microg/kg per hour) or placebo was infused for 96 hours. RESULTS: In ADDRESS and PROWESS, there was a statistically significant interaction between the DrotAA treatment effect and the sequence in which patients were enrolled. In both trials, higher mortality was associated with DrotAA use in the subgroup of patients enrolled first at study sites. Compared with placebo, PROWESS mortality was lower with DrotAA treatment for the second and subsequent patients enrolled, whereas in ADDRESS, mortality remained higher for the second patient enrolled but thereafter was lower for DrotAA-treated patients. Comparison of patients enrolled first with subsequent patients enrolled indicated that the characteristics of patients changed. Subsequently enrolled patients were treated earlier, were less likely to suffer nonserious bleeds (ADDRESS), and experienced fewer protocol violations (PROWESS). CONCLUSIONS: Analyses suggest that an enrollment sequence effect was present in the ADDRESS and PROWESS trials. Analysis of this effect on outcomes suggests that it is most apparent in patients at lower risk of death. In PROWESS, this effect appeared to be associated with a reduction of the DrotAA treatment effect for the first patients enrolled at each site. In ADDRESS, this effect may have contributed to early termination of the study. The finding of an enrollment sequence effect in two separate trials suggests that trial designs, site selection and training, data collection and monitoring, and statistical analysis plans may need to be adjusted for these potentially confounding events. TRIAL REGISTRATION: ADDRESS trial registration number: NCT00568737. PROWESS was completed before trial registration was required
Interaction of suppressor of cytokine signalling 3 with cavin-1 links SOCS3 function and cavin-1 stability
YesEffective suppression of JAK–STAT signalling by the inducible inhibitor “suppressor of
cytokine signalling 3” (SOCS3) is essential for limiting signalling from cytokine receptors.
Here we show that cavin-1, a component of caveolae, is a functionally significant SOCS3-
interacting protein. Biochemical and confocal imaging demonstrate that SOCS3 localisation to
the plasma membrane requires cavin-1. SOCS3 is also critical for cavin-1 stabilisation, such
that deletion of SOCS3 reduces the expression of cavin-1 and caveolin-1 proteins, thereby
reducing caveola abundance in endothelial cells. Moreover, the interaction of cavin-1 and
SOCS3 is essential for SOCS3 function, as loss of cavin-1 enhances cytokine-stimulated
STAT3 phosphorylation and abolishes SOCS3-dependent inhibition of IL-6 signalling by cyclic
AMP. Together, these findings reveal a new functionally important mechanism linking
SOCS3-mediated inhibition of cytokine signalling to localisation at the plasma membrane via
interaction with and stabilisation of cavin-1.This work was supported by project grants to T.M.P. from the Chief Scientist Office (ETM/226), British Heart Foundation (PG12/1/ 29276, PG 14/32/30812), and a National Health Service Greater Glasgow and Clyde Research Endowment Fund (2011REFCH08). P.F.P. was supported by the National Institutes of Health grant DK097708. J.J.L.W. was supported by a doctoral training studentship from the Biotechnology and Biological Sciences Research Council Doctoral Training Programme in Biochemistry and Molecular Biology at the University of Glasgow (BB/F016735/1). N.A. was supported by a Saudi Government PhD Scholarship. This work was also supported in part by equipment grants to T.M.P. from Diabetes UK (BDA 11/0004309) and Alzheimer’s Research UK (ARUK-EG2016A-3)
Amplification of evanescent waves in a lossy left-handed material slab
We carry out finite-difference time-domain (FDTD) simulations, with a
specially-designed boundary condition, on pure evanescent waves interacting
with a lossy left-handed material (LHM) slab. Our results provide the first
full-wave numerical evidence for the amplification of evanescent waves inside a
LHM slab of finite absorption. The amplification is due to the interactions
between the evanescent waves and the coupled surface polaritons at the two
surfaces of the LHM slab and the physical process can be described by a simple
model.Comment: 4 pages, 2 figure
Neutron powder diffraction:New opportunities in hydrogen location in molecular and materials structure
The potential of neutron powder diffraction in the location of hydrogen atoms in molecular materials and inorganic-molecular complexes is reviewed. Advances in instrumentation and data collection techniques that have made this field accessible are reviewed, along with a wide range of applications carried out by our collaboration investigating functional materials, hydrogen-containing minerals and molecular compounds. Some of the limitations in this area, particularly for molecular systems, are also addressed
Complex lithium ion dynamics in simulated LiPO3 glass studied by means of multi-time correlation functions
Molecular dynamics simulations are performed to study the lithium jumps in
LiPO3 glass. In particular, we calculate higher-order correlation functions
that probe the positions of single lithium ions at several times. Three-time
correlation functions show that the non-exponential relaxation of the lithium
ions results from both correlated back-and-forth jumps and the existence of
dynamical heterogeneities, i.e., the presence of a broad distribution of jump
rates. A quantitative analysis yields that the contribution of the dynamical
heterogeneities to the non-exponential depopulation of the lithium sites
increases upon cooling. Further, correlated back-and-forth jumps between
neighboring sites are observed for the fast ions of the distribution, but not
for the slow ions and, hence, the back-jump probability depends on the
dynamical state. Four-time correlation functions indicate that an exchange
between fast and slow ions takes place on the timescale of the jumps
themselves, i.e., the dynamical heterogeneities are short-lived. Hence, sites
featuring fast and slow lithium dynamics, respectively, are intimately mixed.
In addition, a backward correlation beyond the first neighbor shell for highly
mobile ions and the presence of long-range dynamical heterogeneities suggest
that fast ion migration occurs along preferential pathways in the glassy
matrix. In the melt, we find no evidence for correlated back-and-forth motions
and dynamical heterogeneities on the length scale of the next-neighbor
distance.Comment: 12 pages, 13 figure
Anisotropic splitting of intersubband spin plasmons in quantum wells with bulk and structural inversion asymmetry
In semiconductor heterostructures, bulk and structural inversion asymmetry
and spin-orbit coupling induce a k-dependent spin splitting of valence and
conduction subbands, which can be viewed as being caused by momentum-dependent
crystal magnetic fields. This paper studies the influence of these effective
magnetic fields on the intersubband spin dynamics in an asymmetric n-type
GaAs/AlGaAs quantum well. We calculate the dispersions of intersubband spin
plasmons using linear response theory. The so-called D'yakonov-Perel'
decoherence mechanism is inactive for collective intersubband excitations,
i.e., crystal magnetic fields do not lead to decoherence of spin plasmons.
Instead, we predict that the main signature of bulk and structural inversion
asymmetry in intersubband spin dynamics is a three-fold, anisotropic splitting
of the spin plasmon dispersion. The importance of many-body effects is pointed
out, and conditions for experimental observation with inelastic light
scattering are discussed.Comment: 8 pages, 6 figure
Intersubband spin-density excitations in quantum wells with Rashba spin splitting
In inversion-asymmetric semiconductors, spin-orbit coupling induces a
k-dependent spin splitting of valence and conduction bands, which is a
well-known cause for spin decoherence in bulk and heterostructures.
Manipulating nonequilibrium spin coherence in device applications thus requires
understanding how valence and conduction band spin splitting affects carrier
spin dynamics. This paper studies the relevance of this decoherence mechanism
for collective intersubband spin-density excitations (SDEs) in quantum wells. A
density-functional formalism for the linear spin-density matrix response is
presented that describes SDEs in the conduction band of quantum wells with
subbands that may be non-parabolic and spin-split due to bulk or structural
inversion asymmetry (Rashba effect). As an example, we consider a 40 nm
GaAs/AlGaAs quantum well, including Rashba spin splitting of the conduction
subbands. We find a coupling and wavevector-dependent splitting of the
longitudinal and transverse SDEs. However, decoherence of the SDEs is not
determined by subband spin splitting, due to collective effects arising from
dynamical exchange and correlation.Comment: 10 pages, 4 figure
Isotopic composition of fragments in multifragmentation of very large nuclear systems: effects of the chemical equilibrium
Studies on the isospin of fragments resulting from the disassembly of highly
excited large thermal-like nuclear emitting sources, formed in the ^{197}Au +
^{197}Au reaction at 35 MeV/nucleon beam energy, are presented. Two different
decay systems (the quasiprojectile formed in midperipheral reactions and the
unique source coming from the incomplete fusion of projectile and target in the
most central collisions) were considered; these emitting sources have the same
initial N/Z ratio and excitation energy (E^* ~= 5--6 MeV/nucleon), but
different size. Their charge yields and isotopic content of the fragments show
different distributions. It is observed that the neutron content of
intermediate mass fragments increases with the size of the source. These
evidences are consistent with chemical equilibrium reached in the systems. This
fact is confirmed by the analysis with the statistical multifragmentation
model.Comment: 9 pages, 4 ps figure
Statistical Multifragmentation in Central Au+Au Collisions at 35 MeV/u
Multifragment disintegrations, measured for central Au + Au collisions at E/A
= 35 MeV, are analyzed with the Statistical Multifragmentation Model. Charge
distributions, mean fragment energies, and two-fragment correlation functions
are well reproduced by the statistical breakup of a large, diluted and
thermalized system slightly above the multifragmentation threshold.Comment: Latex file, 8 pages + 4 postscript figures available upon request
from [email protected]
- …