3,848 research outputs found
Late radiation sequelae in women after breast-conserving cancer therapy: effects of hyperbaric oxygen therapy
Impact assessment of the European Clinical Trials Directive: a longitudinal, prospective, observational study analyzing patterns and trends in clinical drug trial applications submitted since 2001 to regulatory agencies in six EU countries
<p>Abstract</p> <p>Background</p> <p>Shifts in clinical trial application rates over time indicate if the attractiveness of a country or region for the conduct of clinical trials is growing or decreasing. The purpose of this observational study was to track changes in drug trial application patterns across several EU countries in order to analyze the medium-term impact of the EU Clinical Trials Directive 2001/20/EC on the conduct of drug trials.</p> <p>Methods</p> <p>Rates of Clinical Trial Applications (CTA) for studies with medicinal products in those six countries in the EU, which authorize on average more than 500 trials per year, were analyzed. Publicly available figures on the number of annually submitted CTA, the distribution of trials per phase and the type of sponsorship were tracked; missing data were provided by national drug agencies.</p> <p>Results</p> <p>Since 2001, the number of CTA in Italy and Spain increased significantly (5.0 and 2.5% average annual growth). For Italy, the gain was driven by a strong increase of applications from academic trial sponsors; Spain's growth was due to a rise in trials run by commercial sponsors. The Netherlands, Germany, France and the UK saw a decline (1.9, 2.3, 3.0 and 5.3% average annual diminution; significant (<it>P </it>< 0.05) except for Germany) in clinical drug trials. The decrease in the UK was caused by a sharp fall in academic trial activities. Across the six analyzed countries, no EU-wide trial-phase-specific patterns or trends were observed.</p> <p>Conclusions</p> <p>The EU Clinical Trials Directive 2001/20/EC did not achieve the harmonization of clinical trial requirements across Europe. Rather, it resulted in the leveling of clinical trial activities caused by a continuing decrease in CTA rates in the Netherlands, Germany, France and the UK. Southern European countries, Italy and Spain, benefited to some extent from policy changes introduced by the Directive. In Italy's case, national funding measures helped to considerably promote the conduct of non-commercial trials. On the other hand, the EU Directive-driven transition from liberal policy environments, based on non-explicit trial approval through notifications, towards red-taped processes of trial authorization, contributed to the decreases in trial numbers in Germany and the UK. In the latter case, national research governance concerns had a share in the country's marked decline. However, different EU member states successfully developed best practices, which a new European legislation should take into consideration to resume Europe's attractiveness and international competitiveness for the conduct of clinical trials.</p
Phase structure of a two-fluid bosonic system
The phase diagram of a two-fluid bosonic system is investigated. The
proton-neutron interacting boson model (IBM-2) possesses a rich phase structure
involving three control parameters and multiple order parameters. The surfaces
of quantum phase transition between spherical, axially-symmetric deformed, and
SU*(3) triaxial phases are determined, and the evolution of classical
equilibrium properties across these transitions is investigated. Spectroscopic
observables are considered in relation to the phase diagram.Comment: LaTeX (elsart), 46 pages, as published in Ann. Phys. (N.Y.
Branch Mode Selection during Early Lung Development
Many organs of higher organisms, such as the vascular system, lung, kidney,
pancreas, liver and glands, are heavily branched structures. The branching
process during lung development has been studied in great detail and is
remarkably stereotyped. The branched tree is generated by the sequential,
non-random use of three geometrically simple modes of branching (domain
branching, planar and orthogonal bifurcation). While many regulatory components
and local interactions have been defined an integrated understanding of the
regulatory network that controls the branching process is lacking. We have
developed a deterministic, spatio-temporal differential-equation based model of
the core signaling network that governs lung branching morphogenesis. The model
focuses on the two key signaling factors that have been identified in
experiments, fibroblast growth factor (FGF10) and sonic hedgehog (SHH) as well
as the SHH receptor patched (Ptc). We show that the reported biochemical
interactions give rise to a Schnakenberg-type Turing patterning mechanisms that
allows us to reproduce experimental observations in wildtype and mutant mice.
The kinetic parameters as well as the domain shape are based on experimental
data where available. The developed model is robust to small absolute and large
relative changes in the parameter values. At the same time there is a strong
regulatory potential in that the switching between branching modes can be
achieved by targeted changes in the parameter values. We note that the sequence
of different branching events may also be the result of different growth
speeds: fast growth triggers lateral branching while slow growth favours
bifurcations in our model. We conclude that the FGF10-SHH-Ptc1 module is
sufficient to generate pattern that correspond to the observed branching modesComment: Initially published at PLoS Comput Bio
Misaligned Protoplanetary Disks in a Young Binary System
Many extrasolar planets follow orbits that differ from the nearly coplanar
and circular orbits found in our solar system; orbits may be eccentric or
inclined with respect to the host star's equator, and the population of giant
planets orbiting close to their host stars suggests significant orbital
migration. There is currently no consensus on what produces such orbits.
Theoretical explanations often invoke interactions with a binary companion star
on an orbit that is inclined relative to the planet's orbital plane. Such
mechanisms require significant mutual inclinations between planetary and binary
star orbital planes. The protoplanetary disks in a few young binaries are
misaligned, but these measurements are sensitive only to a small portion of the
inner disk, and the three-dimensional misalignment of the bulk of the
planet-forming disk mass has hitherto not been determined. Here we report that
the protoplanetary disks in the young binary system HK Tau are misaligned by
60{\deg}-68{\deg}, so one or both disks are significantly inclined to the
binary orbital plane. Our results demonstrate that the necessary conditions
exist for misalignment-driven mechanisms to modify planetary orbits, and that
these conditions are present at the time of planet formation, apparently due to
the binary formation process.Comment: Published in Nature, July 31 2014. 18 pages. This version has slight
differences from the final published version. Final version is available at
http://www.nature.com/nature/journal/v511/n7511/full/nature13521.htm
The cometary composition of a protoplanetary disk as revealed by complex cyanides
Observations of comets and asteroids show that the Solar Nebula that spawned
our planetary system was rich in water and organic molecules. Bombardment
brought these organics to the young Earth's surface, seeding its early
chemistry. Unlike asteroids, comets preserve a nearly pristine record of the
Solar Nebula composition. The presence of cyanides in comets, including 0.01%
of methyl cyanide (CH3CN) with respect to water, is of special interest because
of the importance of C-N bonds for abiotic amino acid synthesis. Comet-like
compositions of simple and complex volatiles are found in protostars, and can
be readily explained by a combination of gas-phase chemistry to form e.g. HCN
and an active ice-phase chemistry on grain surfaces that advances
complexity[3]. Simple volatiles, including water and HCN, have been detected
previously in Solar Nebula analogues - protoplanetary disks around young stars
- indicating that they survive disk formation or are reformed in situ. It has
been hitherto unclear whether the same holds for more complex organic molecules
outside of the Solar Nebula, since recent observations show a dramatic change
in the chemistry at the boundary between nascent envelopes and young disks due
to accretion shocks[8]. Here we report the detection of CH3CN (and HCN and
HC3N) in the protoplanetary disk around the young star MWC 480. We find
abundance ratios of these N-bearing organics in the gas-phase similar to
comets, which suggests an even higher relative abundance of complex cyanides in
the disk ice. This implies that complex organics accompany simpler volatiles in
protoplanetary disks, and that the rich organic chemistry of the Solar Nebula
was not unique.Comment: Definitive version of the manuscript is published in Nature, 520,
7546, 198, 2015. This is the author's versio
The Ets dominant repressor En/Erm enhances intestinal epithelial tumorigenesis in ApcMin mice
<p>Abstract</p> <p>Background</p> <p>Ets transcription factors have been widely implicated in the control of tumorigenesis, with most studies suggesting tumor-promoting roles. However, few studies have examined Ets tumorigenesis-modifying functions <it>in vivo </it>using model genetic systems.</p> <p>Methods</p> <p>Using mice expressing a previously characterized Ets dominant repressor transgene in the intestinal epithelium (Villin-En/Erm), we examined the consequences of blocking endogenous Ets-mediated transcriptional activation on tumorigenesis in the Apc<sup>Min </sup>model of intestinal carcinoma.</p> <p>Results</p> <p>En/Erm expression in the intestine, at levels not associated with overt crypt-villus dysmorphogenesis, results in a marked increase in tumor number in Apc<sup>Min </sup>animals. Moreover, when examined histologically, tumors from En/Erm-expressing animals show a trend toward greater stromal invasiveness. Detailed analysis of crypt-villus homeostasis in these En/Erm transgenic animals suggests increased epithelial turnover as one possible mechanism for the enhanced tumorigenesis.</p> <p>Conclusion</p> <p>Our findings provide <it>in vivo </it>evidence for a tumor-restricting function of endogenous Ets factors in the intestinal epithelium.</p
Strategic sourcing supplier selection misalignment with critical success factors:findings from multiple case studies in Germany and the United Kingdom
Strategic sourcing plays an important role in organisations' performance. Strategic sourcing has been researched extensively using empirical studies as well as review work, such as strategic sourcing importance, issues and challenges, processes, source selection criteria and framework. However, there is no research on critical success factors for strategic sourcing specific to industry and country. This research aims to qualitatively evaluate and understand the current role of strategic sourcing, the critical success factors for business performance and its relationship with strategic sourcing, and strategic supplier evaluation criteria from multiple stakeholders' perspectives specific to industry and country. This research studies twenty organisations from Germany and the United Kingdom (UK) covering two industry sectors - electronics manufacturing and construction. We consider five organisations from each industry sector and each country. The findings from twenty case studies reveal comparative analysis of strategic sourcing practices of two countries and two industries
Quantum dynamics in strong fluctuating fields
A large number of multifaceted quantum transport processes in molecular
systems and physical nanosystems can be treated in terms of quantum relaxation
processes which couple to one or several fluctuating environments. A thermal
equilibrium environment can conveniently be modelled by a thermal bath of
harmonic oscillators. An archetype situation provides a two-state dissipative
quantum dynamics, commonly known under the label of a spin-boson dynamics. An
interesting and nontrivial physical situation emerges, however, when the
quantum dynamics evolves far away from thermal equilibrium. This occurs, for
example, when a charge transferring medium possesses nonequilibrium degrees of
freedom, or when a strong time-dependent control field is applied externally.
Accordingly, certain parameters of underlying quantum subsystem acquire
stochastic character. Herein, we review the general theoretical framework which
is based on the method of projector operators, yielding the quantum master
equations for systems that are exposed to strong external fields. This allows
one to investigate on a common basis the influence of nonequilibrium
fluctuations and periodic electrical fields on quantum transport processes.
Most importantly, such strong fluctuating fields induce a whole variety of
nonlinear and nonequilibrium phenomena. A characteristic feature of such
dynamics is the absence of thermal (quantum) detailed balance.Comment: review article, Advances in Physics (2005), in pres
A mathematical model for breath gas analysis of volatile organic compounds with special emphasis on acetone
Recommended standardized procedures for determining exhaled lower respiratory
nitric oxide and nasal nitric oxide have been developed by task forces of the
European Respiratory Society and the American Thoracic Society. These
recommendations have paved the way for the measurement of nitric oxide to
become a diagnostic tool for specific clinical applications. It would be
desirable to develop similar guidelines for the sampling of other trace gases
in exhaled breath, especially volatile organic compounds (VOCs) which reflect
ongoing metabolism. The concentrations of water-soluble, blood-borne substances
in exhaled breath are influenced by: (i) breathing patterns affecting gas
exchange in the conducting airways; (ii) the concentrations in the
tracheo-bronchial lining fluid; (iii) the alveolar and systemic concentrations
of the compound. The classical Farhi equation takes only the alveolar
concentrations into account. Real-time measurements of acetone in end-tidal
breath under an ergometer challenge show characteristics which cannot be
explained within the Farhi setting. Here we develop a compartment model that
reliably captures these profiles and is capable of relating breath to the
systemic concentrations of acetone. By comparison with experimental data it is
inferred that the major part of variability in breath acetone concentrations
(e.g., in response to moderate exercise or altered breathing patterns) can be
attributed to airway gas exchange, with minimal changes of the underlying blood
and tissue concentrations. Moreover, it is deduced that measured end-tidal
breath concentrations of acetone determined during resting conditions and free
breathing will be rather poor indicators for endogenous levels. Particularly,
the current formulation includes the classical Farhi and the Scheid series
inhomogeneity model as special limiting cases.Comment: 38 page
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