4,660 research outputs found
The statistical analysis of a clinical trial when a protocol amendment changed the inclusion criteria
Abstract Background Sometimes, protocol amendments that change the inclusion and exclusion criteria are required in clinical trials. Then, the patient populations before and after the amendment may differ. Methods We propose to perform separate statistical tests for the different phases, i.e. for the patients recruited before and after the amendment, and to combine the tests using Fisher's combination test. After a significant combination test a multiple testing procedure can be applied to identify the phase(s) to which a proof of efficacy refers. We assume that the amendment(s) are not based on any type of unblinded data. The proposed method is investigated within a simulation study. Results The proposed combination approach is superior to the 'naĂŻve' strategy to ignore the differences between the phases and pooling the data to perform just one statistical test. This superiority disappears when there are hardly any differences between the two phases. Conclusion When one or more protocol amendments change the inclusion and exclusion criteria, one should realize that the populations may differ. In this case, separate tests for the different phases together with a combination test are a powerful method that can be applied in a variety of settings. The (first) amendment should specify the combination test to be applied in order to combine the different phases.</p
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AIMES: advanced computation and I/O methods for earth-system simulations
Dealing with extreme scale Earth-system models is challenging from the computer science perspective, as the required computing power and storage capacity are steadily increasing.
Scientists perform runs with growing resolution or aggregate results from many similar smaller-scale runs with slightly different initial conditions (the so-called ensemble runs).
In the fifth Coupled Model Intercomparison Project (CMIP5), the produced datasets require more than three Petabytes of storage and the compute and storage requirements are increasing significantly for CMIP6.
Climate scientists across the globe are developing next-generation models based on improved numerical formulation leading to grids that are discretized in alternative forms such as an icosahedral (geodesic) grid.
The developers of these models face similar problems in scaling, maintaining and optimizing code.
Performance portability and the maintainability of code are key concerns of scientists as, compared to industry projects, model code is continuously revised and extended to incorporate further levels of detail.
This leads to a rapidly growing code base that is rarely refactored.
However, code modernization is important to maintain productivity of the scientist working
with the code and for utilizing performance provided by modern and future architectures.
The need for performance optimization is motivated by the evolution of the parallel architecture landscape from
homogeneous flat machines to heterogeneous combinations of processors with deep memory hierarchy.
Notably, the rise of many-core, throughput-oriented accelerators, such as GPUs, requires non-trivial code changes at minimum and, even worse, may necessitate a substantial rewrite of the existing codebase.
At the same time, the code complexity increases the difficulty for computer scientists and vendors to understand and optimize the code for a given system.
Storing the products of climate predictions requires a large storage and archival system which is expensive.
Often, scientists restrict the number of scientific variables and write interval to keep the costs
balanced.
Compression algorithms can reduce the costs significantly but can also increase the scientific yield of simulation runs.
In the AIMES project, we addressed the key issues of programmability, computational efficiency and I/O limitations that are common in next-generation icosahedral earth-system models.
The project focused on the separation of concerns between domain scientist, computational scientists, and computer scientists
Protective Role of Interleukin-10 in Ozone-Induced Pulmonary Inflammation
BackgroundThe mechanisms underlying ozone (O3)-induced pulmonary inflammation remain unclear. Interleukin-10 (IL-10) is an anti-inflammatory cytokine that is known to inhibit inflammatory mediators.ObjectivesWe investigated the molecular mechanisms underlying interleuken-10 (IL-10)âmediated attenuation of O3-induced pulmonary inflammation in mice.MethodsIl10-deficient (Il10â/â) and wild-type (Il10+/+) mice were exposed to 0.3 ppm O3 or filtered air for 24, 48, or 72 hr. Immediately after exposure, differential cell counts and total protein (a marker of lung permeability) were assessed from bronchoalveolar lavage fluid (BALF). mRNA and protein levels of cellular mediators were determined from lung homogenates. We also used global mRNA expression analyses of lung tissue with Ingenuity Pathway Analysis to identify patterns of gene expression through which IL-10 modifies O3-induced inflammation.ResultsMean numbers of BALF polymorphonuclear leukocytes (PMNs) were significantly greater in Il10â/â mice than in Il10+/+ mice after exposure to O3 at all time points tested. O3-enhanced nuclear NF-ÎșB translocation was elevated in the lungs of Il10â/â compared with Il10+/+ mice. Gene expression analyses revealed several IL-10âdependent and O3-dependent mediators, including macrophage inflammatory protein 2, cathepsin E, and serum amyloid A3.ConclusionsResults indicate that IL-10 protects against O3-induced pulmonary neutrophilic inflammation and cell proliferation. Moreover, gene expression analyses identified three response pathways and several genetic targets through which IL-10 may modulate the innate and adaptive immune response. These novel mechanisms of protection against the pathogenesis of O3-induced pulmonary inflammation may also provide potential therapeutic targets to protect susceptible individuals
Signatures in Shape Analysis: an Efficient Approach to Motion Identification
Signatures provide a succinct description of certain features of paths in a
reparametrization invariant way. We propose a method for classifying shapes
based on signatures, and compare it to current approaches based on the SRV
transform and dynamic programming.Comment: 7 pages, 3 figures. Conference paper for Geometric Science of
Information 201
Diffractive Phenomena and Shadowing in Deep-Inelastic Scattering
Shadowing effects in deep-inelastic lepton-nucleus scattering probe the mass
spectrum of diffractive leptoproduction from individual nucleons. We explore
this relationship using current experimental information on both processes. In
recent data from the NMC and E665 collaboration, taken at small x << 0.1 and
Q^2 < 1 GeV^2, shadowing is dominated by the diffractive excitation and
coherent interaction of low mass vector mesons. If shadowing is explored at
small x > 1 GeV^2 as discussed at HERA, the situation is
different. Here dominant contributions come from the coherent interaction of
diffractively produced heavy mass states. Furthermore we observe that the
energy dependence of shadowing is directly related to the mass dependence of
the diffractive production cross section for free nucleon targets.Comment: 12 pages Latex, 8 figure
Three-dimensional femtosecond laser nanolithography of crystals
Nanostructuring hard optical crystals has so far been exclusively feasible at
their surface, as stress induced crack formation and propagation has rendered
high precision volume processes ineffective. We show that the inner chemical
etching reactivity of a crystal can be enhanced at the nanoscale by more than
five orders of magnitude by means of direct laser writing. The process allows
to produce cm-scale arbitrary three-dimensional nanostructures with 100 nm
feature sizes inside large crystals in absence of brittle fracture. To showcase
the unique potential of the technique, we fabricate photonic structures such as
sub-wavelength diffraction gratings and nanostructured optical waveguides
capable of sustaining sub-wavelength propagating modes inside yttrium aluminum
garnet crystals. This technique could enable the transfer of concepts from
nanophotonics to the fields of solid state lasers and crystal optics.Comment: Submitted Manuscript and Supplementary Informatio
Bilateral Dorsal Cochlear Nucleus Lesions Prevent Acoustic-Trauma Induced Tinnitus in an Animal Model
Animal experiments suggest that chronic tinnitus (âringing in the earsâ) may result from processes that overcompensate for lost afferent input. Abnormally elevated spontaneous neural activity has been found in the dorsal cochlear nucleus (DCN) of animals with psychophysical evidence of tinnitus. However, it has also been reported that DCN ablation fails to reduce established tinnitus. Since other auditory areas have been implicated in tinnitus, the role of the DCN is unresolved. The apparently conflicting electrophysiological and lesion data can be reconciled if the DCN serves as a necessary trigger zone rather than a chronic generator of tinnitus. The present experiment used lesion procedures identical to those that failed to decrease pre-existing tinnitus. The exception was that lesions were done prior to tinnitus induction. Young adult rats were trained and tested using a psychophysical procedure shown to detect tinnitus. Tinnitus was induced by a single unilateral high-level noise exposure. Consistent with the trigger hypothesis, bilateral dorsal DCN lesions made before high-level noise exposure prevented the development of tinnitus. A protective effect stemming from disruption of the afferent pathway could not explain the outcome because unilateral lesions ipsilateral to the noise exposure did not prevent tinnitus and unilateral lesions contralateral to the noise exposure actually exacerbated the tinnitus. The DCN trigger mechanism may involve plastic circuits that, through loss of inhibition, or upregulation of excitation, increase spontaneous neural output to rostral areas such as the inferior colliculus. The increased drive could produce persistent pathological changes in the rostral areas, such as high-frequency bursting and decreased interspike variance, that comprise the chronic tinnitus signal
Nitrogen forms affect root structure and water uptake in the hybrid poplar
The study analyses the effects of two different forms of nitrogen fertilisation (nitrate and ammonium) on root structure and water uptake of two hybrid poplar (Populus maximowiczii x P. balsamifera) clones in a field experiment. Water uptake was studied using sap flow gauges on individual proximal roots and coarse root structure was examined by excavating 18 whole-root systems. Finer roots were scanned and analyzed for architecture. Nitrogen forms did not affect coarse-root system development, but had a significant effect on fine-root development. Nitrate-treated trees presented higher fine:coarse root ratios and higher specific root lengths than control or ammonium treated trees. These allocation differences affected the water uptake capacity of the plants as reflected by the higher sapflow rate in the nitrate treatment. The diameter of proximal roots at the tree base predicted well the total root biomass and length. The diameter of smaller lateral roots also predicted the lateral root mass, length, surface area and the number of tips. The effect of nitrogen fertilisation on the fine root structure translated into an effect on the functioning of the fine roots forming a link between form (architecture) and function (water uptake)
Dual-functioning transcription factors in the developmental gene network of Drosophila melanogaster
Quantitative models for transcriptional regulation have shown great promise for advancing our understanding of the biological mechanisms underlying gene regulation. However, all of the models to date assume a transcription factor (TF) to have either activating or repressing function towards all the genes it is regulating.In this paper we demonstrate, on the example of the developmental gene network in D. melanogaster, that the data-fit can be improved by up to 40% if the model is allowing certain TFs to have dual function, that is, acting as activator for some genes and as repressor for others. We demonstrate that the improvement is not due to additional flexibility in the model but rather derived from the data itself. We also found no evidence for the involvement of other known site-specific TFs in regulating this network. Finally, we propose SUMOylation as a candidate biological mechanism allowing TFs to switch their role when a small ubiquitin-like modifier (SUMO) is covalently attached to the TF. We strengthen this hypothesis by demonstrating that the TFs predicted to have dual function also contain the known SUMO consensus motif, while TFs predicted to have only one role lack this motif.We argue that a SUMOylation-dependent mechanism allowing TFs to have dual function represents a promising area for further research and might be another step towards uncovering the biological mechanisms underlying transcriptional regulation
Liquid-gas phase transition in nuclear multifragmentation
The equation of state of nuclear matter suggests that at suitable beam
energies the disassembling hot system formed in heavy ion collisions will pass
through a liquid-gas coexistence region. Searching for the signatures of the
phase transition has been a very important focal point of experimental
endeavours in heavy ion collisions, in the last fifteen years. Simultaneously
theoretical models have been developed to provide information about the
equation of state and reaction mechanisms consistent with the experimental
observables. This article is a review of this endeavour.Comment: 63 pages, 27 figures, submitted to Adv. Nucl. Phys. Some typos
corrected, minor text change
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