134 research outputs found
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A comparison of methods for treatment selection in seamless phase II/III clinical trials incorporating information on short-term endpoints
In an adaptive seamless phase II/III clinical trial interim
analysis data are used for treatment selection, enabling resources to be focussed on comparison of more effective treatment(s) with a control. In this paper we compare two methods recently proposed to enable use of short-term endpoint data for decision-making at the interim analysis. The comparison focusses on the power and the probability of correctly identifying the most promising treatment. We show that the choice of method depends on how well short-term data predict the best treatment, which may be measured by the correlation between treatment effects on short-term and long-term endpoints
The Efficacy of Conjoint Behavioral Consultation on Parents and Children in the Home Setting: Results of a Randomized Controlled Trial
The present study is a large-scale randomized trial testing the effects of a family-school partnership model (i.e., Conjoint Behavioral Consultation, CBC) for promoting behavioral competence and decreasing problem behaviors of children identified by their teachers as disruptive. CBC is a structured approach to problem solving that involves consultants, parents, and teachers. The effects of CBC on family variables that are commonly associated with important outcomes among school-aged children (i.e., family involvement and parent competence in problem solving), as well as child outcomes at home, were evaluated. Participants were 207 children with disruptive behaviors from 91 classrooms in 21 schools in kindergarten through grade 3 and their parents and teachers. Results indicated that there were significantly different increases in home-school communication and parent competence in problem solving for participants in the CBC relative to control group. Likewise, compared to children in the control group, children in the CBC group showed significantly greater decreases in arguing, defiance, noncompliance, and tantrums. The degree of family risk moderated parents’ competence in problem solving and children’s total problem behaviors, teasing, and tantrums
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Blinded versus unblinded estimation of a correlation coefficient to inform interim design adaptations
Regulatory authorities require that the sample size of a confirmatory trial is calculated prior to the start of the trial. However, the sample size quite often depends on parameters which might not be known in advance of the study. Misspecification of these parameters can lead to under- or overestimation of the sample size. Both situations are unfavourable as the first one decreases the power and the latter one leads to a waste of resources. Hence, designs have been suggested that allow a re-assessment of the sample size in an ongoing trial. These methods usually focus on estimating the variance. However, for some methods the performance depends not only on the variance but also on the correlation between measurements. We develop and compare different methods for blinded estimation of the correlation coefficient which are less likely to introduce operational bias when the blinding is maintained. Their performance with respect to bias and standard error is compared to the unblinded estimator. We simulated two different settings: one assuming that all group means are the same and one assuming that different groups have different means. Simulation results show that the naïve (onesample) estimator is only slightly biased and has a standard error comparable to that of the unblinded estimator. However, if the group means differ, other estimators have better performance depending on the sample size per group and the number of groups
Human-Robot Site Survey and Sampling for Space Exploration
NASA is planning to send humans and robots back to the Moon before 2020. In order for extended missions to be productive, high quality maps of lunar terrain and resources are required. Although orbital images can provide much information, many features (local topography, resources, etc) will have to be characterized directly on the surface. To address this need, we are developing a system to perform site survey and sampling. The system includes multiple robots and humans operating in a variety of team configurations, coordinated via peer-to-peer human-robot interaction. In this paper, we present our system design and describe planned field tests
Early regular egg exposure in infants with eczema: a randomized controlled trial
BackgroundObservational studies suggest that early regular ingestion of allergenic foods might reduce the risk of food allergy.ObjectiveWe sought to determine whether early regular oral egg exposure will reduce subsequent IgE-mediated egg allergy in infants with moderate-to-severe eczema.MethodsIn a double-blind, randomized controlled trial infants were allocated to 1 teaspoon of pasteurized raw whole egg powder (n = 49) or rice powder (n = 37) daily from 4 to 8 months of age. Cooked egg was introduced to both groups after an observed feed at 8 months. The primary outcome was IgE-mediated egg allergy at 12 months, as defined based on the results of an observed pasteurized raw egg challenge and skin prick tests.ResultsA high proportion (31% [15/49]) of infants randomized to receive egg had an allergic reaction to the egg powder and did not continue powder ingestion. At 4 months of age, before any known egg ingestion, 36% (24/67) of infants already had egg-specific IgE levels of greater than 0.35 kilounits of antibody (kUA)/L. At 12 months, a lower (but not significant) proportion of infants in the egg group (33%) were given a diagnosis of IgE-mediated egg allergy compared with the control group (51%; relative risk, 0.65; 95% CI, 0.38-1.11; P = .11). Egg-specific IgG4 levels were significantly (P ConclusionInduction of immune tolerance pathways and reduction in egg allergy incidence can be achieved by early regular oral egg exposure in infants with eczema. Caution needs to be taken when these high-risk infants are first exposed to egg because many have sensitization already by 4 months of age.Debra J. Palmer, Jessica Metcalfe, Maria Makrides, Michael S. Gold, Patrick Quinn, Christina E. West, Richard Loh, and Susan L. Prescot
Mutant IDH1 Differently Affects Redox State and Metabolism in Glial Cells of Normal and Tumor Origin
IDH1R132H (isocitrate dehydrogenase 1) mutations play a key role in the development of low-grade gliomas. IDH1wt converts isocitrate to α-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP+), whereas IDH1R132H uses α-ketoglutarate and NADPH to generate the oncometabolite 2-hydroxyglutarate (2-HG). While the effects of 2-HG have been the subject of intense research, the 2-HG independent effects of IDH1R132H are still ambiguous. The present study demonstrates that IDH1R132H expression but not 2-HG alone leads to significantly decreased tricarboxylic acid (TCA) cycle metabolites, reduced proliferation, and enhanced sensitivity to irradiation in both glioblastoma cells and astrocytes in vitro. Glioblastoma cells, but not astrocytes, showed decreased NADPH and NAD+ levels upon IDH1R132H transduction. However, in astrocytes IDH1R132H led to elevated expression of the NAD-synthesizing enzyme nicotinamide phosphoribosyltransferase (NAMPT). These effects were not 2-HG mediated. This suggests that IDH1R132H cells utilize NAD+ to restore NADP pools, which only astrocytes could compensate via induction of NAMPT. We found that the expression of NAMPT is lower in patient-derived IDH1-mutant glioma cells and xenografts compared to IDH1-wildtype models. The Cancer Genome Atlas (TCGA) data analysis confirmed lower NAMPT expression in IDH1-mutant versus IDH1-wildtype gliomas. We show that the IDH1 mutation directly affects the energy homeostasis and redox state in a cell-type dependent manner. Targeting the impairments in metabolism and redox state might open up new avenues for treating IDH1-mutant gliomas.publishedVersio
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Gradual Ordering in Red Abalone Nacre
Red abalone (Haliotis rufescens) nacre is a layered composite biomineral that contains crystalline aragonite tablets confined by organic layers. Nacre is intensely studied because its biologically controlled microarchitecture gives rise to remarkable strength and toughness, but the mechanisms leading to its formation are not well understood. Here we present synchrotron spectromicroscopy experiments revealing that stacks of aragonite tablet crystals in nacre are misoriented with respect to each other. Quantitative measurements of crystal orientation, tablet size, and tablet stacking direction show that orientational ordering occurs not abruptly but gradually over a distance of 50 {micro}m. Several lines of evidence indicate that different crystal orientations imply different tablet growth rates during nacre formation. A theoretical model based on kinetic and gradual selection of the fastest growth rates produces results in qualitative and quantitative agreement with the experimental data and therefore demonstrates that ordering in nacre is a result of crystal growth kinetics and competition either in addition or to the exclusion of templation by acidic proteins as previously assumed. As in other natural evolving kinetic systems, selection of the fastest-growing stacks of tablets occurs gradually in space and time. These results suggest that the self-ordering of the mineral phase, which may occur completely independently of biological or organic-molecule control, is fundamental in nacre formation
Monsoon circulations and tropical heterogeneous chlorine chemistry in the stratosphere
Model simulations presented in this paper suggest that transport processes associated with the summer monsoons bring increased abundances of hydrochloric acid into contact with liquid sulfate aerosols in the cold tropical lowermost stratosphere, leading to heterogeneous chemical activation of chlorine species. The calculations indicate that the spatial and seasonal distributions of chlorine monoxide and chlorine nitrate near the monsoon regions of the northern hemisphere tropical and subtropical lowermost stratosphere could provide indicators of heterogeneous chlorine processing. In the model, these processes impact the local ozone budget and decrease ozone abundances, implying a chemical contribution to longer-term northern tropical ozone profile changes at 16-19 km
Explosive volcanism on the ultraslow-spreading Gakkel ridge, Arctic Ocean
Author Posting. © Nature Publishing Group, 2008. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in Nature 453 (2008): 1236-1238, doi:10.1038/nature07075.Roughly 60% of the Earth’s outer surface is comprised of oceanic crust formed by volcanic
processes at mid-ocean ridges (MORs). Although only a small fraction of this vast volcanic
terrain has been visually surveyed and/or sampled, the available evidence suggests that
explosive eruptions are rare on MORs, particularly at depths below the critical point for
steam (3000 m). A pyroclastic deposit has never been observed on the seafloor below 3000
m, presumably because the volatile content of mid-ocean ridge basalts is generally too low
to produce the gas fractions required to fragment a magma at such high hydrostatic
pressure. We employed new deep submergence technologies during an International Polar
Year expedition to the Gakkel Ridge in the Arctic Basin at 85°E, to acquire the first-ever
photographic images of ‘zero-age’ volcanic terrain on this remote, ice-covered MOR. Our
imagery reveals that the axial valley at 4000 m water depth is blanketed with
unconsolidated pyroclastic deposits, including bubble wall fragments (limu o Pele),
covering a large area greater than 10 km2. At least 13.5 wt% CO2 is required to fragment
magma at these depths, which is ~10x greater than the highest values measured to-date in
a MOR basalt. These observations raise important questions regarding the accumulation
and discharge of magmatic volatiles at ultra-slow spreading rates on the Gakkel Ridge (6-
14 mm yr-1, full-rate), and demonstrate that large-scale pyroclastic activity is possible
along even the deepest portions of the global MOR volcanic system.This research was
funded by the National Aeronautics and Space Administration, the National Science Foundation,
and the Woods Hole Oceanographic Institution
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