Group sequential testing in dental clinical trials with longitudinal data on multiple outcome variables

In this article, methods are proposed for design and analysis of clinical trials that gather longitudinal data on multiple outcome variables. A valid test of the null hypothesis of no treatment group differences can be obtained for any choice of a working alternative hypothesis and a working covariance matrix for the outcome variables. Increased power can be achieved by accurate modeling of the true treatment effect and covariance structure. Implementation of the procedure is simple using existing software for generalized estimating equations. The procedure is an extension of the 'derived variable' technique (univariate analysis applied to a linear combination of the outcome variables) and also of O'Brien's generalized least squares test. The procedure is extended to allow sequential testing using an arbitrary division of the total type I error rate among repeated hypothesis tests. The methods are illustrated by the design of a study on the safety of dental amalgam fillings, which served as the motivation for the research.     

Major pathway of imipramine metabolism is catalyzed by cytochromes P-450 1A2 and P-450 3A4 in human liver

The metabolism of imipramine by human liver microsomes was examined using a combination of five strategies. Human hepatic microsomes produced N-desmethylimipramine (84%), 2-hydroxyimipramine (10%), and 10-hydroxyimipramine (6%). Preincubation of human hepatocytes in culture with beta-naphthoflavone and macrolides exclusively induced the formation of desmethylimpramine (552%, p < 0.05, and 234%, p < 0.003, respectively). Correlations were obtained between rates of imipramine demethylation and cytochrome P-450 (P-450) 1A2 (r = 0.88, p < 0.001) and P-450 3A (r = 0.80, p < 0.02) concentrations in human liver microsomal preparations from 13 different subjects. Anti-P-450 1A2 and anti-P-450 3A antibodies selectively inhibited N-demethylation (80% and 60%, respectively). N-Demethylation was completely inhibited when anti-1A2 and anti-3A were added simultaneously. Kinetic studies with human microsomes confirm the contribution of two different enzymes in the N-demethylation. The Km of 1A2 was similar to the high affinity Km in human liver microsomes, whereas the Km of 3A was similar to the low affinity Km in human liver microsomes. P-450 1A2 was apparently more efficient than 3A4 (lower Km and higher Vmax) but was expressed in much lower concentration. Human P-450s 1A2 and 3A4 expressed in yeast efficiently produced desmethylimipramine. These results suggest that P-450 1A2 and P-450 3A4 are the major enzymes involved in imipramine N-demethylation in human hepatic microsomes. Similar experiments were conducted using P-450 2D6, and they confirmed that P-450 2D6 catalyzes imipramine 2-hydroxylation. Interindividual variations in 3A4 hepatic content may explain the large variations in imipramine blood levels observed after uniform dosages and thus may explain the variations in clinical efficacy. Caution might be advised in the clinical use of tricyclic antidepressants when drugs are also administered that induce or inhibit P-450s 3A4 and 1A2.     

On the Effect of Tastant Excluded Fillers on Sweetness and Saltiness of a Model Food

ABSTRACT: In this study, the effect on taste due to the addition of air bubbles to a water-based gel was investigated. The gel phase contained either sucrose to give a sweet taste or sodium chloride to give a salty taste. For the sweet gels, taste intensities were evaluated for samples with different volume fractions of the air bubbles (up to 40%, v/v) and different concentrations of the sucrose. For the salty gels, samples were evaluated at 40% volume fraction of air bubbles. It was found that a reduction of the sodium chloride or sucrose by the same weight percentage as the volume fraction of the air bubbles in the samples gave equal taste perception as the nontastant-reduced samples. Moreover, saltiness and sweetness perception were clearly enhanced at 40% volume fractions of air bubbles if the sodium chloride or sucrose was not reduced. Thus, the overall tastes of the samples appeared to depend mainly on the concentration levels of the salt or the sucrose in the aqueous phase irrespective of the volume fraction of the air bubbles. However, the air bubbles were found to change the texture and appearance of the samples. It has been demonstrated that the inclusion of air bubbles offers scope for the reduction of sodium chloride or sucrose in food products.     

Selection criteria for the analysis of data-driven clusters in cerebral FMRI

Functional MRI (fMRI) may be possible without a priori models of the cerebral hemodynamic response. First, such data-driven fMRI requires that all cerebral territories with distinct patterns be identified. Second, a systematic selection method is necessary to prevent the subjective interpretation of the identified territories. This paper addresses the second point by proposing a novel method for the automated interpretation of identified territories in data-driven fMRI. Selection criteria are formulated using: 1) the temporal cross-correlation between each identified territory and the paradigm and 2) the spatial contiguity of the corresponding voxel map. Ten event-design fMRI data sets are analyzed with one prominent algorithm, fuzzy c-means clustering, before applying the selection criteria. For comparison, these data are also analyzed with an established, model-based method: statistical parametric mapping. Both methods produced similar results and identified potential activation in the expected territory of the sensorimotor cortex in all ten data sets. Moreover, the proposed method classified distinct territories in separate clusters. Selected clusters have a mean temporal correlation coefficient of 0.39+/-0.07 (n=19) with a mean 2.7+/-1.4 second response delay. At most, four separate contiguous territories were observed in 87% of these clusters. These results suggest that the proposed method may be effective for exploratory fMRI studies where the hemodynamic response is perturbed during cerebrovascular disease.     

Teaching sustainable design in architecture education: Critical review of Easy Approach for Sustainable and Environmental Design (EASED)

In the current context of climate change and ecological awareness, designing sustainable environments is definitely understood as a shared responsibility. With the construction sector consuming half of the world׳s energy, the role of some key stakeholders such as architects becomes even more critical when providing responsible and relevant design for the built environment. Thus, improving the way our environments are being designed challenges some cultural systems that show evident limits, such as the training of future architects and engineers.In this research, the focus is on architecture students and aims to demonstrate how the use of a new sustainable performance simulation tool, called Easy Approach for Sustainable and Environmental Design (EASED) could contribute to educate them about innovatively sustainable design. This was assessed through the evaluation of student engagement, their use of the tool and its appropriation. Results show that individual work was not convincing, whereas success was met during group work. Limits and improvement possibilities were found in the interface of EASED as well as in the educational set up of the tool.     

The Incorporation of Curcuminoids in Gamma-Cyclodextrins Improves Their Poor Bioaccessibility,Which Is due to Both Their Very Low Incorporation into Mixed Micelles and Their Partial Adsorption on Food

Scope

Turmeric curcuminoids mainly consist of curcumin (CUR), demethoxycurcumin (dCUR), and bisdemethoxycurcumin (bdCUR). CUR displays low bioavailability, partly due to poor solubilization in the intestinal lumen during digestion, while data for dCUR and bdCUR are scarce. The study aims to investigate the bioaccessibility of curcuminoids from turmeric extracts or from gamma-cyclodextrins, considering potential interactions with food.

Methods and results

Using an in vitro digestion model (correlation with CUR bioavailability: r = 0.99), the study shows that curcuminoid bioaccessibility from turmeric extract without food is low: bdCUR (11.5 ± 0.6%) > dCUR (1.8 ± 0.1%) > CUR (0.8 ± 0.1%). Curcuminoids incorporated into gamma-cyclodextrins display higher bioaccessibilities (bdCUR: 21.1 ± 1.6%; dCUR: 14.3 ± 0.9%; CUR: 11.9 ± 0.7%). Curcuminoid bioaccessibility is highest without food (turmeric extract: 2.0 ± 0.1%; gamma-cyclodextrins: 12.4 ± 0.8%) and decreases with a meat- and potato-based meal (turmeric extract: 1.1 ± 0.2%; gamma-cyclodextrins: 2.4 ± 0.3%) or a wheat-based meal (turmeric extract: 0.1 ± 0.0%; gamma-cyclodextrins: 0.3 ± 0.1%). Curcuminoids exhibit low (<10%) incorporation efficiencies into synthetic mixed micelles (bdCUR > dCUR > CUR).

Conclusions

bdCUR and dCUR show greater bioaccessibilities versus CUR. Food diminishes curcuminoid bioaccessibility, likely by adsorption mechanisms. Gamma-cyclodextrins improve curcuminoid bioaccessibility.     

Optimization of Chemical Vapor Deposition Parameters for Fabrication of Oxidation-Resistant Mullite Coatings on Silicon Nitride

Fabrication of mullite (3Al₂O₃·2SiO₂) coatings by chemical vapor deposition (CVD) using AlCl₃–SiCl₄–H₂–CO₂ gas mixtures was studied. The resultant CVD mullite coating microstructures were sensitive to gas-phase composition and deposition temperature. Chemical thermodynamic calculations performed on the AlCl₃–SiCl₄–H₂–CO₂ system were used to predict an equilibrium CVD phase diagram. Results from the thermodynamic analysis, process optimization, and effects of various process parameters on coating morphology are discussed. Dense, adherent crystalline CVD mullite coatings ∼2 μm thick were successfully grown on Si₃N₄ substrates at 1000°C and 10.7 kPa total pressure. The resultant coatings were 001 textured and contained well-faceted grains ∼0.3–0.5 μm in size.