Adaptive Bayesian compound designs for dose finding studies

We consider the problem of how to efficiently and safely design dose finding studies. Both current and novel utility functions are explored using Bayesian adaptive design methodology for the estimation of a maximum tolerated dose (MTD). In particular, we explore widely adopted approaches such as the continual reassessment method and minimizing the variance of the estimate of an MTD. New utility functions are constructed in the Bayesian framework and are evaluated against current approaches. To reduce computing time, importance sampling is implemented to re-weight posterior samples thus avoiding the need to draw samples using Markov chain Monte Carlo techniques. Further, as such studies are generally first-in-man, the safety of patients is paramount. We therefore explore methods for the incorporation of safety considerations into utility functions to ensure that only safe and well-predicted doses are administered. The amalgamation of Bayesian methodology, adaptive design and compound utility functions is termed adaptive Bayesian compound design (ABCD). The performance of this amalgamation of methodology is investigated via the simulation of dose finding studies. The paper concludes with a discussion of results and extensions that could be included into our approach.

Analysis of selection criteria for design-builders through the analysis of Request for Proposals (RFPs)

Selecting an appropriate design-builder is critical to the success of DB projects. The objective of this study is to identify selection criteria for design-builders and compare their relative importance by means of a robust content analysis of 94 Request For Proposals (RFPs) for public DB projects. These DB projects had an aggregate contract value of over US$3.5 billion and were advertised between 2000 and 2010. This study summarized twenty-six selection criteria and classified into ten categories, i.e.: price, experience, technical approach, management approach, qualification, schedule, past performance, financial capability, responsiveness to the RFP, and legal status in descending order of their relative importance. The results showed that even though price still remains as the most important selection category, its relative importance declines significantly in the last decade. The categories of qualification, experience, past performance, by contrast, have been becoming more important to DB owners for selecting design-builders. Finally, it is found that the importance weighting of price in large projects is significantly higher than that in small projects. This study provides a useful reference for owners in selecting their preferred design-builders.

Performance characteristics of compound curved sandwich shell structures

Sandwich shells have recently emerged as aesthetically pleasing, efficient and economical structural systems, with a number of applications. They combine the advantages of sandwich layer technology together with those of shell action. With different materials and thicknesses used in the sandwich layers, their performance characteristics largely remain un-quantified and there are no guidelines at present for their design. This research paper provides verification, through finite element modeling and testing, for the application of this technology to dome styled dwellings with research currently being conducted into the further application to roofing and floor structures.

Determining the optimal proportion of design in design-build request for proposals (RFPs)

The design-build (DB) system is a popular and effective delivery method of construction projects worldwide. After owners decide to procure their projects through the DB system, they may wish to determine the optimal proportion of design to be provided in the DB request for proposals (RFPs), which serve as solicitations for design-builders and describe the scope of work. However, this presents difficulties to DB owners and there is little, if any, systematic research in this area. This paper reports on an empirical study in the USA entailing both an online questionnaire survey and Delphi survey to identify and evaluate the factors influencing owners’ decisions in determining the proportion of design to include in DB RFPs. Eleven factors are identified, i.e. (1) clarity of project scope; (2) applicability of performance specifications; (3) desire for design innovation; (4) site constraints; (5) availability of competent design-builders; (6) project control requirements; (7) user group involvement level; (8) third party requirements; (9) owner experience with DB; (10) project complexity; and (11) schedule constraints. A statistically significant agreement on the eleven factors was also obtained from the (mainly non-owner) Delphi experts. Although some of the experts hold different opinions on how these factors affect the proportion of design, these findings furnish various stakeholders with a better understanding of the delivery process of DB projects and the appropriate provision of project information in DB RFPs. As the result is mainly industry opinion concerning the optimal proportion of design, in addition and for completeness, future studies should be conducted to obtain a big picture of the optimal proportion of design by means of seeking owners’ inputs.

Assessment of tumor prevention in Type 1 Neurofibromatosis using a nitroxide compound

Background Type 1 Neurofibromatosis (NF1) is a genetic disorder linked to mutations of the NF1 gene. Clinical symptoms are varied, but hallmark features of the disease include skin pigmentation anomalies (café au lait macules, skinfold freckling) and dermal neurofibromas. Method These dermal manifestations of NF1 have previously been reported in a mouse model where Nf1+/− mice are topically treated with dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). We adopted this mouse model to test the protective effects of a nitroxide antioxidant, 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (CTMIO). Antioxidants have previously been shown to increase longevity in nf1-deficient fruitflies. Doses of 4 μM and 40 μM CTMIO provided ad libitum in drinking water were given to Nf1-deficient mice. Results Consistent with previous reports, Nf1-deficient mice showed a 4.7-fold increase in papilloma formation (P < 0.036). However, neither dose of CTMIO had any significant affect on papilloma formation. A non-significant decrease in skin pigmentation abnormalities was seen with 4 μM but not 40 μM CTMIO. Subsequent analysis of genomic DNA isolated from papillomas indicated that DMBA/TPA induced tumors did not exhibit a local loss of heterozygosity (LOH) at the Nf1 locus. Conclusion These data reveal that oral antioxidant therapy with CTMIO does not reduce tumor formation in a multistage cancer model, but also that this model does not feature LOH for Nf1.

Effect of a novel compound from Lycopodium obscurum L. on osteogenic activity of osteoblasts in vitro

We investigated the potential of an extract of Lycopodium obscurum L.; stigmastane-3-oxo-21-oic acid (SA), to enhance osteogensis of mouse osteoblastic MC3T3-E1 cells. SA at a concentration of 16 µM was found to have no significant effect upon the viability of the cells, thus concentrations of 8 µM and 16 µM of SA were used in all further experiments. Both concentrations of SA had an inhibitory affect upon alkaline phosphatase activity (ALP) after 8 days incubation, however, after 16 days activity was restored to control levels. However Alizarin red S staining showed increased levels of mineralization for both concentrations after 16 days culture. Real time PCR showed inhibition of genes Runx2 and Osterix genes responsible for the up-regulation of ALP. However early time point (8 days) up-regulation of bone matrix mineralization genes OPN and OCN, and late time point (16 days) up-regulation of both Jun-D and Fra-2 mRNA expression was significantly enhanced. These results suggest a potential me-chanism of SA in enhancing bone fracture healing is through the up-regulating bone matrix minera-lization.

CO2 reforming of toluene as model compound of biomass tar on Ni/Palygorskite

Catalytic CO2 reforming of biomass tar on palygorskite-supported nickel catalysts using toluene as a model compound of biomass tar was investigated. The experiments were performed in a bench scale installation a fixed bed reactor. All experiments were carried out at 650, 750, 800 °C and atmospheric pressure. The effect of Ni loading, reaction temperature and concentration of CO2 on H2 yield and carbon deposit was investigated. Ni/Palygorskite (Ni/PG) catalysts with Ni/PG ratios of 0%, 2%, 5% and 8% were tested, the last two show the best performance. H2 yield and carbon deposit diminished with the increase of reaction temperature, Ni loading, and CO2 concentration.

Request for production of documents – UCPR r 222 – manner of compliance

In John Kallinicos Accountants Pty Ltd v Dundrenan Pty Ltd [2009] QDC 141 Irwin DCJ considered the nature of a party’s obligation under r 222 of the Uniform Civil Procedure Rules 1999 (Qld) (UCPR) to produce documents referred to in the parties’ pleadings, particulars or affidavits. The decision examined whether the approach in Belela Pty Ltd v Menzies Excavation Pty Ltd [2005] 2 QdR 230 in relation to disclosure of documents under UCPR r 214 also applied to production of documents under r 222.

Motor Accident Insurance Act 1994 - request for information

In Angus v Conelius [2007] QCA 190 the Queensland Court of Appeal concluded that the obligations under the Motor Accident Insurance Act 1994 (Qld), and in particular s 45 of the Act (duty of claimant to cooperate with insurer), continue beyond the commencement of court proceedings

A rapid and sensitive UPLC-ESI MS method for analysis of isofraxidin, a natural antistress compound, and its metabolites in rat plasma

Isofraxidin is one of the main bioactive constituents in the root of Acanthopanax senticosus, which has antifatigue, antistress, and immuno-accommondating effects. In this study, an ultraperformance LC (UPLC)-ESI MS method was developed for analyzing isofraxidin and its metabolites in rat plasma. The analysis was performed on a UPLC coupled with ESI MS (quadropole MS tandem TOF MS). The lower LOD (LLOD) for isofraxidin was 0.25 ng/mL, the intraday precision was less than 10%, the interday precision was less than 10%, and the extraction recovery was more than 80%. Isofraxidin and two metabolites (M1 and M2) were detected in rat plasma after oral administration of isofraxidin, and the molecular polarities of M1 and M2 were both increased compared to isofraxidin. The metabolites were identified as 5,6-dihydroxyl-7-methoxycoumarin and 5-hydroxyl-6,7-dimethoxycoumarin when subjected to parent ion spectra, product ion spectra, and extract mass and element composition analyses.

Synthesis and characterization of ternary AL-C-N compound

Efficient hydrogenated diamond-like carbon (DLC) film deposition in a plasma reactor that features both the capacitive and inductively coupled operation regimes is reported. The hydrogenated DLC films have been prepared on silicon wafers using a low-frequency (500 kHz) inductively coupled plasma (LF ICP) chemical vapor deposition (CVD) system. At low RF powers, the system operates as an asymmetric capacitively coupled plasma source, and the film deposition process is undertaken in the electrostatic (E) discharge regime. The films deposited in the electrostatic mode feature graphite-like structure. Above the mode transition threshold, the high-density inductively coupled plasma is produced in the electromagnetic (H) discharge regime. Raman spectrometry suggests the possibility to control relative proportions of sp2 and sp3 hybridized carbon. Variation of the DC substrate bias results in dramatic modification of the film structure from the polymeric (unbiased substrates) to the diamond-like (optimized bias). It has been shown that the deposition rate and hardness of the DLC film are much higher in the H-mode deposition regime. For a 20 m Torr H-mode CH4+Ar gas mixture discharge, the DLC film exhibits mechanical hardness of 18 GPa, Young's modulus of 170 GPa, and compressive stress of 1.3 GPa.