Guideline on the design and conduct of cystic fibrosis clinical trials: The European Cystic Fibrosis Society–Clinical Trials Network (ECFS-CTN)

We describe the rationale for disease specific research networks in general as well as the aims and function of the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN) specifically. The ECFS-CTN was founded in 2009 with the aim of improving the quality and quantity of clinical research in the area of cystic fibrosis (CF) in Europe. A network of 18 clinical trial sites in 8 European countries was established according to uniform state-of-the-art quality criteria. To support the ECFS-CTN in the acquisition, planning and conduct of clinical trials, the network is equipped with a coordinating centre, steering and executive committees, and committees for protocol review, standardization, training and networking as well as a data safety monitoring board. A strong partnership with European CF patient parent organizations aims to increase awareness of the need for efficient clinical research and the participation of patients in clinical trials.

A Phase I Trial of Bortezomib in Combination with Epirubicin, Carboplatin and Capecitabine (VECarboX) in Advanced Gastric and Gastro-oesophageal Junction Adenocarcinoma

PURPOSE:
The protease inhibitor bortezomib attenuates the action of NF-κB and has shown preclinical activity alone and in combination with chemotherapy.

DESIGN:
A Phase I dose-escalation study was performed administering bortezomib (0.7, 1.0, 1.3 and 1.6 mg m(-2) on days 1 and 8 from cycle 2 onwards) in combination with Epirubicin 50 mg m(-2) intravenously on day 1, Carboplatin AUC 5 day 1 and Capecitabine 625 mg m(-2) BD days 1-21 every 21 days (VECarboX regimen), in patients with advanced oesophagogastric adenocarcinoma. The primary objective was to define the maximum tolerated dose (MTD) of Bortezomib when combined with ECarboX.

RESULTS:
18 patients received bortezomib 0.7 (n = 6), 1.0 (n = 3), 1.3 (n = 6) and 1.6 mg m(-2) (n = 3) and a protocol amendment reducing the capecitabine dose to 500 mg m(-2) BD was enacted due to myelotoxicity. Common treatment-related non-haematological adverse events of any grade were fatigue (83.3 %), anorexia (55.6 %), constipation (55.6 %) and nausea (55.6 %). Common Grade 3/4 haematological toxicities were neutropenia (77.8 %) and thrombocytopenia (44.4 %). Objective responses were achieved in 6 patients (33.3 %) and a further 5 patients (27.8 %) had stable disease for >8 weeks.

CONCLUSIONS:
The addition of Bortezomib to ECarboX is well tolerated and response rates are comparable with standard chemotherapy.

Influence of the experimental design of gene expression studies on the inference of gene regulatory networks: environmental factors

The inference of gene regulatory networks gained within recent years a considerable interest in the biology and biomedical community. The purpose of this paper is to investigate the influence that environmental conditions can exhibit on the inference performance of network inference algorithms. Specifically, we study five network inference methods, Aracne, BC3NET, CLR, C3NET and MRNET, and compare the results for three different conditions: (I) observational gene expression data: normal environmental condition, (II) interventional gene expression data: growth in rich media, (III) interventional gene expression data: normal environmental condition interrupted by a positive spike-in stimulation. Overall, we find that different statistical inference methods lead to comparable, but condition-specific results. Further, our results suggest that non-steady-state data enhance the inferability of regulatory networks.

Citizenship and Structured Dependency: the implications of policy design for senior political power

This paper argues that the structured dependency thesis must be extended to incorporate political power. It outlines a political framework of analysis with which to identify who gains and who loses from social policy. I argue that public policy for older people is a product not only of social structures but also of political decision-making. The Schneider and Ingram (1993) ‘ target populations’ model is used to investigate how the social construction of groups as dependent equates with lower levels of influence on policy making. In United Kingdom and European research, older people are identified as politically quiescent, but conversely in the United States seniors are viewed as one of the most influential and cohesive interest groups in the political culture. Why are American seniors perceived as politically powerful, while older people in Europe are viewed as dependent and politically weak? This paper applies the ‘target populations’ model to senior policy in the Republic of Ireland to investigate how theoretical work in the United States may be used to identify the significance of senior power in policy development. I conclude that research must recognise the connections between power, politics and social constructions to investigate how state policies can influence the likelihood that seniors will resist structured dependency using political means.

Feleucins: Novel Bombinin Precursor-Encoded Nonapeptide Amides from the Skin Secretion of <i>Bombina variegatai>

The first amphibian skin antimicrobial peptide (AMP) to be identified was named bombinin, reflecting its origin from the skin of the European yellow-bellied toad (Bombina variegata). Bombinins and their related peptides, the bombinin Hs, were subsequently reported from other bombinid toads. Molecular cloning of bombinin-encoding cDNAs from skin found that bombinins and bombinin Hs were coencoded on the same precursor proteins. Here, we report the molecular cloning of two novel cDNAs from a skin secretion-derived cDNA library of B. variegata whose open-reading frames each encode a novel bombinin (GIGGALLNVGKVALKGLAKGLAEHFANamide) and a C-terminally located single copy of a novel nonapeptide (FLGLLGGLLamide or FLGLIGSLLamide). These novel nonapeptides were named feleucin-BV1 and feleucin-BV2, respectively. The novel bombinin exhibited 89% identity to homologues from the toads, B. microdeladigitora and B. maxima. The feleucins exhibited no identity with any amphibian AMP archived in databases. Synthetic feleucins exhibited a weak activity against Staphylococcus aureus (128–256 mg/L) but feleucin-BV1 exhibited a synergistic action with the novel bombinin. The present report clearly demonstrates that the skin secretions of bombinid toads continue to represent a source of peptides of novel structure that could provide templates for the design of therapeutics.

Balteatide: A Novel Antimicrobial Decapeptide from the Skin Secretion of the Purple-Sided Leaf Frog, <i>Phyllomedusa balteai>

The skin secretions of Neotropical phyllomedusine leaf frogs have proven to be a rich source of biologically-active peptides, including antimicrobials. The major families of antimicrobial peptides (AMPs) reported are the dermaseptins and phylloseptins and the minor families, the dermatoxins, phylloxins, plasticins, distinctins and the medusins. Here, we report a novel AMP of 10 amino acid residues (LRPAILVRIKamide), named balteatide, from the skin secretion of wild Peruvian purple-sided leaf frogs, Phyllomedusa baltea. Balteatide was found to exhibit a 90% sequence identity with sauvatide, a potent myotropic peptide from the skin secretion of Phyllomedusa sauvagei. However, despite both peptides exhibiting only a single amino acid difference (I/T at position 9), sauvatide is devoid of antimicrobial activity and balteatide is devoid of myotropic activity. Balteatide was found to have differential activity against the Gram-positive bacterium, Staphylococcus aureus, the Gram-negative bacterium, Escherichia coli and the yeast, Candida albicans, and unusually for phyllomedusine frog skin AMPs, was most potent (MIC 32 mg/L) against the yeast. Balteatide was also devoid of haemolytic activity up to concentrations of 512 mg/L. Phyllomedusine frog skin secretions thus continue to provide novel AMPs, some of which may provide templates for the rational design of new classes of anti-infective therapeutics.

Rapid design of discrete orthonormal wavelet transforms using silicon IP components

A rapid design methodology for orthonormal wavelet transform cores has been developed. This methodology is based on a generic, scaleable architecture utilising time-interleaved coefficients for the wavelet transform filters. The architecture has been captured in VHDL and parameterised in terms of wavelet family, wavelet type, data word length and coefficient word length. The control circuit is embedded within the cores and allows them to be cascaded without any interface glue logic for any desired level of decomposition. Case studies for stand alone and cascaded silicon cores for single and multi-stage wavelet analysis respectively are reported. The design time to produce silicon layout of a wavelet based system has been reduced to typically less than a day. The cores are comparable in area and performance to handcrafted designs. The designs are portable across a range of foundries and are also applicable to FPGA and PLD implementations.

Design guidelines for developing customised serious games for parkinson's disease rehabilitation using bespoke game sensors

The research presented in this paper proposes a set of design guidelines in the context of a Parkinson's Disease (PD) rehabilitation design framework for the development of serious games for the physical therapy of people with PD. The game design guidelines provided in the paper are informed by the study of the literature review and lessons learned from the pilot testing of serious games designed to suit the requirements of rehabilitation of patients with Parkinson's Disease. The proposed PD rehabilitation design framework employed for the games pilot testing utilises a low-cost, customized and off-the-shelf motion capture system (employing commercial game controllers) developed to cater for the unique requirement of the physical therapy of people with PD. Although design guidelines have been proposed before for the design of serious games in health, this is the first research paper to present guidelines for the design of serious games specifically for PD motor rehabilitation.

An efficient genetic algorithm for the design optimization of cold-formed steel portal frame buildings

The design optimization of a cold-formed steel portal frame building is considered in this paper. The proposed genetic algorithm (GA) optimizer considers both topology (i.e., frame spacing and pitch) and cross-sectional sizes of the main structural members as the decision variables. Previous GAs in the literature were characterized by poor convergence, including slow progress, that usually results in excessive computation times and/or frequent failure to achieve an optimal or near-optimal solution. This is the main issue addressed in this paper. In an effort to improve the performance of the conventional GA, a niching strategy is presented that is shown to be an effective means of enhancing the dissimilarity of the solutions in each generation of the GA. Thus, population diversity is maintained and premature convergence is reduced significantly. Through benchmark examples, it is shown that the efficient GA proposed generates optimal solutions more consistently. A parametric study was carried out, and the results included. They show significant variation in the optimal topology in terms of pitch and frame spacing for a range of typical column heights. They also show that the optimized design achieved large savings based on the cost of the main structural elements; the inclusion of knee braces at the eaves yield further savings in cost, that are significant.

Advanced design optimization of cold-formed steel portal frame buildings

The design optimization of cold-formed steel portal frame buildings is considered in this paper. The objective function is based on the cost of the members for the main frame and secondary members (i.e., purlins, girts, and cladding for walls and roofs) per unit area on the plan of the building. A real-coded niching genetic algorithm is used to minimize the cost of the frame and secondary members that are designed on the basis of ultimate limit state. It iis shown that the proposed algorithm shows effective and robust capacity in generating the optimal solution, owing to the population's diversity being maintained by applying the niching method. In the optimal design, the cost of purlins and side rails are shown to account for 25% of the total cost; the main frame members account for 27% of the total cost, claddings for the walls and roofs accounted for 27% of the total cost.

Testing preference formation in learning design contingent valuation (LDCV) using advanced information and repetitive treatments

Policymakers have largely replaced Single Bounded Discrete Choice (SBDC) valuation by the more statistically efficient repetitive methods; Double Bounded Discrete Choice (DBDC) and Discrete Choice Experiments (DCE) . Repetitive valuation permits classification into rational preferences: (i) a priori well-formed; (ii) consistent non-arbitrary values “discovered” through repetition and experience; (Plott, 1996; List 2003) and irrational preferences; (iii) consistent but arbitrary values as “shaped” by preceding bid level (Tufano, 2010; Ariely et al., 2003) and (iv) inconsistent and arbitrary values. Policy valuations should demonstrate behaviorally rational preferences. We outline novel methods for testing this in DBDC applied to renewable energy premiums in Chile.

pLR-HL: a novel amphibian Bowman-Birk-type trypsin inhibitor from the skin secretion of the broad-folded frog, <i>Hylarana latouchiii>

In this study, we report a novel heptadecapeptide (LIGGCWTKSIPPKPCLV) of the pLR/ranacyclin family, named pLR-HL, whose structure was deduced from its biosynthetic precursor-encoding cDNA cloned from the skin secretion-derived cDNA library of the broad-folded frog, Hylarana latouchii, by employing a "shotgun" cloning technique. It contains a disulphide loop between Cys5 and Cys15 which is consistent with Bowman-Birk-type protease inhibitors. The primary structure of pLR-HL deduced from the cDNA sequence was confirmed by fractionating the skin secretion using reverse phase HPLC and subsequent analysis using MALDI-TOF mass spectrometry and LC/MS/MS fragmentation sequencing. On the basis of the establishment of unequivocal amino acid sequence, a synthetic replicate was synthesised by solid-phase Fmoc chemistry, and it displayed a moderately potent trypsin inhibition with a Ki of 143 nM. The substitution of Lys-8 by Phe (Phe8 -pLR-HL) resulted in abolition of trypsin inhibition but generation of modest inhibition on chymotrypsin with a Ki of 2.141 μM. Additionally, both the disulphide loops of pLR-HL and Phe8 -pLR-HL were synthesised and tested. Both of the catalytic loops retained similar inhibitory potencies towards trypsin or chymotrypsin in comparison with the original intact molecules. Thus, the replacement of reactive site residues could alter the specificity of these protease inhibitors, while the canonical reactive loop alone can independently constitute biologically-active moiety.

An Evaluation of Vaneless Diffuser Modelling Methods as a Means of Improving the Off-Design Performance Prediction of Centrifugal Compressors

An evaluation of existing 1-D vaneless diffuser design tools in the context of improving the off-design performance prediction of automotive turbocharger centrifugal compressors is described. A combination of extensive gas stand test data and single passage CFD simulations have been employed in order to permit evaluation of the different methods, allowing conclusions about the relative benefits and deficiencies of each of the different approaches to be determined. The vaneless diffuser itself has been isolated from the incumbent limitations in the accuracy of 1-D impeller modelling tools through development of a method to fully specify impeller exit conditions (in terms of mean quantities) using only standard test stand data with additional interstage static pressure measurements at the entrance to the diffuser. This method allowed a direct comparison between the test data and 1-D methods through sharing common inputs, thus achieving the aim of diffuser isolation.

Crucial to the accuracy of determining the performance of each of the vaneless diffuser configurations was the ability to quantify the presence and extent of the spanwise aerodynamic blockage present at the diffuser inlet section. A method to evaluate this critical parameter using CFD data is described herein, along with a correlation for blockage related to a new diffuser inlet flow parameter ⚡, equal to the quotient of the local flow coefficient and impeller tip speed Mach number. The resulting correlation permitted the variation of blockage with operating condition to be captured.

Sustainable concrete: design and testing

Producing concrete with secondary raw materials is an excellent way to contribute to a moresustainable world, provided that this concrete has at least the same performance during itsservice life as concrete made with the primary raw materials it replaces. Secondary rawmaterials for Light Weight (LW) aggregates (rigid polyurethane foams, shredded tire rubberand mixed plastic scraps) have been combined with secondary raw materials for the binder(fly ash, slag and perlite tailings) making sustainable concretes that were investigated fortheir suitability as LW, highly insulating concrete for four different types of applications.Compliance to desired engineering properties (workability, setting time) was not alwaysfeasible: it was mostly the low workability of the mixtures that limited their application.Contrary to well established cements, steering the workability by adding water was not anoption for these binders that rely on alkali-activation. Eight successful mixtures have beentested further. The results have shown that it is possible to produce a non-structuralsustainable concrete with good mechanical and thermal insulation properties.Design of concrete made with novel materials is currently not feasible without extensiveexperimentation as no design rules exist other than empirically derived rules based ontraditional materials. As a radical different approach, a flexible concrete mix design has beendeveloped with which the concrete can be modelled in the fresh and hardened state. Thenumerical concrete mix design method proves a promising tool in designing concrete forperformance demands such as elasticity parameters and thermal conductivity