A feasibility study testing four hypotheses with phase II outcomes in advanced colorectal cancer (MRC FOCUS3): a model for randomised controlled trials in the era of personalised medicine?

Background: Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies.

Patients and methods: Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload.

Results: A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival.

Conclusions: Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.

Adaptive Fusion Of Particle Filtering And Spatio-Temporal Motion Energy For Human Tracking

Object tracking is an active research area nowadays due to its importance in human computer interface, teleconferencing and video surveillance. However, reliable tracking of objects in the presence of occlusions, pose and illumination changes is still a challenging topic. In this paper, we introduce a novel tracking approach that fuses two cues namely colour and spatio-temporal motion energy within a particle filter based framework. We conduct a measure of coherent motion over two image frames, which reveals the spatio-temporal dynamics of the target. At the same time, the importance of both colour and motion energy cues is determined in the stage of reliability evaluation. This determination helps maintain the performance of the tracking system against abrupt appearance changes. Experimental results demonstrate that the proposed method outperforms the other state of the art techniques in the used test datasets.

Feleucins: Novel Bombinin Precursor-Encoded Nonapeptide Amides from the Skin Secretion of Bombina variegata

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.

AaeAP1 and AaeAP2: Novel Antimicrobial Peptides from the Venom of the Scorpion, Androctonus aeneas: Structural Characterisation, Molecular Cloning of Biosynthetic Precursor-Encoding cDNAs and Engineering of Analogues with Enhanced Antimicrobial and Anticancer Activities

The main functions of the abundant polypeptide toxins present in scorpion venoms are the debilitation of arthropod prey or defence against predators. These effects are achieved mainly through the blocking of an array of ion channel types within the membranes of excitable cells. However, while these ion channel-blocking toxins are tightly-folded by multiple disulphide bridges between cysteine residues, there are additional groups of peptides in the venoms that are devoid of cysteine residues. These non-disulphide bridged peptides are the subject of much research interest, and among these are peptides that exhibit antimicrobial activity. Here, we describe two novel non-disulphide-bridged antimicrobial peptides that are present in the venom of the North African scorpion, Androctonus aeneas. The cDNAs encoding the biosynthetic precursors of both peptides were cloned from a venom-derived cDNA library using 3'- and 5'-RACE strategies. Both translated precursors contained open-reading frames of 74 amino acid residues, each encoding one copy of a putative novel nonadecapeptide, whose primary structures were FLFSLIPSVIAGLVSAIRN and FLFSLIPSAIAGLVSAIRN, respectively. Both peptides were C-terminally amidated. Synthetic versions of each natural peptide displayed broad-spectrum antimicrobial activities, but were devoid of antiproliferative activity against human cancer cell lines. However, synthetic analogues of each peptide, engineered for enhanced cationicity and amphipathicity, exhibited increases in antimicrobial potency and acquired antiproliferative activity against a range of human cancer cell lines. These data clearly illustrate the potential that natural peptide templates provide towards the design of synthetic analogues for therapeutic exploitation.

A multi-capability sensor for hydrocarbons, synthetic-based fluids and heavy metals:Applications for environmental monitoring during removal of drill cuttings piles

As part of any drilling cuttings pile removal process the requirement for monitoring the release of contaminants into the marine environment will be critical. Traditional methods for such monitoring involve taking samples for laboratory analysis. This process is time consuming and only provides data on spot samples taken from a limited number of locations and time frames. Such processes, therefore, offer very restricted information. The need for improved marine sensors for monitoring contaminants is established. We report here the development and application of a multi-capability optical sensor for the real-time in situ monitoring of three key marine environmental and offshore/oil parameters: hydrocarbons, synthetic-based fluids and heavy metal concentrations. The use of these sensors will be a useful tool for real-time in situ environmental monitoring during the process of decommissioning offshore structures. Multi-capability array sensors could also provide information on the dispersion of contamination from drill cuttings piles either while they are in situ or during their removal.

Relative Contribution of P5 and Hap Surface Proteins to Nontypable Haemophilus influenzae Interplay with the Host Upper and Lower Airways

Nontypable Haemophilus influenzae (NTHi) is a major cause of opportunistic respiratory tract disease, and initiates infection by colonizing the nasopharynx. Bacterial surface proteins play determining roles in the NTHi-airways interplay, but their specific and relative contribution to colonization and infection of the respiratory tract has not been addressed comprehensively. In this study, we focused on the ompP5 and hap genes, present in all H. influenzae genome sequenced isolates, and encoding the P5 and Hap surface proteins, respectively. We employed isogenic single and double mutants of the ompP5 and hap genes generated in the pathogenic strain NTHi375 to evaluate P5 and Hap contribution to biofilm growth under continuous flow, to NTHi adhesion, and invasion/phagocytosis on nasal, pharyngeal, bronchial, alveolar cultured epithelial cells and alveolar macrophages, and to NTHi murine pulmonary infection. We show that P5 is not required for bacterial biofilm growth, but it is involved in NTHi interplay with respiratory cells and in mouse lung infection. Mechanistically, P5NTHi375 is not a ligand for CEACAM1 or α5 integrin receptors. Hap involvement in NTHi375-host interaction was shown to be limited, despite promoting bacterial cell adhesion when expressed in H. influenzae RdKW20. We also show that Hap does not contribute to bacterial biofilm growth, and that its absence partially restores the deficiency in lung infection observed for the ΔompP5 mutant. Altogether, this work frames the relative importance of the P5 and Hap surface proteins in NTHi virulence.

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.

The Robustness of Periodic Orchestrations in Uncertain Evolving Environments

A framework for assessing the robustness of long-duration repetitive orchestrations in uncertain evolving environments is proposed. The model assumes that service-based evaluation environments are stable over short time-frames only; over longer periods service-based environments evolve as demand fluctuates and contention for shared resources varies. The behaviour of a short-duration orchestration E in a stable environment is assessed by an uncertainty profile U and a corresponding zero-sum angel-daemon game Γ(U) [2]. Here the angel-daemon approach is extended to assess evolving environments by means of a subfamily of stochastic games. These games are called strategy oblivious because their transition probabilities are strategy independent. It is shown that the value of a strategy oblivious stochastic game is well defined and that it can be computed by solving a linear system. Finally, the proposed stochastic framework is used to assess the evolution of the Gabrmn IT system.

Establishing a population-based patient-reported outcomes study (PROMs) using national cancer registries across two jurisdictions: The Prostate Cancer Treatment, your experience (PiCTure) study

Objective: To establish an international patient-reported outcomes (PROMs) study among prostate cancer survivors, up to 18 years postdiagnosis, in two countries with different healthcare systems and ethical frameworks. Design: A cross-sectional, postal survey of prostate cancer survivors sampled and recruited via two population-based cancer registries. Healthcare professionals (HCPs) evaluated patients for eligibility to participate. Questionnaires contained validated instruments to assess health-related quality of life and psychological well-being, including QLQ-C30, QLQPR-25, EQ-5D-5L, 21-question Depression, Anxiety and Stress Scale (DASS-21) and the Decisional Regret Scale. Setting: Republic of Ireland (RoI) and Northern Ireland (NI). Primary outcome measures: Registration completeness, predictors of eligibility and response, data missingness, unweighted and weighted PROMs. Results: Prostate cancer registration was 80% (95% CI 75% to 84%) and 91% (95% CI 89% to 93%) complete 2 years postdiagnosis in NI and RoI, respectively. Of 12 322 survivors sampled from registries, 53% (n=6559) were classified as eligible following HCP screening. In the multivariate analysis, significant predictors of eligibility were: being ≤59 years of age at diagnosis (p<0.001), short-term survivor (<5 years postdiagnosis; p<0.001) and from RoI (p<0.001). 3348 completed the questionnaire, yielding a 54% adjusted response rate. 13% of men or their families called the study freephone with queries for assistance with questionnaire completion or to talk about their experience. Significant predictors of response in multivariate analysis were: being ≤59 years at diagnosis (p<0.001) and from RoI (p=0.016). Mean number of missing questions in validated instruments ranged from 0.12 (SD 0.71; EQ-5D-5L) to 3.72 (SD 6.30; QLQ-PR25). Weighted and unweighted mean EQ-5D-5L, QLQ-C30 and QLQ-PR25 scores were similar, as were the weighted and unweighted prevalences of depression, anxiety and distress. Conclusions: It was feasible to perform PROMs studies across jurisdictions, using cancer registries as sampling frames; we amassed one of the largest, international, population-based data set of prostate cancer survivors. We highlight improvements which could inform future PROMs studies, including utilising general practitioners to assess eligibility and providing a freephone service.

Gender, religion, and sociopolitical issues in cross-cultural online education

Cross-cultural education is thought to develop critical consciousness of how unequal distributions of power and privilege affect people’s health. Learners in different sociopolitical settings can join together in developing critical consciousness – awareness of power and privilege dynamics in society – by means of communication technology. The aim of this research was to define strengths and limitations of existing cross-cultural discussions in generating critical consciousness. The setting was the FAIMER international fellowship program for mid-career interdisciplinary health faculty, whose goal is to foster global advancement of health professions education. Fellows take part in participant-led, online, written, task-focused discussions on topics like professionalism, community health, and leadership. We reflexively identified text that brought sociopolitical topics into the online environment during the years 2011 and 2012 and used a discourse analysis toolset to make our content analysis relevant to critical consciousness. While references to participants’ cultures and backgrounds were infrequent, narratives of political-, gender-, religion-, and other culture-related topics did emerge. When participants gave accounts of their experiences and exchanged cross-cultural stories, they were more likely to develop ad hoc networks to support one another in facing those issues than explore issues relating to the development of critical consciousness. We suggest that cross-cultural discussions need to be facilitated actively to transform learners’ frames of reference, create critical consciousness, and develop cultural competence. Further research is needed into how to provide a safe environment for such learning and provide faculty development for the skills needed to facilitate these exchanges.

A bond model for DEM simulation of cementitious materials and deformable structures

There is an increasing use of the discrete element method (DEM) to study cemented (e.g. concrete and rocks) and sintered particulate materials. The chief advantage of the DEM over continuum based techniques is that it does not make assumptions about how cracking and fragmentation initiate and propagate, since the DEM system is naturally discontinuous. The ability for the DEM to produce a realistic representation of a cemented granular material depends largely on the implementation of an inter-particle bonded contact model. This paper presents a new bonded contact model based on the Timoshenko beam theory which considers axial, shear and bending behaviour of the bond. The bond model was first verified by simulating both the bending and dynamic response of a simply supported beam. The loading response of a concrete cylinder was then investigated and compared with the Eurocode equation prediction. The results show significant potential for the new model to produce satisfactory predictions for cementitious materials. A unique feature of this model is that it can also be used to accurately represent many deformable structures such as frames and shells, so that both particles and structures or deformable boundaries can be described in the same DEM framework. 

Amphiphysin is a component of clathrin coats formed during synaptic vesicle recycling at the lamprey giant synapse

Amphiphysin is a protein enriched at mammalian synapses thought to function as a clathrin accessory factor in synaptic vesicle endocytosis. Here we examine the involvement of amphiphysin in synaptic vesicle recycling at the giant synapse in the lamprey. We show that amphiphysin resides in the synaptic vesicle cluster at rest and relocates to sites of endocytosis during synaptic activity. It accumulates at coated pits where its SH3 domain, but not its central clathrin/AP-2-binding (CLAP) region, is accessible for antibody binding. Microinjection of antibodies specifically directed against the CLAP region inhibited recycling of synaptic vesicles and caused accumulation of clathrin-coated intermediates with distorted morphology, including flat patches of coated presynaptic membrane. Our data provide evidence for an activity-dependent redistribution of amphiphysin in intact nerve terminals and show that amphiphysin is a component of presynaptic clathrin-coated intermediates formed during synaptic vesicle recycling.

Spectacle design preferences among Chinese primary and secondary students and their parents: A qualitative and quantitative study

Purpose: To identify the specific characteristics making glasses designs, particularly those compatible with adjustable glasses, more or less appealing to Chinese children and their parents. Patients and Methods: Primary and secondary school children from urban and rural China with < = -1.00 diopters of bilateral myopia and their parents ranked four conventional-style frames identified by local optical shops as popular versus four child-specific frames compatible with adjustable spectacles. Scores based on the proportion of maximum possible ranking were computed for each style. Selected children and their parents also participated in Focus Groups (FGs) discussing spectacle design preference. Recordings were transcribed and coded by two independents reviewers using NVivo software. Results: Among 136 urban primary school children (age range 9-11 years), 290 rural secondary school children (11-17 years) and 16 parents, all adjustable-style frames (scores on 0-100 scale 25.7-62.4) were ranked behind all conventional frames (63.0-87.5). For eight FGs including 12 primary children, 26 secondary children and 16 parents, average kappa values for NVivo coding were 0.81 (students) and 0.70 (parents). All groups agreed that the key changes to make adjustable designs more attractive were altering the round lenses to rectangular or oval shapes and adding curved earpieces for more stable wear. The thick frames of the adjustable designs were considered stylish, and children indicated they would wear them if the lens shape were modified. Conclusions: Current adjustable lens designs are unattractive to Chinese children and their parents, though this study identified specific modifications which would make them more appealing.