Assessing blinding in clinical trials

The interaction between the patient's expected outcome of an intervention and the inherent effects of that intervention can have extraordinary effects. Thus in clinical trials an effort is made to conceal the nature of the administered intervention from the participants in the trial i.e. to blind it. Yet, in practice perfect blinding is impossible to ensure or even verify. The current standard is follow up the trial with an auxiliary questionnaire, which allows trial participants to express their belief concerning the assigned intervention and which is used to compute a measure of the extent of blinding in the trial. If the estimated extent of blinding exceeds a threshold the trial is deemed sufficiently blinded; otherwise, the trial is deemed to have failed. In this paper we make several important contributions. Firstly, we identify a series of fundamental problems of the aforesaid practice and discuss them in context of the most commonly used blinding measures. Secondly, motivated by the highlighted problems, we formulate a novel method for handling imperfectly blinded trials. We too adopt a post-trial feedback questionnaire but interpret the collected data using an original approach, fundamentally different from those previously proposed. Unlike previous approaches, ours is void of any ad hoc free parameters, is robust to small changes in auxiliary data and is not predicated on any strong assumptions used to interpret participants' feedback.

The impact of column connection on band broadening in very high pressure liquid chromatography

A series of experiments was conducted to evaluate the degree of band broadening in very high pressure LC due to column connections. Different column manufacturers use slightly different designs for their column fittings. If the same column connections are repeatedly used to attach columns of different origins, different void volumes form between capillary tubes and column inlets. An Agilent Ultra Low Dispersion Kit (tubing id 75 μm) was installed on an Agilent Infinity 1290 ultra HPLC and used to connect successively an Agilent, a Phenomenex, and a Waters column. A series of uracil (unretained) samples were injected and eluted at a wide range of flow rates with a water/acetonitrile mixture as eluent. In order to determine the variance contribution from column connections as accurately as possible a nonretained probe compound was selected because the variance contribution from the column is the smallest for analytes, which have very low k values. Yet, this effect still has an impact on the resolution for moderately retained compounds (k > 2) for narrow-bore columns packed with fine particles, since variance contributions are additive for linear chromatographic systems. Each injection was replicated five times under the same experimental conditions. Then NanoViper column connections (tubing id 75 μm) were used and the same injections were made. This system was designed to minimize connection void volumes for any column. Band variances were calculated as the second central moment of elution peaks and used to assess the degree of band broadening due to the column connections. Band broadening may increase from 3.8 to 53.9% when conventional metal ferrules were used to join columns to connection sites. The results show that the variance contribution from improper connections can generate as much as 60.5% of the total variance observed. This demonstrates that column connections can play a larger role than the column packing with respect to band dispersion.

Untangling teachers’ images of their futures through their responses to the futures narratives of children

A significant amount of research has been undertaken exploring individuals’ images of a future. What often remains uninterrogated are the ways in which others’ respond to these images of a future, as they are articulated through narrative discourses. This paper, then, seeks to address this void through the presentation of research which considers the ways that teachers’ perceptions of "the future" are consolidated and challenged, as they work with children in a classroom setting.

Getting everyone on the same page : A staff focus group study for library web site redesign

Purpose - Using staff focus groups in the redevelopment of a library web site deploys their knowledge of user navigation issues and search strategies and addresses the unique needs of library staff. This paper seeks to describe the process of planning, recruiting, and conducting staff focus groups and provide a discussion of lessons learned. Design/methodology/approach - A committee of professionals and non-professionals from the University of Calgary Library conducted a series of five focus groups with library staff. The goals were to determine their content and service priorities for the redesigned library web site, and also to ensure that staff was included in the redesign process. Findings - This paper makes recommendations for library staff focus group interviewing, including planning, formulating questions, recruitment, conducting sessions, and analysis and reporting. Practical implications - Focus group interviews can be effectively conducted in-house, with careful planning and adherence to established guidelines. Focus groups are a very useful method for gathering staff input for web site redesign or any other library-planning project. Originality/value - This paper will be useful to librarians interested in assessing staff needs and priorities through focus group interviews. The paper fills a void in the library literature regarding the use of library staff as both focus group leaders and participants.

Prediction of FLD of sheet metals based on crystal plasticity model

 In some advanced sheet metal forming processes such as the incremental forming process, a local fracture strain after necking is very important. In order to accurately predict necking and fracture phenomena, a crystal plasticity model is introduced in the finite element analysis of tensile tests. A tensile specimen is modeled by many grains that have their own crystalline orientation. And each of the grains is discretized by many elements. Using this analysis, necking behavior of a tensile specimen can be predicted without any initial imperfections. A damage model is also implemented to predict sudden drops of load carrying capacity after necking and to reflect the void nucleation and growth of the severely deformed region. From an analysis of the tensile test, the necking behavior is well predicted. Finally, analyses are carried out for various strain paths, and FLDs up to necking and fracture are predicted.

Well-being and Resilience in Education

Compared to previous generations, today’s youth appear to be poorly equipped to meet the life challenges they face. This chapter focuses on two approaches to developing positive and resilient behavior in young people, namely the student well-being approach and the social and emotional learning (SEL) approach. These two approaches have slowly emerged to fill the void created by the failed self-esteem movement that began in the 1970s. Both approaches have strong links with positive psychology, a model that emphasizes the conditions, strengths, and behaviors that enable people to develop well-being, act resiliently, and thrive. Evidence-informed guidelines for developing and implementing universal school-based programs designed to enhance well-being and SEL are identified and examples of national and specific initiatives are outlined.

Epoxy nanocomposites containing magnetite-carbon nanofibers aligned using a weak magnetic field

Abstract Novel magnetite-carbon nanofiber hybrids (denoted by Fe3O4@CNFs) have been developed by coating carbon nanofibers (CNFs) with magnetite nanoparticles in order to align CNFs in epoxy using a relatively weak magnetic field. Experimental results have shown that a weak magnetic field (∼mT) can align these newly-developed nanofiber hybrids to form a chain-like structure in the epoxy resin. Upon curing, the epoxy nanocomposites containing the aligned Fe3O4@CNFs show (i) greatly improved electrical conductivity in the alignment direction and (ii) significantly higher fracture toughness when the Fe3O4@CNFs are aligned normal to the crack surface, compared to the nanocomposites containing randomly-oriented Fe3O4@CNFs. The mechanisms underpinning the significant improvements in the fracture toughness have been identified, including interfacial debonding, pull-out, crack bridging and rupture of the Fe3O4@CNFs, and plastic void growth in the polymer matrix.

New insights into the thermal behaviour of organic ionic plastic crystals: magnetic resonance imaging of polycrystalline morphology alterations induced by solid-solid phase transitions

Organic ionic plastic crystals (OIPCs) show strong potential as solid-state electrolytes for lithium battery applications, demonstrating promising electrochemical performance and eliminating the need for a volatile and flammable liquid electrolyte. The ionic conductivity (σ) in these systems has recently been shown to depend strongly on polycrystalline morphology, which is largely determined by the sample's thermal history. [K. Romanenko et al., J. Am. Chem. Soc., 2014, 136, 15638]. Tailoring this morphology could lead to conductivities sufficiently high for battery applications, so a more complete understanding of how phenomena such as solid-solid phase transitions can affect the sample morphology is of significant interest. Anisotropic relaxation of nuclear spin magnetisation provides a new MRI based approach for studies of polycrystalline materials at both a macroscopic and molecular level. In this contribution, morphology alterations induced by solid-solid phase transitions in triisobutyl(methyl)phosphonium bis(fluorosulfonyl)imide (P1444FSI) and diethyl(methyl)(isobutyl)phosphonium hexafluorophosphate (P1224PF6) are examined using magnetic resonance imaging (MRI), alongside nuclear magnetic resonance (NMR) spectroscopy, diffusion measurements and conductivity data. These observations are linked to molecular dynamics and structural behaviour crucial for the conductive properties of OIPCs. A distinct correlation is established between the conductivity at a given temperature, σ(T), and the intensity of the narrow NMR signal that is attributed to a mobile fraction, fm(T), of ions in the OIPC. To explain these findings we propose an analogy with the well-studied relationship between permeability (k) and void fraction (θ) in porous media, with k(θ) commonly quantified by a power-law dependence that can also be employed to describe σ(fm).

Oral administration of iron-saturated bovine lactoferrin-loaded ceramic nanocapsules for breast cancer therapy and influence on iron and calcium metabolism

We determined the anticancer efficacy and internalization mechanism of our polymeric-ceramic nanoparticle system (calcium phosphate nanocores, enclosed in biodegradable polymers chitosan and alginate nanocapsules/nanocarriers [ACSC NCs]) loaded with iron-saturated bovine lactoferrin (Fe-bLf) in a breast cancer xenograft model. ACSC-Fe-bLf NCs with an overall size of 322±27.2 nm were synthesized. In vitro internalization and anticancer efficacy were evaluated in the MDA-MB-231 cells using multicellular tumor spheroids, CyQUANT and MTT assays. These NCs were orally delivered in a breast cancer xenograft mice model, and their internalization, cytotoxicity, biodistribution, and anticancer efficacy were evaluated. Chitosan-coated calcium phosphate Fe-bLf NCs effectively (59%, P≤0.005) internalized in a 1-hour period using clathrin-mediated endocytosis (P≤0.05) and energy-mediated pathways (P≤0.05) for internalization; 3.3 mg/mL of ACSC-Fe-bLf NCs completely disintegrated (~130-fold reduction, P≤0.0005) the tumor spheroids in 72 hours and 96 hours. The IC50 values determined for ACSC-Fe-bLf NCs were 1.69 mg/mL at 10 hours and 1.62 mg/mL after 20 hours. We found that Fe-bLf-NCs effectively (P≤0.05) decreased the tumor size (4.8-fold) compared to the void NCs diet and prevented tumor recurrence when compared to intraperitoneal injection of Taxol and Doxorubicin. Receptor gene expression and micro-RNA analysis confirmed upregulation of low-density lipoprotein receptor and transferrin receptor (liver, intestine, and brain). Several micro-RNAs responsible for iron metabolism upregulated with NCs were identified. Taken together, orally delivered Fe-bLf NCs offer enhanced antitumor activity in breast cancer by internalizing via low-density lipoprotein receptor and transferrin receptor and regulating the micro-RNA expression. These NCs also restored the body iron and calcium levels and increased the hematologic counts.

Is there a Kuznets' process in Southeast Asia?

Relatively little is known about the determinants of inequality in Southeast Asia. This paper fills this void by comprehensively testing Kuznets’ hypothesis for Southeast Asia. We estimate both unconditional and conditional Kuznets’ curves using panel data for 8 countries. The analysis suggests the existence of a Kuznets’ curve with respect to per capita income; the path of inequality is nonlinear with respect to economic development. There is no evidence of a Kuznets curve with respect to non-agricultural employment. There is some evidence in terms of urbanization, though this is not robust. There is robust evidence on the role of national governments and education in shaping the path of inequality in the region. Government involvement reduces inequality. Education appears to have a non-linear effect on inequality.

Microstructure and texture evolution during tensile deformation of symmetric/asymmetric-rolled low carbon microalloyed steel

The deformation and fracture mechanisms of a low carbon microalloyed steel processed by asymmetric rolling (AsR) and symmetric rolling (SR) were compared by microstructural and texture evolutions during uniaxial tensile deformation. A realistic microstructure-based micromechanical modeling was involved as well. AsR provides more effective grain refinement and beneficial shear textures, leading to higher ductility and extraordinary strain hardening with improved yield and ultimate tensile stresses as well as promoting the occurrence of ductile fracture. This was verified and further explained by means of the different fracture modes during quasi-static uniaxial deformation, the preferred void nucleation sites and crack propagation behavior, and the change in the dislocation density based on the kernel average misorientation (KAM) distribution. The equivalent strain/stress partitioning during tensile deformation of AsR and SR specimens was modeled based on a two-dimensional (2D) representative volume element (RVE) approach. The trend of strain/stress partitioning in the ferrite matrix agrees well with the experimental results.

Iron-free and iron-saturated bovine lactoferrin inhibit survivin expression and differentially modulate apoptosis in breast cancer

BACKGROUND: Iron binding, naturally occurring protein bovine lactoferrin (bLf) has attracted attention as a safe anti-cancer agent capable of inducing apoptosis. Naturally, bLf exists partially saturated (15-20%) with Fe(3+) however, it has been demonstrated that manipulating the saturation state can enhance bLf's anti-cancer activities. METHODS: Apo-bLf (Fe(3+) free) and Fe-bLf (>90% Fe(3+) Saturated) were therefore, tested in MDA-MB-231 and MCF-7 human breast cancer cells in terms of cytotoxicity, proliferation, migration and invasion. Annexin-V Fluos staining was also employed in addition to apoptotic protein arrays and Western blotting to determine the specific mechanism of bLf-induced apoptosis with a key focus on p53 and inhibitor of apoptosis proteins (IAP), specifically survivin. RESULTS: Apo-bLf induced significantly greater cytotoxicity and reduction in cell proliferation in both cancer cells showing a time and dose dependent effect. Importantly, no cytotoxicity was detected in normal MCF-10-2A cells. Both forms of bLf significantly reduced cell invasion in cancer cells. Key apoptotic molecules including p53, Bcl-2 family proteins, IAP members and their inhibitors were significantly modulated by both forms of bLf, though differentially in each cell line. Most interestingly, both Apo-bLf and Fe-bLf completely inhibited the expression of survivin protein (key IAP), after 48 h at 30 and 40 nM in cancer cells. CONCLUSIONS: The capacity of these forms of bLf to target survivin expression and modulation of apoptosis demonstrates an exciting potential for bLf as an anti-cancer therapeutic in the existing void of survivin inhibitors, with a lack of successful inhibitors in the clinical management of cancer.

Competitive inhibition of survivin using a cell-permeable recombinant protein induces cancer-specific apoptosis in colon cancer model

Endogenous survivin expression has been related with cancer survival, drug resistance, and metastasis. Therapies targeting survivin have been shown to significantly inhibit tumor growth and recurrence. We found out that a cell-permeable dominant negative survivin (SurR9-C84A, referred to as SR9) competitively inhibited endogenous survivin and blocked the cell cycle at the G1/S phase. Nanoencapsulation in mucoadhesive chitosan nanoparticles (CHNP) substantially increased the bioavailability and serum stability of SR9. The mechanism of nanoparticle uptake was studied extensively in vitro and in ex vivo models. Our results confirmed that CHNP-SR9 protected primary cells from autophagy and successfully induced tumor-specific apoptosis via both extrinsic and intrinsic apoptotic pathways. CHNP-SR9 significantly reduced the tumor spheroid size (three-dimensional model) by nearly 7-fold. Effects of SR9 and CHNP-SR9 were studied on 35 key molecules involved in the apoptotic pathway. Highly significant (4.26-fold, P≤0.005) reduction in tumor volume was observed using an in vivo mouse xenograft colon cancer model. It was also observed that net apoptotic (6.25-fold, P≤0.005) and necrotic indexes (3.5-fold, P≤0.05) were comparatively higher in CHNP-SR9 when compared to void CHNP and CHNP-SR9 internalized more in cancer stem cells (4.5-fold, P≤0.005). We concluded that nanoformulation of SR9 did not reduce its therapeutic potential; however, nanoformulation provided SR9 with enhanced stability and better bioavailability. Our study presents a highly tumor-specific protein-based cancer therapy that has several advantages over the normally used chemotherapeutics.

Locked nucleic acid modified bi-specific aptamer-targeted nanoparticles carrying survivin antagonist towards effective colon cancer therapy

We investigated the anti-cancer activity of alginate coated chitosan nanoparticles (CHNP) encapsulating cell-permeable dominant negative survivin (SR9) with locked nucleic acid (LNA) aptamers targeting EpCAM and nucleolin (termed as "nanobullets") in vitro (2D and 3D cell culture models) and in vivo (colon cancer mouse xenograft model). We incorporated three LNA modifications in each sequence in order to enhance the stability of these aptamers. Confocal microscopy revealed binding of the LNA-aptamers to their specific markers with high affinity. The muco-adhesive nanobullets showed 6-fold higher internalization in cancer cells when compared to non-cancerous cells, suggesting a tumour specific uptake. A higher intensity of nanobullets was observed in both the periphery and the core of the multicellular tumour spheroids compared to non-targeted CHNP-SR9. The nanobullets were found to be the highly effective as they led to a 2.26 fold (p < 0.05) reduction at 24 h and a 4.95 fold reduction (p ≤ 0.001) in the spheroid size at 72 h. The tumour regression was 4 fold higher in mice fed on a nanobullet diet when compared to a control diet. The nanobullets were able to show a significantly high apoptotic (p ≤ 0.0005) and necrotic index in the tumour cell population (p ≤ 0.005) when compared to void NPs. Therefore, our nanoparticles have shown highly promising results and therefore deliver a new conduit towards the approach of cancer-targeted nanodelivery. This journal is

Multifunctional properties of epoxy nanocomposites reinforced by aligned nanoscale carbon

The present paper compares improvements to the fracture energy and electrical conductivity of epoxy nanocomposites reinforced by one-dimensional carbon nanofibres (CNFs) or two-dimensional graphene nanoplatelets (GNPs). The focus of this investigation is on the effects of the shape, orientation and concentration (i.e. 0.5, 1.0, 1.5 and 2.0 wt%) of nanoscale carbon reinforcements on the property improvements. Alignment of the nano-reinforcements in the epoxy nanocomposites was achieved through the application of an alternating current (AC) electric-field before gelation and curing of the epoxy resin. Alignment of the nano-reinforcements increased the electrical conductivity and simultaneously lowered the percolation threshold necessary to form a conductive network in the nanocomposites. Nano-reinforcement alignment also increased greatly the fracture energy of the epoxy due to a higher fraction of the nano-reinforcement participating in multiple intrinsic (e.g. interfacial debonding and void growth) and extrinsic (e.g. pull-out and bridging) toughening mechanisms. A mechanistic model is presented to quantify the contributions from the different toughening mechanisms induced by CNFs and GNPs to the large improvements in fracture toughness. The model results show that one-dimensional CNFs are more effective than GNPs at increasing the intrinsic toughness of epoxy via void growth, whereas two-dimensional GNPs are more effective than CNFs at improving the extrinsic toughness via crack bridging and pull-out.