A Coordination and Ligand Replacement Based Three-Input Colorimetric Logic Gate Sensing Platform for Melamine, Mercury Ions, and Cysteine

Discrimination of different species in various target scopes within a single sensing platform can provide many advantages such as simplicity, rapidness, and cost effectiveness. Here we design a three-input colorimetric logic gate based on the aggregation and anti-aggregation of gold nanoparticles (Au NPs) for the sensing of melamine, cysteine, and Hg2+. The concept takes advantages of the highly specific coordination and ligand replacement reactions between melamine, cysteine, Hg2+, and Au NPs. Different outputs are obtained with the combinational inputs in the logic gates, which can serve as a reference to discriminate different analytes within a single sensing platform. Furthermore, besides the intrinsic sensitivity and selectivity of Au NPs to melamine-like compounds, the “INH” gates of melamine/cysteine and melamine/Hg2+ in this logic system can be employed for sensitive and selective detections of cysteine and Hg2+, respectively.

Making randomised trials more efficient: report of the first meeting to discuss the Trial Forge platform

Randomised trials are at the heart of evidence-based healthcare, but the methods and infrastructure for conducting these sometimes complex studies are largely evidence free. Trial Forge (www.trialforge.org) is an initiative that aims to increase the evidence base for trial decision making and, in doing so, to improve trial efficiency.

This paper summarises a one-day workshop held in Edinburgh on 10 July 2014 to discuss Trial Forge and how to advance this initiative. We first outline the problem of inefficiency in randomised trials and go on to describe Trial Forge. We present participants' views on the processes in the life of a randomised trial that should be covered by Trial Forge.

General support existed at the workshop for the Trial Forge approach to increase the evidence base for making randomised trial decisions and for improving trial efficiency. Agreed upon key processes included choosing the right research question; logistical planning for delivery, training of staff, recruitment, and retention; data management and dissemination; and close down. The process of linking to existing initiatives where possible was considered crucial. Trial Forge will not be a guideline or a checklist but a 'go to' website for research on randomised trials methods, with a linked programme of applied methodology research, coupled to an effective evidence-dissemination process. Moreover, it will support an informal network of interested trialists who meet virtually (online) and occasionally in person to build capacity and knowledge in the design and conduct of efficient randomised trials.

Some of the resources invested in randomised trials are wasted because of limited evidence upon which to base many aspects of design, conduct, analysis, and reporting of clinical trials. Trial Forge will help to address this lack of evidence.

Design of a Dissolving Microneedle Platform for Transdermal Delivery of a Fixed-Dose Combination of Cardiovascular Drugs

Microneedles (MNs) are a minimally invasive drug delivery platform, designed to enhance transdermal drug delivery by breaching the stratum corneum. For the first time, this study describes the simultaneous delivery of a combination of three drugs using a dissolving polymeric MN system. In the present study, aspirin, lisinopril dihydrate, and atorvastatin calcium trihydrate were used as exemplar cardiovascular drugs and formulated into MN arrays using two biocompatible polymers, poly(vinylpyrrollidone) and poly(methylvinylether/maleic acid). Following fabrication, dissolution, mechanical testing, and determination of drug recovery from the MN arrays, in vitro drug delivery studies were undertaken, followed by HPLC analysis. All three drugs were successfully delivered in vitro across neonatal porcine skin, with similar permeation profiles achieved from both polymer formulations. An average of 126.3 ± 18.1 μg of atorvastatin calcium trihydrate was delivered, notably lower than the 687.9 ± 101.3 μg of lisinopril and 3924 ± 1011 μg of aspirin, because of the hydrophobic nature of the atorvastatin molecule and hence poor dissolution from the array. Polymer deposition into the skin may be an issue with repeat application of such a MN array, hence future work will consider more appropriate MN systems for continuous use, alongside tailoring delivery to less hydrophilic compounds.

Microneedles: an innovative platform for gene delivery

The advent of microneedle (MN) technology has provided a revolutionary platform for the delivery of therapeutic agents, particularly in the field of gene therapy. For over 20 years, the area of gene therapy has undergone intense innovation and progression which has seen advancement of the technology from an experimental concept to a widely acknowledged strategy for the treatment and prevention of numerous disease states. However, the true potential of gene therapy has yet to be achieved due to limitations in formulation and delivery technologies beyond parenteral injection of the DNA. Microneedle-mediated delivery provides a unique platform for the delivery of DNA therapeutics clinically. It provides a means to overcome the skin barriers to gene delivery and deposit the DNA directly into the dermal layers, a key site for delivery of therapeutics to treat a wide range of skin and cutaneous diseases. Additionally, the skin is a tissue rich in immune sentinels, an ideal target for the delivery of a DNA vaccine directly to the desired target cell populations. This review details the advancement of MN-mediated DNA delivery from proof-of-concept to the delivery of DNA encoding clinically relevant proteins and antigens and examines the key considerations for the improvement of the technology and progress into a clinically applicable delivery system.

Implementation of Selective Packet Destruction on Wireless Open-Access Research Platform

Interesting wireless networking scenarios exist wherein network services must be guaranteed in a dynamic fashion for some priority users. For example, in disaster recovery, members need to be able to quickly block other users in order to gain sole use of the radio channel. As it is not always feasible to physically switch off other users, we propose a new approach, termed selective packet destruction (SPD) to ensure service for priority users. A testbed for SPD has been created, based on the Rice University Wireless open-Access Research Platform and been used to examine the feasibility of our approach. Results from the testbed are presented to demonstrate the feasibility of SPD and show how a balance between performance and acknowledgement destruction rate can be achieved. A 90% reduction in TCP & UDP traffic is achieved for a 75% MAC ACK destruction rate.

RNA interference in adult Ascaris suum - an opportunity for the development of a functional genomics platform that supports organism-, tissue- and cell-based biology in a nematode parasite

The sustainable control of animal parasitic nematodes requires the development of efficient functional genomics platforms to facilitate target validation and enhance anthelmintic discovery. Unfortunately, the utility of RNA interference (RNAi) for the validation of novel drug targets in nematode parasites remains problematic. Ascaris suum is an important veterinary parasite and a zoonotic pathogen. Here we show that adult A. suum is RNAi competent, and highlight the induction, spread and consistency of RNAi across multiple tissue types. This platform provides a new opportunity to undertake whole organism-, tissue- and cell-level gene function studies to enhance target validation processes for nematode parasites of veterinary/medical significance.

Platform Competition as Network Contestability

Recent research in industrial organisation has investigated the essential place that middlemen have in the networks that make up our global economy. In this paper we attempt to understand how such middlemen compete with each other through a game theoretic analysis using novel techniques from decision-making under ambiguity.
We model a purposely abstract and reduced model of one middleman who provides a two-sided platform, mediating surplus-creating interactions between two users. The middleman evaluates uncertain outcomes under positional ambiguity, taking into account the possibility of the emergence of an alternative middleman offering intermediary services to the two users.
Surprisingly, we find many situations in which the middleman will purposely extract maximal gains from her position. Only if there is relatively low probability of devastating loss of business under competition, the middleman will adopt a more competitive attitude and extract less from her position.

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

BACKGROUND: Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone.

METHODS: Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544).

FINDINGS: 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc.

INTERPRETATION: Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy.

FUNDING: Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.

A Scalable Runtime for the ECOSCALE Heterogeneous Exascale Hardware Platform

Exascale computation is the next target of high performance computing. In the push to create exascale computing platforms, simply increasing the number of hardware devices is not an acceptable option given the limitations of power consumption, heat dissipation, and programming models which are designed for current hardware platforms. Instead, new hardware technologies, coupled with improved programming abstractions and more autonomous runtime systems, are required to achieve this goal. This position paper presents the design of a new runtime for a new heterogeneous hardware platform being developed to explore energy efficient, high performance computing. By combining a number of different technologies, this framework will both simplify the programming of current and future HPC applications, as well as automating the scheduling of data and computation across this new hardware platform. In particular, this work explores the use of FPGAs to achieve both the power and performance goals of exascale, as well as utilising the runtime to automatically effect dynamic configuration and reconfiguration of these platforms. 

A Wii Bit of Fun: A Novel Platform to Deliver Effective Balance Training to Older Adults

BACKGROUND: Falls and fall-related injuries are symptomatic of an aging population. This study aimed to design, develop, and deliver a novel method of balance training, using an interactive game-based system to promote engagement, with the inclusion of older adults at both high and low risk of experiencing a fall.

STUDY DESIGN: Eighty-two older adults (65 years of age and older) were recruited from sheltered accommodation and local activity groups. Forty volunteers were randomly selected and received 5 weeks of balance game training (5 males, 35 females; mean, 77.18 ± 6.59 years), whereas the remaining control participants recorded levels of physical activity (20 males, 22 females; mean, 76.62 ± 7.28 years). The effect of balance game training was measured on levels of functional balance and balance confidence in individuals with and without quantifiable balance impairments.

RESULTS: Balance game training had a significant effect on levels of functional balance and balance confidence (P < 0.05). This was further demonstrated in participants who were deemed at high risk of falls. The overall pattern of results suggests the training program is effective and suitable for individuals at all levels of ability and may therefore play a role in reducing the risk of falls.

CONCLUSIONS: Commercial hardware can be modified to deliver engaging methods of effective balance assessment and training for the older population.

Eurozone Network Connectedness During Calm and Crisis: Evidence from the MTS Platform for Interdealer Trading of European Sovereign Debt

This paper examines the connectedness of the Eurozone sovereign debt market over the period 2005–2011. By employing measures built from the variance decompositions of approximating models we are able to define weighted, directed networks that enable a deeper understanding of the relationships between the Eurozone countries. We find that connectedness in the Eurozone was very high during the calm market conditions preceding the global financial crisis but decreased dramatically when the crisis took hold, and worsened as the Eurozone sovereign debt crisis emerged. The drop in connectedness was especially prevalent in the case of the peripheral countries with some of the most peripheral countries deteriorating into isolation. Our results have implications for both market participants and regulators.

A telematic platform towards regional connected healthcare

As tecnologias de informação e comunicação na área da saúde não são só um instrumento para a boa gestão de informação, mas antes um fator estratégico para uma prestação de cuidados mais eficiente e segura. As tecnologias de informação são um pilar para que os sistemas de saúde evoluam em direção a um modelo centrado no cidadão, no qual um conjunto abrangente de informação do doente deve estar automaticamente disponível para as equipas que lhe prestam cuidados, independentemente de onde foi gerada (local geográfico ou sistema). Este tipo de utilização segura e agregada da informação clínica é posta em causa pela fragmentação generalizada das implementações de sistemas de informação em saúde. Várias aproximações têm sido propostas para colmatar as limitações decorrentes das chamadas “ilhas de informação” na saúde, desde a centralização total (um sistema único), à utilização de redes descentralizadas de troca de mensagens clínicas. Neste trabalho, propomos a utilização de uma camada de unificação baseada em serviços, através da federação de fontes de informação heterogéneas. Este agregador de informação clínica fornece a base necessária para desenvolver aplicações com uma lógica regional, que demostrámos com a implementação de um sistema de registo de saúde eletrónico virtual. Ao contrário dos métodos baseados em mensagens clínicas ponto-a-ponto, populares na integração de sistemas em saúde, desenvolvemos um middleware segundo os padrões de arquitetura J2EE, no qual a informação federada é expressa como um modelo de objetos, acessível através de interfaces de programação. A arquitetura proposta foi instanciada na Rede Telemática de Saúde, uma plataforma instalada na região de Aveiro que liga oito instituições parceiras (dois hospitais e seis centros de saúde), cobrindo ~350.000 cidadãos, utilizada por ~350 profissionais registados e que permite acesso a mais de 19.000.000 de episódios. Para além da plataforma colaborativa regional para a saúde (RTSys), introduzimos uma segunda linha de investigação, procurando fazer a ponte entre as redes para a prestação de cuidados e as redes para a computação científica. Neste segundo cenário, propomos a utilização dos modelos de computação Grid para viabilizar a utilização e integração massiva de informação biomédica. A arquitetura proposta (não implementada) permite o acesso a infraestruturas de e-Ciência existentes para criar repositórios de informação clínica para aplicações em saúde.