Centre selection for clinical trials and the generalisability of results: a mixed methods study.

BACKGROUND: The rationale for centre selection in randomised controlled trials (RCTs) is often unclear but may have important implications for the generalisability of trial results. The aims of this study were to evaluate the factors which currently influence centre selection in RCTs and consider how generalisability considerations inform current and optimal practice. METHODS AND FINDINGS: Mixed methods approach consisting of a systematic review and meta-summary of centre selection criteria reported in RCT protocols funded by the UK National Institute of Health Research (NIHR) initiated between January 2005-January 2012; and an online survey on the topic of current and optimal centre selection, distributed to professionals in the 48 UK Clinical Trials Units and 10 NIHR Research Design Services. The survey design was informed by the systematic review and by two focus groups conducted with trialists at the Birmingham Centre for Clinical Trials. 129 trial protocols were included in the systematic review, with a total target sample size in excess of 317,000 participants. The meta-summary identified 53 unique centre selection criteria. 78 protocols (60%) provided at least one criterion for centre selection, but only 31 (24%) protocols explicitly acknowledged generalisability. This is consistent with the survey findings (n = 70), where less than a third of participants reported generalisability as a key driver of centre selection in current practice. This contrasts with trialists' views on optimal practice, where generalisability in terms of clinical practice, population characteristics and economic results were prime considerations for 60% (n = 42), 57% (n = 40) and 46% (n = 32) of respondents, respectively. CONCLUSIONS: Centres are rarely enrolled in RCTs with an explicit view to external validity, although trialists acknowledge that incorporating generalisability in centre selection should ideally be more prominent. There is a need to operationalize 'generalisability' and incorporate it at the design stage of RCTs so that results are readily transferable to 'real world' practice

Rapid detection of A. pleuropneumoniae from clinical samples using recombinase polymerase amplification

Actinobacillus pleuropneumoniae (APP) is the causative agent of porcine pleuropneumonia, resulting in high economic impact worldwide. There are currently 19 known serovars of APP, with different ones being predominant in specific geographic regions. Outbreaks of pleuropneumonia, characterized by sudden respiratory difficulties and high mortality, can occur when infected pigs are brought into naïve herds, or by those carrying different serovars. Good biosecurity measures include regular diagnostic testing for surveillance purposes. Current gold standard diagnostic techniques lack sensitivity (bacterial culture), require expensive thermocycling machinery (PCR) and are time consuming (culture and PCR). Here we describe the development of an isothermal point-of-care diagnostic test - utilizing recombinase polymerase amplification (RPA) for the detection of APP, targeting the species-specific apxIVA gene. Our APP-RPA diagnostic test achieved a sensitivity of 10 copies/µL using a strain of APP serovar 8, which is the most prevalent serovar in the UK. Additionally, our APP-RPA assay achieved a clinical sensitivity and specificity of 84.3% and 100%, respectively, across 61 extracted clinical samples obtained from farms located in England and Portugal. Using a small subset (n = 14) of the lung tissue samples, we achieved a clinical sensitivity and specificity of 76.9% and 100%, respectively) using lung imprints made on FTA cards tested directly in the APP- RPA reaction. Our results demonstrate that our APP-RPA assay enables a suitable rapid and sensitive screening tool for this important veterinary pathogen

Strategies to Suppress Hydrogen-Consuming Microorganisms Affect Macro and Micro Scale Structure and Microbiology of Granular Sludge

Treatment of anaerobic granules with heat and two chemical treatments, contacting with 2-bromoethanesulfonate (BES) and with BESþChloroform, were applied to suppress hydrogen-consuming microorganisms. Three mesophilic expanded granular sludge bed (EGSB) reactors— RHeat, RBES, and RBESþChlo—were inoculated with the treated sludges and fed with synthetic sugar-based wastewater (5 gCOD L 1, HRT 20–12 h). Morphological integrity of granules and bacterial communities were assessed by quantitative image analysis and 16S rRNA gene based techniques, respectively. Hydrogen production in RHeat was under 300mLH2 L 1 day 1, with a transient peak of 1,000 mLH2 L 1 day 1 after decreasing HRT. In RBESþChlo hydrogen production rate did not exceed 300mLH2 L 1 day 1 and there was granule fragmentation, release of free filaments from aggregates, and decrease of granule density. In RBES, there was an initial period with unstable hydrogen production, but a pulse of BES triggered its production rate to 700 200mLH2 L 1 day 1. This strategy did not affect granules structure significantly. Bacteria branching within Clostridiaceae and Ruminococcaceae were present in this sludge. This work demonstrates that, methods applied to suppress H2-consuming microorganisms can cause changes in the macro- and microstructure of granular sludge, which can be incompatible with the operation of high-rate reactors.European Community fund FEDER Contract grant number: FCOMP-01-0124-FEDER-007087; PTDC/BIO/69745/2006; SFRH/ BD/29823/2006; SFRH/BD/48965/2008Fundação para a Ciência e a Tecnologia (FCT

The TALP & I2R SMT Systems for IWSLT 2008

This paper gives a description of the statistical machine translation (SMT) systems developed at the TALP Research Center of the UPC (Universitat Polit`ecnica de Catalunya) for our participation in the IWSLT’08 evaluation campaign. We present Ngram-based (TALPtuples) and phrase-based (TALPphrases) SMT systems. The paper explains the 2008 systems’ architecture and outlines translation schemes we have used, mainly focusing on the new techniques that are challenged to improve speech-to-speech translation quality. The novelties we have introduced are: improved reordering method, linear combination of translation and reordering models and new technique dealing with punctuation marks insertion for a phrase-based SMT system. This year we focus on the Arabic-English, Chinese-Spanish and pivot Chinese-(English)-Spanish translation tasks.Postprint (published version

FLICK: Developing and running application-specific network services

Data centre networks are increasingly programmable, with $\textit{application-specific}$ network services proliferating, from custom load-balancers to middleboxes providing caching and aggregation. Developers must currently implement these services using traditional low-level APIs, which neither support natural operations on application data nor provide efficient performance isolation. We describe FLICK, a framework for the programming and execution of application-specific network services on multi-core CPUs. Developers write network services in the FLICK $\textit{language}$, which offers high-level processing constructs and application-relevant data types. FLICK programs are translated automatically to efficient, parallel $\textit{task graphs}$, implemented in C++ on top of a user-space TCP stack. Task graphs have bounded resource usage at runtime, which means that the graphs of multiple services can execute concurrently without interference using cooperative scheduling. We evaluate FLICK with several services (an HTTP load-balancer, a Memcached router and a Hadoop data aggregator), showing that it achieves good performance while reducing development effort.Engineering and Physical Sciences Research CouncilThis is the author accepted manuscript. The final version is available from USENIX via https://www.usenix.org/conference/atc16/technical-sessions/presentation/ali

Cycles of Police Reform in Latin America.

yesOver the last quarter century post-conflict and post-authoritarian transitions in Latin America have been accompanied by a surge in social violence, acquisitive crime, and insecurity. These phenomena have been driven by an expanding international narcotics trade, by the long-term effects of civil war and counter-insurgency (resulting in, inter alia, an increased availability of small arms and a pervasive grammar of violence), and by structural stresses on society (unemployment, hyper-inflation, widening income inequality). Local police forces proved to be generally ineffective in preventing, resolving, or detecting such crime and forms of “new violence”3 due to corruption, frequent complicity in criminal networks, poor training and low pay, and the routine use of excessive force without due sanction. Why, then, have governments been slow to prioritize police reform and why have reform efforts borne largely “limited or nonexistent” long-term results? This chapter highlights a number of lessons suggested by various efforts to reform the police in Latin America over the period 1995-2010 . It focuses on two clusters of countries in Latin America. One is Brazil and the Southern Cone countries (Chile, Argentina, and Uruguay), which made the transition to democracy from prolonged military authoritarian rule in the mid- to late 1980s. The other is Central America and the Andean region (principally El Salvador, Guatemala, Honduras, Peru, and Colombia), which emerged/have been emerging from armed conflict since the mid- 1990s. The chapter examines first the long history of international involvement in police and security sector reform in order to identify long-run tropes and path dependencies. It then focuses on a number of recurring themes: cycles of de- and re-militarization of the policing function; the “security gap” and “democratization dilemmas” involved in structural reforms; the opportunities offered by decentralization for more community-oriented police; and police capacity to resist reform and undermine accountability mechanisms

Closures of regular languages for profinite topologies

The Pin-Reutenauer algorithm gives a method, that can be viewed as a descriptive procedure, to compute the closure in the free group of a regular language with respect to the Hall topology. A similar descriptive procedure is shown to hold for the pseudovariety A of aperiodic semigroups, where the closure is taken in the free aperiodic omega-semigroup. It is inherited by a subpseudovariety of a given pseudovariety if both of them enjoy the property of being full. The pseudovariety A, as well as some of its subpseudovarieties are shown to be full. The interest in such descriptions stems from the fact that, for each of the main pseudovarieties V in our examples, the closures of two regular languages are disjoint if and only if the languages can be separated by a language whose syntactic semigroup lies in V. In the cases of A and of the pseudovariety DA of semigroups in which all regular elements are idempotents, this is a new result.PESSOA French-Portuguese project Egide-Grices 11113YM, "Automata, profinite semigroups and symbolic dynamics".FCT -- Fundação para a Ciência e a Tecnologia, respectively under the projects PEst-C/MAT/UI0144/2011 and PEst-C/MAT/UI0013/2011.ANR 2010 BLAN 0202 01 FREC.AutoMathA programme of the European Science Foundation.FCT and the project PTDC/MAT/65481/2006 which was partly funded by the European Community Fund FEDER

Psoriatic Arthritis and Burden of Disease: Patient Perspectives from the Population-Based Multinational Assessment of Psoriasis and Psoriatic Arthritis (MAPP) Survey

Introduction: Psoriatic arthritis (PsA) is underdiagnosed and has a substantial impact on quality of life, disability, and work productivity. The population-based Multinational Assessment of Psoriasis and Psoriatic Arthritis (MAPP) survey examined the impact of PsA on patients’ activities of daily living and unmet treatment needs. Methods: This large-scale, random digit dialing, telephone survey of patients self-reporting a diagnosis of psoriasis and/or PsA was conducted in North America and Europe. Results: In all, 3426 patients participated in the survey, including 712 (21%) who identified themselves as having PsA. Over half of the patients reported severe PsA involving more than four joints. Eighty-three percent of patients with PsA visited a health-care provider within the past 12 months. Approximately one-quarter saw their primary care provider or dermatologist most often for their disease; 37% responded that their rheumatologist was the health-care provider seen most often for PsA. Patients with PsA reported a substantial impact of disease on physical function. One-third of patients with PsA reported missing work because of their disease and PsA impacted their ability to work full time. Over half of the patients with PsA (58%) reported receiving no treatment or topical therapy only, leaving their joint disease untreated. Factors associated with lack of adherence were perceived lack of efficacy and concerns about long-term safety. Conclusions: The MAPP survey confirms that PsA has a significant impact on physical function and activities of daily living. Undertreatment of PsA suggests a need for improved screening and diagnosis as well as education about treatment options and adherence

Definitions, Criteria and Global Classification of Mast Cell Disorders with Special Reference to Mast Cell Activation Syndromes: A Consensus Proposal

Activation of tissue mast cells (MCs) and their abnormal growth and accumulation in various organs are typically found in primary MC disorders also referred to as mastocytosis. However, increasing numbers of patients are now being informed that their clinical findings are due to MC activation (MCA) that is neither associated with mastocytosis nor with a defined allergic or inflammatory reaction. In other patients with MCA, MCs appear to be clonal cells, but criteria for diagnosing mastocytosis are not met. A working conference was organized in 2010 with the aim to define criteria for diagnosing MCA and related disorders, and to propose a global unifying classification of all MC disorders and pathologic MC reactions. This classification includes three types of `MCA syndromes' (MCASs), namely primary MCAS, secondary MCAS and idiopathic MCAS. MCA is now defined by robust and generally applicable criteria, including (1) typical clinical symptoms, (2) a substantial transient increase in serum total tryptase level or an increase in other MC-derived mediators, such as histamine or prostaglandin D 2, or their urinary metabolites, and (3) a response of clinical symptoms to agents that attenuate the production or activities of MC mediators. These criteria should assist in the identification and diagnosis of patients with MCAS, and in avoiding misdiagnoses or overinterpretation of clinical symptoms in daily practice. Moreover, the MCAS concept should stimulate research in order to identify and exploit new molecular mechanisms and therapeutic targets. Copyright (C) 2011 S. Karger AG, Base