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Activated T cells drive a range of immune-mediated inflammatory diseases. LAG-3 is transiently expressed on recently activated CD4+ and CD8+ T cells. We describe the engineering and first-in-human clinical study (NCT02195349) of GSK2831781 (an afucosylated humanized IgG1 monoclonal antibody enhanced with high affinity for Fc receptors and LAG-3 and antibody-dependent cellular cytotoxicity capabilities), which depletes LAG-3 expressing cells. GSK2831781 was tested in a phase I/Ib, double-blind, placebo-controlled clinical study, which randomized 40 healthy participants (part A) and 27 patients with psoriasis (part B) to single doses of GSK2831781 (up to 0.15 and 5 mg/kg, respectively) or placebo. Adverse events were generally balanced across groups, with no safety or tolerability concern identified. LAG-3+ cell depletion in peripheral blood was observed at doses ≥ 0.15 mg/kg and was dose-dependent. In biopsies of psoriasis plaques, a reduction in mean group LAG-3+ and CD3+ T-cell counts was observed following treatment. Downregulation of proinflammatory genes (IL-17A, IL-17F, IFNγ, and S100A12) and upregulation of the epithelial barrier integrity gene, CDHR1, was observed with the 5 mg/kg dose of GSK2831781. Psoriasis disease activity improved up to day 43 at all GSK2831781 doses (0.5, 1.5, and 5 mg/kg) compared with placebo. Depletion of LAG-3-expressing activated T cells is a novel approach, and this first clinical study shows that GSK2831781 is pharmacologically active and provides encouraging early evidence of clinical effects in psoriasis, which warrants further investigation in T-cell-mediated inflammatory diseases.

A multitude of biotic indices that represent environmental status have been developed over the past decades making status comparisons difficult. However, transferring an existing index to a new region can be problematic due to differing stressors, ecosystem components and lack of knowledge on regional species sensitivities. Here we assess whether calculating species sensitivities to specific stressors based on biological traits offers a solution. We use biological traits of macrofaunal species to assess sensitivity to suspended sediment concentrations and calculated the Benthic Quality Index (BQI) at 47 sites across a suspended sediment gradient. This trait-based modification of the BQI was well correlated (0.82) to suspended sediment. Problems previously highlighted, relating to trait plasticity and differential weightings of indifferent and beneficial species, were investigated but did not strongly affect results. A trait-based approach has the additional benefit that the data could be easily converted to evaluate ecosystem function.

Reduced emissions and environmental burden from shipping are an important aim of tightening emission regulations and ambitious climate change strategy. Renewable methanol produced from biomass or from other renewable sources represents one option to face these challenges. We studied the potential of renewable methanol to offer such benefits in diesel operation in a Scania ethanol engine, which is designed for additized ethanol fuel (ED95) containing ignition improver and lubricity additives. Methanol (MD95) with several types of ignition improver and lubricity additives was studied for use in diesel engines. MD95 fuels were clean-burning, emitting even less gaseous emissions than ED95, particularly when glycerol ethoxylate was used as an ignition improver. Particle mass and number emissions originating from additives in the experimental fuels could be reduced with an oxidation catalyst. Reduced additive dosing in the MD95 fuels was studied with the aid of fuel injection into the intake manifold. Overall, the results showed that the monofuel MD95 concept is a promising solution for smaller vessels equipped with 800-1200 kW engines. © (Less)

Activated T cells drive a range of immune‐mediated inflammatory diseases. LAG‐3 is transiently expressed on recently activated CD4+ and CD8+ T cells. We describe the engineering and first‐in‐human clinical study (NCT02195349) of GSK2831781 (an afucosylated humanized IgG1 monoclonal antibody enhanced with high affinity for Fc receptors and LAG‐3 and antibody‐dependent cellular cytotoxicity capabilities), which depletes LAG‐3 expressing cells. GSK2831781 was tested in a phase I/Ib, double‐blind, placebo‐controlled clinical study, which randomized 40 healthy participants (part A) and 27 patients with psoriasis (part B) to single doses of GSK2831781 (up to 0.15 and 5 mg/kg, respectively) or placebo. Adverse events were generally balanced across groups, with no safety or tolerability concern identified. LAG‐3+ cell depletion in peripheral blood was observed at doses ≥ 0.15 mg/kg and was dose‐dependent. In biopsies of psoriasis plaques, a reduction in mean group LAG‐3+ and CD3+ T‐cell counts was observed following treatment. Downregulation of proinflammatory genes (IL‐17A, IL‐17F, IFNγ, and S100A12) and upregulation of the epithelial barrier integrity gene, CDHR1, was observed with the 5 mg/kg dose of GSK2831781. Psoriasis disease activity improved up to day 43 at all GSK2831781 doses (0.5, 1.5, and 5 mg/kg) compared with placebo. Depletion of LAG‐3‐expressing activated T cells is a novel approach, and this first clinical study shows that GSK2831781 is pharmacologically active and provides encouraging early evidence of clinical effects in psoriasis, which warrants further investigation in T‐cell‐mediated inflammatory diseases.

Aim Interleukin (IL)-7 signalling modulates T cell activity and is implicated in numerous autoimmune diseases. The present study investigated the safety, pharmacokinetics, target engagement, pharmacodynamics and immunogenicity of GSK2618960, an IL-7 receptor-α subunit (CD127) monoclonal antibody. Methods A double-blind (sponsor-unblind) study of a single intravenous infusion of either GSK2618960 (0.6 mg kg-1 or 2.0 mg kg-1 ) or placebo was carried out in 18 healthy subjects over 24 weeks. Results GSK2618960 was well tolerated; there were no serious or significant adverse events. The observed half-life was 5 (±1) days (2.0 mg kg-1 ), with nonlinear pharmacokinetics. Full receptor occupancy (>95%) was observed until day 8 (0.6 mg kg-1 ) and day 22 (2.0 mg kg-1 ). Maximal inhibition of IL-7-mediated signal transducer and activator of transcription 5 (STAT5) phosphorylation was observed in 5/6 subjects until day 22 (2.0 mg kg-1 ). Mean circulating IL-7 and soluble receptor (CD127) levels were increased above baseline during days 2 and 15 (0.6 mg kg-1 ) and days 2 and 22 (2.0 mg kg-1 ). No meaningful changes were observed in absolute numbers or proportions of immune cell populations or inflammatory cytokine profiles (IL-6, tumour necrosis factor-α, interferon-γ, IL-2). Persistent antidrug antibodies (ADAs) were detected in 5/6 subjects administered a dose of 0.6 mg kg-1 (neutralizing in 2/6) and in 6/6 subjects administered 2.0 mg kg-1 (neutralizing in 5/6). Conclusion GSK2618960 was well tolerated and blocked IL-7 receptor signalling upon full target engagement. Although there was no discernible impact on peripheral T cell subsets in healthy subjects, GSK2618960 may effectively modulate the autoinflammatory activity of pathogenic T cells in diseased tissue. A relatively short half-life is likely the result of target-mediated rather than ADA-mediated clearance.

Maritime shipping is essential in global trade. The shipping industry uses fossil fuel with significant environmental impact as a result and a transition to renewable fuels may be part of the solution to reduce emissions. A fuel transition needs to be understood at all stages of the supply chain, ranging from feedstock to use in ships’ engines. The purpose of this paper is to do a synthesis of literature to provide an overview of main challenges and opportunities along potential supply chains of renewable methanol for maritime shipping, with a focus on bio-methanol. It is shown that renewable methanol is a technically viable option to reduce emissions from shipping and there are no major challenges with potential supply chains. Minor economic barriers that currently exist have the potential to be overcome with strengthening of environmental targets for shipping or if fuel oil prices revert to higher levels as seen previously.

Aim: Global warming and eutrophication are major threats to coastal environments worldwide. As a result of differences between temperate and tropical ecosystems in nutrient availability, nitrogen (N): phosphorus (P) coupling and carbon retention, primary productivity and biotic interactions in the tropics are predicted to have stronger responses to increased nutrients than in temperate ecosystems. Habitats that occur across broad climatic ranges, such as mangrove forests, provide an opportunity to test this hypothesis by investigating the responses of herbivores to nutrient enrichment in temperate versus tropical latitudes on the same species.

The release of packaged or containerized dangerous goods during transport can have serious consequences on board a ship. This study was focused on identifying factors contributing to these types of releases and on investigating the contribution of dangerous goods accidents to overall container ship accident rates. Records of dangerous goods releases from a US and a UK database for an 11-year period covering 1998-2008 were analyzed to identify and categorize main contributing factors. The majority of releases, estimated as 97% of the US events and 94% of the UK events, did not follow another primary accident type such as a collision. Faults that occurred during activities such as preparation of the goods for transport, packaging, stuffing containers, and loading the ship were main factors contributing to the release of the dangerous goods on board the ship. For container ship casualties occurring worldwide during the same period, 1998-2008, accidents involving packaged dangerous goods were estimated to account for 15% of all fatalities. Self-ignition or ignition of incorrectly declared dangerous goods was identified as a contributing factor for the fatal accidents. Ensuring that dangerous goods are correctly prepared and documented for marine transport is thus very important for preventing releases and improving on board safety.

PurposeA considerable amount of research has been undertaken with regard to the dispute causation within construction project management. Research has eschewed identifying the interrelatedness of variables, which has blurred researchers understanding of dispute causation and lead to latent work practices being embedded within the contracting environment within which projects are procured. With this in mind, this paper attempts to identify the underlying dynamics influencing disputes through the use of causal modeling.Design/methodology/approachUsing the concept of system dynamics a series of causal models are developed from the literature to demonstrate the complexity associated with dispute causation.FindingsIt is revealed that project management, organization and people are the main sources of disputes. Causal models are constructed for each of these constructs and a series of strategies for avoiding disputations identified.Originality/valueThe research has demonstrated the inherent complexity associated with disputes and identified the interrelatedness of factors that can lead to their causation. It is suggested that further empirical research is required to determine the recurring latent conditions that contribute disputes. Once these conditions are examined then effective strategies for dispute avoidance can be identified and advancement toward improving the performance of construction projects made.

PurposeWhile a considerable amount of knowledge has been accumulated about dispute causation, disputes continue to prevail and disharmonise the process of construction with considerable cost. This paper seeks to identify the underlying pathogens that clients and contractors perceive to contribute to disputes in construction projects. The identification of pathogens can provide an ameliorated understanding of the origin of disputes and therefore enable their prevention.Design/methodology/approachCase law and focus groups with a client and contracting organisation from Western Australia are used to determine the pathogens of disputes.FindingsAnalysis of the case law findings revealed that the underlying issues that were brought to litigation were to do with points of law, namely “civil procedure”. A significant number of disputes are thus settled using alternative dispute resolution methods such as adjudication, arbitration and mediation. For clients the underlying latent conditions that resulted in a dispute were due to the nature of the task being performed (e.g. failure to detect and correct errors) and those arising from people's deliberate practices (e.g. failure to oblige by contractual requirements). For the contractor focus group the circumstances arising from the situation or environment the project was operating in were identified as the main underlying latent condition for disputes (e.g. unforeseen scope changes).Research limitations/implicationsFocus groups are only undertaken with clients and contracting groups as they were identified as the main parties involved in dispute during the analysis of litigation cases within Western Australia. Input from consultants and subcontractors may provide a more balanced perspective as to the perceived causes and costs of disputes.Originality/valueThe research has been able to provide the initial building blocks for understanding the underlying pathogens contributing to disputes. However, more empirical research is required before conclusive findings can be made, particularly with regard to the influences on subcontractors.

This paper presents an evaluation of the cost-effectiveness of a novel passenger monitoring system based on RFID technology for implementation onboard passenger ships. Such a system will be able to detect and keep track of passengers onboard the ship in emergency situations in order to provide crucial decision support to the officer in charge of evacuation. This will lead to increased safety and security on passenger ships. However, this increased safety will come at a certain cost. A methodology in line with Formal Safety Assessment is employed in order to assess the cost-effectiveness of the system, involving a thorough risk analysis.

Dangerous goods that have not been correctly declared when offered for transport have contributed to some serious accidents at sea. Safe handling, stowage, and segregation of packaged dangerous goods cannot be carried out if there is no knowledge of the presence of dangerous goods inside the cargo transport unit (container and/or trailer), or if the goods have been incorrectly declared. Although undeclared dangerous goods are recognized as a safety issue in the shipping industry, there is little information available on the extent of the risk involved. The study described in this paper was carried out to investigate the extent and potential consequences of the maritime transport of undeclared dangerous goods. Dangerous goods incident and inspection reports and ship casualty data were reviewed and analysed. A generic qualitative model was constructed to illustrate contributing factors and potential consequences in incidents involving undeclared dangerous goods.

Commercial shipping of containerized goods involves certain risks for human safety and environment. In order to actively manage these risks, they must be identified, analyzed, modeled, and quantified. This requires a systematical analysis of design and operation of container vessels. Within the EU-funded research project SAFEDOR, a Formal Safety Assessment has been applied to establish the current safety level of generic container ships and to identify potential cost-effective risk control options. This paper describes a structured approach to develop the underlying high-level risk model. It is structured as risk contribution tree consisting of a series of fault trees and event trees for the major accident categories. Statistical analysis of casualty data is used to estimate the probability of occurrence. Finally, the summation overall individual risk contributions yields the current risk pro file for the operation of container vessels is presented as FN-curve.

The Environmental Assessment (EA) process should involve the generation of testable predictions generated using clearly stated methods and followed by the collection of environmental monitoring data. Follow-up programs should aim to determine the accuracy of the initial predictions. We examined the follow-up process for six oil and gas extraction projects in eastern Canada with respect to assessing batch spill (

The National Rugby League (NRL) in Australia introduced a new 'concussion interchange rule' (CIR) in 2014, whereby a player suspected of having sustained a concussion can be removed from play, and assessed, without an interchange being tallied against the player's team. We conducted a video analysis, describing player and injury characteristics, situational factors, concussion signs, and return to play for each "CIR" event for the 2014 season. There were 167 reported uses of the CIR. Apparent loss of consciousness/unresponsiveness was observed in 32% of cases, loss of muscle tone in 54%, clutching the head in 70%, unsteadiness of gait in 66%, and a vacant stare in 66%. More than half of the players who were removed under the CIR returned to play later in the same match (57%). Most incidences occurred from a hit up (62%) and occurred during a tackle where the initial contact was with the upper body (80%). The new concussion interchange rule has been used frequently during the first season of its implementation. In many cases, there appeared to be video evidence of injury but the athlete was cleared to return to play. More research is needed on the usefulness of video review for identifying signs of concussive injury.

Laser desorption/ionization mass spectrometry (LDI-MS) on porous silicon is a promising analytical strategy for the rapid detection of metabolites in biological matrices. We show that both oxidized and unoxidized porous silicon surfaces are useful in detecting protonated/deprotonated molecules from compounds when analyzed in mixtures. We demonstrate the feasibility of using this technique for the simultaneous detection of multiple analytes using a synthetic cocktail of 30 compounds commonly associated with prokaryotic and eukaryotic primary metabolism. The predominantly detected species were the protonated molecules or their sodium/potassium adducts in the positive-ion mode and the deprotonated molecules in the negative-ion mode, as opposed to fragments or other adducts. Surface oxidation appears to influence mass spectral responses; in particular, in the mixture we studied, the signal intensities of the hydrophobic amino acids were noticeably reduced. We show that whilst quantitative changes in individual analytes can be detected, ion suppression effects interfere when analyte levels are altered significantly. However, the response of most analytes was relatively unaffected by changes in the concentration of one of the analytes, so long as it was not allowed to dominate the mixture, which may limit the dynamic range of this approach. The differences in the response of the analytes when analyzed in mixtures could not be accounted for by considering their gas-phase and aqueous basicities alone. The implications of these findings in using the technique for metabolome analyses are discussed.

In this paper we discuss the application of ToF-SIMS with an Au3 + primary ion beam, combined with principal components analysis (PCA) and discriminant function analysis (DFA) for the identification of individual strains of two Bacillus species. The ToF-SIMS PC-DFA methodology is capable of distinguishing bacteria at the strain levelbased onanalysis of surface chemical species. By classifying the data using hierarchical cluster analysis (HCA) we are able to show quantitative separation of species and of these strains. This has taxonomic implications in the areas of rapid identification of pathogenic microbes isolated from the clinic, food and environment. # 2006 Published by Elsevier B.V.

It is not known if peats derived from different areas of Scotland have distinctive chemical constituents that could impact on malt whisky in discernible organoleptic ways. Fourier transform-infrared (FT-IR) spectroscopy was used as a high throughput screening method to investigate discrimination of a large number of peat samples from six different geographical origins around Scotland. The data were analysed statistically (using principal component-discriminant function analysis) and the results showed a difference between peat samples from different geographical origins. Therefore, we have shown that FT-IR spectroscopy provides a quick and simple method for differentiating peat types.

The importance of metabolomic data in functional genomic investigations is increasingly becoming evident, as is its utility in novel biomarker discovery. We demonstrate a simple approach to the screening of metabolic information that we believe will be valuable in generating metabolomic data. Laser desorption ionisation mass spectrometry on porous silicon was effective in detecting 22 of 30 metabolites in a mixture in the negative-ion mode and 19 of 30 metabolites in the positive-ion mode, without the employment of any prior analyte separation steps. Overall, 26 of the 30 metabolites could be covered between the positive and negative-ion modes. Although the response for the metabolites at a given concentration differed, it was possible to generate direct quantitative information for a given analyte in the mixture. This technique was subsequently used to generate metabolic footprints from cell-free supernatants and, when combined with chemometric analysis, enabled us to discriminate haploid yeast single-gene deletants (mutants). In particular, the metabolic footprint of a deletion mutant in a gene encoding a transcriptional activator (Gln3p) showed increased levels of peaks, including one corresponding to glutamate, compared to the other mutants and the wild-type strain tested, enabling its discrimination based on metabolic information.

Forward genetic screens have led to the isolation of several genes involved in secondary cell wall formation. A variety of evidence, however, suggests that the list of genes identified is not exhaustive. To address this problem, microarray data have been generated from tissue undergoing secondary cell wall formation and used to identify genes that exhibit a similar expression pattern to the secondary cell wall-specific cellulose synthase genes IRREGULAR XYLEM1 (IRX1) and IRX3. Cross-referencing this analysis with publicly available microarray data resulted in the selection of 16 genes for reverse genetic analysis. Lines containing an insertion in seven of these genes exhibited a clear irx phenotype characteristic of a secondary cell wall defect. Only one line, containing an insertion in a member of the COBRA gene family, exhibited a large decrease in cellulose content. Five of the genes identified as being essential for secondary cell wall biosynthesis have not been previously characterized. These genes are likely to define entirely novel processes in secondary cell wall formation and illustrate the success of combining expression data with reverse genetics to address gene function.

Sexual victimization of children is a relatively new area of enquiry and initial studies have been directed towards identification and etiology. It is only recently that treatment issues are beginning to be addressed. This paper first reviews the literature on the direct and indirect effects of sexual abuse on the child victim, and outlines five key issues in treatment. The major foci in treatment to date are described and a number of existing models, which have been devised to address these treatment issues, are briefly summarized.

Sixty-four patients with herpes zoster were entered into a randomised double-masked, placebo-controlled trial of 5% acyclovir cream applied five times daily for 5 days. Of these patients, 56 were included in the final analysis (26 acyclovir, 30 placebo). Significant and objective differences in either progression of the rash, severity of acute pain or incidence of post-herpetic neuralgia were not observed. Although significantly more rashes involuted in the acyclovir group, this isolated finding cannot be explained. Twenty-two patients (12 acyclovir, 10 placebo) experienced erythema or desquamation or both during treatment with the cream. The similar incidence of skin reactions in both groups suggests that they were related to the cream base rather than the acyclovir.

ObjectivesAn interferon (IFN) gene signature (IGS) is present in approximately 50% of early, treatment naive rheumatoid arthritis (eRA) patients where it has been shown to negatively impact initial response to treatment. We wished to validate this effect and explore potential mechanisms of action.MethodsIn a multicentre inception cohort of eRA patients (n=191), we examined the whole blood IGS (MxA, IFI44L, OAS1, IFI6, ISG15) with reference to circulating IFN proteins, clinical outcomes and epigenetic influences on circulating CD19+ B and CD4+ T lymphocytes.ResultsWe reproduced our previous findings demonstrating a raised baseline IGS. We additionally showed, for the first time, that the IGS in eRA reflects circulating IFN-α protein. Paired longitudinal analysis demonstrated a significant reduction between baseline and 6-month IGS and IFN-α levels (pPARP9, STAT1,andEPSTI1, associated with baseline IGS/IFNα levels. Differentially methylated CPG sites implicated altered transcription factor binding in B cells (GATA3, ETSI, NFATC2, EZH2) and T cells (p300, HIF1α).ConclusionsOur data suggest that, in eRA, IFN-α can cause a sustained, epigenetically mediated, pathogenic increase in lymphocyte activation and proliferation, and that the IGS is, therefore, a robust prognostic biomarker. Its persistent harmful effects provide a rationale for the initial therapeutic targeting of IFN-α in selected patients with eRA.