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Introduction Bronchiectasis is a long-term lung condition, with dilated bronchi, chronic inflammation, chronic infection and acute exacerbations. Recurrent exacerbations are associated with poorer clinical outcomes such as increased severity of lung disease, further exacerbations, hospitalisations, reduced quality of life and increased risk of death. Despite an increasing prevalence of bronchiectasis, there is a critical lack of high-quality studies into the disease and no treatments specifically approved for its treatment. This trial aims to establish whether inhaled dual bronchodilators (long acting beta agonist (LABA) and long acting muscarinic antagonist (LAMA)) taken as either a stand-alone therapy or in combination with inhaled corticosteroid (ICS) reduce the number of exacerbations of bronchiectasis requiring treatment with antibiotics during a 12 month treatment period.Methods This is a multicentre, pragmatic, double-blind, randomised controlled trial, incorporating an internal pilot and embedded economic evaluation. 600 adult patients (≥18 years) with CT confirmed bronchiectasis will be recruited and randomised to either inhaled dual therapy (LABA+LAMA), triple therapy (LABA+LAMA+ICS) or matched placebo, in a 2:2:1 ratio (respectively). The primary outcome is the number of protocol defined exacerbations requiring treatment with antibiotics during the 12 month treatment period.Ethics and dissemination Favourable ethical opinion was received from the North East—Newcastle and North Tyneside 2 Research Ethics Committee (reference: 21/NE/0020). Results will be disseminated in peer-reviewed publications, at national and international conferences, in the NIHR Health Technology Assessments journal and to participants and the public (using lay language).Trial registration number ISRCTN15988757.

Marlborough is the largest wine-growing region in New Zealand. The seismic events of Lake Grassmere 2013 and Kaikōura 2016 caused severe business disruption to the wineries due to the poor performance of wine storage tanks and connected non-structural components. The damage recorded raised two main discussions concerning the NZSEE 2009 guidelines for seismic design of liquid storage tanks. The first is related to the appropriateness of the determination of the importance level to adopt for the design of tanks. In fact, importance level 1 (IL1) (structures presenting a low degree of hazard to life and other property) was adopted for most wine tanks, and therefore, the horizontal forces designed were extremely low. Adopting importance level 2 (IL2) (normal structures) would have increased the overall seismic demand to design them for and therefore limited their structural damage but potentially increased the structural cost. The second concerns the design detailing of the critical connections. In fact, the current guidelines/standards lack provisions. The authors compare the NZSEE 2009 guideline with Eurocode 8 (EC8) and API 650 through the design of six tanks with typical dimensions used in the New Zealand wine industry. Results show that assigning importance level 1 results in seismic design demand similar to EC8 and API 650, thereby showing that other countries have a similar approach to New Zealand. A further comparative analysis also highlighted that connection detailing design including the hierarchy of strength is totally missing in all three standards/guidelines, which lacks information.

Abstract Background Current evidence demonstrates that few patients complete anterior cruciate ligament reconstruction rehabilitation according to evidence-based guidelines. It is important to investigate the viewpoints of our patients to identify patient-reported barriers and facilitators of anterior cruciate ligament reconstruction rehabilitation. Qualitative analysis can provide insight into potential methods for improving the delivery of rehabilitation services. Methods In this qualitative study, utilising a social constructionism orientation, viewed through the social phenomenological lens, three focus groups were conducted with individuals 1–20 years post anterior cruciate ligament reconstruction (n = 20, 9 males, 11 females, mean 6.5 years post-surgery, 19–51 years old). Utilising a semi-structured interview guide, participants were asked about their experiences during anterior cruciate ligament reconstruction rehabilitation. Focus groups were recorded, transcribed, and coded using an inductive semantic thematic analysis methodology. Results Five organising themes were identified (consisting of 19 sub-themes) to provide a framework to present the data: psychological, physiological, rehabilitation service, rehabilitation characteristics, and interaction with others. Each theme details aspects of rehabilitation, such as exercise delivery, informational support, frequency, and duration of care, kinesiophobia, weight management and interactions with teams and coaches, which present barriers or facilitators for patients to adhere to and participate in rehabilitation. Example quotes are provided for each theme to provide context and the patient’s voice. Conclusions This qualitative investigation identified key aspects of a patient's rehabilitation in which they encounter a variety of barriers and facilitators of ACL reconstruction rehabilitation. These aspects, such as the rehabilitation characteristics, service delivery, psychological and physiological factors, and interactions with others, were consistently identified by this cohort as factors which affected their rehabilitation. The themes may provide targets for clinicians to improve rehabilitation and deliver patient-centred care. However, the themes must be evaluated in future trials to assess whether interventions to remove barriers or enhance facilitators improves subsequent outcomes such as return to sport and re-injury rates.

Environmental concerns and energy efficiency have been driving the transportation innovation in the past decades. In this framework, hybrid city transport has been receiving the attention of the industry. The challenges for this application are the required high-power density, lower maintenance cost and the high-temperature environment due to the integration with the internal combustion engine. A multiport converter is proposed to realise the requirements of the automotive industry to achieve greater performance in driveline electrification. The platform suggests the combination of previously discrete power electronics converter modules into one physical package commonising parts such as the microcontroller, heatsink and busbars. This paper provides an overview of design considerations for engine start-stop within a series-parallel topology and how it is achieved using the multiport converter. Finally, a comparison between the multiport and discrete converter approach is made compared and findings presented, highlighting the advantages of the integrated solution.

Abstract Purpose While the aetiology of rheumatoid arthritis (RA) remains unclear, many of the inflammatory components are well characterised. For diagnosis and therapy evaluation, in vivo insight into these processes would be valuable. Various imaging probes have shown value including dynamic contrast-enhanced (DCE) MRI and PET/CT using 18F-fluorodeoxyglucose (18F-FDG) or tracers targeting the translocator protein (TSPO). To evaluate 18F-GE-180, a novel TSPO PET tracer, for detecting and quantifying disease activity in RA, we compared 18F-GE-180 uptake with that of 18F-FDG and DCE-MRI measures of inflammation. Methods Eight RA patients with moderate-to-high, stable disease activity and active disease in at least one wrist were included in this study (NCT02350426). Participants underwent PET/CT examinations with 18F-GE-180 and 18F-FDG on separate visits, covering the shoulders and from the pelvis to the feet, including hands and wrists. DCE-MRI was performed on one affected hand. Uptake was compared visually between tracers as judged by an experienced radiologist and quantitatively using the maximum standardised uptake value (SUVmax). Uptake for both tracers was correlated with DCE-MRI parameters of inflammation, including the volume transfer coefficient K trans using Pearson correlation (r). Results PET/CT imaging with 18F-GE-180 in RA patients showed marked extra-synovial uptake around the affected joints. Overall sensitivity for detecting clinically affected joints was low (14%). 18F-GE-180 uptake did not or only weakly correlate with DCE-MRI parameters in the wrist (r = 0.09–0.31). 18F-FDG showed higher sensitivity for detecting symptomatic joints (34%), as well as strong positive correlation with DCE-MRI parameters (SUVmax vs. K trans: r = 0.92 for wrist; r = 0.68 for metacarpophalangeal joints). Conclusions The correlations between DCE-MRI parameters and 18F-FDG uptake support use of this PET tracer for quantification of inflammatory burden in RA. The TSPO tracer 18F-GE-180, however, has shown limited use for the investigation of RA due to its poor sensitivity and ability to quantify disease activity in RA.

With the increased necessity of a high power density and efficient system in aerospace and marine industries, integrated motor drives provide an excellent solution in the modern era. Therefore, a close structural and functional integration of passive components has become a prerequisite task to make a compact overall system. This article reviews the existing motor drives system with integrated passive technologies. To start, the design aspect of the traditional and integrated filter inductors, using the area product approach, is discussed. Subsequently, layouts of traditional and integrated inductors are presented. The available capacitor technologies, suitable for integration, are also discussed with pros and cons of each capacitor type.

We report on the benchmarks, participants and results of the third reactive synthesis competition(SYNTCOMP 2016). The benchmark library of SYNTCOMP 2016 has been extended to benchmarks in the new LTL-based temporal logic synthesis format (TLSF), and 2 new sets of benchmarks for the existing AIGER-based format for safety specifications. The participants of SYNTCOMP 2016 can be separated according to these two classes of specifications, and we give an overview of the 6 tools that entered the competition in the AIGER-based track, and the 3 participants that entered the TLSF-based track. We briefly describe the benchmark selection, evaluation scheme and the experimental setup of SYNTCOMP 2016. Finally, we present and analyze the results of our experimental evaluation, including a comparison to participants of previous competitions and a legacy tool.

We summarise our experience developing and using Termite, the first reactive synthesis tool intended for use by software development practitioners. We identify the main barriers to making reactive synthesis accessible to software developers and describe the key features of Termite designed to overcome these barriers, including an imperative C-like specification language, an interactive source-level debugger, and a user-guided code generator. Based on our experience applying Termite to synthesising real-world reactive software, we identify several caveats of the practical use of the reactive synthesis technology. We hope that these findings will help define the agenda for future research on practical reactive synthesis.

We report on the design and results of the second reactive synthesis competition (SYNTCOMP 2015). We describe our extended benchmark library, with 6 completely new sets of benchmarks, and additional challenging instances for 4 of the benchmark sets that were already used in SYNTCOMP 2014. To enhance the analysis of experimental results, we introduce an extension of our benchmark format with meta-information, including a difficulty rating and a reference size for solutions. Tools are evaluated on a set of 250 benchmarks, selected to provide a good coverage of benchmarks from all classes and difficulties. We report on changes of the evaluation scheme and the experimental setup. Finally, we describe the entrants into SYNTCOMP 2015, as well as the results of our experimental evaluation. In our analysis, we emphasize progress over the tools that participated last year.

Structural firefighting is a highly stressful occupation with firefighters performing intense bouts of physical activity in environmental extremes while wearing impermeable, heavy and restrictive personal protective equipment. The aim of this study was to investigate the impact of performing occupational tasks during an active structural fire on firefighters’ hydration status. Nine fully qualified firefighters (mean ± SD age = 39.22 ± 7.89 years) completed a 15 min ‘live’ fire scenario while performing occupational tasks. Urine Specific Gravity (USG), body weight and tympanic membrane temperature were measured pre-scenario and at 0 and 20 min post-scenario. There was a significant decrease in body weight (0 min and 20 min p < 0.0005) and increase in tympanic membrane temperature (0 min and 20 min p < 0.0005) following the fire scenario. There was no significant change in USG post-scenario. Short duration firefighting operations can cause significant fluid loss, as measured by change in body weight but not necessarily USG.

Interferon alpha (IFNα) is used for the treatment of hepatitis B virus infection, and whilst efficacious, it is associated with multiple adverse events caused by systemic exposure to interferon. We therefore hypothesise that targeting IFN directly to the intended site of action in the liver would reduce exposure in blood and peripheral tissue and hence improve the safety and tolerability of IFNα therapy. Furthermore we investigated whether directing IFN to the reservoir of infection in the liver may improve antiviral efficacy by increasing local concentration in target organs and tissues. Our previous results show that the mIFNα2 fused to an ASGPR specific liver targeting antibody, DOM26h-196-61, results in a fusion protein which retains the activity of both fusion partners when measured in vitro. In vivo targeting of the liver by mIFNα2-DOM26h-196-61, hereafter referred to as targeted mIFNα2, was observed in microSPECT imaging studies in mice. In this study we show by pharmacokinetic analysis that antibody mediated liver-targeting results in increased uptake and exposure of targeted mIFNα2 in target tissues, and correspondingly reduced uptake and exposure in systemic circulation, clearance organs and non-target tissues. We also show that cytokine activity and antiviral activity of liver-targeted IFN is observed in vivo, but that, contrary to expectations, liver-targeting of mIFNα2 using ASGPR specific dAbs actually leads to a reduced pharmacodynamic effect in target organs and lower antiviral activity in vivo when compared to non-targeted mIFNα2-dAb fusions.

Interferon alpha (IFNα) is used for the treatment of hepatitis C infection and whilst efficacious it is associated with multiple adverse events including reduced leukocyte, erythrocyte, and platelet counts, fatigue, and depression. These events are most likely caused by systemic exposure to interferon. We therefore hypothesise that targeting the therapeutic directly to the intended site of action in the liver would reduce exposure in blood and peripheral tissue and hence improve the safety and tolerability of IFNα therapy. We genetically fused IFN to a domain antibody (dAb) specific to a hepatocyte restricted antigen, asialoglycoprotein receptor (ASGPR). Our results show that the murine IFNα2 homolog (mIFNα2) fused to an ASGPR specific dAb, termed DOM26h-196-61, could be expressed in mammalian tissue culture systems and retains the desirable biophysical properties and activity of both fusion partners when measured in vitro. Furthermore a clear increase in in vivo targeting of the liver by mIFNα2-ASGPR dAb fusion protein, compared to that observed with either unfused mIFNα2 or mIFNα2 fused to an isotype control dAb VHD2 (which does not bind ASGPR) was demonstrated using microSPECT imaging. We suggest that these findings may be applicable in the development of a liver-targeted human IFN molecule with improved safety and patient compliance in comparison to the current standard of care, which could ultimately be used as a treatment for human hepatitis virus infections.

Background : Inflammation associated with cancer and induced by cancer therapy is associated with clinical signs of sickness behavior that can culminate in the development of symptoms of depression. Intraperitoneal administration of lipopolysaccharide to mice induces depressive-like behavior. Lipopolysaccharide-induced depressive-like behavior is mediated by activation of indoleamine 2,3-dioxygenase (IDO) that degrades tryptophan along the kynurenine pathway and produces kynurenine metabolites such as quinolinic acid that acts as a N-Methyl-D-aspartate (NMDA) receptor agonist. The present study was carried out to determine whether the NMDA receptor antagonist ketamine alleviates lipopolysaccharide-induced depressive-like behavior. Methods : Mice were injected intraperitoneally with ketamine or saline immediately before administration of the cytokine inducer lipopolysaccharide or saline via the same route. Their behavior and bodyweight were monitored up to 28 h post-injection. Depressive-like behavior was measured by increased immobility in the forced swim test and decreased sucrose preference for a sucrose solution. Brain, liver and plasma were collected 6 h and 28 h after treatment to measure biomarkers of inflammation. Results : Lipopolysaccharide induced the expression of cytokine, IDO, tryptophan 2,3-dioxygenase (TDO) and heme oxygenase-1 at the periphery and in the brain. This effect was not altered by ketamine pretreatment. Ketamine blocked the development of depressive-like behavior but had no effect on sickness behavior measured by body weight loss, reduced food intake and decreased motor activity. Conclusions : These data indicate that ketamine is able to abrogate inflammation-induced depressive-like behavior by antagonising the activating effects of kynurenine metabolites on NMDA receptors.