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This article looks at the hospital European Sectoral Social Dialogue Committee (SSDC) through a Community of Practice (CoP) theoretical lens. Based on a 2-year project, qualitative in-depth interviews at the European level and in five Member states, and participant observation of the hospital SSDC, we propose a shift from traditional institutional and resource-based accounts and provide a learning and knowledge-focused understanding of this specific area of European industrial relations. Interpreting the SSDCs as a CoP sheds new light on the role of power relations, participation and informal activities among members and on how they work together; this, we find, can alert those interested in more effective functioning of the European Sectoral Social Dialogue on how to strengthen this supra-national level of industrial relations.

IntroductionMolecular imaging has not been used to support the development of drugs for the treatment of pulmonary disorders. The aim of the present translational study was to advance quantitative pulmonary PET imaging by demonstrating occupancy of the reference asthma drug tiotropium at muscarinic acetylcholine receptors (mAChR).MethodsPET imaging was performed using the muscarinic radioligand [11C]VC-002. The key methodological step involved estimating muscarinic receptor binding while disentangling it from the background of non-specific binding. The relationship between tiotropium exposure and receptor occupancy (RO) was assessed in non-human primates (NHPs) after intravenous injection of tiotropium doses at a broad dose interval (0.03–1 µg/kg). The feasibility of measuring RO in the human lung was then confirmed in seven healthy human subjects after inhalation of a single therapeutic dose of tiotropium (18 µg).ResultsThere was an evident effect of tiotropium on [11C]VC-002 binding to mAChRs in lungs in both NHPs and humans. In NHPs, RO was 11 to 78% and increased in a dose dependent manner. Non-displaceable binding in NHPs was about 10% of total binding. In humans, RO was 6%–65%, and non-displaceable binding was about 20% of total binding at baseline.DiscussionThe results demonstrate that [11C]VC-002 binds specifically to mAChRs in the lungs enabling the assessment of RO following administration of muscarinic antagonist drugs. Furthermore, the methodology has potential not only for dose finding and comparison of drug formulations in future applied studies, but also for evaluating changes in lung receptor distribution during disease or in response to therapy.Clinical Trial RegistrationClinicalTrials.gov, identifier: NCT03097380.

Purpose Molecular imaging has not been used to support the development of drugs for the treatment of pulmonary disorders. The aim of the present translational study was to advance quantitative pulmonary PET imaging by demonstrating occupancy of the reference asthma drug tiotropium at muscarinic acetylcholine receptors (mAChR). Materials and methods PET imaging was performed using the muscarinic radioligand [11C]VC-002. The key methodological step involved estimating muscarinic receptor binding while disentangling it from the background of non-specific binding. The relationship between tiotropium exposure and receptor occupancy (RO) was assessed in non-human primates (NHPs) after intravenous injection of tiotropium doses at a broad dose interval (0.1-1mg/kg). The feasibility of measuring RO in the human lung was then confirmed in seven healthy human subjects after inhalation of a single therapeutic dose of tiotropium (18mg). Results There was an evident effect of tiotropium on [11C]VC-002 binding to mAChRs in lungs in both NHPs and humans. In NHPs, RO was 11 to 78% and increased in a dose dependent manner. Non-displaceable binding in NHPs was about 10% of total binding. In humans, RO was 6-65%, and non-displaceable binding was about 20% of total binding at baseline. Conclusions The results demonstrate that [11C]VC-002 binds specifically to mAChRs in the lungs enabling the assessment of RO following administration of muscarinic antagonist drugs. Furthermore, the methodology has potential not only to support early drug development, but also for evaluating changes in lung receptor distribution in a diagnostic setting, during disease or in response to therapy.

In this article the authors analyse social partner engagement in European sectoral social dialogue, testing two prominent theories to disentangle sector and country dynamics: institutional and resources and capabilities theories. While institutional theory accounted for certain social partner preferences, resources and capability theory proved stronger in predicting participation and provided insight into regulatory preferences. The authors conclude that resources and capability theory better explains their case, associating it with weaknesses of transnational governance. Specifically, limited incentives for participation mean that social partners with fewer resources forego participation, entailing pre-eminence of social partners with greater resources and hindering outcomes reflecting national institutional influences.

This article highlights the importance of organizational resources and individual capabilities for interactions and relationships among social partners in European sectoral social dialogue committees (SSDCs). We use an actor-centred approach to investigate work programme setting in the hospital and metalworking SSDCs. Our research reveals differences in how European social partner organizations coordinate and integrate members in SSDCs. In hospital, European Union (EU)-social partners build bridges that span otherwise separate actors or groups. The findings suggest that the absence of bridging efforts can lead to the dominance of a few actors. In metalworking, small cohesive groups are more effective in forming close networks and determining work programmes. While work programmes in hospital represent issues which are on national agendas, in metalworking, they focus mainly on EU policy areas.

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Background Oral and pharyngeal swallowing dysfunction are common complications in acute stroke patients. This primary aim of this study was to determine whether oral neuromuscular training improves swallowing function in participants with swallowing dysfunction after stroke. A secondary aim was to assess how well results of the timed water-swallow test (TWST) correspond with swallowing dysfunction diagnosed by videofluoroscopy (VFS). Methods This was an intention-to-treat two-centre prospective randomized open-label study with blinded-evaluators (PROBE) design. At 4 weeks after stroke onset, participants with swallowing dysfunction were randomized to 5 weeks of continued orofacial sensory-vibration stimulation with an electric toothbrush or additional oral neuromuscular training with an oral device (Muppy®). Participants were examined with TWST, a lip-force test, and VFS before (baseline), after 5 weeks’ treatment (the end-of-treatment), and 12 months after treatment (follow-up). The baseline VFS results were compared with the TWST results. The primary endpoint was changes in swallowing rate assessed using TWST, from baseline to the end of training and from baseline to follow-up based on intention-to-treat analyses. The secondary endpoint was the corresponding changes in lip-force between baseline, the end of treatment, and follow-up. Results The participants were randomly assigned as controls (n = 20) or for intervention with oral neuromuscular training (n = 20). After treatment, both groups had improved significantly (intervention, P P = 0.001) in TWST but there was no significant between-group difference in swallowing rate. At the 12-month follow-up, the intervention group had improved further whereas the controls had deteriorated, and there were significant between-group differences in swallowing rate (P = 0.032) and lip force (P = 0.001). A TWST Conclusion The 5-week oral neuromuscular training improved swallowing function in participants with post-stroke dysphagia compared with the controls 12 months after intervention, but there was no between-group difference in improvement immediately after treatment. TWST results corresponded with VFS results, making TWST a feasible method for identifying persons with swallowing dysfunction after stroke. Larger randomized controlled trials are required to confirm our preliminary positive long-term results. Trial registration Retrospectively registered at ClinicalTrials.gov: NCT04164420. Registered on 15 November 2019.

Wage formation in Sweden has been decentralized, and the introduction of individual performance‐based pay has increased employer discretion. This article explores practices of local‐level wage determination and argues that existing analyses still have too much focus on the formal (regulatory) institutions to explain what that is going on under the surface. Drawing on interviews with HR, managers, employees and union representatives from both public and private sector organizations, the study concludes that individual and differentiated wage‐setting is delimited locally by small budgets and the actors’ cultural–cognitive and normative expectations. Even though there have been radical changes in collective agreements and policies, we find strong elements of path dependency in local wage determination practices.

Background The radioligand [11C]VC-002 was introduced in a small initial study long ago for imaging of muscarinic acetylcholine receptors (mAChRs) in human lungs using positron emission tomography (PET). The objectives of the present study in control subjects were to advance the methodology for quantification of [11C]VC-002 binding in lung and to examine the reliability using a test-retest paradigm. This work constituted a self-standing preparatory step in a larger clinical trial aiming at estimating mAChR occupancy in the human lungs following inhalation of mAChR antagonists. Methods PET measurements using [11C]VC-002 and the GE Discovery 710 PET/CT system were performed in seven control subjects at two separate occasions, 2–19 days apart. One subject discontinued the study after the first measurement. Radioligand binding to mAChRs in lung was quantified using an image-derived arterial input function. The total distribution volume (VT) values were obtained on a regional and voxel-by-voxel basis. Kinetic one-tissue and two-tissue compartment models (1TCM, 2TCM), analysis based on linearization of the compartment models (multilinear Logan) and image analysis by data-driven estimation of parametric images based on compartmental theory (DEPICT) were applied. The test-retest repeatability of VT estimates was evaluated by absolute variability (VAR) and intraclass correlation coefficients (ICCs). Results The 1TCM was the statistically preferred model for description of [11C]VC-002 binding in the lungs. Low VAR (< 10%) across analysis methods indicated good reliability of the PET measurements. The VT estimates were stable after 60 min. Conclusions The kinetic behaviour and good repeatability of [11C]VC-002 as well as the novel lung image analysis methodology support its application in applied studies on drug-induced mAChR receptor occupancy and the pathophysiology of pulmonary disorders. Trial registration ClinicalTrials.gov identifier: NCT03097380, registered: 31 March 2017.

BackgroundThe aim of the present translational PET study was to estimate occupancy of tiotropium at muscarinic acetylcholine receptors (mAChR) in the lungs in vivo. The relationship between the tiotropium exposure and receptor occupancy (RO) in the lung was assessed in non-human primates (NHPs) after intravenous injection of tiotropium doses at a broad dose interval (0.1-1mg/kg). The feasibility of measuring mAChR occupancy in the human lung was then confirmed in seven healthy human subjects after inhalation of a single therapeutic dose of tiotropium (18mg). PET examinations were performed using radioligand [11C]VC-002. Occupancy in lungs was estimated using Lassen plot analysis of parametric images showing total radioligand binding (total distribution volume, VT).ResultsThere was an evident effect of tiotropium on [11C]VC-002 binding to mAChRs in lungs in both NHPs and humans. In NHPs, the occupancy was 11 to 78%, increasing in a dose dependent manner. The Lassen-plot based estimate of non-displaceable binding in NHPs was about 10% of the VT. In humans, occupancy was 6-65%, and non-displaceable binding (VND) was about 20% of total binding, VT at baseline. ConclusionsThe results demonstrated that [11C]VC-002 binds specifically to mAChRs in the lungs such that it allows for the detection and quantification of lung muscarinic receptor occupancy following administration of an intravenously administered or inhaled muscarinic antagonist drugs. The methodology has potential for dose finding and comparison of drug formulations in future applied studies. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT03097380, registered: 31 March 2017, url: https://clinicaltrials.gov/ct2/show/NCT03097380

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This study analyses the legitimacy of different pay determination principles in Swedish public sector organisations. The aim is to explore what dimensions of worth exist in pay determination and to analyse the extent to which differences in legitimacy can be explained by organisational position, professional identity and organisational context. Theoretically, the article is influenced by “valuation studies” and the “institutional logics” and “orders of worth” approaches in analysing the existence of multiple dimensions of pay determination. Empirically, the study is based on surveys to employees and managers. The main results are that individual performance is the most legitimate dimension of worth, although job requirements and employee behaviour also have a high level of legitimacy. Formal individual competence and market value have a somewhat lower level of legitimacy, while organisational results is the dimension that has least legitimacy. In addition, the perceptions of legitimacy are shown to vary somewhat with position, profession and organisational context.

This study contributes to the evidence on motivational effects from performance-related pay (PRP) in the public sector. The theoretical point of departure is that the practical organization and administration locally affect the motivational effects of PRP. The analysis is based on surveys administered to employees (including managers) in Swedish public sector organizations at municipal, regional, and state levels. One of the main conclusions is that PRP is not motivating or demotivating per se, but can be both motivating and demotivating within in the same organization. The (de/)motivational effect depends on the local level organization and practices of PRP, particularly the quality of the performance appraisal dialogue. While confirming the importance of justice perceptions, it also shows the effects of managers’ and employees’ preparations, knowledge of criteria, the quality of the performance appraisal dialogue, and the manager’s evaluation style, while controlling for justice perceptions and background variables. Bibliografiskt granskad

The Odin satellite is now into its twentieth year of operation, much surpassing its design life of two years. One of its major pursuits was the search for and study of H2O in the Solar System and the Milky Way galaxy. Herschel has observed the central region of NGC 1365 in two positions, and both its SPIRE and PACS observations are available in the Herschel Science Archive. Herschel PACS images have been produced of the 70 and 160 micron infrared emission from the whole galaxy, and also of the cold dust distribution as obtained from the ratio of the 160 to 70 micron images. The Herschel SPIRE observations have been used to produce maps of the 557 GHz o-H2O, 752 GHz p-H2O, 691 GHz CO(6-5), 1037 GHz CO(9-8), 537 GHz CH, 835 GHz CH+, and the 1461 GHz NII lines; however, these observations have no effective velocity resolution. Odin has recently observed the 557 GHz o-H2O ground state line in the central region with high (5 km/s) spectral resolution. The emission and absorption of H2O at 557 GHz, with a velocity resolution of 5 km/s, has been marginally detected in NGC 1365 with Odin. The H2O is predominantly located in a shocked 15" (1.3 kpc) region near some central compact radio sources and hot-spot HII regions, close to the northeast component of the molecular torus surrounding the nucleus. An analysis of the H2O line intensities and velocities indicates that a shock-region is located here. This is corroborated by a statistical image deconvolution of our SEST CO(3-2) observations, yielding 5" resolution, and a study of our VLA HI absorption observations. Additionally, an enticing 20" HI ridge is found to extend south-southeast from the nucleus, coinciding in position with the southern edge of an OIII outflow cone, emanating from the nucleus. The molecular chemistry of the shocked central region is analyzed with special emphasis on the CO, H2O and CH, CH+ results., Comment: 25 pages, 11 figures

The mid/far infrared hosts a wealth of spectral information that allows direct determination of the physical state of matter in a large variety of astronomical objects, unhindered by foreground obscuration. Accessing this domain is essential for astronomers to much better grasp the fundamental physical processes underlying the evolution of many types of celestial objects, ranging from protoplanetary systems in our own milky way to 10-12 billion year old galaxies at the high noon of galaxy formation in our universe. The joint ESA/JAXA SPICA space mission will give such access for the astronomical community at large, by providing an observatory with unprecedented mid- to far-infrared imaging, polarimetric and spectroscopic capabilities. With a launch expected to happen in 2032, it will be the ideal complement of the space based (ATHENA) and ground based facilities available at this time (ELT, TMT, ALMA, SKA), so that the entire high energy to radio electromagnetic spectrum will be accessible to world astronomers with unprecedented power and sensitivity. The SPICA mission, under development as a joint ESA/JAXA project, will combine a 2.5-meter diameter telescope cooled to below 8 K with instruments employing state-of-the-art ultra-sensitive detectors. Instead of using liquid cryogen, a combination of passive cooling and mechanical coolers is employed to cool both the telescope and the instruments, allowing the mission lifetime to extend significantly beyond the required three years. SPICA offers spectroscopy instruments with spectral resolving power ranging from R~50 through 11000 in the 17-230 μm domain as well as R~28.000 spectroscopy between 12 and 18 μm. The state-of-the-art Transition Edge Detectors in the 35-230 μm detectors in the SAFARI spectrometer will provide an unprecedented sensitivity of ~5×10−20 W/m2 (5σ/1hr) - at least two orders of magnitude improvement over what has been attained to date. With the 10'x12' large Field of View SMI imager SPICA will be able to very efficiently do sensitive large area 30-37 μm broad band mapping. In addition the B-BOP instrument will provide accurate polarimetric imaging at 70, 220 and 350 μm With this exceptional leap in performance, new domains in infrared astronomy will become accessible, allowing us, for example, to unravel definitively galaxy evolution and metal production over cosmic time, to study dust formation and evolution from very early epochs onwards, and to trace the gas, dust and ice evolution in planetary systems.

The mid/far infrared hosts a wealth of spectral information that allows direct determination of the physical state of matter in a large variety of astronomical objects, unhindered by foreground obscuration. Accessing this domain is essential for astronomers to much better grasp the fundamental physical processes underlying the evolution of many types of celestial objects, ranging from protoplanetary systems in our own milky way to 10-12 billion year old galaxies at the high noon of galaxy formation in our universe. The joint ESA/JAXA SPICA mission will give such access for the astronomical community at large, by providing an observatory with unprecedented mid- to far-infrared imaging, polarimetric and spectroscopic capabilities.

The spread of performance-based and variable pay systems has affected expectations on employee contributions and remuneration, which have become increasingly personalized and individualized. Based on a theoretical valuation studies approach, this study of performance-based pay systems in Sweden shows that performance appraisals are (e)valuations of employees’ yearly performance in which they are prized and (ap)praised at the same time. Through a document analysis of performance criteria from four organizations, the study analyzes how values expressed refer to Boltanski and Thévenot’s six orders of worth. The analysis resulted in a theoretical construction of a joint ideal of Employees of Greatness, against which employees are measured and remunerated. The existence of the ideal of employee greatness is explained by the increasing congruence of organizational ideals in private and public sectors, as principles from emotional and cognitive forms of capitalist organization are superimposed on traditional industrial capitalist organizational ideals.

Drawing on pragmatism and systems theory, this article analyses how participants in the European Sectoral Social Dialogue in the metal and hospital committees understand its effectiveness. We find that the participants have a broad understanding of effectiveness compared with the European Commission and existing research. Participants do not dismiss the importance of direct effects on working conditions in member states but downplay it in comparison with indirect effects from, and effectiveness in, European Sectoral Social Dialogue. That is, horizontal learning, knowledge sharing and pragmatic bottom‐up work to reach consensus are emphasised as more prominent than top‐down regulatory effectiveness.\ud \ud

This open access book discusses transnational trade union cooperation in Europe – its forms, focuses, conditions, and obstacles. It provides an overview of existing trade union cooperation and includes detailed analyses of two specific questions: the debates on statutory minimum wages and the Posting of Workers Directive. Drawing on empirical research, the authors take a comparative approach, considering national industrial relations regimes as well as individual sectors. With the ongoing processes of integration in Europe, it has become increasingly important for unions to cooperate with regard to employers and EU institutions. The authors illustrate the interconnections between national and European industrial relations, and explore the process of European integration in labour markets. Illustrating the potential for and difficulties involved in deepening trade union cooperation across Europe, this work is a vital read for trade unionists, researchers and students interested in European trade unionism and labour markets.

Most countries in Europe have minimum wage legislation, but there are some exceptions such as the Nordic countries. The issue has clearly divided European trade unions and Nordic unions represent a foothold for the resistance to this kind of regulation. To provide a more detailed picture of European labour organizations’ arguments for and against minimum wage legislation, data from interviews and surveys as well as documents are used. There is obviously a deep cleavage within the European trade union movement and the chapter also describes how the ETUC has handled the diverging positions.

In 2016, the European Commission proposed a revision of the Posting of Workers Directive and it led to a great deal of debate, with a sharp East–West division in the political reactions. The proposal aimed at eliminating certain kinds of social dumping, arguing that the same work in the same place would get the same pay. Ministers and parliaments in several Central and East European countries raised their voice against the revision. Employers’ organizations were generally negative, while the trade union confederations at European level were positive but not uncritical; they wanted a more radical reform. No manifest East–West cleavage became visible in the trade union movement. Even in countries dismissive of the revision, the main labour organizations supported the dominant trade union responses.

This chapter offers an overview of patterns of transnational trade union cooperation—based on empirical data. It begins by providing a brief depiction of the multilevel structures of such cooperation, followed by a presentation of the general views among unions regarding the importance and the potential benefits of cooperating at different levels. A second section entails a more detailed investigation of the importance attributed to various topics to collaborate on. This part also includes an examination of the preferences among unions in different sectors and industrial relations regimes/regions regarding forms of cooperation. The remainder of the chapter section scrutinizes what unions consider to be the most important obstacles to and facilitators for cross-border cooperation.

This chapter gives a general background to the issue of transnational union cooperation in Europe and presents the aim, outline and delimitations of the book. It also pays attention to a number of concepts that can be relevant in the analysis of European trade unions and industrial relations. In this way, a theoretical context is provided for the analyses to come. There is moreover a rather detailed description of the empirical materials and methods used in the following chapters.

Objective The aim of this study was to summarise the pharmacokinetic findings from eight phase I studies in healthy volunteers given oral AZD5069, a selective small-molecule CXCR2 antagonist. Methods 240 healthy volunteers across eight phase I studies received single (0.1–200 mg) or multiple once- or twice-daily (10–120 mg) oral AZD5069 as solution, suspension, capsules or tablets. Pharmacokinetics were evaluated using non-compartmental analysis methods. Results AZD5069 was rapidly absorbed (time to maximum concentration ~ 2 h) under fasting conditions. A high-fat, high-calorie meal delayed and reduced the peak plasma AZD5069 concentration (Cmax) by 50%, but total exposure (AUC) was unchanged (fed:fasting geometric mean ratio 90% confidence interval within 0.80–1.25). The plasma concentration of AZD5069 declined with an initial half-life of 4 h and terminal half-life of 11 h. Steady-state plasma concentrations were achieved within 2–3 days and accumulation was ~ 1.1-fold with twice-daily dosing. Systemic exposure was approximately proportional to dose. Intra- and inter-subject variability in AUC was 3–11 and 29–64%, respectively. Less than 5% of the AZD5069 dose was excreted as parent drug in the urine. Elderly subjects had 39% higher AZD5069 AUC and 21% higher Cmax than younger adults. Japanese subjects had similar or slightly higher exposure to AZD5069 than Caucasian subjects. Co-administration with ketoconazole resulted in 2.1-fold higher AUC and 1.6-fold higher Cmax. All formulations had similar bioavailability. Conclusions AZD5069 demonstrated predictive linear pharmacokinetics with low intra- and moderate inter-subject variability and no major influences from ethnicity, age, food or formulation. Half-life data indicated suitability for twice-daily dosing. Clinicaltrials.gov identifiers NCT00953888, NCT01051505, NCT01083238, NCT01100047, NCT01332903, NCT01480739, NCT01735240, NCT01989520. Electronic supplementary material The online version of this article (10.1007/s40268-018-0236-x) contains supplementary material, which is available to authorized users.

Neutrophil serine proteases (NSPs), such as neutrophil elastase (NE), are activated by dipeptidyl peptidase 1 (DPP1) during neutrophil maturation. High NSP levels can be detrimental, particularly in lung tissue, and inhibition of NSPs is therefore an interesting therapeutic opportunity in multiple lung diseases, including chronic obstructive pulmonary disease (COPD) and bronchiectasis. We conducted a randomized, placebo-controlled, first-in-human study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of the DPP1 inhibitor AZD7986 in healthy subjects. Pharmacokinetic and pharmacodynamic data were analyzed using nonlinear mixed effects modeling and showed that AZD7986 inhibits whole blood NE activity in an exposure-dependent, indirect manner-consistent with in vitro and preclinical predictions. Several dose-dependent, possibly DPP1-related, nonserious skin findings were observed, but these were not considered to prevent further clinical development. Overall, the study results provided confidence to progress AZD7986 to phase II and supported selection of a clinically relevant dose.

In Sweden, performance-based pay has gone furthest in the public sector. This development has placed demands on employers to have a transparent and salient salary review process with which to evaluate employees uniformly and fair – and to act in a unitary manner, as one employer. Pay policies aim to coordinate salary reviews in organizations. However, the transfer of policy to practice is not easy and research has shown a gap between intended and implemented policies. Drawing on a case study in a municipality, this article expands knowledge on policy transfer by exploring and describing how HR, unions, managers and employees perceive implementation and integration of the pay policies, and to what extent the municipality succeeds in a one-employer approach. The findings suggest that the municipality fails to act as one employer and that the units that are most successful in implementing the policy are those closer to top management.

AZD9898 is an oral small molecule inhibitor of LTC4 synthase (LTC4s) developed for the treatment of asthma driven by cysteinyl leukotrienes (CysLTs). It is expected to inhibit the downstream production of leukotrienes LTC4, LTD4 and LTE4, which are important mediators of airway inflammation and bronchoconstriction. The leukotriene LTE4 is a stable metabolite, measurable in urine and has been used as a proof of mechanism biomarker in several clinical studies. We planned to evaluate AZD9898 in an integrated, multi-part, randomized, single-blind, placebo controlled, first-in-human (FIH), Phase I (Ph I) study. In Part 1, single ascending dosing in four cohorts (3 mg, 9 mg, 15 mg and 45 mg) versus placebo was evaluated in healthy subjects to assess safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles. Overall, single doses of AZD9898 were well tolerated in Part 1 and no safety concerns were raised. Measurement of urinary LTE4 (uLTE4) normalised to creatinine was included as a PD marker to evaluate inhibition of LTC4s. The PD data showed that, at the highest dose tested (45 mg), AZD9898 reduced uLTE4 levels for 14 hours post dose with a maximum reduction at 6 hours post dose. The 45 mg dose was the highest dose possible due to exposure limitation margins. The required magnitude and duration of PD effect at a dose of 45 mg was lower than expected. Furthermore, modelling and simulation of data did not support that the required level of effect on uLTE4 inhibition could be reached even with twice daily dosing. Therefore, the decision was made to stop the multi-part Ph I study after only Part 1 and not progress into multiple dosing in healthy subjects or single dosing in asthmatic patients. These data provide an example of how early evaluation of a PD biomarker can be utilized for decision making in early clinical development.

Summary Background Airway neutrophilic inflammation is a pathological feature in some patients with severe asthma. Stimulation of the chemokine receptor CXCR2 mediates neutrophil migration into the airways. We investigated the safety and efficacy of AZD5069, a CXCR2 antagonist, as an add-on therapy in patients with uncontrolled severe asthma. Methods In this multicentre, randomised, double-blind, placebo-controlled, dose-finding trial, we enrolled patients aged 18 years or older with uncontrolled asthma despite combination therapy with long-acting β 2 agonists and medium-dose or high-dose inhaled corticosteroids. Patients were randomised in a 1:1:1:1 ratio via an interactive voice-response or web-response system to receive 5, 15, or 45 mg oral AZD5069 twice daily or matched placebo. The primary endpoint was the number of severe asthma exacerbations in 6 months. Safety was assessed in the 6-month treatment period and an optional 6-month safety extension. This trial is registered with ClinicalTrials.gov, number NCT01704495. Findings 640 patients with a mean age of 52 (SD 11·8) years were randomised, 478 to receive AZD5069 (5 mg n=160, 15 mg n=156, and 45 mg n=162) and 162 placebo. No dose of AZD5069 reduced the rate of severe exacerbations compared with placebo (rate ratio for 5 mg 1·29, 90% CI 0·79–2·11; for 15 mg 1·53, 0·95–2·46; and for 45 mg 1·56, 0·98–2·49). Treatment with AZD5069 was generally well tolerated. The most commonly reported adverse event overall was nasopharyngitis, seen in 18 (11·5%) receiving 5 mg, 13 (8·5%) receiving 15 mg, and 18 (11·2%) receiving 45 mg AZD5069, and 31 (19·5%) of those receiving placebo. Interpretation Treatment with this selective CXCR2 antagonist did not reduce the frequency of severe exacerbations in patients with uncontrolled severe asthma. These findings bring into question the role of CXCR2-mediated neutrophil recruitment in the pathobiology of exacerbations in severe refractory asthma. Funding AstraZeneca.

Measurements in the infrared wavelength domain allow us to assess directly the physical state and energy balance of cool matter in space, thus enabling the detailed study of the various processes that govern the formation and early evolution of stars and planetary systems in the Milky Way and of galaxies over cosmic time. Previous infrared missions, from IRAS to Herschel, have revealed a great deal about the obscured Universe, but sensitivity has been limited because up to now it has not been possible to fly a telescope that is both large and cold. Such a facility is essential to address key astrophysical questions, especially concerning galaxy evolution and the development of planetary systems. SPICA is a mission concept aimed at taking the next step in mid- and far-infrared observational capability by combining a large and cold telescope with instruments employing state-of-the-art ultra-sensitive detectors. The mission concept foresees a 2.5-meter diameter telescope cooled to below 8 K. Rather than using liquid cryogen, a combination of passive cooling and mechanical coolers will be used to cool both the telescope and the instruments. With cooling not dependent on a limited cryogen supply, the mission lifetime can extend significantly beyond the required three years. The combination of low telescope background and instruments with state-of-the-art detectors means that SPICA can provide a huge advance on the capabilities of previous missions. The SPICA instrument complement offers spectral resolving power ranging from ~50 through 11000 in the 17-230 µm domain as well as ~28.000 spectroscopy between 12 and 18 µm. Additionally, SPICA will be capable of efficient 30-37 µm broad band mapping, and small field spectroscopic and polarimetric imaging in the 100-350 µm range. SPICA will enable far infrared spectroscopy with an unprecedented sensitivity of ~5x10-20 W/m2 (5σ/1hr) - at least two orders of magnitude improvement over what has been attained to date. With this exceptional leap in performance, new domains in infrared astronomy will become accessible, allowing us, for example, to unravel definitively galaxy evolution and metal production over cosmic time, to study dust formation and evolution from very early epochs onwards, and to trace the formation history of planetary systems.

AIMS: The aim of the present study was to investigate whether selective antagonism of the cysteine-X-cysteine chemokine receptor-2 (CXCR2) receptor has any adverse effects on the key innate effector functions of human neutrophils for defence against microbial pathogens. METHODS: In a double-blind, crossover study, 30 healthy volunteers were randomized to treatment with the CXCR2 antagonist AZD5069 (100 mg) or placebo, twice daily orally for 6 days. The peripheral blood neutrophil count was assessed at baseline, daily during treatment and in response to exercise challenge and subcutaneous injection of granulocyte-colony stimulating factor (G-CSF). Neutrophil function was evaluated by phagocytosis of Escherichia coli and by the oxidative burst response to E. coli. RESULTS: AZD5069 treatment reversibly reduced circulating neutrophil count from baseline by a mean [standard deviation (SD)] of -1.67 (0.67) ×10(9) l(-1) vs. 0.19 (0.78) ×10(9) l(-1) for placebo on day 2, returning to baseline by day 7 after the last dose. Despite low counts on day 4, a 10-min exercise challenge increased absolute blood neutrophil count, but the effect with AZD5069 was smaller and not sustained, compared with placebo treatment. Subcutaneous G-CSF on day 5 caused a substantial increase in blood neutrophil count in both placebo- and AZD5069-treated subjects. Superoxide anion production in E. coli-stimulated neutrophils and phagocytosis of E. coli were unaffected by AZD5069 (P = 0.375, P = 0.721, respectively vs. baseline, Day 4). AZD5069 was well tolerated. CONCLUSIONS: CXCR2 antagonism did not appear adversely to affect the mobilization of neutrophils from bone marrow into the peripheral circulation, phagocytosis or the oxidative burst response to bacterial pathogens. This supports the potential of CXCR2 antagonists as a treatment option for diseases in which neutrophils play a pathological role.

This randomised double-blind placebo-controlled parallel-group multicentre phase IIa study evaluated the effect of the CXCR2 antagonist AZD5069 on sputum neutrophil counts in adults with bronchiectasis.Patients were randomised 1:1 to receive AZD5069 80 mg or placebo orally twice daily for 28 days. Assessments included blood cell counts, inflammatory markers in blood, morning spontaneous sputum, lung function, safety and tolerability and patients completed daily BronkoTest diary cards. The primary outcome measure was the change in absolute sputum neutrophil count.Of 52 randomised patients, 45 completed treatment, 20 (76.9%) out of 26 receiving AZD5069 and 25 (96.2%) out of 26 receiving placebo. AZD5069 reduced the absolute neutrophil cell count in morning sputum by 69%versusplacebo (p=0.004); percentage sputum neutrophil count was reduced by 36% (p=0.008). The number of infections/exacerbations was similar with AZD5069 and placebo (nineversuseight), but these led to more study discontinuations with AZD5069 (fourversuszero). Sputum interleukin (IL)-6 and growth-regulated oncogene (GRO)-α and serum GRO-α, IL-1ß and IL-8 levels increased with AZD5069versusplacebo (all pAZD5069 markedly reduced absolute sputum neutrophil counts in bronchiectasis patients, although this was not associated with improvements in clinical outcomes in this exploratory study.

This article examines a general trend towards the ‘decentring’ of the policing of economic and white-collar crime in Sweden in recent decades. As a theoretical point of departure, we discuss how th ...

Background Chronic obstructive pulmonary disease (COPD) is characterized by neutrophil-dominated airway mucosal inflammation and elevated neutrophil counts in sputum and lung tissue. CXC chemokine receptor 2 (CXCR2) is predominantly expressed on neutrophils and mediates the migration of neutrophils to inflammatory sites. AZD5069 is a small molecule CXCR2 antagonist with the potential to inhibit neutrophil migration into the airways in patients with COPD. Methods This 4-week, randomized, double-blind, placebo-controlled, parallel-group, multi-center, Phase IIa study evaluated the safety and tolerability of AZD5069 in patients with moderate-to-severe COPD (ClinicalTrials.gov identifier: NCT01233232 ). The pharmacokinetics and effect of AZD5069 on blood neutrophil counts were also assessed. Patients completed daily diary cards and attended weekly clinic visits for safety assessments. Results 87 patients (mean FEV1 56% pred; mean age 64 years; 69% male) were randomized to receive placebo (n = 29), AZD5069 50 mg bid (n = 30) or AZD5069 80 mg bid (n = 28) for 4 weeks. AZD5069 was well tolerated with adverse events (AEs) reported in 9 (31%), 10 (33%) and 6 (21%) patients in the placebo, AZD5069 50 mg and AZD5069 80 mg groups, respectively. AEs were generally mild or moderate in severity. The incidence of infections, the most commonly reported AE, was similar across the three groups (17%, 17% and 11% of patients in the placebo, AZD5069 50 and 80 mg groups, respectively). Blood neutrophil counts decreased on average from baseline by 14–40% and 13–36% in the AZD5069 50 mg and 80 mg groups, respectively, and 4 patients discontinued from the study due to decreased neutrophil count, 3 in the AZD5069 50 mg group and 1 in the 80 mg group. The systemic exposure (AUC and Cmax) of AZD5069 increased less than in proportion to the dose and there was a large overlap in the individual exposures between the two dose levels. Conclusions AZD5069 was well tolerated overall in those patients who completed study treatment, with no increase in infection rates in either dosage group compared with placebo. Further studies with AZD5069 appear to be warranted.