Constitutional Principles and Horizontal Effects: Kücükdeveci revisited

While German labour lawyers were still awaiting the German Constitutional Court’s final verdict on the principles established by the Mangold case, the Court of Justice of the European Union re-visited the question what exactly are the effects of Directive 2000/78 and the constitutional principle of non-discrimination on grounds of age. This article analyses the constitutional relevance of this case in two respects. First, it argues that the Court has accepted neither direct horizontal effects of directives nor direct effects of constitutional principles, but rather - much more cautiously - reiterated the rule that directives on constitutional principles such as non-discrimination can exclude the application of national legislation in horizontal cases. The article also demonstrates that this cautious approach has succeeded in convincing the German Constitutional Court that the Mangold judgment was not ultra vires. Consequently, the claim challenging that judgment was dismissed and a constitutional crisis avoided.

Wetting of compacted clays under laterally restrained conditions: Initial state, overburden pressure and mineralogy

Compacted clay fills are generally placed at the optimum value of water content and, immediately after placement, they are unsaturated. Wetting might subsequently occur due, for example, to rainfall infiltration, which can cause volumetric deformation of the fill (either swell or collapse) with associated loss of shear strength and structural integrity. If swelling takes place under partially restrained deformation, due for example to the presence of a buried rigid structure or a retaining wall, additional stresses will develop in the soil and these can be detrimental to the stability of walling elements and other building assets. Factors such as dry density, overburden pressure, compaction water content and type of clay are known to influence the development of stresses. This paper investigates these factors by means of an advanced stress path testing programme performed on four different clays with different mineralogy, index properties and geological histories. Specimens of kaolin clay, London Clay, Belfast Clay and Ampthill Clay were prepared at different initial states and subjected to ‘controlled’ wetting, whereby the suction was reduced gradually to zero under laterally restrainedconditions (i.e. K0 conditions). The results showed that the magnitude of the increase in horizontal stresses (and therefore the increase of K0) is influenced by the overburden pressure, compaction water content, dry density at the time of compaction and mineralogy.

Genetic studies of body mass index yield new insights for obesity biology

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

A durability performance-index for concrete: developments in a novel test method

Implementation of both design for durability and performance-based standards and specifications are limited by the lack of rapid, simple, science based test methods for characterising the transport properties and deterioration resistance of concrete. This paper presents developments in the application of electrical property measurements as a testing methodology to evaluate the relative performance of a range of concrete mixes. The technique lends itself to in-situ monitoring thereby allowing measurements to be obtained on the as-placed concrete. Conductivity measurements are presented for concretes with and without supplementary cementitious materials (SCM’s) from demoulding up to 350 days. It is shown that electrical conductivity measurements display a continual decrease over the entire test period and attributed to pore structure refinement due to hydration and pozzolanic reaction. The term formation factor is introduced to rank concrete performance in terms of is resistance to chloride penetration.

Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry:A randomised controlled trial

Background: Ivacaftor has shown a clinical benefit in patients with cystic fibrosis who have the G551D-CFTR mutation and reduced lung function. Lung clearance index (LCI) using multiple-breath washout might be an alternative to and more sensitive method than forced expiratory volume in 1 s (FEV₁) to assess treatment response in the growing number of children and young adults with cystic fibrosis who have normal spirometry. The aim of the study was to assess the treatment effects of ivacaftor on LCI in patients with cystic fibrosis, a G551D-CFTR mutation, and an FEV₁ >90% predicted. Methods: This phase 2, multicentre, placebo-controlled, double-blind 2×2 crossover study of ivacaftor treatment was conducted in patients with cystic fibrosis, at least one G551D-CFTR allele, and an FEV₁ >90% predicted. Patients also had to have an LCI higher than 7·4 at screening, age of 6 years or older, and a weight higher than or equal to 15 kg. Eligible patients were randomly allocated to receive one of two treatment sequences (placebo first followed by ivacaftor 150 mg twice daily [sequence 1] or ivacaftor 150 mg twice daily first followed by placebo [sequence 2]) of 28 days' treatment in each period, with a 28-day washout between the two treatment periods. Randomisation (ratio 1:1) was done with block sizes of 4, and all site personnel including the investigator, the study monitor, and the Vertex study team were masked to treatment assignment. The primary outcome measure was change from baseline in LCI. The study is registered at ClinicalTrials.gov, NCT01262352. Findings: Between February and November, 2011, 21 patients were enrolled, of which 11 were assigned to the sequence 1 group, and 10 to the sequence 2 group. 20 of these patients received treatment and 17 completed the trial (eight in sequence 1 group and 9 in sequence 2 group). Treatment with ivacaftor led to significant improvements compared with placebo in LCI (difference between groups in the average of mean changes from baseline at days 15 and 29 was -2·16 [95% CI -2·88 to -1·44]; p<0·0001). Adverse events experienced by study participants were similar between treatment groups; at least one adverse event was reported by 15 (79%) of 19 patients who received placebo and 13 (72%) of 18 patients who received ivacaftor. No deaths occurred during study period. Interpretation: In patients with cystic fibrosis aged 6 years or older who have at least one G551D-CFTR allele, ivacaftor led to improvements in LCI. LCI might be a more sensitive alternative to FEV₁ in detecting response to intervention in these patients with mild lung disease. Funding: Vertex Pharmaceuticals Incorporated. © 2013 Elsevier Ltd.

Insights into the Staggered Nature of Hydrogenation Reactivity over the 4d Transition Metals

Hydrogenation reactions at transition metal surfaces comprise a key set of reactions in heterogeneous catalysis. In this paper, density functional theory methods are employed to take an in-depth look at this fundamental reaction type. The energetics of hydrogenation of atomic C, N, and O have been studied in some detail over low index Zr, Nb, Mo, Tc, Ru, Rh, and Pd surfaces. Detailed bonding analysis has also been employed to track carefully the chemical changes taking place during reaction. A number of interesting horizontal and vertical trends have been uncovered relating to reactant valency and metal d-band filling. A general correlation has also been found between the reaction barriers and the reaction potential energies. Moreover, when each reaction is considered independently, correlation has been found to improve with decreasing reactant valency. Bonding analysis has pointed to this being related to the relative position of the transition state along the reaction coordinate and has shown that as reactant valency decreases, the transition states become progressively later.

Lung Clearance Index in cystic fibrosis subjects treated for Pulmonary Exacerbations

Pulmonary exacerbations are important clinical events for cystic fibrosis (CF) patients. Studies assessing the ability of the lung clearance index (LCI) to detect treatment response for pulmonary exacerbations have yielded heterogeneous results. Here, we conduct a retrospective analysis of pooled LCI data to assess treatment with intravenous antibiotics for pulmonary exacerbations and to understand factors explaining the heterogeneous response.

A systematic literature search was performed to identify prospective observational studies. Factors predicting the relative change in LCI and spirometry were evaluated while adjusting for within-study clustering.

Six previously reported studies and one unpublished study, which included 176 pulmonary exacerbations in both paediatric and adult patients, were included. Overall, LCI significantly decreased by 0.40 units (95% CI -0.60 -0.19, p=0.004) or 2.5% following treatment. The relative change in LCI was significantly correlated with the relative change in forced expiratory volume in 1 s (FEV1), but results were discordant in 42.5% of subjects (80 out of 188). Higher (worse) baseline LCI was associated with a greater improvement in LCI (slope: -0.9%, 95% CI -1.0- -0.4%).

LCI response to therapy for pulmonary exacerbations is heterogeneous in CF patients; the overall effect size is small and results are often discordant with FEV1.

Developing management capability within a horizontal supply chain in performance measurement deployment and evolution: A Dynamic Capabilities and Goal Theory perspective

Complex collaboration in rapidly changing business environments create challenges for management capability in Utility Horizontal Supply Chains (UHSCs) involving the deploying and evolving of performance measures. The aim of the study is twofold. First, there is a need to explore how management capability can be developed and used to deploy and evolve Performance Measurement (PM), both across a UHSC and within its constituent organisations, drawing upon a theoretical nexus of Dynamic Capability (DC) theory and complementary Goal Theory. Second, to make a contribution to knowledge by empirically building theory using these constructs to show the management motivations and behaviours within PM-based DCs. The methodology uses an interpretive theory building, multiple case based approach (n=3) as part of a USHC. The data collection methods include, interviews (n=54), focus groups (n=10), document analysis and participant observation (reflective learning logs) over a five-year period giving longitudinal data. The empirical findings lead to the development of a conceptual framework showing that management capabilities in driving PM deployment and evolution can be represented as multilevel renewal and incremental Dynamic Capabilities, which can be further understood in terms of motivation and behaviour by Goal-Theoretic constructs. In addition three interrelated cross cutting themes of management capabilities in consensus building, goal setting and resource change were identified. These management capabilities require carefully planned development and nurturing within the UHSC.