Perspectives on local government’s place in federal systems and central–local relations

To expand on the themes identified by Tomas Hachard’s paper 'Capacity, voice and opportunity: advancing municipal engagement in Canadian federal relations', the Journal commissioned six personal ‘perspectives’ from a diverse group of other Commonwealth countries – Australia, India, New Zealand, Nigeria, South Africa and the United Kingdom. This replicated the model adopted in Issue 26 for Zack Taylor’s paper on 'Regionalism from above: intergovernmental relations in Canadian metropolitan governance'. Similarly, the purpose was to establish a broader picture of issues and trends across the Commonwealth, rather than ‘review’ Hachard’s work

Investigation of the Ozone Formation Reaction Pathway: Comparisons of Full Configuration Interaction Quantum Monte Carlo and Fixed-Node Diffusion Monte Carlo with Contracted and Uncontracted MRCI

The association/dissociation reaction path for ozone (O2 + O ↔ O3) is notoriously difficult to describe accurately using ab initio electronic structure theory, due to the importance of both strong and dynamic electron correlations. Experimentally, spectroscopic studies of the highest lying recorded vibrational states combined with the observed negative temperature dependence of the kinetics of oxygen isotope exchange reactions confirm that the reaction is barrierless, consistent with the latest potential energy surfaces. Previously reported potentials based on Davidson-corrected internally contracted multireference configuration interaction (MRCI) suffer from a spurious reef feature in the entrance channel even when extrapolated towards the complete basis set limit. Here, we report an analysis of comparisons between a variety of electronic structure methods including internally contracted and uncontracted MRCI (with and without Davidson corrections), as well as full configuration interaction quantum Monte Carlo, fixed-node diffusion Monte Carlo, and density matrix renormalization group

Assessment of intra- and inter-ventricular cardiac dyssynchrony in patients with repaired Tetralogy of Fallot: a cardiac magnetic resonance study

Using radiative magnetohydrodynamic simulations of the magnetized solar photosphere and detailed spectro-polarimetric diagnostics with the Fe I 6301.5 Å and 6302.5 Å photospheric lines in the local thermodynamic equilibrium approximation, we model active solar granulation as if it was observed at the solar limb. We analyze general properties of the radiation across the solar limb, such as the continuum and the line core limb darkening and the granulation contrast. We demonstrate the presence of profiles with both emission and absorption features at the simulated solar limb, and pure emission profiles above the limb. These profiles are associated with the regions of strong linear polarization of the emergent radiation, indicating the influence of the intergranular magnetic fields on the line formation. We analyze physical origins of the emission wings in the Stokes profiles at the limb, and demonstrate that these features are produced by localized heating and torsional motions in the intergranular magnetic flux concentrations

Assessment of intra- and inter-ventricular cardiac dyssynchrony in patients with repaired Tetralogy of Fallot: a cardiac magnetic resonance study

Background Patients with repaired tetralogy of Fallot (TOF) frequently have right bundle branch block. However, the contribution of cardiac dyssynchrony to dysfunction remains controversial. To better understand this phenomenon and ultimately study therapies, we developed a method to quantify left (LV), right (RV) and inter-ventricular cardiac dyssynchrony using standard cine CMR. Methods 30 patients with repaired TOF (age 28 ± 16, 46% female) and 17 healthy controls (age 29 ± 7, 12% female) underwent cine CMR. Patients were imaged twice to assess inter-test reproducibility. Circumferential strain vs time curves were generated with a custom feature tracking algorithm for 12 LV and 12 RV segments in 4-7 slices encompassing the ventricles. For each segment, the temporal offset (TO) of the strain curve relative to a global reference curve derived from the controls was calculated and expressed as a percent of the cardiac cycle. The intra-ventricular dyssynchrony index (DI) for each ventricle was computed as the standard deviation (SD) of the TOs (more dyssynchrony increases the SD). The inter-ventricular DI was calculated as the difference in median RV and median LV TOs. Regional dyssynchrony was quantified in 3 LV (septum, infero-lateral and antero-lateral wall) and 3 RV (septum, sinus, outflow tract) regions using median TOs. Results Compared to controls, patients with repaired TOF had a greater LV, RV and inter-ventricular DI. The greater inter-ventricular delay in the patients was primarily due to a global delay in RV contraction with the RV contracting 4.9 ± 3.5% later than the LV in patients vs 1.4 ± 3.2% earlier in controls. Median TOs were similar in the three LV regions between patients and controls, but all three RV regions were significantly delayed in patients compared to the controls. Contraction patterns in the RV were also distinct: in controls, the earliest contraction was seen in the outflow tract; in patients, contraction occurred first in the septum and last in the outflow tract. Inter-test reproducibility for the three DIs was good with all coefficients of variation Conclusions Patients with repaired TOF suffer from left, right and inter-ventricular cardiac dyssynchrony which can all be quantified from standard cine CMR with good inter-test reproducibility. Future studies need to determine whether these patients may benefit from resynchronization therapy

Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease: study protocol for a randomised controlled trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and health-care costs. An incomplete response to the anti-inflammatory effects of inhaled corticosteroids is present in COPD. Preclinical work indicates that 'low dose' theophylline improves steroid responsiveness. The Theophylline With Inhaled Corticosteroids (TWICS) trial investigates whether the addition of 'low dose' theophylline to inhaled corticosteroids has clinical and cost-effective benefits in COPD. METHOD/DESIGN: TWICS is a randomised double-blind placebo-controlled trial conducted in primary and secondary care sites in the UK. The inclusion criteria are the following: an established predominant respiratory diagnosis of COPD (post-bronchodilator forced expiratory volume in first second/forced vital capacity [FEV1/FVC] of less than 0.7), age of at least 40 years, smoking history of at least 10 pack-years, current inhaled corticosteroid use, and history of at least two exacerbations requiring treatment with antibiotics or oral corticosteroids in the previous year. A computerised randomisation system will stratify 1424 participants by region and recruitment setting (primary and secondary) and then randomly assign with equal probability to intervention or control arms. Participants will receive either 'low dose' theophylline (Uniphyllin MR 200 mg tablets) or placebo for 52 weeks. Dosing is based on pharmacokinetic modelling to achieve a steady-state serum theophylline of 1-5 mg/l. A dose of theophylline MR 200 mg once daily (or placebo once daily) will be taken by participants who do not smoke or participants who smoke but have an ideal body weight (IBW) of not more than 60 kg. A dose of theophylline MR 200 mg twice daily (or placebo twice daily) will be taken by participants who smoke and have an IBW of more than 60 kg. Participants will be reviewed at recruitment and after 6 and 12 months. The primary outcome is the total number of participant-reported COPD exacerbations requiring oral corticosteroids or antibiotics during the 52-week treatment period. DISCUSSION: The demonstration that 'low dose' theophylline increases the efficacy of inhaled corticosteroids in COPD by reducing the incidence of exacerbations is relevant not only to patients and clinicians but also to health-care providers, both in the UK and globally. TRIAL REGISTRATION: Current Controlled Trials ISRCTN27066620 was registered on Sept. 19, 2013, and the first subject was randomly assigned on Feb. 6, 2014

Panels of chemically-modified heparin polysaccharides and natural heparan sulfate saccharides exhibit differences in binding to Slit and Robo, as well as variation between protein binding and cellular activity.

Heparin/ heparan sulfate (HS) glycosaminoglycans are required for Slit-Robo cellular responses. Evidence exists for interactions between each combination of Slit, Robo and heparin/HS and for formation of a ternary complex. Heparin/HS are complex mixtures displaying extensive structural diversity. The relevance of this diversity has been studied to a limited extent using a few select chemically-modified heparins as models of HS diversity. Here we extend these studies by parallel screening of structurally diverse panels of eight chemically-modified heparin polysaccharides and numerous natural HS oligosaccharide chromatographic fractions for binding to both Drosophila Slit and Robo N-terminal domains and for activation of a chick retina axon response to the Slit fragment. Both the polysaccharides and oligosaccharide fractions displayed variability in binding and cellular activity that could not be attributed solely to increasing sulfation, extending evidence for the importance of structural diversity to natural HS as well as model modified heparins. They also displayed differences in their interactions with Slit compared to Robo, with Robo preferring compounds with higher sulfation. Furthermore, the patterns of cellular activity across compounds were different to those for binding to each protein, suggesting that biological outcomes are selectively determined in a subtle manner that does not simply reflect the sum of the separate interactions of heparin/HS with Slit and Robo

Macrosystems ecology: Understanding ecological patterns and processes at continental scales

Macrosystems ecology is the study of diverse ecological phenomena at the scale of regions to continents and their interactions with phenomena at other scales. This emerging subdiscipline addresses ecological questions and environmental problems at these broad scales. Here, we describe this new field, show how it relates to modern ecological study, and highlight opportunities that stem from taking a macrosystems perspective. We present a hierarchical framework for investigating macrosystems at any level of ecological organization and in relation to broader and finer scales. Building on well-established theory and concepts from other subdisciplines of ecology, we identify feedbacks, linkages among distant regions, and interactions that cross scales of space and time as the most likely sources of unexpected and novel behaviors in macrosystems. We present three examples that highlight the importance of this multiscaled systems perspective for understanding the ecology of regions to continents