Multicenter Randomized Controlled Trial of Withdrawal of Inhaled Corticosteroids in Cystic Fibrosis

Rationale: Lung inflammation and injury is critical in cystic fibrosis. An ideal antiinflammatory agent has not been identified but inhaled corticosteroids are widely used despite lack of evidence.

Objectives: To test the safety of withdrawal of inhaled corticosteroids with the hypothesis this would not be associated with an earlier onset of acute chest exacerbations.

Methods: Multicenter randomized double-blind placebo-controlled trial in 18 pediatric and adult UK centers. Eligibility criteria included age > 6.0 yr, FEV1 ? 40% predicted, and corticosteroid use > 3 mo. During the 2-mo run-in period, all patients received fluticasone; they then took either fluticasone or placebo for 6 mo.

Measurements and Main Results: Fluticasone group: n = 84, median age 14.6 yr, mean (SD) FEV1 76% (18); placebo group: n = 87, median age 15.8 yr, mean (SD) FEV1 76% (18). There was no difference in time to first exacerbation (primary outcome) with hazard ratio (95% confidence interval) of 1.07 (0.68 to 1.70) for fluticasone versus placebo. There was no effect of age, atopy, corticosteroid dose, FEV1, or Pseudomonas aeruginosa status. There was no change in lung function or differences in antibiotic or rescue bronchodilator use. Fewer patients in the fluticasone group withdrew from the study due to lung-related adverse events (9 vs. 15%); with a relative risk (95% confidence interval) of 0.59 (0.23–1.48) fluticasone versus placebo.

Conclusions: In this study population (applicable to 40% of patients with cystic fibrosis in the UK), it appears safe to consider stopping inhaled corticosteroids. Potential advantages will be to reduce the drug burden on patients, reduce adverse effects, and make financial savings.

Modelling of Unsteady Gas-Dynamic Flow in a Pipe and at its Exit Using CFD

Traditionally the simulation of the thermodynamic aspects of the internal combustion engine has been undertaken using one-dimensional gas-dynamic models to represent the intake and exhaust systems. CFD analysis of engines has been restricted to modelling of in-cylinder flow structures. With the increasing accessibility of CFD software it is now worth considering its use for complete gas-dynamic engine simulation. This paper appraises the accuracy of various CFD models in comparison to a 1D gas-dynamic simulation. All of the models are compared to experimental data acquired on an apparatus that generates a single gas-dynamic pressure wave. The progress of the wave along a constant area pipe and its subsequent reflection from the open pipe end are recorded with a number of high speed pressure transducers. It was found that there was little to choose between the accuracy of the 1D model and the best CFD model. The CFD model did not require experimentally derived loss coefficients to accurately represent the open pipe end; however, it took several hundred times longer to complete its analysis. The best congruency between the CFD models and the experimental data was achieved using the RNG k-e turbulence model. The open end of the pipe was most effectively represented by surrounding it with a relatively small volume of cells connected to the rest of the environment using a pressure boundary.

Judging Time Intevals using a model of perceptuo-motor control

Estimating a time interval and temporally coordinating movements in space are fundamental skills, but the relationships between these different forms of timing, and the neural processes that they incur, are not well understood. While different theories have been proposed to account for time perception, time estimation, and the temporal patterns of coordination, there are no general mechanisms which unify these various timing skills. This study considers whether a model of perceptuo-motor timing, the tau(GUIDE), can also describe how certain judgements of elapsed time are made. To evaluate this, an equation for determining interval estimates was derived from the tau(GUIDE) model and tested in a task where participants had to throw a ball and estimate when it would hit the floor. The results showed that in accordance with the model, very accurate judgements could be made without vision (mean timing error -19.24 msec), and the model was a good predictor of skilled participants' estimate timing. It was concluded that since the tau(GUIDE) principle provides temporal information in a generic form, it could be a unitary process that links different forms of timing.

Assocation Between Variation in the Actin-Binding Gene Caldesmon and Diabetic Nephropathy in Type 1 Diabetes

Dysfunction of the actin cytoskeleton is a key event in the pathogenesis of diabetic nephropathy. We previously reported that certain cytoskeletal genes are upregulated in mesangial cells exposed to a high extracellular glucose concentration. One such gene, caldesmon, lies on chromosome 7q35, a region linked to nephropathy in family studies, making it a candidate susceptibility gene for diabetic nephropathy. We screened all exons, untranslated regions, and a 5-kb region upstream of the gene for variation using denaturing high-performance liquid chromatography technology. An A>G single nucleotide polymorphism (SNP) at position -579 in the promoter region was associated with nephropathy in a case-control study using 393 type 1 diabetic patients from Northern Ireland (odds ratio [OR] 1.38, 95% CI 1.02–1.86, P = 0.03). A similar trend was found in an independent sample from a second center. When the sample groups were combined (n = 606), the association between the -579G allele and nephropathy remained significant (OR 1.35, 1.07–1.70, P = 0.01). The haplotype structure in the surrounding 7-kb region was determined. No single haplotype was more strongly associated with nephropathy than the -579A>G SNP. These results suggest a role for the caldesmon gene in susceptibility to diabetic nephropathy in type 1 diabetes.

Microbial analysis of soil and groundwater from a gasworks site and comparison to a sequenced biological reactive barrier remediation process (SEREBAR)

Aims: To investigate the distribution of a polymicrobial community of biodegradative bacteria in (i) soil and groundwater at a former manufactured gas plant (FMGP) site and (ii) in a novel SEquential REactive BARrier (SEREBAR) bioremediation process designed to bioremediate the contaminated groundwater. Methods and Results: Culture-dependent and culture-independent analyses using denaturing gradient gel electrophoresis (DGGE) and polymerase chain reaction (PCR) for the detection of 16S ribosomal RNA gene and naphthalene dioxygenase (NDO) genes of free-living (planktonic groundwater) and attached (soil biofilm) samples from across the site and from the SEREBAR process was applied. Naphthalene arising from groundwater was effectively degraded early in the process and the microbiological analysis indicated a dominant role for Pseudomonas and Comamonas in its degradation. The microbial communities appeared highly complex and diverse across both the sites and in the SEREBAR process. An increased population of naphthalene degraders was associated with naphthalene removal. Conclusion: The distribution of micro-organisms in general and naphthalene degraders across the site was highly heterogeneous. Comparisons made between areas contaminated with polycyclic aromatic hydrocarbons (PAH) and those not contaminated, revealed differences in the microbial community profile. The likelihood of noncultured bacteria being dominant in mediating naphthalene removal was evident. Significance and Impact of the Study: This work further emphasizes the importance of both traditional and molecular-based tools in determining the microbial ecology of contaminated sites and highlights the role of noncultured bacteria in the process.

The Cost of Sustainability Capital and the Creation of Sustainable Value by Companies

We develop and apply a valuation methodology to calculate the cost of sustainability capital, and, eventually, sustainable value creation of companies. Sustainable development posits that decisions must take into account all forms of capital rather than just economic capital. We develop a methodology that allows calculation of the costs that are associated with the use of different forms of capital. Our methodology borrows the idea from financial economics that the return on capital has to cover the cost of capital. Capital costs are determined as opportunity costs, that is, the forgone returns that would have been created by alternative investments. We apply and extend the logic of opportunity costs to the valuation not only of economic capital but also of other forms of capital. This allows (a) integrated analysis of use of different forms of capital based on a value-based aggregation of different forms of capital, (b) determination of the opportunity cost of a bundle of different forms of capital used in a company, called cost of sustainability capital, (c) calculation of sustainability efficiency of companies, and (d) calculation of sustainable value creation, that is, the value above the cost of sustainability capital. By expanding the well-established logic of the valuation of economic capital in financial markets to cover other forms of capital, we provide a methodology that allows determination of the most efficient allocation of sustainability capital for sustainable value creation in companies. We demonstrate the practicability of the methodology by the valuation of the sustainability performance of British Petroleum (BP).