Economic evaluation alongside pragmatic randomised trials: developing a standard operating procedure for clinical trials units

Background

There is wide recognition that pragmatic randomised trials are the best vehicle for economic evaluation. This is because trials provide the best chance of ensuring internal validity, not least through the rigorous prospective collection of patient-specific data. Furthermore the marginal cost of collecting economic data alongside clinical data is typically modest. UK Clinical Research Collaboration (UKCRC) does not require a standard operating procedure (SOP) for economic evaluation as a prerequisite for trial unit registration. We judge that such a SOP facilitates the integration of health economics into trials.

Methods

A collaboration between health economists and trialists at Bangor University led to the development of a SOP for economic evaluation alongside pragmatic trials, in addition to the twenty SOPs required by UKCRC for registration, which include randomisation, data management and statistical analysis.

Results

Our recent telephone survey suggests that no other UKCRC-registered trials unit currently has an economic SOP.

Conclusion

We argue that UKCRC should require, from all Trials Units undertaking economic evaluation and seeking registration or re-registration, a SOP for economic evaluation as one of their portfolio of supporting SOPs.     

An agonist-induced conformational change in the growth hormone receptor determines the choice of signalling pathway

The growth and metabolic actions of growth hormone (GH) are believed to be mediated through the GH receptor (GHR) by JAK2 activation. The GHR exists as a constitutive homodimer, with signal transduction by ligand-induced realignment of receptor subunits. Based on the crystal structures, we identify a conformational change in the F'G' loop of the lower cytokine module, which results from binding of hGH but not G120R hGH antagonist. Mutations disabling this conformational change cause impairment of ERK but not JAK2 and STAT5 activation by the GHR in FDC-P1 cells. This results from the use of two associated tyrosine kinases by the GHR, with JAK2 activating STAT5, and Lyn activating ERK1/2. We provide evidence that Lyn signals through phospholipase C gamma, leading to activation of Ras. Accordingly, mice with mutations in the JAK2 association motif respond to GH with activation of hepatic Src and ERK1/2, but not JAK2/STAT5. We suggest that F'G' loop movement alters the signalling choice between JAK2 and a Src family kinase by regulating TMD realignment. Our findings could explain debilitated ERK but not STAT5 signalling in some GH-resistant dwarfs and suggest pathway-specific cytokine agonists.     

Barotrauma is a significant cause of bat fatalities at wind turbines

Bird fatalities at some wind energy facilities around the world have been documented for decades, but the issue of bat fatalities at such facilities — primarily involving migratory species during autumn migration — has been raised relatively recently [1] and [2]. Given that echolocating bats detect moving objects better than stationary ones [3], their relatively high fatality rate is perplexing, and numerous explanations have been proposed [1]. The decompression hypothesis proposes that bats are killed by barotrauma caused by rapid air-pressure reduction near moving turbine blades [1], [4] and [5]. Barotrauma involves tissue damage to air-containing structures caused by rapid or excessive pressure change; pulmonary barotrauma is lung damage due to expansion of air in the lungs that is not accommodated by exhalation. We report here the first evidence that barotrauma is the cause of death in a high proportion of bats found at wind energy facilities. We found that 90% of bat fatalities involved internal haemorrhaging consistent with barotrauma, and that direct contact with turbine blades only accounted for about half of the fatalities. Air pressure change at turbine blades is an undetectable hazard and helps explain high bat fatality rates. We suggest that one reason why there are fewer bird than bat fatalities is that the unique respiratory anatomy of birds is less susceptible to barotrauma than that of mammals.     

Early nutrition and phenotypic development: 'catch-up' growth leads to elevated metabolic rate in adulthood

Resting metabolic rate (RMR) is responsible for up to 50% of total energy expenditure, and so should be under strong selection pressure, yet it shows extensive intraspecific variation and a low heritability. Environmental conditions during growth are thought to have long-term effects through 'metabolic programming'. Here we investigate whether nutritional conditions early in life can alter RMR in adulthood, and whether this is due to growth acceleration or the change in diet quality that prompts it. We manipulated dietary protein levels during the main growth period of zebra finches (Taeniopygia guttata) such that an episode of poor nutrition occurred with and without growth acceleration. This produced different growth trajectories but a similar adult body mass. Only the diet that induced growth acceleration resulted in a significant (19%) elevation of RMR at adulthood, despite all the birds having been on the same diet after the first month. This is the first study to show that dietary-induced differences in growth trajectories can have a long-term effect on adult metabolic rate. It suggests that modification of metabolic efficiency may be one of the mechanisms mediating the observed long-term costs of accelerated growth, and indicates links between early nutrition and the metabolic syndrome.     

Enantioseparation of pharmaceutical compounds by multiplexed capillary electrophoresis using highly sulphated alpha-, beta- and gamma-cyclodextrins

A multiplexed capillary electrophoresis (CE) system equipped with 96 channels was evaluated for high-throughput screening of enantiomers of solutes of pharmaceutical interest. Using highly (DS approximately 12) sulphated alpha-, beta- and gamma-cyclodextrins under acidic conditions (pH 2.5) only 48 channels could be used because of the high conductivity of the chiral selectors. Method transfer from a single channel to a 48 channel CE system is described. Under optimised conditions, the analysis time on the multiplexed 48 channel CE system is ca. five to eight times the analysis time on the single channel CE system. The figures of merit for the multiplexed system are presented as well as performance evaluation including throughput and productivity gain. Intra-day precision (n=6) ranged from 2.0 to 16.5% and from 2.2 to 15.5% for migration time and resolution, respectively. These values increased with ca. 10% for intermediate precision.     

Highly efficient peptide separations in proteomics Part 1. Unidimensional high performance liquid chromatography

Sample complexity and dynamic range constitute enormous challenges in proteome analysis. The back-end technology in typical proteomics platforms, namely mass spectrometry (MS), can only tolerate a certain complexity, has a limited dynamic range per spectrum and is very sensitive towards ion suppression. Therefore, component overlap has to be minimized for successful mass spectrometric analysis and subsequent protein identification and quantification. The present review describes the advances that have been made in liquid-based separation techniques with focus on the recent developments to boost the resolving power. The review is divided in two parts; the first part deals with unidimensional liquid chromatography and the second part with bi- and multidimensional liquid-based separation techniques. Part 1 mainly focuses on reversed-phase HPLC due to the fact that it is and will, in the near future, remain the technique of choice to be hyphenated with MS. The impact of increasing the column length, decreasing the particle diameter, replacing the traditional packed beds by monolithics, amongst others, is described. The review is complemented with data obtained in the laboratories of the authors.     

Hydroxamic acid-containing hydrogels for nonabsorbed iron chelation therapy: synthesis, characterization, and biological evaluation

Iron overload is a severe clinical condition and can be largely prevented by the use of iron-specific chelating agents. A successful iron chelator needs to be orally active, nontoxic, and selective. In this study, hydrogels containing pendant hydroxamic acid groups have been synthesized as potential nonabsorbed chelators for iron in the gastrointestinal tract. The synthetic method employed to introduce hydroxamic acid groups to polymer chains involved reaction of polymer gels based on N-acryloxysuccinimide, acryloyl chloride, and (2-hydroxyethyl)acrylate monomers with hydroxylamine. These hydroxamic acid-functionalized polymer gels swell favorably in water and effectively sequester iron. In vitro iron-binding properties of these hydrogels were evaluated from their binding isotherms by use of iron(II) alone and in the presence of other competing metal ions. These polymers bind iron over a broad pH range. The iron-binding properties of the polymers were found to depend on the concentration of hydroxamate groups on polymer chains. The in vivo iron-binding efficacy of the polymers was evaluated in rat as the animal model. The polymers prevented an increase in serum hemoglobin and hematocrit levels in the animals, thus suggesting the prevention of systemic absorption of dietary iron from the gastrointestinal tract. The animals also maintained normal body weight during the treatment period, indicating the absence of any apparent toxicity associated with these polymers.     

The efficiency of muscle contraction

When a muscle contracts and shortens against a load, it performs work. The performance of work is fuelled by the expenditure of metabolic energy, more properly quantified as enthalpy (i.e., heat plus work). The ratio of work performed to enthalpy produced provides one measure of efficiency. However, if the primary interest is in the efficiency of the actomyosin cross-bridges, then the metabolic overheads associated with basal metabolism and excitation-contraction coupling, together with those of subsequent metabolic recovery process, must be subtracted from the total heat and work observed. By comparing the cross-bridge work component of the remainder to the Gibbs free energy of hydrolysis of ATP, a measure of thermodynamic efficiency is achieved. We describe and quantify this partitioning process, providing estimates of the efficiencies of selected steps, while discussing the errors that can arise in the process of quantification. The dependence of efficiency on animal species, fibre-type, temperature, and contractile velocity is considered. The effect of contractile velocity on energetics is further examined using a two-state, Huxley-style, mathematical model of cross-bridge cycling that incorporates filament compliance. Simulations suggest only a modest effect of filament compliance on peak efficiency, but progressively larger gains (vis-à-vis the rigid filament case) as contractile velocity approaches Vmax. This effect is attributed primarily to a reduction in the component of energy loss arising from detachment of cross-bridge heads at non-zero strain.