Orphan drugs and the NHS: Should we value rarity

Cost effectiveness plays an important part in current decisions about the funding of health technologies. Drugs for rare disease (orphan drugs) are often expensive to produce and, by definition, will benefit only small numbers of patients. Several countries have put measures in place to safeguard research and development of orphan drugs, but few get close to meeting the cost effectiveness criteria for funding by healthcare providers. We examine the justifications for special status for rare diseases and ask whether the cost effectiveness of drugs for rare or very rare diseases should be treated differently from that of other drugs and interventions

Electric field gradients from first-principles and point-ion calculations

Point-ion models have been extensively used to determine "hole numbers" at copper and oxygen sites in high-temperature superconducting cuprate compounds from measured nuclear quadrupole frequencies. The present study assesses the reliability of point-ion models to predict electric field gradients accurately and also the implicit assumption that the values can be calculated from the "holes" and not the total electronic structure. First-principles cluster calculations using basis sets centred on the nuclei have enabled the determination of the charge and spin density distribution in the CuO2-plane. The contributions to the electric field gradients and the magnetic hyperfine couplings are analysed in detail. In particular they are partitioned into regions in an attempt to find a correlation with the most commonly used point-ion model, the Sternheimer equation which depends on the two parameters R and gamma. Our most optimistic objective was to find expressions for these parameters, which would improve our understanding of them, but although estimates of the R parameter were encouraging the method used to obtain the gamma parameter indicate that the two parameters may not be independent. The problem seems to stem from the covalently bonded nature of the CuO2-planes in these structures which severely questions using the Sternheimer equation for such crystals, since its derivation is heavily reliant on the application of perturbation theory to predominantly ionic structures. Furthermore it is shown that the complementary contributions of electrons and holes in an isolated ion cannot be applied to estimates of electric field gradients at copper and oxygen nuclei in cuprates.Comment: 19 pages, 4 figure

Drugs for exceptionally rare diseases: a commentary on Hughes et al

Recently in this journal, Hughes and colleagues discussed special funding status to ultra-orphan drugs. They concluded that there should be a uniform policy for the provision of orphan drugs across Europe; that complete restriction was impractical, and that UK policy should aspire to the values of the EU directive on orphan drugs. We critically assess these arguments, demonstrating that they failed to justify special status for treatments for rare diseases

Design management of sustainable fashion

The aim of this research is to advance an understanding of how design in the fashion industry can be successfully managed to contribute to environmental sustainability. Its objectives are to investigate how fashion businesses establish and support environmentally sustainable strategies, and how design leaders and managers contribute to the setting of these goals. The paper reviews the literature of the fashion industry, its sustainability strategies, and the management of design. Semi-structured interviews and a quantitative survey of designers was undertaken in the UK. A framework based on the level of business engagement in sustainability was used to structure the thematic analysis of the findings. The research demonstrates the relatively weak influence of designers on sustainable fashion strategy and concludes by developing design management theory for sustainability through a modified Design Atlas framework

Drugs for exceptionally rare diseases: a commentary on Hughes et al

Recently in this journal, Hughes and colleagues discussed special funding status to ultra-orphan drugs. They concluded that there should be a uniform policy for the provision of orphan drugs across Europe; that complete restriction was impractical, and that UK policy should aspire to the values of the EU directive on orphan drugs. We critically assess these arguments, demonstrating that they failed to justify special status for treatments for rare diseases

First-Principles Calculation of Electric Field Gradients and Hyperfine Couplings in YBa2Cu3O7

The local electronic structure of YBa2Cu3O7 has been calculated using first-principles cluster methods. Several clusters embedded in an appropriate background potential have been investigated. The electric field gradients at the copper and oxygen sites are determined and compared to previous theoretical calculations and experiments. Spin polarized calculations with different spin multiplicities have enabled a detailed study of the spin density distribution to be made and a simultaneous determination of magnetic hyperfine coupling parameters. The contributions from on-site and transferred hyperfine fields have been disentangled with the conclusion that the transferred spin densities essentially are due to nearest neighbour copper ions only with marginal influence of ions further away. This implies that the variant temperature dependencies of the planar copper and oxygen NMR spin-lattice relaxation rates are only compatible with commensurate antiferromagnetic correlations. The theoretical hyperfine parameters are compared with those derived from experimental data.Comment: 14 pages, 12 figures, accepted to appear in EPJ

Modelling the cost effectiveness of interferon beta and glatiramer acetate in the management of multiple sclerosis

OBJECTIVE: To evaluate the cost effectiveness of four disease modifying treatments (interferon betas and glatiramer acetate) for relapsing remitting and secondary progressive multiple sclerosis in the United Kingdom. DESIGN: Modelling cost effectiveness. SETTING: UK NHS. PARTICIPANTS: Patients with relapsing remitting multiple sclerosis and secondary progressive multiple sclerosis. MAIN OUTCOME MEASURES: Cost per quality adjusted life year gained. RESULTS: The base case cost per quality adjusted life year gained by using any of the four treatments ranged from £42 000 ($66 469; 61 630) to £98 000 based on efficacy information in the public domain. Uncertainty analysis suggests that the probability of any of these treatments having a cost effectiveness better than £20 000 at 20 years is below 20%. The key determinants of cost effectiveness were the time horizon, the progression of patients after stopping treatment, differential discount rates, and the price of the treatments. CONCLUSIONS: Cost effectiveness varied markedly between the interventions. Uncertainty around point estimates was substantial. This uncertainty could be reduced by conducting research on the true magnitude of the effect of these drugs, the progression of patients after stopping treatment, the costs of care, and the quality of life of the patients. Price was the key modifiable determinant of the cost effectiveness of these treatments

Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery.

BACKGROUND: Stroke is the major cause of adult disability. Selective serotonin reuptake inhibitors (SSRIs) have been used for many years to manage depression. Recently, small trials have demonstrated that SSRIs might improve recovery after stroke, even in people who are not depressed. Systematic reviews and meta-analyses are the least biased way to bring together data from several trials. Given the promising effect of SSRIs on stroke recovery seen in small trials, a systematic review and meta-analysis is needed. OBJECTIVES: To determine whether SSRIs improve recovery after stroke, and whether treatment with SSRIs was associated with adverse effects. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (August 2011), Cochrane Depression Anxiety and Neurosis Group Trials Register (November 2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 8), MEDLINE (from 1948 to August 2011), EMBASE (from 1980 to August 2011), CINAHL (from 1982 to August 2011), AMED (Allied and Complementary Medicine) (from 1985 to August 2011), PsycINFO (from 1967 to August 2011) and PsycBITE (Pyschological Database for Brain Impairment Treatment Efficacy) (March 2012). To identify further published, unpublished and ongoing trials we searched trials registers, pharmaceutical websites, reference lists, contacted experts and performed citation tracking of included studies. SELECTION CRITERIA: We included randomised controlled trials that recruited stroke survivors (ischaemic or haemorrhagic) at any time within the first year. The intervention was any SSRI, given at any dose, for any period. We excluded drugs with mixed pharmacological effects. The comparator was usual care or placebo. In order to be included, trials had to collect data on at least one of our primary (dependence and disability) or secondary (impairments, depression, anxiety, quality of life, fatigue, healthcare cost, death, adverse events and leaving the trial early) outcomes. DATA COLLECTION AND ANALYSIS: We extracted data on demographics, type of stroke, time since stroke, our primary and secondary outcomes, and sources of bias. For trials in English, two review authors independently extracted data. For Chinese papers, one review author extracted data. We used standardised mean differences (SMD) to estimate treatment effects for continuous variables, and risk ratios (RR) for dichotomous effects, with their 95% confidence intervals (CIs). MAIN RESULTS: We identified 56 completed trials of SSRI versus control, of which 52 trials (4059 participants) provided data for meta-analysis. There were statistically significant benefits of SSRI on both of the primary outcomes: RR for reducing dependency at the end of treatment was 0.81 (95% CI 0.68 to 0.97) based on one trial, and for disability score, the SMD was 0.91 (95% CI 0.60 to 1.22) (22 trials involving 1343 participants) with high heterogeneity between trials (I(2) = 87%; P < 0.0001). For neurological deficit, depression and anxiety, there were statistically significant benefits of SSRIs. For neurological deficit score, the SMD was -1.00 (95% CI -1.26 to -0.75) (29 trials involving 2011 participants) with high heterogeneity between trials (I(2) = 86%; P < 0.00001). For dichotomous depression scores, the RR was 0.43 (95% CI 0.24 to 0.77) (eight trials involving 771 participants) with high heterogeneity between trials (I(2) = 77%; P < 0.0001). For continuous depression scores, the SMD was -1.91 (95% CI -2.34 to -1.48) (39 trials involving 2728 participants) with high heterogeneity between trials (I(2) = 95%; P < 0.00001). For anxiety, the SMD was -0.77 (95% CI -1.52 to -0.02) (eight trials involving 413 participants) with high heterogeneity between trials (I(2) = 92%; P < 0.00001). There was no statistically significant benefit of SSRI on cognition, death, motor deficits and leaving the trial early. For cognition, the SMD was 0.32 (95% CI -0.23 to 0.86), (seven trials involving 425 participants) with high heterogeneity between trials (I(2) = 86%; P < 0.00001). The RR for death was 0.76 (95% CI 0.34 to 1.70) (46 trials involving 3344 participants) with no heterogeneity between trials (I(2) = 0%; P = 0.85). For motor deficits, the SMD was -0.33 (95% CI -1.22 to 0.56) (two trials involving 145 participants). The RR for leaving the trial early was 1.02 (95% CI 0.86 to 1.21) in favour of control, with no heterogeneity between trials. There was a non-significant excess of seizures (RR 2.67; 95% CI 0.61 to 11.63) (seven trials involving 444 participants), a non-significant excess of gastrointestinal side effects (RR 1.90; 95% CI 0.94 to 3.85) (14 trials involving 902 participants) and a non-significant excess of bleeding (RR 1.63; 95% CI 0.20 to 13.05) (two trials involving 249 participants) in those allocated SSRIs. Data were not available on quality of life, fatigue or healthcare costs.There was no clear evidence from subgroup analyses that one SSRI was consistently superior to another, or that time since stroke or depression at baseline had a major influence on effect sizes. Sensitivity analyses suggested that effect sizes were smaller when we excluded trials at high or unclear risk of bias.Only eight trials provided data on outcomes after treatment had been completed; the effect sizes were generally in favour of SSRIs but CIs were wide. AUTHORS' CONCLUSIONS: SSRIs appeared to improve dependence, disability, neurological impairment, anxiety and depression after stroke, but there was heterogeneity between trials and methodological limitations in a substantial proportion of the trials. Large, well-designed trials are now needed to determine whether SSRIs should be given routinely to patients with stroke

Efficient Value of Information Calculation Using a Nonparametric Regression Approach: An Applied Perspective

Background: Value-of-information (VOI) analysis provides an analytical framework to assess whether obtaining additional evidence is worthwhile to reduce decision uncertainty. The reporting of VOI measures, particularly the expected value of perfect parameter information (EVPPI) and the expected value of sample information (EVSI), is limited because of the computational burden associated with typical two-level Monte-Carlo–based solution. Recently, a nonparametric regression approach was proposed that allows the estimation of multiparameter EVPPI and EVSI directly from a probabilistic sensitivity analysis sample. Objectives: To demonstrate the value of the nonparametric regression approach in calculating VOI measures in real-world cases and to compare its performance with the standard approach of the Monte-Carlo simulation. Methods: We used the regression approach to calculate EVPPI and EVSI in two models, and compared the results with the estimates obtained via the standard Monte-Carlo simulation. Results: The VOI values from the two approaches were very close; computation using the regression method, however, was faster. Conclusion: The nonparametric regression approach provides an efficient and easy-to-implement alternative for EVPPI and EVSI calculation in economic models

Interdisciplinary educational approaches to clothing longevity

How do we encourage and enable interdisciplinary systems thinking approaches to sustainable fashion design and business education? In preparation for a workshop at the 2017 PLATE conference, this paper introduces the context of a toolkit – The Clothing Durability Dozen (Cooper at al, 2016b) – aimed at enabling students to collaborate and learn about clothing longevity across disciplines and creating a better understanding of the roles that different departments can play in placing sustainable design strategies at the heart of the clothing industry. In line with education for sustainable development (ESD) principles, objectives include stimulating learning and promote core competencies, such as critical and systemic thinking, collaborative decision-making, and taking responsibility for present and future generations. In the workshop, participants will trial and contribute to the development of the toolkit and any necessary supporting material, the final version of which will be available for use as an educational tool