Factors influencing multiple sclerosis disease-modifying treatment prescribing decisions in the United Kingdom: A qualitative interview study

Background The proportion of people with relapsing-remitting multiple sclerosis prescribed disease modifying treatments (DMTs) in the United Kingdom (UK) is considered low compared with other countries. There are differences in DMT prescription rates between UK nations (England, Wales, Scotland, Northern Ireland). Despite this, there has been little research into decision-making processes and prescribing practices. Objective To investigate views and experiences of neurologists prescribing DMTs and MS specialist nurses to identify factors influencing prescribing. Methods Semi-structured interviews with 18 consultant neurologists and 16 specialist nurses from diverse settings across the four UK nations. Data were analysed using thematic framework analysis. Results Prescribing practices are influenced by organisational prescribing “cultures”, informal “benchmarking” within peer networks, and prior experience with different DMTs. Health professionals differ in their perceptions of benefits and risks of DMTs and personal “thresholds” for discerning relapses and determining eligibility for DMTs. Prescribers in England felt most constrained by guidelines. Conclusion To achieve equity in access to DMTs for people with MS eligible for treatment, there is a need for public discussion acknowledging differences in health professionals’ interpretations of “relapses” and guidelines and perceptions of DMTs, variation in organisational prescribing “cultures”, and whether the prevailing culture sufficiently meets patients’ needs

Effect of supplementation with n-3 polyunsaturated fatty acids and/or β-glucans on performance, feeding behaviour and immune status of Holstein Friesian bull calves during the pre- and post-weaning periods

peer-reviewedBackground Previous research in both calves and other species has suggested n-3 polyunsaturated fatty acids (PUFA) and β-glucans may have positive effects on immune function. This experiment measured performance, behaviour, metabolite and immunological responses to pre-weaning supplementation of dairy bull calves with n-3 PUFA in the form of fish oil and β-glucans derived from seaweed extract. 44 Holstein Friesian bull calves, aged 13.7 ± 2.5 d and weighing 48.0 ± 5.8 kg were artificially reared using an electronic feeding system. Each calf was offered 5 L (120 g/L) per day of milk replacer (MR) and assigned to one of four treatments included in the MR, (1) Control (CON); (2) 40 g n-3 PUFA per day (FO); (3) 1 g β-glucans per day (GL) and (4) 40 g n-3 PUFA per day & 1 g/d β-glucans (FOGL) in a 2 × 2 factorial design. Milk replacer and concentrate was offered from d 0–62 (pre-weaning), while concentrate provision continued for a further 31 d post-weaning period. Individual daily feed intake and feeding behaviour was recorded throughout, while bodyweight and blood analyte data were collected at regular intervals. Results Overall mean concentrate DMI from d 0–93 was 1.39, 1.27, 1.00 and 0.72 kg/d for CON, FO, GL and FOGL calves, respectively (SEM = 0.037; P < 0.0001). Calves supplemented with GL were significantly lighter (P < 0.0001) at both weaning (d 62) and turnout to pasture (d 93) than un-supplemented calves, with a similar effect (P < 0.0001) evident for calves receiving FO compared to un-supplemented contemporaries. Supplementation with GL reduced the number of unrewarded visits where milk was not consumed (P < 0.0001) while supplementation with FO increased mean drinking speed (P < 0.0001). Supplementation with GL resulted in greater concentrations of haptoglobin (P = 0.034), greater serum osmolality (P = 0.021) and lower lymphocyte levels (P = 0.027). In addition, cells from GL supplemented calves exhibited a lower response than un-supplemented contemporaries to both Phytohaemagglutinin A stimulated IFN-γ (P = 0.019) and Concanavalin A stimulated IFN-γ (P = 0.012) following in vitro challenges. Conclusions Pre-weaning supplementation of bull calves with either n-3 PUFA or β-glucan resulted in reduced voluntary feed intake of concentrate and consequently poorer pre-weaning calf performance. There was no evidence for any beneficial effect of either supplementation strategy on calves’ immune responses

Resonance Raman Spectroscopy of extreme nanowires and other 1D systems

This paper briefly describes how nanowires with diameters corresponding to 1 to 5 atoms can be produced by melting a range of inorganic solids in the presence of carbon nanotubes. These nanowires are extreme in the sense that they are the limit of miniaturization of nanowires and their behavior is not always a simple extrapolation of the behavior of larger nanowires as their diameter decreases. The paper then describes the methods required to obtain Raman spectra from extreme nanowires and the fact that due to the van Hove singularities that 1D systems exhibit in their optical density of states, that determining the correct choice of photon excitation energy is critical. It describes the techniques required to determine the photon energy dependence of the resonances observed in Raman spectroscopy of 1D systems and in particular how to obtain measurements of Raman cross-sections with better than 8% noise and measure the variation in the resonance as a function of sample temperature. The paper describes the importance of ensuring that the Raman scattering is linearly proportional to the intensity of the laser excitation intensity. It also describes how to use the polarization dependence of the Raman scattering to separate Raman scattering of the encapsulated 1D systems from those of other extraneous components in any sample

Time-separated entangled light pulses from a single-atom emitter

The controlled interaction between a single, trapped, laser-driven atom and the mode of a high-finesse optical cavity allows for the generation of temporally separated, entangled light pulses. Entanglement between the photon-number fluctuations of the pulses is created and mediated via the atomic center-of-mass motion, which is interfaced with light through the mechanical effect of atom-photon interaction. By means of a quantum noise analysis we determine the correlation matrix which characterizes the entanglement, as a function of the system parameters. The scheme is feasible in experimentally accessible parameter regimes. It may be easily extended to the generation of entangled pulses at different frequencies, even at vastly different wavelengths.Comment: 17 pages, 5 figures. Modified version, to appear in the New Journal of Physic

Linking Ligand-Induced Alterations in Androgen Receptor Structure to Differential Gene Expression: A First Step in the Rational Design of Selective Androgen Receptor Modulators

We have previously identified a family of novel androgen receptor (AR) ligands that, upon binding, enable AR to adopt structures distinct from that observed in the presence of canonical agonists. In this report, we describe the use of these compounds to establish a relationship between AR structure and biological activity with a view to defining a rational approach with which to identify useful selective AR modulators. To this end, we used combinatorial peptide phage display coupled with molecular dynamic structure analysis to identify the surfaces on AR that are exposed specifically in the presence of selected AR ligands. Subsequently, we used a DNA microarray analysis to demonstrate that differently conformed receptors facilitate distinct patterns of gene expression in LNCaP cells. Interestingly, we observed a complete overlap in the identity of genes expressed after treatment with mechanistically distinct AR ligands. However, it was differences in the kinetics of gene regulation that distinguished these compounds. Follow-up studies, in cell-based assays of AR action, confirmed the importance of these alterations in gene expression. Together, these studies demonstrate an important link between AR structure, gene expression, and biological outcome. This relationship provides a firm underpinning for mechanism-based screens aimed at identifying SARMs with useful clinical profiles

Assessment of genotype imputation methods

Several methods have been proposed to impute genotypes at untyped markers using observed genotypes and genetic data from a reference panel. We used the Genetic Analysis Workshop 16 rheumatoid arthritis case-control dataset to compare the performance of four of these imputation methods: IMPUTE, MACH, PLINK, and fastPHASE. We compared the methods' imputation error rates and performance of association tests using the imputed data, in the context of imputing completely untyped markers as well as imputing missing genotypes to combine two datasets genotyped at different sets of markers. As expected, all methods performed better for single-nucleotide polymorphisms (SNPs) in high linkage disequilibrium with genotyped SNPs. However, MACH and IMPUTE generated lower imputation error rates than fastPHASE and PLINK. Association tests based on allele "dosage" from MACH and tests based on the posterior probabilities from IMPUTE provided results closest to those based on complete data. However, in both situations, none of the imputation-based tests provide the same level of evidence of association as the complete data at SNPs strongly associated with disease