Improving appropriate polypharmacy for older people in primary care: selecting components of an evidence-based intervention to target prescribing and dispensing.

Background
The use of multiple medicines (polypharmacy) is increasingly common in older people. Ensuring that patients receive the most appropriate combinations of medications (appropriate polypharmacy) is a significant challenge. The quality of evidence to support the effectiveness of interventions to improve appropriate polypharmacy is low. Systematic identification of mediators of behaviour change, using the Theoretical Domains Framework (TDF), provides a theoretically robust evidence base to inform intervention design. This study aimed to (1) identify key theoretical domains that were perceived to influence the prescribing and dispensing of appropriate polypharmacy to older patients by general practitioners (GPs) and community pharmacists, and (2) map domains to associated behaviour change techniques (BCTs) to include as components of an intervention to improve appropriate polypharmacy in older people in primary care.

Methods
Semi-structured interviews were conducted with members of each healthcare professional (HCP) group using tailored topic guides based on TDF version 1 (12 domains). Questions covering each domain explored HCPs’ perceptions of barriers and facilitators to ensuring the prescribing and dispensing of appropriate polypharmacy to older people. Interviews were audio-recorded and transcribed verbatim. Data analysis involved the framework method and content analysis. Key domains were identified and mapped to BCTs based on established methods and discussion within the research team.

Results
Thirty HCPs were interviewed (15 GPs, 15 pharmacists). Eight key domains were identified, perceived to influence prescribing and dispensing of appropriate polypharmacy: ‘Skills’, ‘Beliefs about capabilities’, ‘Beliefs about consequences’, ‘Environmental context and resources’, ‘Memory, attention and decision processes’, ‘Social/professional role and identity’, ‘Social influences’ and ‘Behavioural regulation’. Following mapping, four BCTs were selected for inclusion in an intervention for GPs or pharmacists: ‘Action planning’, ‘Prompts/cues’, ‘Modelling or demonstrating of behaviour’ and ‘Salience of consequences’. An additional BCT (‘Social support or encouragement’) was selected for inclusion in a community pharmacy-based intervention in order to address barriers relating to interprofessional working that were encountered by pharmacists.

Conclusions
Selected BCTs will be operationalised in a theory-based intervention to improve appropriate polypharmacy for older people, to be delivered in GP practice and community pharmacy settings. Future research will involve development and feasibility testing of this intervention.

Network signatures based on gene pair expression ratios improve classification and the analysis of muscle-invasive urothelial cancer

Urothelial cancer (UC) is highly recurrent and can progress from non-invasive (NMIUC) to a more aggressive muscle-invasive (MIUC) subtype that invades the muscle tissue layer of the bladder. We present a proof of principle study that network-based features of gene pairs can be used to improve classifier performance and the functional analysis of urothelial cancer gene expression data. In the first step of our procedure each individual sample of a UC gene expression dataset is inflated by gene pair expression ratios that are defined based on a given network structure. In the second step an elastic net feature selection procedure for network-based signatures is applied to discriminate between NMIUC and MIUC samples. We performed a repeated random subsampling cross validation in three independent datasets. The network signatures were characterized by a functional enrichment analysis and studied for the enrichment of known cancer genes. We observed that the network-based gene signatures from meta collections of proteinprotein interaction (PPI) databases such as CPDB and the PPI databases HPRD and BioGrid improved the classification performance compared to single gene based signatures. The network based signatures that were derived from PPI databases showed a prominent enrichment of cancer genes (e.g., TP53, TRIM27 and HNRNPA2Bl). We provide a novel integrative approach for large-scale gene expression analysis for the identification and development of novel diagnostical targets in bladder cancer. Further, our method allowed to link cancer gene associations to network-based expression signatures that are not observed in gene-based expression signatures.

Integration of global SNP-based mapping and expression arrays reveals key regions, mechanisms, and genes important in the pathogenesis of multiple myeloma.

Multiple myeloma is characterized by genomic alterations frequently involving gains and losses of chromosomes. Single nucleotide polymorphism (SNP)-based mapping arrays allow the identification of copy number changes at the sub-megabase level and the identification of loss of heterozygosity (LOH) due to monosomy and uniparental disomy (UPD). We have found that SNP-based mapping array data and fluorescence in situ hybridization (FISH) copy number data correlated well, making the technique robust as a tool to investigate myeloma genomics. The most frequently identified alterations are located at 1p, 1q, 6q, 8p, 13, and 16q. LOH is found in these large regions and also in smaller regions throughout the genome with a median size of 1 Mb. We have identified that UPD is prevalent in myeloma and occurs through a number of mechanisms including mitotic nondisjunction and mitotic recombination. For the first time in myeloma, integration of mapping and expression data has allowed us to reduce the complexity of standard gene expression data and identify candidate genes important in both the transition from normal to monoclonal gammopathy of unknown significance (MGUS) to myeloma and in different subgroups within myeloma. We have documented these genes, providing a focus for further studies to identify and characterize those that are key in the pathogenesis of myeloma.

A global expression-based analysis of the consequences of the t(4;14) translocation in myeloma

Purpose: Our purpose in this report was to define genes and pathways dysregulated as a consequence of the t(4;14) in myeloma, and to gain insight into the downstream functional effects that may explain the different prognosis of this subgroup.Experimental Design: Fibroblast growth factor receptor 3 (FGFR3) overexpression, the presence of immunoglobulin heavy chain-multiple myeloma SET domain (IgH-MMSET) fusion products and the identification of t(4;14) breakpoints were determined in a series of myeloma cases. Differentially expressed genes were identified between cases with (n = 55) and without (n = 24) a t(4;14) by using global gene expression analysis.Results: Cases with a t(4;14) have a distinct expression pattern compared with other cases of myeloma. A total of 127 genes were identified as being differentially expressed including MMSET and cyclin D2, which have been previously reported as being associated with this translocation. Other important functional classes of genes include cell signaling, apoptosis and related genes, oncogenes, chromatin structure, and DNA repair genes. Interestingly, 25% of myeloma cases lacking evidence of this translocation had up-regulation of the MMSET transcript to the same level as cases with a translocation.Conclusions: t(4;14) cases form a distinct subgroup of myeloma cases with a unique gene signature that may account for their poor prognosis. A number of non-t(4;14) cases also express MMSET consistent with this gene playing a role in myeloma pathogenesis.

Physical Layer Security with Threshold-Based Multiuser Scheduling in Multi-antenna Wireless Networks

In this paper, we consider a multiuser downlink wiretap network consisting of one base station (BS) equipped with AA antennas, NB single-antenna legitimate users, and NE single-antenna eavesdroppers over Nakagami-m fading channels. In particular, we introduce a joint secure transmission scheme that adopts transmit antenna selection (TAS) at the BS and explores threshold-based selection diversity (tSD) scheduling over legitimate users to achieve a good secrecy performance while maintaining low implementation complexity. More specifically, in an effort to quantify the secrecy performance of the considered system, two practical scenarios are investigated, i.e., Scenario I: the eavesdropper’s channel state information (CSI) is unavailable at the BS, and Scenario II: the eavesdropper’s CSI is available at the BS. For Scenario I, novel exact closed-form expressions of the secrecy outage probability are derived, which are valid for general networks with an arbitrary number of legitimate users, antenna configurations, number of eavesdroppers, and the switched threshold. For Scenario II, we take into account the ergodic secrecy rate as the principle performance metric, and derive novel closed-form expressions of the exact ergodic secrecy rate. Additionally, we also provide simple and asymptotic expressions for secrecy outage probability and ergodic secrecy rate under two distinct cases, i.e., Case I: the legitimate user is located close to the BS, and Case II: both the legitimate user and eavesdropper are located close to the BS. Our important findings reveal that the secrecy diversity order is AAmA and the slope of secrecy rate is one under Case I, while the secrecy diversity order and the slope of secrecy rate collapse to zero under Case II, where the secrecy performance floor occurs. Finally, when the switched threshold is carefully selected, the considered scheduling scheme outperforms other well known existing schemes in terms of the secrecy performance and complexity tradeoff

Fixed-boundary constituencies and the principle of equal representation in Ireland

The process of constituency boundary revision in Ireland, designed to satisfy what is perceived as a rigid requirement that a uniform deputy-population ratio be maintained across constituencies, has traditionally consumed a great deal of the time of politicians and officials. For almost two decades after a High Court ruling in 1961, the process was a political one, was highly contentious, and was marked by serious allegations of ministerial gerrymandering. The introduction in 1979 of constituency commissions made up of officials neutralised, for the most part, charges that the system had become too politicised, but it continued the process of micro-management of constituency boundaries. This article suggests that the continuing problems caused by this system – notably, the permanently changing nature of constituency boundaries and resulting difficulties of geographical identification – could be resolved by reversion to the procedure that is normal in proportional representation systems: periodic post-census allocation of seats to constituencies whose boundaries are based on those of recognised local government units and which are stable over time. This reform, replacing the principle of redistricting by the principle of reapportionment, would result in more recognisable constituencies, more predictable boundary trajectories over time, and a more efficient, fairer, and speedier process of revision.