Polypharmacy in chronic diseases–Reduction of Inappropriate Medication and Adverse drug events in older populations by electronic Decision Support (PRIMA-eDS): study protocol for a randomized controlled trial

Background: Multimorbidity is increasing in aging populations with a corresponding increase in polypharmacy as well as inappropriate prescribing. Depending on definitions, 25-50 % of patients aged 75 years or older are exposed to at least five drugs. Evidence is increasing that polypharmacy, even when guidelines advise the prescribing of each drug individually, can potentially cause more harm than benefit to older patients, due to factors such as drug-drug and drug-disease interactions. Several approaches reducing polypharmacy and inappropriate prescribing have been proposed, but evidence showing a benefit of these measures regarding clinically relevant endpoints is scarce. There is an urgent need to implement more effective strategies. We therefore set out to develop an evidence-based electronic decision support (eDS) tool to aid physicians in reducing inappropriate prescribing and test its effectiveness in a large-scale cluster-randomized controlled trial.Methods: The “Polypharmacy in chronic diseases–Reduction of Inappropriate Medication and Adverse drug events in older populations” (PRIMA)-eDS tool is a tool comprising an indication check and recommendations for the reduction of polypharmacy and inappropriate prescribing based on systematic reviews and guidelines, the European list of inappropriate medications for older people, the SFINX-database of interactions, the PHARAO-database on adverse effects, and the RENBASE-database on renal dosing. The tool will be evaluated in a cluster-randomized controlled trial involving 325 general practitioners (GPs) and around 3500 patients across five study centres in the United Kingdom, Germany, Austria and Italy. GP practices will be asked to recruit 11 patients aged 75 years or older who are taking at least eight medications and will be cluster-randomized after completion of patient recruitment. Intervention GPs will have access to the PRIMA-eDS tool, while control GPs will treat their patients according to current guidelines (usual care) without access to the PRIMA-eDS tool. After an observation time of 2 years, intervention and control groups will be compared regarding the primary composite endpoint of first non-elective hospitalization or death.Discussion: The principal hypothesis is that reduction of polypharmacy and inappropriate prescribing can improve the clinical composite outcome of hospitalization or death. A positive result of the trial will contribute substantially to the improvement of care in multimorbidity. The trial is necessary to investigate not only whether the reduction of polypharmacy improves outcome, but also whether GPs and patients are willing to follow the recommendations of the PRIMA-eDS tool.Trial registration: This trial has been registered with Current Controlled Trials Ltd. on 31 July 2014 ( ISRCTN10137559 )

Additional file 1: Figure S1. of Polypharmacy in chronic diseases–Reduction of Inappropriate Medication and Adverse drug events in older populations by electronic Decision Support (PRIMA-eDS): study protocol for a randomized controlled trial

Recruitment of 325 practices and 3575 patients for the PRIMA-eDS* trial. Figure describing the flow of recruitment for the PRIMA-eDS trial. (JPG 117 kb

Structural insights into the human GW182-PABC interaction in microRNA-mediated deadenylation

GW182-family proteins are essential for microRNA-mediated translational repression and deadenylation in animal cells. Here we show that a conserved motif in the human GW182 paralog TNRC6C interacts with the C-terminal domain of polyadenylate binding protein 1 (PABC) and present the crystal structure of the complex. Mutations at the complex interface impair mRNA deadenylation in mammalian cell extracts, suggesting that the GW182-PABC interaction contributes to microRNA-mediated gene silencing. MicroRNAs (miRNAs) are short endogenous RNAs that regulate a variety of eukaryotic cell processes, including cell growth, proliferation and differentiation. In Metazoa, miRNAs associate with Argonaute (Ago) proteins in miRNA-induced silencing complexes (miRISCs) to silence target mRNAs by a mechanism involving translational repression and concurrent stimulation of mRNA deadenylation and subsequent degradation1, 2. In addition to Ago proteins, miRNA-mediated silencing requires proteins of the GW182 family3. Tethering of GW182 proteins to mRNA reporters induces translational repression and mRNA decay in the absence of miRNAs and Ago, suggesting that GW182 proteins have silencing functions downstream of Ago4. A direct interaction between Ago and GW182, Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use