Deprescribing is an essential component of safe prescribing, especially for people with higher levels of polypharmacy. Identifying individuals prepared to consider medicine changes may facilitate deprescribing-orientated reviews. We aimed to explore the relationship between revised patient attitudes towards deprescribing (rPATD) scores and medication changes in older people prescribed ≥15 medicines. A secondary analysis of rPATD scores and prescription data from a cluster randomised controlled trial of a GP-delivered, deprescribing-orientated medication review was conducted. The association between number of medicines stopped, started and changed and baseline rPATD scores was assessed using Poisson regression adjusting for patient age, gender, study group allocation, baseline number of medicines and effects of clustering. Participants (n=404) had a mean age of 76.4 years and were prescribed a mean of 17.1 medicines at baseline. Willingness to stop a medicine was associated with higher rates of both deprescribing (IRR: 1.40; 95%CI: 1.06-1.84) and initiating medicines (IRR: 1.43; 95%CI: 1.09-1.88). Satisfaction with current medicines was associated with a lower rate of deprescribing (IRR: 0.69; 95%CI: 0.57-0.85). The rPATD questionnaire could be used as part of a deprescribing intervention to identify participants who may be prepared to engage in deprescribing, enabling more efficient use of clinician time during complex consultations.
The future of deprescribing research: seizing opportunities and learning from the past Michael A. Steinman, MDUniversity of California, San Francisco and the San Francisco VA Medical CenterWord count: 1549References: 10Funding: This work was supported by the National Institute on Aging (grants R24AG064025 and K24AG049057)Disclosures: Dr. Steinman receives royalties from UpToDate and honoraria from the American Geriatrics Society. This manuscript is based on a lecture given at the First International Conference on Deprescribing (ICOD), Kolding, Denmark, September 2022.
VLGR1/ADGRV1 (very large G protein-coupled receptor-1) is the largest known adhesion G protein-coupled receptor. Mutations in VLGR1/ADGRV1 cause Usher syndrome (USH), the most common form of hereditary deaf-blindness, and have been additionally linked to epilepsy. Although VLGR1/ADGRV1 is almost ubiquitously expressed, little is known about the subcellular function and signalling of the VLGR1 protein and thus about mechanisms underlying the development of diseases. Using affinity proteomics, we have identified key components of autophagosomes as putative interacting proteins of VLGR1. In addition, whole transcriptome sequencing of the retinae of the Vlgr1/del7TM mouse model revealed altered expression profiles of gene-related autophagy. Monitoring autophagy by immunoblotting and immunocytochemistry of the LC3 and p62 as autophagy marker proteins revealed evoked autophagy in VLGR1-deficient hTERT-RPE1 cells and USH2C patient-derived fibroblasts. Our data demonstrate the molecular and functional interaction of VLGR1 with key components of the autophagy process and point to an essential role of VLGR1 in the regulation of autophagy at internal membranes. The close association of VLGR1 with autophagy helps to explain the pathomechanisms underlying human USH and epilepsy-related to VLGR1 defects.
VLGR1/ADGRV1 (very large G protein-coupled receptor-1) is the largest adhesion G protein-coupled receptor aGPCRs. Mutations in VLGR1/ADGRV1 are associated with human Usher syndrome (USH), the most common form of deaf-blindness, and also with epilepsy in humans and in mice. Although VLGR1 is almost ubiquitously expressed in CNS and ocular and inner ear sensory cells. Little is known about the pathogenesis of the diseases related to VLGR1. We previously identified VLGR1 as a vital component of focal adhesions (FA) serving as a metabotropic mechanoreceptor that controls cell spreading and migration. FAs are highly dynamic and turnover frequently in response to internal and external signals. Here, we aimed to elucidate how VLGR1 participates in FA turnover. Nocodazole washout assays and live-cell imaging of RFP-paxillin consistently demonstrated that FA disassembly was not altered, de novo assembly of FA was significantly delayed in Vlgr1-deficient astrocytes indicating that VLGR1 is enrolled in the assembly of FAs. In FRAP experiments recovery rates were significantly reduced in Vlgr1-deficient FAs, indicating reduced turnover kinetics in VLGR1-deficient FAs. We showed that VLGR1 regulates cell migration by controlling the FA turnover during their assembly. From this, we expect novel insights into pathomechanisms related to pathogenic dysfunctions of VLGR1.
The present study evaluates the influence of type 2 diabetes (T2D) on important CYP450 isoforms and P-glycoprotein (P-gp) transporter activities before and 3 months after intensifying treatment regimen of 40 patients. Results have been compared with 21 non-T2D healthy participants (control group). CYPs and P-gp activities were assessed after administration of Geneva cocktail. Mean metabolic ratios (MR) for CYP2B6 (1.81±0.93 vs. 2.68±0.87), CYP2C19 (0.420 ± 0.360 vs. 0.687 ± 0.558), and CYP3A4/5 (0.487 ± 0.226 vs. 0.633 ± 0.254) significantly decreased in T2D subjects compared to control group (p<0.05). CYP2C9 (0.089±0.037 vs. 0.069±0.017) activities slightly increased in diabetic subjects and no difference was observed for CYP1A2 (0.154±0.085 vs. 0.136±0.065), CYP2D6 (1.17 ± 0.56 vs. 1.24 ± 0.83) and P-gp activities in comparison with control group. Three months after intensifying treatment regimen, MRs of CYP2C9 (0.080 ± 0.030) and CYP3A4/5 (0.592 ± 0.268) have shown a significant improvement and were not statistically different compared to control group (P>0.05). Several covariables such as inflammatory markers (IL-1β and IL-6), genotypes, diabetes- and demographic-related factors were considered in our analyses. Our results indicate that low chronic inflammatory status associated with T2D modulates CYP450 activities in an isoform specific manner.
The role of betaine in the liver and kidney has been well documented, even from the cellular and molecular point of view. Despite literature reporting positive effects of betaine supplementation in Alzheimer’s, Parkinson’s, and Schizophrenia, the role and function of betaine in the brain are little studied and reviewed. Beneficial effects of betaine in neurodegeneration, excitatory and Inhibitory imbalance, and oxidative stress in the central nervous system have been collected and analyzed with the aim of understanding the main role of betaine in the brain. There are many “dark” aspects needed to complete the picture. The understanding of how this osmolyte is transported across neuron and glial cells is also controversial, as the expression levels and functioning of the known protein capable to transport betaine expressed in the brain, betaine-GABA transporter 1 BGT-1, is itself not well clarified. The reported actions of betaine beyond BGT-1 related to neuronal degeneration and memory impairment are the focus of this work. With this review, we underline the scarcity of detailed molecular and cellular information about betaine action. Consequently, the requirement of detailed focus on and study of the interaction of this molecule with CNS components to sustain the therapeutic use of betaine.