RESUMEN
BACKGROUND: Potentially inappropriate prescribing is common among older adults with multimorbidity due to various reasons, from concurrent application of multiple single-disease clinical guidelines to fragmentation of care. Interventions such as medication review have been implemented worldwide to reduce inappropriate prescribing for older adults. However, the implementability of such interventions are underexplored in the outpatient clinics in Singapore's public hospitals. Hence, the Pro-M study aims to assess the feasibility of implementing a physician-pharmacist collaborative care intervention in geriatric medicine outpatient clinics to facilitate appropriate prescribing for older adults in Singapore. METHODS: This is a single-arm, non-randomised feasibility study using a pre-post evaluation design. This study consists of two parts: (1) implementation phase of the intervention (6 months) and an (2) evaluation phase (3 months). Eligible patients will be recruited from geriatric medicine outpatient clinics at two public hospitals in Singapore through convenience sampling. The main components of the Pro-M intervention are: (1) pharmacist-facilitated medication reviews with feedback on any medication issues and potential recommendations to physicians, and (2) physicians communicating changes to other relevant prescribers. The evaluation phase will involve surveying and interviewing physicians and pharmacists involved in the implementation of the intervention. A mixed-method approach will be employed for data collection and analysis. The quantitative and qualitative findings will be triangulated and reported using Proctor's implementation outcomes: appropriateness, penetration, acceptability, fidelity, feasibility, and sustainability. A basic cost analysis will be conducted alongside the study. DISCUSSION: This is a phase 2 study to test the feasibility of implementing an intervention that was co-created with stakeholders during phase 1 development of an intervention to optimise prescribing for older adults with multimorbidity. The implementation will be assessed using Proctor's implementation outcomes to provide insights on the process and the feasibility of implementing medication reviews for older adults with multimorbidity as a routine practice in outpatient clinics. Data collected from this study will inform a subsequent scale-up study. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05756478. Registered on 06 March 2023.
RESUMEN
BACKGROUND: Neurological disorders have been linked to abnormal excitatory neurotransmission. Perturbations in glutamate cycling can have profound impacts on normal activity, lead to excitotoxicity and neuroinflammation, and induce and/or exacerbate impairments in these diseases. Astrocytes play a key role in excitatory signaling as they both clear glutamate from the synaptic cleft and house enzymes responsible for glutamate conversion to glutamine. However, mechanisms responsible for the regulation of glutamate cycling, including the main astrocytic glutamate transporter excitatory amino acid transporter 2 (EAAT2 or GLT-1 in rodents) and glutamine synthetase (GS) which catalyzes the ATP-dependent reaction of glutamate and ammonia into glutamine, remain largely undefined. METHODS: Gain and loss of function for ß-catenin in human progenitor-derived astrocyte (PDAs) was used to assess EAAT2 and GS levels by PCR, western blot, luciferase reporter assays, and chromatin immunoprecipitation (ChIP). Further, morpholinos were stereotaxically injected into C57BL/6 mice and western blots measured the protein levels of ß-catenin, GLT-1, and GS. RESULTS: ß-Catenin, a transcriptional co-activator and the central mediator of Wnt/ß-catenin signaling pathway, positively regulates EAAT2 and GS at the transcriptional level in PDAs by partnering with T cell factor 1 (TCF-1) and TCF-3, respectively. This pathway is conserved in vivo as the knockdown of ß-catenin in the prefrontal cortex results in reduced GLT-1 and GS expression. CONCLUSIONS: These studies confirm that ß-catenin regulates key proteins responsible for excitatory glutamate neurotransmission in vitro and in vivo and reveal the therapeutic potential of ß-catenin modulation in treating diseases with abnormal glutamatergic neurotransmission and excitotoxicity.
