The impact of frailty Screening of Older adults with muLtidisciplinary assessment of those At Risk during emergency hospital attendance on the quality, safety and cost-effectiveness of care (SOLAR): a randomised controlled trial.

BACKGROUND: Older people account for 25% of all Emergency Department (ED) admissions. This is expected to rise with an ageing demographic. Older people often present to the ED with complex medical needs in the setting of multiple comorbidities. Comprehensive Geriatric Assessment (CGA) has been shown to improve outcomes in an inpatient setting but clear evidence of benefit in the ED setting has not been established. It is not feasible to offer this resource-intensive assessment to all older adults in a timely fashion. Screening tools for frailty have been used to identify those at most risk for adverse outcomes following ED visit. The overall aim of this study is to examine the impact of CGA on the quality, safety and cost-effectiveness of care in an undifferentiated population of frail older people with medical complaints who present to the ED and Acute Medical Assessment Unit. METHODS: This will be a parallel 1:1 allocation randomised control trial. All patients who are ≥ 75 years will be screened for frailty using the Identification of Seniors At Risk (ISAR) tool. Those with a score of ≥ 2 on the ISAR will be randomised. The treatment arm will undergo geriatric medicine team-led CGA in the ED or Acute Medical Assessment Unit whereas the non-treatment arm will undergo usual patient care. A dedicated multidisciplinary team of a specialist geriatric medicine doctor, senior physiotherapist, specialist nurse, pharmacist, senior occupational therapist and senior medical social worker will carry out the assessment, as well as interventions that arise from that assessment. Primary outcomes will be the length of stay in the ED or Acute Medical Assessment Unit. Secondary outcomes will include ED re-attendance, re-hospitalisation, functional decline, quality of life and mortality at 30 days and 180 days. These will be determined by telephone consultation and electronic records by a research nurse blinded to group allocation. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Health Service Executive (HSE) Mid-Western Regional Hospital Research Ethics Committee (088/2020). Our lay dissemination strategy will be developed in collaboration with our Patient and Public Involvement stakeholder panel of older people at the Ageing Research Centre and we will present our findings in peer-reviewed journals and national and international conferences. TRIAL REGISTRATION: ClinicalTrials.gov NCT04629690 . Registered on November 16, 2020.

Targeting the RhoGEF ßPIX/COOL-1 in Glioblastoma: Proof of Concept Studies.

Glioblastoma (GBM), a highly invasive and vascular malignancy is shown to rapidly develop resistance and evolve to a more invasive phenotype following bevacizumab (Bev) therapy. Rho Guanine Nucleotide Exchange Factor proteins (RhoGEFs) are mediators of key components in Bev resistance pathways, GBM and Bev-induced invasion. To identify GEFs with enhanced mRNA expression in the leading edge of GBM tumours, a cohort of GEFs was assessed using a clinical dataset. The GEF ßPix/COOL-1 was identified, and the functional effect of gene depletion assessed using 3D-boyden chamber, proliferation, and colony formation assays in GBM cells. Anti-angiogenic effects were assessed in endothelial cells using tube formation and wound healing assays. In vivo effects of ßPix/COOL-1-siRNA delivered via RGD-Nanoparticle in combination with Bev was studied in an invasive model of GBM. We found that siRNA-mediated knockdown of ßPix/COOL-1 in vitro decreased cell invasion, proliferation and increased apoptosis in GBM cell lines. Moreover ßPix/COOL-1 mediated endothelial cell migration in vitro. Mice treated with ßPix/COOL-1 siRNA-loaded RGD-Nanoparticle and Bev demonstrated a trend towards improved median survival compared with Bev monotherapy. Our hypothesis generating study suggests that the RhoGEF ßPix/COOL-1 may represent a target of vulnerability in GBM, in particular to improve Bev efficacy.