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Steroid-Induced Ocular Hypertension in Mice Is Differentially Reduced by Selective EP2, EP3, EP4, and IP Prostanoid Receptor Agonists
(MDPI, 2024-03-28) Sharif, Najam A.; Millar, J. Cameron; Zode, Gulab S.; Ota, Takashi
We tested five chemically and metabolically stable prostaglandin (PG) receptor agonists in a mouse model of dexamethasone-induced ocular hypertension (OHT). Whilst all compounds significantly (p < 0.05, ANOVA) lowered intraocular pressure (IOP) after twice-daily bilateral topical ocular dosing (5 microg/dose) over three weeks, the time course and magnitude of the responses varied. The onset of action of NS-304 (IP-PG receptor agonist) and rivenprost (EP4-PG receptor agonist) was slower than that of misoprostol (mixed EP2/EP3/EP4-PG receptor agonist), PF-04217329 (EP2-PG receptor agonist), and butaprost (EP2-PG receptor agonist). The rank order of IOP-lowering efficacies aligned with the onset of actions of these compounds. Peak IOP reductions relative to vehicle controls were as follows: misoprostol (74.52%) = PF-04217329 (74.32%) > butaprost (65.2%) > rivenprost (58.4%) > NS-304 (55.3%). A literature survey indicated that few previously evaluated compounds (e.g., latanoprost, timolol, pilocarpine, brimonidine, dorzolamide, cromakalim analog (CKLP1), losartan, tissue plasminogen activator, trans-resveratrol, sodium 4-phenyl acetic acid, etc.) in various animal models of steroid-induced OHT were able to match the effectiveness of misoprostol, PF-04217329 or butaprost. Since a common feature of the latter compounds is their relatively high affinity and potency at the EP2-PG receptor sub-type, which activates the production of intracellular cAMP in target cells, our studies suggest that drugs selective for the EP2-PG receptor may be suited to treat corticosteroid-induced OHT.
Lentiviral mediated delivery of CRISPR/Cas9 reduces intraocular pressure in a mouse model of myocilin glaucoma
(Springer Nature Limited, 2024-03-24) Patil, Shruti V.; Kaipa, Balasankara R.; Ranshing, Sujata; Sundaresan, Yogapriya; Millar, J. Cameron; Nagarajan, Bhavani; Kiehlbauch, Charles; Zhang, Qihong; Jain, Ankur; Searby, Charles C.; Scheetz, Todd E.; Clark, Abbot F.; Sheffield, Val C.; Zode, Gulab S.
Mutations in myocilin (MYOC) are the leading known genetic cause of primary open-angle glaucoma, responsible for about 4% of all cases. Mutations in MYOC cause a gain-of-function phenotype in which mutant myocilin accumulates in the endoplasmic reticulum (ER) leading to ER stress and trabecular meshwork (TM) cell death. Therefore, knocking out myocilin at the genome level is an ideal strategy to permanently cure the disease. We have previously utilized CRISPR/Cas9 genome editing successfully to target MYOC using adenovirus 5 (Ad5). However, Ad5 is not a suitable vector for clinical use. Here, we sought to determine the efficacy of adeno-associated viruses (AAVs) and lentiviruses (LVs) to target the TM. First, we examined the TM tropism of single-stranded (ss) and self-complimentary (sc) AAV serotypes as well as LV expressing GFP via intravitreal (IVT) and intracameral (IC) injections. We observed that LV_GFP expression was more specific to the TM injected via the IVT route. IC injections of Trp-mutant scAAV2 showed a prominent expression of GFP in the TM. However, robust GFP expression was also observed in the ciliary body and retina. We next constructed lentiviral particles expressing Cas9 and guide RNA (gRNA) targeting MYOC (crMYOC) and transduction of TM cells stably expressing mutant myocilin with LV_crMYOC significantly reduced myocilin accumulation and its associated chronic ER stress. A single IVT injection of LV_crMYOC in Tg-MYOC(Y437H) mice decreased myocilin accumulation in TM and reduced elevated IOP significantly. Together, our data indicates, LV_crMYOC targets MYOC gene editing in TM and rescues a mouse model of myocilin-associated glaucoma.
Integrating Fall Prevention Strategies into EMS Services to Reduce Falls and Associated Healthcare Costs for Older Adults
(Dove Press Ltd., 2024-03-27) Camp, Kathlene; Murphy, Sara C.; Pate, Brandon
PURPOSE: The purpose of this study is to detail the implementation of fall prevention initiatives through emergency medical services (EMS) and associated outcomes. METHODS: Paramedics with MedStar Mobile Healthcare utilized the Stopping Elderly Accidents, Deaths, and Injuries (STEADI) fall prevention model to screen and direct intervention through 9-1-1 emergency response, High Utilization Group (HUG), and 30-day Hospital Readmission Avoidance (HRA) programs. Outcomes from 9-1-1 calls measured the number of older adults screened for falls and identified risk factors. The HUG and HRA programs measured change in quality of life with EuroQol-5D, referral service utilization, falls, emergent healthcare utilization, and hospital readmission data. Analysis included costs associated with reduced healthcare usage. RESULTS: Emergency paramedics provided fall risk screening for 50.5% (n=45,090) of adults aged 65 and older and 59.3% were at risk of falls, with 48.1% taking medications known to increase the risk of falls. Services provided through the HUG and HRA programs, along with additional needed referral services, resulted in a 37.2% reduction in fall-related 9-1-1 calls and a 29.5% increase in overall health status related to quality of life. Analysis of the HUG program revealed potential savings of over $1 million with a per-patient enrolled savings of $19,053. The HRA program demonstrated a 16.4% hospital readmission rate, in comparison to a regional average of 30.2%, and a cost-savings of $4.95 million or $15,618 per enrolled patient. CONCLUSION: Implementation of the STEADI model into EMS services provides an effective and cost-saving model for addressing fall prevention for older adults, provides meaningful and impactful improvement for older adults, and could serve as a model for other EMS programs. This study explored the feasibility and impact of implementing an evidence-based fall prevention model into emergency medical services for older adults. The outcomes resulted in an efficient and effective manner to screen older adults for falls during emergency response services and connect high-risk older adults with in-home follow-up care from community paramedics. In addition, fall prevention services were provided for vulnerable adults following a recent discharge from hospital care. These initiatives to address fall prevention resulted in a majority of older adults receiving preventive fall risk screening during emergency response calls, significant changes in quality of life measures for adults with multiple comorbidities and fall risk, and significant potential cost savings in reduced healthcare services.
LAV Report : Library News & Promotions
(University of North Texas Health Science Center, 2022-10-01) Gibson D. Lewis Health Science Library
LAV Report : Library News & Promotions
(University of North Texas Health Science Center, 2022-11-01) Gibson D. Lewis Health Science Library