RESUMEN
OBJECTIVE: There is great variability in the treatment of chronic limb-threatening ischemia, including the practice paradigm, vascular provider specialty, devices utilized, and experience with advanced open and/or endovascular treatments, among other factors. Our unique practice consists of patient-centered, clinically oriented Interventional Radiologists and Vascular Surgeons, with treatments being performed in Office Interventional Suites (OIS), Ambulatory surgery center (ASC), and hospital inpatient/outpatient settings. We evaluate our results, centered on major amputation rates while comparing case complexity and rates with previously published data. METHODS: A retrospective review was performed of all Rutherford 4, 5, and 6 patients who underwent treatment in our practice from 2015 to 2021. Baseline patient characteristics, complexity of lesions, and major amputation rates were collected. Patients with more complex diseases or requiring re-interventions were openly discussed in multidisciplinary fashion to determine the group's approach to revascularization. Limb salvage, clinically driven target lesion revascularization (TLR), repeat interventions, length of follow-up, and mortality were assessed. RESULTS: Treatment was performed in 829 limbs in 351 females and 478 males, with chronic limb-threatening ischemia. Of the 829 cases, 541 cases had at least 1 chronic total occlusion (CTO), including 115 limbs with 2 CTOs and 24 limbs with 3 CTOs with 63.5% of cases requiring multilevel intervention. One year mortality rate was 6.2% with a major lower extremity amputation rate of 2.3% with a mean length of follow-up of 22.3 months. One-year freedom from clinically driven TLR rate was 78.7% with repeat intervention in 163 cases within 12 months. Over the course of the study, within the femoropopliteal stent subset, there was a significant increase in time to reintervention when newer stent technologies were utilized such as woven nitinol and drug-eluting technology (p=0.03). The overall 1-year amputation-free survival (AFS) was 91.5. CONCLUSIONS: Multidisciplinary approach with surgical and endovascular treatment may provide patients with the best chance of AFS. CLINICAL IMPACT: Real world practice of critical limb-threatening ischemia in a multidisciplinary practice demonstrates favorable outcomes for patients with the best reported one year major amputation free survival in a population this large. A strong clinical practice based on close routine follow up and arterial duplex monitoring is a major contributing factor, as well as utilization of the latest technology in drug eluting stents and drug coated balloons for best patient outcomes. We hope this study provides other practices with a guideline for establishing or modifying their practice to attain the best procedural and clinical outcomes.
RESUMEN
The dopamine D4 receptor (D4R) plays important roles in cognition, attention, and decision making. Novel D4R-selective ligands have promise in medication development for neuropsychiatric conditions, including Alzheimer's disease and substance use disorders. To identify new D4R-selective ligands, and to understand the molecular determinants of agonist efficacy at D4R, we report a series of eighteen novel ligands based on the classical D4R agonist A-412997 (1, 2-(4-(pyridin-2-yl)piperidin-1-yl)- N-( m-tolyl)acetamide). Compounds were profiled using radioligand binding displacement assays, ß-arrestin recruitment assays, cyclic AMP inhibition assays, and molecular dynamics computational modeling. We identified several novel D4R-selective ( Ki ≤ 4.3 nM and >100-fold vs other D2-like receptors) compounds with diverse partial agonist and antagonist profiles, falling into three structural groups. These compounds highlight receptor-ligand interactions that control efficacy at D2-like receptors and may provide insights into targeted drug discovery, leading to a better understanding of the role of D4Rs in neuropsychiatric disorders.