Chemogenetics is a technique for obtaining selective pharmacological control over a cell population by expressing an engineered receptor that is selectively activated by an exogenously administered ligand. A promising approach for neuronal modulation involves the use of "Pharmacologically Selective Actuator Modules" (PSAMs); these chemogenetic receptors are selectively activated by ultrapotent "Pharmacologically Selective Effector Molecules" (uPSEMs). To extend the use of PSAM/PSEMs to studies in nonhuman primates, it is necessary to thoroughly characterize the efficacy and safety of these tools. We describe the time course and brain penetrance in rhesus monkeys of two compounds with promising binding specificity and efficacy profiles in in vitro studies, uPSEM792 and uPSEM817, after systemic administration. Rhesus monkeys received subcutaneous (s.c.) or intravenous (i.v.) administration of uPSEM817 (0.064 mg/kg) or uPSEM792 (0.87 mg/kg), and plasma and cerebrospinal fluid samples were collected over 48 h. Both compounds exhibited good brain penetrance, relatively slow washout, and negligible conversion to potential metabolites�varenicline or hydroxyvarenicline. In addition, we found that neither of these uPSEMs significantly altered the heart rate or sleep. Our results indicate that both compounds are suitable candidates for neuroscience studies using PSAMs in nonhuman primates.

The number of Medicare beneficiaries increases as the population of the United States grows and ages. 1 In 2010, the number of beneficiaries was estimated to be 42 million, climbing to 60 million in 2020. By 2030, it is projected that 80 million citizens will be covered by Medicare. 2 In the private insurance sector, reimbursement largely relies on the feefor-service model, which is derived from the national fee schedule established by Medicare. In procedural-based care, all procedures are reimbursed by means of their CPT code. Each CPT code is assigned a work relative value unit (wRVU). The wRVU value assigns a numeric value to a physician's "work product," which when factored in geographically, corresponds to a specific physician reimbursement. 3 Many studies have compared the relationship between inflation and physician reimbursement for procedures within other surgical specialties. [4][5][6][7][8] These studies demonstrate that Medicare reimbursement remained stagnant despite increases Background: Over the past decade across multiple surgical specialties, Medicare reimbursement rates have remained stagnant, failing to keep pace with inflation. An internal comparison of subspecialties within plastic surgery has not yet been attempted. The goal of this study was to investigate the trends in reimbursement from 2010 to 2020 and compare across the subspecialties of plastic surgery. Methods: The Physician/Supplier Procedure Summary was used to extract the annual case volume for the top 80% most-billed CPT codes within plastic surgery. Codes were defined into the following subspecialties: microsurgery, craniofacial surgery, breast surgery, hand surgery, and general plastic surgery. The Medicare physician reimbursement was weighted by case volume. The growth rate and compound annual growth rate were calculated and compared against an inflation-adjusted reimbursement value. Results: On average, inflation-adjusted growth in reimbursement for the procedures analyzed in this study was −13.5%. The largest decrease in growth rate was within the field of microsurgery (−19.2%), followed by craniofacial surgery (−17.6%). These subspecialties also had the lowest compound annual growth rate (−2.11% and −1.91%, respectively). For case volumes, microsurgery increased case volumes by an average of 3% per year, whereas craniofacial surgery increased case volumes by an average of 5% per year. Conclusions: After adjusting for inflation, all subspecialties had a decrease in growth rate. This was particularly evident in the fields of craniofacial surgery and microsurgery. Consequently, practice patterns and patient access may be negatively affected. Further advocacy and physician participation in reimbursement rate negotiation may be essential to adjust for variance and inflation.

Background: The relationship between procedural complexity and relative value units (RVUs) awarded has been studied within some specialties, but it has not yet been compared across different surgical disciplines. This study aims to analyze the association of RVUs with operative time as a surrogate for complexity across surgical specialties, with a focus on plastic surgery. Methods: A retrospective review of surgical cases was conducted with the 2019 National Surgical Quality Improvement Program database. The top 10 most performed procedures per surgical specialty were identified based on case volume. Only cases with a single CPT code were analyzed. A subanalysis of plastic surgery procedures was also conducted to include unilateral and bilateral procedures with a frequency greater than 20. Results: Overall, operative time correlated strongly with work RVUs (R = 0.86). Orthopedic surgery had one of the shortest average operative times with the greatest work RVUs per hour, in contrast to plastic surgery, with the greatest average operative time and one of the lowest work RVUs per hour. Of the plastic surgery procedures analyzed, only five were valued on par with the average calculated from all other specialties. The most poorly rewarded procedure for time spent is unilateral free flap breast reconstruction. Conclusions: Of all the surgical specialties, plastic surgery has the lowest RVUs per hour and the highest average operative time, leading to severe potential undervaluation compared with other specialties. This study suggests that further reevaluation of the current RVU system is needed to account for complexity more equitably as well as encourage value-based care.

Chemogenetics is a technique for obtaining selective pharmacological control over a cell population by expressing an engineered receptor that is selectively activated by an exogenously administered ligand. A promising approach for neuronal modulation involves the use of Pharmacologically Selective Actuator Modules (PSAMs); these chemogenetic receptors are selectively activated by ultrapotent Pharmacologically Selective Effector Molecules (uPSEMs). To extend the use of PSAM/PSEMs to studies in nonhuman primates it is necessary to thoroughly characterize the efficacy and safety of these tools. We describe the time course and brain penetrance in rhesus monkeys of two compounds with promising binding specificity and efficacy profiles in in vitro studies, uPSEM792 and uPSEM817, after systemic administration. Rhesus macaques received subcutaneous (s.c.) or intravenous (i.v.) administration of uPSEM817(0.064 mg/kg) or uPSEM792 (0.87 mg/kg) and plasma and CSF samples were collected over the course of 48 hours. Both compounds exhibited good brain penetrance, relatively slow washout and negligible conversion to potential metabolites - varenicline or hydroxyvarenicline. In addition, we found that neither of these uPSEMs significantly altered heart rate or sleep. Our results indicate that both compounds are suitable candidates for neuroscience studies using PSAMs in nonhuman primates.

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