Patient Perception of Orthopedic Surgeon Reimbursement.

Significant attention has been directed at evaluating reimbursement rates to orthopedic surgeons for various surgical procedures. To evaluate patients' understanding of the surgeon reimbursement process, studies using patient surveys have been conducted to determine patients' perceptions of orthopedic surgeon compensation. To date, there has been no systematic review to consolidate the data of these studies. This study aimed to synthesize the findings of these individual studies across multiple subspecialties of orthopedic surgery to evaluate the potential discrepancy between how much patients believe orthopedic surgeons are reimbursed and the actual reimbursement rate. We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify studies that report findings of patient perceptions of orthopedic surgeon reimbursement for various procedures. Searches were conducted using MEDLINE through PubMed, Embase, and Scopus. Summary estimates of reimbursement discrepancies across subspecialties and overall were reported as unweighted averages of the individual study results within each group. Twelve studies were identified that met inclusion criteria, constituting 4309 surveys. These survey studies measured patients' perceptions of how much orthopedic surgeons are reimbursed for common procedures, including anterior cruciate ligament reconstruction, arthroscopic meniscectomy, carpal tunnel release, rotator cuff repair, multiple spine procedures and total shoulder, hip, and knee arthroplasty. It was found that patients reported reasonable surgeon's fees to be 11.2 times more than actual Medicare reimbursement. Among individual studies, the largest discrepancies were seen in total hip arthroplasty (26 times), whereas the smallest difference was in anterior cruciate ligament reconstruction (1.6 times). On average, patients estimated Medicare reimbursement rates to be 5.9 times higher than the actual surgeon reimbursement. Patients consistently overestimate how much orthopedic surgeons are reimbursed for common orthopedic procedures. The results of this systematic review suggest that patients may value these procedures more than what Medicare reimburses. Such information may help educate the public, direct policy, and increase transparency between orthopedic surgeons and patients.

Carcinogenicity assessment of the Hedgehog pathway inhibitor, vismodegib in Tg.rasH2 mice and Sprague-Dawley rats.

Vismodegib (also known as GDC-0449) is a novel small molecule inhibitor of the Hedgehog (Hh) signaling pathway currently approved for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) in humans. Its tumorigenic potential was assessed in dedicated carcinogenicity studies in rasH2 transgenic (Tg.rasH2) mice and Sprague Dawley (SD) rats. Tumorigenicity potential of vismodegib was identified in rats only and was limited to benign hair follicle tumors, including pilomatricomas and keratoacanthomas at exposures of ≥0.1-fold and ≥0.6-fold, respectively, of the steady-state exposure (AUC0-24h) of the recommended human dose. No malignant tumors were identified in either species. Overall, the totality of pharmacology and nonclinical safety data (lack of genotoxicity, in vitro secondary pharmacological binding, and immunoregulatory effects, and limited effects on the endocrine system) suggests that the development of the benign hair follicle tumors may be related to pharmacologically-mediated disruption of hair follicle morphogenesis, although the exact mechanism of tumorigenesis is unclear. Hair follicle tumors have not been reported in vismodegib-treated patients. The relevance of this finding in rats to patients is uncertain.

Learning Weighted Lower Linear Envelope Potentials in Binary Markov Random Fields.

Markov random fields containing higher-order terms are becoming increasingly popular due to their ability to capture complicated relationships as soft constraints involving many output random variables. In computer vision an important class of constraints encode a preference for label consistency over large sets of pixels and can be modeled using higher-order terms known as lower linear envelope potentials. In this paper we develop an algorithm for learning the parameters of binary Markov random fields with weighted lower linear envelope potentials. We first show how to perform exact energy minimization on these models in time polynomial in the number of variables and number of linear envelope functions. Then, with tractable inference in hand, we show how the parameters of the lower linear envelope potentials can be estimated from labeled training data within a max-margin learning framework. We explore three variants of the lower linear envelope parameterization and demonstrate results on both synthetic and real-world problems.

Translational value of mouse models in oncology drug development.

Much has been written about the advantages and disadvantages of various oncology model systems, with the overall finding that these models lack the predictive power required to translate preclinical efficacy into clinical activity. Despite assertions that some preclinical model systems are superior to others, no single model can suffice to inform preclinical target validation and molecule selection. This perspective provides a balanced albeit critical view of these claims of superiority and outlines a framework for the proper use of existing preclinical models for drug testing and discovery. We also highlight gaps in oncology mouse models and discuss general and pervasive model-independent shortcomings in preclinical oncology work, and we propose ways to address these issues.

Preclinical assessment of novel BRAF inhibitors: integrating pharmacokinetic-pharmacodynamic modelling in the drug discovery process.

The objective of these studies were to determine the preclinical disposition of the two BRAF inhibitors, G-F and G-C, followed by pharmacokinetic (PK)-pharmacodynamic (PD) modelling to characterize the concentration-efficacy relationship of these compounds in the Colo205 mouse xenograft model. With G-F, the relationship of pERK inhibition to concentration was also characterized. Compounds G-F and G-C were administered to mice, rats and dogs and the pharmacokinetics of G-F and G-C was determined. In addition, using indirect response models the concentration-efficacy relationship was described. The clearance of G-F was low; 0.625 and 4.65 mL/min/kg in rat and dog respectively. Similarly, the clearance of G-C was low in rat and dog, 0.490 and 4.43 mL/min/kg, respectively. Both compounds displayed low volumes of distribution (0.140-0.267 L/kg), resulting in moderate half-lives across species (~2.5 to 4 h). Bioavailability was formulation dependent and decreased with increasing dose. Using the indirect response models, the KC(50) (50% K(max); maximal response) value for tumor growth inhibition for G-F and G-C were 84.5 and 19.2 µM, respectively. The IC(50) for pERK inhibition in Colo205 tumors by G-F was estimated to be 29.2 µM. High exposures of G-F and G-C were required for efficacy. Despite good PK properties of low CL and moderate half-life, limitations in obtaining exposures adequate for safety testing in rat and dog resulted in development challenges.