Exceptionally high-affinity Ras binders that remodel its effector domain.

The Ras proteins are aberrantly activated in a wide range of human cancers, often endowing tumors with aggressive properties and resistance to therapy. Decades of effort to develop direct Ras inhibitors for clinical use have thus far failed, largely because of a lack of adequate small-molecule-binding pockets on the Ras surface. Here, we report the discovery of Ras-binding miniproteins from a naïve library and their evolution to afford versions with midpicomolar affinity to Ras. A series of biochemical experiments indicated that these miniproteins bind to the Ras effector domain as dimers, and high-resolution crystal structures revealed that these miniprotein dimers bind Ras in an unprecedented mode in which the Ras effector domain is remodeled to expose an extended pocket that connects two isolated pockets previously found to engage small-molecule ligands. We also report a Ras point mutant that stabilizes the protein in the open conformation trapped by these miniproteins. These findings provide new tools for studying Ras structure and function and present opportunities for the development of both miniprotein and small-molecule inhibitors that directly target the Ras proteins.

Is Elective Soft Tissue Hand Surgery Associated with Periprosthetic Joint Infection after Total Joint Arthroplasty?

BACKGROUND: Although current guidelines do not recommend the routine use of surgical antibiotic prophylaxis to reduce the risk of surgical site infection following clean, soft tissue hand surgery, antibiotics are nevertheless often used in patients with an existing joint prosthesis to prevent periprosthetic joint infection (PJI), despite little data to support this practice. QUESTIONS/PURPOSES: (1) Is clean, soft tissue hand surgery after THA or TKA associated with PJI risk? (2) Does surgical antibiotic prophylaxis before hand surgery decrease PJI risk in patients with recent THA or TKA? METHODS: We assessed all patients who underwent THA or TKA between January 2007 and December 2015 by retrospective analysis of the IBM® MarketScan® Databases, which provide a longitudinal view of all healthcare services used by a nationwide sample of millions of patients under commercial and supplemental Medicare insurance coverage-particularly advantageous given the relatively low frequency of hand surgery after THA/TKA and of subsequent PJI. The initial search yielded 940,861 patients, from which 509,896 were excluded for not meeting continuous enrollment criteria, having a diagnosis of PJI before the observation period, or having another arthroplasty procedure before or during the observation period; the final study cohort consisted of 430,965 patients of which 147,398 underwent THA and 283,567 underwent TKA. In the treated cohort, 8489 patients underwent carpal tunnel release, trigger finger release, ganglion or retinacular cyst excision, de Quervain's release, or soft-tissue mass excision within 2 years of THA or TKA. The control cohort was comprised of 422,476 patients who underwent THA or TKA but did not have subsequent hand surgery. The primary outcome was diagnosis or surgical management of a PJI within 90 days of the index hand surgery for the treated cohort, or within a randomly assigned 90-day observation period for each patient in the control group. Propensity score matching was used to match treated and control cohorts by patient and treatment characteristics and previously-reported risk factors for PJI. Logistic regression before and after propensity score matching was used to assess the association of hand surgery with PJI risk and the association of surgical antibiotic prophylaxis before hand surgery with PJI risk in the treated cohort. Other possible PJI risk factors were also explored in multivariable logistic regression. Statistical significance was assessed at α = 0.01. RESULTS: Hand surgery was not associated with PJI risk after propensity score matching of treated and control cohorts (OR, 1.39; 99% CI, 0.60-3.22; p = 0.310). Among patients who underwent hand surgery after arthroplasty, surgical antibiotic prophylaxis before hand surgery was not associated with decreased PJI risk (OR 0.42; 99% CI, 0.03-6.08; p = 0.400). CONCLUSIONS: Clean, soft-tissue hand surgery was not found to be associated with PJI risk in patients who had undergone primary THA or TKA within 2 years before their hand procedure. While the effect of PJIs can be devastating, we do not find increased risk of infection with hand surgery nor data supporting routine use of surgical antibiotic prophylaxis in this setting. LEVEL OF EVIDENCE: Level III, therapeutic study.

Prophylactic Fixation Can Be Cost-effective in Preventing a Contralateral Bisphosphonate-associated Femur Fracture.

BACKGROUND: Bisphosphonates reduce the risk of fractures associated with osteoporosis but increase the risk of atypical subtrochanteric femur fractures. After unilateral atypical femur fracture, there is risk of contralateral fracture, but the indications for prophylactic fixation are controversial. QUESTIONS/PURPOSES: The purpose of this study is to use Markov modeling to determine whether contralateral prophylactic femur fracture fixation is cost-effective after a bisphosphonate-associated atypical femur fracture and, if so, what patient-related factors may influence that determination. METHODS: Markov modeling was used to determine the cost-effectiveness of contralateral prophylactic fixation after an initial atypical femur fracture. Simulated patients aged 60 to 90 years were included and separated into standard and high fracture risk cohorts. Patients with standard fracture risk were defined as those presenting with one atypical femur fracture but without symptoms or findings in the contralateral femur, whereas patients with high fracture risk were typified as those with more than one risk factor, including Asian ethnicity, prodromal pain, femoral geometry changes, or radiographic findings in the contralateral femur. Outcome probabilities and utilities were derived from studies matching to patient characteristics, and fragility fracture literature was used when atypical femur fracture data were not available. Associated costs were largely derived from Medicare 2015 reimbursement rates. Sensitivity analysis was performed on all model parameters within defined ranges. RESULTS: Prophylactic fixation for a 70-year-old patient with standard risk for fracture costs USD 131,300/quality-adjusted life-year (QALY) and for high-risk patients costs USD 22,400/QALY. Sensitivity analysis revealed that prophylaxis for high-risk patients is cost-effective at USD 100,000/QALY when the cost of prophylaxis was less than USD 29,400, the probability of prophylaxis complications was less than 21%, or if the patient was younger than 89 years old. The parameters to which the model was most sensitive were the cost of prophylaxis, patient age, and probability of prophylaxis-related complications. CONCLUSIONS: Prophylactic fixation of the contralateral side after unilateral atypical femur fracture is not cost-effective for standard-risk patients but is cost-effective among high-risk patients between 60 and 89 years of age with a high risk for an atypical femur fracture defined by patients with more than one risk factor such as Asian ethnicity, prodromal pain, varus proximal femur geometry, femoral bowing, or radiographic changes such as periosteal beaking and a transverse radiolucent line. However, our findings are based on several key assumptions for modeling such as the probability of fractures and complications, the costs associated for each health state, and the risks of surgical treatment. Future research should prospectively evaluate the degree of risk contributed by known radiographic and demographic parameters to guide management of the contralateral femur after a patient presents with an atypical femur fracture. LEVEL OF EVIDENCE: Level III, economic and decision analyses.

Diagnostic staging laparoscopy in gastric cancer treatment: A cost-effectiveness analysis.

BACKGROUND AND OBJECTIVES: Accurate preoperative staging helps avert morbidity, mortality, and cost associated with non-therapeutic laparotomy in gastric cancer (GC) patients. Diagnostic staging laparoscopy (DSL) can detect metastases with high sensitivity, but its cost-effectiveness has not been previously studied. We developed a decision analysis model to assess the cost-effectiveness of preoperative DSL in GC workup. METHODS: Analysis was based on a hypothetical cohort of GC patients in the U.S. for whom initial imaging shows no metastases. The cost-effectiveness of DSL was measured as cost per quality-adjusted life-year (QALY) gained. Drivers of cost-effectiveness were assessed in sensitivity analysis. RESULTS: Preoperative DSL required an investment of $107 012 per QALY. In sensitivity analysis, DSL became cost-effective at a threshold of $100 000/QALY when the probability of occult metastases exceeded 31.5% or when test sensitivity for metastases exceeded 86.3%. The likelihood of cost-effectiveness increased from 46% to 93% when both parameters were set at maximum reported values. CONCLUSIONS: The cost-effectiveness of DSL for GC patients is highly dependent on patient and test characteristics, and is more likely when DSL is used selectively where procedure yield is high, such as for locally advanced disease or in detecting peritoneal and superficial versus deep liver lesions.

Effectiveness of Preoperative Antibiotics in Preventing Surgical Site Infection After Common Soft Tissue Procedures of the Hand.

BACKGROUND: Antibiotic prophylaxis is a common but controversial practice for clean soft tissue procedures of the hand, such as carpal tunnel release or trigger finger release. Previous studies report no substantial reduction in the risk of surgical site infection (SSI) after antibiotic prophylaxis, yet are limited in power by low sample sizes and low overall rates of postoperative infection. QUESTIONS/PURPOSES: Is there evidence that antibiotic prophylaxis decreases the risk of SSI after soft tissue hand surgery when using propensity score matching to control for potential confounding variables such as demographics, procedure type, medication use, existing comorbidities, and postoperative events? METHODS: This retrospective analysis used the Truven Health MarketScan databases, large, multistate commercial insurance claims databases corresponding to inpatient and outpatient services and outpatient drug claims made between January 2007 and December 2014. The database includes records for patients enrolled in health insurance plans from self-insured employers and other private payers. Current Procedural Terminology codes were used to identify patients who underwent carpal tunnel release, trigger finger release, ganglion and retinacular cyst excision, de Quervain's release, or soft tissue mass excision, and to assign patients to one of two cohorts based on whether they had received preoperative antibiotic prophylaxis. We identified 943,741 patients, of whom 426,755 (45%) were excluded after meeting one or more exclusion criteria: 357,500 (38%) did not have 12 months of consecutive insurance enrollment before surgery or 1 month of enrollment after surgery; 60,693 (6%) had concomitant bony, implant, or incision and drainage or débridement procedures; and 94,141 (10%) did not have complete data. In all, our initial cohort consisted of 516,986 patients, among whom 58,201 (11%) received antibiotic prophylaxis. Propensity scores were calculated and used to create cohorts matched on potential risk factors for SSI, including age, procedure type, recent use of steroids and immunosuppressive agents, diabetes, HIV/AIDs, tobacco use, obesity, rheumatoid arthritis, alcohol abuse, malnutrition, history of prior SSI, and local procedure volume. Multivariable logistic regression before and after propensity score matching was used to test whether antibiotic prophylaxis was associated with a decrease in the risk of SSI within 30 days after surgery. RESULTS: After controlling for patient demographics, hand procedure type, medication use, existing comorbidities (eg, diabetes, HIV/AIDs, tobacco use, obesity), and postoperative events through propensity score matching, we found that the risk of postoperative SSI was no different between patients who had received antibiotic prophylaxis and those who had not (odds ratio, 1.03; 95% CI, 0.93-1.13; p = 0.585). CONCLUSIONS: Antibiotic prophylaxis for common soft tissue procedures of the hand is not associated with reduction in postoperative infection risk. While our analysis cannot account for factors that are not captured in the billing process, this study nevertheless provides strong evidence against unnecessary use of antibiotics before these procedures, especially given the difficulty of conducting a randomized prospective study with a sample size large enough to detect the effect of prophylaxis on the low baseline risk of infection. LEVEL OF EVIDENCE: Level III, therapeutic study.

The Impact of Subspecialty Fellows on Orthopaedic Resident Surgical Experience: A Multicenter Study of 51,111 Cases.

INTRODUCTION: Meaningful participation in surgery is important for orthopaedic resident education. This study aimed to quantify the effect of fellows on resident surgical experience. We hypothesized that as fellowship programs expanded, resident caseload would decrease, whereas "double-scrubbed" cases would increase. METHODS: This multicenter retrospective study included 9 years of surgical caselog data from two orthopaedic residency programs. Six subspecialty services on which fellow number varied over time were included (trauma, spine, foot and ankle, adult reconstruction, and hand). Case volume and personnel composition per case were extracted. Statistical analysis was performed with two-sample equal variance Student t-tests. RESULTS: A total of 51,111 cases were assessed. Surgical volume increased across all sites/services over time. Fellow numbers did not affect average resident caseload. However, in years with more fellows, an 11% decrease in one-on-one resident-attending cases (P = 0.002) and a 17% increase in resident-fellow-attending "double-scrubbed" cases was observed (P < 0.001). DISCUSSION: Increasing orthopaedic fellows did not affect resident case volume but resulted in fewer one-on-one cases with the attending and more "double-scrubbed" cases with a fellow. The implications of these findings to resident education require further study, but orthopaedic educators should be aware of these findings to try to maximize educational opportunities. LEVEL OF EVIDENCE: Level III.

Percutaneous Versus Open Treatment of Posterior Pelvic Ring Injuries: Changes in Practice Patterns Over Time.

OBJECTIVE: To determine how the utilization of open versus percutaneous treatment of posterior pelvic ring injuries in early-career orthopaedic surgeons has changed over time. METHODS: Case log data from surgeons testing in the trauma subspecialty for part II of the American Board of Orthopaedic Surgery examination from 2003 to 2015 were evaluated. Current procedural terminology codes for percutaneous fixation (27216) and open fixation (27218) of the posterior pelvic ring were evaluated using a regression analysis. RESULTS: A total of 377 candidates performed 2095 posterior ring stabilization procedures (1626 percutaneous, 469 open). Total case volume was stable over time [ß = -1.7 (1.1), P = 0.14]. There was no significant change in the number of posterior pelvic ring fracture surgery cases performed per candidate per test year [ß = 0.1 (0.1), P = 0.50]. The proportion of posterior pelvic ring cases performed percutaneously increased significantly from 49% in 2003 to 79% in 2015 [ß = 1.0 (0.4), P = 0.03]. There was a significant decrease in the number of open cases reported per candidate [ß = -0.07 (0.03), P = 0.008]. DISCUSSION AND CONCLUSION: Early-career orthopaedic surgeons are performing more percutaneous fixation of the posterior pelvic ring and less open surgery. The impact of this change in volume on surgeon proficiency is unknown and warrants additional research.

Are factor Xa inhibitors effective thromboprophylaxis following hip fracture surgery?: A large national database study.

INTRODUCTION: The purpose of this study was to evaluate the effectiveness of Factor Xa inhibitors (XaI) for thromboprophylaxis following hip fracture surgery in a large cohort of patients, and compare XaI against warfarin and enoxaparin. METHODS: Patients undergoing hip fracture surgery from 2007 to 2015 were identified in a large claims database. Patients prescribed warfarin, XaI, or enoxaparin within 2 weeks of surgery were identified and grouped into cohorts. Medical comorbidities and complication incidences, including deep venous thrombosis (DVT), pulmonary embolism (PE), and bleeding complications were calculated. Chi-square analysis was performed and adjusted residuals calculated to determine significant differences. RESULTS: DVT rates were significantly different between groups at thirty days only (5.03% warfarin, 2.91% XaI, 3.48% enoxaparin, p=0.047). PE rates were significantly different at all time points; enoxaparin had the lowest rates. There were no differences in the rates of other complications. DISCUSSION: XaI are an option for thromboprophylaxis in hip fracture patients, although their possible decreased effectiveness against PE compared to enoxaparin should be considered. CONCLUSIONS: This study compares the effectiveness of Factor Xa inhibitors to warfarin and enoxaparin for hip fracture patients, using a large national database. In this study, Factor Xa inhibitors had similar effectiveness for DVT prophylaxis compared to these agents.