Christina L Boulton

Interests

Research

Trauma, complex fracture care, nonunion/malunion correction.

Teaching

Trauma, complex fracture care, nonunion/malunion correction.

Courses

No activities entered.

Scholarly Contributions

Chapters

• Boulton, C., & O'Toole, R. V. (2014). Tibia and fibula shaft fractures. In Skeletal Trauma. Wolters Kluwer Health Adis (ESP).
• Ryan, S. P., Boulton, C. L., & O'toole, R. V. (2013). Open Diaphyseal Tibia Fractures. In Orthopedic Traumatology: An Evidence Based Approach. Springer, New York, NY. doi:10.1007/978-1-4614-3511-2_21
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  MI is a 24-year-old male who presents to the emergency department with a chief complaint of left leg pain after being thrown off of his ATV while riding in woods. He denies any other injuries or pain. On primary survey he demonstrates a GCS of 15, a patent airway, and is hemodynamically stable. On secondary survey he demonstrates a gross deformity to the left leg with a large open wound and exposed bone. His past medical history is consistent with depression. His only medication is Lexapro® (escitalopram, a selective serotonin reuptake inhibitor) and he has no allergies.

Journals/Publications

• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., et al. (2025). A Portfolio of Secondary Analyses from the PREP-IT Trial. Journal of Bone and Joint Surgery, 107. doi:10.2106/jbjs.24.01376
• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., et al. (2025). Alcohol-Based Versus Aqueous Skin Antisepsis Before Surgical Fixation of Open Fractures A Combined Analysis of 2 Cluster-Randomized Crossover Trials. Journal of Bone and Joint Surgery, 107. doi:10.2106/jbjs.24.01244
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  Background: Skin antisepsis remains a vital component in prophylaxis against surgical site infection (SSI); however, for open fractures, it is unclear whether alcohol-based or aqueous solutions should be preferred. The purpose of this study was to compare the use of alcohol-based and aqueous skin antisepsis solutions, using data from the 2 PREP-IT trials, with respect to the risks of SSI and unplanned reoperation following surgery for an open fracture. Methods: Individual patient data from the 2 cluster-randomized, crossover clinical trials were combined to create a single data set of patients undergoing surgery for an open fracture. A regression model was used to analyze the effects of an alcohol-based versus an aqueous solution, as well as for potential interaction with the use of chlorhexidine or iodine as the primary agent. The primary outcome was SSI within 90 days. Results: A total of 3,338 participants undergoing surgery for an open fracture were included in the final analysis, with 1,700 receiving an alcohol-based solution and 1,638 receiving an aqueous solution. Overall, the use of an alcohol-based skin antiseptic solution, compared with an aqueous solution, did not reduce the risk of SSI at 90 days (odds ratio [OR], 0.99; 95% confidence interval [CI], 0.66 to 1.48; p = 0.95), or the risk of unplanned reoperation at 1 year (OR, 0.98; 95% CI, 0.75 to 1.28; p = 0.88). Planned subgroup analyses also found no significant difference in the risk of SSI or unplanned reoperation when participants were stratified by Gustilo-Anderson type, fracture location, or the primary ingredient of the skin preparation solution (chlorhexidine versus iodophor). Conclusions: This analysis found no difference in the risk of SSI or reoperation when comparing alcohol-based and aqueous skin preparation solutions. Furthermore, this analysis demonstrated no harm with use of an alcohol-based solution for open fractures, and the PREPARE trial found that skin preparation with 0.7% iodine povacrylex in 74% isopropyl alcohol was associated with a reduced risk of SSI for closed fractures. Given these findings, surgeons may wish to consider streamlining their policy by treating all fractures with a single skin antiseptic, 0.7% iodine povacrylex in 74% isopropyl alcohol.
• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., et al. (2025). Chlorhexidine Gluconate Bathing Has Limited Ability to Prevent Surgical Site Infection Following Operative Fixation of Extremity and Pelvic Fractures. Journal of Bone and Joint Surgery, 107(Issue 1). doi:10.2106/jbjs.24.01224
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  Background:A preoperative chlorhexidine gluconate (CHG) bath is used to reduce the risk of surgical site infection (SSI) in elective surgery, but its efficacy in the trauma setting is unknown. We compared the incidence of SSI between patients who did versus did not receive a CHG bath before operative fixation of extremity and/or pelvic fractures.Methods:We conducted a secondary analysis of the PREP-IT cluster-randomized crossover trials that enrolled patients undergoing operative treatment for open or closed extremity or pelvic fractures. Preoperative CHG bathing (yes or no) was recorded for each patient per study protocol. The association between CHG bathing and SSI within 90 days after definitive fracture surgery was assessed. We performed multivariable regression to adjust for prognostic variables. We also conducted a separate instrumental variable analysis to compare SSI rates between study sites that used CHG bathing for >90% of participants and those that used CHG bathing for
• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., et al. (2025). Deep Infections after Open and Closed Fractures. Journal of Bone and Joint Surgery, 107(Issue 1). doi:10.2106/jbjs.24.01249
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  Background:The purpose of this study was to describe the culture and speciation results of patients with surgical site infection (SSI) from the PREPARE and Aqueous-PREP studies from the PREP-IT Investigators.Methods:Patients with suspected SSI underwent collection of deep or organ tissue samples for culture. The culture positivity rate was estimated as a percentage along with the exact binomial 95% confidence interval (CI). Microbial species were reported as percentages. Comparisons between open and closed fractures were conducted with the Z-test for proportions. Significance was set at p < 0.05.Results:Among the 2 primary studies, a total of 484 cases (defined as an anatomic fracture area; some patients had multiple fractures, which were each defined as a case if they developed an infection) had culture samples taken from deep or organ tissue. The culture positivity rate was 96.7% (95% CI, 94.7% to 98.0% [468 of 484 cases]). There were no significant differences (p = 0.507) in culture positivity between open fractures (97.2% [95% CI, 94.5% to 98.6%]; 273 of 281 cases) and closed fractures (96.1% [95% CI, 92.4% to 98.0%]; 195 of 203 cases). There was information on microbial species in 84.4% (395) of 468 cases. For patients with positive cultures, 43.3% (171 of 395 cases) were polymicrobial infections. Open fractures (47.8% [111 of 232 cases]), compared with closed fractures (36.8% [60 of 163 cases]), were more likely to be polymicrobial (p = 0.029). Staphylococcus aureus microbes (methicillin-sensitive S. aureus, methicillin-resistant S. aureus, and coagulase-negative S. aureus) accounted for 43.3% (462 of 1,066) of all positive cultures. The median time to infection was 58.5 days (95% CI, 49.0 to 67.0 days). The median time to infection was not significantly different in cases of open fractures (61.0 days [95% CI, 51.0 to 71.0 days]) compared with closed fractures (54.0 days [95% CI, 43.0 to 67.0 days]) (hazard ratio [HR], 0.92 [95% CI, 0.72 to 1.12]). SSIs associated with gram-negative bacteria had a shorter median time to infection at 46.0 days (95% CI, 36.0 to 58.0 days) compared with SSIs not associated with gram-negative bacteria at 70.0 days (95% CI, 56.0 to 88.0 days) (HR, 1.79 [95% CI, 1.55 to 2.03]). There was also a shorter median time to infection for patients with polymicrobial infections (47.0 days [95% CI, 38.8 to 52.1 days]) compared with patients with monomicrobial infections (78.6 days [95% CI, 57.2 to 86.8 days]) (HR, 1.26 [95% CI, 1.03 to 1.49]).Conclusions:In patients with SSI, tissue samples yielded high rates of microbial culture results. There was a higher proportion of gram-negative organisms in open fractures. Gram-negative infections were also associated with earlier time to infection. Clinicians should not hesitate to take deep-tissue culture samples in patients with suspected SSI and should be prepared to encounter polymicrobial infections.
• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., et al. (2025). Differences in Practice Patterns in the Use of Temporary External Fixation for the Management of Open Lower-Extremity Fractures. Journal of Bone and Joint Surgery, 107. doi:10.2106/jbjs.24.01250
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  Background: External fixation is often used in the management of open lower-extremity fractures. The objectives of this study were to identify hospital characteristics that are associated with greater use of temporary external fixation and to determine if external fixation reduces the odds of surgical site infection (SSI) and unplanned reoperation among patients with open lower-extremity fractures. Methods: This is a secondary analysis of the Aqueous-PREP and PREPARE-Open trials involving open lower-extremity fractures. Wilcoxon rank-sum and Fisher exact tests were used to assess if temporary external fixation use varied between hospital clusters. Mixed-effects logistic regression models controlling for hospital cluster and participant characteristics estimated the associations between temporary external fixation and SSI or unplanned reoperation. Results: There were 2,438 patients with an open lower-extremity fracture identified, with 568 (23.3%) undergoing temporary external fixation. There were 34 participating hospitals with a median external fixation rate of 21.5%. Hospitals with higher temporary external fixation use had a higher number of surgeons treating patients with fracture (p = 0.02). There was no difference in SSI at 90 days (odds ratio [OR], 1.16 [95% confidence interval (CI), 0.82 to 1.66]; p = 0.40) or 1 year (OR, 1.30 [95% CI, 0.97 to 1.75]; p = 0.08) between patients who did and did not undergo temporary external fixation. Patients who underwent temporary external fixation were more likely to have unplanned reoperations within 1 year (OR, 1.40 [95% CI, 0.96 to 1.79]; p = 0.05). Conclusions: More temporary external fixation for open lower-extremity fractures was performed at hospitals with more surgeons treating fractures. There was no difference in SSI at 90 days or 1 year between patients who did and did not undergo temporary external fixation. Temporary external fixation tended to be used in more critically ill patients and patients with more severe fractures but was not associated with increased unplanned reoperations at 90 days or at 1 year.
• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., et al. (2025). Higher Reoperation Rates in Planned, Staged Treatment of Open Fractures Compared with Fix-and-Close: A Propensity Score-Matched Analysis. Journal of Bone and Joint Surgery, 107. doi:10.2106/jbjs.24.01223
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  Background:Initial surgical management of Gustilo-Anderson type-I to IIIA open fractures varies from surgical fixation of the fracture with immediate closure of the traumatic wound to various combinations of staged fracture and wound management. The decision to choose staged management has historically been based on wound contamination and the severity of the open fracture. The purpose of this study was to compare the rates of surgical site infection (SSI), wound complication, nonunion, and 1-year reoperation between patients with type-I to IIIA open fractures who underwent fix-and-close treatment and those who underwent planned, staged treatment.Methods:This is a secondary analysis of participants who were enrolled in the Aqueous-PREP and PREPARE-Open studies, excluding those with type-IIIB and IIIC open fractures. Participants were divided into fix-and-close or planned, staged groups and were matched using propensity scores that were computed with multiple variables, including patient and injury characteristics. Associations between treatment type and outcomes were analyzed.Results:A total of 3,170 participants (staged, 872: 70% White, 20% Black, and 10% other or unknown race; fix-and-close, 2,298: 62% White, 21% Black, and 17% other) with Gustilo-Anderson type-I to IIIA open fractures were identified. Eight hundred and thirty-six participants who underwent planned, staged treatment were propensity score-matched to 836 participants who underwent fix-and-close treatment. Staged treatment was significantly associated with increased odds of deep SSI within 90 days (odds ratio [OR], 2.0 [95% confidence interval (CI), 1.15 to 3.47]; p = 0.01) and reoperation specifically for infection within 1 year (OR, 1.47 [95% CI, 1.06 to 2.04]; p = 0.02) but was not associated with increased odds of wound dehiscence (OR, 0.85 [95% CI, 0.49 to 1.49]; p = 0.57), wound necrosis or failure of the wound to heal (OR, 1.37 [95% CI, 0.83 to 2.25]; p = 0.21), reoperation requiring any free or local flap coverage (OR, 0.96 [95% CI, 0.55 to 1.68]; p = 0.89), or reoperation for delayed union or nonunion (OR, 1.30 [95% CI, 0.92 to 1.83]; p = 0.14).Conclusions:Fix-and-close treatment of open fractures of type IIIA and lower was associated with decreased odds of deep SSI within 90 days and reoperation for infection within 1 year without an increased risk of wound complications or nonunion and may be considered even in fractures with embedded contamination provided that adequate debridement is performed.
• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., et al. (2025). Impact of Living in a Food Desert on Complications After Fracture Surgery. Journal of Bone and Joint Surgery, 107. doi:10.2106/jbjs.24.01184
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  Background: Food deserts-communities with limited access to healthy food-have been linked with poor surgical outcomes; however, their impact on orthopaedic trauma outcomes remains unknown. The aims of this study were to determine the prevalence of food desert residency among orthopaedic trauma patients and to investigate the impact of food desert residency on the rate of unplanned reoperation with use of a large, high-quality, prospectively collected dataset with adjudicated outcomes. We hypothesized that orthopaedic trauma patients would reside in food deserts at a higher rate than the general U.S. population and that living in a food desert would be independently associated with an increased rate of unplanned reoperation. Methods: We included all patients from the Aqueous-PREP and PREPARE trials who had documented ZIP codes. The primary outcome was unplanned reoperation within 1 year, and the secondary outcomes included the reasons for reoperation. Residing in a food desert was the independent variable and was defined by the United States Department of Agriculture (USDA). Census tracts were converted to ZIP codes in order to assign food access for an individual s residence with use of the USDA Food Access Research Atlas. Results: Of the 2,607 patients included, 1,453 (55.7%) lived in a ZIP code containing a food desert compared with 49% of the U.S. population. Patients residing in a food desert were 42% female, 26.6% non-White, and 64% employed prior to injury, whereas patients not residing in a food desert were 41% female, 15% non-White, and 63% employed prior to injury, all of which was collected via patient self-report. Multivariable analysis demonstrated that living in a food desert was independently associated with 40% higher odds of unplanned reoperation (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.06 to 1.85; p = 0.019). This was driven by reoperation for delayed union or nonunion (OR, 1.75; 95% CI, 1.19 to 2.57; p = 0.004) and reoperation for a wound-healing complication (OR, 1.60; 95% CI, 1.01 to 2.54; p = 0.044). Conclusions: This study found a strong association between residing in a ZIP code containing a food desert and an increased rate of unplanned reoperation, which was primarily driven by delayed union or nonunion and wound-healing complications. Addressing nutritional deficiencies in this populationmay help to effectively triage the use of health-care resources. Further research should focus on clarifying specific deficiencies and assessing the effectiveness of targeted interventions.
• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., et al. (2025). Local Antibiotics and the Risk of Antimicrobial Resistance in Extremity Fractures Complicated by Fracture-Related Infection. Journal of Bone and Joint Surgery, 107. doi:10.2106/jbjs.24.01178
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  Background: We evaluated antimicrobial resistance (AMR) patterns following local antibiotic use in a large cohort of patients with fractures from the PREP-IT (A Program of Randomized Trials to Evaluate Preoperative Antiseptic Skin Solutions in Orthopaedic Trauma) study. We hypothesized that, among patients with extremity fractures who developed fracture-related infection (FRI), there would be no difference in AMR rates between those who had or had not received local antibiotic therapy with surgical fixation. Methods: This was a secondary analysis of all patients in the PREP-IT trial who developed FRI. Patient demographics, injury and fracture characteristics, and the primary outcome of the presence of an antimicrobial-resistant FRI were evaluated on the basis of whether the patient had or had not received local antibiotics in the operating room prior to, or at, definitive fixation. Results: A total of 555 FRIs in 546 patients (mean age, 50 years; 39% female; and 82% White) were included. A total of 268 fractures (264 patients) received local antibiotics. The Injury Severity Score and the proportion of open fractures were higher among patients and fractures that received local antibiotics, respectively. There were more Gustilo-Anderson type- IIIB or IIIC fractures in the local antibiotic group, but the rate did not differ significantly from that in the group with no local antibiotics (20% versus 14%; p = 0.14). Other baseline and fracture characteristics were similar between the groups, with the exception of age (lower in the group with local antibiotics). When examining FRIs with gram-positive organisms, we found that 3 (1.7%) of the FRIs in fractures that had been treated with local vancomycin had organisms resistant to vancomycin compared with 2 (0.9%) of the FRIs in fractures for which local vancomycin had not been used (p = 0.67). When examining FRIs with gram-negative organisms, the number of FRIs with aminoglycoside-resistant organisms was 8 (11.6%) among fractures that received local aminoglycosides and 10 (6.2%) among fractures that did not receive local aminoglycosides (p = 0.26). Conclusions: Among extremity fractures that developed FRI, we were unable to detect differences in the rates of AMR between fractures treated with or without local antibiotic prophylactic strategies in our analysis of a randomized trial of various skin preparation solutions for extremity trauma surgery. These findings provide cautious reassurance regarding the safety of local antibiotics but underscore the need for further prospective analysis.
• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., et al. (2025). Outcomes Associated with Choice of Prophylactic Antibiotics in Open Fractures. Journal of Bone and Joint Surgery, 107(Issue 1). doi:10.2106/jbjs.24.01123
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  Background:The ideal antibiotic prophylaxis for open fractures is unknown. We evaluated outcomes following different antibiotic prophylaxis regimens for open fractures.Methods:This is a secondary analysis of data from PREP-IT. Prophylactic antibiotics were defined as any intravenous antibiotic given on the day of admission. The outcomes were surgical site infection (SSI) within 90 days and reoperation within 1 year. Logistic regression and an instrumental variable analysis that leveraged site-level variation accounted for confounding. Subgroup variation was evaluated by stratifying by Gustilo-Anderson classification (Types I and II versus III).Results:Of the 3,331 included participants, the mean age was 45 ± 18 years, 63% were male, 73% were White, 21% were Black, 2% were Asian, and 10% were Hispanic. Cefazolin monotherapy (58% of patients), ceftriaxone monotherapy (10%), and cefazolin plus gentamicin (6%) were the most common regimens. In the instrumental variable analysis, the odds of infection did not significantly differ with ceftriaxone use (odds ratio [OR], 1.24; 95% confidence interval [CI], 0.70 to 2.20; p = 0.45) or cefazolin plus gentamicin use (OR, 0.25; 95% CI, 0.03 to 2.04; p = 0.20) compared with cefazolin monotherapy. There were no significant differences between the regimens with respect to infection when stratified by Gustilo-Anderson type. However, we did observe a nearly 3-fold increase in the odds of infection with ceftriaxone use compared with cefazolin monotherapy (OR, 2.73; 95% CI, 0.96 to 7.79; p = 0.06) in Type-I and II fractures, and a 75% decrease in the odds of infection with cefazolin plus gentamicin use (OR, 0.25; 95% CI, 0.03 to 2.02; p = 0.19) compared with cefazolin monotherapy in Type-III fractures.Conclusions:Among patients with open fractures, antibiotic prophylaxis with ceftriaxone monotherapy did not provide significant benefits compared with cefazolin monotherapy in preventing infection in Type-I and II fractures. The findings suggest that cefazolin plus gentamicin might reduce the odds of infection in Type-III fractures compared with cefazolin monotherapy, but this difference was not statistically significant.
• Stewart, C. C., Reider, L., Soifer, R., Namiri, N. K., O'toole, R. V., Karunakar, M. A., Potter, B. K., Bosse, M., Morshed, S., Hsu, J. R., Kempton, L. B., Robinson, K. S., Seymour, R. B., Sims, S. H., Churchill, C., Carroll, E. A., Pilson, H. T., Goodman, J. B., Holden, M. B., , McAndrew, C. M., et al. (2025). What is the Surgical Burden of Treatment for High-Energy Lower Extremity Trauma? A Secondary Analysis of the OUTLET Study. Journal of Orthopaedic Trauma, 39(Issue 5). doi:10.1097/bot.0000000000002959
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  OBJECTIVES: To describe and enumerate surgeries for patients who underwent reconstruction or amputation after severe distal tibial, ankle, and mid- to hindfoot injuries. METHODS: Design: Secondary analysis of a multicenter prospective observational study. Setting: Thirty-one US level I trauma centers and 3 military treatment facilities. Patient Selection Criteria: Participants aged 18 to 60 years with Gustilo type-III pilon fracture (Orthopaedic Trauma Association [OTA] 43B or 43C), IIIB or C ankle fracture (OTA 44A, 44B, or 44C), type-III talar or calcaneal fracture (OTA 81B, 82B, or 82C), or open or closed crush or blast injuries to the hindfoot or midfoot who underwent limb reconstruction or amputation from 2012 to 2017. Outcome Measurements and Comparisons: The number of temporizing, definitive, and complication surgeries was compared by treatment and injury. RESULTS: Five hundred seventy-four participants with 221 ankle and pilon injuries, 140 talus and calcaneal injuries, and 213 other foot injuries were followed for 18 months. The mean age was 38 (range 8-64) years, and 33% were female. Participants underwent reconstruction (n = 472), primary amputation (n = 76), and failed reconstruction followed by amputation (n = 26). Eight hundred forty-one temporizing, 958 definitive, and 501 complication surgeries were performed. The number of surgeries was highest for those who underwent failed reconstruction [mean 5.8, 95% confidence interval (CI), 4.9-6.8, range 3-13] compared with reconstruction (mean 3.8, 95% CI, 3.5-4.0, range 1-21) and primary amputation (mean 4.9, 95% CI, 4.3-5.5, range 2-14) (P < 0.01). Those with ankle and pilon injuries required more surgeries (4.7, 95% CI, 4.3-5.1, range 1-21) than those with hindfoot (3.4, 95% CI, 3.0-3.7, range 1-10) and other foot (3.7, 95% CI, 3.4-4.0, range 1-14) injuries (P < 0.01). The average participant would complete definitive treatment 23 days after their injury, and those who required surgery for a complication spent 41 days in the complication phase of treatment. CONCLUSIONS: Patients with high-energy lower extremity trauma underwent nearly 4 surgeries over 3 weeks until completion of definitive treatment, regardless of whether they underwent limb reconstruction or amputation. Those with ankle or pilon injuries and failed reconstruction attempts experienced the most operations, and those with complications required over an additional month of surgical care. These data may inform a shared decision-making process around limb optimization.
• Estes, W., Latt, L. D., Robishaw-Denton, J., Repp, M. L., Suri, Y., Chadaz, T., Boulton, C., & Riaz, T. (2024). Musculoskeletal manifestations of lower-extremity coccidioidomycosis: a case series. Journal of Bone and Joint Infection, 9(Issue 4). doi:10.5194/jbji-9-197-2024
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  Background: Coccidioidomycosis is a fungal infection endemic to the southwestern United States. Musculoskeletal manifestations are uncommon and seen in disseminated disease. While the involvement of the axial skeleton has been well described, the literature is limited on diseases involving the lower extremity. Methods: We identified three patients, at two regional academic medical centers in southern Arizona, who demonstrated different manifestations of osteoarticular coccidioidomycosis involving the lower extremity. Results: Case 1 is a 41-year-old male, with a history of HIV/AIDS and vertebral coccidioidomycosis, who presented with abscesses in the left hemipelvis and left proximal femoral osteomyelitis. He was treated with staged surgical debridement, including the use of amphotericin B impregnated beads. He remains on indefinite oral posaconazole suppression. Case 2 is a 46-year-old female, who presented with suspected right knee osteoarthritis. An MRI revealed septic arthritis and osteomyelitis. Necrotic bone was debrided, and synovial fluid cultures were positive for Coccidioides. She underwent a resection of the native knee joint with the insertion of an amphotericin B and voriconazole impregnated spacer. She continues oral itraconazole and awaits a total knee arthroplasty. Case 3 is a 76-year-old male, who presented with a draining right heel ulcer. Radiographs revealed bony destruction consistent with Charcot arthropathy. Irrigation and debridement revealed the gelatinous destruction of the talus and calcaneus, and cultures confirmed Coccidioides infection. A polymethyl methacrylate voriconazole spacer was placed. He subsequently underwent arthrodesis and remains on lifelong fluconazole. Conclusion: Lower-extremity osteoarticular coccidioidomycosis has various debilitating presentations that frequently mimic non-infectious etiologies. Treatment warrants surgical debridement, and prolonged antifungal therapy should be considered.
• Estes, W., Latt, L. D., Robishaw-Denton, J., Repp, M. L., Suri, Y., Chadaz, T., Boulton, C., & Riaz, T. (2024). Musculoskeletal manifestations of lower-extremity coccidioidomycosis: a case series. Journal of bone and joint infection, 9(4), 197-205.
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  : Coccidioidomycosis is a fungal infection endemic to the southwestern United States. Musculoskeletal manifestations are uncommon and seen in disseminated disease. While the involvement of the axial skeleton has been well described, the literature is limited on diseases involving the lower extremity. : We identified three patients, at two regional academic medical centers in southern Arizona, who demonstrated different manifestations of osteoarticular coccidioidomycosis involving the lower extremity. : Case 1 is a 41-year-old male, with a history of HIV/AIDS and vertebral coccidioidomycosis, who presented with abscesses in the left hemipelvis and left proximal femoral osteomyelitis. He was treated with staged surgical debridement, including the use of amphotericin B impregnated beads. He remains on indefinite oral posaconazole suppression. Case 2 is a 46-year-old female, who presented with suspected right knee osteoarthritis. An MRI revealed septic arthritis and osteomyelitis. Necrotic bone was debrided, and synovial fluid cultures were positive for . She underwent a resection of the native knee joint with the insertion of an amphotericin B and voriconazole impregnated spacer. She continues oral itraconazole and awaits a total knee arthroplasty. Case 3 is a 76-year-old male, who presented with a draining right heel ulcer. Radiographs revealed bony destruction consistent with Charcot arthropathy. Irrigation and debridement revealed the gelatinous destruction of the talus and calcaneus, and cultures confirmed infection. A polymethyl methacrylate voriconazole spacer was placed. He subsequently underwent arthrodesis and remains on lifelong fluconazole. : Lower-extremity osteoarticular coccidioidomycosis has various debilitating presentations that frequently mimic non-infectious etiologies. Treatment warrants surgical debridement, and prolonged antifungal therapy should be considered.
• Fram, B. R., Bosse, M. J., Odum, S. M., Reider, L., Gary, J. L., Gordon, W. T., Teague, D., Alkhoury, D., Mackenzie, E. J., Seymour, R. B., Karunakar, M. A., Fox, W. E., Hsu, J. R., Kempton, L., Robinson, K. S., Sims, S. H., Churchill, C., Teasdall, R. D., Carroll, E. A., , Scott, A. T., et al. (2024). Do Transtibial Amputations Outperform Amputations of the Hind- and Midfoot Following Severe Limb Trauma? A Secondary Analysis of the OUTLET Study. Journal of Bone and Joint Surgery, 106(Issue 9). doi:10.2106/jbjs.23.00878
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  Background:The purpose of this study was to compare 18-month clinical and patient-reported outcomes between patients with severe lower-limb injuries treated with a transtibial amputation or a hind- or midfoot amputation. Despite the theoretical benefits of hind- and midfoot-level amputation, we hypothesized that patients with transtibial amputations would report better function and have fewer complications.Methods:The study included patients 18 to 60 years of age who were treated with a transtibial amputation (n = 77) or a distal amputation (n = 17) and who were enrolled in the prospective, multicenter Outcomes Following Severe Distal Tibial, Ankle, and/or Foot Trauma (OUTLET) study. The primary outcome was the difference in Short Musculoskeletal Function Assessment (SMFA) scores, and secondary outcomes included pain, complications, amputation revision, and amputation healing.Results:There were no significant differences between patients with distal versus transtibial amputation in any of the domains of the SMFA: dysfunction index [distal versus transtibial], 31.2 versus 22.3 (p = 0.13); daily activities, 37.3 versus 26.0 (p = 0.17); emotional status, 41.4 versus 29.3 (p = 0.07); mobility, 36.5 versus 27.8 (p = 0.20); and bother index, 34.4 versus 23.6 (p = 0.14). Rates of complications requiring revision were higher for distal amputations but not significantly so (23.5% versus 13.3%; p = 0.28). One distal and no transtibial amputees required revision to a higher level (p = 0.18). A higher proportion of patients with distal compared with transtibial amputation required local surgical revision (17.7% versus 13.3%; p = 0.69). There was no significant difference between the distal and transtibial groups in scores on the Brief Pain Index at 18 months post-injury.Conclusions:Surgical complication rates did not differ significantly between patients who underwent transtibial versus hind- or midfoot amputation for severe lower-extremity injury. The average SMFA scores were higher (worse), although not significantly different, for patients undergoing distal compared with transtibial amputation, and more patients with distal amputation had a complication requiring surgical revision. Of note, more patients with distal amputation required closure with an atypical flap, which likely contributed to less favorable outcomes.Level of Evidence:Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
• O'Hara, N. N., Frey, K. P., Stein, D. M., Levy, J. F., Slobogean, G. P., Castillo, R., Firoozabadi, R., Karunakar, M. A., Gary, J. L., Obremskey, W. T., Seymour, R. B., Cuschieri, J., Mullins, C. D., O'Toole, R. V., Carlini, A. R., Fowler, B. E., Taylor, T. J., Wegener, S. T., Weston-Farber, E., , Herndon, S. C., et al. (2024). Effect of Aspirin Versus Low-Molecular-Weight Heparin Thromboprophylaxis on Medication Satisfaction and Out-of-Pocket Costs: A Secondary Analysis of a Randomized Clinical Trial. Journal of Bone and Joint Surgery, 106(Issue 7). doi:10.2106/jbjs.23.00824
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  Background:Current guidelines recommend low-molecular-weight heparin for thromboprophylaxis after orthopaedic trauma. However, recent evidence suggests that aspirin is similar in efficacy and safety. To understand patients' experiences with these medications, we compared patients' satisfaction and out-of-pocket costs after thromboprophylaxis with aspirin versus low-molecular-weight heparin.Methods:This study was a secondary analysis of the PREVENTion of CLots in Orthopaedic Trauma (PREVENT CLOT) trial, conducted at 21 trauma centers in the U.S. and Canada. We included adult patients with an operatively treated extremity fracture or a pelvic or acetabular fracture. Patients were randomly assigned to receive 30 mg of low-molecular-weight heparin (enoxaparin) twice daily or 81 mg of aspirin twice daily for thromboprophylaxis. The duration of the thromboprophylaxis, including post-discharge prescription, was based on hospital protocols. The study outcomes included patient satisfaction with and out-of-pocket costs for their thromboprophylactic medication measured on ordinal scales.Results:The trial enrolled 12,211 patients (mean age and standard deviation [SD], 45 ± 18 years; 62% male), 9725 of whom completed the question regarding their satisfaction with the medication and 6723 of whom reported their out-of-pocket costs. The odds of greater satisfaction were 2.6 times higher for patients assigned to aspirin than those assigned to low-molecular-weight heparin (odds ratio [OR]: 2.59; 95% confidence interval [CI]: 2.39 to 2.80; p < 0.001). Overall, the odds of incurring any out-of-pocket costs for thromboprophylaxis medication were 51% higher for patients assigned to aspirin compared with low-molecular-weight heparin (OR: 1.51; 95% CI: 1.37 to 1.66; p < 0.001). However, patients assigned to aspirin had substantially lower odds of out-of-pocket costs of at least $25 (OR: 0.15; 95% CI: 0.12 to 0.18; p < 0.001).Conclusions:Use of aspirin substantially improved patients' satisfaction with their medication after orthopaedic trauma. While aspirin use increased the odds of incurring any out-of-pocket costs, it protected against costs of ≥$25, potentially improving health equity for thromboprophylaxis.Level of Evidence:Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.
• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., et al. (2023). The impact of heterotopic ossification prophylaxis after surgical fixation of acetabular fractures: national treatment patterns and related outcomes. Injury, 54(Issue 6). doi:10.1016/j.injury.2023.03.001
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  Background: Heterotopic ossification (HO) is a common complication after surgical fixation of acetabular fractures. Numerous strategies have been employed to prevent HO formation, but results are mixed and optimal treatment strategy remains controversial. The purpose of the study was to describe current national heterotopic ossification (HO) prophylaxis patterns among academic trauma centers, determine the association between prophylaxis type and radiographic HO, and identify if heterogeneity in treatment effects exist based on outcome risk strata. Methods: We used data from a subset of participants enrolled in the Pragmatic Randomized Trial Evaluating Pre-Operative Alcohol Skin Solutions in Fractured Extremities (PREPARE) trial. We included only patients with closed AO-type 62 acetabular fractures that were surgically treated via a posterior (Kocher-Langenbeck), combined anterior and posterior, or extensile exposure. PREPARE Clinical Trial Registration Number: NCT03523962 Patient population This cohort study was nested within the Pragmatic Randomized Trial Evaluating Pre-Operative Alcohol Skin Solutions in Fractured Extremities (PREPARE) trial. The PREPARE trial is a multicenter cluster-randomized crossover trial evaluating the effectiveness of two alcohol-based pre-operative antiseptic skin solutions. All PREPARE trial clinical centers that enrolled at least one patient with a closed AO-type 62 acetabular fracture were invited to participate in the nested study. Results: 277 patients from 20 level 1 and level 2 trauma centers in the U.S. and Canada were included in this study. 32 patients (12%) received indomethacin prophylaxis, 100 patients (36%) received XRT prophylaxis, and 145 patients (52%) received no prophylaxis. Administration of XRT was associated with a 68% reduction in the adjusted odds of overall HO (OR 0.32, 95% CI, 0.14 – 0.69, p = 0.005). The overall severe HO (Brooker classes III or IV) rate was 8% for the entire cohort; XRT reduced the rate of severe HO in high-risk patients only (p=0.03). Conclusion: HO prophylaxis patterns after surgical fixation of acetabular fractures have changed dramatically over the last two decades. Most centers included in this study did not administer HO prophylaxis. XRT was associated with a marked reduction in the rate of overall HO and the rate of severe HO in high-risk patients. Randomized trials are needed to fully elucidate the potential benefit of XRT. PREPARE Clinical Trial Registration Number: NCT03523962.
• , M. E., O'Toole, R. V., Stein, D. M., O'Hara, N. N., Frey, K. P., Taylor, T. J., Scharfstein, D. O., Carlini, A. R., Sudini, K., Degani, Y., Slobogean, G. P., Haut, E. R., Obremskey, W., Firoozabadi, R., Bosse, M. J., Goldhaber, S. Z., Marvel, D., & Castillo, R. C. (2023). Aspirin or Low-Molecular-Weight Heparin for Thromboprophylaxis after a Fracture. The New England journal of medicine, 388(3), 203-213.
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  Clinical guidelines recommend low-molecular-weight heparin for thromboprophylaxis in patients with fractures, but trials of its effectiveness as compared with aspirin are lacking.
• Boulton, C. L. (2022). Aqueous skin antisepsis before surgical fixation of open fractures (Aqueous-PREP): a multiple-period, cluster-randomised, crossover trial. Lancet (London, England), 400(10360), 1334-1344.
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  Chlorhexidine skin antisepsis is frequently recommended for most surgical procedures; however, it is unclear if these recommendations should apply to surgery involving traumatic contaminated wounds where povidone-iodine has previously been preferred. We aimed to compare the effect of aqueous 10% povidone-iodine versus aqueous 4% chlorhexidine gluconate on the risk of surgical site infection in patients who required surgery for an open fracture.
• Gitajn, I. L., Werth, P., Fernandes, E., Sprague, S., O'Hara, N. N., Bzovsky, S., Marchand, L. S., Patterson, J. T., Lee, C., Slobogean, G. P., & , P. I. (2022). Association of Patient-Level and Hospital-Level Factors With Timely Fracture Care by Race. JAMA network open, 5(11), e2244357.
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  Racial disparities in treatment benchmarks have been documented among older patients with hip fractures. However, these studies were limited to patient-level evaluations.
• Leroux, A., Frey, K. P., Crainiceanu, C. M., Obremskey, W. T., Stinner, D. J., Bosse, M. J., Karunakar, M. A., O-Toole, R. V., Carroll, E. A., Hak, D. J., Hayda, R., Alkhoury, D., Schmidt, A. H., Hsu, J. R., Seymour, R. B., Sims, S. H., Churchill, C., Stahel, P. F., Trujillo, C. H., , Westberg, J. R., et al. (2022). Defining Incidence of Acute Compartment Syndrome in the Research Setting: A Proposed Method from the PACS Study. Journal of Orthopaedic Trauma, 36(Issue). doi:10.1097/bot.0000000000002284
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  Objective: To compare the retrospective decision of an expert panel who assessed likelihood of acute compartment syndrome (ACS) in a patient with a high-risk tibia fracture with decision to perform fasciotomy. Design: Prospective observational study. Setting: Seven Level 1 trauma centers. Patients/Participants: One hundred eighty-two adults with severe tibia fractures. Main Outcome Measurements: Diagnostic performance (sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and receiver-operator curve) of an expert panel's assessment of likelihood ACS compared with fasciotomy as the reference diagnostic standard. Secondary Outcomes: The interrater reliability of the expert panel as measured by the Krippendorff alpha. Expert panel consensus was determined using the percent of panelists in the majority group of low (expert panel likelihood of ≤0.3), uncertain (0.3-0.7), or high (>0.7) likelihood of ACS. Results: Comparing fasciotomy (the diagnostic standard) and the expert panel's assessment as the diagnostic classification (test), the expert panel's determination of uncertain or high likelihood of ACS (threshold >0.3) had a sensitivity of 0.90 (0.70, 0.99), specificity of 0.95 (0.90, 0.98), PPV of 0.70 (0.50, 0.86), and NPV of 0.99 (0.95, 1.00). When a threshold of >0.7 was set as a positive diagnosis, the expert panel assessment had a sensitivity of 0.67 (0.43, 0.85), specificity of 0.98 (0.95, 1.00), PPV of 0.82 (0.57, 0.96), and NPV of 0.96 (0.91, 0.98). Conclusion: In our study, the retrospective assessment of an expert panel of the likelihood of ACS has good specificity and excellent NPV for fasciotomy, but only low-to-moderate sensitivity and PPV. The discordance between the expert panel-assessed likelihood of ACS and the decision to perform fasciotomy suggests that concern regarding potential diagnostic bias in studies of ACS is warranted.
• O'Hara, N. N., Heels-Ansdell, D., Bzovsky, S., Dodds, S., Thabane, L., Bhandari, M., Guyatt, G., Devereaux, P. J., Slobogean, G. P., Sprague, S., & , P. I. (2022). A pragmatic randomized trial evaluating pre-operative aqueous antiseptic skin solutions in open fractures (Aqueous-PREP): statistical analysis plan. Trials, 23(1), 772.
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  Approximately 1 in 10 patients with a surgically treated open fracture will develop a surgical site infection. The Aqueous-PREP trial will investigate the effect of 10% povidone-iodine versus 4% chlorhexidine in aqueous antiseptic solutions in reducing infections after open fracture surgery. The study protocol was published in April 2020.
• Slobogean, G. P., Sciadini, M. F., Pollak, A. N., O'toole, R. V., O'hara, N. N., Nascone, J. W., Manson, T. T., Lebrun, C. T., & Boulton, C. L. (2022). Open reduction and internal fixation alone versus open reduction and internal fixation plus total hip arthroplasty for displaced acetabular fractures in patients older than 60 years: A prospective clinical trial.. Injury, 53(2), 523-528. doi:10.1016/j.injury.2021.09.048
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  The optimal treatment of elderly patients with an acetabular fracture is unknown. We conducted a prospective clinical trial to compare functional outcomes and reoperation rates in patients older than 60 years with acetabular fracture treated with open reduction and internal fixation (ORIF) alone versus ORIF plus concomitant total hip arthroplasty (ORIF + THA). Our hypothesis was that patients who had ORIF + THA would have better patient reported outcomes and lower reoperation rates postoperatively..Inclusion criteria were patients older than 60 years with acetabular fracture plus at least one of three fracture characteristics: dome impaction, femoral head fracture, or posterior wall component. Eligible patients were operative candidates based on fracture displacement, ambulatory status, and physiological appropriateness. Patients received either ORIF alone or ORIF + THA (accomplished at same surgery through same incision). Outcome measurements included Western Ontario and McMaster Universities Osteoarthritis Index hip score, Short Form 36, Harris Hip Score, and Patient Satisfaction Questionnaire Short Form scores. Additionally, patients were monitored for any unplanned reoperation within 2 years..Forty-seven of 165 eligible patients with an average age of 70.7 years were included. The mean Harris Hip Score difference favored ORIF + THA (mean difference, 12.3, [95% confidence interval (CI), -0.3 to 24.9, p = 0.07]). No clinically important differences were detected in any other validated outcome score or patient satisfaction score 1 year after surgery. ORIF + THA decreased the absolute risk of reoperation by 28% (95% CI, 13% to 44%, p < 0.01). No postoperative hip dislocation occurred in either group..In patients older than 60 years with an operative displaced acetabular fracture with specific fracture features (dome impaction, femoral head fracture, or posterior wall component), treatment with ORIF + THA resulted in fewer reoperations than treatment with ORIF alone. No differences in patient satisfaction and other validated outcome measures were detected.
• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., et al. (2021). Pragmatic randomized trial evaluating pre-operative aqueous antiseptic skin solution in open fractures (Aqueous-PREP): the feasibility of a cluster randomized crossover study. Pilot and Feasibility Studies, 7(Issue 1). doi:10.1186/s40814-021-00800-8
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  Background: Preoperative antiseptic skin solutions are used prior to most surgical procedures; however, there is no definitive research comparing infection-related outcomes following use of the various solutions available to orthopedic trauma surgeons. The objective of this pilot study was to test the feasibility of a cluster randomized crossover trial that assesses the comparative effectiveness of a 10% povidone-iodine solution versus a 4% chlorhexidine gluconate solution for the management of open fractures. Methods: Two orthopedic trauma centers participated in this pilot study. Each of these clinical sites was randomized to a starting solution (povidone-iodine solution or chlorhexidine gluconate) then subsequently crossed over to the other treatment after 2 months. During the 4-month enrollment phase, we assessed compliance, enrollment rates, participant follow-up, and accurate documentation of the primary clinical outcome. Feasibility outcomes included (1) the implementation of the interventions during a run-in period; (2) enrollment of participants during two 2-month enrollment phases; (3) application of the trial interventions as per the cluster randomization crossover scheme; (4) participant follow-up; and (5) accurate documentation of the primary outcome (surgical site infection). Feasibility outcomes were summarized using descriptive statistics reported as means (standard deviation) or medians (first quartile, third quartile) for continuous variables depending on their distribution and counts (percentage) for categorical variables. Corresponding 95% confidence intervals (CIs) were also reported. Results: All five of the criteria for feasibility were met. During the run-in phase, all 18 of the eligible patients identified at the two clinical sites received the correct cluster-assigned treatment. A total of 135 patients were enrolled across both sites during the 4-month recruitment phase, which equates to 92% (95% CI 85.9 to 96.4%) of eligible patients being enrolled. Compliance with the assigned treatment in the pilot study was 98% (95% CI 93.5 to 99.8%). Ninety-eight percent (95% CI 93.5 to 99.8%) of participants completed the 90-day post-surgery follow-up and the primary outcome (SSI) was accurately documented for 100% (95% CI 96.6 to 100.0%) of the participants. Conclusions: These results confirm the feasibility of a definitive study comparing antiseptic solutions using a cluster randomized crossover trial design. Building upon the infrastructure established during the pilot phase, a definitive study has been successfully initiated. Trial registration: ClincialTrials.gov, number NCT03385304. Registered December 28, 2017.
• , M. E., O'Toole, R. V., Joshi, M., Carlini, A. R., Murray, C. K., Allen, L. E., Huang, Y., Scharfstein, D. O., O'Hara, N. N., Gary, J. L., Bosse, M. J., Castillo, R. C., Bishop, J. A., Weaver, M. J., Firoozabadi, R., Hsu, J. R., Karunakar, M. A., Seymour, R. B., Sims, S. H., , Churchill, C., et al. (2021). Effect of Intrawound Vancomycin Powder in Operatively Treated High-risk Tibia Fractures: A Randomized Clinical Trial. JAMA surgery, 156(5), e207259.
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  Despite the widespread use of systemic antibiotics to prevent infections in surgically treated patients with fracture, high rates of surgical site infection persist.
• Bosse, M. J., Carroll, E. A., Firoozabadi, R., Gary, J. L., Gordon, W. T., Jones, C. B., Morshed, S., Teague, D., Scharfstein, D. O., Luly, J., Mackenzie, E. J., Reider, L., Andrews Mcarthur, E., Hsu, J. R., Karunakar, M. A., Sample Robinson, K., Seymour, R. B., Sims, S. H., Churchill, C., , Fox, W. E., et al. (2021). Outcomes Following Severe Distal Tibial, Ankle, and/or Mid/Hindfoot Trauma: Comparison of Limb Salvage and Transtibial Amputation (OUTLET). Journal of Bone and Joint Surgery, 103(Issue 17). doi:10.2106/jbjs.20.01320
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  Background: Selecting the best treatment for patients with severe terminal lower-limb injury remains a challenge. For some injuries, amputation may result in better outcomes than limb salvage. This study compared the outcomes of patients who underwent limb salvage with those that would have been achieved had they undergone amputation. Methods: This multicenter prospective observational study included patients 18 to 60 years of age in whom a Type-III pilon or IIIB or C ankle fracture, a Type-III talar or calcaneal fracture, or an open or closed blast/crush foot injury had been treated with limb salvage (n = 488) or amputation (n = 151) and followed for 18 months. The primary outcome was the Short Musculoskeletal Function Assessment (SMFA). Causal effect estimates of the improvement that amputation would have provided if it had been performed instead of limb salvage were calculated for the SMFA score, physical performance, pain, participation in vigorous activities, and return to work. Results: The patients who underwent limb salvage would have had small differences in most outcomes had they undergone amputation. The most notable difference was an improvement in the SMFA mobility score of 7 points (95% confidence interval [CI] = 2.0 to 10.7). Improvements were largest for pilon/ankle fractures and complex injury patterns. Conclusions: Amputation should be considered a treatment option rather than a last resort for the most complex terminal lower-limb injuries.
• Boulton, C. L. (2021). Outcomes Following Severe Distal Tibial, Ankle, and/or Mid/Hindfoot Trauma: Comparison of Limb Salvage and Transtibial Amputation (OUTLET). The Journal of bone and joint surgery. American volume, 103(17), 1588-1597.
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  Selecting the best treatment for patients with severe terminal lower-limb injury remains a challenge. For some injuries, amputation may result in better outcomes than limb salvage. This study compared the outcomes of patients who underwent limb salvage with those that would have been achieved had they undergone amputation.
• Gitajn, I. L., Werth, P. M., Sprague, S., O'Hara, N., Della Rocca, G., Zura, R., Marmor, M., Domes, C. M., Hill, L. C., Churchill, C., Townsend, C., Van, C., Hogan, N., Girardi, C., Slobogean, G. P., & , P. I. (2021). Association of COVID-19 With Achieving Time-to-Surgery Benchmarks in Patients With Musculoskeletal Trauma. JAMA health forum, 2(10), e213460.
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  In response to the COVID-19 pandemic, many hospital systems were forced to reduce operating room capacity and reallocate resources. The outcomes of these policies on the care of injured patients and the maintenance of emergency services have not been adequately reported.
• Manson, T. T., Slobogean, G. P., Nascone, J. W., Sciadini, M. F., LeBrun, C. T., Boulton, C. L., O'Hara, N. N., Pollak, A. N., & O'Toole, R. V. (2021). Open reduction and internal fixation alone versus open reduction and internal fixation plus total hip arthroplasty for displaced acetabular fractures in patients older than 60 years: A prospective clinical trial. Injury.
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  The optimal treatment of elderly patients with an acetabular fracture is unknown. We conducted a prospective clinical trial to compare functional outcomes and reoperation rates in patients older than 60 years with acetabular fracture treated with open reduction and internal fixation (ORIF) alone versus ORIF plus concomitant total hip arthroplasty (ORIF + THA). Our hypothesis was that patients who had ORIF + THA would have better patient reported outcomes and lower reoperation rates postoperatively.
• Medeiros, M., Love, T. R., Slobogean, G. P., Sprague, S., Perfetto, E. M., O'Hara, N. N., Mullins, C. D., & , P. I. (2021). Patient and stakeholder engagement learnings: PREP-IT as a case study. Journal of comparative effectiveness research, 10(6), 439-442.
• O'Toole, R. V., Joshi, M., Carlini, A. R., Murray, C. K., Allen, L. E., Huang, Y., Scharfstein, D. O., O'Hara, N. N., Gary, J. L., Bosse, M. J., Castillo, R. C., Bishop, J. A., Weaver, M. J., Firoozabadi, R., Hsu, J. R., Karunakar, M. A., Seymour, R. B., Sims, S. H., Churchill, C., , Brennan, M. L., et al. (2021). Effect of Intrawound Vancomycin Powder in Operatively Treated High-risk Tibia Fractures: A Randomized Clinical Trial. JAMA Surgery, 156(Issue 5). doi:10.1001/jamasurg.2020.7259
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  Importance: Despite the widespread use of systemic antibiotics to prevent infections in surgically treated patients with fracture, high rates of surgical site infection persist. Objective: To examine the effect of intrawound vancomycin powder in reducing deep surgical site infections. Design, Setting, and Participants: This open-label randomized clinical trial enrolled adult patients with an operatively treated tibial plateau or pilon fracture who met the criteria for a high risk of infection from January 1, 2015, through June 30, 2017, with 12 months of follow-up (final follow-up assessments completed in April 2018) at 36 US trauma centers. Interventions: A standard infection prevention protocol with (n = 481) or without (n = 499) 1000 mg of intrawound vancomycin powder. Main Outcomes and Measures: The primary outcome was a deep surgical site infection within 182 days of definitive fracture fixation. A post hoc comparison assessed the treatment effect on gram-positive and gram-negative-only infections. Other secondary outcomes included superficial surgical site infection, nonunion, and wound dehiscence. Results: The analysis included 980 patients (mean [SD] age, 45.7 [13.7] years; 617 [63.0%] male) with 91% of the expected person-time of follow-up for the primary outcome. Within 182 days, deep surgical site infection was observed in 29 of 481 patients in the treatment group and 46 of 499 patients in the control group. The time-to-event estimated probability of deep infection by 182 days was 6.4% in the treatment group and 9.8% in the control group (risk difference, -3.4%; 95% CI, -6.9% to 0.1%; P =.06). A post hoc analysis of the effect of treatment on gram-positive (risk difference, -3.7%; 95% CI, -6.7% to -0.8%; P =.02) and gram-negative-only (risk difference, 0.3%; 95% CI, -1.6% to 2.1%; P =.78) infections found that the effect of vancomycin powder was a result of its reduction in gram-positive infections. Conclusions and Relevance: Among patients with operatively treated tibial articular fractures at a high risk of infection, intrawound vancomycin powder at the time of definitive fracture fixation reduced the risk of a gram-positive deep surgical site infection, consistent with the activity of vancomycin. Trial Registration: ClinicalTrials.gov Identifier: NCT02227446.
• O'Toole, R. V., Stein, D. M., Frey, K. P., O'Hara, N. N., Scharfstein, D. O., Slobogean, G. P., Taylor, T. J., Haac, B. E., Carlini, A. R., Manson, T. T., Sudini, K., Mullins, C. D., Wegener, S. T., Firoozabadi, R., Haut, E. R., Bosse, M. J., Seymour, R. B., Holden, M. B., Gitajn, I. L., , Goldhaber, S. Z., et al. (2021). PREVENTion of CLots in Orthopaedic Trauma (PREVENT CLOT): a randomised pragmatic trial protocol comparing aspirin versus low-molecular-weight heparin for blood clot prevention in orthopaedic trauma patients. BMJ open, 11(3), e041845.
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  Patients who sustain orthopaedic trauma are at an increased risk of venous thromboembolism (VTE), including fatal pulmonary embolism (PE). Current guidelines recommend low-molecular-weight heparin (LMWH) for VTE prophylaxis in orthopaedic trauma patients. However, emerging literature in total joint arthroplasty patients suggests the potential clinical benefits of VTE prophylaxis with aspirin. The primary aim of this trial is to compare aspirin with LMWH as a thromboprophylaxis in fracture patients.
• Pechero, G., Pfaff, B., Rao, M., Pogorzelski, D., McKay, P., Spicer, E., Howe, A., Demyanovich, H. K., Sietsema, D. L., McTague, M. F., Ramsey, L., Holden, M., Rudnicki, J., Wells, J., Medeiros, M., Slobogean, G. P., Sprague, S., , P. I., Slobogean, G. P., , Sprague, S., et al. (2021). Implementing stakeholder engagement to explore alternative models of consent: An example from the PREP-IT trials. Contemporary clinical trials communications, 22, 100787.
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  Cluster randomized crossover trials are often faced with a dilemma when selecting an optimal model of consent, as the traditional model of obtaining informed consent from participant's before initiating any trial related activities may not be suitable. We describe our experience of engaging patient advisors to identify an optimal model of consent for the PREP-IT trials. This paper also examines surrogate measures of success for the selected model of consent.
• Pogorzelski, D., Nguyen, U., McKay, P., Thabane, L., Camara, M., Ramsey, L., Seymour, R., Goodman, J. B., McGee, S., Fraifogl, J., Hudgins, A., Tanner, S. L., Bhandari, M., Slobogean, G. P., Sprague, S., , P. I., , S. C., , A. C., , D. a., , , R. M., et al. (2021). Managing work flow in high enrolling trials: The development and implementation of a sampling strategy in the PREPARE trial. Contemporary clinical trials communications, 21, 100730.
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  Pragmatic trials in comparative effectiveness research assess the effects of different treatment, therapeutic, or healthcare options in clinical practice. They are characterized by broad eligibility criteria and large sample sizes, which can lead to an unmanageable number of participants, increasing the risk of bias and affecting the integrity of the trial. We describe the development of a sampling strategy tool and its use in the PREPARE trial to circumvent the challenge of unmanageable work flow.
• Slobogean, G. P., Sprague, S., Bzovsky, S., Scott, T., Thabane, L., Heels-Ansdell, D., O'Toole, R. V., Howe, A., Gaski, G. E., Hill, L. C., Brown, K. M., Viskontas, D., Zomar, M., Della Rocca, G. J., O'Hara, N. N., Bhandari, M., Malekzadeh, A. S., Nauth, A., Perdue, A., , Mamun, A., et al. (2021). Fixation using Alternative Implants for the Treatment of Hip Fractures (FAITH-2): The Exploratory Health-Related Quality of Life and Patient-Reported Functional Outcomes of a Multi-Centre 2 × 2 Factorial Randomized Controlled Pilot Trial in Young Femoral Neck Fracture Patients. Injury, 52(Issue 10). doi:10.1016/j.injury.2021.02.030
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  Purpose: Femoral neck fractures in young patients are typically managed with internal fixation using either cancellous screws or a sliding hip screw (SHS). Although fixation preserves the hip joint, patients are still at risk of complications and poor clinical outcomes which lead to diminished function and health related quality of life (HRQL). The Fixation using Alternative Implants for the Treatment of Hip Fractures (FAITH-2) pilot randomized controlled factorial trial evaluated the effect of surgical fixation (cancellous screws vs. SHS) and vitamin D supplementation vs. placebo on patient-reported function and HRQL. Methods: Patients between the ages of 18-60 years with a femoral neck fracture requiring surgical fixation were eligible. Eligible patients were randomized to receive either a sliding hip screw or cancellous screws for fracture fixation AND vitamin D3 4,000 IU or placebo daily for 6 months. Patient-reported function (Hip Outcome Score) and HRQL (Short Form-12) were assessed at standardized time points in the 12 months following their fixation surgery. Patient-reported function and HRQL were summarized using means, SD, and 95% confidence intervals (CIs), or percentages and counts. Longitudinal data analysis with mixed models was used to explore the effect of treatment group and time on the patient-reported function and HRQL. Results: 86 of the 91 patients randomized into the FAITH-2 pilot study were deemed eligible. There were no significant differences in patient-reported function or HRQL between the treatment groups at 12 months post-fracture. At the 6- and 9-month assessments, a potential benefit in hip function was seen in the cancellous screw group. In all treatment groups, participants reported lower function and HRQL at 12 months post-fracture as compared to their pre-injury assessment. Conclusions: Few differences were found in function and HRQL among the treatment groups in the FAITH-2 pilot study. Despite modern implants and vitamin D supplementation, neither function nor HRQL returns to baseline in this population. Additional efforts to improve the outcomes of these challenging injuries are still needed. Level of Evidence: Therapeutic Level II
• Slobogean, G. P., Sprague, S., Bzovsky, S., Scott, T., Thabane, L., Heels-Ansdell, D., O'Toole, R. V., Howe, A., Gaski, G. E., Hill, L. C., Brown, K. M., Viskontas, D., Zomar, M., Della Rocca, G. J., O'Hara, N. N., Bhandari, M., & , F. I. (2021). Fixation using Alternative Implants for the Treatment of Hip Fractures (FAITH-2): The Exploratory Health-Related Quality of Life and Patient-Reported Functional Outcomes of a Multi-Centre 2 × 2 Factorial Randomized Controlled Pilot Trial in Young Femoral Neck Fracture Patients. Injury, 52(10), 3051-3059.
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  Femoral neck fractures in young patients are typically managed with internal fixation using either cancellous screws or a sliding hip screw (SHS). Although fixation preserves the hip joint, patients are still at risk of complications and poor clinical outcomes which lead to diminished function and health related quality of life (HRQL). The Fixation using Alternative Implants for the Treatment of Hip Fractures (FAITH-2) pilot randomized controlled factorial trial evaluated the effect of surgical fixation (cancellous screws vs. SHS) and vitamin D supplementation vs. placebo on patient-reported function and HRQL.
• Sprague, S., Guyatt, P., Bzovsky, S., Nguyen, U., Bhandari, M., Thabane, L., Petrisor, B., Johal, H. S., Leonard, J., Dodds, S., Mossuto, F., O'Toole, R. V., Howe, A., Demyanovich, H. K., Camara, M., O'Hara, N. N., Slobogean, G. P., & , P. I. (2021). Pragmatic randomized trial evaluating pre-operative aqueous antiseptic skin solution in open fractures (Aqueous-PREP): the feasibility of a cluster randomized crossover study. Pilot and feasibility studies, 7(1), 61.
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  Preoperative antiseptic skin solutions are used prior to most surgical procedures; however, there is no definitive research comparing infection-related outcomes following use of the various solutions available to orthopedic trauma surgeons. The objective of this pilot study was to test the feasibility of a cluster randomized crossover trial that assesses the comparative effectiveness of a 10% povidone-iodine solution versus a 4% chlorhexidine gluconate solution for the management of open fractures.
• , P. o., Slobogean, G. P., Sprague, S., Wells, J., Bhandari, M., Rojas, A., Garibaldi, A., Wood, A., Howe, A., Harris, A. D., Petrisor, B. A., Mullins, D. C., Pogorzelski, D., Marvel, D., Heels-Ansdell, D., Mossuto, F., Grissom, F., Del Fabbro, G., Guyatt, G. H., , Della Rocca, G. J., et al. (2020). Effectiveness of Iodophor vs Chlorhexidine Solutions for Surgical Site Infections and Unplanned Reoperations for Patients Who Underwent Fracture Repair: The PREP-IT Master Protocol. JAMA network open, 3(4), e202215.
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  The risk of developing a surgical site infection after extremity fracture repair is nearly 5 times greater than in most elective orthopedic surgical procedures. For all surgical procedures, it is standard practice to prepare the operative site with an antiseptic solution; however, there is limited evidence to guide the choice of solution used for orthopedic fracture repair.
• Gitajn, I. L., Reider, L., Scharfstein, D. O., OʼToole, R. V., Bosse, M. J., Castillo, R. C., Jevsevar, D. S., Pollak, A. N., & , M. (2020). Variability in Discharge Disposition Across US Trauma Centers After Treatment for High-Energy Lower Extremity Injuries. Journal of orthopaedic trauma, 34(3), e78-e85.
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  To evaluate the association between patient- and center-level characteristics and discharge to an inpatient facility versus home after treatment for lower extremity trauma, as well as examine the variability in discharge disposition across clinical centers after controlling for these factors.
• Hale, D., Marvel, D., Wells, J., & , P. I. (2020). What's Important: Patient Engagement in Research. The Journal of bone and joint surgery. American volume, 102(20), 1836-1838.
• Schmidt, A. H., Di, J., Zipunnikov, V., Frey, K. P., Scharfstein, D. O., O'Toole, R. V., Bosse, M. J., Obremskey, W. T., Stinner, D. J., Hayda, R., Karunakar, M. A., Hak, D. J., Carroll, E. A., Collins, S. C., MacKenzie, E. J., & , M. (2020). Perfusion Pressure Lacks Diagnostic Specificity for the Diagnosis of Acute Compartment Syndrome. Journal of orthopaedic trauma, 34(6), 287-293.
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  To evaluate the diagnostic performance of perfusion pressure (PP) thresholds for fasciotomy.
• Sprague, S., Scott, T., Dodds, S., Pogorzelski, D., McKay, P., Harris, A. D., Wood, A., Thabane, L., Bhandari, M., Mehta, S., Gaski, G., Boulton, C., Marcano-Fernández, F., Guerra-Farfán, E., Hebden, J., O'Hara, L. M., & Slobogean, G. P. (2020). Cluster identification, selection, and description in cluster randomized crossover trials: The PREP-IT trials. Trials, 21(Issue 1). doi:10.1186/s13063-020-04611-9
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  Background: In cluster randomized crossover (CRXO) trials, groups of participants (i.e., clusters) are randomly allocated to receive a sequence of interventions over time (i.e., cluster periods). CRXO trials are becoming more comment when they are feasible, as they require fewer clusters than parallel group cluster randomized trials. However, CRXO trials have not been frequently used in orthopedic fracture trials and represent a novel methodological application within the field. To disseminate the early knowledge gained from our experience initiating two cluster randomized crossover trials, we describe our process for the identification and selection of the orthopedic practices (i.e., clusters) participating in the PREP-IT program and present data to describe their key characteristics. Methods: The PREP-IT program comprises two ongoing pragmatic cluster randomized crossover trials (Aqueous-PREP and PREPARE) which compare the effect of iodophor versus chlorhexidine solutions on surgical site infection and unplanned fracture-related reoperations in patients undergoing operative fracture management. We describe the process we used to identify and select orthopedic practices (clusters) for the PREP-IT trials, along with their characteristics. Results: We identified 58 potential orthopedic practices for inclusion in the PREP-IT trials. After screening each practice for eligibility, we selected 30 practices for participation and randomized each to a sequence of interventions (15 for Aqueous-PREP and 20 for PREPARE). The majority of orthopedic practices included in the Aqueous-PREP and PREPARE trials were situated in level I trauma centers (100% and 87%, respectively). Orthopedic practices in the Aqueous-PREP trial operatively treated a median of 149 open fracture patients per year, included a median of 11 orthopedic surgeons, and had access to a median of 5 infection preventionists. Orthopedic practices in the PREPARE trial treated a median of 142 open fracture and 1090 closed fracture patients per year, included a median of 7.5 orthopedic surgeons, and had access to a median of 6 infection preventionists. Conclusions: The PREP-IT trials provide an example of how to follow the reporting standards for cluster randomized crossover trials by providing a clear definition of the cluster unit, a thorough description of the cluster identification and selection process, and sufficient description of key cluster characteristics. Trial registration: Both trials are registered at ClinicalTrials.gov (A-PREP: NCT03385304 December 28, 2017, and PREPARE: NCT03523962 May 14, 2018).
• Sprague, S., Scott, T., Dodds, S., Pogorzelski, D., McKay, P., Harris, A. D., Wood, A., Thabane, L., Bhandari, M., Mehta, S., Gaski, G., Boulton, C., Marcano-Fernández, F., Guerra-Farfán, E., Hebden, J., O'Hara, L. M., Slobogean, G. P., & , P. I. (2020). Cluster identification, selection, and description in cluster randomized crossover trials: the PREP-IT trials. Trials, 21(1), 712.
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  In cluster randomized crossover (CRXO) trials, groups of participants (i.e., clusters) are randomly allocated to receive a sequence of interventions over time (i.e., cluster periods). CRXO trials are becoming more comment when they are feasible, as they require fewer clusters than parallel group cluster randomized trials. However, CRXO trials have not been frequently used in orthopedic fracture trials and represent a novel methodological application within the field. To disseminate the early knowledge gained from our experience initiating two cluster randomized crossover trials, we describe our process for the identification and selection of the orthopedic practices (i.e., clusters) participating in the PREP-IT program and present data to describe their key characteristics.
• Sprague, S., Scott, T., Dodds, S., Pogorzelski, D., McKay, P., Harris, A. D., Wood, A., Thabane, L., Bhandari, M., Mehta, S., Gaski, G., Boulton, C., Marcano-Fernández, F., Guerra-Farfán, E., Hebden, J., O'Hara, L. M., Slobogean, G. P., & , P. I. (2020). Correction to: Cluster identification, selection, and description in Cluster randomized crossover trials: the PREP-IT trials. Trials, 21(1), 821.
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  An amendment to this paper has been published and can be accessed via the original article.
• , F. I., Slobogean, G. P., Sprague, S., Bzovsky, S., Heels-Ansdell, D., Thabane, L., Scott, T., & Bhandari, M. (2019). Fixation using alternative implants for the treatment of hip fractures (FAITH-2): design and rationale for a pilot multi-centre 2 × 2 factorial randomized controlled trial in young femoral neck fracture patients. Pilot and feasibility studies, 5, 70.
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  Femoral neck fractures in patients ≤ 60 years of age are often very different injuries compared to low-energy, hip fractures in elderly patients and are difficult to manage because of inherent problems associated with high-energy trauma mechanisms and increased functional demands for recovery. Internal fixation, with multiple cancellous screws or a sliding hip screw (SHS), is the most common treatment for this injury in young patients. However, there is no clinical consensus regarding which surgical technique is optimal. Additionally, there is compelling rationale to use vitamin D supplementation to nutritionally optimize bone healing in young patients. This pilot trial will determine feasibility and provide preliminary clinical data for a larger definitive trial.
• Sanal, H. T., Boulton, C., Neyisci, C., Erdem, Y., & Lowe, J. (2019). Imaging of Pelvic and Femoral Fixation Hardware: Normal Findings and Hardware Failure. Seminars in musculoskeletal radiology, 23(2), e1-e19.
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  Good outcomes following treatment of pelvic ring injuries, acetabular fractures, and femur fractures rely on restoration of native pelvic or limb alignment, anatomical reduction and rigid stability of articular fractures, and early postoperative mobilization. Multiple surgical approaches, reduction aids, and orthopaedic implants are available to stabilize these fractures. Despite best practices, complications including hardware failure, nonunions, malunions, and infections occur. This article discusses common fracture classification systems, implants, and imaging findings associated with unwanted complications in fractures of the pelvis, acetabulum, and femur.
• Shah, J., Titus, A. J., O'Toole, R. V., Sciadini, M. F., Boulton, C., Castillo, R., Breazeale, S., Schoonover, C., Berger, P., & Gitajn, I. L. (2019). Are geriatric patients who sustain high-energy traumatic injury likely to return to functional independence?. Journal of orthopaedic trauma.
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  To evaluate physical function and return to independence of geriatric trauma patients, to compare physical function outcomes of geriatric patients who sustained high-energy trauma with that of those who sustained low-energy trauma, and to identify predictors of physical function outcomes.
• Matuszewski, P. E., Boulton, C. L., & O'Toole, R. V. (2016). Orthopaedic trauma patients and smoking: Knowledge deficits and interest in quitting. Injury, 47(Issue 6). doi:10.1016/j.injury.2016.03.018
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  Background Smoking is associated with increased complications in fracture care. Smoking cessation has a positive impact on outcomes. It is unknown whether orthopaedic trauma patients understand the ill effects of smoking on fracture care and whether knowledge can improve cessation interest. We hypothesized that (1) smokers less fully understand the negative effects of smoking than do nonsmokers, (2) an increased proportion of orthopaedic trauma patients are further in the process of change to quit smoking, (3) increased knowledge predicts increased readiness to quit, and (4) minimal education through a survey can improve interest in smoking cessation. Methods Single-centre cross-sectional cohort survey study. Patients were approached consecutively for participation. Patients 18 years or older with a new fracture in our clinic for follow-up were eligible. Smokers and nonsmokers were included and surveyed regarding demographics. Smokers were asked questions about fractures and general knowledge questions regarding the effects of smoking on health. Smokers' interest in smoking cessation was assessed with direct questions, and transtheoretical model stage of change was queried before and after survey administration. Results One hundred twelve patients participated (44 smokers, 68 nonsmokers; 75 male patients, 37 female patients). Forty-eight percent of smokers stated that the fracture made them more likely to quit. Smokers answered more questions incorrectly than did nonsmokers (p = 0.003). An increased percentage of smokers were in favourable stages of change compared with a population-based tobacco survey (68% versus 54%, p = 0.008). Survey administration increased interest in quitting in 48%, and 11% modified their stage of change towards quitting. Smokers scoring higher on knowledge questions had more than 2-fold increased odds of being in a favourable stage of change (p = 0.013; odds ratio, 2.13; 95% confidence interval, 1.744-3.855). Conclusions Compared with nonsmokers, smokers less fully understand the negative effects of smoking on fracture care and general health. A large proportion of orthopaedic trauma patients who smoke are interested in smoking cessation and are possibly further along the pathway to change than expected. Brief education through a survey can increase interest in quitting. Formal education intervention may improve cessation rates and fracture outcomes.
• Matuszewski, P. E., Boulton, C. L., & O'Toole, R. V. (2016). Orthopaedic trauma patients and smoking: Knowledge deficits and interest in quitting. Injury, 47(6), 1206-11.
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  Smoking is associated with increased complications in fracture care. Smoking cessation has a positive impact on outcomes. It is unknown whether orthopaedic trauma patients understand the ill effects of smoking on fracture care and whether knowledge can improve cessation interest. We hypothesized that (1) smokers less fully understand the negative effects of smoking than do nonsmokers, (2) an increased proportion of orthopaedic trauma patients are further in the process of change to quit smoking, (3) increased knowledge predicts increased readiness to quit, and (4) minimal education through a survey can improve interest in smoking cessation.
• Mir, H. R., Boulton, C. L., Russell, G. V., & Archdeacon, M. (2016). Lower Extremity Fracture Reduction: Tips, Tricks, and Techniques So That You Leave the Operating Room Satisfied. Instructional course lectures, 65(Issue).
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  It can be challenging for surgeons to obtain proper alignment and to create stable constructs for the maintenance of many lower extremity fractures until union is achieved. Whether lower extremity fractures are treated with plates and screws or intramedullary nails, there are numerous pearls that may help surgeons deal with these difficult injuries. Various intraoperative techniques can be used for lower extremity fracture reduction and stabilization. The use of several reduction tools, tips, and tricks may facilitate the care of lower extremity fractures and, subsequently, improve patient outcomes.
• Mir, H. R., Boulton, C. L., Russell, G. V., & Archdeacon, M. (2016). Lower Extremity Fracture Reduction: Tips, Tricks, and Techniques So That You Leave the Operating Room Satisfied. Instructional course lectures, 65, 25-39.
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  It can be challenging for surgeons to obtain proper alignment and to create stable constructs for the maintenance of many lower extremity fractures until union is achieved. Whether lower extremity fractures are treated with plates and screws or intramedullary nails, there are numerous pearls that may help surgeons deal with these difficult injuries. Various intraoperative techniques can be used for lower extremity fracture reduction and stabilization. The use of several reduction tools, tips, and tricks may facilitate the care of lower extremity fractures and, subsequently, improve patient outcomes.
• Boulton, C. L., & Pollak, A. N. (2015). Special topic: Ipsilateral femoral neck and shaft fractures - Does evidence give us the answer?. Injury, 46(Issue 3). doi:10.1016/j.injury.2014.11.021
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  Ipsilateral fractures of the femoral neck and shaft are rare, high-energy injuries that typically occur in young polytrauma patients. The associated fracture of the neck is often vertical in nature and is more frequently non-displaced than in isolated femoral neck fractures. Historically the diagnosis of an associated femoral neck fracture was delayed or missed in approximately one third of cases. Studies have shown that detection can be significantly improved with the implementation of a protocolized approach to hip imaging in all patients with femoral shaft fractures. Prompt recognition of an associated femoral neck fracture allows for timely stabilization and may decrease the risks of non-union and avascular necrosis. In contrast, failure to recognize a non-displaced or minimally displaced associated neck fracture prior to fixation of the shaft can lead to displacement, a decrease in neck fixation options, a technically challenging secondary procedure and increased risk of long-term sequelae. A vast array of treatment strategies have been described for this combined injury. Published options range from spica casting to open reduction and internal fixation of both fractures and include almost all conceivable combinations in between. While timely surgical stabilization is now universally recommended for both shaft and neck, no consensus exists as to the most appropriate method of fixation for either fracture. Most authors recommend prompt, but not emergent, surgery with priority given to anatomic reduction and stabilization of the neck fracture by either closed or open methods. Fixation of the shaft fracture follows as patient condition allows. The rare nature of this injury makes it very challenging to study and most published series' are retrospective with very small sample sizes. In short, no scientificallycompelling study is available to definitively support any one implant choice or method of stabilzation over another for the treatment of associated fractures of the femoral neck and shaft.
• Boulton, C. L., & Pollak, A. N. (2015). Special topic: Ipsilateral femoral neck and shaft fractures--does evidence give us the answer?. Injury, 46(3), 478-83.
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  Ipsilateral fractures of the femoral neck and shaft are rare, high-energy injuries that typically occur in young polytrauma patients. The associated fracture of the neck is often vertical in nature and is more frequently non-displaced than in isolated femoral neck fractures. Historically the diagnosis of an associated femoral neck fracture was delayed or missed in approximately one third of cases. Studies have shown that detection can be significantly improved with the implementation of a protocolized approach to hip imaging in all patients with femoral shaft fractures. Prompt recognition of an associated femoral neck fracture allows for timely stabilization and may decrease the risks of non-union and avascular necrosis. In contrast, failure to recognize a non-displaced or minimally displaced associated neck fracture prior to fixation of the shaft can lead to displacement, a decrease in neck fixation options, a technically challenging secondary procedure and increased risk of long-term sequelae. A vast array of treatment strategies have been described for this combined injury. Published options range from spica casting to open reduction and internal fixation of both fractures and include almost all conceivable combinations in between. While timely surgical stabilization is now universally recommended for both shaft and neck, no consensus exists as to the most appropriate method of fixation for either fracture. Most authors recommend prompt, but not emergent, surgery with priority given to anatomic reduction and stabilization of the neck fracture by either closed or open methods. Fixation of the shaft fracture follows as patient condition allows. The rare nature of this injury makes it very challenging to study and most published series' are retrospective with very small sample sizes. In short, no scientificallycompelling study is available to definitively support any one implant choice or method of stabilzation over another for the treatment of associated fractures of the femoral neck and shaft.
• Eagan, M., Kim, H., Manson, T. T., Gary, J. L., Russell, J. P., Hsieh, A. H., O'Toole, R. V., & Boulton, C. L. (2015). Internal anterior fixators for pelvic ring injuries: Do monaxial pedicle screws provide more stiffness than polyaxial pedicle screws?. Injury, 46(Issue 6). doi:10.1016/j.injury.2015.01.040
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  Objectives Little is known about the mechanical properties of internal anterior fixators (known as INFIX), which have been proposed as subcutaneous alternatives to traditional anterior external fixators for pelvic ring disruptions. We hypothesised that INFIX has superior biomechanical performance compared with traditional external fixators because the distance from the bar to the bone is reduced. Methods Using a commercially available synthetic bone model, 15 unstable pelvic ring injuries were simulated by excising the pubic bone through the bilateral superior and inferior rami anteriorly and the sacrum through the bilateral sacral foramen posteriorly. Three test groups were established: (1) traditional supra-acetabular external fixation, (2) INFIX with polyaxial screws, (3) INFIX with monaxial screws. Load was applied, simulating lateral compression force. Outcome measure was construct stiffness. Results The traditional external fixator constructs had an average stiffness of 6.21 N/mm ± 0.40 standard deviation (SD). INFIX with monaxial screws was 23% stiffer than the traditional external fixator (mean stiffness, 7.66 N/mm ± 0.86 SD; p =.01). INFIX with polyaxial screws was 26% less stiff than INFIX with monaxial screws (mean stiffness, 5.69 N/mm ± 1.24 SD; p =.05). No significant difference was noted between polyaxial INFIX and external fixators (mean stiffness, 6.21 N/mm ± 0.40 SD; p =.65). Conclusions The performance of INFIX depends on the type of screw used, with monaxial screws providing significantly more stiffness than polyaxial screws. Despite the mechanical advantage of being closer to the bone, polyaxial INFIX was not stiffer than traditional external fixation.
• Eagan, M., Kim, H., Manson, T. T., Gary, J. L., Russell, J. P., Hsieh, A. H., O'Toole, R. V., & Boulton, C. L. (2015). Internal anterior fixators for pelvic ring injuries: Do monaxial pedicle screws provide more stiffness than polyaxial pedicle screws?. Injury, 46(6), 996-1000.
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  Little is known about the mechanical properties of internal anterior fixators (known as INFIX), which have been proposed as subcutaneous alternatives to traditional anterior external fixators for pelvic ring disruptions. We hypothesised that INFIX has superior biomechanical performance compared with traditional external fixators because the distance from the bar to the bone is reduced.
• Boulton, C. L., Kim, H., Shah, S. B., Ryan, S. P., Metzger, T. A., Hsieh, A. H., & O'Toole, R. V. (2014). Do locking screws work in plates bent at holes?. Journal of Orthopaedic Trauma, 28(Issue 4). doi:10.1097/bot.0b013e3182a73a77
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  OBJECTIVES:: To assess whether plate bending at a hole significantly changes the biomechanical properties of a locked screw. METHODS:: Coronal plane bends of 5-, 15-, or 45-degree angles were placed in 3.5-mm locking compression plates with the apex at a locking hole. An additional 45-degree angle test group was created in which a threaded screw head insert was placed before bending. Ten plates were tested in each group and compared with nonbent controls in a stepwise cyclic loading protocol. RESULTS:: Statistically significant differences in protocol survival were shown between the control group and the 15-degree angle (P = 0.006) and 45-degree angle (P = 0.0007) groups. An apparent decrease in protocol survival in the 5-degree angle group did not reach statistical significance (P = 0.17). The average number of cycles survived was significantly different between the control group and the 15-degree angle (P = 0.027) and 45-degree angle (P = 0.0002) groups. The mean cycles to failure for the 5-degree angle group was 16% lower than for controls but did not reach statistical significance (P = 0.37). The test group bent to an angle of 45 degrees after placement of a threaded screw head insert showed no difference in protocol survival or in mean number of cycles survived compared with the regular 45-degree angle group. CONCLUSION:: Bending of a 3.5-mm locking compression plate by more than 5 degrees at a locking hole results in a statistically significant decrease in survival of the corresponding locked screw. This effect cannot be prevented by the placement of a threaded screw head insert before bending. © 2013 by Lippincott Williams & Wilkins.
• Boulton, C. L., Kim, H., Shah, S. B., Ryan, S. P., Metzger, T. A., Hsieh, A. H., & O'Toole, R. V. (2014). Do locking screws work in plates bent at holes?. Journal of orthopaedic trauma, 28(4), 189-94.
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  To assess whether plate bending at a hole significantly changes the biomechanical properties of a locked screw.
• Rodriguez, E. K., Boulton, C., Weaver, M. J., Herder, L. M., Morgan, J. H., Chacko, A. T., Appleton, P. T., Zurakowski, D., & Vrahas, M. S. (2014). Predictive factors of distal femoral fracture nonunion after lateral locked plating: A retrospective multicenter case-control study of 283 fractures. Injury, 45(Issue 3). doi:10.1016/j.injury.2013.10.042
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  Introduction Reported initial success rates after lateral locked plating (LLP) of distal femur fractures have led to more concerning outcomes with reported nonunion rates now ranging from 0 to 21%. Reported factors associated with nonunion include comorbidities such as obesity, age and diabetes. In this study, our goal was to identify patient comorbidities, injury and construct characteristics that are independent predictors of nonunion risk in LLP of distal femur fractures; and to develop a predictive algorithm of nonunion risk, irrespective of institutional criteria for clinical intervention variability. Patients and methods A retrospective review of 283 distal femoral fractures in 278 consecutive patients treated with LLP at three Level1 academic trauma centers. Nonunion was liberally defined as need for secondary procedure to manage poor healing based on unrestricted surgeon criteria. Patient demographics (age, gender), comorbidities (obesity, smoking, diabetes, chronic steroid use, dialysis), injury characteristics (AO type, periprosthetic fracture, open fracture, infection), and management factors (institution, reason for intervention, time to intervention, plate length, screw density, and plate material) were obtained for all participants. Multivariable analysis was performed using logistic regression to control for confounding in order to identify independent risk factors for nonunion. Results 28 of the 283 fractures were treated for nonunion, 13 were referred to us from other institutions. Obesity (BMI > 30), open fracture, occurrence of infection, and use of stainless steel plate were significant independent risk factors (P < 0.01). A predictive algorithm demonstrates that when none of these variables are present (titanium instead of stainless steel) the risk of nonunion requiring intervention is 4%, but increases to 96% with all factors present. When a stainless plate is used, obesity alone carries a risk of 44% while infection alone a risk of 66%. While Chi-square testing suggested no institutional differences in nonunion rates, the time to intervention for nonunion varied inversely with nonunion rates between institutions, indicating varying trends in management approach. Discussion Obesity, open fracture, occurrence of infection, and the use of stainless steel are prognostic risk factors of nonunion in distal femoral fractures treated with LLP independent of differing trends in how surgeons intervene in the management of nonunion. © 2013 Elsevier Ltd © 2013 Published by Elsevier Ltd. All rights reserved.
• Rodriguez, E. K., Boulton, C., Weaver, M. J., Herder, L. M., Morgan, J. H., Chacko, A. T., Appleton, P. T., Zurakowski, D., & Vrahas, M. S. (2014). Predictive factors of distal femoral fracture nonunion after lateral locked plating: a retrospective multicenter case-control study of 283 fractures. Injury, 45(3), 554-9.
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  Reported initial success rates after lateral locked plating (LLP) of distal femur fractures have led to more concerning outcomes with reported nonunion rates now ranging from 0 to 21%. Reported factors associated with nonunion include comorbidities such as obesity, age and diabetes. In this study, our goal was to identify patient comorbidities, injury and construct characteristics that are independent predictors of nonunion risk in LLP of distal femur fractures; and to develop a predictive algorithm of nonunion risk, irrespective of institutional criteria for clinical intervention variability.
• Findlay, J. M., Keogh, M. J., Boulton, C., Forward, D. P., & Moran, C. G. (2011). Ward-based rather than team-based junior surgical doctors reduce mortality for patients with a fracture of the proximal femur: Results from a two-year observational study. Journal of Bone and Joint Surgery - Series B, 93(Issue 3). doi:10.1302/0301-620x.93b3.25730
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  We performed a retrospective study of a departmental database to assess the efficacy of a new model of orthopaedic care on the outcome of patients with a fracture of the proximal femur. All 1578 patients admitted to a university teaching hospital with a fracture of the proximal femur between December 2007 and December 2009 were included. The allocation of Foundation doctors years 1 and 2 was restructured from individual teams covering several wards to pairs covering individual wards. No alterations were made in the numbers of doctors, their hours, out-of-hours cover, or any other aspect of standard patient care. Outcome measures comprised 30-day mortality and cause, complications and length of stay. Mortality was reduced from 11.7% to 7.6% (p = 0.007, Cox's regression analysis); adjusted odds ratio was 1.559 (95% confidence interval 1.128 to 2.156). Reductions were seen in Clostridium difficile colitis (p = 0.017), deep wound infection (p = 0.043) and gastrointestinal haemorrhage (p = 0.033). There were no differences in any patient risk factors (except the prevalence of chronic obstructive pulmonary disease), cause of death and length of stay before and after intervention. The underlying mechanisms are unclear, but may include improved efficiency and medical contact time. These findings may have implications for all specialties caring for patients on several wards, and we believe they justify a prospective trial to further assess this effect. ©2011 British Editorial Society of Bone and Joint Surgery.
• Phillips, J. R., Boulton, C., Moran, C. G., & Manktelow, A. R. (2011). What is the financial cost of treating periprosthetic hip fractures?. Injury, 42(Issue 2). doi:10.1016/j.injury.2010.06.003
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  A total of 146 patients were identified from a prospective database of all hip fractures over a 10-year period at a United Kingdom teaching hospital. The financial costs were calculated and analysed and then compared with the money recovered through the tariff produced by Payment by Results. A total of 62% of the study group were female; mean age of 79 years; mean length of stay of 39 days. Fractures occurred around total hip replacement (THR) in 63 cases, revision THR in 27 cases and hemiarthroplasty in 56 cases. Fixation of the fracture was performed in 61 cases, revision arthroplasty in 62 cases and 23 were treated non-operatively. The mean cost of treatment was £23,469 per patient (range £615-£223,000; median £18,031). Ward costs were responsible for 80.3%, theatre costs 5.7%, implants 6.7% and investigations 7.3%. The difference in cost was statistically significant when further surgery was required (p = 0.01) and length of stay was greater than 30 days (p < 0.0001), and when compared with the money recovered by the Trust (mean £3702; p < 0.0001). These results reveal the significant economic impact of treating this group of patients at specialist centres. © 2010 Elsevier Ltd. All rights reserved.
• Boulton, C. L., Salzler, M., & Mudgal, C. S. (2010). Intramedullary cannulated headless screw fixation of a comminuted subcapital metacarpal fracture: Case report. Journal of Hand Surgery, 35(Issue 8). doi:10.1016/j.jhsa.2010.04.032
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  This case report describes an alternative technique for the fixation of displaced comminuted subcapital fractures of the metacarpal with limited distal bone stock. Using a cannulated headless screw as an intramedullary device placed through the articular surface, we were able to secure proximal and distal bone purchase without excessive soft tissue stripping or disruption of the fracture hematoma. This technique allows early rehabilitation, and our patient went on to uneventful healing with excellent functional results. © 2010 Published by Elsevier Inc.
• Boulton, C. L., Salzler, M., & Mudgal, C. S. (2010). Intramedullary cannulated headless screw fixation of a comminuted subcapital metacarpal fracture: case report. The Journal of hand surgery, 35(8), 1260-3.
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  This case report describes an alternative technique for the fixation of displaced comminuted subcapital fractures of the metacarpal with limited distal bone stock. Using a cannulated headless screw as an intramedullary device placed through the articular surface, we were able to secure proximal and distal bone purchase without excessive soft tissue stripping or disruption of the fracture hematoma. This technique allows early rehabilitation, and our patient went on to uneventful healing with excellent functional results.
• Lee, B. H., Williams, I. R., Anastasiadou, E., Boulton, C. L., Joseph, S. W., Amaral, S. M., Curley, D. P., Duclos, N., Huntly, B. J., Fabbro, D., Griffin, J. D., & Gilliland, D. G. (2005). FLT3 internal tandem duplication mutations induce myeloproliferative or lymphoid disease in a transgenic mouse model. Oncogene, 24(53), 7882-92.
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  Activating FMS-like tyrosine kinase 3 (FLT3) mutations have been identified in approximately 30% of patients with acute myelogenous leukemia (AML), and recently in a smaller subset of patients with acute lymphoblastic leukemia (ALL). To explore the in vivo consequences of an activating FLT3 internal tandem duplication mutation (FLT3-ITD), we created a transgenic mouse model in which FLT3-ITD was expressed under the control of the vav hematopoietic promoter. Five independent lines of vav-FLT3-ITD transgenic mice developed a myeloproliferative disease with high penetrance and a disease latency of 6-12 months. The phenotype was characterized by splenomegaly, megakaryocytic hyperplasia, and marked thrombocythemia, but without leukocytosis, polycythemia, or marrow fibrosis, displaying features reminiscent of the human disease essential thrombocythemia (ET). Clonal immature B- or T-lymphoid disease was observed in two additional founder mice, respectively, that could be secondarily transplanted to recipient mice that rapidly developed lymphoid disease. Treatment of these mice with the FLT3 tyrosine kinase inhibitor, PKC412, resulted in suppression of disease and a statistically significant prolongation of survival. These results demonstrate that FLT3-ITD is capable of inducing myeloproliferative as well as lymphoid disease, and indicate that small-molecule tyrosine kinase inhibitors may be an effective treatment for lymphoid malignancies in humans that are associated with activating mutations in FLT3.
• Mohi, M. G., Williams, I. R., Dearolf, C. R., Chan, G., Kutok, J. L., Cohen, S., Morgan, K., Boulton, C., Shigematsu, H., Keilhack, H., Akashi, K., Gilliland, D. G., & Neel, B. G. (2005). Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations. Cancer cell, 7(2), 179-91.
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  The SH2-containing tyrosine phosphatase Shp2 (PTPN11) is required for growth factor and cytokine signaling. Germline Shp2 mutations cause Noonan Syndrome (NS), which is associated with increased risk of juvenile myelomonocytic leukemia (JMML). Somatic Shp2 mutations occur in sporadic JMML and other leukemias. We found that Shp2 mutants associated with sporadic leukemias transform murine bone marrow cells, whereas NS mutants are less potent in this assay. Transformation requires multiple domains within Shp2 and the Shp2 binding protein Gab2, and is associated with hyperactivation of the Erk, Akt, and Stat5 pathways. Mutant Shp2-transduced BM causes a fatal JMML-like disorder or, less commonly, lymphoproliferation. Shp2 mutants also cause myeloproliferation in Drosophila. Mek or Tor inhibitors potently inhibit transformation, suggesting new approaches to JMML therapy.
• Laurencon, A., Orme, C. M., Peters, H. K., Boulton, C. L., Vladar, E. K., Langley, S. A., Bakis, E. P., Harris, D. T., Harris, N. J., Wayson, S. M., Hawley, R. S., & Burtis, K. C. (2004). A large-scale screen for mutagen-sensitive loci in Drosophila. Genetics, 167(1), 217-31.
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  In a screen for new DNA repair mutants, we tested 6275 Drosophila strains bearing homozygous mutagenized autosomes (obtained from C. Zuker) for hypersensitivity to methyl methanesulfonate (MMS) and nitrogen mustard (HN2). Testing of 2585 second-chromosome lines resulted in the recovery of 18 mutants, 8 of which were alleles of known genes. The remaining 10 second-chromosome mutants were solely sensitive to MMS and define 8 new mutagen-sensitive genes (mus212-mus219). Testing of 3690 third chromosomes led to the identification of 60 third-chromosome mutants, 44 of which were alleles of known genes. The remaining 16 mutants define 14 new mutagen-sensitive genes (mus314-mus327). We have initiated efforts to identify these genes at the molecular level and report here the first two identified. The HN2-sensitive mus322 mutant defines the Drosophila ortholog of the yeast snm1 gene, and the MMS- and HN2-sensitive mus301 mutant defines the Drosophila ortholog of the human HEL308 gene. We have also identified a second-chromosome mutant, mus215(ZIII-2059), that uniformly reduces the frequency of meiotic recombination to
• Mohi, M. G., Boulton, C., Gu, T. L., Sternberg, D. W., Neuberg, D., Griffin, J. D., Gilliland, D. G., & Neel, B. G. (2004). Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proceedings of the National Academy of Sciences of the United States of America, 101(9), 3130-5.
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  Abnormal protein tyrosine kinases (PTKs) cause many human leukemias. For example, BCR/ABL causes chronic myelogenous leukemia (CML), whereas FLT3 mutations contribute to the pathogenesis of acute myelogenous leukemia. The ABL inhibitor Imatinib (Gleevec, STI571) has remarkable efficacy for treating chronic phase CML, and FLT3 inhibitors (e.g., PKC412) show similar promise in preclinical studies. However, resistance to PTK inhibitors is a major emerging problem that may limit long-term therapeutic efficacy. Development of rational combination therapies will probably be required to effect cures of these and other neoplastic disorders. Here, we report that the mTOR inhibitor rapamycin synergizes with Imatinib against BCR/ABL-transformed myeloid and lymphoid cells and increases survival in a murine CML model. Rapamycin/Imatinib combinations also inhibit Imatinib-resistant mutants of BCR/ABL, and rapamycin plus PKC412 synergistically inhibits cells expressing PKC412-sensitive or -resistant leukemogenic FLT3 mutants. Biochemical analyses raise the possibility that inhibition of 4E-BP1 phosphorylation may be particularly important for the synergistic effects of PTK inhibitor/rapamycin combinations. Addition of a mitogen-activated protein kinase kinase inhibitor to rapamycin or rapamycin plus PTK inhibitor further increases efficacy. Our results suggest that simultaneous targeting of more than one signaling pathway required by leukemogenic PTKs may improve the treatment of primary and relapsed CML and/or acute myelogenous leukemia caused by FLT3 mutations. Similar strategies may be useful for treating solid tumors associated with mutant and/or overexpressed PTKs.
• Cools, J., Stover, E. H., Boulton, C. L., Gotlib, J., Legare, R. D., Amaral, S. M., Curley, D. P., Duclos, N., Rowan, R., Kutok, J. L., Lee, B. H., Williams, I. R., Coutre, S. E., Stone, R. M., DeAngelo, D. J., Marynen, P., Manley, P. W., Meyer, T., Fabbro, D., , Neuberg, D., et al. (2003). PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRα-induced myeloproliferative disease. Cancer cell, 3(5), 459-69.
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  FIP1L1-PDGFRalpha causes hypereosinophilic syndrome (HES) and is inhibited by the tyrosine kinase inhibitor imatinib (Gleevec). Imatinib is a potent inhibitor of ABL, ARG, PDGFRalpha, PDGFRbeta, and KIT and induces durable hematologic responses in HES patients. However, we observed relapse with resistance to imatinib as consequence of a T674I mutation in FIP1L1-PDGFRalpha, analogous to the imatinib-resistant T315I mutation in BCR-ABL. We developed a murine bone marrow transplant model of FIP1L1-PDGFRalpha-induced myeloproliferative disease to evaluate the efficacy of PKC412, an alternative inhibitor of PDGFRalpha, for the treatment of HES. PKC412 is effective for treatment of FIP1L1-PDGFRalpha-induced disease and of imatinib-induced resistance due to the T674I mutation. Our data establish PKC412 as molecularly targeted therapy for HES and other diseases expressing activated PDGFRalpha and demonstrate the potential of alternative kinase inhibitors to overcome resistance in target tyrosine kinases.
• Kelly, L. M., Kutok, J. L., Williams, I. R., Boulton, C. L., Amaral, S. M., Curley, D. P., Ley, T. J., & Gilliland, D. G. (2002). PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model. Proceedings of the National Academy of Sciences of the United States of America, 99(12), 8283-8.
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  Acute promyelocytic leukemia (APL) cells invariably express aberrant fusion proteins involving the retinoic acid receptor alpha (RARalpha). The most common fusion partner is promyelocytic leukemia protein (PML), which is fused to RARalpha in the balanced reciprocal chromosomal translocation, t(15;17)(q22:q11). Expression of PML/RARalpha from the cathepsin G promoter in transgenic mice causes a nonfatal myeloproliferative syndrome in all mice; about 15% go on to develop APL after a long latent period, suggesting that additional mutations are required for the development of APL. A candidate target gene for a second mutation is FLT3, because it is mutated in approximately 40% of human APL cases. Activating mutations in FLT3, including internal tandem duplication (ITD) in the juxtamembrane domain, transform hematopoietic cell lines to factor independent growth. FLT3-ITDs also induce a myeloproliferative disease in a murine bone marrow transplant model, but are not sufficient to cause AML. Here, we test the hypothesis that PML/RARalpha can cooperate with FLT3-ITD to induce an APL-like disease in the mouse. Retroviral transduction of FLT3-ITD into bone marrow cells obtained from PML/RARalpha transgenic mice results in a short latency APL-like disease with complete penetrance. This disease resembles the APL-like disease that occurs with long latency in the PML/RARalpha transgenics, suggesting that activating mutations in FLT3 can functionally substitute for the additional mutations that occur during mouse APL progression. The leukemia is transplantable to secondary recipients and is ATRA responsive. These observations document cooperation between PML/RARalpha and FLT3-ITD in development of the murine APL phenotype.
• Kelly, L. M., Liu, Q., Kutok, J. L., Williams, I. R., Boulton, C. L., & Gilliland, D. G. (2002). FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood, 99(1), 310-8.
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  FLT3 receptor tyrosine kinase is expressed on lymphoid and myeloid progenitors in the hematopoietic system. Activating mutations in FLT3 have been identified in approximately 30% of patients with acute myelogenous leukemia, making it one of the most common mutations observed in this disease. Frequently, the mutation is an in-frame internal tandem duplication (ITD) in the juxtamembrane region that results in constitutive activation of FLT3, and confers interleukin-3 (IL-3)-independent growth to Ba/F3 and 32D cells. FLT3-ITD mutants were cloned from primary human leukemia samples and assayed for transformation of primary hematopoietic cells using a murine bone marrow transplantation assay. FLT3-ITDs induced an oligoclonal myeloproliferative disorder in mice, characterized by splenomegaly and leukocytosis. The myeloproliferative phenotype, which was associated with extramedullary hematopoiesis in the spleen and liver, was confirmed by histopathologic and flow cytometric analysis. The disease latency of 40 to 60 days with FLT3-ITDs contrasted with wild-type FLT3 and enhanced green fluorescent protein (EGFP) controls, which did not develop hematologic disease (> 200 days). These results demonstrate that FLT3-ITD mutant proteins are sufficient to induce a myeloproliferative disorder, but are insufficient to recapitulate the AML phenotype observed in humans. Additional mutations that impair hematopoietic differentiation may be required for the development of FLT3-ITD-associated acute myeloid leukemias. This model system should be useful to assess the contribution of additional cooperating mutations and to evaluate specific FLT3 inhibitors in vivo.
• Kelly, L. M., Yu, J. C., Boulton, C. L., Apatira, M., Li, J., Sullivan, C. M., Williams, I., Amaral, S. M., Curley, D. P., Duclos, N., Neuberg, D., Scarborough, R. M., Pandey, A., Hollenbach, S., Abe, K., Lokker, N. A., Gilliland, D. G., & Giese, N. A. (2002). CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML). Cancer cell, 1(5), 421-32.
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  Up to 30% of acute myelogenous leukemia (AML) patients harbor an activating internal tandem duplication (ITD) within the juxtamembrane domain of the FLT3 receptor, suggesting that it may be a target for kinase inhibitor therapy. For this purpose we have developed CT53518, a potent antagonist that inhibits FLT3, platelet-derived growth factor receptor (PDGFR), and c-Kit (IC(50) approximately 200 nM), while other tyrosine or serine/threonine kinases were not significantly inhibited. In Ba/F3 cells expressing different FLT3-ITD mutants, CT53518 inhibited IL-3-independent cell growth and FLT3-ITD autophosphorylation with an IC(50) of 10-100 nM. In human FLT3-ITD-positive AML cell lines, CT53518 induced apoptosis and inhibited FLT3-ITD phosphorylation, cellular proliferation, and signaling through the MAP kinase and PI3 kinase pathways. Therapeutic efficacy of CT53518 was demonstrated both in a nude mouse model and in a murine bone marrow transplant model of FLT3-ITD-induced disease.
• Weisberg, E., Boulton, C., Kelly, L. M., Manley, P., Fabbro, D., Meyer, T., Gilliland, D. G., & Griffin, J. D. (2002). Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer cell, 1(5), 433-43.
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  Constitutively activating FLT3 receptor mutations have been found in 35% of patients with acute myeloblastic leukemia (AML). Here we report the identification of a small molecule FLT3 tyrosine kinase inhibitor PKC412, which selectively induced G1 arrest and apoptosis of Ba/F3 cell lines expressing mutant FLT3 (IC(50) < 10 nM) by directly inhibiting the tyrosine kinase. Ba/F3-FLT3 cell lines made resistant to PKC412 demonstrated overexpression of mutant FLT3, confirming that FLT3 is the target of this drug. Finally, progressive leukemia was prevented in PKC412-treated Balb/c mice transplanted with marrow transduced with a FLT3-ITD-expressing retrovirus. PKC412 is a potent inhibitor of mutant FLT3 and is a candidate for testing as an antileukemia agent in AML patients with mutant FLT3 receptors.

Presentations

• Boulton, C. (2022). Basic Principles of Fracture Managment/ Course in 9/17 and 9/23. AO Trauma NA Blended Course.
• Boulton, C. (2022). Limb Threatening Injuries. U of A General Surgery Trauma Fellow Didactics.
• Boulton, C. (2022). Southwest Regioanl Trauma Conference - Orthopedic Emergencies. Southwest Regioanl Trauma Conference.