Dysfunctional natural killer cells can be reprogrammed to regain anti-tumor activity.

Natural killer (NK) cells are critical to the innate immune system, as they recognize antigens without prior sensitization, and contribute to the control and clearance of viral infections and cancer. However, a significant proportion of NK cells in mice and humans do not express classical inhibitory receptors during their education process and are rendered naturally "anergic", i.e., exhibiting reduced effector functions. The molecular events leading to NK cell anergy as well as their relation to those underlying NK cell exhaustion that arises from overstimulation in chronic conditions, remain unknown. Here, we characterize the "anergic" phenotype and demonstrate functional, transcriptional, and phenotypic similarities to the "exhausted" state in tumor-infiltrating NK cells. Furthermore, we identify zinc finger transcription factor Egr2 and diacylglycerol kinase DGKα as common negative regulators controlling NK cell dysfunction. Finally, experiments in a 3D organotypic spheroid culture model and an in vivo tumor model suggest that a nanoparticle-based delivery platform can reprogram these dysfunctional natural killer cell populations in their native microenvironment. This approach may become clinically relevant for the development of novel anti-tumor immunotherapeutic strategies.

Folding molecular origami from ribosomal RNA.

Approximately 80 percent of the total RNA in cells is ribosomal RNA (rRNA), making it an abundant and inexpensive natural source of long, single-stranded nucleic acid, which could be used as raw material for the fabrication of molecular origami. In this study, we demonstrate efficient and robust construction of 2D and 3D origami nanostructures utilizing cellular rRNA as a scaffold and DNA oligonucleotide staples. We present calibrated protocols for the robust folding of contiguous shapes from one or two rRNA subunits that are efficient to allow folding using crude extracts of total RNA. We also show that RNA maintains stability within the folded structure. Lastly, we present a novel and comprehensive analysis and insights into the stability of RNA:DNA origami nanostructures and demonstrate their enhanced stability when coated with polylysine-polyethylene glycol in different temperatures, low Mg2+ concentrations, human serum, and in the presence of nucleases (DNase I or RNase H). Thus, laying the foundation for their potential implementation in emerging biomedical applications, where folding rRNA into stable structures outside and inside cells would be desired.

Orthopaedic surgery residents report little subjective or objective familiarity with healthcare costs.

PURPOSE: Residents have limited education regarding the cost of orthopaedic interventions. Orthopaedic residents' knowledge was surveyed in three scenarios involving an intertrochanteric femur fracture: 1) uncomplicated course with 2-day hospital stay; 2) complicated course necessitating ICU admission; and 3) readmission for pulmonary embolism management. METHODS: From 2018 to 2020, 69 orthopaedic surgery residents were surveyed. Respondents estimated hospital charges and collections; professional charges and collections; implant cost; and level of knowledge depending on the scenario. RESULTS: Most residents (83.6%) reported feeling "not knowledgeable". Respondents reporting "somewhat knowledgeable" did not perform better than those who reported "not knowledgeable". In the uncomplicated scenario, residents underestimated hospital charges and collections (p < 0.01; p = 0.87), and overestimated hospital charges and collections and professional collections (all p < 0.01) with an average percent error of 57.2%. Most residents (88.4%) were aware the sliding hip screw construct costs less than a cephalomedullary nail. In the complex scenario, while residents underestimated the hospital charges (p < 0.01), the estimated collections were closer to the actual figure (p = 0.16). In the third scenario, residents overestimated the charges and collections (p = 0.04; p = 0.04). CONCLUSIONS: Orthopaedic surgery residents receive little education regarding healthcare economics and feel unknowledgeable therefore a role for formal economic education during orthopaedic residency may exist.

Actin retrograde flow controls natural killer cell response by regulating the conformation state of SHP-1.

Natural killer (NK) cells are a powerful weapon against viral infections and tumor growth. Although the actin-myosin (actomyosin) cytoskeleton is crucial for a variety of cellular processes, the role of mechanotransduction, the conversion of actomyosin mechanical forces into signaling cascades, was never explored in NK cells. Here, we demonstrate that actomyosin retrograde flow (ARF) controls the immune response of primary human NK cells through a novel interaction between ß-actin and the SH2-domain-containing protein tyrosine phosphatase-1 (SHP-1), converting its conformation state, and thereby regulating NK cell cytotoxicity. Our results identify ARF as a master regulator of the NK cell immune response. Since actin dynamics occur in multiple cellular processes, this mechanism might also regulate the activity of SHP-1 in additional cellular systems.

WASp family verprolin-homologous protein-2 (WAVE2) and Wiskott-Aldrich syndrome protein (WASp) engage in distinct downstream signaling interactions at the T cell antigen receptor site.

T cell antigen receptor (TCR) engagement has been shown to activate pathways leading to actin cytoskeletal polymerization and reorganization, which are essential for lymphocyte activation and function. Several actin regulatory proteins were implicated in regulating the actin machinery, such as members of the Wiskott-Aldrich syndrome protein (WASp) family. These include WASp and the WASp family verprolin-homologous protein-2 (WAVE2). Although WASp and WAVE2 share several structural features, the precise regulatory mechanisms and potential redundancy between them have not been fully characterized. Specifically, unlike WASp, the dynamic molecular interactions that regulate WAVE2 recruitment to the cell membrane and specifically to the TCR signaling complex are largely unknown. Here, we identify the molecular mechanism that controls the recruitment of WAVE2 in comparison with WASp. Using fluorescence resonance energy transfer (FRET) and novel triple-color FRET (3FRET) technology, we demonstrate how WAVE2 signaling complexes are dynamically regulated during lymphocyte activation in vivo. We show that, similar to WASp, WAVE2 recruitment to the TCR site depends on protein-tyrosine kinase, ZAP-70, and the adaptors LAT, SLP-76, and Nck. However, in contrast to WASp, WAVE2 leaves this signaling complex and migrates peripherally together with vinculin to the membrane leading edge. Our experiments demonstrate that WASp and WAVE2 differ in their dynamics and their associated proteins. Thus, this study reveals the differential mechanisms regulating the function of these cytoskeletal proteins.

The calcium feedback loop and T cell activation: how cytoskeleton networks control intracellular calcium flux.

During T cell activation, the engagement of a T cell with an antigen-presenting cell (APC) results in rapid cytoskeletal rearrangements and a dramatic increase of intracellular calcium (Ca(2+)) concentration, downstream to T cell antigen receptor (TCR) ligation. These events facilitate the organization of an immunological synapse (IS), which supports the redistribution of receptors, signaling molecules and organelles towards the T cell-APC interface to induce downstream signaling events, ultimately supporting T cell effector functions. Thus, Ca(2+) signaling and cytoskeleton rearrangements are essential for T cell activation and T cell-dependent immune response. Rapid release of Ca(2+) from intracellular stores, e.g. the endoplasmic reticulum (ER), triggers the opening of Ca(2+) release-activated Ca(2+) (CRAC) channels, residing in the plasma membrane. These channels facilitate a sustained influx of extracellular Ca(2+) across the plasma membrane in a process termed store-operated Ca(2+) entry (SOCE). Because CRAC channels are themselves inhibited by Ca(2+) ions, additional factors are suggested to enable the sustained Ca(2+) influx required for T cell function. Among these factors, we focus here on the contribution of the actin and microtubule cytoskeleton. The TCR-mediated increase in intracellular Ca(2+) evokes a rapid cytoskeleton-dependent polarization, which involves actin cytoskeleton rearrangements and microtubule-organizing center (MTOC) reorientation. Here, we review the molecular mechanisms of Ca(2+) flux and cytoskeletal rearrangements, and further describe the way by which the cytoskeletal networks feedback to Ca(2+) signaling by controlling the spatial and temporal distribution of Ca(2+) sources and sinks, modulating TCR-dependent Ca(2+) signals, which are required for an appropriate T cell response. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Hervé.

Open Reduction And Internal Fixation of Tarsometatarsal (Lisfranc) Fracture Dislocations-Is Arthrodesis Necessary?

INTRODUCTION: Controversy remains regarding the optimal management of tarsometatarsal (Lisfranc) fracture dislocations. Open reduction and internal fixation (ORIF) and ORIF with primary arthrodesis (PA) have been described in the treatment of these injuries, although adverse sequelae remain problematic. Previous work has yielded small cohorts with heterogenous results. We aimed to describe the outcomes of Lisfranc fracture dislocations managed with ORIF and/or PA to identify risk factors for complications, such as nonunion and revision surgery. METHODS: A retrospective review of 206 consecutive tarsometatarsal fracture dislocations that underwent surgical repair between 2015 and 2021 was performed. Time to radiographic union was noted. Complications were recorded, including revision surgery, infection, symptomatic implant removal, posttraumatic arthritis, secondary arthrodesis, and nonunion. A comparative subgroup analysis of outcomes by treatment modality (ie, PA versus ORIF) and by injury severity (isolated injury versus concomitant lower extremity fracture) were performed. Logistic regression analysis was performed to assess factors associated with revision surgery. RESULTS: 104 patients met the inclusion criteria with a mean 13-month follow-up. Ninety-three (n = 93) patients underwent ORIF, and 11 patients underwent PA. Radiographic union was achieved in 94.2% of cases (98/104) at an average 106 days. Complications included superficial infection (3.8%), deep infection (7.7%), symptomatic implant removal (19.2%), posttraumatic arthritis (12.5%), secondary arthrodesis (4.8%), and nonunion (2.9%). No difference existed in the complication rates between those who underwent ORIF and those who underwent PA ( P = 0.50). Revision surgery rates were similar between patients who sustained isolated injuries and those with concomitant lower extremity fractures ( P = 0.31). Risk factors for revision surgery included open fractures (OR 4.01, P = 0.042) and previous psychiatric illness (OR 5.77, P = 0.016). DISCUSSION: The vast spectrum of injury in Lisfranc fracture dislocations makes uniform treatment challenging. In this large consecutive series, few failed to achieve union or required secondary arthrodesis. Open fractures and previous psychiatric illness portended worse clinical outcomes. ORIF without PA remains a viable treatment in these injuries. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Biodistribution and function of coupled polymer-DNA origami nanostructures.

Spatial control over the distribution of therapeutics is a highly desired feature, which could limit the side effects of many drugs. Here we describe a nanoscale agent, fabricated from a coupled polymer-DNA origami hybrid that exhibits stability in serum and slow diffusion through tissues, in a manner correlating with shape and aspect ratio. Coupling to fragments of polyethylene glycol (PEG) through polyamine electrostatic interactions resulted in marked stability of the agents in-vivo, with > 90% of the agents maintaining structural integrity 5 days following subcutaneous injection. An agent functionalized with aptamers specific for human tumor necrosis factor TNF-alpha, significantly abrogated the inflammatory response in a delayed-type hypersensitivity model in humanized TNF-alpha mice. These findings highlight polymer-DNA hybrid nanostructures as a programmable and pharmacologically viable update to mainstream technologies such as monoclonal antibodies, capable of exerting an additional layer of control across the spatial dimension of drug activity.

Fixation of displaced intra-articular calcaneus fractures is safe using either sinus tarsi or extensile lateral approach.

INTRODUCTION: Management of displaced intra-articular calcaneus fractures continues to challenge surgeons. Use of the extensile lateral surgical approach (ELA) had been standard practice however wound necrosis and infection have become deterrents. The sinus tarsi approach (STA) has gained popularity as a less invasive technique to optimize articular reduction while minimizing soft tissue injury. Our aim was to compare wound complications and infections following calcaneus fractures treated using ELA versus STA. METHODS: Retrospective review of 139 displaced intra-articular calcaneus fractures (AO/OTA 82C; Sanders II-IV injuries) treated operatively at 2 level-I trauma centers using STA (n = 84) or ELA (n = 55) over a 3-year period with minimum 1-year follow up was performed. Demographic, injury, and treatment-related characteristics were collected. Primary outcomes of interest included wound complications, infection, reoperation, and American Orthopaedic Foot and Ankle Society ankle and hindfoot scores. Univariate comparisons between groups were conducted using Chi-Square, Mann-Whitney, and independent sample t-tests at the p < 0.05 significance level, where appropriate. Multivariable regression analysis was performed to identify risk factors for poor outcomes. RESULTS: Demographic characteristics were homogenous between cohorts. Most sustained falls from height (77%). Sanders III fractures were most common (42%). Patients treated with STA went to surgery earlier (6.0 days STA vs 13.2 ELA, p < 0.001). No differences were seen in restoration of Bohler's angle, varus/valgus angle, or calcaneal height, yet the ELA significantly improved calcaneal width (-2 mm STA vs -13.3 mm ELA, p < 0.001). There were no significant differences in wound necrosis or deep infection based on surgical approach (12% STA vs 22% ELA, p = 0.15). Seven patients underwent subtalar arthrodesis for arthrosis (4% STA vs 7% ELA). No differences in AOFAS scores were seen. Risk factors for reoperation included Sanders type IV patterns (OR = 6.6, p = 0.001), increasing BMI (OR = 1.2, p = 0.021), and advanced age (OR = 1.1, p = 0.005), not surgical approach. CONCLUSION: Despite prior concerns, use of ELA versus STA for fixation of displaced intra-articular calcaneus fractures was not associated with more complication risk, illustrating both are safe when indicated and executed appropriately.

Surgeon Learning Curve for the Sinus Tarsi Approach to Intra-articular Calcaneus Fractures - Improvement with Experience.

OBJECTIVE: To analyze the relationship between surgeon experience with the sinus tarsi approach (STA) and outcomes in the treatment of displaced intra-articular calcaneus fractures (DIACF). SETTING: Single level 1 trauma center. DESIGN: Retrospective.Patients/Participants: 103 consecutive DIACF (OTA/AO 82C; Sanders II-IV) treated operatively using STA from 2015 to 2021. INTERVENTION: Open management using the STA performed by two fellowship-trained orthopaedic traumatologists. MAIN OUTCOME MEASUREMENT: Quality of anatomic reduction based on postoperative CT scans and standard radiographs. RESULTS: Sixty-six patients met inclusion criteria. Patients were primarily men (75.8%) with mean age 41 years (range 20-71 years), including 14 smokers (21.2%), 9 diabetics (13.6%), and 10 open fractures (15.2%). Sanders III fractures were most common (68.2% vs 28.5% and 6.1% Sanders II/IV respectively). Reduction quality was predominantly Good (59.1%, n=39) or Excellent (25.8%, n=17). Complications included wound necrosis (1), superficial infection (1), deep infection (1), and symptomatic posttraumatic arthritis requiring arthrodesis (3). There was a 29.3% reduction in likelihood of surgical complication with each year in surgeon experience with the STA and an 8.9% reduction per case (p<0.001). The likelihood of achieving a Good or Excellent reduction was 1.8 and 2.3 times greater than achieving a Fair reduction, respectively, for each year increase in surgeon experience with the STA (p=0.012 and 0.007, respectively). For each successive case, there was a 1.2 times greater likelihood of achieving a Good reduction (p=0.03). CONCLUSION: Surgeon experience plays a critical role in outcomes. We found that outcomes (reduction, complications) improve with each cumulative case and year of experience with the STA to treat DIACF. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Outcomes of Geriatric Periprosthetic Distal Femur Fractures: Comparison of Fixation Versus Reconstruction.

OBJECTIVE: Comparing outcomes of periprosthetic distal femur fractures treated with open reduction and internal fixation (ORIF) versus distal femoral replacement (DFR). SETTING: Three major academic hospitals within one metropolitan area. DESIGN: Retrospective. PATIENTS/PARTICIPANTS: Three hundred seventy patients >64 years old with periprosthetic distal femur fractures were identified and 115 were included (65 ORIF vs. 50 DFR). INTERVENTION: ORIF with locked plating versus DFR. MAIN OUTCOME MEASUREMENT: One-year mortality, ambulatory status at 1 year, reoperations, and hospital readmissions. RESULTS: No differences were observed between ORIF and DFR cohorts regarding demographics or medical history, including Charleston Comorbidity Index. DFR was associated with longer hospital stay (6.09 days ORIF vs. 9.08 days DFR, P < 0.001) and more frequent blood transfusion (12.3% ORIF vs. 44.0% DFR, P < 0.001). Logistic regression analysis using propensity score matching (PSM) demonstrated no statistically significant difference in reoperation, hospital readmission, ambulatory status at 1 year, or 1-year mortality between the 2 cohorts. Finally, applying Bayesian model averaging using PSM to identify risk factors for 1-year mortality demonstrated that increasing age, length of index hospital stay, and 90-day hospital readmission were significantly associated with 1-year mortality, regardless of type of surgical treatment. CONCLUSION: Rehospitalization, reoperation, ambulatory status, and 1-year mortality are no different between ORIF and DFR in the treatment of geriatric periprosthetic distal femur fractures when PSM is applied to mitigate selection bias. Further study is warranted to elucidate functional outcomes, long-term sequelae, and costs of care related to these treatment options to better guide treatment planning. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Use of Anatomic Radiographic Horizons for the Lateral Center-Edge Angle in the Classification of Hip Dysplasia.

BACKGROUND: The lateral center-edge angle of Wiberg (LCEA) and Tönnis angle (TA) rely on a "horizon" that functions as a reference point for measurements of hip dysplasia on weightbearing anteroposterior pelvis radiographs. There are 3 different horizons that are currently utilized depending on surgeon preference: (1) a line parallel to the radiographic floor (F), (2) a line that connects the inferior portions of the acetabular teardrops (ATs), or (3) a line that connects the ischial tuberosities (ITs). It is imperative to accurately assess the degree of hip dysplasia on initial workup to select the appropriate surgical intervention. PURPOSE: To assess how the choice of a radiographic horizon affects the measurements of the LCEA and TA. The secondary purpose was to assess how the horizon affected the classification of hips as either normal, borderline dysplastic, or dysplastic. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 3. METHODS: The LCEA and TA were measured on all preoperative weightbearing anteroposterior pelvis radiographs for 186 consecutive patients who underwent hip preservation surgery between February 2016 and November 2020 (140 hip arthroscopic procedures, 46 combined hip arthroscopic procedures with periacetabular osteotomy), 3 times per hip, each time using an F, AT, and IT horizon. The Student t test was used to analyze the differences in the measurements of the LCEA and TA, and discordance rates in the dysplasia classification between horizons were quantified. RESULTS: For the entire study population, the mean LCEAF (23.4°± 7.4°) was significantly greater than the mean LCEAIT (23.1°± 7.2°) (95% CI, -0.634 to -0.003; P = .047) and mean LCEAAT (23.0°± 7.1°) (95% CI, -0.723 to -0.139; P = .004). There was no difference between the LCEAIT and LCEAAT (95% CI, -0.305 to 0.080; P = .251). When stratified by hip arthroscopic surgery, the mean LCEAF (26.3°± 5.6°) was significantly greater than the mean LCEAAT (25.8°± 5.3°) (95% CI, -0.845 to -0.162; P = .004). Overall, there was a 17.7% and 18.3% discordance rate in the dysplasia classification using the LCEAIT and LCEAAT compared with the LCEAF, respectively. There were no statistically significant differences between the mean TAIT, TAAT, and TAF for the entire study population, the arthroscopic surgery group, and the combined arthroscopic surgery and periacetabular osteotomy group. CONCLUSION: There was no statistical difference between the AT and IT horizons for LCEA measurements. The dysplasia classification was in better agreement between the 2 anatomic horizons compared with the F horizon. The TA was not affected by changes in the horizon.

"Did You Think You Would Die?": Fear of Death and Its Relationship to the Development of Posttraumatic Stress Disorder After Traumatic Injury.

INTRODUCTION: Patient-specific factors may influence posttraumatic stress disorder (PTSD) development and warrant further examination. This study investigates potential association between patient-reported fear of death at the time of injury and development of PTSD. METHODS: Over 35 months, 250 patients were screened for PTSD at their first posthospitalization clinic visit and were asked "Did you think you were going to die from this injury?" (yes or no). PTSD screening was conducted using the PTSD checklist for DSM-5 questionnaire. A score ≥33 was considered positive for PTSD, and patients were offered ancillary psychiatric services. Retrospectively, medical records were reviewed for baseline demographics and injury information. RESULTS: Forty-three patients (17%) indicated a fear of death. The mean age was 46 years, with patients who feared death being younger (36 versus 48, P < 0.001), and 62% were male. The most common mechanisms of injury were motor vehicle or motorcycle collisions (30%) and ground-level falls (21%). Gunshot wounds were more common among patients who feared death from trauma (44% versus 7%, P < 0.001). PTSD questionnaires were completed a median of 26 days after injury, with an average score of 12.6. PTSD scores were higher for patients with fear of death (32.7 versus 8.5), and these patients required more acute interventions (47% versus 7%), both P < 0.001. After multivariable logistic regression, patients who thought that they would die from their trauma had >13 times higher odds of developing PTSD (odds ratios: 13.42, P < 0.0001). Apart from positive psychiatric history (OR: 5.46, P = 0.001), no factors (ie, age, sex, mechanism, or any injury or treatment characteristic) were predictive of positive PTSD scores on regression. DICUSSION: Patients who reported fear of death at the time of injury were 13 times more likely to develop PTSD. Simply asking patients whether they thought that they would die at the time of injury may prospectively identify PTSD risk. LEVEL OF EVIDENCE: Prognostic Level II.

Inhibition of SHP-1 activity by PKC-θ regulates NK cell activation threshold and cytotoxicity.

Natural killer (NK) cells play a crucial role in immunity, killing virally infected and cancerous cells. The balance of signals initiated upon engagement of activating and inhibitory NK receptors with cognate ligands determines killing or tolerance. Nevertheless, the molecular mechanisms regulating rapid NK cell discrimination between healthy and malignant cells in a heterogeneous tissue environment are incompletely understood. The SHP-1 tyrosine phosphatase is the central negative NK cell regulator that dephosphorylates key activating signaling proteins. Though the mechanism by which SHP-1 mediates NK cell inhibition has been partially elucidated, the pathways by which SHP-1 is itself regulated remain unclear. Here, we show that phosphorylation of SHP-1 in NK cells on the S591 residue by PKC-θ promotes the inhibited SHP-1 'folded' state. Silencing PKC-θ maintains SHP-1 in the active conformation, reduces NK cell activation and cytotoxicity, and promotes tumor progression in vivo. This study reveals a molecular pathway that sustains the NK cell activation threshold through suppression of SHP-1 activity.

Bicondylar Tibial Plateau Fractures: What Predicts Infection?

OBJECTIVES: The purpose of this study was to identify the patient, injury, and treatment factors associated with infection of bicondylar plateau fractures and to evaluate whether center variation exists. DESIGN: Retrospective review. SETTING: Eighteen academic trauma centers. PATIENTS/PARTICIPANTS: A total of 1,287 patients with 1,297 OTA type 41-C bicondylar tibia plateau fractures who underwent open reduction and internal fixation were included. Exclusion criteria were follow-up less than 120 days, insufficient documentation, and definitive treatment only with external fixation. INTERVENTION: Open reduction and internal fixation. MAIN OUTCOME MEASUREMENTS: Superficial and deep infection. RESULTS: One hundred one patients (7.8%) developed an infection. In multivariate regression analysis, diabetes (DM) (OR [odds ratio] 3.24; P ≤ 0.001), alcohol abuse (EtOH) (OR 1.8; P = 0.040), dual plating (OR 1.8; P ≤ 0.001), and temporary external fixation (OR 2.07; P = 0.013) were associated with infection. In a risk-adjusted model, we found center variation in infection rates (P = 0.030). DISCUSSION: In a large series of patients undergoing open reduction and internal fixation of bicondylar plateau fractures, the infection rate was 7.8%. Infection was associated with DM, EtOH, combined dual plating, and temporary external fixation. Center expertise may also play a role because one center had a statistically lower rate and two trended toward higher rates after adjusting for confounders. LEVEL OF EVIDENCE: Level IV-Therapeutic retrospective cohort study.

Weight-bearing status may influence rates of radiographic healing following reamed, intramedullary fixation of diaphyseal femur fractures.

OBJECTIVE: To investigate the effect of weight-bearing status on radiographic healing of diaphyseal femur fractures. DESIGN: Retrospective 1:1 matched cohort study. SETTING: Single-level 1 trauma center. PARTICIPANTS: One-hundred forty-four (N = 154) patients matched 1:1 in non-weight bearing (NWB) and weight-bearing as tolerated (WBAT) groups. INTERVENTION: Non-weight bearing following reamed, statically locked intramedullary fixation of diaphyseal femur fracture, generally due to concurrent lower extremity fracture. MAIN OUTCOME MEASUREMENT: Postoperative radiographic healing using modified Radiographic Union Scale for Tibia fractures (mRUST) scores. RESULTS: Groups were well matched on age, sex, race, prevalence of tobacco and alcohol use, diabetes mellitus status, Injury Severity Score, fracture pattern and shaft location, vascular injury, open fracture prevalence, and operative characteristics. Radiographic follow-up was similar between groups (231 vs 228 days, P = .914). At 6 to 8 weeks status post intramedullary fixation, the median mRUST score in the NWB group (9) was lower than that of the WBAT group (10) (mean: 8.4 vs 9.7, P = .004). At 12 to 16 weeks, the median mRUST in the NWB group (10) was again lower than the WBAT group (12) (mean: 9.9 vs 11.7, P = .003). The median number of days to 3 cortices of bridging callous was 85 in the WBAT group, compared with 122 in the NWB group (P = .029). Median time to mRUST scores of 12 (111 vs 162 days, P = .008), 13 (218 vs 278 days, P = .023), and 14 (255 vs 320 days, P = .028) were all longer in the NWB group compared with the WBAT group. CONCLUSIONS: Non-weight bearing after intramedullary fixation of diaphyseal femur fractures delays radiographic healing, with median time to 3 cortices of bridging callous increased from 85 days in WBAT groups to 122 days in NWB groups. These results provide clinicians with an understanding of the expected postoperative course, as well as further support the need to expeditiously advance weight-bearing status.Level of Evidence: IV.

Acute Fixation of Displaced Intra-articular Calcaneus Fractures Is Safe Using the Sinus Tarsi Approach.

OBJECTIVE: To analyze the correlation between surgical timing and outcomes for calcaneus fractures treated using a sinus tarsi approach (STA). SETTING: Single Level-1 trauma center. DESIGN: Retrospective. PATIENTS/PARTICIPANTS: Seventy consecutive intra-articular calcaneus fractures (OTA/AO 82C; Sanders II-IV) treated operatively using STA with a minimum of 1-year follow-up. INTERVENTION: Open management using STA. MAIN OUTCOME MEASUREMENT: Surgery timing, wound complications, American Orthopaedic Foot and Ankle Society ankle and hindfoot and Patient-reported Outcomes Measurement System scores. RESULTS: Patients were primarily men (68.6%) averaging 46 years (range, 18-77 years). Nineteen (27%) were obese, 27 (38.6%) were smokers, and 3 (4.3%) were diabetic, and 10 (14.3%) had open fractures. Sanders III fracture patterns were most common (45.7%). Mean time to surgery was 4.9 days (range, 0-23 days). Three patients (4.2%) developed postoperative infections requiring surgical debridement and antibiotics. Forty patients (57%) underwent operative repair within 72 hours of injury, 9 (22.5%) of which had open fractures. Of this group, only one patient developed wound necrosis. Restoration of Bohler angle and angle of Gissane and reductions in calcaneal varus angle and heel width were achieved (all P < 0.001). No differences in Ankle Society ankle and hindfoot or Patient-reported Outcomes Measurement System scores were noted between patients treated within or beyond 72 hours from injury. CONCLUSION: Intra-articular calcaneus fractures can be treated acutely within 72 hours of injury using STA with minimal wound complications and without compromising short-term functional outcome. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Risk Factors for Posttraumatic Stress Disorder in Acute Trauma Patients.

OBJECTIVE: To identify risk factors for posttraumatic stress disorder (PTSD) after traumatic injury. SETTING: Single urban Level I trauma center. DESIGN: Prospective. PATIENTS/PARTICIPANTS: Three hundred men (66%) and 152 women treated for traumatic injuries were administered the PTSD checklist for a Diagnostic and Statistical Manual of Mental Disorders fifth edition (PCL-5) survey during their first post-hospital visit over a 15-month period. INTERVENTION: Screening for PTSD in trauma patients. MAIN OUTCOME MEASUREMENT: The prevalence of disease and risk factors for the development of PTSD based on demographic, medical, injury, and treatment variables. RESULTS: One hundred three patients screened positive for PTSD (26%) after a mean of 86 days after injury. Age less than 45 years was an independent risk factor for the development of PTSD [odds ratio (OR) 2.64, 95% confidence interval (CI) (1.40-4.99)]. Mechanisms of injury associated with the development of PTSD included pedestrians struck by motor vehicles [OR 7.35, 95% CI (1.58-34.19)], motorcycle/all terrain vehicle crash [OR 3.17, 95% CI (1.04-9.65)], and victims of crime [OR 3.49, 95% CI (0.99-9.20)]. Patients sustaining high-energy mechanism injuries and those who were victims of crime scored higher on the PCL-5 [OR 2.39, 95% CI (1.35-4.22); OR 4.50, 95% CI (2.52-8.05), respectively]. CONCLUSIONS: One quarter of trauma patients screened positive for PTSD at 3 months after their injury. A mechanism of injury is a risk factor for PTSD, and younger adults, victims of crime, and pedestrians struck by motor vehicles are at higher risk. These findings offer the potential to more effectively target and refer vulnerable patient populations to appropriate treatment. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a compete description of levels of evidence.

Evaluation of International Normalized Ratio Thresholds for Complications in Hip Fractures Treated With Intramedullary Nailing: Analysis of 15,323 Cases.

INTRODUCTION: In hip fracture patients with elevated international normalized ratios (INRs), the risks of delaying surgery for correction of INR are controversial. We examined the association of (1) preoperative INR values and (2) surgical delay with postoperative complications after intramedullary nailing of hip fractures. METHODS: Using the National Surgical Quality Improvement Program database, we retrospectively identified patients that underwent intramedullary nailing for hip fractures from 2005 to 2016. Patients aged older than 55 years with preoperative INR recorded ≤1 day before surgery were included. Patients were stratified into five cohorts-(1) INR ≤ 1.0, (2) 1 < INR ≤ 1.25 (INR [1 to 1.25]), (3) 1.25 < INR ≤ 1.5 (INR [1.25 to 1.5]), (4) 1.5 < INR ≤ 2.0 (INR [1.5 to 2.0]), and (5) INR > 2.0. The primary outcomes of interest were postoperative bleeding requiring transfusion, surgical site infection, and 30-day mortality. Multivariate regression analysis was done to adjust for potential confounding variables. RESULTS: In total, 15,323 patients were included in this analysis. Adjusting for potential confounders, INR [1 to 1.25], INR [1.25 to 1.5], and INR [1.5 to 2.0] were associated with increased mortality (adjusted odds ratio [aOR]: 1.501, P < 0.001; aOR: 2.226, P < 0.001; aOR: 2.524, P < 0.001, respectively) and surgical delay >48 hours (aOR: 1.655, P < 0.001; aOR: 3.434, P < 0.001; aOR: 2.382, P < 0.001, respectively). The INR > 2.0 cohort was not associated with mortality (P = 0.181) or surgical delay (P = 0.529). Surgical delay was associated with mortality (aOR: 1.531, P = 0.004). The INR > 2.0 cohort was associated with increased rate of transfusions (aOR: 1.388, P = 0.039). CONCLUSION: Elevated preoperative INR value within 1 day of surgery between 1.0 and 2.0 was associated with increased risk of 30-day mortality and surgical delay >48 hour, which may represent attempts at INR correction. An INR greater than 2.0 was not associated with mortality or surgical delay but was associated with increased transfusions. Surgical delay was independently associated with increased risk of 30-day mortality. We therefore recommend that INR reversal be attempted but not delay surgical fixation of geriatric hip fractures over 48 hours and counsel patients and their families regarding the risks of surgery with elevated INR. LEVEL OF EVIDENCE: Prognostic-level III/retrospective cohort study.

Factors influencing functional outcomes following open reduction internal fixation of acetabular fractures.

INTRODUCTION: Recent large series of patient-reported outcomes after acetabulum fracture are limited, and potentially modifiable risk factors may be unidentified. The goal of this study was to describe patient and injury factors which negatively influence functional outcomes following operative management of acetabular fractures. METHODS: 699 patients with acetabular fractures were treated with open reduction and internal fixation (ORIF). Musculoskeletal Function Assessment (MFA) questionnaire was completed after a minimum 12 months post-injury by 283 adults. MFA scores range from 1 to 100 and higher scores represent greater dysfunction. Factors were assessed for potential association with MFA scores, and univariate and multiple linear regression analyses were performed. RESULTS: Survey respondents were more severely injured than non-respondents, with more chest injury (38% vs 22%, p<0.001) and higher Injury Severity Score (19.3 vs 16.8, p=0.003). Patients were 69% male with mean age 44.0 years. Approximately one-third were smokers (31%), while 14% had comorbid diabetes mellitus type II. The majority of injuries occurred during a motor vehicle collision (65%); low-energy mechanisms were rare (4.2%). The most common fracture pattern was isolated posterior wall (23%), followed by transverse/posterior wall (21%). Heterotopic ossification (HO) was noted in 22%: Brooker 1: 29.5%, 2: 23.0%, 3: 32.8%, and 4: 14.8%. Tobacco use (ß = 18.4, p<0.001), obesity (ß = 0.39, p=0.009), diabetes (ß = 8.2, p=0.029), post-traumatic arthrosis (PTA) (ß = 5.94 p=0.035), and increasing HO severity (ß = 8.93, p<0.001) were independently associated with worse MFA scores. Tobacco use had the strongest association, followed by the severity of HO. CONCLUSION: In a large series of patient-reported functional outcomes following fixation of acetabular fractures, tobacco use, obesity, comorbid diabetes, PTA, and HO were associated with worse MFA scores. Further study to mitigate HO should be considered. LEVEL OF EVIDENCE: III.