Oxidative metabolism is impaired by phosphate deficiency during fracture healing and is mechanistically related to BMP induced chondrocyte differentiation.

Prior studies of acute phosphate restriction during the endochondral phase of fracture healing showed delayed chondrocyte differentiation was mechanistically linked to decreased bone morphogenetic protein signaling. In the present study, transcriptomic analysis of fracture callus gene expression in three strains of mice was used to identify differentially expressed (FDR = q ≤ 0.05) genes in response to phosphate (Pi) restriction. Ontology and pathway analysis of these genes showed that independent of genetic background, a Pi-deficient diet downregulated (p = 3.16 × 10-23) genes associated with mitochondrial oxidative phosphorylation pathways as well as multiple other pathways of intermediate metabolism. Temporal clustering was used to identify co-regulation of these specific pathways. This analysis showed that specific Ox/Phos, tricarboxylic acid cycle, pyruvate dehydrogenase. Arginine, proline metabolism genes, and prolyl 4-hydroxylase were all co-regulated in response to dietary Pi restriction. The murine C3H10T½ mesenchymal stem cell line was used to assess the functional relationships between BMP2-induced chondrogenic differentiation, oxidative metabolism and extracellular matrix formation. BMP2-induced chondrogenic differentiation of C3H10T½ was carried out in culture media in the absence or presence of ascorbic acid, the necessary co-factor for proly hydroxylation, and in media with normal and 25 % phosphate levels. BMP2 treatment led to decreased proliferation, increased protein accumulation and increased collagen and aggrecan gene expression. Across all conditions, BMP2 increased total oxidative activity and ATP synthesis. Under all conditions, the presence of ascorbate further increased total protein accumulation, proly-hydroxylation and aggrecan gene expression, oxidative capacity and ATP production. Lower phosphate levels only diminished aggrecan gene expression with no other effects of metabolic activity being observed. These data suggest that dietary phosphate restriction controls endochondral growth in vivo indirectly through BMP signaling, which upregulates oxidative activity that is linked to overall protein production and collagen hydroxylation.

Postoperative Complications of Hip Fractures Patients on Chronic Coumadin: A Comparison Based on Operative International Normalized Ratio.

In current clinical practice, orthopedic surgeons often delay the surgery intervention on geriatric hip fracture patients to optimize the international normalized ratio (INR), in order to decrease the risk of postoperative hematological complications. However, some evidence suggests that full reversal protocols may not be necessary, especially for patients with prior thromboembolic history. Our study aims to compare the surgical outcomes of patients with normal versus elevated INR values. We conducted a retrospective chart review on 217 patients who underwent surgeries on hip fractures at two academic trauma centers. We found that in our group (n = 124) of patients with an INR value of 1.5-3.0, there was only one reoperation for a hematoma, but there was a trend for more blood transfusions. There was no statistically significant difference in the odds of reoperation or overall complications. Nevertheless, there were significantly more events of postoperative anemia in this high INR patient group.

The Role of Value-Based Implants in Orthopedic Trauma.

Health care costs in the United States continue to rise, and economic pressures influencing the care of the orthopedic trauma patient have never been greater. Value-based health care is vital to the survival of the current health care system, and the use of value-based implants is central to success. Value-based implants have similar clinical outcomes to conventional implants; however, multiple barriers exist. Despite biomechanical equivalence and significant cost savings, surgeons have difficultly changing implant use without financial incentive. The rise of physician-owned surgery centers, bundled payments, and gain sharing and comanagement agreements will likely drive this change.

The Role of Business Education in the Orthopedic Curriculum.

The field of orthopedics is becoming increasingly complex as the demands for success are not merely clinical competence and good interpersonal skills. To achieve practice stability strategic planning, contract negotiation, health care law, practice management, health care economics, and personal finance are all needed skills. Unfortunately, most of these areas of professional growth require some basic background in business principles. This is an area that most recent residency graduates feel is neglected as a core educational competency. In these changing times, it is imperative that orthopedic residents and fellows obtain some formal business education.

Correlation between RUST assessments of fracture healing to structural and biomechanical properties.

Radiographic Union Score for Tibia (RUST) and modified RUST (mRUST) are radiographic tools for quantitatively evaluating fracture healing using a cortical scoring system. This tool has high intra-class correlation coefficients (ICCs); however, little evidence has evaluated the scores against the physical properties of bone healing. Closed, stabilized fractures were made in the femora of C3H/HeJ male mice (8-12 week-old) of two dietary groups: A control and a phosphate restricted diet group. Micro-computed tomography (µCT) and torsion testing were carried out at post-operative days (POD) 14, 21, 35, and 42 (n = 10-16) per group time-point. Anteroposterior and lateral radiographic views were constructed from the µCT scans and scored by five raters. The raters also indicated if the fracture were healed. ICCs were 0.71 (mRUST) and 0.63 (RUST). Both RUST scores were positively correlated with callus bone mineral density (BMD) (r = 0.85 and 0.80, p < 0.001) and bone volume fraction (BV/TV) (r = 0.86 and 0.80, p < 0.001). Both RUST scores positively correlated with callus strength (r = 0.35 and 0.26, p < 0.012) and rigidity (r = 0.50 and 0.39, p < 0.001). Radiographically healed calluses had a mRUST ≥13 and a RUST ≥10 and had excellent relationship to structural and biomechanical metrics. Effect of delayed healing due to phosphate dietary restrictions was found at later time points with all mechanical properties (p < 0.011), however no differences found in the RUST scores (p > 0.318). Clinical relevance of this study is both RUST scores showed high correlation to physical properties of healing and generally distinguished healed vs. non-healed fractures. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:945-953, 2018.

Serum proteomic assessment of the progression of fracture healing.

A targeted proteomic analysis of murine serum over a 35-day course of fracture healing was carried out to determine if serum proteomic changes could be used to monitor the biological progression of fracture healing. Transverse, closed femoral fractures where generated and stabilized with intramedullary fixation. A single stranded DNA aptamer-based multiplexed proteomic approach was used to assay 1,310 proteins. The transcriptomic profiles for genes matching the 1,310 proteins were obtained by microarray analysis of callus mRNA. Of the 1,310 proteins analyzed, 850 proteins showed significant differences among the time points (p-value <0.05). Ontology assessment associated these proteins with osteoblasts, monocyte/macrophage lineages, mesenchymal stem cell lines, hepatic tissues, and lymphocytes. Temporal clustering of these data identified proteins associated with inflammation, cartilage formation and bone remodeling stages of healing. VEGF, Wnt, and TGF-ßsignaling pathways were restricted to the period of cartilage formation. Comparison of the proteomic and transcriptomic profiles showed that 87.5% of proteins in serum had concordant expression to their mRNA expression in the callus, while 12.5% of the protein and mRNA expression patterns were discordant. The discordant proteins that were elevated in the serum but down regulated in callus mRNA expression were related to clotting functions, allograft rejection, and complement function. While proteins down regulated in the serum and elevated in callus mRNA were associated with osteoblast function, NF-ĸb, and activin signaling. These data show the serum proteome may be used to monitor the different biological stages of fracture healing and have translational potential in assessing human fracture healing. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1153-1163, 2018.

APC Injuries With Symphyseal Fixation: What Affects Outcome?

OBJECTIVE: To evaluate the influence of the symphyseal position at union, implant failure, and the type of posterior ring injury on validated outcome measures. DESIGN: Retrospective review with prospectively collected validated outcome data. SETTING: Two academic level 1 trauma centers. PATIENTS/PARTICIPANTS: We evaluated 54 patients with operatively treated anterior-posterior compression (APC) type 2 and 3 injuries. INTERVENTION: Thirty-five APC type 2 and 19 APC type 3 injuries were reviewed at a minimum of 2 years after surgery. Average follow-up was 7 years. MAIN OUTCOME MEASURES: Patients were evaluated with validated EuroQol five dimensions (EQ5D), EuroQol health index, Visual Analog Score (VAS) pain, Majeed pelvic scores, and change in work status. The final anterior-posterior (AP) radiograph available was reviewed for implant failure and displacement. Revision surgery was documented based on implant status and displacement at final follow-up. RESULTS: There were trends toward better outcomes for APC type 2 for EQ5D and VAS pain. Patients with injury severity score (ISS) >16 had worse reported health, Majeed scores, and VAS pain. Nineteen patients had failure of fixation. There were no differences in any outcome measure; trends toward better Majeed score were found for patients with intact fixation. Displacements >15 mm anteriorly at final follow-up negatively affect outcomes with significantly worse EQ5D, reported health, and Majeed score. Two patients required revision surgery. There were no differences in final outcomes. CONCLUSIONS: No significant differences were found for APC type 2 versus type 3 injuries. Higher injury severity score resulted in worse outcomes and more pain. Outcomes were not effected by implant failure; however, major loss of reduction (>15 mm) anteriorly did negatively impact outcomes. Patients with failure who were revised to union did not have worse outcomes. LEVEL OF EVIDENCE: Prognostic level IV. See Instructions for Authors for a complete description of levels of evidence.

Using a Posterior Compartment Fasciotomy and Paratenon Closure in Acute Achilles Tendon Repair.

Soft tissue management, dissection, and handling are of paramount importance during Achilles tendon repair. Although surgical repairs of Achilles tendons have predictably excellent outcomes, complications including wound infection and stiffness are not uncommon. The authors' surgical technique for Achilles tendon repair includes tagging the posterior paratenon for later layered repair and incising the posterior fascia, exposing the flexor hallucis longus muscle belly. This posterior compartment fasciotomy allows for both hematoma evacuation away from the tenuous posterior skin and mobilization of the posterior paratendon for complete closure over the repaired Achilles tendon. With this modified technique, the authors report a 1% infection rate and a 1% failure rate. [Orthopedics. 2016; 39(4):e790-e793.].

Does Removal of the Symphyseal Cartilage in Symphyseal Dislocations Have Any Effect on Final Alignment and Implant Failure?

OBJECTIVES: To compare final symphyseal alignment, incidence of implant failure, and revision surgery with and without symphyseal cartilage excision in patients with symphyseal dislocations treated operatively. DESIGN: Retrospective review. SETTING: Two academic level 1 trauma centers. PATIENTS/PARTICIPANTS: We reviewed the records of 96 patients (89 men, 7 women) who had anterior posterior compression (APC) type 2 and 3 injuries requiring anterior plating. The average age was 46 years, and the average Injury Severity Score was 15.6. INTERVENTION: Fifty patients were treated with symphyseal cartilage removal, whereas a second cohort of 46 patients was treated without removal of the symphyseal cartilage at the time of symphyseal open reduction and internal fixation during the same time period in a different center. Operative indications were the same for both centers, with iliosacral screws used only for type 3 injuries. Both centers used 6-hole plates through a rectus sparing approach. MAIN OUTCOME MEASUREMENTS: Symphyseal separation was measured radiographically on preoperative and postoperative anteroposterior (AP) and outlet projections. The incidence of implant failure was recorded from the final postoperative radiograph available. Revision surgery was documented. RESULTS: The symphyseal space after cartilage excision was less than if retained, which was maintained through union. The incidence of implant failure was statistically lower when symphyseal cartilage was excised. There were 2 revisions of symphyseal fixation in the symphyseal retention group for implant failure versus none when excised. CONCLUSIONS: Symphyseal cartilage excision led to closer apposition of the symphyseal bodies, which correlated with substantially lower rates of implant failure, and revision surgery. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Mouse models of bone healing: fracture, marrow ablation, and distraction osteogenesis.

Three commonly used murine surgical models of bone healing [closed fracture with intramedullary fixation, distraction osteogenesis (DO), and marrow ablation by reaming] are presented. Detailed surgical protocols for each model are outlined. The nature of the regenerative processes and the types of research questions that may be addressed with these models are briefly outlined. The relative strengths and weaknesses of these models are compared to a number of other surgical models that are used to address similar research questions.

Overview of biological mechanisms and applications of three murine models of bone repair: closed fracture with intramedullary fixation, distraction osteogenesis, and marrow ablation by reaming.

Fractures are one of the most common large-organ, traumatic injuries in humans, and osteoporosis-related fractures are the fastest growing health care problem of aging. Elective orthopedic surgeries of the bones and joints also represent some of most common forms of elective surgeries performed. Optimal repair of skeletal tissues is necessary for successful outcomes of these many different orthopedic surgical treatments. Research focused on post-natal skeletal repair is therefore of immense clinical importance and of particular relevance in situations in which bone tissue healing is compromised due to the extent of tissue trauma or specific medical co-morbidities. Three commonly used murine surgical models of bone healing, closed fracture with intramedullary fixation, distraction osteogenesis (DO), and marrow ablation by reaming, are presented. The biological aspects of these models are contrasted and the types of research questions that may be addressed with these models are presented.

Identifying protein interactions with metal-modified DNA using microarray technology.

Protein microarrays have been used extensively to identify protein-protein interactions; however, this technology has not been widely applied to protein-DNA interactions. In particular, this work demonstrates the utility of this technique for rapidly identifying interactions of proteins with metal-modified DNA. Protein macroarray experiments were carried out with high mobility group protein 1 (HMG-1) and cisplatin- and chromium-modified 50-mer oligonucleotides to demonstrate "proof of principle." Commercially available protein microarrays containing many different classes of human proteins were then employed to search for additional interactions with cisplatin-modified DNA. The results of the microarray experiments confirmed some known interactions and, more importantly, identified many novel protein interactions, demonstrating the utility of this method as a rapid, high-throughput technique to discover proteins that interact with metal-modified DNA.