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Category: Ankle; Trauma Introduction/Purpose: Ankle fractures are extremely common orthopaedic injuries that frequently require surgical fixation. In the post-operative setting these fractures are routinely monitored with radiographs. However, the utility of routine post-operative imaging in clinically asymptomatic patients is unclear. This study sought to examine how frequently post-operative radiographs result in management changing decisions for operatively treated ankle fractures. We further sought to identify whether the indication for the study would play a role in the clinical utility of the examination. Methods: This was a retrospective study conducted at a single level 1 trauma center. A detailed review of the hospital’s electronic health record was performed. All patients with operatively treated ankle fractures over a two-year period were identified. Patients required at least one post-operative xray for inclusion. Xrays were divided into surveillance xrays and clinically correlated xrays. Surveillance xrays were those obtained in otherwise asymptomatic patients ordered as part of standard clinic workflow. Clinically indicated xrays were defined as any xrays taken outside of the standard workflow or those in which there was a documented concern noted by the patient or provider. To quantify the cost associated with xrays, we performed a cost analysis. A multivariate logistic regression was then performed using patient demographic variables, fracture characteristics (open vs closed, comminution, syndesmotic injury), and whether the study was performed with a clinical concern or as part of standard asymptomatic follow-up screening. Results: A total of 193 patients with 438 xrays met inclusion criteria. Overall, five asymptomatic radiographs were determined to have changed management (1.3% of all asymptomatic xrays), while 18 clinically correlated xrays were determined to have resulted in a change in management or clinical decision making(38.3%). The difference between number of management changing studies between asymptomatic vs clinically driven xrays was significant (p < 0.001). The elimination of all asymptomatic xrays over the study period would have resulted in a savings of 21,825.62 USD per year. In the logistic regression, the only factor found to be significant in predicting a change in management was the presence of a documented clinical concern voiced by the patient (p < 0001). Conclusion: Screening radiographs in clinically asymptomatic patients with operatively managed ankle fractures have a low likelihood (Approx. 1%) of changing management. Such imaging represents costs to the healthcare system, increased time for patients during clinic visits, and radiation exposure. Such studies remain commonplace because of the concern for missed or delayed diagnosis. Future surveillance protocols must strike a careful balance between minimizing unnecessary studies, maximizing early complication detection, and being personalized towards individual patient level factors so as to optimize care and efficiency for both patient and health system.

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Existing primary evidence comparing fibular intramedullary fixation (IMF) with traditional plate fixation (PF) for the treatment of distal fibular fractures remains limited by modest sample sizes. Using a large national database, this study aims to compare use rates, fracture patterns, patient characteristics, time to surgery, complication rates, and cost between fibular IMF and PF within the United States. Adults treated with fibular IMF or PF between October 2015 and October 2021 were identified within the PearlDiver Database. The ratio of IMF-treated to PF-treated patients was tracked temporally to compare use rates. Fracture patterns were determined using fracture diagnoses within one-month preceding surgery. Further comparisons of IMF- and PF-treated groups only included patients with at least 12 months of follow-up, and patients with upper tibia or tibia shaft fractures were excluded. An analysis of cohorts matched at a 1 : 4 (IMF: PF) ratio to control for risk factors was performed to compare time to surgery, complication rates (infection, nonunion, malunion, revision, hardware removal, pulmonary embolism, and deep vein thrombosis), and cost. 39329 patients (2294 IMF and 37035 PF) were identified. IMF use trended upwards relative to PF use over time. Tibia and fibula shaft fractures were the most common injuries in IMF patients versus bimalleolar and trimalleolar fractures in PF patients. A higher proportion of IMF patients had open fractures. IMF patients were younger, with higher mean ECI, fewer female patients, and higher rates of CKD. Percutaneous approaches were more common among IMF patients. There were no significant differences in time to surgery or complication rates. IMF was less costly. The popularity of IMF trended upwards across the study period. IMF was used more commonly in injuries involving higher energy trauma and soft tissue disruption. Overall, IMF patients were younger with more comorbidities. When used in similar populations, IMF appears to be a cost-effective alternative to PF.

Category: Trauma; Ankle Introduction/Purpose: The traditional surgical treatment for distal fibula fractures is open reduction and plate fixation (PF). However, intramedullary fixation (IMF) has been shown to provide advantages over plate fixation, particularly in patients and injuries with higher risks of soft tissue complications. Current evidence comparing the two fixation types remains scarce and is limited by modest sample sizes. Using a large national database, this retrospective cohort study aims to examine differences in use rates, associated fracture patterns, patient characteristics (e.g. age, gender, comorbidities, Elixhauser Comorbidity Index (ECI)), and complication rates between fibular IMF and PF within the United States. Methods: Patients (age≥18) with lower leg or ankle fractures treated with fibular IMF or PF between October 2015 and October 2021 were identified using a United States insurance claims database. The monthly ratio of IMF-treated patients to PF-treated patients was tracked over time to compare use rates. Fracture patterns were determined using fracture diagnoses within one month preceding surgery. Further analyses of patient characteristics and complication rates only included fibula fracture patients with 12 months of post-operative follow-up, and patients with concomitant upper tibia or tibia shaft fractures were excluded. To compare complication rates, a 1:4 (IMF:PF) matched comparison was performed, controlling for age, gender, high-energy (i.e. pilon, lower tibia, and trimalleolar) fractures, diabetes, tobacco use, obesity, and chronic kidney disease (CKD). Comparisons were conducted using chi-squared tests for categorical variables and t-tests for means. Ordinary least squares regression was used to visualize the trend in monthly relative use rates. Results: In total, 39329 patients (2294 IMF, 37035 PF) were identified. IMF use trended upwards relative to PF use over time (Figure 1). Tibia and fibula shaft fractures were the most common fractures in IMF patients versus trimalleolar and bimalleolar fractures in PF patients. A higher proportion of IMF patients had open fractures (p < 0.01). 627 IMF and 29703 PF patients were included for further analysis of patient characteristics and complications. The IMF cohort was younger, with higher mean ECI, fewer females, and higher rates of CKD (ps < 0.01). No significant differences in diabetes, tobacco use, or obesity rates were identified. Among 316 IMF and 1254 PF matched patients, no significant differences in infection, nonunion, malunion, revision, hardware removal, pulmonary embolism, and deep vein thrombosis rates were found. Conclusion: The upward trend in the ratio of IMF-treated to PF-treated patients suggests that the popularity of IMF is steadily rising. The higher rate of concomitant tibia shaft fractures and open fractures seen among IMF-treated patients in this study is consistent with the use of fibular IMF in cases involving higher-energy trauma and soft-tissue disruption. Higher ECI scores and rates of CKD in IMF patients also suggest that IMF is used more frequently in medically complex patients with impaired wound healing. Lastly, fibular IMF appears to be a viable alternative to PF when used in similar populations.

Plasmid DNA (pDNA) isolation from bacterial cells is one of the most common and critical steps in molecular cloning and biomedical research. Almost all pDNA purification involves disruption of bacteria, removal of membrane lipids, proteins and genomic DNA, purification of pDNA from bulk lysate, and concentration of pDNA for downstream applications. While many liquid-phase and solid-phase pDNA purification methods are used, the final pDNA preparations are usually contaminated with varied degrees of host RNA, which cannot be completely digested by RNase A. To develop a simple, cost-effective, and yet effective method for RNA depletion, we investigated whether commercially available size selection magnetic beads (SSMBs), such as Mag-Bind® TotalPure NGS Kit (or Mag-Bind), can completely deplete bacterial RNA in pDNA preparations. In this proof-of-principle study, we demonstrated that, compared with RNase A digestion and two commercial plasmid affinity purification kits, the SSMB method was highly efficient in depleting contaminating RNA from pDNA minipreps. Gene transfection and bacterial colony formation assays revealed that pDNA purified from SSMB method had superior quality and integrity to pDNA samples cleaned up by RNase A digestion and/or commercial plasmid purification kits. We further demonstrated that the SSMB method completely depleted contaminating RNA in large-scale pDNA samples. Furthermore, the Mag-bind-based SSMB method costs only 5–10% of most commercial plasmid purification kits on a per sample basis. Thus, the reported SSMB method can be a valuable and inexpensive tool for the removal of bacterial RNA for routine pDNA preparations.

Notch is a cell–cell signaling pathway that is involved in a host of activities including development, oncogenesis, skeletal homeostasis, and much more. More specifically, recent research has demonstrated the importance of Notch signaling in osteogenic differentiation, bone healing, and in the development of the skeleton. The craniofacial skeleton is complex and understanding its development has remained an important focus in biology. In this review we briefly summarize what recent research has revealed about Notch signaling and the current understanding of how the skeleton, skull, and face develop. We then discuss the crucial role that Notch plays in both craniofacial development and the skeletal system, and what importance it may play in the future.

RNA interference (RNAi) is mediated by an ∼21-nt double-stranded small interfering RNA (siRNA) and shows great promise in delineating gene functions and in developing therapeutics for human diseases. However, effective gene silencing usually requires the delivery of multiple siRNAs for a given gene, which is often technically challenging and time-consuming. In this study, by exploiting the type IIS restriction endonuclease-based synthetic biology methodology, we developed the fast assembly of multiplex siRNAs (FAMSi) system. In our proof-of-concept experiments, we demonstrated that multiple fragments containing three, four, or five siRNA sites targeting common Smad4 and/or BMPR-specific Smad1, Smad5, and Smad8 required for BMP9 signaling could be assembled efficiently. The constructed multiplex siRNAs effectively knocked down the expression of Smad4 and/or Smad1, Smad5, and Smad8 in mesenchymal stem cells (MSCs), and they inhibited all aspects of BMP9-induced osteogenic differentiation in bone marrow MSCs (BMSCs), including decreased expression of osteogenic regulators/markers, reduced osteogenic marker alkaline phosphatase (ALP) activity, and diminished in vitro matrix mineralization and in vivo ectopic bone formation. Collectively, we demonstrate that the engineered FAMSi system provides a fast-track platform for assembling multiplexed siRNAs in a single vector, and thus it may be a valuable tool to study gene functions or to develop novel siRNA-based therapeutics.

Abstract Introduction: Many institutions are attempting to implement patient-reported outcome (PRO) measures. Because PROs often change clinical workflows significantly for patients and providers, implementation choices can have major impact. While various implementation guides exist, a stepwise list of decision points covering the full implementation process and drawing explicitly on a sociotechnical conceptual framework does not exist. Methods: To facilitate real-world implementation of PROs in electronic health records (EHRs) for use in clinical practice, members of the EHR Access to Seamless Integration of Patient-Reported Outcomes Measurement Information System (PROMIS) Consortium developed structured PRO implementation planning tools. Each institution pilot tested the tools. Joint meetings led to the identification of critical sociotechnical success factors. Results: Three tools were developed and tested: (1) a PRO Planning Guide summarizes the empirical knowledge and guidance about PRO implementation in routine clinical care; (2) a Decision Log allows decision tracking; and (3) an Implementation Plan Template simplifies creation of a sharable implementation plan. Seven lessons learned during implementation underscore the iterative nature of planning and the importance of the clinician champion, as well as the need to understand aims, manage implementation barriers, minimize disruption, provide ample discussion time, and continuously engage key stakeholders. Conclusions: Highly structured planning tools, informed by a sociotechnical perspective, enabled the construction of clear, clinic-specific plans. By developing and testing three reusable tools (freely available for immediate use), our project addressed the need for consolidated guidance and created new materials for PRO implementation planning. We identified seven important lessons that, while common to technology implementation, are especially critical in PRO implementation.

Cartilage, especially articular cartilage, is a unique connective tissue consisting of chondrocytes and cartilage matrix that covers the surface of joints. It plays a critical role in maintaining joint durability and mobility by providing nearly frictionless articulation for mechanical load transmission between joints. Damage to the articular cartilage frequently results from sport-related injuries, systemic diseases, degeneration, trauma, or tumors. Failure to treat impaired cartilage may lead to osteoarthritis, affecting more than 25% of the adult population globally. Articular cartilage has a very low intrinsic self-repair capacity due to the limited proliferative ability of adult chondrocytes, lack of vascularization and innervation, slow matrix turnover, and low supply of progenitor cells. Furthermore, articular chondrocytes are encapsulated in low-nutrient, low-oxygen environment. While cartilage restoration techniques such as osteochondral transplantation, autologous chondrocyte implantation (ACI), and microfracture have been used to repair certain cartilage defects, the clinical outcomes are often mixed and undesirable. Cartilage tissue engineering (CTE) may hold promise to facilitate cartilage repair. Ideally, the prerequisites for successful CTE should include the use of effective chondrogenic factors, an ample supply of chondrogenic progenitors, and the employment of cell-friendly, biocompatible scaffold materials. Significant progress has been made on the above three fronts in past decade, which has been further facilitated by the advent of 3D bio-printing. In this review, we briefly discuss potential sources of chondrogenic progenitors. We then primarily focus on currently available chondrocyte-friendly scaffold materials, along with 3D bioprinting techniques, for their potential roles in effective CTE. It is hoped that this review will serve as a primer to bring cartilage biologists, synthetic chemists, biomechanical engineers, and 3D-bioprinting technologists together to expedite CTE process for eventual clinical applications.

Bone is a dynamic organ with high regenerative potential and provides essential biological functions in the body, such as providing body mobility and protection of internal organs, regulating hematopoietic cell homeostasis, and serving as important mineral reservoir. Bone defects, which can be caused by trauma, cancer and bone disorders, pose formidable public health burdens. Even though autologous bone grafts, allografts, or xenografts have been used clinically, repairing large bone defects remains as a significant clinical challenge. Bone tissue engineering (BTE) emerged as a promising solution to overcome the limitations of autografts and allografts. Ideal bone tissue engineering is to induce bone regeneration through the synergistic integration of biomaterial scaffolds, bone progenitor cells, and bone-forming factors. Successful stem cell-based BTE requires a combination of abundant mesenchymal progenitors with osteogenic potential, suitable biofactors to drive osteogenic differentiation, and cell-friendly scaffold biomaterials. Thus, the crux of BTE lies within the use of cell-friendly biomaterials as scaffolds to overcome extensive bone defects. In this review, we focus on the biocompatibility and cell-friendly features of commonly used scaffold materials, including inorganic compound-based ceramics, natural polymers, synthetic polymers, decellularized extracellular matrix, and in many cases, composite scaffolds using the above existing biomaterials. It is conceivable that combinations of bioactive materials, progenitor cells, growth factors, functionalization techniques, and biomimetic scaffold designs, along with 3D bioprinting technology, will unleash a new era of complex BTE scaffolds tailored to patient-specific applications.

Category: Ankle, Diabetes, Hindfoot, Lesser Toes, Midfoot/Forefoot, Infection Introduction/Purpose: Osteomyelitis of the foot and ankle is a common condition with a high economic burden in the United States, particularly in the context of diabetes mellitus. The timely and accurate diagnosis of osteomyelitis is important to initiate treatment and possibly reduce overall healthcare costs. Plain radiographs are the initial study of choice given their widespread availability and low cost. Magnetic resonance imaging (MRI) is generally considered the most sensitive imaging modality for detecting osteomyelitis, however it is associated with significant cost and may not change overall treatment as compared to plain radiographs. The purpose of our retrospective study is to determine whether the use of MRI at our institution changed clinical decision making and calculate the financial impact in patients with foot and ankle osteomyelitis. Methods: We retrospectively identified patients at our tertiary care, academic center treated for a diagnosis of osteomyelitis using ICD-9 codes 730.07, 730.17, and 730.27. Demographic data including age, sex, race and ethnicity and patient comorbidities was collected. The use of plain radiographs, MRI, and any operative procedures up to 2 years after the index encounter for each patient were identified. An impact MRI was defined as an MRI that led to an operative procedure within the same admission encounter. The cost of an impact MRI was estimated using the equation: (average MRI cost)*(total MRIs/impact MRIs). Chi- squared test was used to statistically compare patients that underwent procedures in the MRI group vs. those in non-MRI group. Results: 619 patients undergoing osteomyelitis treatment between January 2009 and September 2015 at our institution were identified, of which 40.4% were female and 59.6% were male. 151 patients had a total of 227 MRIs of the lower extremity performed vs. 468 patients that did not have MRIs performed. Of the MRI cohort, 104/151 patients (68.9%) had subsequent operative procedures, whereas in the non-MRI cohort 299/468 patients (63.9%) had subsequent operative procedures (p = 0.26). Of the 227 MRIs performed, 85 were deemed impactful MRIs and 142 were deemed non-impactful MRIs. Average MRI cost at our institution for the lower extremity with and without contrast was $5069.75. Using our previous definition, the cost of an impact MRI was calculated to be effectively $13,539.21. Conclusion: MRI can be an effective modality in aiding the clinical diagnosis of osteomyelitis, however, it can be an unnecessary cost when not used to guide treatment. In our study, we did not find a significant difference in the operative rate between patients undergoing MRIs vs. those that did not. We also found that the effective cost of an MRI that led to a change in treatment was $13,539, almost 2.7 times higher than the average cost of an MRI at our institution.

Category: Ankle, Ankle Arthritis Introduction/Purpose: Patients living with end stage ankle arthritis suffer significant disability. They are two standard deviations below population scores for all symptom and function SF-36 sub-scales. In addition, they tend to be younger and still active in the workforce. The economic impact of disability attributable to end0stage ankle arthritis has not been quantified. In the era of cost- effectiveness, policy makers want to see tangible evidence to justify the cost of treatment. One common metric has been quality adjusted life years (QALYs). The purpose of this study is to determine the gain in QALYs attributable to surgical treatment of end- stage arthritis. Methods: This study is based on an existing longitudinal cohort of end stage ankle arthritis patients. The study cohort included 180 subjects (45% female, 55% male) with an average age of 61 years, treated with either ankle arthrodesis or arthroplasty. Patients responses to the SF-36 questionnaire were transformed to SF-6D using SF-6D preference based algorithm licensed software (University of Sheffield, UK) to calculate the health utility value at time of surgical consent and at one year postoperatively. The difference in health utility value was assumed to be the gain in health attributable to end-stage ankle arthritis surgery. Using three theoretical valuations per QALY; $20000, $50000, and $100000, based on previously published cost per QUALY for other orthopedic conditions, we calculated the valuation per QALY for treating ankle arthritis at one year post surgery. Results: The mean pre-surgical health utility value was 0.603, and post-surgically it was 0.690, an average gain in health in one year of 0.087 QALY. This is greater than what is considered the minimally important difference threshold. We then calculated the economic gain at QALY valuations of $20000, $50000, and $100000; at $20000/QALY the cost per QALY is $1740. At $50000 the gain is $4350 cost per QALY, and at $100000 it is $8700 per QALY. Conclusion: From this study cohort, surgically treating end-stage ankle arthritis has a meaningful health benefit for a range of cost per QALYs. Moreover, spending on surgical treatment of end-stage ankle arthritis is cost-effective. These results from this cohort provide valuable empirical insights into treating end-stage ankle arthritis - these findings are meaningful for policy makers faced with resource allocation demands.