The subacromial bursa modulates tendon healing after rotator cuff injury in rats.

Rotator cuff injuries result in more than 500,000 surgeries annually in the United States, many of which fail. These surgeries typically involve repair of the injured tendon and removal of the subacromial bursa, a synovial-like tissue that sits between the rotator cuff and the acromion. The subacromial bursa has been implicated in rotator cuff pathogenesis and healing. Using proteomic profiling of bursa samples from nine patients with rotator cuff injury, we show that the bursa responds to injury in the underlying tendon. In a rat model of supraspinatus tenotomy, we evaluated the bursa's effect on the injured supraspinatus tendon, the uninjured infraspinatus tendon, and the underlying humeral head. The bursa protected the intact infraspinatus tendon adjacent to the injured supraspinatus tendon by maintaining its mechanical properties and protected the underlying humeral head by maintaining bone morphometry. The bursa promoted an inflammatory response in injured rat tendon, initiating expression of genes associated with wound healing, including Cox2 and Il6. These results were confirmed in rat bursa organ cultures. To evaluate the potential of the bursa as a therapeutic target, polymer microspheres loaded with dexamethasone were delivered to the intact bursae of rats after tenotomy. Dexamethasone released from the bursa reduced Il1b expression in injured rat supraspinatus tendon, suggesting that the bursa could be used for drug delivery to reduce inflammation in the healing tendon. Our findings indicate that the subacromial bursa contributes to healing in underlying tissues of the shoulder joint, suggesting that its removal during rotator cuff surgery should be reconsidered.

The subacromial bursa is a key regulator of the rotator cuff and a new therapeutic target for improving repair.

Rotator cuff injuries result in over 500,000 surgeries performed annually, an alarmingly high number of which fail. These procedures typically involve repair of the injured tendon and removal of the subacromial bursa. However, recent identification of a resident population of mesenchymal stem cells and inflammatory responsiveness of the bursa to tendinopathy indicate an unexplored biological role of the bursa in the context of rotator cuff disease. Therefore, we aimed to understand the clinical relevance of bursa-tendon crosstalk, characterize the biologic role of the bursa within the shoulder, and test the therapeutic potential for targeting the bursa. Proteomic profiling of patient bursa and tendon samples demonstrated that the bursa is activated by tendon injury. Using a rat to model rotator cuff injury and repair, tenotomy-activated bursa protected the intact tendon adjacent to the injured tendon and maintained the morphology of the underlying bone. The bursa also promoted an early inflammatory response in the injured tendon, initiating key players in wound healing. In vivo results were supported by targeted organ culture studies of the bursa. To examine the potential to therapeutically target the bursa, dexamethasone was delivered to the bursa, prompting a shift in cellular signaling towards resolution of inflammation in the healing tendon. In conclusion, contrary to current clinical practice, the bursa should be retained to the greatest extent possible and provides a new therapeutically target for improving tendon healing outcomes. One Sentence Summary: The subacromial bursa is activated by rotator cuff injury and regulates the paracrine environment of the shoulder to maintain the properties of the underlying tendon and bone.

Subspecialty Selection Impacts Research Productivity and Faculty Rank of Academic Orthopaedic Surgeons.

BACKGROUND: Faculty promotion and research productivity are important for the overall career trajectory of academic orthopaedic surgeons. The purpose of this study was to investigate the role that subspecialty and demographic factors play in research productivity and academic advancement among orthopaedic surgeons. METHODS: We conducted a retrospective cross-sectional analysis of academic rank among orthopaedic surgeons in 2018. We identified academic orthopaedic programs in the United States from the Fellowship and Residency Electronic Interactive Database (FREIDA) and collected publicly available data for surgeons, including fellowship training, gender, faculty rank, geographic region, and years since residency, from institutional websites. Research productivity was defined with the Hirsch index (h-index) from Scopus, and the m-index was calculated from the surgeon's h-index and the date of the first publication. Multivariate regression analyses were performed to determine the variables that are associated with associate professorship, full professorship, and the h-index. RESULTS: In this study, we identified and included 2,879 academic orthopaedic surgeons. Completion of a fellowship in foot and ankle (odds ratio [95% confidence interval]: 2.45 [1.17 to 5.15]), sports medicine (2.15 [1.12 to 4.15]), trauma (2.83 [1.42 to 5.66]), hand and upper extremity (2.20 [1.13 to 4.28]), musculoskeletal oncology (3.28 [1.49 to 7.21]), or upper-extremity reconstruction (3.20 [1.31 to 7.81]) was associated with associate professorship. Completion of a trauma fellowship was associated with full professorship (2.93 [1.27 to 6.77]). Completion of a fellowship in adult reconstruction (difference in least-squares means [95% confidence interval]: 5.01 [1.22 to 8.81]), sports medicine (4.52 [1.00 to 8.04]), spine (5.40 [1.63 to 9.18]), or upper-extremity reconstruction (10.64 [6.15 to 15.12]) or the completion of multiple fellowships (5.12 [1.27 to 8.94]) were independently associated with a higher h-index. Women had significantly lower h-indices than men at the assistant (median [interquartile range]: 3 [1 to 6] versus 4 [2 to 8]) and full professor (17 [12 to 26] versus 22 [13 to 34]) levels. There were no differences in the m-index between men and women at any academic rank. CONCLUSIONS: Orthopaedic subspecialty selection is independently associated with research productivity and academic rank. The differences in research productivity may be important to consider when evaluating orthopaedic surgeons for promotion. While female surgeons had lower h-indices than their male counterparts, this difference was not seen when using the m-index.

Transient neonatal shoulder paralysis causes early osteoarthritis in a mouse model.

Neonatal brachial plexus palsy (NBPP) occurs in approximately 1.5 of every 1,000 live births. The majority of children with NBPP recover function of the shoulder. However, the long-term risk of osteoarthritis (OA) in this population is unknown. The purpose of this study was to investigate the development of OA in a mouse model of transient neonatal shoulder paralysis. Neonatal mice were injected twice per week for 4 weeks with saline in the right supraspinatus muscle (Saline, control) and botulinum toxin A (BtxA, transient paralysis) in the left supraspinatus muscle, and then allowed to recover for 20 or 36 weeks. Control mice received no injections, and all mice were sacrificed at 24 or 40 weeks. BtxA mice exhibited abnormalities in gait compared to controls through 10 weeks of age, but these differences did not persist into adulthood. BtxA shoulders had decreased bone volume (-9%) and abnormal trabecular microstructure compared to controls. Histomorphometry analysis demonstrated that BtxA shoulders had higher murine shoulder arthritis scale scores (+30%), and therefore more shoulder OA compared to controls. Articular cartilage of BtxA shoulders demonstrated stiffening of the tissue. Compared with controls, articular cartilage from BtxA shoulders had 2-fold and 10-fold decreases in Dkk1 and BMP2 expression, respectively, and 3-fold and 14-fold increases in Col10A1 and BGLAP expression, respectively, consistent with established models of OA. In summary, a brief period of paralysis of the neonatal mouse shoulder was sufficient to generate early signs of OA in adult cartilage and bone.

Statistical Fragility of Surgical Clinical Trials in Orthopaedic Trauma.

INTRODUCTION: The Fragility Index (FI) and the Fragility Quotient (FQ) are powerful statistical tools that can aid clinicians in assessing clinical trial results. The purpose of this study was to use the FI and FQ to evaluate the statistical robustness of widely cited surgical clinical trials in orthopaedic trauma. METHODS: We performed a PubMed search for orthopaedic trauma clinical trials in high-impact orthopaedics-focused journals and calculated the FI and FQ for all identified dichotomous, categorical outcomes. RESULTS: We identified 128 studies with 545 outcomes. The median FI was 5, and the median FQ was 0.0482. For statistically significant and not statistically significant outcomes, the median FIs were 3 and 5, and the mean FQs were 0.0323 and 0.0526, respectively. The FI was greater than the number of patients lost to follow-up in most outcomes. CONCLUSIONS: The orthopaedic trauma literature is of equal or higher quality than research in other orthopaedic subspecialties, suggesting that other orthopaedic subspecialties may benefit from modeling their clinical trials after those in orthopaedic trauma.

Eponyms in Pediatric Sports Medicine: A Historical Review.

The use of eponyms in the orthopedics literature has come under scrutiny, and there is a growing body of literature evaluating the utility of these terms in modern healthcare delivery. Although the field of pediatric orthopedic sports medicine is a relatively modern subspecialty, it is built on a foundation of over 100 years of pediatric musculoskeletal medicine. As a result, eponyms account for a significant portion of the vernacular used in the field. The purpose of this review is to summarize and describe the history of common eponyms relevant to pediatric sports pathology, examination maneuvers, classification systems, and surgical procedures. Use of eponyms in medicine is flawed. However, an improved understanding of these terms allows for informed use in future scientific discourse, patient care and medical education and may encourage future innovation and research into understanding pediatric orthopedic pathologies.

Statistical fragility of randomized clinical trials in shoulder arthroplasty.

BACKGROUND: The P value is a statistical tool used to assess the statistical significance of clinical trial outcomes in orthopedic surgery. However, the P value does not evaluate research quality or clinical significance. The Fragility Index (FI) is an alternative statistical method that can be used to assess the quality and significance of clinical research and is defined as the number of patients in a study intervention group necessary to convert an outcome from statistically significant to statistically insignificant or vice versa. The primary purpose of this study was to evaluate the statistical robustness of clinical trials regarding shoulder arthroplasty using the FI. The secondary goal was to identify trial characteristics associated greater statistical fragility. METHODS: A systematic review of randomized clinical trials in shoulder arthroplasty was performed. The FI was calculated for all dichotomous, categorical study outcomes discussed in the identified studies. Descriptive statistics and the Pearson correlation coefficient were used to evaluate all studies and characterize associations between study variables. RESULTS: A total of 13 randomized controlled trials were identified and evaluated; these trials had a median sample size of 47 patients (mean, 54 patients; range, 26-102 patients) and a median of 7 patients (mean, 5.8 patients; range, 0-14 patients) lost to follow-up. The median FI was 6 (mean, 5; range, 1-11), a higher FI than what has been observed in other orthopedic subspecialties. However, the majority of outcomes (74.4%) had an FI that was less than the number of patients lost to follow-up, and most outcomes (89.7%) were statistically insignificant. CONCLUSION: Randomized controlled trials in shoulder arthroplasty have comparable statistical robustness to the literature in other orthopedic surgical subspecialties. We believe that the inclusion of the FI in future comparative studies in the shoulder arthroplasty literature will allow surgeons to better assess the statistical robustness of future research.

Statistical Fragility of Surgical and Procedural Clinical Trials in Orthopaedic Oncology.

The fragility index (FI) is a powerful tool that can be used to assess the statistical strength of a study outcome. This metric is defined as the number of patients who would need to have an alternative outcome to convert a clinical trial result from statistically significant to not statistically significant, or vice versa. No studies to date have used the FI to evaluate surgical and procedural clinical trials in the orthopaedic oncology literature. The primary purpose of this study was to use the FI to evaluate the statistical strength of widely cited surgical and procedural clinical trials in orthopaedic oncology. Methods: We performed a PubMed search for orthopaedic oncology clinical trials in high impact orthopaedics-focused, oncology-focused, and general medicine journals. For each study included in this analysis, we calculated the FI for all identified dichotomous, categorical outcomes. Results: We identified 23 studies with 48 outcomes. Twelve of these outcomes were statistically significant, with a median FI of two. Nine studies addressed the number of patients lost to follow up, and the FI was less than the number of patients lost to follow up for most outcomes (60%) in these studies. Conclusions: The orthopaedic oncology literature has substantial statistical fragility, likely explained by a high number of patients lost to follow up and small sample sizes. More multicenter, cooperative studies are necessary to increases the robustness of clinical research in orthopaedic oncology.

Men Receive Three Times More Industry Payments than Women Academic Orthopaedic Surgeons, Even After Controlling for Confounding Variables.

BACKGROUND: In 2016, orthopaedic surgeons received nearly USD 300 million from industry, with the top 10% of recipients making more than 95% of the total amount. The degree to which gender may be associated with industry compensation has not been well explored; however, this may be confounded by a number of variables, including academic productivity, experience, and other factors. We wished to explore the variability in payment distribution by gender after controlling for these factors. QUESTIONS/PURPOSES: (1) Do men or women academic orthopaedic surgeons receive more payments from industry? (2) To what degree do any observed differences between the genders persist, even after accounting for identifiable factors, including academic rank, scholarly productivity, regional location of university, subspecialty selection as identified by fellowships completed, and years since completion of residency? METHODS: This study was a cross-sectional retrospective analysis of surgeons practicing in orthopaedic surgery academic departments in the United States. Academic orthopaedic surgery departments were identified using the Fellowship and Residency Electronic Interactive Database. Publicly available data on gender, academic rank, scholarly productivity, regional location of university, fellowships completed, and years since residency graduation were collected from institutional websites. Industry funding data for 2016 were obtained from the Centers for Medicare & Medicaid Services Open Payments Database, and scholarly productivity data through 2017 were collected from Scopus. A total of 2939 academic orthopaedic surgeons, 2620 (89%) men and 319 (11%) women from 126 programs were identified. Men and women surgeons were different in most of the variables collected, and all except region of university were associated with differences in industry payments. RESULTS: The median payment for men surgeons was greater than that for women (USD 1027 [interquartile range USD 125-USD 9616] versus USD 177 [IQR USD 47-USD 1486]; difference of medians, USD 850; p < 0.001]. After accounting for potentially confounding variables like faculty rank, years since residency, H-index and subspecialty choice, women faculty members still received only 29% of payments received by otherwise comparable men orthopaedists (beta coefficient for gender = 0.29 [95% CI 0.20 to 0.44; p < 0.001]). CONCLUSIONS: Women academic orthopaedic surgeons received only 29% of the industry payments received by men, even after controlling for faculty rank, years since residency, H-index, and subspecialty selection. This gender-related disparity may hinder the career advancement of women orthopaedic surgeons. CLINICAL RELEVANCE: Increased transparency by companies can help guide orthopaedic surgeons who wish to receive industry funding.

Variability in rehabilitation protocols following pediatric anterior cruciate ligament (ACL) reconstruction.

Objectives: The objective of this study was to assess the variability of publicly available pediatric anterior cruciate ligament (ACL) reconstruction rehabilitation protocols produced by academic orthopedic surgery departments and children's hospitals.Methods: A web-based search was performed to identify rehabilitation protocols. Protocol and literature review guided the development of a comprehensive scoring rubric that was used to assess protocols for the presence and timing of postoperative adjunctive therapy and physical therapy recommendations.Results: A search of 180 academic orthopedic surgery programs and 250 children's hospitals identified 21 rehabilitation protocols. A majority of these protocols (90%) recommended postoperative adjunctive therapies such as bracing (81%), cryotherapy (43%), electrical muscle stimulation (24%), and/or continuous passive motion (14%). Several protocols (57%) recommended a specific weight-bearing status in the immediate postoperative period, but there was minimal consensus on that status. Conversely, there was more agreement amongst protocols that recommended strength exercises (52%); a majority of protocols suggested quad sets (91%), ankle pumps (73%), leg press (64%), and/or double-leg squats (55%). Ten protocols (48%) recommended initiation of stretches in the first week following surgery, and most commonly suggested patella mobilizations start at an average of 1.9 weeks postop (range 0-8 weeks). Twelve protocols (57%) discussed return to play, with an average recommended return to play at 7.5 months (range 3-11 months) postoperatively. However, few protocols recommended that patients get approval from their surgeon (19%) or pass specific tests (24%) prior to return to play.Conclusion: Few academic departments of orthopedic surgery or children's hospitals publish pediatric ACL reconstruction protocols online. Given the substantial variability observed amongst these protocols and recent findings that patients increasingly turn to the internet for medical information, this study suggests that standardization of pediatric ACL reconstruction rehabilitation has the potential to further optimize patient care.

Perfusion is Not Measurably Decreased in Idiopathic Clubfoot.

BACKGROUND: Vascular aberration has been accepted as a potential etiology of clubfoot, and abnormal vasculature has been observed in as high as 85% of children with severe clubfoot. The perfusion index (PI) corresponds to the ratio of pulsatile to nonpulsatile blood flow at a monitoring site and can be used to quantify perfusion of the extremities. The purpose of this study was to use PI to compare the perfusion of clubfeet to controls in order to further assess the role of abnormal vasculature in clubfoot. METHODS: A Masimo Radical 7 Pulse Oximeter (Masimo Corporation, Irvine, California) was used to measure the PI and oxygen saturation (SpO2) of the feet of children 5 years of age and younger with and without clubfoot. The sensor was placed on the great toe. Patients with clubfoot undergoing non-operative treatment and control patients undergoing treatment in a clinic for orthopedic concerns not involving the foot and with no known vascular issues were assessed. The PI and SpO2 for the following three groups were compared: 1. affected feet of patients with bilateral or unilateral clubfoot, 2. unaffected feet of patients with unilateral clubfoot, and 3. control feet. RESULTS: One hundred and twenty-eight patients were enrolled, 64 with clubfoot (31 bilateral and 33 unilateral) and 64 controls. No significant differences in PI or SpO2 were found between: 64 clubfeet and 64 feet of controls (PI of 2.9 vs. 2.9, p = 0.984; SpO2 of 97.1 vs. 98.1, p = 0.192); unaffected feet of 30 patients with unilateral clubfoot and 64 controls (PI of 3.0 vs.2.9, p = 0.907; SpO2 of 96.9 vs. 98.1, p = 0.224); and affected and unaffected feet of 30 patients with unilateral clubfoot (PI of 3.3 vs.3.0, p = 0.500; SpO2 of 97.4 vs. 96.9, p = 0.527). CONCLUSIONS: No difference was observed in the PI or SpO2 when comparing affected clubfoot limbs with unaffected limbs, suggesting that vascular anomalies cannot fully explain the development of clubfoot.

Notch suppresses angiogenesis and progression of hepatic metastases.

The Notch pathway plays multiple key roles in tumorigenesis, and its signaling components have therefore aroused great interest as targets for emerging therapies. Here, we show that inhibition of Notch, using a soluble receptor Notch1 decoy, unexpectedly caused a remarkable increase in liver metastases from neuroblastoma and breast cancer cells. Increased liver metastases were also seen after treatment with the γ-secretase inhibitor PF-03084014. Transgenic mice with heterozygous loss of Notch1 demonstrated a marked increase in hepatic metastases, indicating that Notch1 signaling acts as metastatic suppressor in the liver microenvironment. Inhibition of DLL1/4 with ligand-specific Notch1 decoys increased sprouting of sinusoidal endothelial cells into micrometastases, thereby supporting early metastatic angiogenic growth. Inhibition of tumor-derived JAG1 signaling activated hepatic stellate cells, increasing their recruitment to vasculature of micrometastases, thereby supporting progression to macrometastases. These results demonstrate that inhibition of Notch causes pathologic activation of liver stromal cells, promoting angiogenesis and growth of hepatic metastases. Our findings have potentially serious implications for Notch inhibition therapy.