Faculty Bibliography

OBJECTIVES/OBJECTIVE:Osteoarthritis (OA) is the most common joint disease; however, the indeterminate nature of mechanisms by which OA develops has restrained advancement of therapeutic targets. TNF signalling has been implicated in the pathogenesis of OA. TNFR1 primarily mediates inflammation, whereas emerging evidences demonstrate that TNFR2 plays an anti-inflammatory and protective role in several diseases and conditions. This study aims to decipher TNFR2 signalling in chondrocytes and OA. METHODS:Biochemical copurification and proteomics screen were performed to isolate the intracellular cofactors of TNFR2 complex. Bulk and single cell RNA-seq were employed to determine 14-3-3 epsilon (14-3-3ε) expression in human normal and OA cartilage. Transcription factor activity screen was used to isolate the transcription factors downstream of TNFR2/14-3-3ε. Various cell-based assays and genetically modified mice with naturally occurring and surgically induced OA were performed to examine the importance of this pathway in chondrocytes and OA. RESULTS:Signalling molecule 14-3-3ε was identified as an intracellular component of TNFR2 complexes in chondrocytes in response to progranulin (PGRN), a growth factor known to protect against OA primarily through activating TNFR2. 14-3-3ε was downregulated in OA and its deficiency deteriorated OA. 14-3-3ε was required for PGRN regulation of chondrocyte metabolism. In addition, both global and chondrocyte-specific deletion of 14-3-3ε largely abolished PGRN's therapeutic effects against OA. Furthermore, PGRN/TNFR2/14-3-3ε signalled through activating extracellular signal-regulated kinase (ERK)-dependent Elk-1 while suppressing nuclear factor kappa B (NF-κB) in chondrocytes. CONCLUSIONS:This study identifies 14-3-3ε as an inducible component of TNFR2 receptor complex in response to PGRN in chondrocytes and presents a previously unrecognised TNFR2 pathway in the pathogenesis of OA.

AIMS/OBJECTIVE:Physician burnout and its consequences have been recognized as increasingly prevalent and important issues for both organizations and individuals involved in healthcare delivery. The purpose of this study was to describe and compare the patterns of self-reported wellness in orthopaedic surgeons and trainees from multiple nations with varying health systems. METHODS:A cross-sectional survey of 774 orthopaedic surgeons and trainees in five countries (Australia, Canada, New Zealand, UK, and USA) was conducted in 2019. Respondents were asked to complete the Mayo Clinic Well-Being Index and the Stanford Professional Fulfillment Index in addition to 31 personal/demographic questions and 27 employment-related questions via an anonymous online survey. RESULTS:A total of 684 participants from five countries (Australia (n = 74), Canada (n = 90), New Zealand (n = 69), UK (n = 105), and USA (n = 346)) completed both of the risk assessment questionnaires (Mayo and Stanford). Of these, 42.8% (n = 293) were trainees and 57.2% (n = 391) were attending surgeons. On the Mayo Clinic Well-Being Index, 58.6% of the overall sample reported feeling burned out (n = 401). Significant differences were found between nations with regards to the proportion categorized as being at risk for poor outcomes (27.5% for New Zealand (19/69) vs 54.4% for Canada (49/90) ; p = 0.001). On the Stanford Professional Fulfillment Index, 38.9% of the respondents were classified as being burned out (266/684). Prevalence of burnout ranged from 27% for Australia (20/74 up to 47.8% for Canadian respondents (43/90; p = 0.010). Younger age groups (20 to 29: RR 2.52 (95% confidence interval (CI) 1.39 to 4.58; p = 0.002); 30 to 39: RR 2.40 (95% CI 1.36 to 4.24; p = 0.003); 40 to 49: RR 2.30 (95% CI 1.35 to 3.9; p = 0.002)) and trainee status (RR 1.53 (95% CI 1.15 to 2.03 p = 0.004)) were independently associated with increased relative risk of having a 'at-risk' or 'burnout' score. CONCLUSIONS: 2021;2(11):932-939.

Methotrexate (MTX) is widely used for the treatment of rheumatoid arthritis due to its well-known anti-inflammatory role in immune cells but its impact on brown and beige adipose tissue biology has not yet been investigated. Here, we present the novel evidence that MTX treatment increases the gene expression of thermogenic genes in brown and beige adipose tissues in a fat cell autonomous manner. Furthermore, we show that treatment of mice with MTX is associated with cold resistance, improved glucose homeostasis, decreased inflammation, and reduced hepatosteatosis in high-fat diet states. Overall, our data provide novel evidence of a role of MTX on thermogenic tissues not previously appreciated.

BACKGROUND:The purpose of this study is to describe a Level 1 Trauma Center's orthopedic response to the COVID-19 pandemic, and to compare outcomes of acute fracture patients pre-COVID versus during the COVID-19 pandemic. METHODS:All inpatient fracture cases performed over a 5-month period were identified and retrospective chart review performed. Patients were divided into pre- and COVID-era groups based on when surgery was performed relative to March 16, 2020 (the date elective operations were ceased), and groups were statistically compared. Patients with a COVID test result were further sub-divided into COVID negative and positive groups, and statistically compared. Statistical analysis was performed using independent t-test for continuous variables and chi-square analysis for categorical variables. RESULTS:One hundred and nineteen patients were identified, 38% females with average age of 58 years. Average length of stay was 7 days with average time from injury to surgery of 3 days and average time from admission to surgery of 1.3 days. Overall in-hospital complication rate was 29.4%, and 30-day mortality and readmission rates were 2.5% and 5%, respectively. Sixty-nine patients comprised the pre-COVID group, and 50 in the COVID-era group. There was no significant difference with respect to length of stay, time from injury to surgery, time from admission to surgery, need for post-operative ICU stay, in-hospital complication rate, 30-day mortality rate and 30-day readmission rate. Thirty-four patients had COVID testing, with 24 negative and 10 positive. COVID-positive patients had longer time from injury to surgery (8.5 days vs. 2 days, p = 0.003) and longer time from admission to surgery (2.7 days vs. 1.2 days, p = 0.034). While more COVID-positive patients required ICU admission post-operatively (60% vs. 21%, p = 0.036), there was no difference in overall complication rate. CONCLUSIONS:Orthopedic care of acute fracture patients was not affected by a global pandemic. The response of our Level 1 Trauma Center's orthopedic department can guide other hospitals if and when new surges in COVID cases arise, in order to prevent compromising appropriate orthopedic care. LEVEL OF EVIDENCE/METHODS:Prognostic III.

OBJECTIVES/OBJECTIVE:To evaluate the outcomes of patients who underwent soft tissue flap coverage during treatment of a tibia fracture nonunion. DESIGN/METHODS:Retrospective analysis on prospectively collected data. SETTING/METHODS:Academic medical center. PATIENTS/PARTICIPANTS/METHODS:157 patients were treated for a fracture nonunion following a tibia fracture over a 15-year period. Sixty-six had sustained an open tibial fracture initially and 25 of these patients underwent soft tissue flaps for their open tibia fracture nonunion. INTERVENTION/METHODS:Manipulation of soft tissue flaps, either placement or elevation for graft placement in ununited previously open tibial fractures. MAIN OUTCOME MEASUREMENTS/METHODS:Bony healing, time to union, ultimate soft tissue status, postoperative complications, and functional outcome scores using the Short Musculoskeletal Functional Assessment (SMFA). This group was compared to a group of open tibial fracture nonunions that did not undergo soft tissue transfer. RESULTS:Bony healing was achieved in 24/25 patients (96.0%) who received flaps at a mean time to union of 8.7 ± 3.3 months compared to 39/41 patients (95.1%) at a mean 7.5 ± 3.2 months (p > 0.05) in the non-coverage group. Healing rate and time to union did not differ between groups. At latest follow-up, the flap coverage group reported a mean SMFA index of 17.1 compared to an SMFA index of 27.7 for the non-coverage group (p = 0.037). CONCLUSIONS:Utilization of soft tissue flaps in the setting of open tibia shaft nonunion repair surgery are associated with a high union rate (>90%). Coverage with or manipulation of soft tissue flaps did not result in improved bony healing rate or time to union compared to those who did not require flaps. However, soft tissue flap coverage was associated with higher functional scores at long-term follow-up. LEVEL OF EVIDENCE/METHODS:Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

SUMMARY/CONCLUSIONS:Operative management of sternoclavicular fracture-dislocations is recommended in the setting of symptomatic nonunion. Treatment options include open reduction internal fixation, fragment excision, and ligamentous reconstruction. We present a 29-year-old man with a medial clavicle fracture nonunion that previously failed open reduction internal fixation and was treated with sternoclavicular joint reconstruction using tendon allograft.

»:The induced membrane technique (IMT) takes advantage of an osteoinductive environment that is created by the placement of a cement spacer into a bone defect. »:Most commonly, a polymethylmethacrylate (PMMA) spacer has been used, but spacers made from other materials have emerged and achieved good clinical outcomes. »:The IMT has demonstrated good results for long-bone repair; however, more research is required in order to optimize union rates as well as delineate more precise indications and surgical timing.

Although distal radius fractures are quite common, bilateral distal radius fractures seldomly occur. Due to this, treatment is primarily based on surgeon experience with unilateral fractures, however bi- lateral fractures add a level of complexity : loss of functional independence. The purpose of this study was to examine a cohort of patients with bilateral distal radius fractures to identify differences in demographics, mechanism of injury, and outcomes to further our understanding of these rare injuries. 23 patients were identified retrospectively over a 5-year period that met inclusion criteria. The medical records were reviewed with multiple demographic and clinical parameters recorded and analyzed. Males were more likely to sustain high-energy mechanisms (80% vs. 53%). Patients <50 years old were more likely to sustain high-energy mechanisms (90% vs. 46%) and were more likely to be treated operatively (80% vs. 62%). The most commonly associated injury was a head injury (30%). All patients treated non-operatively reported minimal/no pain upon final follow-up where 57% of patients treated operatively noted regular pain. 75% of patients with medical comorbidities had minimal/no pain upon final follow- up. Conclusions : Patients with bilateral fractures were more likely to be younger males who suffered from higher energy mechanisms. Age was a critical factor in determining treatment strategy. Rates of associated head injuries were elevated, which is an important factor for the clinician to keep in mind when treating this population. As we further our understanding of this unique population, we can improve our treatment approaches and subsequently attain better outcomes.

Interest and research in biologic approaches for tissue healing are exponentially growing for a variety of musculoskeletal conditions. The recent hype concerning musculoskeletal biological therapies (including viscosupplementation, platelet-rich plasma, and cellular therapies, or "stem cells") is driven by several factors, including demand by patients promising regenerative evidence supported by substantial basic and translational work, as well as commercial endeavors that complicate the scientific and lay understanding of biological therapy outcomes. While significant improvements have been made in the field, further basic and preclinical research and well-designed randomized clinical trials are needed to better elucidate the optimal indications, processing techniques, delivery, and outcome assessment. Furthermore, biologic treatments may have potential devastating complications when proper methods or techniques are ignored. For these reasons, an association comprising several scientific societies, named the Biologic Association (BA), was created to foster coordinated efforts and speak with a unified voice, advocating for the responsible use of biologics in the musculoskeletal environment in clinical practice, spearheading the development of standards for treatment and outcomes assessment, and reporting on the safety and efficacy of biologic interventions. This article will introduce the BA and its purpose, provide a summary of the 2020 first annual Biologic Association Summit, and outline the future strategic plan for the BA.

Adult bone regeneration is orchestrated by the precise actions of osteoprogenitor cells (OPCs). However, the mechanisms by which OPC proliferation and differentiation are linked and thereby regulated are yet to be defined. Here, we present evidence that during intramembranous bone formation OPC proliferation is controlled by Notch signaling, while differentiation is initiated by activation of canonical Wnt signaling. The temporospatial separation of Notch and Wnt signal activation during the early stages of bone regeneration suggests crosstalk between the two pathways. In vitro and in vivo manipulation of the two essential pathways demonstrate that Wnt activation leads to initiation of osteogenic differentiation and at the same time inhibits Notch signaling, which results in termination of the proliferative phase. Here, we establish canonical Wnt signaling as a key regulator that facilitates the crosstalk between OPC proliferation and differentiation during intramembranous, primary bone healing.