MicroRNA-29a: a novel target for non-operative management of symptomatic lumbar spinal stenosis.

PURPOSE: Lumbar spinal stenosis (LSS) is the most common reason for spinal surgery in patients over the age of 65, and there are few effective non-surgical treatments. Therefore, the development of novel treatment or preventative modalities to decrease overall cost and morbidity associated with LSS is an urgent matter. The cause of LSS is multifactorial; however, a significant contributor is ligamentum flavum hypertrophy (LFH) which causes mechanical compression of the cauda equina or nerve roots. We assessed the role of a novel target, microRNA-29a (miR-29a), in LFH and investigated the potential for using miR-29a as a therapeutic means to combat LSS. METHODS: Ligamentum flavum (LF) tissue was collected from patients undergoing decompressive surgery for LSS and assessed for levels of miR-29a and pro-fibrotic protein expression. LF cell cultures were then transfected with either miR-29a over-expressor (agonist) or inhibitor (antagonist). The effects of over-expression and under-expression of miR-29a on expression of pro-fibrotic proteins was assessed. RESULTS: We demonstrated that LF at stenotic levels had a loss of miR-29a expression. This was associated with greater LF tissue thickness and higher mRNA levels of collagen I and III. We also demonstrated that miR29-a plays a direct role in the regulation of collagen gene expression in ligamentum flavum. Specifically, agents that increase miR-29a may attenuate LFH, while those that decrease miR-29a promote fibrosis and LFH. CONCLUSION: This study demonstrates that miR-29a may potentially be used to treat LFH and provides groundwork to initiate the development of a therapeutic product for LSS.

Dynamic Changes in Lumbar Spine Kinematics During Gait May Explain Improvement in Back Pain and Disability in Patients With Hip-Spine Syndrome.

STUDY DESIGN: Prospective cohort. OBJECTIVE: Determine if total hip arthroplasty (THA) changes lumbar spine kinematics during gait in a manner that explains the improvements in back pain seen in patients with hip-spine syndrome. SUMMARY OF BACKGROUND DATA: For patients with hip-spine syndrome, improvements in both hip and back pain have been demonstrated after THA; however, the exact mechanism of improvement in back pain remains unknown, as no corresponding changes in lumbar spine static radiographic parameters have been identified. METHODS: Thirteen patients with severe, unilateral hip osteoarthritis scheduled to undergo THA with concomitant back pain and disability were tested at baseline and 6 months after THA. Harris Hip Score (HHS) and Oswestry Disability Index questionnaires were completed; the static orientation of the spine and pelvis were measured on standing radiographs, and lumbar spine kinematics were measured during treadmill walking using a validated measurement system that matched subject-specific bone models created from CT scans to dynamic biplane radiographs. RESULTS: After THA, both the Oswestry Disability Index (36.3-11.3, P <0.001) and Harris Hip Score (55.7-77.9, P <0.001) improved; however, there were no changes in static intervertebral or pelvis orientation. During gait after THA, the overall lumbar spine (L1 to L5) was less lordotic from heel strike to contralateral toe off ( P <0.001), the L4 and L5 vertebra were less anteriorly tilted by 3.9° ( P =0.038) from midstance to contralateral heel strike and by 3.9° ( P =0.001) during stance, respectively. CONCLUSION: The decreased anterior tilt of the 2 lowest lumbar vertebrae and the corresponding loss of lumbar lordosis may reduce facet loading during the stance phase of gait after THA. This change in lumbar spine kinematics during gait is a potential mechanism to explain the observed improvements in back pain and disability after THA. LEVEL OF EVIDENCE: 4.

Pre-Operative Bariatric Surgery Imparts An Increased Risk of Infection, Re-Admission and Operative Intervention Following Elective Instrumented Lumbar Fusion.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: To evaluate the impact of bariatric surgery on patient outcomes following elective instrumented lumbar fusion. METHODS: A retrospective review of a prospectively collected database was performed. Patients who underwent a bariatric procedure prior to an elective instrumented lumbar fusion were evaluated. Lumbar procedures were performed at a large academic medical center from 1/1/2012 to 1/1/2018. The primary outcome was surgical site infection (SSI) requiring surgical debridement. Secondary outcomes were prolonged wound drainage requiring treatment, implant failure requiring revision, revision secondary to adjacent segment disease (ASD), and chronic pain states. A randomly selected, surgeon and comorbidity-matched group of 59 patients that underwent an elective lumbar fusion during that period was used as a control. Statistical analysis was performed using Student's two-way t-tests for continuous data, with significance defined as P < .05. RESULTS: Twenty-five patients were identified who underwent bariatric surgery prior to elective lumbar fusion. Mean follow-up was 2.4 ± 1.9 years in the bariatric group vs. 1.5 ± 1.3 years in the control group. Patients with a history of bariatric surgery had an increased incidence of SSI that required operative debridement, revision surgery due to ASD, and a higher incidence of chronic pain. Prolonged wound drainage and implant failure were equivalent between groups. CONCLUSION: In the present study, bariatric surgery prior to elective instrumented lumbar fusion was associated increased risk of surgical site infection, adjacent segment disease and chronic pain when compared to non-bariatric patients.

To Cross the Cervicothoracic Junction? Terminating Posterior Cervical Fusion Constructs Proximal to the Cervicothoracic Junction Does Not Impart Increased Risk of Reoperation in Patients With Cervical Spondylotic Myelopathy.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: To evaluate the effect of caudal instrumentation level on revision rates following posterior cervical laminectomy and fusion. METHODS: A retrospective review of a prospectively collected database was performed. Minimum follow-up was one year. Patients were divided into two groups based on the caudal level of their index fusion construct (Group 1-cervical and Group 2- thoracic). Reoperation rates were compared between the two groups, and preoperative demographics and radiographic parameters were compared between patients who required revision and those who did not. Multivariate binomial regression analysis was performed to determine independent risk factors for revision surgery. RESULTS: One hundred thirty-seven (137/204) patients received fusion constructs that terminated at C7 (Group 1), while 67 (67/204) received fusion constructs that terminated at T1 or T2 (Group 2). The revision rate was 8.33% in the combined cohort, 7.3% in Group 1, and 10.4% in Group 2. There was no significant difference in revision rates between the 2 groups (P = .43). Multivariate regression analysis did not identify any independent risk factors for revision surgery. CONCLUSION: This study shows no evidence of increased risk of revision in patients with fusion constructs terminating in the cervical spine when compared to patients with constructs crossing the cervicothoracic junction. These findings support terminating the fusion construct proximal to the cervicothoracic junction when indicated. LEVEL OF EVIDENCE: III.

Percutaneous lumbar annular puncture: A rat model to study intervertebral disc degeneration and pain-related behavior.

Background: Previous animal models of intervertebral disc degeneration (IDD) rely on open surgical approaches, which confound the degenerative response and pain behaviors due to injury to surrounding tissues during the surgical approach. To overcome these challenges, we developed a minimally invasive percutaneous puncture procedure to induce IDD in a rat model. Methods: Ten Fischer 344 male rats underwent percutaneous annular puncture of lumbar intervertebral discs (IVDs) at L2-3, L3-4, and L4-5. Ten unpunctured rats were used as controls. Magnetic resonance imagings (MRIs), serum biomarkers, and behavioral tests were performed at baseline and 6, 12, and 18 weeks post puncture. Rats were sacrificed at 18 weeks and disc histology, immunohistochemistry, and glycosaminoglycan (GAG) assays were performed. Results: Punctured IVDs exhibited significant reductions in MRI signal intensity and disc volume. Disc histology, immunohistochemistry, and GAG assay results were consistent with features of IDD. IVD-punctured rats demonstrated significant changes in pain-related behaviors, including total distance moved, twitching frequency, and rearing duration. Conclusions: This is the first reported study of the successful establishment of a reproducible rodent model of a percutaneous lumbar annular puncture resulting in discogenic pain. This model will be useful to test therapeutics and elucidate the basic mechanisms of IDD and discogenic pain.

In Vivo Evidence of Early Instability and Late Stabilization in Motion Segments Immediately Superior to Anterior Cervical Arthrodesis.

STUDY DESIGN: Prospective cohort study. OBJECTIVE: The aim was to identify patient factors that affect adjacent segment kinematics after anterior cervical discectomy and fusion (ACDF) as measured by biplane radiography. SUMMARY OF BACKGROUND DATA: The etiology of adjacent segment disease (ASD) may be multifactorial. Previous studies have investigated associations between patient factors and ASD, although few attempted to link patient factors with mechanical changes in the spine that may explain ASD development. Previous studies manually measured intervertebral motion from static flexion/extension radiographs, however, manual measurements are unreliable, and those studies failed to measure intervertebral motion during rotation. METHODS: Patients had continuous cervical spine flexion/extension and axial rotation movements captured at 30 images per second in a dynamic biplane radiography system preoperatively and 1 year after ACDF. Digitally reconstructed radiographs generated from subject-specific computed tomography scans were matched to the biplane radiographs using a validated tracking process. Dynamic kinematics and preoperative disc height were calculated from this tracking process. Preoperative magnetic resonance imagings were evaluated for disc bulge. Patient age, sex, body mass index, smoking status, diabetes, psychiatric history, presence of an inciting event, and length of symptoms were collected. Multivariate linear regression was performed to identify patient factors associated with 1-year postoperative changes in adjacent segment kinematics. RESULTS: Sixty-three patients completed preoperative and postoperative testing. Superior adjacent segment disc height and disc bulge predicted the change in superior adjacent segment range of motion after surgery. Inferior adjacent segment disc bulge, smoking history, and the use of psychiatric medications predicted the change in inferior adjacent segment flexion/extension range of motion after surgery. CONCLUSIONS: Preexisting adjacent segment disc degeneration, as indicated by disc height and disc bulge, was associated with reduced adjacent segment motion after ACDF, while lack of preexisting adjacent disc degeneration was associated with increased adjacent segment motion after ACDF. These findings provide in vivo evidence supporting early instability and late stabilization in the pathophysiology of disc degeneration.

Increased Medial Displacement of the Humeral Shaft of at Least 40% Correlates With an Increased Incidence of Nerve Injury in Proximal Humerus Fractures.

BACKGROUND: Peripheral nerve and infraclavicular brachial plexus injury following proximal humerus fractures are commonplace, but diagnosing a concomitant nerve injury in the acute setting is challenging. Fracture displacement has been identified as a qualitative risk factor for nerve injury, and additional attention should be paid to the neurologic exams of patients with proximal humerus fractures with significant medial shaft displacement. However, a quantitative relationship between the risk of nerve injury and medialization of the humeral shaft has not been shown, and additional risk factors for this complication have not been assessed. The aim of this study was to identify the risk factors for a neurologic deficit following a proximal humerus fracture, with particular interest in the utility of the magnitude of medial shaft displacement as a predictor of neurologic dysfunction. METHODS: A retrospective chart review was performed on all proximal humerus fractures in a 3-year period (2012-2015) at a level one trauma center. Isolated greater tuberosity fractures (OTA 11-A1) were excluded. Fracture displacement was measured on initial injury AP shoulder radiograph and expressed as a percentage of humeral diaphyseal width. All orthopedic inpatient documentation was assessed to identify clinical neurologic deficits. RESULTS: We identified 139 patients for inclusion. There were 22 patients (16%) with new neurologic deficits at presentation (8 axillary nerve, 2 radial nerve, 12 infraclavicular brachial plexus or multiple nerve injuries). The average shaft medial displacement in patients with neurologic injuries was 59% vs. 21% without nerve deficits (p=0.03). Using a 40% medial displacement threshold, the odds ratio for a nerve injury was 5.24 (95% CI 1.54 - 17.77, p=.008). CONCLUSION: Increased medial displacement of the humeral shaft following proximal humerus fracture is associated with an increased incidence of nerve injury at the time of initial presentation. This finding is not meant to be a surrogate for a high-quality neurologic exam in all patients with proximal humerus fractures. However, improved knowledge of the specific risk factors for an occult neurologic injury will improve the clinician's ability to accurately diagnose and properly treat proximal humerus fractures and their sequelae.Level of Evidence: III.

Residual Motion and Graft Type Do Not Influence Patient-reported Outcomes Following One- or Two-level Anterior Cervical Discectomy and Fusion.

STUDY DESIGN: Prospective cohort. OBJECTIVE: The aim of this study was to determine the effect of graft type on residual motion and the relationship among residual motion, smoking, and patient-reported outcome (PRO) scores following anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: Although most patients develop solid fusion based on static imaging following ACDF, dynamic imaging has revealed that many patients continue to have residual motion at the arthrodesis. METHODS: Forty-eight participants performed dynamic neck flexion/extension and axial rotation within a biplane radiography system 1 year following ACDF (21 one-level, 27 two-level). PRO scores included the Short Form-36, Neck Disability Index, and Cervical Spine Outcomes Questionnaire. An automated model-based tracking process matched subject-specific bone models to the biplane radiographs with sub-millimeter accuracy. Residual motion was measured across the entire arthrodesis site for both one- and two-level fusions in patients who received either allograft or autograft. Patients were divided into "pseudarthrosis" (>3° of flexion/extension residual motion) and "solid fusion" groups. Residual motion and PROs were compared between groups using Student t tests. RESULTS: Patients who received allograft showed more total flexion/extension residual motion (4.1° vs. 2.8°, P = 0.12), although this failed to reach significance. No differences were noted in PROs based on graft type (all P > 0.08) or the presence of pseudarthrosis (all P > 0.13). No differences were noted in residual motion between smokers and nonsmokers (all P > 0.15); however, smokers who received allograft reported worse outcomes than nonsmokers who received allograft and smokers who received autograft. CONCLUSION: Allograft may result in slightly more residual motion at the arthrodesis site 1 year after ACDF. However, there is minimal evidence that PROs are adversely affected by slightly increased residual motion, suggesting that the current definition of pseudarthrosis correlates poorly with clinically significant findings. Additionally, autograft appears to result in superior outcomes in patients who smoke.Level of Evidence: 2.

Conflict of interest disclosure in orthopaedic and general surgical trauma literature.

SIGNIFICANCE: Financial relationships between industry and physicians are a key aspect for the advancement of surgical practice and training, but these relationships also result in a conflict of interest with respect to research. Financial payments to physicians are public within the United States in the Open Payments Database, but the rate of accurate financial disclosure of payments has not previously been studied in trauma surgery publications. OBJECTIVE: To determine the rate of accurate financial disclosure in major surgical trauma journals compared with the Open Payments Database. MATERIALS AND METHODS: The names of all authors publishing in The Journal of Orthopaedic Trauma, Injury, and The Journal of Trauma and Acute Care Surgery between 2015 and 2018 were obtained from MEDLINE. Non-physicians, physicians outside of the United States, physicians without payments in the Open Payments Database, and physicians with payments types of only "Food and Drink" were excluded. Financial disclosure statements were obtained from the journal websites and manually compared against Open Payments Database entries the year prior to submission and during the year of submission up until 3 months prior to publication for each individual physician. Main outcomes were accuracy of disclosure published with each article, total amount of payments received (disclosure or undisclosed), surgical subspecialty of the reporting physician. Statistical comparisons were made using Chi-square testing with significance defined as p<0.05. RESULTS: Between 2015 and 2018, 5070 articles were published involving 28,948 authors. 2945 authors met inclusion criteria. 490 authors accurately disclosed their financial relationships with industry (16.6%). The median value of undisclosed payments was $22,140 [IQR $6465, $77,221] which was significantly less than the medial value of disclosed payment of $66,433 [IQR $24,624, $161,886], p<0.001 Orthopaedic surgeons disclosed at a higher rate (26.3%, 479/1818) than general surgeons (4.8%, 47/971), p<0.001. CONCLUSIONS: Physician-industry relationships are key for advancing surgical practice and providing training to physicians. These relationships are not inherently unethical, but there is consistently high inaccuracy of financial disclosure across multiple trauma surgery journals which may indicate the need for further education on financial disclosures during surgical training or active obtainment of publicly available financial disclosures by journals.

Assessing the biofidelity of in vitro biomechanical testing of the human cervical spine.

In vitro biomechanical studies of the osteoligamentous spine are widely used to characterize normal biomechanics, identify injury mechanisms, and assess the effects of degeneration and surgical instrumentation on spine mechanics. The objective of this study was to determine how well four standards in vitro loading paradigms replicate in vivo kinematics with regards to the instantaneous center of rotation and arthrokinematics in relation to disc deformation. In vivo data were previously collected from 20 asymptomatic participants (45.5 ± 5.8 years) who performed full range of motion neck flexion-extension (FE) within a biplane x-ray system. Intervertebral kinematics were determined with sub-millimeter precision using a validated model-based tracking process. Ten cadaveric spines (51.8 ± 7.3 years) were tested in FE within a robotic testing system. Each specimen was tested under four loading conditions: pure moment, axial loading, follower loading, and combined loading. The in vivo and in vitro bone motion data were directly compared. The average in vitro instant center of rotation was significantly more anterior in all four loading paradigms for all levels. In general, the anterior and posterior disc heights were larger in the in vitro models than in vivo. However, after adjusting for gender, the observed differences in disc height were not statistically significant. This data suggests that in vitro biomechanical testing alone may fail to replicate in vivo conditions, with significant implications for novel motion preservation devices such as cervical disc arthroplasty implants.

Rabbit Annulus Fibrosus Cells Express Neuropeptide Y, Which Is Influenced by Mechanical and Inflammatory Stress.

OBJECTIVE: Rabbit annulus fibrosus (AF) cells were exposed to isolated or combined mechanical and inflammatory stress to examine the expression of neuropeptide Y (NPY). This study aims to explore the ability of AF cells to produce NPY in response to mechanical and inflammatory stress. METHODS: Lumbar AF cells of 6- to 8-month-old female New Zealand white rabbits were harvested and exposed to combinations of inflammatory (interleukin-1ß) and mechanical (6% or 18%) tensile stress using the Flexcell System. NPY concentrations were measured in the media via enzyme-linked immunosorbent assay. The presence of NPY receptor-type 1 (NPY-1R) in AF cells of rabbit intervertebral discs was also analyzed via immunohistochemistry and immunofluorescence. RESULTS: Exposure to inflammatory stimuli showed a significant increase in the amount of NPY expression compared to control AF cells. Mechanical strain alone did not result in a significant difference in NPY expression. While combined inflammatory and mechanical stress did not demonstrate an increase in NPY expression at low (6%) levels of strain, at 18% strain, there was a large-though not statistically significant-increase in NPY expression under conditions of inflammatory stress. Lastly, immunofluorescence and immunohistochemistry of AF cells and tissue, respectively, demonstrated the presence of NPY-1R. CONCLUSION: These findings demonstrate that rabbit AF cells are capable of expressing NPY, and expression is enhanced in response to inflammatory and mechanical stress. Because both inflammatory and mechanical stress contribute to intervertebral disc degeneration (IDD), this observation raises the potential of a mechanistic link between low back pain and IDD.