Pulsed Electromagnetic Fields Reduce Interleukin-6 Expression in Intervertebral Disc Cells Via Nuclear Factor-κβ and Mitogen-Activated Protein Kinase p38 Pathways Study Design. This is an in vitro study of bovine disc cells exposed to pulsed electromagnetic fields. Objective. The purpose of the present study was to investigate whether pulsed electromagnetic fields (PEMF) effects on the expression of interleukin-6 (IL-6) expression is mediated by two known inflammation regulators, nuclear factor-κB (NF-κβ) and phosphorylated mitogen-activated protein kinase p38 (p38-MAPK) signaling pathways Summary of Background Data. Inflammatory cytokines play a dominant role in the pathogenesis of disc degeneration. Increasing evidence showed that PEMF, a noninvasive biophysical stimulation, can have physiologically beneficial effects on inflammation and tissue repair. Our previous research shows that PEMF treatment can reduce IL-6 expression by intervertebral disc cells. However, the underlying mechanisms of PEMF action are yet to be uncovered. Methods. Intervertebral disc nuclear pulposus cells were challenged with interleukin-1α (IL-1α) (for mimicking inflammatory microenvironment) and treated with PEMF simultaneously up to 4 hours. Cells were then collected for NF-κβ and phosphorylated p38-MAPK protein detection with Western blot. Additionally, the RelA (p65) subunit of NF-κβ was examined with immunostaining for assessment of NF-κβ activation. Results. As expected, Western blot results showed that both NF-κβ and phosphorylated p38 expression were significantly increased by IL-1α treatment. This induction was significantly inhibited to control condition levels by PEMF treatment. Immunostaining demonstrated similar trends, that PEMF treatment reduced the NF-κβ activation induced by IL-1α exposure. Conclusion. Our data indicate that the previously-reported inhibitory effect of PEMF treatment on disc inflammation is mediated by NF-κβ and phosphorylated p38-MAPK signaling pathways. These results further establish PEMFs anti-inflammatory activity, and may inform potential future clinical uses for management of inflammation associated with disc degeneration. Level of Evidence: N/A

A Prospective, Psychometric Validation of National Institutes of Health Patient-Reported Outcomes Measurement Information System Physical Function, Pain Interference, and Upper Extremity Computer Adaptive Testing in Cervical Spine Patients: Successes and Key Limitations Study Design. Prospective Cohort Study Objective. The aim of this study was to validate the Patient Reported Outcomes Measurement Information System (PROMIS) against existing patient-reported outcomes in the cervical spine. Summary of Background Data. Current patient-reported outcomes in cervical spine have substantial limitations. PROMIS offers the potential for improved psychometric properties with reduced questionnaire burden. Methods. Adult patients undergoing cervical spine surgery at a single institution between 2016 and 2018 were prospectively enrolled. Patients completed questionnaires (36-Item Short Form Health Survey [SF-36], Neck Disability Index (NDI), Visual Analog Scale arm/neck, and PROMIS pain Interference [PI], physical Function [PF], and Upper Extremity [UE]) preoperatively and at 6 months postoperatively. Demographic data, diagnosis, and procedural data were recorded. Validation of the instruments was completed with a Rasch Model as well as measurement of coverage, efficiency, test–retest reliability, responsiveness, and convergent validity. Results. Of 197 patients who completed the preoperative survey, 164 were eligible for 6-month follow-up and 139 completed 6-month postoperative surveys. The most common diagnoses were radiculopathy (37.6%), myeloradiculopathy (30.5%), and myelopathy (28.4%). All studied instruments had acceptable fit to a Rasch model. PROMIS computer adaptive testings (CATs) demonstrated improved average time to completion for PI (39 seconds), PF (47 seconds), and UE (54  seconds), compared to NDI (117 s) and SF-36 PCS (175 seconds). Responsiveness for PROMIS CATs was similar to NDI and SF-36, test–retest reliability was lower for PI (intraclass correlation: 0.68), PF (0.70), and UE (0.59), compared to NDI (0.86) and PCS (0.85). For convergent validity, PI was strongly correlated to NDI and PF to SF-36 PCS. There were no significant floor or ceiling effects for the PROMIS domains, although UE had preoperative clustering (n = 18) at a high score (56.4) and PI had postoperative clustering (n = 27) at a low score (38.7). Conclusion. PROMIS CATs demonstrate several advantages, including efficiency and responsiveness, while demonstrating good convergent validity with legacy instruments. Nevertheless, CATs had lower test–retest reliability and had significant clustering at higher levels of function for the PI and UE CATs. These limitations must be considered before broad adoption of CATs in cervical spine patients. Level of Evidence: 3

National Trends and Complications in the Surgical Management of Ossification of the Posterior Longitudinal Ligament (OPLL) Study Design. A retrospective database analysis. Objective. The aim of this study was to analyze US trends in surgical approaches for ossification of the posterior longitudinal ligament (OPLL); and to compare US patient and hospital characteristics, length of stay, total charges, and 30-day complications by surgical approach in OPLL management. Summary of Background Data. A robust literature on surgical management of OPLL in East Asian countries, where OPLL has a higher prevalence, exists. However, there is a paucity of literature evaluating the surgical management of OPLL in non-Asian countries. Methods. Using the Nationwide Inpatient Sample (NIS), we identified surgically treated OPLL patients from 2003 to 2014. Data on patient characteristics, surgical approaches, complications, hospital characteristics, length of stay, and hospital charges were extracted and analyzed. Analysis of variance (ANOVA) and Chi-squared tests were used to assess variation across categorical variables. Linear regression was used to evaluate the trend of surgical management for OPLL over the study timeframe. Results. Five thousand two hundred twelve patients fit our inclusion criteria. The overall complication rate was 21.5%, but the highest complication rate was for patients undergoing a combined anterior-posterior decompression/fusion (44.7%). Patients undergoing a combined anterior-posterior decompression/fusion had a longer length of stay and higher total charges (P < 0.01). Overall, surgical OPLL cases significantly increased from 2003 to 2014 (336–920; P < 0.01). Conclusion. To our knowledge, this is the largest study examining the surgical treatment of OPLL in a non-Asian country. OPLL surgical cases increased over the study timeframe and the overall surgical complication rate was 21.5%. The percentage of Asians or Pacific Islanders with OPLL undergoing surgical intervention was 10.8%, which is higher than the prevalence in the US population (4.9%). This suggests a potential genetic component to OPLL. Future work is warranted to determine how best to decrease the high complication rate. Level of Evidence: 4

Inpatient Pain Scores and Narcotic Utilization Based on American Society of Anesthesiologists Score Following Anterior Cervical Discectomy and Fusion Study Design. Retrospective. Objective. To examine the relationship between American Society of Anesthesiologists (ASA) score and inpatient pain and narcotics consumption following anterior cervical discectomy and fusion (ACDF). Summary of Background Data. Higher ASA scores have been previously linked to increased postoperative complication rates, healthcare costs, length of stay, and hospital readmissions. However, to our knowledge, there have not been previous investigations into the association between ASA scores and postoperative inpatient pain and narcotics utilization following ACDF. Methods. Patients who underwent a single-level, primary ACDF were retrospectively reviewed and stratified into two cohorts based on ASA score less than or equal to 2 or ASA score more than 2. ASA score was tested for association with demographic variables and perioperative characteristics using student's t test, chi-squared analysis, and Fisher exact test. Inpatient pain scores and narcotics consumption on each postoperative day were then compared between cohorts using bivariate linear regression. Results. Two hundred eleven patients who underwent ACDF were included: 184 had an ASA score less than or equal to 2 and 27 had an ASA score more than 2. Higher ASA score was associated with older age, higher comorbidity burden as measured by the modified Charlson Comorbidity Index (CCI), and lower prevalence of obesity. Higher ASA scores were associated with longer duration of hospital stay, while other perioperative characteristics were similar between ASA score cohorts. There were no differences in inpatient Visual Analog Scale (VAS) pain scores, or hourly, daily, and cumulative inpatient narcotic consumption between cohorts on any postoperative day. Conclusion. This retrospective investigation demonstrated that a higher ASA score is associated with increased operative time following ACDF. However, ASA score was determined not to be an independent risk factor that can predict postoperative pain or narcotics consumption among patients who undergo ACDF. Therefore, postoperative pain in the inpatient setting can be managed with similar modalities regardless of ASA score for patients undergoing ACDF. Level of Evidence: 3

Broad External Validation and Update of a Prediction Model for Persistent Neck Pain After 12 Weeks Study Design. A prospective observational study. Objective. To externally validate the prediction model developed by Schellingerhout and colleagues predicting global perceived effect at 12 weeks in patients with neck pain and to update and internally validate the updated model. Summary of Background Data. Only one prediction model for neck pain has undergone some external validation with good promise. However, the model needs testing in other populations before implementation in clinical practice. Methods. Patients with neck pain (n = 773) consulting Norwegian chiropractors were followed for 12 weeks. Parameters from the original prediction model were applied to this sample for external validation. Subsequently, two random samples were drawn from the full study sample. One sample (n = 436) was used to update the model; by recalibration, removing noninformative covariates, and adding new possible predictors. The updated model was tested in the other sample (n = 303) using stepwise logistic regression analysis. Main outcomes for performance of models were discrimination and calibration plots. Results. Three hundred seventy patients (47%) in the full study sample reported persistent pain at 12 weeks. The performance of the original model was poor, area under the receiver operating characteristics curve was 0.55 with a Confidence Interval of 0.51–0.59. The updated model included Radiating pain to shoulder and/or elbow, education level, physical activity, consultation-type (first- time, follow-up or maintenance consultation), expected course of neck pain, previous course of neck pain, number of pain sites, and the interaction term Physical activity##Number of pain sites. The area under the receiver operating characteristics curve was 0.65 with a 95% Confidence Interval of 0.58–0.71 for the updated model. Conclusion. The predictive accuracy of the original model performed insufficiently in the sample of patients from Norwegian chiropractors and the model is therefore not recommended for that setting. Only one predictor from the original model was retained in the updated model, which demonstrated reasonable good performance predicting outcome at 12 weeks. Before considering clinical use, a new external validation is required. Level of Evidence: 3

Reciprocal Changes in Cervical Alignment After Thoracolumbar Arthrodesis for Adult Spinal Deformity Study Design. Multicenter database review of consecutive adult spinal deformity (ASD) patients. Objective. The aim of this study was to identify associations between changes in spinopelvic parameters and cervical alignment after thoracolumbar arthrodesis for ASD. Summary of Background Data. Reciprocal cervical changes occur after instrumented thoracic spinal arthrodesis. The timing and relationship of these changes to sagittal alignment and upper instrumented vertebra (UIV) selection are unknown. Methods. In 171 ASD patients treated with thoracolumbar arthrodesis from 2008 to 2012, we assessed changes from baseline to 6-week, 1-year, and 2-year follow-up in C2-C7 sagittal vertical axis (SVA), T1 slope, and C2-C7 lordosis. We used multivariate models to analyze associations between these parameters and UIV selection (T9 or distal vs. proximal to T9) and changes at each time point in thoracic kyphosis (TK), lumbar lordosis (LL), C7-S1 SVA, pelvic incidence, pelvic tilt, and sacral slope. Results. Two-year changes in C2-C7 SVA and T1 slope were significantly associated with baseline to 6-week changes in TK and LL and with UIV selection. Baseline to 2-year changes in C2-C7 lordosis were associated with baseline to 6-week changes in C7-S1 SVA (P = 0.004). Most changes in C2-C7 SVA occurred during the first 6 weeks postoperatively (mean 6-week change in C2-C7 SVA: 2.7 cm, 95% confidence interval [CI]: 0.7–4.7 cm; mean 2-year change in SVA: 2.3 cm, 95% CI: −0.1 to 4.6 cm). At 2 years, on average, there was decrease in C2-C7 lordosis, most of which occurred during the first 6 weeks postoperatively (mean 6-week change: −3.2°, 95% CI: −4.8° to −1.2°; mean 2-year change: –1.3°, 95% CI: − 3.2° to 0.5°). Conclusion. After thoracolumbar arthrodesis, reciprocal changes in cervical alignment are associated with postoperative changes in TK, LL, and C7-S1 SVA and with UIV selection. The largest changes occur during the first 6 weeks and persist during 2-year follow-up. Level of Evidence: 3

Ten-year Longitudinal Follow-up MRI Study of Age-related Changes in Thoracic Intervertebral Discs in Asymptomatic Subjects Study Design. Prospective longitudinal study. Objective. The aim of this study was to evaluate long-term degenerative changes in intervertebral discs in the thoracic spine in healthy asymptomatic subjects. Summary of Background Data. Longitudinal magnetic resonance imaging (MRI) studies of intervertebral disc degeneration have been reported for the cervical and lumbar but not the thoracic spine. Methods. In this longitudinal study (average follow-up 10.0 ± 0.6 years), we assessed degenerative changes in the thoracic spine of 103 volunteers (58 men) of 223 healthy volunteers in the initial MRI study of the thoracic spine (follow-up rate 46.2%). The mean age at the initial study was 45.0 ± 11.5 years (24–77 years). Initial and follow-up thoracic-spine MRIs were graded for the following 4 factors of degenerative changes: decrease in signal intensity of intervertebral disc (DSI), posterior disc protrusion (PDP), anterior compression of dura and spinal cord (AC), and disc-space narrowing (DSN) from T1–2 to T12–L1. We assessed associations between changes in MRI grade and demographical factors such as age, sex, body mass index, smoking habits, sports activities, and disc degeneration in the cervical spine. Results. MRIs revealed that 63.1% of the subjects had degenerative changes in the thoracic intervertebral discs that had progressed at least one grade during the follow-up period. DSI progressed in 44.7% of subjects, PDP in 21.4%, and AC in 18.4% during the 10-year period. No DSN progression was seen. DSI was frequently observed in the upper thoracic spine (T1–2 to T4–5). Disc degeneration was relatively scarce in the lower thoracic spine (T9–10 to T12–L1). PDP was frequently observed in the middle thoracic spine (T5–6 toT8–9). We found significant associations between DSI and cervical-spine degeneration (P = .004) and between AC and smoking (P = .04). Conclusion. Progressive thoracic disc degeneration, observed in 63.1% of subjects; was significantly associated with smoking and with cervical-spine degeneration. Level of Evidence: 2

Syndromic Scoliosis: National Trends in Surgical Management and Inpatient Hospital Outcomes: A 12-Year Analysis Study Design. Retrospective cohort study. Objective. Evaluate the trends in management and inpatient outcomes in patients with syndromic scoliosis undergoing spinal deformity correction. Summary of Background Data. Syndromic scoliosis (SS) refers to scoliosis that is most commonly associated with systemic disease including Ehler Danhlos syndrome (EDS), Marfan syndrome (MF), Down syndrome (DS), Achondroplasia (AP), and Prader-Willi syndrome (PWS). Limited data exist evaluating hospital outcomes in patients with SS undergoing spinal deformity correction. Methods. The Kids’ Inpatient Database (KIDS) was queried from 2001 to 2012 to identify all pediatric patients with scoliosis undergoing spinal fusion. These patients were then sub-divided into two cohorts: (1) patients with idiopathic scoliosis (IS) and (2) patients with syndromic scoliosis. Trends in surgical management, and postoperative morbidity and mortality were assessed. Length of stay and total hospital charges were additionally analyzed. A sub-analysis to characterize outcomes in each syndrome was also performed. Results. An estimated 1071 patients with SS were identified and compared with 24,989 pediatric patients with IS. MF (36.8%), Down syndrome (16.0%), and PWS (14.9%) were the most common diagnoses among patients with SS. Between 2001 and 2012, there was a significant decline in the number of anterior procedures performed in both cohorts. Conversely, the number of posterior based procedures increased. SS was associated with increased major complications (2.7% compared with 1.0% in IS; P < 0.001) and minor complication rates (41.0% compared with 28.5% in IS; P < 0.001). Patients with AP incurred the highest rate of major complications (10.7%), minor complications (60.8%), and intraoperative durotomies (6.1%). Total hospital charges increased significantly over the 12-year span. Conclusion. Trends in management of syndromic scoliosis have paralleled that of idiopathic scoliosis. Syndromic scoliosis is associated with increased risks with surgical deformity correction. Further prospective studies are warranted to evaluate the reasons for these differences. Level of Evidence: 3

Are 15-Year Trajectories of Low Back Pain and Sciatica Associated With Cardiovascular Autonomic Function in the General Population?: The Northern Finland Birth Cohort 1966 Study Study Design. A population-based cohort study. Objective. The aim of this study was to examine whether 15-year trajectories of low back pain (LBP) and sciatica are associated with cardiovascular autonomic function in a large general population sample. Summary of Background Data. Previous studies using mainly small patient samples have suggested that LBP and sciatica are associated with abnormal cardiovascular autonomic function, namely altered heart rate variability (HRV) and baroreflex sensitivity (BRS). We examined this association in a large general population sample. Methods. The data collections of the Northern Finland Birth Cohort 1966 consisted of pain questionnaires at 31 and 46 years (history of LBP, sciatica, and other musculoskeletal pains during the previous year; yes/no for each) and measurements of HRV and BRS at 46 years (heart rate, HR; root mean square of successive differences in beat-to-beat intervals, rMSSD; low-frequency systolic blood pressure variability, SBPV; cross-spectral BRS, BRS; each while seated and standing). The data collections also comprised several confounders. Trajectories for LBP, sciatica, and both together (“no pain,” “decreasing,” “increasing,” “long-term pain”) were constructed and general linear models were used to perform comparisons between trajectories (for HR/rMSSD, n = 3398; for SBPV/BRS, n = 1667). Results. In the crude models, LBP and sciatica were associated with higher HR, lower rMSSD, higher SBPV, and lower BRS, but these associations were mostly attenuated by adjustments. Regarding both LBP and sciatica, only the “increasing” trajectory was associated with two of the eight outcomes (standing SBPV, seated BRS) after adjustments. Regarding LBP, the “increasing” trajectory was associated with three (standing SBPV, seated BRS, standing BRS), the “long-term pain” trajectory with one (standing BRS), and the “decreasing” trajectory with one outcome (seated SBPV) after adjustments. Sciatica showed no association with the outcomes after adjustments. Conclusion. We conclude that the 15-year trajectories of LBP and sciatica do not have a consistent independent association with cardiovascular autonomic function among the general population. Level of Evidence: 3