The association between inflammatory biomarkers and low back disorder: a systematic review and meta-analysis.

INTRODUCTION: Low back disorder (LBD) is a major cause of disability worldwide. Inflammation results in proliferation of cytokines or consequent degradation products (collectively known as inflammatory biomarkers) that activate pain pathways which can result in non-specific LBD. This systematic review and meta-analysis aim to evaluate the relationship between inflammatory biomarkers and clinical outcomes in patients with LBD. METHODS: The PRISMA guideline was followed for the systematic reivew. Three online databases were searched. Four RCTs and sixteen observational studies with 1142 LBD patients were analysed. The primary outcomes were back and leg pain scores, back-specific disability scores and expression of inflammatory biomarkers. Standardized mean difference (SMD) and their 95% confidence intervals (CI) were evaluated. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to summarize the strength of evidence. RESULTS: Four RCTs and sixteen observational studies were included in the analysis of 1142 patients with LBD. There was a statistically significant reduction in back pain score and IL-1 beta and increase in the expression of CTX-1 and IL-10 levels post treatment. There was a significant relationship between increase in the expression of MCP- and reduction in the expression of hsCRP with increase in back pain. Significant relationship was also observed between increase in the expression of MCP-1 and reduction in the expression of IL-6 with increase in leg pain. Increase in the expression of IL-8 and reduction in the expression of hsCRP was also associated with increased disability score. CONCLUSION: Inflammatory biomarkers play a significant role in the pathogenesis of LBD. CTX-1, IL-10 and IL-1 beta may be responsible for the decrease in back pain scores post treatment. There is a relationship between MCP-1, IL-6, IL-8 and hsCRP with clinical and functional assessments for LBD. Further studies will improve understanding of the pathogenesis of LBD and aid in targeted management strategies.

In subjects with chronic low back pain, does neuropathia exclusively correlated to neuronal compression? A correlation study of PainDETECT questionnaire and corresponding MRI and X-ray findings.

INTRODUCTION: Understanding the complex nature of low back pain (LBP) is crucial for effective management. The PainDETECT questionnaire is a tool that distinguishes between neuropathic (NeP), nociceptive (NoP), and ambiguous pain. This study aimed to investigate the relationship between pain classification and lumbar intervertebral degenerative parameters obtained from imaging. METHODS: A cohort study was conducted involving 279 patients, aged 18 years and above, who completed PainDETECT questionnaires and underwent lumbar MRI and/or X-ray scans. RESULTS: The study included 102 patients with NoP, 78 with ambiguous pain, and 99 with NeP. The NeP group had lower mean age (58.21 vs. 53.63, p < 0.05) and higher mean numerical rating scale score (7.9 vs. 5.9, p < 0.001) compared to the NoP group. A negative correlation was found between PainDETECT scores and pelvic incidence (τ = - 0.177, p = 0.043). The NeP group exhibited significantly higher severity of foraminal stenosis (U = 18.962, p = 0.002), spinal stenosis (U = 14.481, p = 0.005), and Pfirrmann grade (U = 14.221, p = 0.028) compared to the NoP group. A higher proportion of NeP patients had intervertebral disk bulge (96% vs. 78% vs. 78%, p = 0.002) and high-intensity zones (51% vs. 41% vs. 19%, p < 0.001) compared to those with NoP and ambiguous pain. CONCLUSION: NeP, as determined by the PainDETECT questionnaire, is associated with more severe neural compression, increased presence of discogenic disease and inflammatory disk severity, and decreased pelvic incidence. This pioneering study establishes a connection between pathological findings and pain categorization, providing clinicians with valuable guidance for formulating tailored management plans and reducing the need for unnecessary pharmacotherapy, imaging, and non-targeted surgical interventions.

Reconsidering high intensity zones: its role in intervertebral disk degeneration and low back pain.

PURPOSE: High intensity zones (HIZ) in the lumbar intervertebral disk (IVD) can be associated with degenerative changes which may ultimately manifest as low back pain (LBP). However, the relationship between the prevalence of HIZ and lumbar degenerative parameters is still unclear. The purpose of this study was to determine the prevalence of HIZ in the lumbar spine, analyze the independent relationship between HIZ and lumbar degenerative parameters measured on MRI and X-ray and determine the association between HIZ and the presence of LBP. METHODS: A retrospective review of MRI data, X-ray data, and radiology reports for 136 consecutively recruited patients, above 18-years-age and with both lumbar MRI and X-ray scans was conducted. 57 patients with HIZ were identified. Patients without HIZ (n = 79) made up the control group. RESULTS: HIZ was prevalent in 41.9% of patients and in 11.0% of all lumbar IVDs. The odds of developing HIZ were 6.4 (Exp(B) 6.4, 95%CI [3.157-12.988]) and 3.0 (Exp(B) 3.0, 95%CI [1.603, 5.674]) times higher in IVDs with disk bulge/protrusion and nucleus degeneration, respectively. Odds of HIZ was also increased in disks with larger IVD angle (Exp(B) 1.1, 95%CI [1.034, 1.169]). The odds of patients presenting to imaging with LBP was 3.0 (OR 3.0, 95%CI [1.478-6.338]) times higher in the HIZ compared to the control group. CONCLUSIONS: HIZ was prevalent in 41.9% of participants that were recruited in this study. Nucleus degeneration, disk bulge/protrusion and increased IVD angle were found to be independently associated with HIZ and since there is an increased likelihood of LBP, we posit that HIZ is likely a symptomatic and clinically meaningful diagnostic tool in the assessment of LBP.

Age-based exclusion is common and multifactorial in spinal RCTs: a systematic review and quantitative analysis.

Most diseases of the spine disproportionately impact older persons, with the modal (i.e., commonest) patient a female in their 8th decade of life. We examined the corpus of spinal RCTs to determine how many included "average" spine patients. We searched PubMed for randomized clinical trials published in the top 7 spine journals over a period of 5 years from 2016 to 2020 and extracted nominal upper age cut-offs and the distribution of ages actually recruited. We identified 186 trials of 26,238 patients. We found that only 4.8% of trials could be applied to an "average" 75-year-old patient. This age-based exclusion was not dependent on funding source. Age-based exclusion was exacerbated by explicit upper age cut-offs, however, the age-based exclusion went beyond explicit age cut-offs. Only few trials were applicable to older patients even amongst trials with no age cut-off specified. Age-based exclusion from clinical trials starts at late middle age. The mismatch between spinal patient's age seen in clinical practice and spinal patient's age in trials was so severe that over the 5 years (2016-2020) almost no RCT evidence was produced applicable to the "average" aged-patient across the body of literature available. In conclusion, age-based exclusion is ubiquitous, multifactorial, and happens on a supratrial level. Eliminating age-based exclusion involves more than an arbitrary lifting of explicitly stated upper age cut-offs. Instead, recommendations include increasing input from geriatricians and ethics committees, establishing updated or new models of cares, and creating new protocols to facilitate further research.

Clinical effectiveness of reduction and fusion versus in situ fusion in the management of degenerative lumbar spondylolisthesis: a systematic review and meta-analysis.

PURPOSE: To compare the clinical effectiveness of reduction and fusion with in situ fusion in the management of patients with degenerative lumbar spondylolisthesis (DLS). METHODS: The systematic review was conducted following the PRISMA guidelines. Relevant studies were identified from PubMed, Embase, Scopus, Cochrane Library, ClinicalTrials.gov, and Google Scholar. The inclusion criteria were: (1) comparative studies of reduction and fusion versus in situ fusion for DLS patients, (2) outcomes reported as VAS/NRS, ODI, JOA score, operating time, blood loss, complication rate, fusion rate, or reoperation rate, (3) randomized controlled trials and observational studies published in English from the inception of the databases to January 2023. The exclusion criteria included: (1) reviews, case series, case reports, letters, and conference reports, (2) in vitro biomechanical studies and computational modeling studies, (3) no report on study outcomes. The risk of bias 2 (RoB2) tool and the Newcastle-Ottawa scale was conducted to assess the risk of bias of RCTs and observational studies, respectively. RESULTS: Five studies with a total of 704 patients were included (375 reduction and fusion, 329 in situ fusion). Operating time was significantly longer in the reduction and fusion group compared to in situ fusion group (weighted mean difference 7.20; 95% confidence interval 0.19, 14.21; P = 0.04). No additional significant intergroup differences were noted in terms of other outcomes analyzed. CONCLUSION: While the reduction and fusion group demonstrated a statistically longer operating time compared to the in situ fusion group, the clinical significance of this difference was minimal. The findings suggest no substantial superiority of lumbar fusion with reduction over without reduction for the management of DLS.

Clinicians' perceptions around discectomy surgery for lumbar disc herniation: a survey of orthopaedic and neuro-surgeons in Australia and New Zealand.

INTRODUCTION: Understanding practice-based differences in treatment of lumbar disc herniations (LDHs) is vital for reducing unwarranted variation in the delivery of spine surgical health care. Identifying factors that influence surgeons' decision-making will offer useful insights for developing the most cost-effective and safest surgical strategy as well as developing surgeon education materials for common lumbar pathologies. This study was to capture any variation in techniques used by surgeons in Australia and New Zealand (ANZ) region, and perceived complications of different surgical procedures for primary and recurrent LDH (rLDH). MATERIALS AND METHODS: Web-based survey study was emailed to orthopaedic and neurosurgeons who routinely performed spinal surgery in ANZ from Decmber 20, 2018 to February 20, 2020. The response data were analyzed to assess for differences based on geography, practice setting, speciality, practice experience, practice length, and operative volume. RESULTS: Invitations were sent to 150 surgeons; 96 (64%) responded. Most surgeons reported microdiscectomy as their surgical technique of choice for primary LDH (73%) and the first rLDH (72%). For the second rLDH, the preferred choice for most surgeons was fusion surgery (82%). A surgeon's practice setting (academic/private/hybrid) was a statistically significant factor in what surgical procedure was chosen for the first rLDH (P = 0.014). When stratifying based on surgeon experience, there were statisfically significant differences based on the annual volume of spine surgeries performed (perceived reherniation rates following primary discectomy, P = 0.013; perceived reherniation rates following revision surgeries, P = 0.017; perceived intraoperative complications rates following revision surgeries, P = 0.016) and based on the annual volume of lumbar discectomies performed (perceived reherniation rates following revision surgeries, P = 0.022; perceived intraoperative complications rates following revision surgeries, P = 0.036; perceived durotomy rates following primary discectomy, P = 0.023). CONCLUSIONS: Surgeons' annual practice volume and practice setting have significant influences in the selection of surgical procedures and the perception of surgical complications when treating LDHs.

Gut-disc axis: A cause of intervertebral disc degeneration and low back pain?

PURPOSE: Low back pain (LBP), a widely prevalent and costly disease around the world, is mainly caused by intervertebral disc (IVD) degeneration (IDD). Although numerous factors may trigger this degenerative process, microbiome dysbiosis has recently been implicated as one of the likely causes. However, the exact relationship between the microbiome and IDD is not well understood. This review summarizes the potential mechanisms and discusses microbiome dysbiosis's possible influence on IDD and LBP. METHODS: Prospective literature review. RESULTS: Alterations in microbiome composition and host responses to the microbiota causing pathological bone development and involution, led to the concept of gut-bone marrow axis and gut-bone axis. Moreover, the concept of the gut-disc axis was also proposed to explain the microbiome's role in IDD and LBP. According to the existing evidence, the microbiome could be an important factor for inducing and aggravating IDD through changing or regulating the outside and inside microenvironment of the IVD. Three potential mechanisms by which the gut microbiota can induce IVD and cause LBP are: (1) translocation of the bacteria across the gut epithelial barrier and into the IVD, (2) regulation of the mucosal and systemic immune system, and (3) regulation of nutrient absorption and metabolites formation at the gut epithelium and its diffusion into the IVD. Furthermore, to investigate whether IVD is initiated by pathogenic bacteria and establish the correlation between the presence of certain microbial groups with the disease in question, microbiome diversity analysis based on16S rRNA data can be used to characterise stool/blood microbiota from IVD patients. CONCLUSION: Future studies on microbiome, fungi and viruses in IDD is necessary to revolutionize our thinking about their possible role in the development of IVD diseases. Furthermore, we believe that inflammation inhibition and interruption of amplification of cascade reaction in IVD by targeting the gut and IVD microbiome is worthwhile for the treatment of IDD and LBP. LEVEL OF EVIDENCE I: Diagnostic: individual cross-sectional studies with the consistently applied reference standard and blinding.

The association between pain scores and disc height change following discectomy surgery in lumbar disc herniation patients: a systematic review and meta-analysis.

PURPOSE: To evaluate the impact of discectomy on disc height (DH) in lumbar disc herniation (LDH) patients following discectomy surgery and address the association of DH change with pain score change. METHODS: We searched three online databases for randomized controlled trials (RCTs) and observational studies. In LDH patients, eligible for discectomy surgery, the changes in pre- and post-operative back and/or leg pain score and DH and/or disc height index (DHI) were considered as primary outcomes. Standardize mean difference (SMD) and their 95% confidence intervals (CI) were evaluated. The GRADE approach was used to summarize the strength of evidence. RESULTS: Two RCTs and sixteen observational studies were included in the analysis of 893 LDH patients undergoing discectomy surgery. The mean overall follow-up was 211 weeks. There was a statistically significant reduction in DH (14.4% reduction: SMD = -0.74 (95% CI = -0.86 to -0.61)) and DHI (11.5% reduction: SMD = -0.81 (95% CI = -0.97 to -0.65)) following discectomy surgery. There was a significant relationship between the reduction in DH and decrease in back pain score (r = 0.68, (95% CI = 0.07-1.30), p = 0.034) after discectomy surgery. No significant relationship between DHI change and decrease in clinical pain scores (back and leg pain) could be established. CONCLUSION: Discectomy surgery produces significant and quantifiable reductions in DH and DHI. Additionally, the reduction in DH is responsible for the decrease in back pain scores post discectomy, but further studies will improve understanding and aid preoperative counselling.

Surgeon-defined assessment is a poor predictor of knee balance in total knee arthroplasty: a prospective, multicenter study.

BACKGROUND: The accuracy of surgeon-defined assessment (SDA) of soft tissue balance in total knee arthroplasty (TKA) is poorly understood despite balance being considered a significant determinant of surgical success. The study's hypothesis was that intra-operative SDA is a poor predictor of coronal balance in TKA. METHODS: A prospective, multicenter study assessing accuracy of SDA of balance was conducted in 250 patients (285 TKAs). Eight surgeons and thirteen trainees participated, and all were blinded to sensor measurements. The primary outcome was test accuracy of SDA measured at 10°, 45° and 90° compared to sensor measures as the gold standard test. Cohen's kappa coefficient was calculated to determine chance-corrected agreement. Secondary outcomes include the relationship of SDA to level of surgical experience, analysis of between-surgeon differences, and the influence of patient and operative factors on SDA accuracy. RESULTS: Average accuracy of SDA was 58.3%, 61.2% and 66.5% at 10°, 45° and 90° respectively. Cohen's kappa coefficient was 0.18 at all angles and rated as "slight agreement". SDA sensitivities to correctly identify a balanced knee (76.2% at 10°; 82.6% at 45°; 83.2% at 90°) were approximately twice specificities to correctly identify an unbalanced knee (42.6% at 10°; 34.1% at 45°; 41.4% at 90°). Surgical experience (surgeon versus trainee) had no effect on capacity to determine balance. Considerable between-surgeon variability was found (33-65% at 10°, 41-73% at 45°, 55-89% at 90°). CONCLUSION: SDA was a poor predictor of balance, particularly when assessing the unbalanced TKA. Surgeon experience had no effect on test accuracy and considerable between-surgeon variability was recorded. These findings question the accuracy of SDA in TKA. TRIAL REGISTRATION NUMBER: ACTRN# 12618000817246.

Does the Use of Intraoperative Pressure Sensors for Knee Balancing in Total Knee Arthroplasty Improve Clinical Outcomes? A Comparative Study With a Minimum Two-Year Follow-Up.

BACKGROUND: It is undetermined whether using sensors for knee balancing in total knee arthroplasty (TKA) improves patient outcomes. The purpose of this study was to compare clinical outcomes of sensor balance (SB) with manual balance (MB) TKA with a minimum two-year follow-up. METHODS: A consecutive series of 207 MB TKAs was compared with 222 SB TKAs between April 2014 and April 2017. A single surgeon performed all surgeries, using the same prosthesis. The primary end point was the aggregated mean change in four subscales of the Knee injury and Osteoarthritis Outcome Score (KOOS4) between preoperative and two-year time points. Secondary outcomes included mean differences between groups in all five KOOS subscales, proportions of knee balancing procedures, and rates of reoperations including revisions and manipulations for stiffness. RESULTS: The mean changes in the KOOS4 aggregated means for MB TKA (42.4; standard deviation, 29.1) and SB TKA (41.5; standard deviation, 25.0) were not significantly different (mean difference, 0.9; 95% confidence interval: -2.6 to 4.4, P = .62). There were significantly more balancing procedures in the SB group (55.9% versus 16.9%; P < .01). There were no significant differences in the number of reoperations (1.4% SB versus 1.4% MB; P = .71) or manipulations for stiffness (3.7% SB versus 4.4% MB; P = .69). CONCLUSION: The use of sensors in TKA to achieve knee balance did not result in improved clinical outcomes, despite significantly increasing the number of surgical interventions required to achieve a balanced knee. Sensors did not alter the rates of revision surgery or requirements for manipulation. It remains to be determined whether precise soft-tissue balancing improves prosthetic survivorship and joint biomechanics.

Complication rates of different discectomy techniques for symptomatic lumbar disc herniation: a systematic review and meta-analysis.

PURPOSE: This meta-analysis aims to compare the complication rates of discectomy/microdiscectomy (OD/MD), microendoscopic discectomy (MED), percutaneous endoscopic lumbar discectomy (PELD), percutaneous laser disc decompression (PLDD), and tubular discectomy for symptomatic lumbar disc herniation (LDH) using general classification and modified Clavien-Dindo classification (MCDC) schemes. METHODS: We searched three online databases for randomized controlled trials (RCTs) and cohort studies. Overall complication rates and complication rates per the above-mentioned classification schemes were considered as primary outcomes. Risk ratio (RR) and their 95% confidence intervals (CI) were evaluated. RESULTS: Seventeen RCTs and 20 cohort studies met the eligibility criteria. RCTs reporting OD/MD, MED, PELD, PLDD, and tubular discectomies had overall complication rates of 16.8% and 16.1%, 21.2%, 5.8%, 8.4%, and 25.8%, respectively. Compared with the OD/MD, there was moderate-quality evidence suggesting that PELD had a lower risk of overall complications (RR = 0.52, 95% CI 0.29-0.91) and high-quality evidence suggesting a lower risk of Type I complications per MCDC (RR = 0.37, 95% CI 0.16-0.81). Compared with the OD/MD data from cohort studies, there was low-quality evidence suggesting a higher risk of Type III complications per MCDC (RR = 10.83, 95% CI 1.29-91.18) for MED, higher risk of reherniations (RR = 1.67,95% CI 1.05-2.64) and reoperations (RR = 1.75, 95% CI 1.20-2.55) for PELD, lower risk of overall complication rates (RR = 0.42, 95% CI 0.25-0.70), post-operative complication rates (RR = 0.42, 95% CI 0.25-0.70), Type III complications per MCDC (RR = 0.39, 95% CI 0.22-0.69), reherniations (RR = 0.56, 95% CI 0.33-0.97) and reoperations (RR = 0.39, 95% CI 0.22-0.69) for PLDD. CONCLUSIONS: Compared with the OD/MD, results of this meta-analysis suggest that PELD has a lower risk of overall complications and a lower risk of complications necessitating conservative treatment. These slides can be retrieved under Electronic Supplementary Material.

Morphological characteristics of the kangaroo lumbar intervertebral discs and comparison with other animal models used in spine research.

PURPOSE: Animal models are frequently used to elucidate pathomechanism and pathophysiology of various disorders of the human intervertebral disc (IVD) and also to develop therapeutic approaches. Here we report morphological characteristics of the kangaroo lumbar IVDs and compare them with other animal models used in spine research. METHODS: Twenty-five fresh-frozen cadaveric lumbar spines (T12-S1) derived from kangaroo carcases (Macropus giganteus) of undetermined age were first scanned in a C-Arm X-ray machine. A photograph of the axial section of the disc including a calibrated metric scale was also acquired. The digital radiographs and photographs were processed in ImageJ to determine the axial and sagittal plane dimensions for the whole disc (WD) and the nucleus pulposus (NP) and the mid-sagittal disc height for all the lumbar levels. RESULTS: Our results suggest that the L6-S1 IVD in kangaroos is distinctly large compared with the upper lumbar IVDs. Based on previously published data, human lumbar IVDs are the largest of all the animal IVDs used in spine research, with camelid cervical IVDs being the closest relative in absolute dimensions (llamas: 78% in disc height, 40% in WD volume, and 38% in NP volume). Kangaroo L6-S1 IVD was approximately 51% in height, 20% in WD volume, and 20% in NP volume of the human lumbar IVD. CONCLUSIONS: We conclude that morphological similarities exist between a kangaroo and human lumbar IVD, especially with the lima bean shape in the axial plane, wedge shape in the sagittal plane, convexity at the cephalad endplates, and percentage volume occupied by the NP in the IVD. These slides can be retrieved under Electronic Supplementary Material.

Assessment of degenerative cervical stenosis on T2-weighted MR imaging: sensitivity to change and reliability of mid-sagittal and axial plane metrics.

STUDY DESIGN: A retrospective cross-sectional study. OBJECTIVE: To assess the sensitivity to change and reliability of various mid-sagittal and axial plane metrics in the assessment of patients with single-level degenerative cervical stenosis on T2-weighted MR imaging. SETTING: A diagnostic MR imaging facility in Sydney (Australia). METHODS: We retrospectively reviewed T2-weighted MR images of 85 consecutive patients (48 M and 37 F) with single-level degenerative cervical stenosis. Canal compromise and cord compression were evaluated using three mid-sagittal plane metrics (M1, M2, and M3) and two axial plane metrics (M4 and M5), at the level of stenosis and nonstenotic cephalad and caudal levels (controls). Sensitivity to change (SC) for each metric was evaluated as the percentage deviation of the measured value from the estimated normal value based on cephalad and caudal controls. Reliability for each metric was evaluated using intraclass correlation coefficients. RESULTS: Degenerative cervical stenosis showed a bimodal distribution peaking at C5-6 (n = 32) and C3-4 (n = 29) levels. The changes in the canal and cord geometry along the rostrocaudal axis were inconsistent. Across all individual subjects (reflecting a range of stenosis severity), M3 (-32.87% ± 10.60%) was more sensitive to change compared with M1 (16.64% ± 16.48%) and M2 (-23.95% ± 11.12%). Similarly, M4 (-24.62% ± 12.17%) was more sensitive to change compared with M5 (-6.71% ± 11.08%). The level of reliability was "moderate" to "excellent" for mid-sagittal plane measurements, and "poor" to "excellent" for axial plane measurements. CONCLUSION: Changes in canal dimensions in the mid-sagittal plane and cord shape in the axial plane are sensitive indicators of degenerative cervical stenosis on T2-weighted MR images.

Advanced Strategies for the Regeneration of Lumbar Disc Annulus Fibrosus.

Damage to the annulus fibrosus (AF), the outer region of the intervertebral disc (IVD), results in an undesirable condition that may accelerate IVD degeneration causing low back pain. Despite intense research interest, attempts to regenerate the IVD have failed so far and no effective strategy has translated into a successful clinical outcome. Of particular significance, the failure of strategies to repair the AF has been a major drawback in the regeneration of IVD and nucleus replacement. It is unlikely to secure regenerative mediators (cells, genes, and biomolecules) and artificial nucleus materials after injection with an unsealed AF, as IVD is exposed to significant load and large deformation during daily activities. The AF defects strongly change the mechanical properties of the IVD and activate catabolic routes that are responsible for accelerating IVD degeneration. Therefore, there is a strong need to develop effective therapeutic strategies to prevent or reconstruct AF damage to support operational IVD regenerative strategies and nucleus replacement. By the way of this review, repair and regenerative strategies for AF reconstruction, their current status, challenges ahead, and future outlooks were discussed.

Regenerative Response of Degenerate Human Nucleus Pulposus Cells to GDF6 Stimulation.

Growth differentiation factor (GDF) family members have been implicated in the development and maintenance of healthy nucleus pulposus (NP) tissue, making them promising therapeutic candidates for treatment of intervertebral disc (IVD) degeneration and associated back pain. GDF6 has been shown to promote discogenic differentiation of mesenchymal stem cells, but its effect on NP cells remains largely unknown. Our aim was to investigate GDF6 signalling in adult human NP cells derived from degenerate tissue and determine the signal transduction pathways critical for GDF6-mediated phenotypic changes and tissue homeostatic mechanisms. This study demonstrates maintained expression of GDF6 receptors in human NP and annulus fibrosus (AF) cells across a range of degeneration grades at gene and protein level. We observed an anabolic response in NP cells treated with recombinant GDF6 (increased expression of matrix and NP-phenotypic markers; increased glycosaminoglycan production; no change in catabolic enzyme expression), and identified the signalling pathways involved in these responses (SMAD1/5/8 and ERK1/2 phosphorylation, validated by blocking studies). These findings suggest that GDF6 promotes a healthy disc tissue phenotype in degenerate NP cells through SMAD-dependent and -independent (ERK1/2) mechanisms, which is important for development of GDF6 therapeutic strategies for treatment of degenerate discs.

Bony stress in the lumbar spine is associated with intervertebral disc degeneration and low back pain: a retrospective case-control MRI study of patients under 25 years of age.

PURPOSE: Abnormal stress in the lumbar vertebra, also known as bony stress, can be a precursor to degenerative changes which may manifest as low back pain (LBP). However, the prevalence of bony stress in the lumbar spine and its relationship with degenerative changes and LBP is unclear. The purpose of this study was to evaluate the prevalence of bony stress in the lumbar spine and its relationship with intervertebral disc (IVD) degeneration, facet osteoarthritis and LBP in patients under 25 years of age. METHODS: A retrospective case-control study of 130 patients under 25 years of age was conducted from a population of 493 patients who had lumbar MRI across three imaging centres over three years. A cohort of 55 consecutive patients with bony stress was identified. A control group of consecutive patients (n = 75) without bony stress was also selected from the population. RESULTS: Bony stress was prevalent in 11% (95% CI [8.4-14.5%]) of patients and was not diagnosed in 36% (95% CI [22-55%]) of these cases. Patients with bony stress had over twofold (OR 2.3, 95% CI [1.1-4.8]) and fivefold (OR 5.3, 95% CI [2.11-13.3]) higher likelihood of having IVD degeneration and LBP, respectively, when compared with the control group. Bony stress was not found to be associated with facet osteoarthritis. CONCLUSION: Bony stress in the lumbar spine was prevalent in 11% of patients under 25 years of age. It was commonly undiagnosed in radiology reports (not reported in 36% of the cases). Being significantly associated and with an increased likelihood of IVD degeneration and LBP, we posit that bony stress is likely a symptomatic and clinically meaningful diagnostic entity in the assessment of LBP. These slides can be retrieved under Electronic Supplementary Material.

Complication rates of different discectomy techniques for the treatment of lumbar disc herniation: a network meta-analysis.

PURPOSE: The aim of this network meta-analysis (NMA) was to compare the complication rates of discectomy/microdiscectomy, percutaneous laser disc decompression (PLDD), percutaneous endoscopic lumbar discectomy (PELD), microendoscopic discectomy (MED), and tubular discectomy for symptomatic lumbar disc herniation (LDH). METHODS: We searched three online databases for randomized controlled trials (RCTs). Overall complication rates, complication rates per general and modified Clavien-Dindo classification schemes, and reoperation rates were considered as primary outcomes. Odds ratio with 95% confidence intervals for direct comparisons and 95% credible intervals for NMA results were reported. Surface under cumulative ranking curve (SUCRA) was used to estimate ranks for each discectomy technique based on the complication rates. RESULTS: In total, 18 RCTs with 2273 patients were included in this study. Our results showed that there was no significant difference in any of the pairwise comparisons. PELD (SUCRA: 0.856) ranked the lowest for overall complication rates. Discectomy/microdiscectomy (SUCRA: 0.599) and PELD (SUCRA: 0.939) ranked the lowest for intraoperative and post-operative complication rates, respectively. Concerning modified Clavien-Dindo classification scheme, PELD (SUCRA: 0.803), MED (SUCRA: 0.730), and PLDD (SUCRA: 0.605) ranked the lowest for the occurrence of type I, II, and III complications, respectively. Tubular discectomy (SUCRA: 0.699) ranked the lowest for reoperation rates. CONCLUSIONS: The results of this NMA suggest that discectomy/microdiscectomy and PELD are the safest procedures for LDH with minimal intraoperative and post-operative complications, respectively. PELD, MED, and PLDD are the safest procedures for LDH in terms of minimal rates for complications necessitating conservative, pharmacological, and surgical treatment, respectively. These slides can be retrieved under Electronic Supplementary Material.

Correction to: ISSLS PRIZE IN BASIC SCIENCE 2018: Growth differentiation factor-6 attenuated pro-inflammatory molecular changes in the rabbit anular-puncture model and degenerated disc-induced pain generation in the rat xenograft radiculopathy model.

The author "Ashish D. Diwan" receives educational consultant fees from Nuvasive Inc.

Is L5-S1 motion segment different from the rest? A radiographic kinematic assessment of 72 patients with chronic low back pain.

PURPOSE: The relationship between biomechanical instability and degenerative changes in the lumbar spine in chronic low back pain (CLBP) patients remains controversial. The main objective of this retrospective radiographical study was to evaluate changes in kinematics at different lumbar levels (in particular the L5-S1 level) with progressive grades of disc degeneration and facet joint osteoarthritis in CLBP patients. METHODS: Using standing neutral and dynamic flexion/extension (Fx/Ex) radiographs of the lumbar spine, in vivo segmental kinematics at L1-L2 through L5-S1 were evaluated in 72 consecutive CLBP patients. Disc degeneration was quantified using changes in signal intensity and central disc height on mid-sagittal T2-weighted magnetic resonance (MR) scans. Additionally, the presence or absence of facet joint osteoarthritis was noted on T2-weighted axial MR scans. RESULTS: Disc degeneration and facet joint osteoarthritis occurred independent of each other at the L5-S1 level (p = 0.188), but an association was observed between the two at L4-L5 (p < 0.001) and L3-L4 (p < 0.05) levels. In the absence of facet joint osteoarthritis, the L5-S1 segment showed a greater range of motion (ROM) in Ex (3.3° ± 3.6°) and a smaller ROM in Fx (0.6° ± 4.2°) compared with the upper lumbar levels (p < 0.05), but the differences diminished in the presence of it. In the absence of facet joint osteoarthritis, no change in L5-S1 kinematics was observed with progressive disc degeneration, but in its presence, restabilisation of the L5-S1 segment was observed between mild and severe disc degeneration states. CONCLUSION: The L5-S1 motion segment exhibited unique degenerative and kinematic characteristics compared with the upper lumbar motion segments. Disc degeneration and facet joint osteoarthritis occurred independent of each other at the L5-S1 level, but not at the other lumbar levels. Severe disc degeneration in the presence of facet joint osteoarthritis biomechanically restabilised the L5-S1 motion segment.

ISSLS PRIZE IN BASIC SCIENCE 2018: Growth differentiation factor-6 attenuated pro-inflammatory molecular changes in the rabbit anular-puncture model and degenerated disc-induced pain generation in the rat xenograft radiculopathy model.

PURPOSE: To elucidate the effects of growth differentiation factor-6 (GDF6) on: (i) gene expression of inflammatory/pain-related molecules and structural integrity in the rabbit intervertebral disc (IVD) degeneration model, and (ii) sensory dysfunction and changes in pain-marker expression in dorsal nerve ganglia (DRGs) in the rat xenograft radiculopathy model. METHODS: Forty-six adolescent rabbits received anular-puncture in two non-consecutive lumbar IVDs. Four weeks later, phosphate-buffered saline (PBS) or GDF6 (1, 10 or 100 µg) was injected into the nucleus pulposus (NP) of punctured discs and followed for 4 weeks for gene expression analysis and 12 weeks for structural analyses. For pain assessment, eight rabbits were sacrificed at 4 weeks post-injection and NP tissues of injected discs were transplanted onto L5 DRGs of 16 nude rats to examine mechanical allodynia. The rat DRGs were analyzed immunohistochemically. RESULTS: In GDF6-treated rabbit NPs, gene expressions of interleukin-6, tumor necrosis factor-α, vascular endothelial growth factor, prostaglandin-endoperoxide synthase 2, and nerve growth factor were significantly lower than those in the PBS group. GDF6 injections resulted in partial restoration of disc height and improvement of MRI disc degeneration grades with statistical significance in rabbit structural analyses. Allodynia induced by xenograft transplantation of rabbit degenerated NPs onto rat DRGs was significantly reduced by GDF6 injection. Staining intensities for ionized calcium-binding adaptor molecule-1 and calcitonin gene-related peptide in rat DRGs of the GDF6 group were significantly lower than those of the PBS group. CONCLUSION: GDF6 injection may change the pathological status of degenerative discs and attenuate degenerated IVD-induced pain.