Therapeutic CRISPR epigenome editing of inflammatory receptors in the intervertebral disc.

Low back pain (LBP) ranks among the leading causes of disability worldwide and generates a tremendous socioeconomic cost. Disc degeneration, a leading contributor to LBP, can be characterized by the breakdown of the extracellular matrix of the intervertebral disc (IVD), disc height loss, and inflammation. The inflammatory cytokine tumor necrosis factor α (TNF-α) has multiple signaling pathways, including proinflammatory signaling through tumor necrosis factor receptor 1 superfamily, member 1a (TNFR1 or TNFRSF1A), and has been implicated as a primary mediator of disc degeneration. We tested our ability to regulate the TNFR1 signaling pathway in vivo, utilizing CRISPR epigenome editing to slow the progression of disc degeneration in rats. Sprague-Dawley rats were treated with TNF-α and CRISPR interference (CRISPRi)-based epigenome-editing therapeutics targeting TNFR1, showing decreased behavioral pain in a disc degeneration model. Surprisingly, while treatment with the vectors alone was therapeutic, the TNF-α injection became therapeutic after TNFR1 modulation. These results suggest direct inflammatory receptor modulation as a potent strategy for treating disc degeneration.

Intervertebral disc-intrinsic Hedgehog signaling maintains disc cell phenotypes and prevents disc degeneration through both cell autonomous and non-autonomous mechanisms.

Intervertebral disc degeneration is closely related to abnormal phenotypic changes in disc cells. However, the mechanism by which disc cell phenotypes are maintained remains poorly understood. Here, Hedgehog-responsive cells were found to be specifically localized in the inner annulus fibrosus and cartilaginous endplate of postnatal discs, likely activated by Indian Hedgehog. Global inhibition of Hedgehog signaling using a pharmacological inhibitor or Agc1-CreERT2-mediated deletion of Smo in disc cells of juvenile mice led to spontaneous degenerative changes in annulus fibrosus and cartilaginous endplate accompanied by aberrant disc cell differentiation in adult mice. In contrast, Krt19-CreER-mediated deletion of Smo specifically in nucleus pulposus cells led to healthy discs and normal disc cell phenotypes. Similarly, age-related degeneration of nucleus pulposus was accelerated by genetic inactivation of Hedgehog signaling in all disc cells, but not in nucleus pulposus cells. Furthermore, inactivation of Gli2 in disc cells resulted in partial loss of the vertebral growth plate but otherwise healthy discs, whereas deletion of Gli3 in disc cells largely corrected disc defects caused by Smo ablation in mice. Taken together, our findings not only revealed for the first time a direct role of Hedgehog-Gli3 signaling in maintaining homeostasis and cell phenotypes of annuls fibrosus and cartilaginous endplate, but also identified disc-intrinsic Hedgehog signaling as a novel non-cell-autonomous mechanism to regulate nucleus pulposus cell phenotype and protect mice from age-dependent nucleus pulposus degeneration. Thus, targeting Hedgehog signaling may represent a potential therapeutic strategy for the prevention and treatment of intervertebral disc degeneration.

DNMT3a-mediated methylation of PPARγ promote intervertebral disc degeneration by regulating the NF-κB pathway.

Intervertebral disc degeneration (IVDD) is a common chronic musculoskeletal disease that causes chronic low back pain and imposes an immense financial strain on patients. The pathological mechanisms underlying IVDD have not been fully elucidated. The development of IVDD is closely associated with abnormal epigenetic changes, suggesting that IVDD progression may be controlled by epigenetic mechanisms. Consequently, this study aimed to investigate the role of epigenetic regulation, including DNA methyltransferase 3a (DNMT3a)-mediated methylation and peroxisome proliferator-activated receptor γ (PPARγ) inhibition, in IVDD development. The expression of DNMT3a and PPARγ in early and late IVDD of nucleus pulposus (NP) tissues was detected using immunohistochemistry and western blotting analyses. Cellularly, DNMT3a inhibition significantly inhibited IL-1ß-induced apoptosis and extracellular matrix (ECM) degradation in rat NP cells. Pretreatment with T0070907, a specific inhibitor of PPARγ, significantly reversed the anti-apoptotic and ECM degradation effects of DNMT3a inhibition. Mechanistically, DNMT3a modified PPARγ promoter hypermethylation to activate the nuclear factor-κB (NF-κB) pathway. DNMT3a inhibition alleviated IVDD progression. Conclusively, the results of this study show that DNMT3a activates the NF-κB pathway by modifying PPARγ promoter hypermethylation to promote apoptosis and ECM degradation. Therefore, we believe that the ability of DNMT3a to mediate the PPARγ/NF-κB axis may provide new ideas for the potential pathogenesis of IVDD and may become an attractive target for the treatment of IVDD.

The enhanced connectivity between the frontoparietal, somatomotor network and thalamus as the most significant network changes of chronic low back pain.

The prolonged duration of chronic low back pain (cLBP) inevitably leads to changes in the cognitive, attentional, sensory and emotional processing brain regions. Currently, it remains unclear how these alterations are manifested in the interplay between brain functional and structural networks. This study aimed to predict the Oswestry Disability Index (ODI) in cLBP patients using multimodal brain magnetic resonance imaging (MRI) data and identified the most significant features within the multimodal networks to aid in distinguishing patients from healthy controls (HCs). We constructed dynamic functional connectivity (dFC) and structural connectivity (SC) networks for all participants (n = 112) and employed the Connectome-based Predictive Modeling (CPM) approach to predict ODI scores, utilizing various feature selection thresholds to identify the most significant network change features in dFC and SC outcomes. Subsequently, we utilized these significant features for optimal classifier selection and the integration of multimodal features. The results revealed enhanced connectivity among the frontoparietal network (FPN), somatomotor network (SMN) and thalamus in cLBP patients compared to HCs. The thalamus transmits pain-related sensations and emotions to the cortical areas through the dorsolateral prefrontal cortex (dlPFC) and primary somatosensory cortex (SI), leading to alterations in whole-brain network functionality and structure. Regarding the model selection for the classifier, we found that Support Vector Machine (SVM) best fit these significant network features. The combined model based on dFC and SC features significantly improved classification performance between cLBP patients and HCs (AUC=0.9772). Finally, the results from an external validation set support our hypotheses and provide insights into the potential applicability of the model in real-world scenarios. Our discovery of enhanced connectivity between the thalamus and both the dlPFC (FPN) and SI (SMN) provides a valuable supplement to prior research on cLBP.

Analysis of Intestinal Bacterial Microbiota in Individuals with and without Chronic Low Back Pain.

Low back pain is a health problem that represents the greatest cause of years lived with disability. This research seeks to evaluate the bacterial composition of the intestinal microbiota of two similar groups: one with chronic low back pain (PG) and the control group (CG). Clinical data from 73 participants and bacterial genome sequencing data from stool samples were analyzed. There were 40 individuals in PG and 33 in CG, aged between 20 and 50 years and with a body mass index of up to 30 kg/m2. Thus, the intragroup alpha diversity and intergroup beta diversity were analyzed. The significant results (p < 0.05) showed greater species richness in PG compared to CG. Additionally, a greater abundance of the species Clostridium difficile in PG was found along with 52 species with significantly different average relative abundances between groups (adjusted p < 0.05), with 36 more abundant species in PG and 16 in CG. We are the first to unveil significant differences in the composition of the intestinal bacterial microbiota of individuals with chronic low back pain who are non-elderly, non-obese and without any other serious chronic diseases. It could be a reference for a possible intestinal bacterial microbiota signature in chronic low back pain.

The effects of telehealth-delivered mindfulness meditation, cognitive therapy, and behavioral activation for chronic low back pain: a randomized clinical trial.

BACKGROUND: Chronic low back pain (CLBP) is a significant problem affecting millions of people worldwide. Three widely implemented psychological techniques used for CLBP management are cognitive therapy (CT), mindfulness meditation (MM), and behavioral activation (BA). This study aimed to evaluate the relative immediate (pre- to post-treatment) and longer term (pre-treatment to 3- and 6-month follow-ups) effects of group, videoconference-delivered CT, BA, and MM for CLBP. METHODS: This is a secondary analysis of a three-arm, randomized clinical trial comparing the effects of three active treatments-CT, BA, and MM-with no inert control condition. Participants were N = 302 adults with CLBP, who were randomized to condition. The primary outcome was pain interference, and other secondary outcomes were also examined. The primary study end-point was post-treatment. Intent-to-treat analyses were undertaken for each time point, with the means of the changes in outcomes compared among the three groups using an analysis of variance (ANOVA). Effect sizes and confidence intervals are also reported. RESULTS: Medium-to-large effect size reductions in pain interference were found within BA, CT, and MM (ds from - .71 to - 1.00), with gains maintained at both follow-up time points. Effect sizes were generally small to medium for secondary outcomes for all three conditions (ds from - .20 to - .71). No significant between-group differences in means or changes in outcomes were found at any time point, except for change in sleep disturbance from pre- to post-treatment, improving more in BA than MM (d = - .49). CONCLUSIONS: The findings from this trial, one of the largest telehealth trials of psychological treatments to date, critically determined that group, videoconference-delivered CT, BA, and MM are effective for CLBP and can be implemented in clinical practice to improve treatment access. The pattern of results demonstrated similar improvements across treatments and outcome domains, with effect sizes consistent with those observed in prior research testing in-person delivered and multi-modal psychological pain treatments. Thus, internet treatment delivery represents a tool to scale up access to evidence-based chronic pain treatments and to overcome widespread disparities in healthcare. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03687762.

First trans-diagnostic experiences with a novel micro-choice based concentrated group rehabilitation for patients with low back pain, long COVID, and type 2 diabetes: a pilot study.

BACKGROUND: The health care is likely to break down unless we are able to increase the level of functioning for the growing number of patients with complex, chronic illnesses. Hence, novel high-capacity and cost-effective treatments with trans-diagnostic effects are warranted. In accordance with the protocol paper, we aimed to examine the acceptability, satisfaction, and effectiveness of an interdisciplinary micro-choice based concentrated group rehabilitation for patients with chronic low back pain, long COVID, and type 2 diabetes. METHODS: Patients with low back pain > 4 months sick-leave, long COVID, or type 2 diabetes were included in this clinical trial with pre-post design and 3-month follow-up. The treatment consisted of three phases: (1) preparing for change, (2) the concentrated intervention for 3-4 days, and (3) integrating change into everyday life. Patients were taught and practiced how to monitor and target seemingly insignificant everyday micro-choices, in order to break the patterns where symptoms or habits contributed to decreased levels of functioning or increased health problems. The treatment was delivered to groups (max 10 people) with similar illnesses. Client Satisfaction Questionnaire (CSQ-8)) (1 week), Work and Social Adjustment Scale (WSAS), Brief Illness Perception Questionnaire (BIPQ), and self-rated health status (EQ-5D-5L) were registered at baseline and 3-month follow-up. RESULTS: Of the 241 included participants (57% women, mean age 48 years, range 19-84), 99% completed the concentrated treatment. Treatment satisfaction was high with a 28.9 (3.2) mean CSQ-8-score. WSAS improved significantly from baseline to follow-up across diagnoses 20.59 (0.56) to 15.76 (0.56). BIPQ improved from: 22.30 (0.43) to 14.88 (0.47) and EQ-5D-5L: 0.715 (0.01) to 0.779 (0.01)), all P<0.001. CONCLUSIONS: Across disorders, the novel approach was associated with high acceptability and clinically important improvements in functional levels, illness perception, and health status. As the concentrated micro-choice based treatment format might have the potential to change the way we deliver rehabilitation across diagnoses, we suggest to proceed with a controlled trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT05234281.

Assessing the performance of AI chatbots in answering patients' common questions about low back pain.

OBJECTIVES: The aim of this study was to assess the accuracy and readability of the answers generated by large language model (LLM)-chatbots to common patient questions about low back pain (LBP). METHODS: This cross-sectional study analysed responses to 30 LBP-related questions, covering self-management, risk factors and treatment. The questions were developed by experienced clinicians and researchers and were piloted with a group of consumer representatives with lived experience of LBP. The inquiries were inputted in prompt form into ChatGPT 3.5, Bing, Bard (Gemini) and ChatGPT 4.0. Responses were evaluated in relation to their accuracy, readability and presence of disclaimers about health advice. The accuracy was assessed by comparing the recommendations generated with the main guidelines for LBP. The responses were analysed by two independent reviewers and classified as accurate, inaccurate or unclear. Readability was measured with the Flesch Reading Ease Score (FRES). RESULTS: Out of 120 responses yielding 1069 recommendations, 55.8% were accurate, 42.1% inaccurate and 1.9% unclear. Treatment and self-management domains showed the highest accuracy while risk factors had the most inaccuracies. Overall, LLM-chatbots provided answers that were 'reasonably difficult' to read, with a mean (SD) FRES score of 50.94 (3.06). Disclaimer about health advice was present around 70%-100% of the responses produced. CONCLUSIONS: The use of LLM-chatbots as tools for patient education and counselling in LBP shows promising but variable results. These chatbots generally provide moderately accurate recommendations. However, the accuracy may vary depending on the topic of each question. The reliability level of the answers was inadequate, potentially affecting the patient's ability to comprehend the information.

Goodbye to the term 'ankylosing spondylitis', hello 'axial spondyloarthritis': time to embrace the ASAS-defined nomenclature.

Ankylosing spondylitis (AS) is the historic term used for decades for the HLA-B27-associated inflammatory disease affecting mainly the sacroiliac joints (SIJ) and spine. Classification criteria for AS have radiographic sacroiliitis as a dominant characteristic. However, with the availability of MRI of SIJ, it could be demonstrated that the disease starts long before definite SIJ changes become visible on radiographs. The Assessment of SpondyloArthritis international Society, representing a worldwide group of experts reached consensus on changes in the nomenclature pertaining to axial spondyloarthritis (axSpA), such as the terminology of diagnosis and of assessment of disease activity tools. These are important changes in the field, as experts in axSpA are now in agreement that the term axSpA is the overall term for the disease. A further differentiation, of which radiographic versus non-radiographic is only one aspect, may be relevant for research purposes. Another important decision was that the terms AS and radiographic axSpA (r-axSpA) can be used interchangeably, but that the preferred term is r-axSpA. Based on the decision that axSpA is the correct terminology, a proposal was made to officially change the meaning of the ASDAS acronym to 'Axial Spondyloarthritis Disease Activity Score'. In addition, for simplification it was proposed that the term ASDAS (instead of ASDAS-CRP) should be preferred and applied to the ASDAS calculated with C reactive protein (CRP). It is hoped that these changes will be used consequently for education, in textbooks, manuscripts and presentations.

Allogenic bone marrow-derived mesenchymal stromal cell-based therapy for patients with chronic low back pain: a prospective, multicentre, randomised placebo controlled trial (RESPINE study).

OBJECTIVES: To assess the efficacy of a single intradiscal injection of allogeneic bone marrow mesenchymal stromal cells (BM-MSCs) versus a sham placebo in patients with chronic low back pain (LBP). METHODS: Participants were randomised in a prospective, double-blind, controlled study to receive either sham injection or intradiscal injection of 20 million allogeneic BM-MSC, between April 2018 and December 2022. The first co-primary endpoint was the rate of responders defined by improvement of the Visual Analogue Scale (VAS) for pain of at least 20% and 20 mm, or improvement of the Oswestry Disability Index (ODI) of 20% between baseline and month 12. The secondary structural co-primary endpoint was assessed by the disc fluid content measured by quantitative MRI T2, between baseline and month 12. Secondary endpoints included pain VAS, ODI, the Short Form (SF)-36 and the minimal clinically important difference in all timepoints (1, 3, 6, 12 and 24 months). We determined the immune response associated with allogeneic cell injection between baseline and 6 months. Serious adverse events (SAEs) were recorded. RESULTS: 114 patients were randomised (n=58, BM-MSC group; n=56, sham placebo group). At 12 months, the primary outcome was not reached (74% in the BM-MSC group vs 69% in the placebo group; p=0.77). The groups did not differ in all secondary outcomes. No SAE related to the intervention occurred. CONCLUSIONS: While our study did not conclusively demonstrate the efficacy of allogeneic BM-MSCs for LBP, the procedure was safe. Long-term outcomes of MSC therapy for LBP are still being studied. TRIAL REGISTRATION NUMBER: EudraCT 2017-002092-25/ClinicalTrials.gov: NCT03737461.

CD206+ M2-like macrophages protect against intervertebral disc degeneration partially by targeting R-spondin-2.

OBJECTIVE: This study aimed to explore the specific function of M2 macrophages in intervertebral disc degeneration (IDD). METHODS: Intervertebral disc (IVD) samples from normal (n = 4) and IDD (n = 6) patients were collected, and the expression of M2-polarized macrophage marker, CD206, was investigated using immunohistochemical staining. Nucleus pulposus cells (NPCs) in a TNF-α environment were obtained, and a mouse caudal IVD puncture model was established. Mice with Rheb deletions, specifically in the myeloid lineage, were generated and subjected to surgery-induced IDD. IDD-induced damage and cell apoptosis were measured using histological scoring, X-ray imaging, immunohistochemical staining, and TdT-mediated dUTP nick end labeling (TUNEL) assay. Finally, mice and NPCs were treated with R-spondin-2 (Rspo2) or anti-Rspo2 to investigate the role of Rspo2 in IDD. RESULTS: Accumulation of CD206 in human and mouse IDD tissues was detected. Rheb deletion in the myeloid lineage (RheBcKO) increased the number of CD206+ M2-like macrophages (mean difference 18.6% [15.7-21.6%], P < 0.001), decreased cell apoptosis (mean difference -15.6% [-8.9 to 22.2%], P = 0.001) and attenuated the IDD process in the mouse IDD model. NPCs treated with Rspo2 displayed increased extracellular matrix catabolism and apoptosis; co-culture with a conditioned medium derived from RheBcKO mice inhibited these changes. Anti-Rspo2 treatment in the mouse caudal IVD puncture model exerted protective effects against IDD. CONCLUSIONS: Promoting CD206+ M2-like macrophages could reduce Rspo2 secretion, thereby alleviating experimental IDD. Rheb deletion may help M2-polarized macrophages accumulate and attenuate experimental IDD partially by inhibiting Rspo2 production. Hence, M2-polarized macrophages and Rspo2 may serve as therapeutic targets for IDD.

Somatisation differentiates fibromyalgia from low back pain: a comparative, cross-sectional cohort study.

OBJECTIVES: To examine whether somatisation, depression, anxiety, fatigue, coping dimensions, pain, physical and social function, or sociodemographic characteristics can differentiate fibromyalgia from low back pain in a cross-sectional cohort setting of our Zurzach Interdisciplinary Pain Programme. METHODS: Fibromyalgia and low back pain (not fulfilling the diagnostic criteria for fibromyalgia) were compared using the Symptom Checklist-90R (SCL-90R) Somatisation scale, the Quantification Inventory for Somatoform Syndromes (QUISS) Number of somatoform symptoms, and other standardised instruments. Standardised mean differences (SMDs) quantified the score differences, and binomial logistic regression modelling with various co-variates differentiated fibromyalgia from low back pain. RESULTS: The largest differences indicating worse health in fibromyalgia (n = 131) were in somatisation (SCL-90R: SMD=-0.971, QUISS: SMD=-0.960), followed by affective health, pain and coping (SMDs between -0.632 and -0.280). Physical and social functioning were comparable in the two conditions (n = 262 low back pain). The two somatisation scales both with odds ratios (OR)=0.966 (p≤ 0.002) plus female sex (OR = 3.396, p< 0.001) predicted 74.3% of the cases correctly (accuracy) with a positive predictive value of 65.3% and a specificity of 87.0% for fibromyalgia. In the female subsample (n = 280), the model remained stable with an accuracy of 71.9%. CONCLUSION: Somatisation stood out from all other somatic, psychosocial, and coping dimensions and sociodemographics as the one significant specific predictor distinguishing fibromyalgia from low back pain. The fibromyalgia phenotype is characterised by the generalisation of painful loci but equally prominently by generalised somatoform symptoms. Assessment of somatisation is recommended to ensure accurate identification and understanding of the multifaceted syndrome of fibromyalgia.

Validation of a questionnaire for Central nervous system Aspects of joint Pain: the CAP questionnaire.

BACKGROUND AND AIMS: Neuropathic-like pain, fatigue, cognitive difficulty, catastrophising, anxiety, sleep disturbance, depression, and widespread pain associate with a single factor in people with knee pain. We report the Central Aspects of Pain questionnaire (CAP) to characterise this across painful musculoskeletal conditions. METHODS: CAP was derived from the 8 item CAP-Knee questionnaire, and completed by participants with joint pain in the Investigating Musculoskeletal Health and Wellbeing survey. Subgroups had osteoarthritis, back pain or fibromyalgia. Acceptability was evaluated by feedback and data missingness. Correlation coefficients informed widespread pain scoring threshold in relation to the other items, and evaluated associations with pain. Factor analysis assessed CAP structure. Intraclass Correlation Coefficient (ICC) between paper and electronic administration assessed reliability. Friedman test assessed score stability over 4 years in people reporting knee osteoarthritis. RESULTS: Data were from 3579 participants (58% female, median age; 71 years), including subgroups with osteoarthritis (n = 1158), back pain (n = 1292) or fibromyalgia (n = 177). Across the 3 subgroups, ≥10/26 painful sites on the manikin scored widespread pain. Reliability was high (ICC= 0.89 (95% CI: 0.84-0.92)) and CAP scores fit to 1 and 2 factor model, with a total CAP score that was associated with pain severity and quality (r = 0.50-0.72). In people with knee pain, CAP scores were stable over 4 years at the group level, but displayed significant temporal heterogeneity within individual participants. CONCLUSIONS: Central Aspects of Pain is reliably measured by the CAP questionnaire across a range of painful musculoskeletal conditions, and is a changeable state.

Trends in Chiropractic Care and Physical Rehabilitation Use Among Adults with Low Back Pain in the United States, 2002 to 2018.

BACKGROUND: While nonpharmacologic treatments are increasingly endorsed as first-line therapy for low back pain (LBP) in clinical practice guidelines, it is unclear if use of these treatments is increasing or equitable. OBJECTIVE: Examine national trends in chiropractic care and physical rehabilitation (occupational/physical therapy (OT/PT)) use among adults with LBP. DESIGN/SETTING: Serial cross-sectional analysis of the National Health Interview Survey, 2002 to 2018. PARTICIPANTS: 146,087 adults reporting LBP in prior 3 months. METHODS: We evaluated the association of survey year with chiropractic care or OT/PT use in prior 12 months. Logistic regression with multilevel linear splines was used to determine if chiropractic care or OT/PT use increased after the introduction of clinical guidelines. We also examined trends in use by age, sex, race, and ethnicity. When trends were similar over time, we present differences by these demographic characteristics as unadjusted ORs using data from all respondents. RESULTS: Between 2002 and 2018, less than one-third of adults with LBP reported use of either chiropractic care or OT/PT. Rates did not change until 2016 when uptake increased with the introduction of clinical guidelines (2016-2018 vs 2002-2015, OR = 1.15; 95% CI: 1.10-1.19). Trends did not differ significantly by sex, race, or ethnicity (p for interactions > 0.05). Racial and ethnic disparities in chiropractic care or OT/PT use were identified and persisted over time. For example, compared to non-Hispanic adults, either chiropractic care or OT/PT use was lower among Hispanic adults (combined OR = 0.62, 95% CI: 0.65-0.73). By contrast, compared to White adults, Black adults had similar OT/PT use (OR = 0.98; 95% CI: 0.94-1.03) but lower for chiropractic care use (OR = 0.50; 95% CI: 0.47-0.53). CONCLUSIONS: Although use of chiropractic care or OT/PT for LBP increased after the introduction of clinical guidelines in 2016, only about a third of US adults with LBP reported using these services between 2016 and 2018 and disparities in use have not improved.

Evaluation of the Reproducibility of MR Elastography Measurements of the Lumbar Back Muscles.

BACKGROUND: MR elastography (MRE) may provide quantitative imaging biomarkers of lumbar back muscles (LBMs), complementing MRI in spinal diseases by assessing muscle mechanical properties. However, reproducibility analyses for MRE of LBM are lacking. PURPOSE: To assess technical failure, within-day and inter-day reproducibility, robustness with the excitation source positioning, and inter-observer agreement of MRE of muscles. STUDY TYPE: Prospective. SUBJECTS: Seventeen healthy subjects (mean age 28 ± 4 years; 11 females). FIELD STRENGTH/SEQUENCE: 1.5 T, gradient-echo MRE, T1-weighted turbo spin echo. ASSESSMENT: The pneumatic driver was centered at L3 level. Four MRE were performed during two visits, 2-4 weeks apart, each consisting of two MRE with less than 10 minutes inter-scan interval. At Visit 1, after the first MRE, the coil and driver were removed, then reinstalled. The MRE was repeated. At Visit 2, following the first MRE, only the driver was moved down 5 cm. The MRE was repeated. Two radiologists segmented the multifidus and erector spinae muscles. STATISTICAL TESTS: Paired t-test, analysis of variance, intraclass correlation coefficients (ICCs). P-values <0.05 were considered statistically significant. RESULTS: Mean stiffness of LBM ranged from 1.44 to 1.60 kPa. Mean technical failure rate was 2.5%. Inter-observer agreement was excellent (ICC ranging from 0.82 [0.64-0.96] to 0.99 [0.98-0.99] in the multifidus, and from 0.85 [0.69-0.92] to 0.99 [0.97-0.99] in the erector spinae muscles). Within-day reproducibility was fair in the multifidus (ICC: 0.53 [0.47-0.77]) and good in the erector spinae muscles (ICC: 0.74 [0.48-0.88]). Reproducibility after moving the driver was excellent in both multifidus (ICC: 0.85 [0.69-0.93]) and erector spinae muscles (ICC: 0.84 [0.67-0.92]). Inter-day reproducibility was excellent in the multifidus (ICC: 0.76 [0.48-0.89]) and poor in the erector spinae muscles (ICC: 0.23 [-0.61 to 0.63]). DATA CONCLUSION: MRE of LBM provides measurements of stiffness with fair to excellent reproducibility and excellent inter-observer agreement. However, inter-day reproducibility in the multifidus muscles indicated that the herein used MRE protocol may not be optimal for this muscle. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

The role of miR-155-5p in inflammation and mechanical loading during intervertebral disc degeneration.

BACKGROUND: Intervertebral disc (IVD) degeneration is a multifactorial pathological process resulting in the dysregulation of IVD cell activity. The catabolic shift observed in IVD cells during degeneration leads to increased inflammation, extracellular matrix (ECM) degradation, aberrant intracellular signaling and cell loss. Importantly, these pathological processes are known to be interconnected and to collectively contribute to the progression of the disease. MicroRNAs (miRNAs) are known as strong post-transcriptional regulators, targeting multiple genes simultaneously and regulating numerous intracellular pathways. Specifically, miR-155-5p has been of particular interest since it is known as a pro-inflammatory mediator and contributing factor to diseases like cancer and osteoarthritis. This study investigated the role of miR-155-5p in IVD degeneration with a specific focus on inflammation and mechanosensing. METHODS: Gain- and loss-of-function studies were performed through transfection of human Nucleus pulposus (NP) and Annulus fibrosus (AF) cells isolated from degenerated IVDs with miR-155-5p mimics, inhibitors or their corresponding non-targeting control. Transfected cells were then subjected to an inflammatory environment or mechanical loading. Conditioned media and cell lysates were collected for phosphorylation and cytokine secretion arrays as well as gene expression analysis. RESULTS: Increased expression of miR-155-5p in AF cells resulted in significant upregulation of interleukin (IL)-8 cytokine secretion during cyclic stretching and a similar trend in IL-6 secretion during inflammation. Furthermore, miR-155-5p mimics increased the expression of the brain-derived neurotrophic factor (BDNF) in AF cells undergoing cyclic stretching. In NP cells, miR-155-5p gain-of-function resulted in the activation of the mitogen-activated protein kinase (MAPK) signaling pathway through increased phosphorylation of p38 and p53. Lastly, miR-155-5p inhibition caused a significant increase in the anti-inflammatory cytokine IL-10 in AF cells and the tissue inhibitor of metalloproteinases (TIMP)-4 in NP cells respectively. CONCLUSION: Overall, these results show that miR-155-5p contributes to IVD degeneration by enhancing inflammation through pro-inflammatory cytokines and MAPK signaling, as well as by promoting the catabolic shift of AF cells during mechanical loading. The inhibition of miR-155-5p may constitute a potential therapeutic approach for IVD degeneration and low back pain.

Physical job demands in pregnancy and associated musculoskeletal health and employment outcomes: a systematic review.

OBJECTIVE: A decline in musculoskeletal health during pregnancy is an underappreciated adverse outcome of pregnancy that can have immediate and long-term health consequences. High physical job demands are known risk factors for nontraumatic musculoskeletal disorders in the general working population. Evidence from meta-analyses suggest that occupational lifting and prolonged standing during pregnancy may increase risk of adverse pregnancy outcomes. This systematic review examined associations between occupational lifting or postural load in pregnancy and associated musculoskeletal disorders and related sequalae. DATA SOURCES: Five electronic databases (Medline, Embase, CINAHL, NIOSHTIC-2, and Ergonomic Abstracts) were searched from 1990 to July 2022 for studies in any language. A Web of Science snowball search was performed in December 2022. Reference lists were manually reviewed. STUDY ELIGIBILITY CRITERIA: Eligible studies reported associations between occupational lifting or postural load and musculoskeletal health or sequelae (eg, employment outcomes) among pregnant and postpartum workers. METHODS: Data were extracted using a customized form to document study and sample characteristics; and details of exposures, outcomes, covariates, and analyses. Investigators independently assessed study quality for 7 risk-of-bias domains and overall utility, with discrepant ratings resolved through discussion. A narrative synthesis was conducted due to heterogeneity. RESULTS: Sixteen studies (11 cohort studies, 2 nested case-control studies, and 3 cross-sectional studies) from 8 countries were included (N=142,320 pregnant and N=1744 postpartum workers). Limited but consistent evidence with variable quality ratings, ranging from critical concern to high, suggests that pregnant workers exposed to heavy lifting (usually defined as ≥22 lbs or ≥10 kg) may be at increased risk of functionally limiting pelvic girdle pain and antenatal leave. Moreover, reports of dose-response relationships suggest graded risk levels according to lifting frequency, ranging from 21% to 45% for pelvic girdle pain and 58% to 202% for antenatal leave. Limited but consistent evidence also suggests that postural load increases the risk of employment cessation. CONCLUSION: Limited but consistent evidence suggests that pregnant workers exposed to heavy lifting and postural load are at increased risk of pelvic girdle pain and employment cessation. Job accommodations to reduce exposure levels may promote safe sustainable employment for pregnant workers.

Gait assessment in a female rat Sprague Dawley model of disc-associated low back pain.

PURPOSE: Gait disturbances are common in human low back pain (LBP) patients, suggesting potential applicability to rodent LBP models. This study aims to assess the influence of disc-associated LBP on gait in female Sprague Dawley rats and explore the utility of the open-source Gait Analysis Instrumentation and Technology Optimized for Rodents (GAITOR) suite as a potential alternative tool for spontaneous pain assessment in a previously established LBP model. MATERIALS AND METHODS: Disc degeneration was surgically induced using a one-level disc scrape injury method, and microcomputed tomography was used to assess disc volume loss. After disc injury, axial hypersensitivity was evaluated using the grip strength assay, and an open field test was used to detect spontaneous pain-like behavior. RESULTS: Results demonstrated that injured animals exhibit a significant loss in disc volume and reduced grip strength. Open field test did not detect significant differences in distance traveled between sham and injured animals. Concurrently, animals with injured discs did not display significant gait abnormalities in stance time imbalance, temporal symmetry, spatial symmetry, step width, stride length, and duty factor compared to sham. However, comparisons with reference values of normal gait reported in prior literature reveal that injured animals exhibit mild deviations in forelimb and hindlimb stance time imbalance, forelimb temporal symmetry, and hindlimb spatial symmetry at some time points. CONCLUSIONS: This study concludes that the disc injury may have very mild effects on gait in female rats within 9 weeks post-injury and recommends future in depth dynamic gait analysis and longer studies beyond 9 weeks to potentially detect gait.

A Stratified Approach for Managing Patients With Low Back Pain in Primary Care (SPLIT Program): A Before-and-After Study.

PURPOSE: To determine the effects of stratified primary care for low back pain (SPLIT program) in decreasing back-related disability for patients with low back pain (LBP) in primary care. METHODS: We conducted a before-and-after study. We compared health-related outcomes for 2 sequential, independent cohorts of patients with LBP recruited at 7 primary care units in Portugal. The first prospective cohort study characterized usual care (UC) and collected data from February to September 2018. The second was performed when the SPLIT program was implemented and collected data from November 2018 to October 2021. Between cohorts, physical therapists were trained in the implementation of the SPLIT program, which used the STarT Back Screening Tool to categorize patients for matched treatment. We compared back-related disability (Roland-Morris Disability Questionnaire, 0-24 points), pain (Numeric Pain Rating Scale, 0-10 points), perceived effect of treatment (Global Perceived Effect Scale, -5 to +5 points), and health-related quality of life (EuroQoL 5 dimensions 3 levels index, 0-1 points). RESULTS: We enrolled a total of 447 patients: 115 in the UC cohort (mostly treated with pharmacologic treatment) and 332 in the SPLIT cohort (all referred for a physical therapy intervention program). Over the study period of 6 months, patients in the SPLIT program showed significantly greater improvements in back-related disability (ß, -2.94; 95% CI, -3.63 to -2.24; P ≤ .001), pain (ß, -0.88; 95% CI, -1.18 to -0.57; P ≤ .001), perceived effect of treatment (ß, 1.40; 95% CI, 0.97 to 1.82; P ≤ .001), and health-related quality of life (ß, 0.11; 95% CI, 0.08 to 0.14; P ≤ .001) compared with UC. CONCLUSIONS: Patients in the SPLIT program for LBP showed greater benefits regarding health-related outcomes than those receiving UC.

Differences in the organization of the primary motor cortex in people with and without low back pain and associations with motor control and sensory tests.

Differences in organization of the primary motor cortex and altered trunk motor control (sensing, processing and motor output) have been reported in people with low back pain (LBP). Little is known to what extent these differences are related. We investigated differences in 1) organization of the primary motor cortex and 2) motor and sensory tests between people with and without LBP, and 3) investigated associations between the organization of the primary motor cortex and motor and sensory tests. We conducted a case-control study in people with (N=25) and without (N=25) LBP. The organization of the primary motor cortex (Center of Gravity (CoG) and Area of the cortical representation of trunk muscles) was assessed using neuronavigated transcranial magnetic stimulation, based on individual MRIs. Sensory tests (quantitative sensory testing, graphaesthesia, two-point discrimination threshold) and a motor test (spiral-tracking test) were assessed. Participants with LBP had a more lateral and lower location of the CoG and a higher temporal summation of pain. For all participants combined, better vibration test scores were associated with a more anterior, lateral, and lower CoG and a better two-point discrimination threshold was associated with a lower CoG. A small subset of variables showed significance. Although this aligns with the concept of altered organization of the primary motor cortex in LBP, there is no strong evidence of the association between altered organization of the primary motor cortex and motor and sensory test performance in LBP. Focusing on subgroup analyses regarding pain duration can be a topic for future research.