The temporal sequence of lumbar spine degeneration (trajectory) is difficult to characterize due to limited availability of longitudinal imaging data. The aim of this cross-sectional study was to discover degeneration trajectories and their clinical relevance by applying an innovative computational approach to an extensive dataset from chronic low back pain patients. Clinical MRI exams from 423 patients in the comeBACK study were graded for disc degeneration, facet osteoarthritis, and other pathoanatomical features. We then trained an event-based model, which is specifically designed to infer longitudinal trajectories from cross-sectional data, to model spine degeneration trajectory subtypes. The clinical significance of the identified trajectories was assessed using propensity score matching of trajectory subtypes and subsequent generalized linear mixed-effects modeling. Pain characteristics included the Fear-Avoidance Beliefs Questionnaire, neuropathic pain (painDETECT), pain impact score, and chronic widespread pain (CWP). Two distinct trajectories were identified. A “disc-first” subtype (n = 260, 61

Background:Modic type 1 changes (MC1) are vertebral endplate bone marrow lesions associated with chronic low back pain (CLBP), but their underlying pathobiology remains unclear. Disc-bone marrow crosstalk that includes Cutibacterium acnes (C. acnes) infection of the disc and immune system activation in the adjacent vertebrae may be a defining feature of some MC1. Methods:In a prospective analysis of patients from the UCSF comeBACK cohort, we quantified intradiscal propionic acid (PA) - a metabolic product of C. acnes - using magnetic resonance spectroscopy (MRS). Patients were stratified into tertiles based on intradiscal PA content, and the uppermost (PA-high) and lowermost (PA-low) tertiles were compared for systemic immune signatures, including whole-blood transcriptomics (n = 196), flow cytometry immunophenotyping (n = 224), and serum cytokine profiling (n = 398). Results:High intradiscal PA was associated with distinct systemic immune responses in patients with MC1 but not in patients with Modic type 2 changes or without Modic changes. Transcriptomic analysis revealed enrichment of adaptive immune pathways and B cell activation signatures in PA-high MC1. Flow cytometry identified the expansion of immunosuppressive ectonucleotidases CD39 and CD73-expressing B cells in PA-high MC1 patients. Finally, intradiscal PA levels were correlated with circulating B cells and serum cytokine concentrations. Conclusions:Intradiscal PA levels measured by MRS associate with biologically distinct blood profiles characterised by systemic B cell activation in patients with MC1. These findings suggest a systemic immune component in the pathobiology of MC1 and highlight the potential of MRS-derived intradiscal PA levels to stratify patients with MC1-related chronic low back pain into biologically distinct subgroups.

BACKGROUND CONTEXT:Vertebral endplate bone marrow lesions ("Modic changes," MC) are a putative cause of chronic low back pain in some individuals. However, associations between MC subtypes and clinical symptoms are variable, which limits the utility of conventional imaging in diagnosing and treating chronic low back pain patients with MC. PURPOSE:Develop a quantitative imaging biomarker for measuring compositional abnormalities in MC-affected endplates using water-fat MRI and test for associations with patient-reported outcomes, conventional MC type classification, and longitudinal conversion of MC types. DESIGN/SETTING:Single center prospective longitudinal observational cohort study. PATIENT SAMPLE:A total of 125 adults with nonspecific chronic low back pain, 59 of whom (47%) had radiologist-diagnosed lumbar MC at baseline. Follow-up imaging (12-months) was collected for 37 participants (14 with MC). OUTCOME MEASURES:A novel measure of MC composition from water-fat MRI, defined as the percentage of the endplate region with abnormally hypo-fatty or hyper-fatty bone marrow. Conventional evaluation of MC presence/absence and type, and ordinal scores for MC height and area as evaluated by a musculoskeletal radiologist on T1- and T2-weighted MRI. Patient-reported outcome measures included the Oswestry Disability Index; the Pain, Enjoyment, and General Activity scale; the visual analogue scale; and the PROMIS physical function and pain interference scales. METHODS:Multivariable linear regression models adjusted for age, sex, and MC count were used to test for associations between patient-reported outcomes and 1) water-fat MRI biomarker values; and 2) conventional MC parameters (presence/absence, type, height, area). Cohen's f2 was used to evaluate effect size (f2≥0.02: small effect, f2≥0.15: medium effect, f2≥0.35: large effect). Linear regression with a Tukey post hoc test was used to test for differences in bone marrow composition (water-fat MRI) within and between MC types. Longitudinal changes in biomarker values were compared with longitudinal changes in MC type classification. RESULTS:There was substantial heterogeneity in marrow composition among MC-affected endplates, including within lesions of the same MC type. Independent of MC type, more extensive hypo-fatty involvement was associated with worse pain and disability across multiple outcome measures (ODI: p=.0007, Cohen's f²=0.26; PEG, p=.026, Cohen's f²=0.11; VAS, p=.018, Cohen's f²=0.12; PROMIS physical function, p=.018, Cohen's f²=0.12), whereas the extent of hyper-fatty involvement was not associated with patient-reported outcomes (p>.41). In contrast, conventional MC type classification was not associated with patient-reported outcomes (p>.25). Longitudinally, large changes in marrow composition were observed in individual lesions without corresponding changes in MC type classification. CONCLUSIONS:Water-fat MRI biomarkers capture pathoanatomic variation in MC-affected marrow that associate more strongly with patient-reported pain, disability, and physical function than conventional MC type classification. Greater hypo-fatty involvement, indicating more severe fibrovascular/edematous changes, is the compositional feature most closely linked to worse symptoms. These biomarkers could improve patient stratification for treatments for vertebrogenic pain.

Modic type 1 changes (MC1) are vertebral endplate bone marrow lesions strongly associated with chronic low back pain (CLBP), but their underlying pathobiology remains unclear. Recent findings suggest that disc–bone marrow crosstalk that includes Cutibacterium acnes (C. acnes) infection of the disc, and immune system activation in the adjacent vertebrae may play a significant role. In a prospective analysis of patients from the UCSF comeBACK cohort, we quantified intradiscal propionic acid (PA) – a metabolic product of C. acnes – using magnetic resonance spectroscopy (MRS). Patients were stratified into tertiles based on intradiscal PA content, and the uppermost (PA-high) and lowest (PA-low) tertiles were compared for systemic immune signatures, including whole-blood transcriptomics (n=196), flow cytometry immunophenotyping (n=224), and serum cytokine profiling (n=398). Elevated intradiscal PA was associated with distinct systemic immune responses in patients with MC1 but not in patients with Modic type 2 or without Modic changes. Transcriptomic analysis revealed enrichment of adaptive immune pathways and B cell activation signatures in PA-high MC1. Flow cytometry identified the expansion of immunosuppressive ectonucleotidases-expressing B cells in PA-high MC1 patients. Finally, the correlation profiles of intradiscal PA levels and circulating B cells with serum cytokine concentrations were highly similar. Together, these data consistently indicate that systemic B cell activation is a hallmark of PA-high MC1. Intradiscal PA, measurable non-invasively by MRS, stratifies MC1 patients into biologically distinct subgroups characterised by systemic B cell activation. These findings suggest a systemic immune component to MC1 pathobiology and highlight B cells as candidate biomarkers and therapeutic targets for MC1-related chronic low back pain.

Background:Vertebral endplate bone marrow lesions (Modic changes, MC) are linked to vertebrogenic pain and to structural defects of the bony and cartilaginous endplates (CEP). However, the immune mechanisms that may perpetuate CEP damage in MC remain unclear. Objective:To (i) characterize neutrophils in MC bone marrow and (ii) test whether activated neutrophils can degrade human CEP tissue. Methods:In low back pain patients undergoing lumbar fusion, paired bone marrow aspirates were collected intraoperatively from an MC level and an adjacent non-MC vertebra (intra-patient control). MC neutrophils were characterized by bulk RNA sequencing of sorted CD45+CD66b+ cells (n = 7), flow cytometry (activation (CD66b); neutrophil maturation subsets), and neutrophil elastase (NE) activity in short-term culture supernatants. To model CEP degradation, conditioned media from healthy-donor blood neutrophils incubated ± neutrophil activator phorbol 12-myristate 13-acetate (PMA) (12.5 or 25 Mio cells/mL) were applied to human CEP explants (18 h). Proteoglycan loss (sGAG) and collagen loss (hydroxyproline) were quantified as release fractions, normalized to media-only controls. Results:MC neutrophils showed an activated, pro-inflammatory transcriptomic signature, including enrichment of calcium-associated processes consistent with degranulation. Flow cytometry demonstrated higher CD66b intensity in MC neutrophils versus intra-patient controls (125.4 ± 34.2%, p = 0.022) and a trend toward increased band neutrophils (126.7 ± 33.4%, p = 0.069). NE release was higher in 4/6 patients (191.2 ± 142.7%, p = 0.178) and correlated with band neutrophil abundance (r = 0.67, p = 0.033). PMA activation markedly increased NE activity in conditioned media and was cell-number dependent. CEP exposure to activated neutrophil conditioned media induced significant sGAG release (25 Mio/mL: 380.1 ± 177.0%, p = 0.012; 12.5 Mio/mL: 123.7 ± 22.3%, p = 0.048), while hydroxyproline release was not significantly increased. Conclusions:Neutrophils within MC bone marrow have an activated pro-inflammatory phenotype, and activated neutrophils can degrade CEP proteoglycans ex vivo. These findings support a potential immune-mediated mechanism contributing to CEP weakening and indicate that MC are not just reactive changes but themselves have degenerative effects.

Objectives:Modic changes (MC) are vertebral endplate bone marrow lesions frequently observed in patients with chronic low back pain (CLBP), but their immunogenetic underpinnings remain unknown. We investigated HLA allele associations to uncover immune-mediated mechanisms and potential biomarkers for patient stratification. Methods:We analysed the blood transcriptome from 257 patients with CLBP aged ≥40 years, consisting of 187 patients with MC (types 1-3) and 70 without MC. Bootstrapped LASSO regression identified candidate HLA alleles, which were correlated with MC status using multivariate logistic regression adjusted for demographic covariates. Key findings were validated against US population allele frequencies from 8830 subjects stratified by race and ethnicity. Results:HLA-A*26:01 was strongly associated with MC in CLBP patients (OR = 18.9; FDR = 0.041), and enrichment was independently confirmed by comparison with external population data (OR = 2.15; FDR = 0.008). HLA-DQA1*03:03 was associated with reduced risk of MC (OR = 0.09; FDR = 0.0038). A trend toward positive association was noted for HLA-DRB1*11:01 (OR = 6.0; FDR = 0.069). Conclusions:This is the first study to identify significant associations between HLA and MC. The link to HLA-A*26:01 highlights the significance of CD8 + T-cell-mediated immune responses in MC pathobiology. These findings suggest HLA typing may enable personalised treatment strategies in chronic low back pain patients with MC. Key messages:What is already known: MC are inflammatory spinal lesions common in CLBP, but their immunogenetic basis is undefined.What this study adds: We identify HLA-A*26:01 as a novel risk allele for MC, validated across external population datasets.How this may affect research, practice or policy: HLA typing may help stratify patients with MC for targeted therapy or inclusion in immunomodulatory trials.

OBJECTIVE:Chronic low back pain (cLBP) is a common condition that impacts quality of life and function. There are many evidence-based treatments to address cLBP; however, treatment effects are modest, perhaps in part due to individual variation in treatment response. The Biomarkers for Evaluating Spine Treatments (BEST) trial was designed as the collaborative centerpiece of the Back Pain Consortium (BACPAC) research program. This consortium was sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) as part of the Helping to End Addiction Long-term (HEAL) Initiative. DESIGN:The BEST trial was a sequential multiple assignment randomized trial (SMART) designed with the primary goal of identifying in whom different treatments show optimal response. The primary focus of the study was to use patient features, including biomarkers and phenotypic measures, to identify subsets of persons with cLBP who respond best to specific common treatments. METHODS:Four interventions were chosen for the trial: Enhanced Self-Care, Acceptance and Commitment Therapy, Duloxetine, and Evidence-Based Exercise and Manual Therapy. Following a run-in period and baseline assessment, participants were randomized to 1 of the 4 treatments for the first 12-week intervention period. Participants were reassessed and based on their self-reported response to initial treatment, continued that initial treatment, were augmented with an additional randomly assigned treatment, or were switched to a new treatment. CONCLUSION:This trial was designed to deliver rich phenotypic data that will both potentially aid in the discovery of phenotypic characteristics that predict treatment response and provide a greater mechanistic understanding of cLBP. CLINICAL TRIAL REGISTRATION NUMBER:The Biomarkers for Evaluating Spine Treatments (BEST) trial is registered on ClinicalTrials.gov (Registration number: NCT05396014; https://clinicaltrials.gov/study/NCT05396014).

Background/Objectives: This study aimed to create a pipeline for standardized data extraction from lumbar-spine MRI radiology reports using a large language model (LLM) and assess the agreement of the extracted data with research-grade semi-quantitative scoring. Methods: We included a subset of data from a multi-site NIH-funded cohort study of chronic low back pain (cLBP) participants. After initial prompt development, a secure application programming interface (API) deployment of OpenAIs GPT-4 was used to extract different classes of pathology from the clinical radiology report. Unsupervised UMAP and agglomerative clustering of the pathology terms’ embeddings provided insight into model comprehension for optimized prompt design. Model extraction was benchmarked against human extraction (gold standard) with F1 scores and false-positive and false-negative rates (FPR/FNR). Then, an expert MSK radiologist provided comprehensive research-grade scores of the images, and agreement with report-extracted data was calculated using Cohen’s kappa. Results: Data from 230 patients with cLBP were included (mean age 53.2 years, 54% women). The overall model performance for extracting data from clinical reports was excellent, with a mean F1 score of 0.96 across pathologies. The mean FPR was marginally higher than the FNR (5.1% vs. 3.0%). Agreement with comprehensive scoring was moderate (kappa 0.424), and the underreporting of lateral recess stenosis (FNR 63.6%) and overreporting of disc pathology (FPR 42.7%) were noted. Conclusions: LLMs can accurately extract highly detailed information on lumbar spine imaging pathologies from radiology reports. Moderate agreement between the LLM and comprehensive scores underscores the need for less subjective, machine-based data extraction from imaging.

Objective Chronic low back pain (cLBP) is a significant public health problem in the United States. A method to identify treatments that are most likely effective for an individual patient based on their unique characteristics is needed.Methods The Biomarkers for Evaluating Spine Treatments (BEST) Trial is a sequential, multiple assignment, randomized trial designed to estimate an optimal treatment or combination of treatments to reduce pain intensity and interference at 24 weeks in individuals with cLBP.Results We describe the patient-reported characteristics of the BEST Trial at the Baseline visit. Data collection for extensive required phenotyping is reported. We analyzed the run-in period of the BEST Trial to evaluate predictors of run-in failure. The BEST Trial enrolled 1019 participants and randomized 805 participants (61.6% female, mean age 50.4, 12.5% Black or African American) to the first stage of treatment. We collected extensive required phenotyping on all 805 randomized BEST Trial participants, and additional optional phenotyping on 510 (63.4%) participants.Conclusions The BEST Trial successfully enrolled a racially and geographically diverse sample of chronic low back pain patients and completed rich phenotypic assessments to inform our primary goal of identifying in whom different treatments show optimal response. We demonstrated the feasibility of collecting extensive phenotypic assessments in a multi-site clinical trial of cLBP.Clinical trial registration number The Biomarkers for Evaluating Spine Treatments (BEST) Trial is registered on ClinicalTrials.gov. Registration number: NCT05396014 (https://clinicaltrials.gov/study/NCT05396014).

This study sought to identify spatial patterns of elevated fat infiltration (FI) in the multifidus associated with chronic low back pain (cLBP) chronicity (duration) and physical activity levels. On 223 cLBP patients, we mapped the FI distribution in the multifidus at L4L5 and L5S1 using 3T MRI and advanced sequences (IDEAL). Using statistical parametric mapping, we identified FI patterns independently associated with increased cLBP chronicity and decreased physical activity levels. Then, we used linear mixed-effects modeling to identify associations between cLBP chronicity, physical activity level and two FI measures, the FI

Modic type 1 changes (MC1) are vertebral endplate bone marrow lesions and are a source of low back pain. Concomitant cartilage endplate (CEP) damage and severity of MC1 suggest a causal relationship. Dysregulated neutrophil maturation has been reported in MC1, and in rheumatoid arthritis, neutrophils damage joint cartilage. We hypothesize that i) MC1 bone marrow neutrophils are activated, ii) activated neutrophils degrade CEP and iii) MC1 bone marrow neutrophils release CEP degrading enzymes. From MC1 patients undergoing lumbar spondylodesis, CEP tissue was collected, and bone marrow neutrophils were isolated from aspirates from MC1 and an intra-patient control vertebra. First, RNA of CD45 + CD66b + neutrophils ( n = 7+7) was sequenced and dysregulated pathways identified. Expression of activation marker CD66b ( n = 10+10) and the proportion of immature band neutrophils (CD66b + CD10 - CD11b high )( n = 7+7) was measured with flow cytometry. MC1 data was compared to intra-patient controls using paired t-tests. Second, CEP biopsies were incubated with conditioned media from PMA-activated neutrophils and compared to unstimulated neutrophils, media only, and collagenase P exposure (positive control). Release of sulphated glycosaminoglycan (sGAG) was quantified with alcian blue assay and compared against media control (100%). Third, neutrophil elastase (NE) activity - an cartilage degrading enzyme [3]- was compared in media conditioned for 3h with neutrophils from MC1 vs. intra-patient control bone marrow using a fluorogenic NE substrate (paired t-test). Transcriptomic analysis of MC1 neutrophils revealed upregulated processes associated with inflammation and neutrophil activation. Upregulation of calcium signaling (not shown) supports neutrophil activation, indicating enhanced degranulation. Higher CD66b intensity on MC1 neutrophils supports neutrophil activation. 6/7 patients had increased fractions of pro-inflammatory immature band neutrophils (Fig.1b). Exposure of CEPs to neutrophil supernatants caused dose-dependent release of sGAG from the CEP tissues, showing that activated neutrophils degrade CEPs. NE activity was higher in conditioned media from MC1 vs. intra-patient control bone marrow neutrophils in 4/5 patients. Neutrophils are activated in MC1, shifted towards a pro-inflammatory band neutrophil population, and can degrade CEP, possibly through release of NE. Hence, neutrophils may contribute to the inflammatory pathomechanisms in MC1 and to CEP damaging. CEP damage promotes a pro-inflammatory disc/BM crosstalk and coincides with increased nerve fiber density. Hence, these findings could have implications for treatment strategies to mitigate inflammation and CEP damage in MC.

Non-specific chronic low back pain (nsCLBP) likely constitutes a heterogeneous group of conditions, and identifying an inflammatory phenotype may improve treatment stratification. The objective of this study was to determine associations between inflammatory back pain (IBP) features and MRI findings in subjects with nsCLBP. Participants were selected from the longitudinal Clinical Cohort for Comprehensive Deep Phenotyping of Chronic Low-Back Pain Adults Study (comeBACK), a cohort of adults with nsCLBP. IBP features (morning stiffness, nocturnal LBP, symptom improvement with exercise / worsening with rest, insidious onset, onset < 40 years) were assessed via questionnaire. MRI scans of the lumbar spine were interpreted by a radiologist, using a comprehensive scoring system: Modic changes (MC), endplate erosion, facet joint arthritis, central canal stenosis and degeneration of the sacroiliac joints (SIJ). Logistic regression was performed (presence IBP feature as dependent variable and MRI findings as independent variables). A total of 290 individuals (159 female) were included. Both endplate erosion and MC1 changes were positively associated with overall IBP (erosion: OR 2.1, 95

BACKGROUND CONTEXT:Chronic low back pain (cLBP) patients often have elevated fat infiltration (FI) in the multifidus (MF), but it is unclear how this relates to pain and degenerative spine features. Most prior work assess MF degeneration as the average whole-muscle fat content even though deep and superficial fascicles of the MF have different structural and functional characteristics. Assessing the spatial distribution of MF FI may provide regional context for causal mechanisms which may have distinct regional presentations within the muscle. PURPOSE:This study assesses spatial patterns of MF FI at each lumbar level to identify regional differences associated with cLBP symptoms and degenerative spine features. STUDY DESIGN:This is an observational cross-sectional study. PATIENT SAMPLE:Our study sample consisted of 230 cLBP patients from the BACPAC comeback cohort who reported low back pain that has persisted for the past 3 months. OUTCOME MEASURES:Measures included MF fat-maps-a FI curve showing the spatial distribution of fat moving radially through the MF-created at each lumbar level (L1L2-L5S1). Other measures included average fat fraction in the deepest 15% of the MF (deep15 FI%), average whole-muscle fat fraction (overall FI%) and the Pain, Enjoyment of Life, and General Activity (PEG) survey score. METHODS:We collected 3T MRI and used advanced sequences (IDEAL) to map the spatial distribution of MF FI at each lumbar level. We used statistical parametric mapping to identify spatial patterns of fat in the MF associated with age, sex, and BMI. Then, we tested for differences in spatial patterns of MF FI associated with pain and adjacent disc degeneration. Next, we calculated the fat fraction in a region of interest in the deepest 15% of the MF (deep15 FI%) and used linear mixed effects modeling to compare how age, sex, BMI, pain, and degenerative spine features associate with the deep15 FI% and the overall FI% separately. Lastly, we used linear regression models of PEG to compare FI measures as predictors for pain. RESULTS:Elevated FI associated with PEG and adjacent disc degeneration only within the deepest 10% (p<.05) and deepest 25% (p<.01) of the MF respectively at the lower lumbar levels. Associations between demographic factors and FI were not specific to the deep MF. Older age and female sex associated with elevated FI throughout the muscle (p<.001) while higher BMI associated with elevated FI in only the superficial 60% of the MF (p<.001). Lastly, higher mean deep15 FI% but not mean overall FI% at the lower lumbar levels associated with higher PEG (p=.023). CONCLUSIONS:FI in deep regions of the MF at L4L5 and L5S1 is more strongly associated with pain and adjacent disc degeneration and less associated with age, sex, and BMI than overall FI%. We identify regional differences in MF FI related to pain which improves our understanding of cLBP-related MF degeneration and provides additional context for possible causal mechanisms of FI. Further, the "deep15" FI% is a novel MF FI measure, and possible biomarker, more strongly associated with cLBP than summary measures.

Introduction:Chronic low back pain (cLBP) is highly prevalent in the United States and globally, resulting in functional impairment and lowered quality of life. While many treatments are available for cLBP, clinicians have little information about which specific treatment(s) will work best for individual patients or subgroups of patients. The Back Pain Research Consortium, part of the National Institutes of Health Helping to End Addiction Long-termSM (HEAL) Initiative, will conduct a collaborative clinical trial, which seeks to develop a personalized medicine algorithm to optimize patient and provider treatment selection for patients with cLBP. Objective:The primary objective of this article is to provide an update on evidence-based cLBP interventions and describe the process of reviewing and selecting interventions for inclusion in the clinical trial. Methods:A working group of cLBP experts reviewed and selected interventions for inclusion in the clinical trial. The primary evaluation measures were strength of evidence and magnitude of treatment effect. When available in the literature, duration of effect, onset time, carryover effect, multimodal efficacy, responder subgroups, and evidence for the mechanism of treatment effect or biomarkers were considered. Conclusion:The working group selected 4 leading, evidence-based treatments for cLBP to be tested in the clinical trial and for use in routine clinical treatment. These treatments include (1) duloxetine, (2) acceptance and commitment therapy, (3) a classification-based exercise and manual therapy intervention, and (4) a self-management approach. These interventions each had a moderate to high level of evidence to support a therapeutic effect and were from different therapeutic classes.

BACKGROUND CONTEXT Chronic low back pain (cLBP) is a major global cause of disability, with health care costs exceeding $100 billion annually in the US. Its treatment poses a complex challenge due to the interplay of biological, psychological, and social factors. Understanding the diversity of cLBP is crucial for effective treatment, especially precision medicine for nonspecific cLBP. Unsupervised clustering methods have been increasingly used for patient phenotyping, yet the outcomes and interpretations of these methods heavily depend on the implementation and decisions made during analysis. PURPOSE Utilizing multimodal data from a cLBP prospective cohort, our aim was to systematically evaluate different clustering algorithms for unsupervised patient phenotyping. We critically assessed the effectiveness and reliability of these algorithms in our analysis. STUDY DESIGN/SETTING N/A PATIENT SAMPLE N/A OUTCOME MEASURES N/A METHODS We analyzed multimodal data (demographics, clinical characteristics, imaging, biomechanics, and psychosocial factors) from a preliminary 244 participants in the UCSF ComeBACK cohort study, collected between 2019 to 2023. After consulting domain experts, 679 variables were selected, and missing value imputation was performed. The data underwent dimensional reduction using Multiple Factor Analysis (MFA) or Isometric Mapping (ISOMAP). Systematic clustering algorithms applied included K-means (KM), Fuzzy K-means (Fuzzy), Agglomerative Clustering (AGC), Gaussian Mixture Model (GMM), Bayesian Gaussian Mixture Model (BGMM), and Spectral Clustering (SPC). After grid search for number of clusters (2-10), we plotted gap statistics (GAP) and silhouette scores (SS), two distinct metrics of clustering performance, exploring optimal cluster numbers and evaluating findings. RESULTS Visually, common clustering tendencies across different algorithms were observed. Specifically, a commonality around 6 clusters was noted, with shared clusters identifiable in 6 regions (top, right, center, top-left, bottom-left, and bottom) of the plot, except for AGC. Subsequently, the effectiveness of systematic cluster metrics was calculated. Both GAP and SS, metrics considering the density within clusters and separation between clusters, were used to measure clustering quality. The inflection point where the increase in GAP values slows down indicates the appropriate number of clusters, while higher SS signify better cluster separation and cohesion. A common trend was observed across both MFA and ISOMAP processed data for each metric. Particularly in ISOMAP, for KM, GMM, and SPC, a slight inflection point around 6 clusters was noted, supporting the visual observations from the scatter plots. Also, multiple algorithms showed an increase in SS around 6-7 clusters. However, inconsistencies between the metrics were noted; while SS consistently indicated optimal separation at two clusters, GAP suggested differently. CONCLUSIONS This analysis revealed both variations and common trends dependent on clustering algorithms and evaluation metrics, underscoring the importance of systematic and comprehensive method application for robust analysis. Furthermore, in this data, both visual observations and clustering metrics suggested that clusters of sizes 2 and 6-7 could represent significant data structures. Building on this foundational analysis, the next step will focus on creating robust clusters using ensemble clustering and assessing their clinical relevance. FDA Device/Drug Status This abstract does not discuss or include any applicable devices or drugs.

Academic researchers faced a multitude of challenges posed by the COVID-19 pandemic, including widespread shelter-in-place orders, workplace closures, and cessation of in-person meetings and laboratory activities. The extent to which these challenges impacted musculoskeletal researchers, specifically, is unknown. We developed an anonymous web-based survey to determine the pandemic's impact on research productivity and career prospects among musculoskeletal research trainees and faculty. There were 116 musculoskeletal (MSK) researchers with varying demographic backgrounds who completed the survey. Of respondents, 48.3% (n = 56) believed that musculoskeletal funding opportunities decreased because of COVID-19, with faculty members more likely to hold this belief compared to nonfaculty researchers (p = 0.008). Amongst MSK researchers, 88.8% (n = 103) reported research activity was limited by COVID-19, and 92.2% (n = 107) of researchers reported their research was not able to be refocused on COVID-19-related topics, with basic science researchers less likely to be able to refocus their research compared to clinical researchers (p = 0.030). Additionally, 47.4% (n = 55) reported a decrease in manuscript submissions since the onset of the pandemic. Amongst 51 trainee researchers, 62.8% (n = 32) reported a decrease in job satisfaction directly attributable to the COVID-19 pandemic. In summary, study findings indicated that MSK researchers struggled to overcome challenges imposed by the pandemic, reporting declines in funding opportunities, research productivity, and manuscript submission. Trainee researchers experienced significant disruptions to critical research activities and worsening job satisfaction. Our findings motivate future efforts to support trainees in developing their careers and target the recovery of MSK research from the pandemic stall.

Objective:The University of California, San Francisco (UCSF) Core Center for Patient-centric, Mechanistic Phenotyping in Chronic Low Back Pain (REACH) is one of the three NIH Back Pain Consortium (BACPAC) Research Programs Mechanistic Research Centers (MRCs). The goal of UCSF REACH is to define cLBP phenotypes and pain mechanisms that can lead to effective, personalized treatments for patients across the population. The primary objective of this research project is to address the critical need for new diagnostic and prognostic markers, and associated patient classification protocols for chronic low back pain (cLBP) treatment. Design:To meet this objective, REACH is conducting two large investigator-initiated translational research cohort studies called: The Longitudinal Clinical Cohort for Comprehensive Deep Phenotyping of Chronic Low-Back Pain (cLBP) Adults Study (comeBACK) and the Chronic Low-Back Pain (cLBP) in Adults Study (BACKHOME). Setting:comeBACK is a longitudinal multicenter in-person observational study of 450 adults with chronic low back pain designed to perform comprehensive deep phenotyping. While, the BACKHOME study is a site-less longitudinal observational e-cohort of approximately 3000 U.S. adults with cLBP. To our knowledge, BACKHOME is the largest prospective remote registry of nationwide adults with cLBP. Methods:Both the comeBACK and BACKHOME studies are collecting a robust and comprehensive set of risk factors, outcomes, and covariates in order to perform deep phenotyping of cLBP patients based on combined biopsychosocial variables to: define cLBP subtypes, establish phenotyping tools for routine clinical evaluation, and lead to improved cLBP outcomes in the future. The data from both studies will be used to establish techniques to develop a patient-centric definition of treatment success and to analyze cLBP patient traits to define clinically useful cLBP phenotypes, using a combination of traditional data analyses and deep learning methods. Conclusions:These 2 pivotal studies, in conjunction with the ancillary studies being performed in both comeBACK and BACKHOME, and the other BACPAC-consortium research projects, we will be able to address a number of diagnostic and therapeutic issues in this complex and diverse patient population with cLBP. These studies will help clarify biopsychosocial mechanisms of cLBP with the aim to provide a foundation to improve the evaluation of treatment effectiveness and to spur new avenues of therapeutic research, including personalized outcome measures that constitute a clinically meaningful treatment effect for individual cLBP patients.

Purpose Bullying, harassment, and discrimination (BHD) are prevalent in academic, scientific, and clinical departments, particularly orthopedic surgery, and can have lasting effects on victims. As it is unclear how BHD affects musculoskeletal (MSK) researchers, the following study assessed BHD in the MSK research community and whether the COVID-19 pandemic, which caused hardships in other industries, had an impact. Methods A web-based anonymous survey was developed in English by ORS Spine Section members to assess the impact of COVID-19 on MSK researchers in North America, Europe, and Asia, which included questions to evaluate the personal experience of researchers regarding BHD. Results 116 MSK researchers completed the survey. Of respondents, 34.5% (n = 40) focused on spine, 30.2% (n = 35) had multiple areas of interest, and 35.3% (n = 41) represented other areas of MSK research. BHD was observed by 26.7% (n = 31) of respondents and personally experienced by 11.2% (n = 13), with mid-career faculty both observing and experiencing the most BHD. Most who experienced BHD (53.8%, n = 7) experienced multiple forms. 32.8% (n = 38) of respondents were not able to speak out about BHD without fear of repercussions, with 13.8% (n = 16) being unsure about this. Of those who observed BHD, 54.8% (n = 17) noted that the COVID-19 pandemic had no impact on their observations. Conclusions To our knowledge, this is the first study to address the prevalence and determinants of BHD among MSK researchers. MSK researchers experienced and observed BHD, while many were not comfortable reporting and discussing violations to their institution. The COVID-19 pandemic had mixed-effects on BHD. Awareness and proactive policy changes may be warranted to reduce/eliminate the occurrence of BHD in this community.