Pain-related single nucleotide polymorphisms: association with lumbar spinal stenosis patient experience and non-surgical treatment outcomes.

PURPOSE: Lumbar spinal stenosis (LSS) is common in our aging population resulting in pain and functional impairment. Recent advances in pain research have identified several single nucleotide polymorphisms (SNP) associated with inter-individual symptom and treatment response. The goal of the current study was to investigate the association of SNPs in Neuropeptide Y (NPY) and Catechol-O-methyltransferase (COMT) with pain, function, and treatment outcomes in Lumbar spinal stenosis (LSS) patients receiving non-surgical treatments. METHODS: An exploratory observational biomarker study was performed ancillary to a previously published clinical trial evaluating three different non-surgical treatments for LSS. Saliva samples were obtained for single nucleotide polymorphism genotyping and blood samples were collected for NPY protein. Data on pain and function collected as part of the clinical trial at baseline, 2 and 6 months were examined for association with known polymorphisms in NPY and COMT. RESULTS: Subjects with the NPY rs16147 TT genotype exhibited higher baseline symptom severity but also a higher likelihood of responding to non-surgical treatments. Subjects with the COMT rs4680 GG genotype also exhibited higher baseline symptom severity but did not demonstrate greater response to treatment. CONCLUSIONS: NPY rs16147 and COMT rs4680 are important potential biomarkers associated with pain and function. NPY genotype may be useful in predicting response to non-surgical treatments in older adults with LSS.

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

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

Protocol for Biospecimen Collection and Analysis Within the BACPAC Research Program.

The Biospecimen Collection and Processing Working Group of the National Institutes of Health (NIH) HEAL Initiative BACPAC Research Program was charged with identifying molecular biomarkers of interest to chronic low back pain (cLBP). Having identified biomarkers of interest, the Working Group worked with the New York University Grossman School of Medicine, Center for Biospecimen Research and Development-funded by the Early Phase Pain Investigation Clinical Network Data Coordinating Center-to harmonize consortium-wide and site-specific efforts for biospecimen collection and analysis. Biospecimen collected are saliva, blood (whole, plasma, serum), urine, stool, and spine tissue (paraspinal muscle, ligamentum flavum, vertebral bone, facet cartilage, disc endplate, annulus fibrosus, or nucleus pulposus). The omics data acquisition and analyses derived from the biospecimen include genomics and epigenetics from DNA, proteomics from protein, transcriptomics from RNA, and microbiomics from 16S rRNA. These analyses contribute to the overarching goal of BACPAC to phenotype cLBP and will guide future efforts for precision medicine treatment.

Toward the Identification of Distinct Phenotypes: Research Protocol for the Low Back Pain Biological, Biomechanical, and Behavioral (LB3P) Cohort Study and the BACPAC Mechanistic Research Center at the University of Pittsburgh.

As a member of the Back Pain Consortium (BACPAC), the University of Pittsburgh Mechanistic Research Center's research goal is to phenotype chronic low back pain using biological, biomechanical, and behavioral domains using a prospective, observational cohort study. Data will be collected from 1,000 participants with chronic low back pain according to BACPAC-wide harmonized and study-specific protocols. Participation lasts 12 months with one required in person baseline visit, an optional second in person visit for advanced biomechanical assessment, and electronic follow ups at months 1, 2, 3, 4, 5, 6, 9, and 12 to assess low back pain status and response to prescribed treatments. Behavioral data analysis includes a battery of patient-reported outcomes, social determinants of health, quantitative sensory testing, and physical activity. Biological data analysis includes omics generated from blood, saliva, and spine tissue. Biomechanical data analysis includes a physical examination, lumbopelvic kinematics, and intervertebral kinematics. The statistical analysis includes traditional unsupervised machine learning approaches to categorize participants into groups and determine the variables that differentiate patients. Additional analysis includes the creation of a series of decision rules based on baseline measures and treatment pathways as inputs to predict clinical outcomes. The characteristics identified will contribute to future studies to assist clinicians in designing a personalized, optimal treatment approach for each patient.

The Back Pain Consortium (BACPAC) Research Program: Structure, Research Priorities, and Methods.

In 2019, the National Health Interview survey found that nearly 59% of adults reported pain some, most, or every day in the past 3 months, with 39% reporting back pain, making back pain the most prevalent source of pain, and a significant issue among adults. Often, identifying a direct, treatable cause for back pain is challenging, especially as it is often attributed to complex, multifaceted issues involving biological, psychological, and social components. Due to the difficulty in treating the true cause of chronic low back pain (cLBP), an over-reliance on opioid pain medications among cLBP patients has developed, which is associated with increased prevalence of opioid use disorder and increased risk of death. To combat the rise of opioid-related deaths, the National Institutes of Health (NIH) initiated the Helping to End Addiction Long-TermSM (HEAL) initiative, whose goal is to address the causes and treatment of opioid use disorder while also seeking to better understand, diagnose, and treat chronic pain. The NIH Back Pain Consortium (BACPAC) Research Program, a network of 14 funded entities, was launched as a part of the HEAL initiative to help address limitations surrounding the diagnosis and treatment of cLBP. This paper provides an overview of the BACPAC research program's goals and overall structure, and describes the harmonization efforts across the consortium, define its research agenda, and develop a collaborative project which utilizes the strengths of the network. The purpose of this paper is to serve as a blueprint for other consortia tasked with the advancement of pain related science.

Role of autophagy in intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) is a leading contributor to low back pain. The intervertebral disc (IVD) is composed of three tissue types: the central gelatinous nucleus pulposus (NP) tissue, the surrounding annulus fibrosus (AF) tissue, and the inferior and superior cartilage endplates. The IVD microenvironment is hypoxic, acidic, hyperosmotic, and low in nutrients because it is mostly avascular. The cellular processes that underlie IDD initiation and progression are still poorly understood. Specifically, a lack of understanding regarding NP cell metabolism and physiology hinders the development of effective therapeutics to treat IDD patients. Autophagy is a vital intracellular degradation process that removes damaged organelles, misfolded proteins, and intracellular pathogens and recycles the degraded components for cellular energy and function. NP cells have adapted to survive within their harsh tissue microenvironment using processes that are largely unknown, and we postulate autophagy is one of these undiscovered mechanisms. In this review, we describe unique features of the IVD tissue, review how physiological stressors impact autophagy in NP cells in vitro, survey the current understanding of autophagy regulation in the IVD, and assess the relationship between autophagy and IDD. Published studies confirm autophagy markers are present in IVD tissue, and IVD cells can regulate autophagy in response to cellular stressors in vitro. However, data are still lacking to determine the exact mechanisms regulating autophagy in IVD cells. More in-depth research is needed to establish whether autophagy is necessary to maintain IVD cell health and validate autophagy as a relevant therapeutic target for treating IDD.

Challenges and opportunities for omics-based precision medicine in chronic low back pain.

PURPOSE: Chronic low back pain (cLBP) is a common health condition worldwide and a leading cause of disability with an estimated lifetime prevalence of 80-90% in industrialized countries. However, we have had limited success in treating cLBP likely due to its non-specific heterogeneous nature that goes beyond detectable anatomical changes. We propose that omics technologies as precision medicine tools are well suited to provide insight into its pathophysiology and provide diagnostic markers and therapeutic targets. Therefore, in this review, we explore the current state of omics technologies in the diagnosis and classification of cLBP. We identify factors that may serve as markers to differentiate between acute and chronic cases of low back pain (LBP). Finally, we also discuss some challenges that must be overcome to successfully apply precision medicine to the diagnosis and treatment of cLBP. METHODS: A literature search for the current applications of omics technologies to chronic low back pain was performed using the following search terms- "back pain," "low back pain," "proteomics," "transcriptomics", "epigenomics," "genomics," "omics." We reviewed molecular markers identified from 35 studies which hold promise in providing information regarding molecular insights into cLBP. RESULTS: GWAS studies have found evidence for the role of single nucleotide polymorphisms (SNPs) associated with pain pathways in individuals with cLBP. Epigenomic modifications in patients with cLBP have been found to be enriched among genes involved in immune signaling and inflammation. Transcriptomics profiles of patients with cLBP show multiple lines of evidence for the role of inflammation in cLBP. The glycomics profiles of patients with cLBP are similar to those of patients with inflammatory conditions. Proteomics and microbiomics show promise but have limited studies currently. CONCLUSION: Omics technologies have identified associations between inflammatory and pain pathways in the pathophysiology of cLBP. However, in order to integrate information across the range of studies, it is important for the field to identify and adopt standardized definitions of cLBP and control patients. Additionally, most papers have applied a single omics method to a sampling of cLBP patients which have yielded limited insight into the pathophysiology of cLBP. Therefore, we recommend a multi-omics approach applied to large global consortia for advancing subphenotyping and better management of cLBP, via improved identification of diagnostic markers and therapeutic targets.

An unexpected connection: A narrative review of the associations between Gut Microbiome and Musculoskeletal Pain.

PURPOSE: Multiple diverse factors contribute to musculoskeletal pain, a major cause of physical dysfunction and health-related costs worldwide. Rapidly growing evidence demonstrates that the gut microbiome has overarching influences on human health and the body's homeostasis and resilience to internal and external perturbations. This broad role of the gut microbiome is potentially relevant and connected to musculoskeletal pain, though the literature on the topic is limited. Thus, the literature on the topic of musculoskeletal pain and gut microbiome was explored. METHODS: This narrative review explores the vast array of reported metabolites associated with inflammation and immune-metabolic response, which are known contributors to musculoskeletal pain. Moreover, it covers known modifiable (e.g., diet, lifestyle choices, exposure to prescription drugs, pollutants, and chemicals) and non-modifiable factors (e.g., gut architecture, genetics, age, birth history, and early feeding patterns) that are known to contribute to changes to the gut microbiome. Particular attention is devoted to modifiable factors, as the ultimate goal of researching this topic is to implement gut microbiome health interventions into clinical practice. RESULTS: Overall, numerous associations exist in the literature that could converge on the gut microbiome's pivotal role in musculoskeletal health. Particularly, a variety of metabolites that are either directly produced or indirectly modulated by the gut microbiome have been highlighted. CONCLUSION: The review highlights noticeable connections between the gut and musculoskeletal health, thus warranting future research to focus on the gut microbiome's role in musculoskeletal conditions.

ISSLS Prize in Bioengineering Science 2022: low rate cyclic loading as a therapeutic strategy for intervertebral disc regeneration.

BACKGROUND: The intervertebral disc degenerates with age and has a poor propensity for regeneration. Small molecule transport plays a key role in long-term degradation and repair. Convection (bulk flow), induced by low rate cyclic loading of the intervertebral disc, has been shown to increase transport of small molecules. However, the potential therapeutic benefit of low rate cyclic loading on degenerated discs has not been described. The purpose of this study was to determine if a sustained (daily) low rate cyclic loading regimen could slow, arrest, or reverse intervertebral disc degeneration in the rabbit lumbar spine. METHODS: Fifty-six New Zealand white rabbits (>12 months old) were designated as either Control (no disc puncture), 8D (disc puncture followed by 8 weeks of degeneration), 16D (disc puncture followed by 16 weeks of degeneration), or Therapy (disc puncture followed by 8 weeks of degeneration and then 8 weeks of daily low rate cyclic loading). Specimens were evaluated by T2 mapping, Pfirrmann scale grading, nucleus volume, disc height index, disc morphology and structure, and proteoglycan content. RESULTS: In every metric, mean values for the Therapy group fell between Controls and 8D animals. These results suggest that sustained low rate cyclic loading had a therapeutic effect on the already degenerated disc and the regimen promoted signs of regeneration. If these results translate clinically, this approach could fulfil a significant clinical need by providing a means of non-invasively treating intervertebral disc degeneration.

The association of biomarkers with pain and function in acute and subacute low back pain: a secondary analysis of an RCT.

BACKGROUND: Low back pain (LBP) is a common musculoskeletal condition and a major cause of disability worldwide. Previous studies have found associations of biomarkers with pain and pain-related disability in LBP patients. This study aimed to explore the association between serum biomarkers and pain and disability in patients with acute or subacute axial LBP. METHODS: This study was ancillary to a parent randomized controlled trial. Enrolled participants were randomized into three intervention groups: one of two types of spinal manipulation or medical care. In the parent study, 107 adults who experienced a new episode of LBP within 3 months prior to enrollment were recruited. For this study, 90 of these 107 participants consented to have blood samples obtained, which were drawn immediately before the beginning of treatment. Seven biomarkers were chosen based on previous literature and analyzed. Clinical outcomes were pain and Oswestry Disability Index (ODI) evaluated at baseline and 4 weeks. Spearman's |r| was used to study the association of initial levels of each biomarker with pain and ODI scores at baseline and with changes in outcome scores from baseline to 4 weeks (end of treatment) within each intervention group. RESULTS: At baseline, 4 of 7 biomarkers had an association with pain that was |r| ≥ .20: neuropeptide Y (NPY) (r = 0.23, p = .028), E-Selectin (r = 0.22, p = .043), vitamin D ((r = - 0.32, p = .002), and c-reactive protein (CRP) (r = 0.37, p = .001). No baseline biomarker had an association with disability that was |r| ≥ 0.20. For the correlations of baseline biomarkers with 4-week change in outcomes, vitamin D showed a correlation with change in disability and/or pain (|r| ≥ 0.20, p > .05) in manipulation-related groups, while CRP, NPY, and E-selectin along with TNFα, Substance P and RANTES showed at least one correlation with change in pain or disability (|r| ≥ 0.20, p > .05) in at least one of the treatment groups. CONCLUSIONS: In 90 LBP patients, the analyzed biomarkers, especially vitamin D, represent a small set of potential candidates for further research aimed at individualizing patient care. Overall, the associations investigated in the current study are an initial step in identifying the direct mechanisms of LBP and predicting outcomes of manipulation-related treatments or medical care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01211613, Date of Registration: September 29, 2010, https://clinicaltrials.gov/ct2/show/NCT01211613?term=schneider&cond=Low+Back+Pain&cntry=US&state=US%3APA&draw=2&rank=1.

Ionizing Radiation Induces Disc Annulus Fibrosus Senescence and Matrix Catabolism via MMP-Mediated Pathways.

Previous research has identified an association between external radiation and disc degeneration, but the mechanism was poorly understood. This study explores the effects of ionizing radiation (IR) on inducing cellular senescence of annulus fibrosus (AF) in cell culture and in an in vivo mouse model. Exposure of AF cell culture to 10-15 Gy IR for 5 min followed by 5 days of culture incubation resulted in almost complete senescence induction as evidenced by SA-ßgal positive staining of cells and elevated mRNA expression of the p16 and p21 senescent markers. IR-induced senescent AF cells exhibited increased matrix catabolism, including elevated matrix metalloproteinase (MMP)-1 and -3 protein expression and aggrecanolysis. Analogous results were seen with whole body IR-exposed mice, demonstrating that genotoxic stress also drives disc cellular senescence and matrix catabolism in vivo. These results have important clinical implications in the potential adverse effects of ionizing radiation on spinal health.

ISSLS prize in basic science 2021: a novel inducible system to regulate transgene expression of TIMP1.

PURPOSE: Inflammatory and oxidative stress upregulates matrix metalloproteinase (MMP) activity, leading to intervertebral disc degeneration (IDD). Gene therapy using human tissue inhibitor of metalloproteinase 1 (hTIMP1) has effectively treated IDD in animal models. However, persistent unregulated transgene expression may have negative side effects. We developed a recombinant adeno-associated viral (AAV) gene vector, AAV-NFκB-hTIMP1, that only expresses the hTIMP1 transgene under conditions of stress. METHODS: Rabbit disc cells were transfected or transduced with AAV-CMV-hTIMP1, which constitutively expresses hTIMP1, or AAV-NFκB-hTIMP1. Disc cells were selectively treated with IL-1ß. NFκB activation was verified by nuclear translocation. hTIMP1 mRNA and protein expression were measured by RT-PCR and ELISA, respectively. MMP activity was measured by following cleavage of a fluorogenic substrate. RESULTS: IL-1ß stimulation activated NFκB demonstrating that IL-1ß was a surrogate for inflammatory stress. Stimulating AAV-NFκB-hTIMP1 cells with IL-1ß increased hTIMP1 expression compared to unstimulated cells. AAV-CMV-hTIMP1 cells demonstrated high levels of hTIMP1 expression regardless of IL-1ß stimulation. hTIMP1 expression was comparable between IL-1ß stimulated AAV-NFκB-hTIMP1 cells and AAV-CMV-hTIMP1 cells. MMP activity was decreased in AAV-NFκB-hTIMP1 cells compared to baseline levels or cells exposed to IL-1ß. CONCLUSION: AAV-NFκB-hTIMP1 is a novel inducible transgene delivery system. NFκB regulatory elements ensure that hTIMP1 expression occurs only with inflammation, which is central to IDD development. Unlike previous inducible systems, the AAV-NFκB-hTIMP1 construct is dependent on endogenous factors, which minimizes potential side effects caused by constitutive transgene overexpression. It also prevents the unnecessary production of transgene products in cells that do not require therapy.

Serum and nutrient deprivation increase autophagic flux in intervertebral disc annulus fibrosus cells: an in vitro experimental study.

PURPOSE: The loss of nutrient supply is a suspected contributor of intervertebral disc degeneration. However, the extent to which low nutrition affects disc annulus fibrosus (AF) cells is unknown as nutrient deprivation has mainly been investigated in disc nucleus pulposus cells. Hence, an experimental study was designed to clarify the effects of limited nutrients on disc AF cell fate, including autophagy, the process by which cells recycle their own damaged components. METHODS: Rabbit disc AF cells were cultured in different media with varying serum concentrations under 5% oxygen. Cellular responses to changes in serum and nutrient concentrations were determined by measuring proliferation and metabolic activity. Autophagic flux in AF cells was longitudinally monitored using imaging cytometry and Western blotting for LC3, HMGB1, and p62/SQSTM1. Apoptosis (TUNEL staining and cleaved caspase-3 immunodetection) and cellular senescence (senescence-associated ß-galactosidase assay and p16/INK4A immunodetection) were measured. RESULTS: Markers of apoptosis and senescence increased, while cell proliferation and metabolic activity decreased under the withdrawal of serum and of nutrients other than oxygen, confirming cellular stress. Time-dependent increases in autophagy markers, including LC3 puncta number per cell, LC3-II expression, and cytoplasmic HMGB1, were observed under conditions of reduced nutrition, while an autophagy substrate, p62/SQSTM1, decreased over time. Collectively, these findings suggest increased autophagic flux in disc AF cells under serum and nutrient deprivation. CONCLUSION: Disc AF cells exhibit distinct responses to serum and nutrient deprivation. Cellular responses include cell death and quiescence in addition to reduced proliferation and metabolic activity, as well as activation of autophagy under conditions of nutritional stress. These slides can be retrieved under Electronic Supplementary Material.

Inflammatory Mediators Associated With Pressure Ulcer Development in Individuals With Pneumonia After Traumatic Spinal Cord Injury: A Pilot Study.

OBJECTIVE: To identify the inflammatory mediators around the time of pneumonia onset associated with concurrent or later onset of pressure ulcers (PUs). DESIGN: Retrospective. SETTING: Acute hospitalization and inpatient rehabilitation unit of a university medical center. PARTICIPANTS: Individuals (N=86) with traumatic spinal cord injury (SCI) were included in the initial analyses. Fifteen of the 86 developed pneumonia and had inflammatory mediator data available. Of these 15, 7 developed PUs and 8 did not. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Twenty-three inflammatory mediators in plasma and urine were assayed. The differences in concentrations of plasma and urine inflammatory mediators between the closest time point before and after the diagnosis of pneumonia were calculated. RESULTS: Initial chi-square analysis revealed a significant (P=.02) association between pneumonia and PUs. Individuals with SCI and diagnosed pneumonia had nearly double the risk for developing PUs compared with those with no pneumonia. In individuals with pneumonia, Mann-Whitney U exact tests suggested an association (P<.05) between the formation of a first PU and a slight increase in plasma concentrations of tumor necrosis factor-alpha (TNF-α), and a decrease in urine concentrations of TNF-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin (IL)-15 after onset of pneumonia. CONCLUSIONS: These findings suggest that a relatively small increase in plasma TNF-α, and decreases in urine TNF-α, GM-CSF, and IL-15 from just before to just after the diagnosis of pneumonia could be markers for an increased risk of PUs in individuals with pneumonia after traumatic SCI.

A Computational, Tissue-Realistic Model of Pressure Ulcer Formation in Individuals with Spinal Cord Injury.

People with spinal cord injury (SCI) are predisposed to pressure ulcers (PU). PU remain a significant burden in cost of care and quality of life despite improved mechanistic understanding and advanced interventions. An agent-based model (ABM) of ischemia/reperfusion-induced inflammation and PU (the PUABM) was created, calibrated to serial images of post-SCI PU, and used to investigate potential treatments in silico. Tissue-level features of the PUABM recapitulated visual patterns of ulcer formation in individuals with SCI. These morphological features, along with simulated cell counts and mediator concentrations, suggested that the influence of inflammatory dynamics caused simulations to be committed to "better" vs. "worse" outcomes by 4 days of simulated time and prior to ulcer formation. Sensitivity analysis of model parameters suggested that increasing oxygen availability would reduce PU incidence. Using the PUABM, in silico trials of anti-inflammatory treatments such as corticosteroids and a neutralizing antibody targeted at Damage-Associated Molecular Pattern molecules (DAMPs) suggested that, at best, early application at a sufficiently high dose could attenuate local inflammation and reduce pressure-associated tissue damage, but could not reduce PU incidence. The PUABM thus shows promise as an adjunct for mechanistic understanding, diagnosis, and design of therapies in the setting of PU.

Deconstructing Chronic Low Back Pain in the Older Adult-Step by Step Evidence and Expert-Based Recommendations for Evaluation and Treatment: Part X: Sacroiliac Joint Syndrome.

OBJECTIVE: To present an algorithm of sequential treatment options for managing sacroiliac joint (SIJ) pain in the setting of chronic low back pain (CLBP) in the older adult. This is the tenth part in a series, and includes an illustrative clinical case. METHODS: The stepped care drug table and evaluation and treatment algorithm were created following a thorough literature review of approaches and subsequent analysis through a modified Delphi process. The principal investigator developed the initial draft, which was refined for content by an interdisciplinary panel of five experts. The refined materials were then assessed for the feasibility of implementation and validity of recommendations for older adults in a primary care setting by a panel of nine primary care providers. While not exclusive to Veteran's Health Administration (VHA) facilities, an emphasis was made to include resources and medications available to providers in the VHA. RESULTS: The algorithm and drug table developed to systematically identify and address SIJ pain in the older adult is presented here. The process should begin with recognizing the presenting symptoms of CLBP stemming from the SI region, and supporting physical exam testing using the compression test and thigh thrust maneuver. Identification of the SIJ as a pain generator is followed by assessment and treatment of contributory factors. SIJ pain treatment should begin with education and self-management including exercise, and may escalate to include interventional procedures and/or referral to a pain rehabilitation program. CONCLUSIONS: Pain originating from the SIJ is often under-recognized, but a structured and consistent approach can help identify older patients who would benefit from treatment of this contributor to CLBP. KEY WORDS: Chronic Low Back Pain; Sacroiliac Joint Pain; Older Adults.

Deconstructing Chronic Low Back Pain in the Older Adult-Step by Step Evidence and Expert-Based Recommendations for Evaluation and Treatment. Part VI: Lumbar Spinal Stenosis.

OBJECTIVE: . To present the sixth in a series of articles designed to deconstruct chronic low back pain (CLBP) in older adults. This article focuses on the evaluation and management of lumbar spinal stenosis (LSS), the most common condition for which older adults undergo spinal surgery. METHODS: . The evaluation and treatment algorithm, a table articulating the rationale for the individual algorithm components, and stepped-care drug recommendations were developed using a modified Delphi approach. The Principal Investigator, a five-member content expert panel and a nine-member primary care panel were involved in the iterative development of these materials. The illustrative clinical case was taken from the clinical practice of a contributor's colleague (SR). RESULTS: . We present an algorithm and supportive materials to help guide the care of older adults with LSS, a condition that occurs not uncommonly in those with CLBP. The case illustrates the importance of function-focused management and a rational approach to conservative care. CONCLUSIONS: . Lumbar spinal stenosis exists not uncommonly in older adults with CLBP and management often can be accomplished without surgery. Treatment should address all conditions in addition to LSS contributing to pain and disability.

Early Detection of Pressure Ulcer Development Following Traumatic Spinal Cord Injury Using Inflammatory Mediators.

OBJECTIVE: To identify changes in concentrations of inflammatory mediators in plasma and urine after traumatic spinal cord injury (SCI) and before the occurrence of a first pressure ulcer. DESIGN: Retrospective; secondary analysis of existing data. SETTING: Acute hospitalization and inpatient rehabilitation sites at a university medical center. PARTICIPANTS: Individuals with a pressure ulcer and plasma samples (n=17) and individuals with a pressure ulcer and urine samples (n=15) were matched by age and plasma/urine sample days to individuals with SCI and no pressure ulcer (N=35). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Plasma and urine samples were assayed in patients with SCI, capturing samples within 4 days after the SCI to a week before the formation of the first pressure ulcer. The Wilcoxon signed-rank test was performed to identify changes in the inflammatory mediators between the 2 time points. RESULTS: An increase in concentration of the chemokine interferon-γ-induced protein of 10kd/CXCL10 in plasma (P<.01) and a decrease in concentration of the cytokine interferon-α in urine (P=.01) were observed before occurrence of a first pressure ulcer (∼4d) compared with matched controls. CONCLUSIONS: Altered levels of inflammatory mediators in plasma and urine may be associated with pressure ulcer development after traumatic SCI. These inflammatory mediators should be explored as possible biomarkers for identifying individuals at risk for pressure ulcer formation.

Mechanical role of the posterior column components in the cervical spine.

PURPOSE: To quantify the mechanical role of posterior column components in human cervical spine segments. METHODS: Twelve C6-7 segments were subjected to resection of (1) suprasinous/interspinous ligaments (SSL/ISL), (2) ligamenta flavum (LF), (3) facet capsules, and (4) facets. A robot-based testing system performed repeated flexibility testing of flexion-extension (FE), axial rotation (AR), and lateral bending (LB) to 2.5Nm and replayed kinematics from intact flexibility tests for each state. Range-of-motion, stiffness, moment resistance and resultant forces were calculated. RESULTS: The LF contributes largely to moment resistance, particularly in flexion. Facet joints were primary contributors to AR and LB mechanics. Moment/force responses were more sensitive and precise than kinematic outcomes. CONCLUSIONS: The LF is mechanically important in the cervical spine; its injury could negatively impact load distribution. Damage to facets in a flexion injury could lead to AR or LB hypermobility. Quantifying the contribution of spinal structures to moment resistance is a sensitive, precise process for characterizing structural mechanics.