Dissecting Genetic Mechanisms of Differential Locomotion, Depression, and Allodynia after Spinal Cord Injury in Three Mouse Strains.

Strain differences have been reported for motor behaviors, and only a subset of spinal cord injury (SCI) patients develop neuropathic pain, implicating genetic or genomic contribution to this condition. Here, we evaluated neuropsychiatric behaviors in A/J, BALB/c, and C57BL/6 male mice and tested genetic or genomic alterations following SCI. A/J and BALB/c naive mice showed significantly less locomotor activity and greater anxiety-like behavior than C57BL/6 mice. Although SCI elicited locomotor dysfunction, C57BL/6 and A/J mice showed the best and the worst post-traumatic recovery, respectively. Mild (m)-SCI mice showed deficits in gait dynamics. All moderate/severe SCI mice exhibited similar degrees of anxiety/depression. mSCI in BALB/c and A/J mice resulted in depression, whereas C57BL/6 mice did not exhibit depression. mSCI mice had significantly lower mechanical thresholds than their controls, indicating high cutaneous hypersensitivity. C57BL/6, but not A/J and BLAB/c mice, showed significantly lower heat thresholds than their controls. C57BL/6 mice exhibited spontaneous pain. RNAseq showed that genes in immune responses and wound healing were upregulated, although A/J mice showed the largest increase. The cell cycle and the truncated isoform of trkB genes were robustly elevated in SCI mice. Thus, different genomics are associated with post-traumatic recovery, underscoring the likely importance of genetic factors in SCI.

Nociceptive and Transcriptomic Responses in a Swine Diabetic Wound Model Treated With a Topical Angiotensin 1 Receptor Antagonist.

BACKGROUND: Painful, treatment-resistant wounds are prevalent among diabetic patients and significantly affect health-related quality of life (HRQOL). Topical treatments may help alleviate pain without risk of dependence or side effects. However, there is a lack of topical wound compounds targeting pain-specific receptors. One possible target is proinflammatory angiotensin 1 receptor (AT1R), which is upregulated in diabetic skin and has been implicated in nociception. OBJECTIVES: We investigated the effects of topical valsartan, an AT1R antagonist, on pain (nociceptive thresholds) and gene expression changes (transcriptomics) in a swine model of diabetic wounds. METHODS: Eight wounds were surgically induced in diabetic, hyperglycemic Yucatan miniature swine ( n = 4). Topical AT1R antagonist was applied to wounds on one side and vehicle on the other side. Nocifensive testing was conducted at baseline and then weekly, beginning 7 days after wound induction. Mechanical and thermal stimuli were applied to the wound margins until a nocifensive reaction was elicited or a predetermined cutoff was reached. After 7 weeks of testing, tissue from the dorsal horn, dorsal root ganglion, and wounds were sequenced and analyzed with DESeq2. Unbiased pathway analyses using Metascape were conducted on differentially expressed genes. RESULTS: There was no significant difference in mechanical tolerance threshold between AT1R antagonist-treated and vehicle-treated wounds ( p = .106). Thermal tolerance was significantly higher in AT1R antagonist-treated wounds compared to vehicle-treated ( p = .015). Analysis of differentially expressed genes revealed enriched pathways of interest: interleukin-18 signaling in dorsal horn laminae IV-V and sensory perception of mechanical stimulus in wound tissue. DISCUSSION: In this study, wounds modeling diabetic ulcers were created in hyperglycemic swine and treated with a topical AT1R antagonist. AT1R-antagonist-treated wounds had a higher tolerance threshold than vehicle-treated wounds for thermal hyperalgesia, but not mechanical allodynia. Pathway analyses of differentially expressed genes revealed several pathways of interest for future pain research. Although further studies are needed to confirm the findings, this study can improve nursing care by providing information about a potential future treatment that may be used to decrease pain and improve HRQOL in patients with diabetic wounds.

Differential Gene Expression in Pain-Related Genes are not Affected by the Presence of Dementia.

BACKGROUND: Prior work has demonstrated differences in the transcriptome between those with and without chronic musculoskeletal pain. AIMS: The aim of this study was to explore whether pain-related gene expression is similar between individuals with and without dementia. DESIGN: This was a descriptive study using a one-time assessment. SETTINGS: PARTICIPANTS/SUBJECTS: A total of 20 older adults living in a continuing care retirement community, 50% of whom had dementia were inlcuded in this study. All were female and the mean age of participants was 89 (SD = 6). METHODS: Pain was evaluated based on the PROMIS Pain Intensity Short Form 3a. Whole blood was collected by venipuncture into Tempus vacutainer tubes (3 ml) and the RNA was extracted at the Translational Genomics Laboratory at the University of Maryland Baltimore. Analyses included a differential expression analysis, a weighted gene co-expression network analysis, and a pathway enrichment analysis. RESULTS: Eighty-three genes were differentially expressed between individuals with and without pain (p <.05). After normalizing gene counts and removing the low expressed genes, 18,028 genes were left in the final analysis. There was no clustering of the samples related to study variables of pain or dementia. CONCLUSION: The findings from this study provided some preliminary support that pain-related gene expression is similar between individuals with and without dementia.

Dietary Composition, Meal Timing, and Cancer-Related Fatigue: Insights From the Women's Healthy Eating and Living Study.

BACKGROUND: Cancer-related fatigue is difficult to treat, and dietary interventions are promising yet underused. OBJECTIVE: We explored associations between dietary patterns and fatigue, and the effect of a dietary intervention versus control on fatigue using Women's Healthy Eating and Living study data, plus mediators and moderators of the intervention effect. METHODS: The Women's Healthy Eating and Living study was a randomized controlled trial among early-stage breast cancer survivors. The 4-year intervention encouraged fruits, vegetables, fiber, and 15% to 20% calories from fat. Fatigue outcomes included a 9-item energy scale and a single-item tiredness question. Dietary quality was estimated using a modified Healthy Eating Index (24-hour dietary recall) and serum carotenoid concentrations. Nutrient timing was obtained from 4-day food logs. RESULTS: Among 2914 total participants, lower body mass index was associated with less tiredness and more energy at baseline (P < .001 for both). Earlier start and end times for daily eating windows were associated with less tiredness (P = .014 and P = .027, respectively) and greater energy (P = .006 and P = .102, respectively). The intervention did not lead to improvements in fatigue on average (P > .125). However, the intervention was more effective for participants who were younger, had fewer comorbidities, and did not have radiation treatment. Mediators included increases in serum carotenoids, increases in the modified Healthy Eating Index, and weight loss/maintenance. CONCLUSION: Diet quality and earlier eating windows were associated with less fatigue. IMPLICATIONS FOR PRACTICE: Programs that encourage high diet quality and a morning meal and discourage nighttime eating should be tested for efficacy in reducing cancer-related fatigue in survivorship.

Sex Differences in the Serum Proteomic Profile During Acute Low Back Pain-A Preliminary Study of the Relationship to Future Low Back Pain.

The molecular processes driving the transition from acute to chronic low back pain (LBP) remain poorly understood and are likely to be sexually dimorphic. This study aimed to explore sex differences in the serum proteomic profile of people experiencing an acute LBP episode and determine if serum protein concentrations were associated with three-month outcome. Serum samples were collected through venepuncture from 30 female and 29 male participants experiencing an acute LBP episode. Serum samples underwent trypsin digestion and fractionation using hydrophobic interaction chromatography and were then analysed using mass-spectrometry. Mass-spectrometry spectra were searched in the Swissprot database for protein identification. Sex differences in protein abundance changes were evident upon inspection of fold changes. Multivariable data analysis identified 21 serum proteins during the acute episode that correctly classified 93% of males and 23 serum proteins that correctly classified 90% of females with ongoing LBP at 3 months. Pathway analysis suggested the differentially expressed proteins during acute LBP were frequently involved in immune, inflammatory, complement, or coagulation responses. This data provides preliminary evidence that biological processes during an acute LBP episode may contribute to the resolution, or persistence, of LBP symptoms at 3 months, however, these processes differ between males and females. PERSPECTIVE: Differential expression of serum proteins was observed between male and female participants during an acute LBP episode. This preliminary work provides a foundation for future research targeting distinct immune system processes in males and females that may interfere with the transition from acute to chronic LBP.

Feasibility and Acceptability of an Online Yoga Study Among Individuals with Irritable Bowel Syndrome (IBS).

Irritable bowel syndrome (IBS) is a gastrointestinal disorder characterized by chronic abdominal pain that is often comorbid with psychiatric disorders and other pain-related conditions. The practice of yoga improves symptoms among patients with IBS, although the virtual delivery of yoga in this patient population remains understudied. The purpose of this article is to report feasibility and acceptability of a 6-week pilot yoga intervention among IBS and healthy control participants, which was transitioned to an online format in response to the COVID-19 pandemic. Participants attended 3 virtual study visits and received 60-minute private yoga sessions twice weekly for 6 weeks via Zoom. Sixteen females (n = 8 in IBS group, n = 8 in control group) with a mean age of 34.7 identified as White (87.5%) and Asian (12.5%). All participants attended all 3 study visits; 14 participants attended 12 yoga sessions, 1 attended 11, and 1 attended 9. At the end of the study, 81.3% of participants strongly agreed that participating in the online study was beneficial and convenient, and 87.5% strongly agreed that participating in the online yoga program was beneficial. Our online study and yoga intervention was feasible and acceptable; future studies with larger and more diverse populations will be conducted to investigate health effects among individuals with IBS.

Genome wide association joint analysis reveals 99 risk loci for pain susceptibility and pleiotropic relationships with psychiatric, metabolic, and immunological traits.

Chronic pain is at epidemic proportions in the United States, represents a significant burden on our public health system, and is coincident with a growing opioid crisis. While numerous genome-wide association studies have been reported for specific pain-related traits, many of these studies were underpowered, and the genetic relationship among these traits remains poorly understood. Here, we conducted a joint analysis of genome-wide association study summary statistics from seventeen pain susceptibility traits in the UK Biobank. This analysis revealed 99 genome-wide significant risk loci, 65 of which overlap loci identified in earlier studies. The remaining 34 loci are novel. We applied leave-one-trait-out meta-analyses to evaluate the influence of each trait on the joint analysis, which suggested that loci fall into four categories: loci associated with nearly all pain-related traits; loci primarily associated with a single trait; loci associated with multiple forms of skeletomuscular pain; and loci associated with headache-related pain. Overall, 664 genes were mapped to the 99 loci by genomic proximity, eQTLs, and chromatin interaction and ~15% of these genes showed differential expression in individuals with acute or chronic pain compared to healthy controls. Risk loci were enriched for genes involved in neurological and inflammatory pathways. Genetic correlation and two-sample Mendelian randomization indicated that psychiatric, metabolic, and immunological traits mediate some of these effects.

Factors Related to Fatigue and Physical Function in COPD: A Secondary Analysis Using National Survey Data.

Fatigue in chronic obstructive pulmonary disease (COPD) is debilitating and associated with considerable morbidity. The aim of this study is to present a model based on the Theory of Unpleasant Symptoms of physiologic, psychologic, and situational factors with COPD-related fatigue and the relationship with physical functioning. This study used data collected from Wave 2 (2010-2011) of the National Social, Health, and Aging Project (NSHAP). A total of 518 adults with self-reported COPD were included in this study. Path analysis was used for hypothesis testing. Depression was the only psychologic factor found to have a direct relation to both fatigue (ß = 0.158, p < .001) and physical function (ß = -0.131, p = .001). Factors related to physical function included fatigue, depression, sleep, loneliness, and pain. Additionally, fatigue was indirectly associated with physical function via depression (ß = -0.064, p = .012). These findings suggest avenues for future research on predictors of COPD-related fatigue in relation to physical functioning.

COPD-Related Fatigue: A Scoping Review.

Millions of people worldwide have chronic obstructive pulmonary disease (COPD), and one of the most common and troublesome symptoms that must be managed is fatigue. While there are existing interventions to address COPD-related fatigue, not all patients experience benefit. A better understanding of the factors associated with COPD-fatigue could elucidate new approaches to address COPD-related fatigue, thereby offering relief to a greater number of patients. The purpose of this review was to identify the physiologic, psychologic, and situational factors associated with COPD-related fatigue. A total of four databases, PubMed, CINAHL, Scopus, and Google Scholar, were searched. Those that were peer reviewed, in English, and published between 2000 and 2021, were included in the review. A total of 25 articles were included in this scoping review. The following factors were related to fatigue in COPD: dyspnea, pain, anxiety, depression, and sleep. Fatigue is a debilitating symptom with factors influential to the symptom and outcomes. Research is indicated to explore targeted and personalized interventions addressing the factors related to fatigue to mitigate this widespread symptom.

Protein Changes After 6 weeks of Walking and the Relationship to Pain in Adults with Knee Osteoarthritis.

Background: Knee osteoarthritis (KOA) affects 22.9% of individuals over the age of 40 and causes significant pain and disability. Pain is the most prevalent and troublesome symptom of KOA leading patients to seek medical interventions for relief. Knee osteoarthritis pain has both peripheral and central mechanisms that vary by individual. Non-pharmacological pain management strategies such as walking is the first step in reducing KOA pain. However, initiation of a walking regime can induce knee pain for some and the mechanism by which habitual walking reduces KOA pain is unclear. Purpose: The purpose of this study was to use a discovery proteomics approach and quantitative sensory testing (QST) to determine the molecular changes that occur after habitual walking and their relationship to pain sensitivity. Research Design and Study Sample: We conducted a pre-test/post-test study using QST to measure neurophysiological parameters at the knee and contralateral forearm and examined platelet protein signatures before and after 6 weeks of walking 3 days per week for 30 minutes among six adults with KOA and six healthy controls. Results: Knee pain sensitivity did not change significantly after 6 weeks of walking among either KOA or healthy participants. However, forearm pressure pain sensitivity decreased for both groups after walking, indicating reduction in central pain pathways. Protein signatures showed downregulation of immune and inflammatory, pathways among KOA participants after walking which were upregulated in healthy controls. Conclusion: These differences may contribute differences in centralized pain thresholds seen between KOA and healthy participants.

Inflammatory and Immune Protein Pathways Possible Mechanisms for Pain Following Walking in Knee Osteoarthritis.

BACKGROUND: Knee osteoarthritis affects nearly 30% of adults aged 60 years or older and causes significant pain and disability. Walking is considered a "gold standard" treatment option for reducing knee osteoarthritis pain and maintaining joint mobility but does not reduce pain for all adults with knee osteoarthritis pain and may induce pain-particularly when starting a walking routine. The mechanism by which walking is helpful for knee osteoarthritis pain is unclear. Quantitative sensory testing has revealed that knee osteoarthritis pain has both peripheral and central components, which vary by individual. OBJECTIVE: The purpose of this study was to better understand the mechanisms underlying the value of walking for knee pain. METHODS: We conducted a pretest/posttest study using quantitative sensory testing to measure neurophysiological parameters and examined systemic protein signatures. Adults with knee osteoarthritis and healthy controls underwent quantitative sensory testing and blood draw for platelet proteomics before and after a 30-minute walk at 100 steps per minute. RESULTS: A single 30-minute walk moderately increased pressure pain sensitivity at the affected knee among persons with knee osteoarthritis. Healthy adults showed no difference in pain sensitivity. Protein signatures among participants with knee osteoarthritis indicated changes in inflammatory and immune pathways, including the complement system and SAA1 protein that coincided with changes in pain with walking and differed from healthy participants. DISCUSSION: One goal of developing individualized interventions for knee osteoarthritis pain is to elucidate the mechanisms by which self-management interventions affect pain. The addition of therapies that target the complement system or SAA1 expression may improve the pain sensitivity after a moderate walk for adults with knee osteoarthritis.

Neurophysiological and transcriptomic predictors of chronic low back pain: Study protocol for a longitudinal inception cohort study.

Chronic low back pain is one of the most common, costly, and debilitating pain conditions worldwide. Increased mechanistic understanding of the transition from acute to chronic low back and identification of predictive biomarkers could enhance the clinical assessment performed by healthcare providers and enable the development of targeted treatment to prevent and/or better manage chronic low back pain. This study protocol was designed to identify the neurological and transcriptomic biomarkers predictive of chronic low back pain at low back pain onset. This is a prospective descriptive longitudinal inception cohort study that will follow 340 individuals with acute low back pain and 40 healthy controls over 2 years. To analyze the neurophysiological and transcriptomic biomarkers of low back pain, the protocol includes psychological and pain-related survey data that will be collected beginning within 6 weeks of low back pain onset (baseline, 6, 12, 24, 52 weeks, and 2 years) and remotely at five additional time points (8, 10, 16, 20 weeks, and 18 months). Quantitative sensory testing and collection of blood samples for RNA sequencing will occur during the six in-person visits. The study results will describe variations in the neurophysiological and transcriptomic profiles of healthy pain-free controls and individuals with low back pain who either recover to pain-free status or develop chronic low back pain.

The Relationship Between Pain, Function, Behavioral, and Psychological Symptoms of Dementia and Quality of Life.

BACKGROUND: This study evaluated the association between age, sex, comorbidities, cognition, and administration of opioids with pain and the impact of all of these variables plus function, agitation, resistiveness to care, and depression on quality of life among residents in nursing home with severe dementia. DESIGN: This was a descriptive study using baseline data from the Evidence Integration Triangle for Behavioral and Psychological Symptoms of Dementia implementation study. METHODS: Model testing was done using structural equation modeling. The sample included 553 residents from 55 nursing homes with a mean age of 83.88 (standard deviation = 10.44) and mean Brief Interview of Mental Status of 4.30 (standard deviation = 3.50). RESULTS: There were significant associations showing those who were older, male, had fewer comorbidities, better cognition, and were black were more likely to have pain. Pain, in combination with the demographic and descriptive variables, explained 32% of the variance in function, 75% of the variance in depression, 88% of the variance in agitation, 98% of the variance in resistiveness to care, and 92% of the variance in quality of life. The model however did not show a good fit to the data. SETTING: The study was done in 55 nursing homes in Maryland and Pennsylvania. PARTICIPANTS/SUBJECTS: A total of 553 residents were included in the study. CONCLUSIONS: The model did not have a good fit with the data which likely was due to the lack of variance in outcomes. The hypothesized paths, with the exception of opioid use, were significant.

Cannabinoids: an Effective Treatment for Chemotherapy-Induced Peripheral Neurotoxicity?

Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most frequent side effects of antineoplastic treatment, particularly of lung, breast, prostate, gastrointestinal, and germinal cancers, as well as of different forms of leukemia, lymphoma, and multiple myeloma. Currently, no effective therapies are available for CIPN prevention, and symptomatic treatment is frequently ineffective; thus, several clinical trials are addressing this unmet clinical need. Among possible pharmacological treatments of CIPN, modulation of the endocannabinoid system might be particularly promising, especially in those CIPN types where analgesia and neuroinflammation modulation might be beneficial. In fact, several clinical trials are ongoing with the specific aim to better investigate the changes in endocannabinoid levels induced by systemic chemotherapy and the possible role of endocannabinoid system modulation to provide relief from CIPN symptoms, a hypothesis supported by preclinical evidence but never consistently demonstrated in patients. Interestingly, endocannabinoid system modulation might be one of the mechanisms at the basis of the reported efficacy of exercise and physical therapy in CIPN patients. This possible virtuous interplay will be discussed in this review.

Prior Night Sleep Affects Next-Day Pain Interference Among Community-Dwelling Older Adults With Lower Extremity Chronic Pain.

Emergent work suggests that sleep is a robust biobehavioral predictor of pain; however, it remains unclear how sleep is prospectively linked to pain on a day-to-day basis among older adults. The current prospective study examined how sleep duration (total sleep time), quality (sleep efficiency, wake after sleep onset), and late and irregular sleep timing influenced next-day pain perception among community-dwelling older adults (N = 10; 65 matched observations) with lower extremity chronic pain over 1 week. Multilevel modeling estimated the association between sleep (Actigraph GT9X Link) and pain perception (Brief Pain Inventory Short Form). Increased wake after sleep onset (B = 0.19, p = 0.04), sleep variability (B = 0.02, p = 0.01), and later midsleep time (B = 0.40, p < 0.05) were associated with increased pain interference the following day. Findings support the idea that timely sleep interventions may reduce the effect of poor sleep on next-day pain in older adults. [Research in Gerontological Nursing, 14(4), 173-179.].

Quantitative Sensory Testing Across Chronic Pain Conditions and Use in Special Populations.

Chronic pain imposes a significant burden to the healthcare system and adversely affects patients' quality of life. Traditional subjective assessments, however, do not adequately capture the complex phenomenon of pain, which is influenced by a multitude of factors including environmental, developmental, genetic, and psychological. Quantitative sensory testing (QST), established as a protocol to examine thermal and mechanical sensory function, offers insight on potential mechanisms contributing to an individual's experience of pain, by assessing their perceived response to standardized delivery of stimuli. Although the use of QST as a research methodology has been described in the literature in reference to specific pain populations, this manuscript details application of QST across a variety of chronic pain conditions. Specific conditions include lower extremity chronic pain, knee osteoarthritis, chronic low back pain, temporomandibular joint disorder, and irritable bowel syndrome. Furthermore, we describe the use of QST in placebo/nocebo research, and discuss the use of QST in vulnerable populations such as those with dementia. We illustrate how the evaluation of peripheral sensory nerve function holds clinical promise in targeting interventions, and how using QST can enhance patient education regarding prognostic outcomes with particular treatments. Incorporation of QST methodology in research investigations may facilitate the identification of common mechanisms underlying chronic pain conditions, guide the development of non-pharmacological behavioral interventions to reduce pain and pain-related morbidity, and enhance our efforts toward reducing the burden of chronic pain.

Invariance of the PAINAD Scale Between the Black and White Residents Living With Dementia.

The purpose of this study was to test the reliability and validity of the Pain Assessment in Advanced Dementia (PAINAD) and particularly consider whether or not this measure was invariant when used among the Black and White residents. Baseline data from an implementation study testing that included a sample of 553 residents, 30% of who were Black, from 55 nursing were included in this study. The Winsteps statistical program was used to perform the Rasch analysis and evaluate the reliability and validity of the measure based on internal consistency, infit and outfit statistics, mapping, and a differential item functioning (DIF) analysis. The AMOS statistical program was used for confirmatory factor analysis. The findings supported the reliability and validity of the PAINAD when used with these individuals and demonstrated that there was no evidence of invariance between the Black and White residents. All the items fit the model, but there was not a good spread of the items across the pain level of the participants. The majority of the participants (75%) were so low in pain signs or symptoms that they could not be differentiated. Based on the clinical practice and observations, it is recommended that additional items can be added to the measure such as observing the individual for evidence of resisting care, retropulsion when trying to stand, hitting or kicking when turning in bed, hitting or kicking when transferring from bed to chair, hitting or kicking when ambulating, or hitting or kicking when raising arms, less engagement with others, and decreased participation in the activities previously enjoyed.

Function and Mechanisms of Truncated BDNF Receptor TrkB.T1 in Neuropathic Pain.

Brain-derived neurotrophic factor (BDNF), a major focus for regenerative therapeutics, has been lauded for its pro-survival characteristics and involvement in both development and recovery of function within the central nervous system (CNS). However, studies of tyrosine receptor kinase B (TrkB), a major receptor for BDNF, indicate that certain effects of the TrkB receptor in response to disease or injury may be maladaptive. More specifically, imbalance among TrkB receptor isoforms appears to contribute to aberrant signaling and hyperpathic pain. A truncated isoform of the receptor, TrkB.T1, lacks the intracellular kinase domain of the full length receptor and is up-regulated in multiple CNS injury models. Such up-regulation is associated with hyperpathic pain, and TrkB.T1 inhibition reduces neuropathic pain in various experimental paradigms. Deletion of TrkB.T1 also limits astrocyte changes in vitro, including proliferation, migration, and activation. Mechanistically, TrkB.T1 is believed to act through release of intracellular calcium in astrocytes, as well as through interactions with neurotrophins, leading to cell cycle activation. Together, these studies support a potential role for astrocytic TrkB.T1 in hyperpathic pain and suggest that targeted strategies directed at this receptor may have therapeutic potential.

Transition From Acute to Chronic Pain in Lower Extremity Fracture Patients: A Pain Phenotyping Protocol.

BACKGROUND: Traumatic injury is a major source of chronic pain, particularly for individuals with traumatic fracture of the fibula and/or tibia (lower extremity fracture [LEFx]). Although several factors (e.g., older age, being female, high pain intensity at time of initial injury) have been identified as risk factors for chronic pain associated with LEFx. Comprehensive biopsychosical models to predict the odds of transitioning from acute to chronic pain after LEFx are needed to better understand the underlying processes, predict risk for chronic pain, and develop personalized therapies for individuals at higher risk for developing chronic pain. OBJECTIVE: The aim of the study was to outline the study design that will be used to examine the physiological, psychological, and genetic/genomic variables-models that predict the transition from acute to chronic pain after LEFx. METHOD: This prospective descriptive cohort study will enroll 240 participants with a fibula and/or tibia fracture and 40 controls with no LEFx. Data will be collected during an in-hospital baseline visit, five in-person clinic visits (6 weeks, 12 weeks, 24 weeks, 52 weeks, and 24 months), and seven online between-visit surveys (2 weeks, 4 weeks, 8 weeks, 10 weeks, 16 weeks, 20 weeks, and 18 months) from participants with LEFx and at concordant intervals from controls. Measures will consist of 19 questionnaires characterizing pain and psychological status, neurophysiological testing for peripheral sensory nerve function, and peripheral blood samples collections for RNA sequencing. Illumina standard protocols will be used to sequence RNA, and read counts will be used to measure gene expression. ANALYSIS: Direct-entry, multiple logistic regression will be used to produce odds ratios expressing the relative risk on each explanatory variable when controlling for other predictors/covariates in the model. CONCLUSION: This study is one of the first to longitudinally characterize the biopsychosocial variables associated with a clinically relevant problem of the transition from acute to chronic posttraumatic fracture pain in individuals with LEFx. Results from this study will be used to construct predictive risk models of physiological, psychological, and genetic/genomic variables associated with increased risk for transitioning from acute to chronic pain status after LEFx. This work will lead to a better understanding of the trajectory of pain and relevant variables over time; initiate a better understanding of variables associated with risk for transitioning from acute to chronic pain; and, in the future, could provide a foundation for the identification of novel therapeutic targets to improve the outcomes of individuals with LEFx.

Whole blood transcriptomic profiles can differentiate vulnerability to chronic low back pain.

The mechanisms underlying the transition from acute to chronic pain remain unclear. Here, we sought to characterize the transcriptome associated with chronic low back pain as well as the transcriptome of the transition from acute to chronic low back pain. For the analysis, we compared the whole blood transcriptome of: (a) patients at the onset of low back pain who no longer had pain within 6 weeks after onset (acute) with patients who developed chronic low back pain at 6 months (chronic T5); and, (b) patients at the onset of low back pain (chronic T1) who developed chronic pain at 6 months with healthy pain-free (normal) controls. The majority of differentially expressed genes were protein coding. We illustrate a unique chronic low back pain transcriptome characterized by significant enrichment for known pain genes, extracellular matrix genes, and genes from the extended major histocompatibility complex (MHC) genomic locus. The transcriptome of the transition from acute to chronic low back pain was characterized by significant upregulation of antigen presentation pathway (MHC class I and II) genes and downregulation of mitochondrial genes associated with oxidative phosphorylation, suggesting a unique genomic signature of vulnerability to low back pain chronicity.