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.

Pharmacogenetic and clinical risk factors for bevacizumab-related gastrointestinal hemorrhage in prostate cancer patients treated on CALGB 90401 (Alliance).

The objective of this study was to discover clinical and pharmacogenetic factors associated with bevacizumab-related gastrointestinal hemorrhage in Cancer and Leukemia Group B (Alliance) 90401. Patients with metastatic castration-resistant prostate cancer received docetaxel and prednisone ± bevacizumab. Patients were genotyped using Illumina HumanHap610-Quad and assessed using cause-specific risk for association between single nucleotide polymorphisms (SNPs) and gastrointestinal hemorrhage. In 1008 patients, grade 2 or higher gastrointestinal hemorrhage occurred in 9.5% and 3.8% of bevacizumab (n = 503) and placebo (n = 505) treated patients, respectively. Bevacizumab (P < 0.001) and age (P = 0.002) were associated with gastrointestinal hemorrhage. In 616 genetically estimated Europeans (n = 314 bevacizumab and n = 302 placebo treated patients), grade 2 or higher gastrointestinal hemorrhage occurred in 9.6% and 2.0% of patients, respectively. One SNP (rs1478947; HR 6.26; 95% CI 3.19-12.28; P = 9.40 × 10-8) surpassed Bonferroni-corrected significance. Grade 2 or higher gastrointestinal hemorrhage rate was 33.3% and 6.2% in bevacizumab-treated patients with the AA/AG and GG genotypes, versus 2.9% and 1.9% in the placebo arm, respectively. Prospective validation of these findings and functional analyses are needed to better understand the genetic contribution to treatment-related gastrointestinal hemorrhage.

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.

Software-based interventions for low back pain management: A systematic review and meta-analysis.

INTRODUCTION: Using software for self-management interventions can improve health outcomes for individuals with low back pain, but there is a dearth of research to confirm its effectiveness. Additionally, no known research has evaluated the effective elements of software-based interventions for low back pain self-management components. This study aimed to synthesize the effectiveness of software-based interventions to promote self-management health outcomes among individuals with low back pain. DESIGN: A systematic review and meta-analysis was conducted. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement, relevant studies up to July 2022 were searched via four electronic databases: PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, and Web of Science. RESULTS: 4908 adults with low back pain who participated in 23 studies were included. Software-based interventions were effective in reducing fear avoidance (mean difference [MD] = -0.95, 95% CI: -1.45 to -0.44), pain catastrophizing (MD = -1.31, 95% CI: -1.84 to -0.78), disability (MD = -8.21, 95% CI: -13.02 to -3.39), and pain intensity (MD = -0.86, 95% CI: -1.17 to -0.55). Specifically, interventions that included an exercise component were more effective in reducing pain and disability. Additionally, cognitive behavioral therapy (CBT) intervention significantly reduced fear avoidance and pain catastrophizing but had no noticeable impact on disability and pain compared to standard treatment. The certainty of the evidence in this review varied from very low to high across outcomes. The heterogeneity of the study results was significant, suggesting that future studies in this area could optimize the design, time points, measures, and outcomes to strengthen the evidence. CONCLUSIONS: Low back pain self-management interventions delivered through software-based programs effectively reduce pain intensity, disability, fear avoidance, and pain catastrophizing. CLINICAL RELEVANCE: Low back pain is among the most common reasons for seeking healthcare visits. Combining exercise and counseling through soft-based programs may effectively address this issue and its associated suffering and disability.

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.

Multi-Omics Analysis of Gut Microbiota and Host Transcriptomics Reveal Dysregulated Immune Response and Metabolism in Young Adults with Irritable Bowel Syndrome.

The integrated dysbiosis of gut microbiota and altered host transcriptomics in irritable bowel syndrome (IBS) is yet to be known. This study investigated the associations among gut microbiota and host transcriptomics in young adults with IBS. Stool and peripheral blood samples from 20 IBS subjects and 21 healthy controls (HCs) collected at the baseline visit of an RCT were sequenced to depict the gut microbiota and transcriptomic profiles, respectively. The diversities, composition, and predicted metabolic pathways of gut microbiota significantly differed between IBS subjects and HCs. Nine genera were significantly abundant in IBS stool samples, including Akkermansia, Blautia, Coprococcus, Granulicatella, Holdemania, Oribacterium, Oscillospira, Parabacteroides, and Sutterella. There were 2264 DEGs found between IBS subjects and HCs; 768 were upregulated, and 1496 were downregulated in IBS participants compared with HCs. The enriched gene ontology included the immune system process and immune response. The pathway of antigen processing and presentation (hsa04612) in gut microbiota was also significantly different in the RNA-seq data. Akkermansia, Blautia, Holdemania, and Sutterella were significantly correlated with ANXA2P2 (upregulated, positive correlations), PCSK1N (downregulated, negative correlations), and GLTPD2 (downregulated, negative correlations). This study identified the dysregulated immune response and metabolism in IBS participants revealed by the altered gut microbiota and transcriptomic profiles.

Differential Gene Expression Among Patients With Heart Failure Experiencing Pain.

BACKGROUND: Chronic pain is frequently experienced by patients with heart failure (HF) and is associated with higher mortality, higher symptom burden, and worsened health-related quality of life. However, the genomic mechanisms underlying chronic pain in HF are understudied. Building an understanding of the mechanistic underpinnings of pain may inform novel interventions. OBJECTIVE: The objective was to identify genes associated with pain from messenger RNA sequence data collected from patients with HF with and without pain. METHODS: The current study analyzed data from 40 patients with HF previously enrolled in a clinical trial. Pain presence was measured using the Health Utilities Index Mark-3. Genes were tested for differential expression using DESeq2, and differentially expressed genes were analyzed for protein-protein interaction (PPI) and relevant ontological pathways using Metascape. Genes located within the core of the PPI network were considered key in disease-relevant biological pathways. Differentially expressed genes within this PPI network were reviewed in existing literature to narrow down candidate genes of interest. These target genes of interest were reanalyzed in a second sample of 24 patients with HF using validation quantitative polymerase chain reaction. RESULTS: A total of 334 genes (279 upregulated, 55 downregulated) were differentially expressed between patients with and without pain in the primary sample of 40. These genes were largely aligned with neutrophil degranulation pathways. Seven genes of interest were identified from a core network of 15 co-expressed genes in the PPI network and existing literature. Three of these seven genes, matrix metallopeptidase 8 ( MMP8 ), proprotein convertase subtilisin/kexin type 9 ( PCSK9 ), and neutrophil defensin 3 ( DEFA3 ), were upregulated in patients with pain versus without pain in both the primary and validation samples. All seven genes of interest are involved in immune, inflammatory, and atherosclerotic processes. DISCUSSION: These results identify potential genes that may play a mechanistic role in chronic pain in HF. Further research is needed to evaluate these potential genes among clearly delineated pain phenotypes.

Factors Associated With Function-Focused Care Among Hospitalized Older Adults Living With Dementia.

This article reports a study that was designed to describe the incidence of pain among older hospitalized patients with dementia and to evaluate the factors that influence pain among these individuals. It was hypothesized that function, behavioral and psychological symptoms of dementia, delirium, pain treatment, and patient exposure to care interventions would be associated with pain. Patients who performed more functional activities had less delirium. They also experienced higher quality-of-care interactions and were less likely to have pain. The findings from this study support the relationship between function, delirium, and quality-of-care interactions and pain. It suggests that it may be useful to encourage patients with dementia to engage in functional and physical activity to prevent or manage pain. This study serves as a reminder to avoid neutral or negative care interactions among patients with dementia as a strategy to mediate delirium and pain.

Pain self-management plus activity tracking and nurse-led support in adults with chronic low back pain: feasibility and acceptability of the problem-solving pain to enhance living well (PROPEL) intervention.

BACKGROUND: Chronic low back pain can lead to individual suffering, high medical expenditures, and impaired social well-being. Although the role of physical activity in pain management is well established, the underlying mechanisms of biological and clinical outcomes are unknown. This study aimed to assess the feasibility and acceptability of a pain self-management intervention, Problem-Solving Pain to Enhance Living Well, which employs wearable activity tracking technology and nurse consultations for people with chronic low back pain. METHODS: This one-arm longitudinal study recruited 40 adults aged 18-60 years with chronic low back pain. Over 12 weeks, participants watched 10 short video modules, wore activity trackers, and participated in nurse consultations every 2 weeks. At baseline and the 12-week follow-up, they completed study questionnaires, quantitative sensory testing, and blood sample collection. RESULTS: Forty participants were recruited, and their mean age was 29.8. Thirty-two participants completed the survey questionnaire, quantitative sensory testing, Fitbit activity tracker, and bi-weekly nurse consultation, and 25 completed the evaluation of biological markers. The overall satisfaction with the Problem-Solving Pain to Enhance Living Well video modules, nurse consultations, and Fitbit in pain management was rated as excellent. No adverse events were reported. Between the baseline and 12-week follow-up, there was a significant decrease in pain intensity and interference and an increase in the warm detection threshold at the pain site. CONCLUSIONS: Despite concerns about the participant burden due to multidimensional assessment and intensive education, the feasibility of the Problem-Solving Pain to Enhance Living Well intervention was favorable. Technology-based self-management interventions can offer personalized strategies by integrating pain phenotypes, genetic markers, and physical activity types affecting pain conditions. TRIAL REGISTRATION: This pilot study was registered with ClinicalTrials.gov [NCT03637998, August 20, 2018]. The first participant was enrolled on September 21, 2018.

Tonic pain alters functional connectivity of the descending pain modulatory network involving amygdala, periaqueductal gray, parabrachial nucleus and anterior cingulate cortex.

INTRODUCTION: Resting state functional connectivity (FC) is widely used to assess functional brain alterations in patients with chronic pain. However, reports of FC accompanying tonic pain in pain-free persons are rare. A network we term the Descending Pain Modulatory Network (DPMN) is implicated in healthy and pathologic pain modulation. Here, we evaluate the effect of tonic pain on FC of specific nodes of this network: anterior cingulate cortex (ACC), amygdala (AMYG), periaqueductal gray (PAG), and parabrachial nuclei (PBN). METHODS: In 50 pain-free participants (30F), we induced tonic pain using a capsaicin-heat pain model. functional MRI measured resting BOLD signal during pain-free rest with a 32 °C thermode and then tonic pain where participants experienced a previously warm temperature combined with capsaicin. We evaluated FC from ACC, AMYG, PAG, and PBN with correlation of self-report pain intensity during both states. We hypothesized tonic pain would diminish FC dyads within the DPMN. RESULTS: Of all hypothesized FC dyads, only PAG and subgenual ACC was weakly altered during pain (F = 3.34; p = 0.074; pain-free>pain d = 0.25). After pain induction sACC-PAG FC became positively correlated with pain intensity (R = 0.38; t = 2.81; p = 0.007). Right PBN-PAG FC during pain-free rest positively correlated with subsequently experienced pain (R = 0.44; t = 3.43; p = 0.001). During pain, this connection's FC was diminished (paired t=-3.17; p = 0.0026). In whole-brain analyses, during pain-free rest, FC between left AMYG and right superior parietal lobule and caudate nucleus were positively correlated with subsequent pain. During pain, FC between left AMYG and right inferior temporal gyrus negatively correlated with pain. Subsequent pain positively correlated with right AMYG FC with right claustrum; right primary visual cortex and right temporo-occipitoparietal junction CONCLUSION: We demonstrate sACC-PAG tonic pain FC positively correlates with experienced pain and resting right PBN-PAG FC correlates with subsequent pain and is diminished during tonic pain. Finally, we reveal PAG- and right AMYG-anchored networks which correlate with subsequently experienced pain intensity. Our findings suggest specific connectivity patterns within the DPMN at rest are associated with subsequently experienced pain and modulated by tonic pain. These nodes and their functional modulation may reveal new therapeutic targets for neuromodulation or biomarkers to guide interventions.

Randomized Controlled Trial of a Cognitive Intervention to Improve Memory in Heart Failure.

BACKGROUND: The objective of this 3-arm randomized controlled trial was to evaluate the efficacy of computerized cognitive training (CCT) in improving primary outcomes of delayed-recall memory and serum brain-derived neurotrophic factor (BDNF) levels; and the secondary outcomes were working memory, instrumental activities of daily living (IADLs) and health-related quality of life (HRQL) in patients with heart failure (HF). METHODS AND RESULTS: Patients (n = 256) were randomly assigned to 8 weeks of CCT using BrainHQ, computerized crossword puzzles active control intervention, and usual care. All patients received weekly nurse-enhancement interventions. Data were collected at enrollment and baseline visits and at 10 weeks and 4 and 8 months. In mixed effects models, there were no statistically significant group or group-by-time differences in outcomes. There were statistically significant differences over time in all outcomes in all groups. Patients improved over time on measures of delayed-recall memory, working memory, IADLs, and HRQL and had decreased serum BDNF. CONCLUSIONS: CCT did not improve outcomes compared with the active control intervention and usual care. Nurse-enhancement interventions may have led to improved outcomes over time. Future studies are needed to test nurse-enhancement interventions in combination with other cognitive interventions to improve memory in persons with HF.

Exploring the relationship between DNA methylation age measures and psychoneurological symptoms in women with early-stage breast cancer.

PURPOSE: The epigenetic clock has been acknowledged as an indicator for molecular aging, but few studies have examined possible associations of DNA methylation (DNAm) age or age acceleration (AA) with symptom burden in individuals who are treated for cancer. This study explored the association of DNAm age or AA with psychoneurological (PN) symptoms, including cognitive impairment, fatigue, sleep disturbances, pain, and depressive symptoms, in breast cancer survivors over a 2-year period. METHODS: We measured PN symptoms using reliable instruments and DNAm levels by Infinium HumanMethylation450K BeadChip (N = 72). DNAm age was calculated by the Horvath, Grim, and Hannum-based intrinsic and extrinsic age estimations. AA was defined by the residual regressing estimated epigenetic age on chronological age. Mixed regression models were fitted for AA and changes in AA to study the association over time. Separate linear regression models and a mixed-effects model were fitted for AA at each time point. RESULTS: Horvath-AA, Grim-AA, and extrinsic epigenetic AA were significantly changed over time, while intrinsic epigenetic AA did not exhibit any temporal changes. Increased AA was associated with greater anxiety and fatigue, as well as worse cognitive memory, adjusting for race, BMI, income, chemotherapy, radiation therapy, and chronological age. Increased DNAm age was associated with greater anxiety over 2 years. CONCLUSION: Our findings suggest DNAm age and AA may be associated with PN symptoms over the course of cancer treatment and survivorship. Some PN symptoms may be amenable to preventive interventions targeted to epigenetic clocks that influence aging-associated processes.

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.

Exploratory Analysis of Associations Between Whole Blood Mitochondrial Gene Expression and Cancer-Related Fatigue Among Breast Cancer Survivors.

BACKGROUND: Cancer-related fatigue is a prevalent, debilitating, and persistent condition. Mitochondrial dysfunction is a putative contributor to cancer-related fatigue, but relationships between mitochondrial function and cancer-related fatigue are not well understood. OBJECTIVES: We investigated the relationships between mitochondrial DNA (mtDNA) gene expression and cancer-related fatigue, as well as the effects of fish and soybean oil supplementation on these relationships. METHODS: A secondary analysis was performed on data from a randomized controlled trial of breast cancer survivors 4-36 months posttreatment with moderate-severe cancer-related fatigue. Participants were randomized to take 6 g fish oil, 6 g soybean oil, or 3 g each daily for 6 weeks. At pre- and postintervention, participants completed the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire and provided whole blood for assessment of mtDNA gene expression. The expression of 12 protein-encoding genes was reduced to a single dimension using principal component analysis for use in regression analysis. Relationships between mtDNA expression and cancer-related fatigue were assessed using linear regression. RESULTS: Among 68 participants, cancer-related fatigue improved and expression of all mtDNA genes decreased over 6 weeks with no effect of treatment group on either outcome. Participants with lower baseline mtDNA gene expression had greater improvements in cancer-related fatigue. No significant associations were observed between mtDNA gene expression and cancer-related fatigue at baseline or changes in mtDNA gene expression and changes in cancer-related fatigue. DISCUSSION: Data from this exploratory study add to the growing literature that mitochondrial dysfunction may contribute to the etiology and pathophysiology of cancer-related fatigue.

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.

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.

Symptom cluster profiles following traumatic orthopedic injuries: A protocol.

Traumatic injuries affect millions of Americans annually, resulting in $671 billion in healthcare costs and lost productivity. Postinjury symptoms, like pain, sleep disturbance, anxiety, depression, and stressor-related disorders are highly prevalent following traumatic orthopedic injuries (TOI) and may contribute to negative long-term outcomes. Symptoms rarely present in isolation, but in clusters of two or more symptoms that co-occur to affect health in aggregate. Identifying symptom cluster profiles following TOI may identify those at highest risk for negative outcomes. Dysregulation of brain-derived neurotrophic factor (BDNF) is a potential biological mechanism responsible for symptom cluster profile membership after TOI and may be targeted in future precision-health applications. The purpose of this paper is to present the protocol of a cross-sectional study designed to identify symptom cluster profiles and measure the extent to which the BDNF val66met mutation and serum concentration of BDNF are associated with membership in symptom cluster profiles. We plan to recruit 150 TOI survivors within the first 72 h of injury. The study aims are to (1) describe TOI survivors' membership in symptom cluster profiles, indicated by pain, sleep disturbance, and symptoms of anxiety, depression, and stressor-related disorders, immediately following a TOI; (2) examine associations between demographic and clinical factors and symptom cluster profile membership among TOI survivors; (3) test the hypothesis that low serum concentrations of BDNF are associated with membership among symptom cluster profiles following TOI; and (4) test the hypothesis that the presence of the val66met mutation on one or both alleles of the BDNF gene is associated with membership among symptom cluster profiles following TOI.

An Integrative Review of Brain-Derived Neurotrophic Factor and Serious Cardiovascular Conditions.

BACKGROUND: There is emerging evidence that supports a role for brain-derived neurotrophic factor (BDNF) in the risk and presence of serious cardiovascular conditions. However, few existing literature reviews methodically describe empirical findings regarding this relationship. OBJECTIVES: The purpose of this integrative review was to (a) evaluate BDNF (serum/plasma BDNF levels, BDNF Val66Met genotype) among humans at risk for or with serious cardiovascular conditions and (b) investigate the relationship between BDNF and risk/presence of serious cardiovascular conditions in humans. METHODS: An integrative review was conducted. Articles in English included human subjects, a measure of BDNF levels or BDNF gene, serious cardiovascular conditions, and quantitative data analyses. The search resulted in 475 unique titles, with the final sample including 35 articles representing 30 studies. Articles that received "good" or "fair" ratings (n = 31) using the National Heart, Lung, and Blood Institute Study Quality Assessment Tools were included for synthesis. RESULTS: The retrieved articles were largely nonexperimental, with sample sizes ranging from 20 to 5,510 participants. Overall, BDNF levels were lower in patients with chronic heart failure and stroke, but higher in patients with unstable angina and recent myocardial infarction. Lower BDNF levels were associated with higher incidence of cardiovascular events in patients with a prior history of serious cardiovascular conditions and decreased cardiovascular risk in healthy samples. For BDNF genotype, on average, 36.3% of participants had Met alleles. The frequency of the BDNF Met allele varied across race/ethnicity and cardiovascular conditions and in terms of association with serious cardiovascular condition incidence/risk. DISCUSSION: These findings indicate an emerging area of science. Future investigation is needed on serious cardiovascular condition phenotypes in relationship to BDNF in the same study conditions. Results also suggest for use of standardized BDNF measurement across studies and additional investigation in cardiovascular inflammatory processes that affect BDNF. Moreover, within specific populations, the frequency of Met alleles may be too low to be detected in sample sizes normally found in these types of studies.

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.

Patients' and physicians' interpretation of chemotherapy-induced peripheral neurotoxicity.

To test if and how chemotherapy-induced peripheral neurotoxicity (CIPN) is perceived differently by patients and physicians, making assessment and interpretation challenging. We performed a secondary analysis of the CI-PeriNomS study which included 281 patients with stable CIPN. We tested: (a) the association between patients' perception of activity limitation in performing eight common tasks and neurological impairment and (b) how the responses to questions related to these daily activities are interpreted by the treating oncologist. To achieve this, we compared patients' perception of their activity limitation with neurological assessment and the oncologists' blind interpretation. Distribution of the scores attributed by oncologists to each daily life maximum limitation ("impossible") generated three groups: Group 1 included limitations oncologists attributed mainly to motor impairment; Group 2 ones mainly attributed to sensory impairment and Group 3 ones with uncertain motor and sensory impairment. Only a subset of questions showed a significant trend between severity in subjective limitation, reported by patients, and neurological impairment. In Group 1, neurological examination confirmed motor impairment in only 51%-65% of patients; 76%-78% of them also had vibration perception impairment. In Group 2, sensory impairment ranged from 84% to 100%; some degree of motor impairment occurred in 43%-56% of them. In Group 3 strength reduction was observed in 49%-50% and sensory perception was altered in up to 82%. Interpretation provided by the panel of experienced oncologists was inconsistent with the neurological impairment. These observations highlight the need of a core set of outcome measures for future CIPN trials.