Relationship Between Extreme Pain Phenotypes and Psychosocial Outcomes in Persons With Chronic Pain Following Traumatic Brain Injury: A NIDILRR and VA TBI Model Systems Collaborative Project.

OBJECTIVE: To examine the relationship between extreme pain phenotypes (interference and improvement) and psychosocial outcomes among those with chronic pain after traumatic brain injury (TBI). SETTING: Community. PARTICIPANTS: In total, 1762 TBI Model Systems (TBIMS) participants 1 to 30 years postinjury reporting chronic pain. DESIGN: Multisite, cross-sectional, observational cohort study. PRIMARY MEASURES: Life satisfaction, posttraumatic stress, depression and anxiety symptoms, sleep and participation, the Brief Pain Inventory (BPI) interference scale, and the Patient's Global Impression of Change (PGIC). RESULTS: Persons in the extreme high interference phenotype (vs extreme low interference phenotype) and/or extreme no change phenotype (vs extreme improvement phenotype) had poorer psychosocial outcomes, with extreme pain interference phenotypes having a larger effect on outcomes than extreme perceived improvement phenotypes. After controlling for covariates, large effect sizes (ES) related to pain interference were observed for posttraumatic stress symptoms (ES = -1.14), sleep quality (ES = -1.10), depression (ES = -1.08), anxiety (ES = -0.82), and life satisfaction (ES = 0.76); effect sizes for participation outcomes, although significant, were relatively small (ES = 0.21-0.36). Effect sizes related to perceived improvement were small for life satisfaction (ES = 0.20) and participation (ES = 0.16-0.21) outcomes. Pain intensity was identified as a meaningful confounding factor of the relationships between extreme phenotypes and posttraumatic stress, depression, anxiety, and sleep quality. CONCLUSIONS: Examination of extreme phenotypes provides important insights into the experience of individuals living with chronic pain and TBI. Results suggest that the relationships among a variety of characteristics of the person, their experience with pain, and treatment of pain are complex. Further research is needed to better understand these complex relationships and how differences in pain interference and perceived improvement from treatment can assist in assessment and treatment of chronic pain after TBI.

Cost-Effectiveness of Sleep Apnea Diagnosis and Treatment in Hospitalized Persons With Moderate to Severe Traumatic Brain Injury.

OBJECTIVE: To assess the cost-effectiveness of alternative approaches to diagnose and treat obstructive sleep apnea (OSA) in patients with traumatic brain injury (TBI) during inpatient rehabilitation. SETTING: Data collected during the Comparison of Sleep Apnea Assessment Strategies to Maximize TBI Rehabilitation Participation and Outcome (C-SAS) clinical trial (NCT03033901) on an inpatient rehabilitation TBI cohort were used in this study. STUDY DESIGN: Decision tree analysis was used to determine the cost-effectiveness of approaches to diagnosing and treating sleep apnea. Costs were determined using 2021 Centers for Medicare and Medicaid Services reimbursement codes. Effectiveness was defined in terms of the appropriateness of treatment. Costs averted were extracted from the literature. A sensitivity analysis was performed to account for uncertainty. Analyses were performed for all severity levels of OSA and a subgroup of those with moderate to severe OSA. Six inpatient approaches using various phases of screening, testing, and treatment that conform to usual care or guideline-endorsed interventions were evaluated: (1) usual care; (2) portable diagnostic testing followed by laboratory-quality testing; (3) screening with the snoring, tiredness, observed apnea, high BP, BMI, age, neck circumference, and male gender (STOP-Bang) questionnaire; (4) Multivariable Apnea Prediction Index (MAPI) followed by portable diagnostic testing and laboratory-quality testing; (5) laboratory-quality testing for all; and (6) treatment for all patients. MAIN MEASURES: Cost, Effectiveness, and Incremental Cost-Effectiveness Ratio (ICER). RESULTS: Phased approaches utilizing screening and diagnostic tools were more effective in diagnosing and allocating treatment for OSA than all alternatives in patients with mild to severe and moderate to severe OSA. Usual care was more costly and less effective than all other approaches for mild to severe and moderate to severe OSA. CONCLUSIONS: Diagnosing and treating OSA in patients with TBI is a cost-effective strategy when compared with usual care.

Characterizing Extreme Phenotypes for Pain Interference in Persons With Chronic Pain Following Traumatic Brain Injury: A NIDILRR and VA TBI Model Systems Collaborative Project.

OBJECTIVE: To define and characterize extreme phenotypes based on pain interference for persons with chronic pain following traumatic brain injury (TBI). SETTING: Eighteen Traumatic Brain Injury Model System (TBIMS) Centers. PARTICIPANTS: A total of 1762 TBIMS participants 1 to 30 years post-injury reporting chronic pain at their most recent follow-up interview. PRIMARY MEASURES: The Brief Pain Inventory (BPI) interference scale, sociodemographic, injury, functional outcome, pain, and treatment characteristics. RESULTS: Participants were predominantly male (73%), White (75%), middle-aged (mean 46 years), and who were injured in motor vehicle accidents (53%) or falls (20%). Extreme phenotypes were identified based on upper and lower 25th percentiles to create low-interference ( n = 441) and high-interference ( n = 431) extreme phenotypes. Bivariate comparisons found several sociodemographic, injury, function, pain, and treatment differences between extreme phenotype groups, including significant differences ( P < .001) on all measures of concurrent function with those in the low-interference extreme phenotype experiencing better function than those in the high-interference extreme phenotype. Lasso regression combined with logistic regression identified multivariable predictors of low- versus high-interference extreme phenotypes. Reductions in the odds of low- versus high-interference phenotypes were significantly associated with higher pain intensity (odds ratio [OR] = 0.33), having neuropathic pain (OR = 0.40), migraine headache (OR = 0.41), leg/feet pain (OR = 0.34), or hip pain (OR = 0.46), and more pain catastrophizing (OR = 0.81). CONCLUSION: Results suggest that for those who experience current chronic pain, there is high variability in the experience and impact of pain. Future research is needed to better understand how pain experience impacts individuals with chronic pain and TBI given that pain characteristics were the primary distinguishing factors between phenotypes. The use of extreme phenotypes for pain interference may be useful to better stratify samples to determine efficacy of pain treatment for individuals with TBI.

Characterizing Extreme Phenotypes for Perceived Improvement From Treatment in Persons With Chronic Pain Following Traumatic Brain Injury: A NIDILRR and VA TBI Model Systems Collaborative Project.

OBJECTIVE: To define and characterize extreme phenotypes based on perceived improvement in pain for persons with chronic pain following traumatic brain injury (TBI). SETTING: Eighteen Traumatic Brain Injury Model System (TBIMS) Centers. PARTICIPANTS: A total of 1762 TBIMS participants 1 to 30 years post-injury reporting chronic pain at their most recent follow-up interview. PRIMARY MEASURES: The Patient's Global Impression of Change (PGIC) related to pain treatment. Sociodemographic, injury, functional outcome, pain, and pain treatment characteristics. RESULTS: Participants were mostly male (73%), White (75%), middle-aged (mean 46 years), injured in motor vehicle accidents (53%), or falls (20%). Extreme phenotypes were created for an extreme improvement phenotype ( n = 512, 29.8%) defined as "moderately better" or above on the PGIC and an extreme no-change group ( n = 290, 16.9%) defined as no change or worse. Least absolute shrinkage and selection operator (LASSO) regression combined with logistic regression identified multivariable predictors of improvement versus no-change extreme phenotypes. Higher odds of extreme improvement phenotype were significantly associated with being female (odds ratio [OR] = 1.85), married versus single (OR = 2.02), better motor function (OR = 1.03), lower pain intensity (OR = 0.78), and less frequent pain, especially chest pain (OR = 0.36). Several pain treatments were associated with higher odds of being in the extreme improvement versus no-change phenotypes including pain medication (OR = 1.85), physical therapy (OR = 1.51), yoga (OR = 1.61), home exercise program (OR = 1.07), and massage (OR = 1.69). CONCLUSION: Investigation of extreme phenotypes based on perceived improvement with pain treatment highlights the ability to identify characteristics of individuals based on pain treatment responsiveness. A better understanding of the biopsychosocial characteristics of those who respond and do not respond to pain treatments received may help inform better surveillance, monitoring, and treatment. With further research, the identification of risk factors (such as pain intensity and frequency) for treatment response/nonresponse may provide indicators to prompt changes in care for individuals with chronic pain after TBI.

Stakeholder Engagement to Identify Implementation Strategies to Overcome Barriers to Delivering Chronic Pain Treatments: A NIDILRR and VA TBI Model Systems Collaborative Project.

OBJECTIVE: The purpose of this article is to illustrate the process of stakeholder-engaged intervention mapping approach to identify implementation strategies to overcome data-driven prioritized barriers to receiving chronic pain services for persons with traumatic brain injury (TBI). SETTING: Community. PARTICIPANTS: Healthcare providers (n = 63) with 2 or more years' experience treating persons with TBI, interviewed between October 2020 and November 2021 provided data for identification of barriers. TBI, chronic pain, and qualitative research subject matter experts (SMEs) participated in the mapping approach. DESIGN: Participatory-based research design, using descriptive and intervention mapping approaches. RESULTS: Four barriers to accessing chronic pain treatment by persons with TBI which emerged from provider interviews were prioritized for intervention mapping: cognitive deficits of patients (67%); patient comorbidities (63%); mental health and/or substance abuse issues (59%); and patient participation (62%). SMEs used prioritized barriers to develop 4 primary objectives and implementation strategies designed to: (1) engage consumers to validate and identify strategies; (2) tailor pain treatment and delivery to overcome barriers; (3) develop and disseminate guidelines and best practices when delivering care to persons with TBI to support spread; and (4) increase awareness, skills, and readiness of workforce to deliver pain treatment to persons with TBI. SMEs used an evidence-based approach to develop a mapping matrix of the prioritized barriers, implementation objectives, and aligned implementation strategies to impact change. CONCLUSION: Implementation science is needed to facilitate knowledge translation into practice for this complex population to overcome barriers to care. Implementation strategies to address barriers to accessing chronic pain care for individuals with TBI were chosen through a participatory approach to engaging SMEs to support these rehabilitation implementation efforts. Future work includes gathering input from individuals with TBI and chronic pain and to move the intervention (implementation) mapping matrix forward to inform future implementation research, policy, and practice.

The Interaction of Opiate Misuse and Marijuana Use on Behavioral Health Outcomes Using the Traumatic Brain Injury Model Systems Pain Collaborative Dataset.

OBJECTIVE: To determine if the interaction of opiate misuse and marijuana use frequency is associated with behavioral health outcomes. SETTING: Community. PARTICIPANTS: Three thousand seven hundred fifty participants enrolled in the Traumatic Brain Injury Model Systems who completed the Pain Survey and had complete opioid use and marijuana use information. DESIGN: Cross-sectional, secondary analysis from a multisite observational cohort. MAIN OUTCOME MEASURES: Clinically significant behavioral health symptoms for posttraumatic stress disorder (PTSD), depression, anxiety, and sleep quality. RESULTS: Three thousand five hundred thirty-five (94.3%) participants did not misuse opiates, 215 (5.7%) did misuse opiates (taking more opioid pain medication than prescribed and/or using nonprescription opioid pain medication); 2683 (70.5%) participants did not use marijuana, 353 (9.3%) occasionally used marijuana (less than once a week), and 714 (18.8%) regularly used marijuana (once a week or more frequently). There was a statistically significant relationship (P < .05) between the interaction of opiate misuse and marijuana use frequency and all behavioral health outcomes and several covariates (age, sex, cause of injury, severity of injury, and pain group category). Pairwise comparisons confirm that statistically significant associations on behavioral health outcomes are driven by endorsing opiate misuse and/or regular marijuana use, but occasional marijuana use was not associated. CONCLUSIONS: Higher odds of clinically significant PTSD, depression, anxiety, and poor sleep quality are present in people with traumatic brain injury (TBI) who misuse opiates and/or who use marijuana regularly. In the absence of opiate misuse, regular marijuana use had higher odds of worse behavioral health outcomes than occasional and no use. The interaction of opiate misuse and regular marijuana use yielded the highest odds. Individuals with TBI should be informed of the relationship of substance use and behavioral health outcomes and that current chronic pain may mediate the association.

Characterization and Treatment of Chronic Pain After Traumatic Brain Injury-Comparison of Characteristics Between Individuals With Current Pain, Past Pain, and No Pain: A NIDILRR and VA TBI Model Systems Collaborative Project.

OBJECTIVE: To estimate the prevalence of chronic pain after traumatic brain injury (TBI) and identify characteristics that differ from those without chronic pain. SETTING: Community. PARTICIPANTS: A total of 3804 TBI Model Systems (TBIMS) participants who completed the Pain Survey at TBIMS follow-up. DESIGN: A multisite, cross-sectional observational cohort study. MAIN OUTCOME MEASURES: Functional outcomes, pain experience, and treatment. RESULTS: 46% reported current chronic pain, 14% reported past (post-injury) chronic pain, and 40% reported no chronic pain. Bivariate differences in sociodemographic and injury characteristics between the 3 pain groups were generally small in effect size, reflecting little clinical difference. However, medium effect sizes were seen for all functional outcomes, such that individuals with current chronic pain had worse functional outcomes compared with individuals in the past pain or no pain groups. Treatment utilization rates were higher for individuals with current chronic pain compared with past pain, with medical treatments being most frequently utilized. Individuals with past pain perceived more improvement with treatment than did those with current chronic pain as represented by a large effect size. CONCLUSIONS: Chronic pain affects approximately 60% of those living with TBI. The implications of chronic pain for functional outcomes support inclusion of pain metrics in prognostic models and observational studies in this population. Future research is needed to proactively identify those at risk for the development of chronic pain and determine the efficacy and access to pain treatment.

Provider Perspectives of Facilitators and Barriers to Reaching and Utilizing Chronic Pain Healthcare for Persons With Traumatic Brain Injury: A Qualitative NIDILRR and VA TBI Model Systems Collaborative Project.

OBJECTIVE: To identify facilitators and barriers to reaching and utilizing chronic pain treatments for persons with traumatic brain injury (TBI) organized around an Access to Care framework, which includes dimensions of access to healthcare as a function of supply (ie, provider/system) and demand (ie, patient) factors for a specified patient population. SETTING: Community. PARTICIPANTS: Clinicians (n = 63) with experience treating persons with TBI were interviewed between October 2020 and November 2021. DESIGN: Descriptive, qualitative study. MAIN MEASURES: Semistructured open-ended interview of chronic pain management for persons with TBI. Informed by the Access to Care framework, responses were coded by and categorized within the core domains (reaching care, utilizing care) and relevant subdimensions from the supply (affordability of providing care, quality, coordination/continuity, adequacy) and demand (ability to pay, adherence, empowerment, caregiver support) perspective. RESULTS: Themes from provider interviews focused on healthcare reaching and healthcare utilization resulted in 19 facilitators and 9 barriers reaching saturation. The most themes fell under the utilization core domain, with themes identified that impact the technical and interpersonal quality of care and care coordination/continuity. Accessibility and availability of specialty care and use of interdisciplinary team that permitted matching patients to treatments were leading thematic facilitators. The leading thematic barrier identified primarily by medical providers was cognitive disability, which is likely directly linked with other leading barriers including high rates of noncompliance and poor follow-up in health care. Medical and behavioral health complexity was also a leading barrier to care and potentially interrelated to other themes identified. CONCLUSION: This is the first evidence-based study to inform policy and planning for this complex population to improve access to high-quality chronic pain treatment. Further research is needed to gain a better understanding of the perspectives of individuals with TBI/caregivers to inform interventions to improve access to chronic pain treatment for persons with TBI.

Provider Perceived Facilitators and Barriers to Identifying, Perceiving, and Seeking Healthcare for Chronic Pain After TBI: A Qualitative NIDILRR and VA TBI Model Systems Collaborative Project.

OBJECTIVE: Identify determinants to chronic pain healthcare for persons with traumatic brain injury (TBI) informed by an Access to Care Framework. Findings related to the Access Framework's core domains of identifying a need, perceptions of the need, and seeking healthcare are reported. SETTING: Community. PARTICIPANTS: Healthcare providers (n = 63) with 2 or more years of experience treating persons with TBI interviewed between October 2020 and November 2021. DESIGN: Descriptive, qualitative study. MAIN MEASURES: Semi-structured interviews with open-ended questions of chronic pain management for persons with TBI. Informed by the Access Framework, responses were coded by and categorized within the domains of identifying healthcare needs, perceptions of needs, and factors related to healthcare seeking from the supply and demand perspective. RESULTS: For the overall sample, 14 facilitators and 6 barriers were endorsed by more than 20% of the provider cohort. Top facilitators included on-site availability of needed resources and treatments (94%), adequate time and provider capability to ensure patient comprehension of diagnosis and treatment plans (83%), and establishing patient motivation and buy-in with the treatment plan (75%). Barriers most endorsed included policies impacting access (46%), wait times for services (41%), and patient uncertainty regarding telehealth commonly due to cognitive and physical challenges (37%). Unique determinants are reported across civilian versus Department of Veterans Affairs (VA) healthcare systems and different provider types. CONCLUSION: This is the first evidence-based study to inform policy and planning to improve access to high-quality chronic pain treatments for persons with TBI. Results will inform future interventions at the systems, patient, and policy levels of healthcare that can be tailored to healthcare settings (VA, Civilian) and types of providers (rehabilitation therapists, psychologists, and medical). Evidence-informed interventions may help minimize healthcare disparities experienced by persons with TBI and facilitate access to high-quality, evidence-informed chronic pain care.

Associations of Chronic Pain With Psychosocial Outcomes After Traumatic Brain Injury: A NIDILRR and VA TBI Model Systems Collaborative Project.

OBJECTIVE: To examine the differences in participation, life satisfaction, and psychosocial outcomes among individuals with traumatic brain injury (TBI) endorsing current, past, or no chronic pain. SETTING: Community. PARTICIPANTS: Three thousand eight hundred four TBI Model Systems participants 1 to 30 years of age postinjury classified into 1 of 3 groups based on their pain experience: current pain, past pain, no pain completed a Pain Survey at their usual follow-up appointment which on average was approximately 8 years postinjury. DESIGN: Multisite, cross-sectional observational cohort study. MAIN OUTCOME MEASURES: Sociodemographic and injury characteristics and psychosocial outcomes (ie, satisfaction with life, depression, anxiety, posttraumatic stress disorder [PTSD], sleep quality, community participation). RESULTS: Persons with current chronic pain demonstrated higher scores on measures of PTSD, anxiety, and depression, and the lower scores on measures of sleep quality, community participation and satisfaction with life. Those with resolved past pain had mean scores for these outcomes that were all between the current and no chronic pain groups, but always closest to the no pain group. After adjusting for sociodemographic and function in multivariate analysis, having current chronic pain was associated with more negative psychosocial outcomes. The largest effect sizes (ES; in absolute value) were observed for the PTSD, depression, anxiety, and sleep quality measures (ES = 0.52-0.81) when comparing current pain to past or no pain, smaller ES were observed for life satisfaction (ES = 0.22-0.37) and out and about participation (ES = 0.16-0.18). When comparing past and no pain groups, adjusted ES were generally small for life satisfaction, PTSD, depression, anxiety, and sleep quality (ES = 0.10-0.23) and minimal for participation outcomes (ES = 0.02-0.06). CONCLUSIONS: Chronic pain is prevalent among individuals with TBI and is associated with poorer psychosocial outcomes, especially for PTSD, depression, anxiety, and sleep disturbance. The results from this study highlight the presence of modifiable comorbidities among those with chronic pain and TBI. Persons who experience persistent pain following TBI may be at greater risk for worse psychosocial outcomes.

Coping With Chronic Pain After Traumatic Brain Injury: Role of Race/Ethnicity and Effect on Participation Outcomes in a TBI Model Systems Sample.

OBJECTIVE: To investigate catastrophizing and self-efficacy for managing pain among Non-Hispanic Whites, Non-Hispanic Blacks, and Hispanics with chronic pain after traumatic brain injury (TBI), and whether coping interacts with race/ethnicity to predict participation outcomes. SETTING: Community after discharge from inpatient rehabilitation. PARTICIPANTS: 621 individuals with moderate to severe TBI and chronic pain, who completed follow-up as part of a national longitudinal study of TBI and also participated in a collaborative study on chronic pain. DESIGN: Multicenter, cross-sectional, survey study. MAIN MEASURES: Catastrophizing subscale from the Coping With Pain Scale; Pain Self-Efficacy Questionnaire; Participation Assessment With Recombined Tools-Objective. RESULTS: After controlling for relevant sociodemographic variables, a significant interaction was observed between race/ethnicity and insurance status, such that Blacks who had public health insurance reported greater catastrophizing in response to pain compared with Whites. Race/ethnicity and self-efficacy for managing pain were unrelated. Greater catastrophizing was associated with lower participation but did not interact with race/ethnicity. Blacks reported lower participation relative to Whites, independent of catastrophizing. CONCLUSIONS: Black individuals who have TBI and chronic pain, and who have public insurance, may be vulnerable to difficulties managing pain. They are more likely to cope by catastrophizing, and catastrophizing is related to worse participation outcomes. The results suggest that access to care may affect response to chronic pain after TBI.

Disparities in Chronic Pain Experience and Treatment History Among Persons With Traumatic Brain Injury: A Traumatic Brain Injury Model Systems Study.

OBJECTIVE: To determine disparities in pain severity, pain interference, and history of pain treatment for non-Hispanic Whites, non-Hispanic Blacks, and Hispanics with traumatic brain injury (TBI) and chronic pain. SETTING: Community following discharge from inpatient rehabilitation. PARTICIPANTS: A total of 621 individuals with medically documented moderate to severe TBI who had received acute trauma care and inpatient rehabilitation (440 non-Hispanic Whites, 111 non-Hispanic Blacks, and 70 Hispanics). DESIGN: A multicenter, cross-sectional, survey study. MAIN MEASURES: Brief Pain Inventory; receipt of opioid prescription; receipt of nonpharmacologic pain treatments; and receipt of comprehensive interdisciplinary pain rehabilitation. RESULTS: After controlling for relevant sociodemographic variables, non-Hispanic Blacks reported greater pain severity and greater pain interference relative to non-Hispanic Whites. Race/ethnicity interacted with age, such that the differences between Whites and Blacks were greater for older participants (for severity and interference) and for those with less than a high school education (for interference). There were no differences found between the racial/ethnic groups in the odds of having ever received pain treatment. CONCLUSIONS: Among individuals with TBI who report chronic pain, non-Hispanic Blacks may be more vulnerable to difficulties managing pain severity and to interference of pain in activities and mood. Systemic biases experienced by many Black individuals with regard to social determinants of health must be considered in a holistic approach to assessing and treating chronic pain in individuals with TBI.

Examining the Relationship Between Sleep Apnea Diagnosis and Suicide Risk in Veterans With Traumatic Brain Injury: A VA TBI Model Systems Study.

OBJECTIVE: Obstructive sleep apnea (OSA) is a common sleep disorder in people with traumatic brain injury (TBI). Although sleep disturbances have been associated with an increased risk of suicide compared with the general population, the relationship between OSA and suicide risk after TBI is not well documented. In this study, we hypothesized that OSA diagnosis would predict suicide risk in veterans with TBI. SETTING: Five Veterans Affairs (VA) Polytrauma Rehabilitation Centers. PARTICIPANTS: Participants were drawn from the VA TBI Model Systems study, with follow-up interviews at year 1 ( n = 392), year 2 ( n = 444), year 5 ( n = 498), or year 10 ( n = 252) post-TBI (7.8%-14.5% follow-up attrition). DESIGN: This was a retrospective analysis from observational data using logistic regression with repeated measurements. Suicide ideation and suicide attempts were examined as outcomes at each follow-up to evaluate the relationship between OSA and suicide risk after adjusting for other risk factors determined a priori via literature review. MAIN MEASURES: Suicidal ideation (Patient Health Questionnaire-9 item 9), suicide attempt during the past year (self-reported), and OSA diagnosis (self-reported). RESULTS: Contrary to study hypotheses, OSA diagnosis had no statistically significant association with suicide ideation or attempt after accounting for known predictors. However, greater depression symptoms, headache severity, and pre-TBI suicidal ideation and attempts predicted suicide risk at follow-up after accounting for other predictors. CONCLUSIONS: Results of this study did not support a relationship between OSA and suicide risk, possibly due to methodological limitations of OSA measurement. Future research on this topic should include objective measures of OSA severity and OSA treatment including adherence. Although suicide is a low base rate occurrence, the impact is disastrous and further research is needed to mitigate suicide risk.

Acupuncture use for pain after traumatic brain injury: a NIDILRR Traumatic Brain Injury Model Systems cohort study.

BACKGROUND: Pain after traumatic brain injury (TBI) is common and can become chronic. Acupuncture is an increasingly popular non-pharmacologic option in the United States and is commonly used for pain. OBJECTIVE: We explored demographics, injury characteristics, and pain characteristics of individuals who reported using acupuncture for chronic pain after TBI. METHODS: We analyzed a subset of data collected as part of the Pain After Traumatic Brain Injury collaborative study and identified individuals reporting a history of acupuncture as part of management for chronic pain after TBI. We characterized and compared basic demographic data, pain treatment engagements, pain severity, pain interference, functional independence, and pain locations using descriptive and inferential statistics. RESULTS: Our sample included 1,064 individuals. Acupuncture use (n = 208) was lower proportionally among females, Blacks/African Americans, Asians, less educated, and nonmilitary service members. Insurance type varied between acupuncture and non-acupuncture users. Functional and pain outcomes were similar, but acupuncture users reported a higher number of pain sites. DISCUSSION: Acupuncture is one treatment utilized by individuals with TBI and chronic pain. Further investigation would be helpful to understand the barriers and facilitators of acupuncture use to inform clinical trials to examine the potential benefit of acupuncture on pain outcomes after TBI.

HLA-A*02:01-directed chimeric antigen receptor/forkhead box P3-engineered CD4+ T cells adopt a regulatory phenotype and suppress established graft-versus-host disease.

BACKGROUND AIMS: To investigate the feasibility of using CD4 + T cells genetically modified to express an allo-HLA directed CAR and FOXP3 to suppress T cell proliferation and cytokine secretion in GvHD. METHODS: Human CD4+ T cells from A*02:01 negative donors were transduced to express A*02 CAR and FOXP3 and co-cultured in mixed lymphocyte reaction assays to demonstrate T cell suppression. A*02- CAR/FOXP CD4+ T cells were then injected into mice engrafted with allogeneic T cells in a GvHD mouse model. RESULTS: CD4+ T cells genetically modified to express allo-HLA-directed CAR and FOXP3 proliferate rapidly, downregulate CD127 and interferon-γ, express high CD25 and Helios and convert to a stable antigen-dependent suppressive phenotype. In mixed lymphocyte reaction assays, these cells potently suppressed T-cell proliferation and secreted IL-10. In a graft-versus-host disease model, A*02-CAR/FOXP3 CD4+ T cells outperformed polyclonal Tregs by reducing liver and lung inflammation, inhibiting pro-inflammatory cytokine production and limiting grafted CD3+ T-cell expansion. CONCLUSIONS: CD4 + T cells expressing allo-antigen directed HLA-specific CAR and FOXP3 act as potent, specific and stable suppressors of inflammation that out-perform their Treg counterparts both in vitro and in vivo.

The Impact of Opioid Medications on Sleep Architecture and Nocturnal Respiration During Acute Recovery From Moderate to Severe Traumatic Brain Injury: A TBI Model Systems Study.

OBJECTIVES: To describe patient and clinical characteristics associated with receipt of opioid medications and identify differences in sleep quality, architecture, and sleep-related respiration between those receiving and not receiving opioid medications. SETTING: Acute inpatient rehabilitation care for moderate to severe traumatic brain injury (TBI). PARTICIPANTS: A total of 248 consecutive admissions for inpatient rehabilitation care following moderate to severe TBI (average age of 43.6 years), who underwent level 1 polysomnography (PSG) (average time since injury: 120 days) across 6 sites. DESIGN: Cross-sectional, secondary analyses. MAIN MEASURES: The PSG sleep parameters included total sleep time (TST), sleep efficiency (SE), wake after sleep onset, rapid eye movement (REM) latency, sleep staging, and arousal and awakening indices. Respiratory measures included oxygen saturation, central apnea events per hour, obstructive apnea and hypopnea events per hour, and total apnea-hypopnea index. RESULTS: After adjustment for number of prescribed medication classes, those receiving opioid medications on the day of PSG experienced increased TST relative to those not receiving opioid medications (estimated mean difference [EMD] = 31.58; 95% confidence interval [CI], 1.9-61.3). Other indices of sleep did not differ significantly between groups. Among respiratory measures those receiving opioids on the day of PSG experienced increased frequency of central sleep apnea events during total (EMD = 2.92; 95% CI, 0.8-5.0) and non-REM sleep (EMD = 3.37; 95% CI, 1.0-5.7) and higher frequency of obstructive sleep apnea events during REM sleep (EMD = 6.97; 95% CI, 0.1-13.8). Compared with those who did not, receiving opioids was associated with lower oxygen saturation nadir during total sleep (EMD = -3.03; 95% CI, -5.6 to -0.4) and a greater number of oxygen desaturations across REM (EMD = 8.15; 95% CI, 0.2-16.1), non-REM (EMD = 7.30; 95% CI, 0.3-14.4), and total sleep (EMD = 8.01; 95% CI, 0.8-15.2) Greater total apnea-hypopnea index was observed during REM (EMD = 8.13; 95% CI, 0.8-15.5) and total sleep (EMD = 7.26; 95% CI, 0.08-14.4) for those receiving opioids. CONCLUSION: Opioid use following moderate to severe TBI is associated with an increase in indicators of sleep-related breathing disorders, a modifiable condition that is prevalent following TBI. As sleep-wake disorders are associated with poorer rehabilitation outcomes and opioid medications may frequently be administered following traumatic injury, additional longitudinal investigations are warranted in determining whether a causal relation between opioids and sleep-disordered breathing in those following moderate to severe TBI exists. Given current study limitations, future studies can improve upon methodology through the inclusion of indication for and dosage of opioid medications in this population when examining these associations.

Whole Health Options and Pain Education (wHOPE): A Pragmatic Trial Comparing Whole Health Team vs Primary Care Group Education to Promote Nonpharmacological Strategies to Improve Pain, Functioning, and Quality of Life in Veterans-Rationale, Methods, and Implementation.

BACKGROUND: The Whole Health model of the U.S. Department of Veterans Affairs (VA) emphasizes holistic self-care and multimodal approaches to improve pain, functioning, and quality of life. wHOPE (Whole Health Options and Pain Education) seeks to be the first multisite pragmatic trial to establish evidence for the VA Whole Health model for chronic pain care. DESIGN: wHOPE is a pragmatic randomized controlled trial comparing a Whole Health Team (WHT) approach to Primary Care Group Education (PC-GE); both will be compared to Usual VA Primary Care (UPC). The WHT consists of a medical provider, a complementary and integrative health (CIH) provider, and a Whole Health coach, who collaborate with VA patients to create a Personalized Health Plan emphasizing CIH approaches to chronic pain management. The active comparator, PC-GE, is adapted group cognitive behavioral therapy for chronic pain. The first aim is to test whether the WHT approach is superior to PC-GE and whether both are superior to UPC in decreasing pain interference in functioning in 750 veterans with moderate to severe chronic pain (primary outcome). Secondary outcomes include changes in pain severity, quality of life, mental health symptoms, and use of nonpharmacological and pharmacological therapies for pain. Outcomes will be collected from the VA electronic health record and patient-reported data over 12 months of follow-up. Aim 2 consists of an implementation-focused process evaluation and budget impact analysis. SUMMARY: This trial is part of the Pain Management Collaboratory, which seeks to create national-level infrastructure to support evidence-based nonpharmacological pain management approaches for veterans and military service personnel.

Early pH Changes in Musculoskeletal Tissues upon Injury-Aerobic Catabolic Pathway Activity Linked to Inter-Individual Differences in Local pH.

Local pH is stated to acidify after bone fracture. However, the time course and degree of acidification remain unknown. Whether the acidification pattern within a fracture hematoma is applicable to adjacent muscle hematoma or is exclusive to this regenerative tissue has not been studied to date. Thus, in this study, we aimed to unravel the extent and pattern of acidification in vivo during the early phase post musculoskeletal injury. Local pH changes after fracture and muscle trauma were measured simultaneously in two pre-clinical animal models (sheep/rats) immediately after and up to 48 h post injury. The rat fracture hematoma was further analyzed histologically and metabolomically. In vivo pH measurements in bone and muscle hematoma revealed a local acidification in both animal models, yielding mean pH values in rats of 6.69 and 6.89, with pronounced intra- and inter-individual differences. The metabolomic analysis of the hematomas indicated a link between reduction in tricarboxylic acid cycle activity and pH, thus, metabolic activity within the injured tissues could be causative for the different pH values. The significant acidification within the early musculoskeletal hematoma could enable the employment of the pH for novel, sought-after treatments that allow for spatially and temporally controlled drug release.

Cervical Spinal Cord Stimulator Lead Migration and Transection Adjacent to the Foramen Magnum: A Case Report.

BACKGROUND: Spinal cord stimulation (SCS) is a relatively safe therapy for the treatment of pain but has the potential for several complications, including lead migration and breakage. While instances of lead breakage and electrode shearing have been described, there are no reported cases of stimulator lead transection and migration to the foramen magnum. AIMS: We describe the case of a 53-year-old woman who reported that her cervical spinal cord stimulator was no longer functioning after a traumatic fall. CASE: Fluoroscopy of the neck revealed that one of the MRI conditional leads had migrated cephalad, and the distal aspect appeared to be transected. This was confirmed by computerized tomography, which showed a transected portion of the lead in the epidural space, just inferior to the posterior aspect of the foramen magnum. An SCS device revision was performed to replace the lead, but the distal transected tip was left in place in the epidural space adjacent to the foramen magnum to avoid complications of retrieval. DISCUSSION/CONCLUSION: Given the location of the transected portion of the lead, we recommended avoiding MRI imaging. In addition, we advised the patient that a repeat x-ray may be necessary if she has increased neck pain or any other concerning symptoms. In this report, we discuss the known complications with SCS, as well as management of a retained lead fragment.

Short PlGF-derived peptides bind VEGFR-1 and VEGFR-2 in vitro and on the surface of endothelial cells.

The placental growth factor (PlGF), a member of VEGF family, plays a crucial role in pathological angiogenesis, especially ischemia, inflammation, and cancer. This activity is mediated by its selective binding to VEGF receptor 1 (VEGFR-1), which occurs predominantly through receptor domains 2 and 3. The PlGF ß-hairpin region spanning residues Q87 to V100 is one of the key binding elements on the protein side. We have undertaken a study on the design, preparation, and functional characterization of the peptide reproducing this region and of a set of analogues where glycine 94, occurring at the corner of the hairpin in the native protein, is replaced by charged as well as hydrophobic residues. Also, some peptides with arginine 96 replaced by other residues have been studied. We find that the parent peptide weakly binds VEGFR-1, but replacement of G94 with residues bearing H-bond donating residues significantly improves the affinity. Replacement of R96 instead blocks the interaction between the peptide and the domain. The strongest affinity is observed with the G94H (peptide PlGF-2) and G94W (peptide PlGF-10) mutants, while the peptide PlGF-8, bearing the R96G mutation, is totally inactive. The PlGF-1 and PlGF-2 peptides also bind the VEGFR-2 receptors, though with a reduced affinity, and are able to interfere with the VEGF-induced receptor signaling on endothelial cells. The peptides also bind VEGFR-2 on the surface of cells, while PlGF-8 is inactive. Data suggest that these peptides have potential applications as PlGF/VEGF mimic in various experimental settings.