Jacob C. Ulirsch

Incidence and predictors of neck and widespread pain after motor vehicle collision among US litigants and nonlitigants

Summary Most individuals with pain sequelae 6 weeks after motor vehicle collision are not engaged in litigation. Evidence supports bidirectional effects between litigation and post–motor vehicle collision musculoskeletal pain outcomes. ABSTRACT Debate continues regarding the influence of litigation on pain outcomes after motor vehicle collision (MVC). In this study we enrolled European Americans presenting to the emergency department (ED) in the hours after MVC (n = 948). Six weeks later, participants were interviewed regarding pain symptoms and asked about their participation in MVC‐related litigation. The incidence and predictors of neck pain and widespread pain 6 weeks after MVC were compared among those engaged in litigation (litigants) and those not engaged in litigation (nonlitigants). Among the 859 of 948 (91%) participants completing 6‐week follow‐up, 711 of 849 (83%) were nonlitigants. Compared to nonlitigants, litigants were less educated and had more severe neck pain and overall pain, and a greater extent of pain at the time of ED evaluation. Among individuals not engaged in litigation, persistent pain 6 weeks after MVC was common: 199 of 711 (28%) had moderate or severe neck pain, 92 of 711 (13%) had widespread pain, and 29 of 711 (4%) had fibromyalgia‐like symptoms. Incidence of all 3 outcomes was significantly higher among litigants. Initial pain severity in the ED predicted pain outcomes among both litigants and nonlitigants. Markers of socioeconomic disadvantage predicted worse pain outcomes in litigants but not nonlitigants, and individual pain and psychological symptoms were less predictive of pain outcomes among those engaged in litigation. These data demonstrate that persistent pain after MVC is common among those not engaged in litigation, and provide evidence for bidirectional influences between pain outcomes and litigation after MVC.

Polymorphisms in the glucocorticoid receptor co-chaperone FKBP5 predict persistent musculoskeletal pain after traumatic stress exposure.

&NA; An association is demonstrated between genetic polymorphisms in the gene coding for a key regulatory molecule in the hypothalamic‐pituitary‐adrenal axis and persistent pain after trauma. &NA; Individual vulnerability factors influencing the function of the hypothalamic‐pituitary‐adrenal axis may contribute to the risk of the development of persistent musculoskeletal pain after traumatic stress exposure. The objective of the study was to evaluate the association between polymorphisms in the gene encoding FK506 binding protein 51, FKBP5, a glucocorticoid receptor co‐chaperone, and musculoskeletal pain severity 6 weeks after 2 common trauma exposures. The study included data from 2 prospective emergency department‐based cohorts: a discovery cohort (n = 949) of European Americans experiencing motor vehicle collision and a replication cohort of adult European American women experiencing sexual assault (n = 53). DNA was collected from trauma survivors at the time of initial assessment. Overall pain and neck pain 6 weeks after trauma exposure were assessed using a 0–10 numeric rating scale. After adjustment for multiple comparisons, 6 FKBP5 polymorphisms showed significant association (minimum P < 0.0001) with both overall and neck pain in the discovery cohort. The association of rs3800373, rs9380526, rs9394314, rs2817032, and rs2817040 with neck pain and/or overall pain 6 weeks after trauma was replicated in the sexual assault cohort, showing the same direction of the effect in each case. The results of this study indicate that genetic variants in FKBP5 influence the severity of musculoskeletal pain symptoms experienced during the weeks after motor vehicle collision and sexual assault. These results suggest that glucocorticoid pathways influence the development of persistent posttraumatic pain, and that such pathways may be a target of pharmacologic interventions aimed at improving recovery after trauma.

Vimentin DNA methylation predicts survival in breast cancer

The Vimentin gene plays a pivotal role in epithelial-to-mesenchymal transition and is known to be overexpressed in the prognostically poor basal-like breast cancer subtype. Recent studies have reported Vimentin DNA methylation in association with poor clinical outcomes in other solid tumors, but not in breast cancer. We therefore quantified Vimentin DNA methylation using MALDI-TOF mass spectrometry in breast tumors and matched normal pairs in association with gene expression and survival in a hospital-based study of breast cancer patients. Gene expression data via qRT-PCR in cell lines and oligomicroarray data from breast tissues were correlated with percent methylation in the Vimentin promoter. A threshold of 20 percent average methylation compared with matched normal pairs was set for bivariate and multivariate tests of association between methylation and tumor subtype, tumor histopathology, and survival. Vimentin was differentially methylated in luminal breast cancer cell lines, and in luminal A, luminal B, and HER2-enriched breast tumor subtypes, but was rare in basal-like cell lines and tumors. Increased methylation was strongly correlated with decreased mRNA expression in cell lines, and had a moderate inverse correlation in breast tumors. Vimentin methylation predicted poor overall survival independent of race, subtype, stage, nodal status, or metastatic disease and holds promise as a new prognostic biomarker for breast cancer patients.

Pain and somatic symptoms are sequelae of sexual assault: results of a prospective longitudinal study.

Cross‐sectional studies have shown that chronic musculoskeletal pain and somatic symptoms are frequently reported by sexual assault (SA) survivors; however, prospective studies examining pain and somatic symptoms in the months after SA have not been performed.

No man is an island: living in a disadvantaged neighborhood influences chronic pain development after motor vehicle collision.

&NA; Pain recovery after trauma is influenced by neighborhood socioeconomic characteristics. These findings are independent of individual characteristics, and moderated by genetic variation in FKBP5. &NA; Living in a lower socioeconomic status neighborhood has been shown to alter stress system function and is associated with a number of adverse health outcomes, but its influence on musculoskeletal pain (MSP) outcomes after traumatic stress exposures such as motor vehicle collision (MVC) has not been assessed. We performed a multicenter, prospective study that enrolled 948 European‐American individuals within 24 hours of MVC who were discharged home after emergency department evaluation. Follow‐up evaluations were completed via telephone or Internet survey 6 weeks, 6 months, and 1 year after MVC on 91%, 89%, and 91% of participants, respectively. A robust aggregate measure of census tract neighborhood disadvantage was derived, and individual‐level characteristics assessed included socioeconomic and demographic characteristics, pain prior to MVC, litigation status, and opioid use. MSP was assessed in the emergency department; MSP and pain interference with daily activity were assessed at 6 weeks, 6 months, and 1 year. After adjustment for individual‐level factors, living in more disadvantaged neighborhoods was associated with increased MSP (P = 0.0009) and increased pain interference with daily function (P < 0.0001). The relationship between neighborhood disadvantage and MSP was moderated by a common single nucleotide polymorphism, rs2817038, 5′ of the gene encoding FKBP5, a functional regulator of glucocorticoid receptor sensitivity (interaction P‐value = 0.0015). These data support the hypothesis that low neighborhood socioeconomic status increases the likelihood of worse MSP outcomes after traumatic stress exposures such as MVC, and that this influence is mediated in part via its influence on stress system function.

Association of Epidemiologic Factors and Genetic Variants Influencing Hypothalamic-Pituitary-Adrenocortical Axis Function With Postconcussive Symptoms After Minor Motor Vehicle Collision

Objectives To determine the influence of epidemiologic factors and the influence of genetic variants affecting FKBP5, a protein known to modulate hypothalamic-pituitary-adrenocortical axis function, on the severity of somatic symptoms commonly termed “postconcussive” 6 and 12 months after motor vehicle collision (MVC). Methods European Americans 18 to 65 years of age who presented to one of eight emergency departments (EDs) after MVC were enrolled. Exclusion criteria included hospital admission. Blood samples were collected in the ED for genotyping. Participants completed evaluations including an adapted Rivermead Post-Concussive Symptoms Questionnaire in the ED and at 6 weeks, 6 months, and 1 year. Repeated-measures analysis of covariance was used to evaluate the association between epidemiologic factors (sociodemographic, pre-MVC health, collision characteristics, head injury, peritraumatic pain, and stress), FKBP5 genetic variants, and postconcussive symptom severity. Results Among 943 patients recruited in the ED, follow-up was completed on 835 (88%) at 6 months and 857 (90%) at 1 year. Self-reported head impact during collision was not associated with chronic postconcussive symptom severity. After correction for multiple testing, three FKBP5 single-nucleotide polymorphisms (rs3800373, rs7753746, and rs9380526) predicted chronic postconcussive symptom severity, with an average symptom severity of 1.10 (95% confidence interval = 0.96–1.24), 1.36 (1.21–1.51), and 1.55 (1.23–1.88) for one, two, or three copies of minor allele at rs3800373 (p = .001). Similar effect sizes were observed for the minor alleles of rs7753746 and rs9380526. Conclusions Postconcussive symptoms after minor MVC are not generally related to the severity of mild brain injury. This study shows that neurobiologic stress systems may play a role in the pathogenesis of postconcussive symptoms.