Derivation and validation of risk prediction for posttraumatic stress symptoms following trauma exposure.

BACKGROUND: Posttraumatic stress symptoms (PTSS) are common following traumatic stress exposure (TSE). Identification of individuals with PTSS risk in the early aftermath of TSE is important to enable targeted administration of preventive interventions. In this study, we used baseline survey data from two prospective cohort studies to identify the most influential predictors of substantial PTSS. METHODS: Self-identifying black and white American women and men (n = 1546) presenting to one of 16 emergency departments (EDs) within 24 h of motor vehicle collision (MVC) TSE were enrolled. Individuals with substantial PTSS (⩾33, Impact of Events Scale - Revised) 6 months after MVC were identified via follow-up questionnaire. Sociodemographic, pain, general health, event, and psychological/cognitive characteristics were collected in the ED and used in prediction modeling. Ensemble learning methods and Monte Carlo cross-validation were used for feature selection and to determine prediction accuracy. External validation was performed on a hold-out sample (30% of total sample). RESULTS: Twenty-five percent (n = 394) of individuals reported PTSS 6 months following MVC. Regularized linear regression was the top performing learning method. The top 30 factors together showed good reliability in predicting PTSS in the external sample (Area under the curve = 0.79 ± 0.002). Top predictors included acute pain severity, recovery expectations, socioeconomic status, self-reported race, and psychological symptoms. CONCLUSIONS: These analyses add to a growing literature indicating that influential predictors of PTSS can be identified and risk for future PTSS estimated from characteristics easily available/assessable at the time of ED presentation following TSE.

Cardiac-Specific Overexpression of ERRγ in Mice Induces Severe Heart Dysfunction and Early Lethality.

Proper cardiac function depends on the coordinated expression of multiple gene networks related to fuel utilization and mitochondrial ATP production, heart contraction, and ion transport. Key transcriptional regulators that regulate these gene networks have been identified. Among them, estrogen-related receptors (ERRs) have emerged as crucial modulators of cardiac function by regulating cellular metabolism and contraction machinery. Consistent with this role, lack of ERRα or ERRγ results in cardiac derangements that lead to functional maladaptation in response to increased workload. Interestingly, metabolic inflexibility associated with diabetic cardiomyopathy has been recently associated with increased mitochondrial fatty acid oxidation and expression of ERRγ, suggesting that sustained expression of this nuclear receptor could result in a cardiac pathogenic outcome. Here, we describe the generation of mice with cardiac-specific overexpression of ERRγ, which die at young ages due to heart failure. ERRγ transgenic mice show signs of dilated cardiomyopathy associated with cardiomyocyte hypertrophy, increased cell death, and fibrosis. Our results suggest that ERRγ could play a role in mediating cardiac pathogenic responses.

Genes known to escape X chromosome inactivation predict co-morbid chronic musculoskeletal pain and posttraumatic stress symptom development in women following trauma exposure.

Co-morbid chronic musculoskeletal pain (CMSP) and posttraumatic stress symptoms (PTSS) are frequent sequelae of motor vehicle collision, are associated with greater disability than either outcome alone, and are more prevalent in women than men. In the current study we assessed for evidence that gene transcripts originating from the X chromosome contribute to sex differences in vulnerability to CMSP and PTSS after motor vehicle collision. Nested samples were drawn from a longitudinal study of African American individuals, and CMSP (0-10 numeric rating scale) and PTSS (impact of events scale, revised) outcomes were assessed 6 months following motor vehicle collision. Blood RNA were sequenced (n = 101) and the relationship between X chromosome mRNA expression levels and co-morbid CMSP and PTSS outcomes was evaluated using logistic regression analyses. A disproportionate number of peritraumatic X chromosome mRNA predicting CMSP and PTSS in women were genes previously found to escape X chromosome inactivation (11/40, z = -2.9, p = .004). Secondary analyses assessing gene ontology relationships between these genes identified an enrichment in genes known to influence neuronal plasticity. Further, the relationship of expression of two critical regulators of X chromosome inactivation, X-inactive specific transcript (XIST) and Yin Yang 1 (YY1), was different in women developing CMSP and PTSS. Together, these data suggest that X chromosome genes that escape inactivation may contribute to sex differences in vulnerability to CMSP and PTSS after motor vehicle collision.

MicroRNA circulating in the early aftermath of motor vehicle collision predict persistent pain development and suggest a role for microRNA in sex-specific pain differences.

BACKGROUND: Molecular mediators influencing the transition from acute to persistent musculoskeletal pain following common stress exposures such as motor vehicle collision (MVC) remain poorly understood. In this exploratory, proof of concept study, we compared circulating microRNA (miRNA) expression profiles in the early aftermath of MVC among individuals who did and did not subsequently develop persistent pain. Blood RNA samples were obtained from African American individuals (n = 53) who presented to the emergency department after MVC and were discharged to home after evaluation. The presence or absence of severe pain in the axial region, the most common and morbid region in which post-MVC pain occurs, was assessed 6 weeks following MVC via standardized questionnaire. miRNA expression was determined using miRNA-sequencing; nonparametric analyses were used to compare miRNA expression levels among individuals with and without persistent pain. RESULTS: Thirty-two mature miRNA were differentially expressed (p < 0.05) in those with and without severe axial pain at 6 weeks. miR-135a-5p, a regulator of the serotonin receptor that is known to be stress-responsive, differed most significantly between groups (p = 3 × 10(-4)). This miRNA, and miR-3613-3p (p = 0.001) survived correction for multiple testing (FDR = 0.15) in this small sample. Interestingly, differentially expressed miRNA were enriched for X chromosome location. In secondary analyses, the eight X chromosome miRNA were (a) more significantly associated with axial pain in women than men, (b) expressed more highly in the peripheral blood of women than men, and (c) predicted in pathway analyses (DIANA miRPath v 2.0) to regulate neuronal and neuroendocrine pathways previously implicated in various pain pathologies. CONCLUSIONS: These results show that circulating miRNA predict persistent severe axial pain after MVC and suggest that they may be involved in the pathogenesis of post-traumatic musculoskeletal pain. However, further studies are needed to determine if these miRNA play a direct causal role.

A novel simulation model for tube thoracostomy.

Objective: Tube thoracostomy is a life-saving procedure that must be performed competently and expeditiously by emergency care providers. The primary objective of this project was to develop a simple, easily-reproducible, and realistic simulation model for tube thoracostomy placement by learners of emergency medicine. Methods: This chest tube simulator utilizes two slabs of pork ribs with associated intercostal muscle and fascial planes to aid learners in identifying anatomic landmarks, palpating intercostal spaces, and performing blunt dissection in a manner that approximates human anatomy. Holes are cut on both sides of a 1.8-bushel capacity rectangular plastic clothing hamper, and rib slabs are secured to the hamper with zip ties or metal wire. A bed pillow with plastic cover is then placed inside of the plastic hamper to simulate lung tissue. The rib-hamper complex is then wrapped with cellophane or elastic compression bandages to further anchor the rib slabs and simulate skin and subcutaneous tissues. Results: The initial cost of our thoracostomy model is approximately $50, much less than the $1,000-$3,000 cost for a commercial model. Although the hamper and pillow can be reused an indefinite number of times, the other components of our model must be replaced occasionally. Assuming a lifespan of 1,000 uses, our model costs approximately $1.78 per attempt, compared to $4.00 per attempt with the cheapest commercial mannequin system. In fact, assuming a longer useful lifespan for the mannequin does not substantially improve this comparison (e.g. $3.10 versus $1.77 per attempt for a 10,000 attempt lifespan for the commercial mannequin), largely due to the higher cost of commercial replacement skin pads when compared to the components consumed in our model with each attempt. Conclusions: We describe a porcine thoracostomy model that simulates the look and feel of human ribs for purposes of tube thoracostomy training, although it could also be used for thoracentesis and thoracotomy simulation. This model is relatively cheap (costing around $50) and easy to produce within a few minutes utilizing commonly-available materials. Further study is needed to determine whether an inexpensive model like ours provides the same educational value as more expensive commercial mannequin models.

CpG Methylation Levels in HPA Axis Genes Predict Chronic Pain Outcomes Following Trauma Exposure.

Chronic post-traumatic musculoskeletal pain (CPTP) is a common outcome of traumatic stress exposure. Biological factors that influence the development of CPTP are poorly understood, though current evidence indicates that the hypothalamic-pituitary-adrenal (HPA) axis plays a critical role in its development. Little is known about molecular mechanisms underlying this association, including epigenetic mechanisms. Here, we assessed whether peritraumatic DNA methylation levels at 248 5'-C-phosphate-G-3' (CpG) sites in HPA axis genes (FKBP5, NR3C1, CRH, CRHR1, CRHR2, CRHBP, POMC) predict CPTP and whether identified CPTP-associated methylation levels influence expression of those genes. Using participant samples and data collected from trauma survivors enrolled into longitudinal cohort studies (n = 290), we used linear mixed modeling to assess the relationship between peritraumatic blood-based CpG methylation levels and CPTP. A total of 66 (27%) of the 248 CpG sites assessed in these models statistically significantly predicted CPTP, with the three most significantly associated CpG sites originating from the POMC gene region (ie, cg22900229 [ß = .124, P < .001], cg16302441 [ß = .443, P < .001], cg01926269 [ß = .130, P < .001]). Among the genes analyzed, both POMC (z = 2.36, P = .018) and CRHBP (z = 4.89, P < .001) were enriched in CpG sites significantly associated with CPTP. Further, POMC expression was inversely correlated with methylation levels in a CPTP-dependent manner (6-months NRS<4: r = -.59, P < .001; 6-months NRS ≥ 4: r = -.18, P = .2312). Our results suggest that methylation of HPA axis genes including POMC and CRHBP predict risk for and may contribute to vulnerability to CPTP. PERSPECTIVE: Peritraumatic blood levels of CpG methylation sites in HPA axis genes, particularly CpG sites in the POMC gene, predict CPTP development. This data substantially advances our understanding of epigenetic predictors and potential mediators of CPTP, a highly common, morbid, and hard-to-treat form of chronic pain.

Calorie Restriction and SIRT1 Overexpression Induce Different Gene Expression Profiles in White Adipose Tissue in Association with Metabolic Improvement.

INTRODUCTION: Calorie restriction (CR) exerts multiple effects on health, including the amelioration of systemic insulin resistance. Although the precise mechanisms by which CR improves glucose homeostasis remain poorly defined, SIRT1 has been suggested to act as a central mediator of the cellular responses to CR. Here, we aim at identifying the mechanisms by which CR and SIRT1 modulate white adipose tissue (WAT) function, a key tissue in the control of glucose homeostasis. MATERIAL AND METHODS: A gene expression profiling study using DNA microarrays is conducted in WAT of control and SIRT1 transgenic mice fed ad libitum (AL) and mice subjected to 40% CR. RESULTS: Gene expression profiling reveals a relatively low degree of overlap between the transcriptional programs regulated by SIRT1 and CR. Gene networks related to extracellular matrix appear commonly downregulated by SIRT1/CR, whereas mitochondrial biogenesis is enhanced exclusively by CR. Moreover, WAT inflammation is reduced by CR and SIRT1, although their anti-inflammatory effects appeared to be achieved by regulating different gene networks related to the immune system. CONCLUDING REMARKS: In WAT, SIRT1 does not mediate most of the effects of CR on gene expression. Still, gene networks differentially regulated by SIRT1 and CR converge to reduce WAT inflammation.

Peritraumatic 17ß-estradiol levels influence chronic posttraumatic pain outcomes.

ABSTRACT: Biologic factors that predict risk for and mediate the development of common outcomes of trauma exposure such as chronic posttraumatic pain (CPTP) are poorly understood. In the current study, we examined whether peritraumatic circulating 17ß-estradiol (E2) levels influence CPTP trajectories. 17ß-estradiol levels were measured in plasma samples (n = 254) collected in the immediate aftermath of trauma exposure from 3 multiethnic longitudinal cohorts of men and women trauma survivors. Chronic posttraumatic pain severity was evaluated 6 weeks, 6 months, and 1 year after traumatic stress exposure. Repeated measures mixed models were used to test the relationship between peritraumatic E2 levels and prospective CPTP. Secondary analyses in a nested cohort assessed the influence of participant body mass index on the E2-CPTP relationship. In women, a statistically significant inverse relationship between peritraumatic E2 and CPTP was observed (ß = -0.280, P = 0.043) such that higher E2 levels predicted lower CPTP severity over time. Secondary analyses identified an E2 * body mass index interaction in men from the motor vehicle collision cohort such that obese men with higher E2 levels were at greater risk of developing CPTP. In nonobese men from the motor vehicle collision cohort and in men from the major thermal burn injury cohort, no statistically significant relationship was identified. In conclusion, peritraumatic circulating E2 levels predict CPTP vulnerability in women trauma survivors. In addition, these data suggest that peritraumatic administration of E2 might improve CPTP outcomes for women; further research is needed to test this possibility.

Vitamin D insufficiency increases risk of chronic pain among African Americans experiencing motor vehicle collision.

African Americans experience an increased burden of motor vehicle collision (MVC), post-MVC musculoskeletal pain, and vitamin D insufficiency. In this prospective multicenter study, we tested the hypothesis that African Americans (n = 133) presenting to the emergency department after MVC with low peritraumatic vitamin D levels would have worse chronic musculoskeletal pain outcomes compared to individuals with sufficient vitamin D. Vitamin D levels were assessed in the early aftermath of MVC through enzyme-linked immunosorbent assay, and pain severity was assessed using the 0 to 10 numeric rating scale at 6 weeks, 6 months, and 1 year. In repeated-measures analysis, African American MVC survivors with vitamin D insufficiency experienced more severe chronic pain (ß = 1.18, P = 0.031). In secondary analyses, we assessed for evidence that the effect of vitamin D on post-MVC pain outcomes is mediated, at least in part, by the influence of vitamin D on genetic variants in genes involved in immune system regulation (IL-10 and NLRP3). Genotyping was performed using a genome-wide microarray using collected DNA samples. Secondary analyses suggest that the effect of vitamin D on post-MVC pain outcomes may be influenced by genetic variation in IL-10 and NLRP3. Further studies are needed to assess the impact of vitamin D insufficiency on pain outcomes in African Americans experiencing MVC and other common trauma exposures, to assess factors affecting this relationship, and to assess the efficacy of administering vitamin D in the immediate aftermath of MVC to prevent chronic pain. Such low-cost, nonopioid interventions are urgently needed to address chronic pain development after MVC.

MicroRNA-19b predicts widespread pain and posttraumatic stress symptom risk in a sex-dependent manner following trauma exposure.

Posttraumatic widespread pain (PTWP) and posttraumatic stress symptoms (PTSS) are frequent comorbid sequelae of trauma that occur at different rates in women and men. We sought to identify microRNA (miRNA) that may contribute to sex-dependent differences in vulnerability to these outcomes. Monte Carlo simulations (x10,000) identified miRNA in which predicted targeting of PTWP or PTSS genes was most enriched. Expression of the leading candidate miRNA to target PTWP/PTSS-related genes, miR-19b, has been shown to be influenced by estrogen and stress exposure. We evaluated whether peritraumatic miR-19b blood expression levels predicted PTWP and PTSS development in women and men experiencing trauma of motor vehicle collision (n = 179) and in women experiencing sexual assault trauma (n = 74). A sex-dependent relationship was observed between miR-19b expression levels and both PTWP (ß = -2.41, P = 0.034) and PTSS (ß = -3.01, P = 0.008) development 6 months after motor vehicle collision. The relationship between miR-19b and PTSS (but not PTWP) was validated in sexual assault survivors (ß = -0.91, P = 0.013). Sex-dependent expression of miR-19b was also observed in blood and nervous tissue from 2 relevant animal models. Furthermore, in support of increasing evidence indicating a role for the circadian rhythm (CR) in PTWP and PTSS pathogenesis, miR-19b targets were enriched in CR gene transcripts. Human cohort and in vitro analyses assessing miR-19b regulation of key CR transcripts, CLOCK and RORA, supported the potential importance of miR-19b to regulating the CR pathway. Together, these results highlight the potential role that sex-dependent expression of miR-19b might play in PTWP and PTSS development after trauma/stress exposure.

The presence of a family witness impacts physician performance during simulated medical codes.

OBJECTIVE: To determine whether the presence and behavior of a family witness to cardiopulmonary resuscitation (CPR) impacts critical actions performed by physicians. DESIGN: This was a randomized comparison study of physicians' performance during a simulated cardiac arrest with three different family witness states. SETTING: This study was conducted at the Wayne State University Eugene Applebaum College of Pharmacy and Health Science's Center for Healthcare Simulation. SUBJECTS: Second-year and third-year emergency medicine (EM) residents from the Wayne State University Department of Emergency Medicine-affiliated residency programs and Michigan State University-affiliated EM residency programs. INTERVENTION: Thirty teams comprised of one second-year and one third-year EM resident were randomly assigned to one of the three groups: 1) no family witness; 2) a nonobstructive "quiet" family witness; and 3) a family witness displaying an overt grief reaction. MEASUREMENTS AND MAIN RESULTS: Each pair was assessed for time to critical actions (e.g., minutes to CPR and drug administration) and for resuscitation-based performance outcomes (e.g., number of shocks) during a simulated cardiac arrest. The time to critical events was similar across groups with respect to initiating CPR, attempting to intubate the patient, and pronouncing the death of the patient. However, the time to deliver the first defibrillation shock was longer for the overt reaction witness group (2.57 minutes) as compared with the quiet (1.77 minutes) and no family witness (1.67 minutes) groups. Additionally, fewer total shocks were delivered in the overt reaction witness groups (4.0 minutes) vs. the quiet (6.5 minutes) and no family witness groups (6.0 minutes). CONCLUSION: The presence of a family witness may have a significant impact on physicians' ability to perform critical actions during simulated medical resuscitations. Further study is necessary to see if this effect crosses over into real clinical practice and if training ameliorates this effect.

MicroRNA 320a Predicts Chronic Axial and Widespread Pain Development Following Motor Vehicle Collision in a Stress-Dependent Manner.

Study Design Prospective human cohort study combined with molecular studies. Background A microRNA is a small, noncoding RNA molecule that can play a role in disease onset. Recent studies found that circulating levels of microRNA 320a (miR-320a) are associated with musculoskeletal pain conditions and that miR-320a is stress responsive. Objectives To investigate whether circulating expression levels of miR-320a in the peritraumatic period predict persistent axial musculoskeletal pain 6 months after motor vehicle collision (MVC). Methods We evaluated whether (1) circulating miR-320a and related members of the miR-320a family predict axial musculoskeletal pain and other musculoskeletal pain outcomes 6 months following MVC, and (2) miR-320a regulates stress system and pain-related transcripts in cell culture. Given the wealth of data suggesting that biological mechanisms influencing pain outcomes are often sex and/or stress dependent, interactions between miR-320a, stress, and sex were evaluated. Results In primary analyses (n = 69), a significant crossover interaction was observed between the influence of circulating miR-320a and peritraumatic distress (ß = -0.01, P = .002) on post-MVC axial musculoskeletal pain. Reduced peritraumatic miR-320a expression levels predicted axial musculoskeletal pain in distressed individuals (ß = -0.12, P = .006) but not nondistressed individuals. In secondary analyses, miR-320a predicted widespread musculoskeletal pain, and related members of the miR-320a family also predicted axial and widespread musculoskeletal pain. In cell culture, miR-320a bound stress and pain-associated 3'UTR transcripts (FKBP5, ADCYAP1, PER2, and NR3C1). Conclusion These data suggest that miR-320a may help mediate regional and widespread changes in pain sensitivity after MVC. J Orthop Sports Phys Ther 2016;46(10):911-919. doi:10.2519/jospt.2016.6944.

Methodology of AA CRASH: a prospective observational study evaluating the incidence and pathogenesis of adverse post-traumatic sequelae in African-Americans experiencing motor vehicle collision.

INTRODUCTION: A motor vehicle collision (MVC) is one of the most common life-threatening events experienced by individuals living in the USA. While most individuals recover following MVC, a significant proportion of individuals develop adverse post-traumatic sequelae such as post-traumatic stress disorder or persistent musculoskeletal pain. Adverse post-traumatic sequelae are common, morbid and costly public health problems in the USA and other industrialised countries. The pathogenesis of these disorders following MVC remains poorly understood. In the USA, available data suggest that African-Americans experience an increased burden of adverse post-traumatic sequelae after MVC compared to European Americans, but to date no studies examining the pathogenesis of these disorders among African-Americans experiencing MVC have been performed. METHODS AND ANALYSIS: The African-American CRASH (AA CRASH) study is an NIH-funded, multicentre, prospective study that enrols African-Americans (n=900) who present to the emergency department (ED) within 24 hours of MVC. Participants are enrolled at 13 ED sites in the USA. Individuals who are admitted to the hospital or who report a fracture or tissue injury are excluded. Participants complete a detailed ED interview that includes an assessment of crash history, current post-traumatic symptoms and health status prior to the MVC. Blood samples are also collected in the ED using PAXgene DNA and PAXgene RNA tubes. Serial mixed-mode assessments 6 weeks, 6 months and 1 year after MVC include an assessment of adverse sequelae, general health status and health service utilisation. The results from this study will provide insights into the incidence and pathogenesis of persistent pain and other post-traumatic sequelae in African-Americans experiencing MVC. ETHICS AND DISSEMINATION: AA CRASH has ethics approval in the USA, and the results will be published in a peer-reviewed journal.