Plasma biomarkers associated with deployment trauma and its consequences in post-9/11 era veterans: initial findings from the TRACTS longitudinal cohort.

Mild traumatic brain injury (mTBI) is among the most common injuries sustained by post-9/11 veterans; however, these injuries often occur within the context of psychological trauma. Blast exposure, even in the absence of a diagnosable TBI, leads to changes in neural connectivity and congitive functioning. Therefore, considering clinical comorbidities and injury characteristics is critical to understanding the long-term effects of mTBI. Research is moving towards identifying diagnostic and prognostic blood-based biomarkers for TBI; however, few studies include other prevalent clinical and medical comorbidities related to deployment. Here, we present the initial cross-sectional relationships between plasma biomarkers, clinical, and medical comorbidities in a well-characterized longitudinal sample of 550 post-9/11 veteran men and women. We examined biomarkers associated with inflammation (interleukin 6 and 10, tumor necrosis factor α, and eotaxin) and neurodegeneration (neurofilament light, glial fibrillary acidic protein (GFAP), tau, brain derived neurotrophic factor, amyloid ß 40 and 42, phosphorylated neurofilament heavy chain, and neuron specific enolase). Univariate analyses of covariance (ANCOVA) were conducted to determine mean level differences between close blast (blasts that occur within 0-10 meters) and mTBI groups. Our primary findings were twofold: (1) Inflammatory markers were consistently higher in participants exposed to close blasts and were strongly related to deployment-related psychopathology. (2) GFAP was consistently lower in participants exposed to blast and mTBI and lower GFAP was associated with more severe psychological symptoms. More research is clearly needed; however, our findings indicate that chronic increased inflammation and decreased GFAP may be related to close blast exposure.

Composite contributions of cerebrospinal fluid GABAergic neurosteroids, neuropeptide Y and interleukin-6 to PTSD symptom severity in men with PTSD.

Given that multiple neurobiological systems, as well as components within these systems are impacted by stress, and may interact in additive, compensatory and synergistic ways to promote or mitigate PTSD risk, severity, and recovery, we thought that it would be important to consider the collective, as well as separate effects of these neurobiological systems on PTSD risk. With this goal in mind, we conducted a proof-of-concept study utilizing cerebrospinal fluid (CSF) collected from unmedicated, tobacco- and illicit substance-free men with PTSD (n = 13) and trauma-exposed healthy controls (TC) (n = 17). Thirteen neurobiological factors thought to contribute to PTSD risk or severity based on previous studies were assayed. As the small but typical sample size of this lumbar puncture study limited the number of factors that could be considered in a hierarchical regression model, we included only those five factors with at least a moderate correlation (Spearman rho > 0.30) with total Clinician-Administered PTSD Scale (CAPS-IV) scores, and that did not violate multicollinearity criteria. Three of the five factors meeting these criteria-CSF allopregnanolone and pregnanolone (Allo + PA: equipotent GABAergic metabolites of progesterone), neuropeptide Y (NPY), and interleukin-6 (IL-6)-were found to account for over 75% of the variance in the CAPS-IV scores (R2 = 0.766, F = 8.75, p = 0.007). CSF Allo + PA levels were negatively associated with PTSD severity (ß = -0.523, p = 0.02) and accounted for 47% of the variance in CAPS-IV scores. CSF NPY was positively associated with PTSD severity (ß = 0.410, p = 0.04) and accounted for 14.7% of the CAPS-IV variance. There was a trend for a positive association between PTSD severity and CSF IL-6 levels, which accounted for 15.3% of the variance in PTSD severity (ß = 0.423, p = 0.05). Z-scores were then computed for each of the three predictive factors and used to depict the varying relative degrees to which each contributed to PTSD severity at the individual PTSD patient level. This first of its kind, proof-of-concept study bears replication in larger samples. However, it highlights the collective effects of dysregulated neurobiological systems on PTSD symptom severity and the heterogeneity of potential biological treatment targets across individual PTSD patients-thus supporting the need for precision medicine approaches to treatment development and prescribing in PTSD.

Cardiorespiratory Fitness Is Associated With Better Cardiometabolic Health and Lower PTSD Severity in Post-9/11 Veterans.

INTRODUCTION: Post-traumatic stress disorder (PTSD) is associated with an increased risk of cardiovascular and metabolic diseases and physical inactivity. Cardiorespiratory fitness (CRF), which is modifiable by physical activity, is a strong independent predictor of cardiometabolic health. However, the relationship between CRF and cardiometabolic health in veterans with PTSD is unknown. Thus, this study aimed to explore the cross-sectional relationships among CRF, indices of cardiometabolic health (ie, HbA1c, blood lipids, blood pressure, waist-hip ratio, and body mass index), and PTSD severity in veterans with PTSD. MATERIALS AND METHODS: This study was approved by the local Institutional Review Board. All participants were informed of the study risks and provided consent prior to participation. Participants (n = 13) completed a cardiopulmonary exercise test, a fasting blood draw, and the Clinician Administered PTSD Scale. Correlations between CRF and cardiometabolic health were examined with Spearman's rank correlations, and differences in PTSD symptom severity were explored as a function of CRF (ie, low-to-moderate vs. high CRF), using multiple linear regression. RESULTS: Peak oxygen uptake ($\dot{\mathrm{V}}$O2peak) was correlated with high-density lipoproteins rho = 0.60, P = 0.04 and diastolic blood pressure rho = -0.56, P = 0.05. Ventilatory threshold was correlated with HbA1c rho = -0.61, P = 0.03 and diastolic blood pressure rho = -0.56, P = 0.05. Higher CRF was associated with lower total PTSD severity standardized ß = -0.84, P = 0.01, adjusted R2 = 0.47, total Cluster C symptoms (avoidance/numbing) ß = -0.71, P = 0.02, adjusted R2 = 0.49, and total Cluster D symptoms (hyperarousal) ß = -0.89, P = 0.01, adjusted R2 = 0.41, while adjusting for age and smoking status. CONCLUSIONS: These preliminary findings suggest that CRF and by proxy physical activity may be important factors in understanding the increased risk of cardiovascular and metabolic disease associated with PTSD.

Tobacco dependence is associated with increased risk for multi-morbid clustering of posttraumatic stress disorder, depressive disorder, and pain among post-9/11 deployed veterans.

RATIONALE: Tobacco use is highly prevalent among individuals with posttraumatic stress disorder (PTSD), depressive disorders, and pain. Research has revealed pairwise relationships among these conditions but has not examined more complex relationships that may influence symptom severity, chronicity, and treatment outcome. OBJECTIVE: To examine the clustering of current PTSD, depressive disorders, and clinically significant pain according to current tobacco use and dependence among post-9/11 deployed veterans. METHODS: Logistic regression was used to examine the clustering of these conditions in relationship to current tobacco use/dependence, while adjusting for age and total combat exposure, in 343 post-9/11 deployed veterans enrolled in the Translational Research Center for TBI and Stress Disorders (TRACTS) cohort (Mage = 32.1 + 8.3 years; 38% current tobacco use; 25% low and 12% moderate/high tobacco dependence). RESULTS: A three-way clustering of PTSD, depressive disorder, and pain was more likely than any single or pairwise combination of these conditions in moderate/high tobacco-dependent veterans compared to tobacco non-users (adjusted ORs = 3.50 to 4.18). This multi-morbidity cluster also was associated with increased PTSD severity. CONCLUSIONS: Moderate to high dependence on tobacco is associated with substantially increased clustering of PTSD, depression, and clinically significant pain in veterans. Research examining synergistic interactions among these conditions, biological vulnerabilities shared among them, and the direct impact of tobacco use on the pathophysiology of PTSD, depression, and pain is needed. The results of such work may spur development of more effective integrated treatments to reduce the negative impact of these multi-morbid conditions on veterans' wellbeing and long-term health.

Medication Complexity, Medication Number, and Their Relationships to Medication Discrepancies.

BACKGROUND: Medication reconciliation to identify discrepancies is a National Patient Safety Goal. Increasing medication number and complex medication regimens are associated with discrepancies, nonadherence, and adverse events. The Medication Regimen Complexity Index (MRCI) integrates information about dosage form, dosing frequency, and additional directions. OBJECTIVE: This study evaluates the association of MRCI scores and medication number with medication discrepancies and commissions, a discrepancy subtype. METHODS: This was a retrospective cohort study of a convenience sample of 104 ambulatory care patients seen from April 2010 to July 2011 within the Department of Veterans Affairs. Primary outcomes included any medication discrepancy and commissions. Primary exposures included MRCI scores and medication number. Multivariable logistic regression models associated MRCI scores and medication number with discrepancies. Receiver operating characteristic (ROC) curves provided discrepancy thresholds. RESULTS: For the 104 patients analyzed, the median MRCI score was 25 (interquartile range [IQR] = 14-43), and the median medication number was 8 (IQR = 5-13); 60% of patients had any discrepancy, whereas 36% had a commission. In adjusted analyses, patients with MRCI scores ≥25 or medication number ≥8 were more likely to have commissions (odds ratio [OR] = 3.64, 95% CI = 1.41-9.41; OR = 4.51, 95% CI = 1.73-11.73, respectively). The unadjusted ROC threshold for commissions was 36 for MRCI (sensitivity, 59%; specificity, 82%) and 9 for medication number (sensitivity 68%; specificity 67%). CONCLUSION: Patients with either MRCI scores ≥25 or ≥8 medications were more likely to have commissions. Given equal performance in predicting discrepancies, the efficiency and simplicity of medication number supports its use in identifying patients for intensive medication review beyond medication reconciliation.

Transfusion burden among patients with chronic kidney disease and anemia.

BACKGROUND AND OBJECTIVES: Although well-described for patients who require dialysis, information on transfusion burden related to anemia in the nondialysis patient population with chronic kidney disease (CKD) is lacking. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: A retrospective study was conducted of patients with CKD and chronic anemia from 2002 through 2007 in the Veterans Administration Healthcare System. Included patients had stage 3 CKD or higher and anemia (one or more hemoglobin [Hb] levels <11 g/dl or received anemia therapy [erythropoiesis-stimulating agents [ESAs], iron, or both]). The outcome of interest was transfusion events, which was evaluated in relation to the absolute Hb level and changes in Hb levels overall and according to the type of treatment received (no treatment, iron therapy, ESA therapy, or ESA and iron therapy) concurrent with each Hb measurement. RESULTS: Among 97,636 patients with CKD and anemia, we observed 68,556 transfusion events (61 events per 100 person-years), 86.6% of which occurred in inpatient settings. At all Hb levels, transfusion events were highest during periods of no treatment and increased with declining Hb levels. Between an Hb of 10.0 and 10.9 g/dl, the transfusion rate was 2.0% for those who received an ESA, iron, or both and 22% for those who received no treatment; at an Hb level of 7.0 to 7.9 g/dl, the transfusion rate was 10 to 12% for treated and 58% for untreated patients. Low absolute Hb levels but not Hb changes was most predictive of a transfusion even after adjustment for patient case mix. CONCLUSIONS: Transfusions are still used to treat anemia in patients who have CKD and do not require dialysis, although they occur considerably less frequently in patients who receive other available anemia therapies.