Comorbidity and polypharmacy impact neurobehavioral symptoms and symptom validity failure among post-9/11 veterans with mild traumatic brain injury.

Objective: The study aimed to examine the association between post-concussive comorbidity burdens [post-traumatic stress disorder (PTSD), depression, and/or headache] and central nervous system (CNS) polypharmacy (five or more concurrent medications) with reported neurobehavioral symptoms and symptom validity screening among post-9/11 veterans with a history of mild traumatic brain injury (mTBI). Setting: Administrative medical record data from the Department of Veterans Affairs (VA) were used in the study. Participants: Post-9/11 veterans with mTBI and at least 2 years of VA care between 2001 and 2019 who had completed the comprehensive traumatic brain injury evaluation (CTBIE) were included in the study. Design: Retrospective cross-sectional design was used in the study. Main measures: Neurobehavioral Symptom Inventory (NSI), International Classification of Diseases, Ninth Revision, and Clinical Modification diagnosis codes were included in the study. Results: Of the 92,495 veterans with a history of TBI, 90% had diagnoses of at least one identified comorbidity (PTSD, depression, and/or headache) and 28% had evidence of CNS polypharmacy. Neurobehavioral symptom reporting and symptom validity failure was associated with comorbidity burden and polypharmacy after adjusting for sociodemographic characteristics. Veterans with concurrent diagnoses of PTSD, depression, and headache were more than six times more likely [Adjusted odds ratio = 6.55 (99% CI: 5.41, 7.92)]. to fail the embedded symptom validity measure (Validity-10) in the NSI. Conclusion: TBI-related multimorbidity and CNS polypharmacy had the strongest association with neurobehavioral symptom distress, even after accounting for injury and sociodemographic characteristics. Given the regular use of the NSI in clinical and research settings, these findings emphasize the need for comprehensive neuropsychological evaluation for individuals who screen positively for potential symptom overreporting, the importance of multidisciplinary rehabilitation to restore functioning following mTBI, and the conscientious utilization of symptom validity measures in research efforts.

Development of complexity categories for an investigational drug services complexity scoring tool to assess pharmacy effort in clinical trial initiation and maintenance.

PURPOSE: Research pharmacy effort required to safely and compliantly manage investigational products (IP) varies between studies. No validated tool exists in the United States to evaluate these differences in effort. The Vizient Pharmacy Research Committee Investigational Drug Services (IDS) Subcommittee previously developed a systematic complexity scoring tool (CST) through expert consensus to assign a complexity score for pharmacy effort. This project seeks to develop and validate complexity categories based on CST scores. METHODS: Vizient member institutions in IDS assigned a CST complexity score and a perceived complexity category (low, medium, or high) for study initiation and maintenance. Receiver operating characteristic (ROC) curve analysis defined the best CST score cutoff points for each complexity category. Comparing the CST-assigned to the user-perceived complexity category determined whether the CST-assigned complexity category aligned with practitioner assignment. RESULTS: A total of 322 responses were used to determine complexity score categories. The AUC values for study initiation and maintenance were 0.79 (P < 0.001) for the low/medium boundary and 0.80 (P < 0.001) for the medium/high boundary, suggesting the performance of the CST is good. The agreement between CST-assigned and user-perceived complexity categories was 60% for study initiation and 58% for maintenance. The Kendall rank correlation coefficient between the raters and ROC categories was strong, with a value of 0.48 for study initiation and 0.47 for maintenance. CONCLUSION: Development of the CST allows IDS pharmacies to objectively measure the complexity of clinical trials, which is a significant step towards assessing workload and guiding resource allocation.

Complex pain phenotypes: Suicidal ideation and attempt through latent multimorbidity.

BACKGROUND: Given the relatively high rates of suicidal ideation and attempt among people with chronic pain, there is a need to understand the underlying factors to target suicide prevention efforts. To date, no study has examined the association between pain phenotypes and suicide related behaviors among those with mild traumatic brain injuries. OBJECTIVE: To determine if pain phenotypes were independently associated with suicidal ideation / attempt or if comorbidities within the pain phenotypes account for the association between pain phenotypes and suicide related behaviors. METHODS: This is a longitudinal retrospective cohort study of suicide ideation/attempts among pain phenotypes previously derived using general mixture latent variable models of the joint distribution of repeated measures of pain scores and pain medications/treatment. We used national VA inpatient, outpatient, and pharmacy data files for Post-9/11 Veterans with mild traumatic injury who entered VA care between fiscal years (FY) 2007 and 2009. We considered a counterfactual causal modeling framework to assess the extent that the pain phenotypes during years 1-5 of VA care were predictive of suicide ideation/attempt during years 6-8 of VA care conditioned on covariates being balanced between pain phenotypes. RESULTS: Without adjustment, pain phenotypes were significant predictors of suicide related behaviors. When we used propensity scores to balance the comorbidities present in the pain phenotypes, the pain phenotypes were no longer significantly associated with suicide related behaviors. CONCLUSION: These findings suggest that suicide ideation/attempt is associated with pain trajectories primarily through latent multimorbidity. Therefore, it is critical to identify and manage comorbidities (e.g., depression, post-traumatic stress disorder) to prevent tragic outcomes associated with suicide related behaviors throughout the course of chronic pain and mild traumatic brain injury management.

Five-year Pain Intensity and Treatment Trajectories of Post-9/11 Veterans With Mild Traumatic Brain Injury.

Pain is a pervasive problem that affects nearly half of the U.S. Veterans deployed in support of the Global War on Terror (Post-9/11 Veterans) and over half of the Post-9/11 Veterans with diagnosed traumatic brain injury (TBI). The goal of the current study was to identify pain phenotypes based on distinct longitudinal patterns of pain scores in light of pain treatment among Post-9/11 Veterans over 5 years of care using latent growth mixture analysis stratified by TBI status. Five pain phenotypes emerged: 1) simple low impact stable pain, 2) complex low impact stable pain, 3) complex low impact worsening pain, 4) complex moderate impact worsening pain, and 5) complex high impact stable pain. Baseline pain scores and slopes were significantly higher in Veterans with mild TBI for some phenotypes. The mild TBI cohort was younger, had more men, more whites, less blacks, less education, more unmarried, more Marines and Army, more active duty in comparison to the no TBI cohort. Distinct trajectories in pain treatment were apparent among the pain intensity subgroups. PERSPECTIVE: The complexity of pain in patients with mTBI is categorically different than those with no TBI. Pain in patients with mTBI is heterogeneous with distinct phenotypes which may explain poor outcomes in this group. Identification of the individual differences may have a significant impact on the success of interventions.

Patterns of zolpidem use among Iraq and Afghanistan veterans: A retrospective cohort analysis.

BACKGROUND: Although concern exists regarding the adverse effects and rate of zolpidem use, especially long-term use, limited information is available concerning patterns of zolpidem use. OBJECTIVE: To examine the prevalence and correlates of zolpidem exposure in Iraq and Afghanistan Veterans (IAVs). METHODS: A retrospective cohort study of zolpidem prescriptions was performed with National Veterans Health Administration (VHA) data. We gathered national VA inpatient, outpatient, and pharmacy data files for IAV's who received VA care between fiscal years (FY) 2013 and 2014. The VA pharmacy database was used to identify the prevalence of long term (>30 days), high-dose zolpidem exposure (>10mg immediate-release; >12.5mg extended-release) and other medications received in FY14. Baseline characteristics (demographics, diagnoses) were identified in FY13. Bivariate and multivariable analyses were used to examine the demographic, clinical, and medication correlates of zolpidem use. RESULTS: Of 493,683 IAVs who received VHA care in FY 2013 and 2014, 7.6% (n = 37,422) were prescribed zolpidem in FY 2014. Women had lower odds of high-dose zolpidem exposure than men. The majority (77.3%) of IAVs who received zolpidem prescriptions had long-term use with an average days' supply of 189.3 days and a minority (0.9%) had high-dose exposure. In multivariable analyses, factors associated with long-term zolpidem exposure included age greater than 29 years old, PTSD, insomnia, Selim Index, physical 2-3 conditions, opioids, antidepressants, benzodiazepines, atypical antipsychotics, and stimulants. High dose exposure was associated with PTSD, depression, substance use disorder, insomnia, benzodiazepines, atypical antipsychotics, and stimulant prescriptions. CONCLUSION: The current practices of insomnia pharmacotherapy in IAVs fall short of the clinical guidelines and may reflect high-risk zolpidem prescribing practices that put Iraq and Afghanistan Veterans at risk for adverse effects of zolpidem and poor health outcomes.

Prevalence of Central Nervous System Polypharmacy and Associations with Overdose and Suicide-Related Behaviors in Iraq and Afghanistan War Veterans in VA Care 2010-2011.

BACKGROUND: The increase in the quantities of central nervous system (CNS)-acting medications prescribed has coincided with increases in overdose mortality, suicide-related behaviors, and unintentional deaths in military personnel deployed in support of the wars in Iraq and Afghanistan. Data on the extent and impact of prescribing multiple CNS drugs among Iraq and Afghanistan Veterans (IAVs) are sparse. OBJECTIVES: We sought to identify the characteristics of IAVs with CNS polypharmacy and examine the association of CNS polypharmacy with drug overdose and suicide-related behaviors controlling for known risk factors. METHODS: This cross-sectional cohort study examined national data of Iraq and Afghanistan Veterans (N = 311,400) who used the Veterans Health Administration (VHA) during the fiscal year 2011. CNS polypharmacy was defined as five or more CNS-acting medications; drug/alcohol overdose and suicide-related behaviors were identified using ICD-9-CM codes. Demographic and clinical characteristics associated with CNS polypharmacy were identified using a multivariable logistic regression model. RESULTS: We found that 25,546 (8.4 %) of Iraq and Afghanistan Veterans had CNS polypharmacy. Those with only post-traumatic stress disorder (PTSD) (adjusted odds ratio (AOR) 6.50, 99 % confidence interval (CI) 5.96-7.10), only depression (AOR 6.42, 99 % CI 5.86-7.04), co-morbid PTSD and depression (AOR 12.98, 99 % CI 11.97-14.07), and co-morbid traumatic brain injury (TBI), PTSD, and depression (AOR 15.30, 99 % CI 14.00-16.73) had the highest odds of CNS polypharmacy. After controlling for these co-morbid conditions, CNS polypharmacy was significantly associated with drug/alcohol overdose and suicide-related behavior. CONCLUSION: CNS polypharmacy was most strongly associated with PTSD, depression, and TBI, and independently associated with overdose and suicide-related behavior after controlling for known risk factors. These findings suggest that CNS polypharmacy may be used as an indicator of risk for adverse outcomes. Further research should evaluate whether CNS polypharmacy may be used as a trigger for evaluation of the current care provided to these individuals.

Optimizing multimodal analgesia with intravenous acetaminophen and opioids in postoperative bariatric patients.

STUDY OBJECTIVE: To evaluate the effect of therapeutic doses of intravenous acetaminophen (IV APAP) on postoperative opioid use following bariatric surgery. DESIGN: Retrospective review of medical records. SETTING: A 654-bed academic hospital. PATIENTS: Records for 104 patients who underwent laparoscopic sleeve gastrectomy (LSG; 44 patients) or laparoscopic Roux-en-Y gastric bypass (LRYGB; 60 patients) were reviewed. Patients received IV APAP 1 g every 6 hours postoperatively (22 LSG patients and 30 LRYGB patients) or no IV APAP (22 LSG patients and 30 LRYGB patients). MEASUREMENTS AND MAIN RESULTS: Baseline demographic features were similar for both groups. Patients receiving IV APAP required fewer intravenous morphine equivalents than patients treated with opioids alone. Reductions in morphine equivalents with IV APAP were 21 mg (LSG), 33 mg (LRYGB), and 28 mg (all patients) (p<0.001 for all comparisons). IV APAP was associated with a shorter hospital length of stay (LOS) for the LRYGB (mean difference 1.47 days; p=0.039) and combined groups (mean difference 0.95 days; p=0.025). Patients who received IV APAP had earlier return of bowel sounds and flatus. IV APAP did not reduce mean pain scores in any group. CONCLUSION: Patients undergoing bariatric surgery who received IV APAP during the 24-hour postoperative period consumed fewer intravenous morphine equivalents and had similar pain scores as patients who were treated with opioids alone. Use of IV APAP reduced the hospital LOS and resulted in earlier return of bowel sounds and passage of flatus.

Possible novel therapy for malignant gliomas with secretable trimeric TRAIL.

Malignant gliomas are the most common primary brain tumors. Despite intensive clinical investigation and many novel therapeutic approaches, average survival for the patients with malignant gliomas is only about 1 year. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown potent and cancer-selective killing activity and drawn considerable attention as a promising therapy for cancers, but concerns over delivery and toxicity have limited progress. We have developed a secretable trimeric TRAIL (stTRAIL) and here evaluated the therapeutic potential of this stTRAIL-based gene therapy in brain tumors. An adenovirus (Ad-stTRAIL) delivering stTRAIL was injected into intra-cranial human glioma tumors established in nude mice and tumor growth monitored using the magnetic resonance imaging (MRI). Ad-stTRAIL gene therapy showed potent tumor suppressor activity with no toxic side effects at therapeutically effective doses. When compared with 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU), a conventional therapy for malignant gliomas, Ad-stTRAIL suppressed tumor growth more potently. The combination of Ad-stTRAIL and BCNU significantly increased survival compared to the control mice or mice receiving Ad-stTRAIL alone. Our data indicate that Ad-stTRAIL, either alone or combined with BCNU, has promise as a novel therapy for malignant gliomas.

Thymidylate synthase, thymidine phosphorylase, VEGF and p53 protein expression in primary colorectal cancer for predicting response to 5-fluorouracil-based chemotherapy.

PURPOSE: In the treatment of advanced metastatic colorectal cancer, several new agents, such as irinotecan and oxaliplatin, have been developed, which have improved both disease free and overall survivals. Among these agents, 5-fluorouracil (5-FU) still remains one of the most active agents, and the selection of patients who can benefit from 5-FU-based chemotherapy is still important, as those unlikely to benefit could be spared the harmful side effects. The expression levels of thymidylate synthase (TS), thymidine phosphorylase (TP) and p53 have been known to be associated with the clinical response to 5-FU-based therapy as well as the prognosis, and that of vascular endothelial growth factor (VEGF) is associated with poor survival. MATERIALS AND METHODS: The relationship between the expressions of TS, TP, VEGF and p53 in primary tumors, using immunohistochemistry, and the response of 45 metastatic colorectal cancer patients (M:F=25:20, median age 59 yrs) to 5-FU-based chemotherapy were evaluated. RESULTS: Thirty-seven patients were treated with 5-FU/LV/irinotecan (FOLFIRI) and 8 with 5-FU/LV/oxaplatin (FOLFOX). The overall response rate was 28.9% (13/45). When immunohistochemically analyzed with monoclonal antibodies against TS, TP, VEGF and p53, 55.6% of the patients (25/45) were positive for TS, 48.9% (22/45) for TP, 82.2% (37/45) for VEGF, and 80% (36/45) for p53. There was a significant difference in the intensity of TS expression between the clinical responders and non-responders (p=0.036). In terms of the staining pattern of TS expression, diffuse staining was correlated with a poor response (p=0.012) and poor survival (p=0.045). However, there was no correlation between the expressions of TP, VEGF or P53 and the response to chemotherapy. CONCLUSION: These results suggest that the expression of TS in primary colorectal cancer might be an important prognostic factor for chemotherapy response and survival, and might be a useful therapeutic marker for the response of chemotherapy.