Jeri E. Forster

Development of a DNA vaccine designed to induce cytotoxic T lymphocyte responses to multiple conserved epitopes in HIV-1.

Epitope-based vaccines designed to induce CTL responses specific for HIV-1 are being developed as a means for addressing vaccine potency and viral heterogeneity. We identified a set of 21 HLA-A2, HLA-A3, and HLA-B7 restricted supertype epitopes from conserved regions of HIV-1 to develop such a vaccine. Based on peptide-binding studies and phenotypic frequencies of HLA-A2, HLA-A3, and HLA-B7 allelic variants, these epitopes are predicted to be immunogenic in greater than 85% of individuals. Immunological recognition of all but one of the vaccine candidate epitopes was demonstrated by IFN-γ ELISPOT assays in PBMC from HIV-1-infected subjects. The HLA supertypes of the subjects was a very strong predictor of epitope-specific responses, but some subjects responded to epitopes outside of the predicted HLA type. A DNA plasmid vaccine, EP HIV-1090, was designed to express the 21 CTL epitopes as a single Ag and tested for immunogenicity using HLA transgenic mice. Immunization of HLA transgenic mice with this vaccine was sufficient to induce CTL responses to multiple HIV-1 epitopes, comparable in magnitude to those induced by immunization with peptides. The CTL induced by the vaccine recognized target cells pulsed with peptide or cells transfected with HIV-1 env or gag genes. There was no indication of immunodominance, as the vaccine induced CTL responses specific for multiple epitopes in individual mice. These data indicate that the EP HIV-1090 DNA vaccine may be suitable for inducing relevant HIV-1-specific CTL responses in humans.

Human Prion Disease and Relative Risk Associated with Chronic Wasting Disease

Colorado death certificate data from 1979 through 2001 show that the risk for Creutzfeldt-Jakob disease did not increase for residents of counties where chronic wasting disease is endemic among deer and elk.

Prevalence and screening of traumatic brain injury among veterans seeking mental health services.

Objectives:To assess the prevalence of traumatic brain injury (TBI) among Veterans seeking mental health services using a 4-item tool, the Traumatic Brain Injury–4 (TBI-4), and to establish the classification accuracy of the TBI-4 using the Ohio State University TBI-Identification Method as the criterion standard. Study Design:Archival and observational data collected from individuals seeking care at a Mountain State VA Medical Center. Participants:The sample for the archival study was 1810. Three hundred sixteen Veterans completed observational study measures. Main Measures:For the archival study, TBI-4 and demographic data extracted from electronic medical records. For the observational study, the Ohio State University TBI-Identification Method and a demographic questionnaire were used. TBI-4 data were also obtained from electronic medical records. Results:The prevalence of probable TBI among those seeking VA MH treatment was 45%. Sensitivity and specificity of the TBI-4 were 0.74 and 0.56, respectively. Veterans with all levels of TBI severity sought care within this VA mental health setting. Conclusions:The prevalence of TBI in this VA mental health treatment population was higher than expected. Additional research is required to assess the clinical utility of screening for TBI among this population of Veterans.

Clinical Phase 1 Testing of the Safety and Immunogenicity of an Epitope-Based DNA Vaccine in Human Immunodeficiency Virus Type 1-Infected Subjects Receiving Highly Active Antiretroviral Therapy

ABSTRACT A DNA vaccine encoding sequence-conserved human immunodeficiency virus type 1 (HIV-1)-derived cytotoxic T-lymphocyte (CTL) epitopes from multiple HIV-1 gene products (designated EP HIV-1090) was evaluated in a placebo-controlled, dose escalation phase 1 clinical trial of HIV-1-infected subjects receiving potent combination antiretroviral therapy. Patients received four intramuscular immunizations with EP HIV-1090 over a 4-month period at one of four doses (0.5, 1.0, 2.0, or 4.0 mg) or received a placebo. The vaccine was determined to be safe and well tolerated at all doses tested. CTL responses were measured from cryopreserved peripheral blood mononuclear cells using gamma interferon enzyme-linked immunospot assays, with and without in vitro peptide stimulation (IVS). Responses to one or more vaccine epitopes were detected throughout the course of vaccination in 37.5% (12/32) and 47% (15/32) of vaccine recipients measured without and with IVS, respectively, indicating possible vaccine-induced priming of epitope-specific T cells. However, differences in rates of response to HIV-1 epitopes between vaccine and placebo recipients did not achieve statistical significance. The HIV-1 epitope-specific CTL responses measured in the peripheral blood after vaccination were often low level and short-lived, and therefore, alternative immunization schedules, routes of delivery, or vaccine formulations may be required to increase vaccine potency.

Traumatic Brain Injury and Posttraumatic Stress Disorder

Given the upsurge of research in posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI), much of which has focused on military samples who served in Iraq and Afghanistan, the purpose of this article is to review the literature published after September 11th, 2001 that addresses the epidemiology, pathophysiology, evaluation, and treatment of PTSD in the context of TBI.

Psychiatric diagnoses, mental health utilization, high-risk behaviors, and self-directed violence among veterans with comorbid history of traumatic brain injury and substance use disorders.

Objectives:To describe various characteristics of veterans with co-occurring histories of traumatic brain injury (TBI) and substance use disorder (SUD) for purposes of hypothesis generation. Study Design:Archival data collected over a period of 4 years. Participants:Sixty-five veterans across eras of service with confirmed histories of TBI and SUD. Methods:Demographic and TBI information were obtained from an archival clinical database. Electronic medical records were reviewed for mental health utilization, psychiatric diagnoses, self-directed violence, and risk-taking behaviors. Results:In addition to a SUD, veterans were reported to have an average of 3 additional psychiatric diagnoses and a median of 3 TBIs per person. All utilized various mental health services in addition to substance use treatment. Individuals were found to have engaged in a variety of risky behaviors. There were significant associations between suicidal ideation and assaultive behaviors, as well as between suicide attempt and impulsivity. Conclusions:This study describes a sample of veterans with co-occurring histories of TBI, SUD, risk-taking behaviors, and self-directed violence. More research is needed to examine these complex interrelationships and to identify specific risk factors for intervention/prevention strategies.

Traumatic brain injury, executive functioning, and suicidal behavior: a brief report.

OBJECTIVE The aim of this pilot study was to explore the relationship between executive dysfunction and suicidal behavior in two groups of participants: (Group 1, n = 18) veterans with traumatic brain injury (TBI) and a history of at least one suicide attempt (SA), and (Group 2, n = 29) veterans with TBI and no history of SA. Controlling for the severity of TBI, it was hypothesized that participants in Group 1 would perform more poorly than those in Group 2 on measures of executive functioning. DESIGN The primary outcome variable was decision making as assessed by performance on the Iowa Gambling Task (IGT). Secondary outcome variables included laboratory-measured impulsivity as measured by the Immediate and Delayed Memory Test (IMT/DMT), abstract reasoning as measured by the Wisconsin Card Sorting Test (WCST), and aggression as measured by the Lifetime History of Aggression (LHA) scale. RESULTS Among those in Group 1, time between TBI and first suicide attempt postinjury varied widely (months to nearly 30 years). Only the WCST perseverative errors score differed significantly between individuals with and without histories of one or more suicide attempts (SAs). CONCLUSION Suggestions for future study of SA among those with TBI are provided. When working with individuals with TBI, clinicians are encouraged to incorporate suicide risk assessment into their practice. Augmenting this process with a measure of perseveration may be beneficial.

Maternal Lopinavir/Ritonavir Is Associated with Fewer Adverse Events in Infants than Nelfinavir or Atazanavir

Combination antiretroviral therapy (cART) is successfully used for prevention of perinatal HIV transmission. To investigate safety, we compared adverse events (AE) among infants exposed to different maternal cART regimens. We reviewed 158 HIV-uninfected infants born between 1997 and 2009, using logistic regression to model grade ≥1 AE and grade ≥3 AE as a function of maternal cART and confounding variables (preterm, C-section, illicit drug use, race, ethnicity, infant antiretrovirals, and maternal viremia). Frequently used cART regimens included zidovudine (63%), lamivudine (80%), ritonavir-boosted lopinavir (37%), nelfinavir (26%), and atazanavir (10%). At birth, anemia occurred in 13/140 infants (9%), neutropenia in 27/107 (25%), thrombocytopenia in 5/133 (4%), and liver enzyme elevation in 21/130 (16%). Corresponding rates of AE at 4 weeks were 59/141 (42%), 54/130 (42%), 3/137 (2%), and 3/104 (3%), respectively. Serious AE (grade ≥ 3) exceeded 2% only for neutropenia (13% at birth; 9% at 4 weeks). Compared with infants exposed to maternal lopinavir/ritonavir, infants exposed to nelfinavir and atazanavir had a 5-fold and 4-fold higher incidence of AE at birth, respectively. In conclusion, hematologic and hepatic AE were frequent, but rarely serious. In this predominantly protease inhibitor-treated population, lopinavir/ritonavir was associated with the lowest rate of infant AE.

Challenges Associated With Screening for Traumatic Brain Injury Among US Veterans Seeking Homeless Services

We identified the prevalence of traumatic brain injury (TBI) among homeless veterans and assessed the TBI-4, a screening tool created to identify TBI history. Between May 2010 and October 2011, 800 US veterans from two hospitals, one eastern (n = 122) and one western (n = 678) completed some or all measures. Findings suggested that 47% of veterans seeking homeless services had a probable history of TBI (data for prevalence obtained only at the western hospital). However, psychometric results from the screening measure suggested that this may be an underestimate and supported comprehensive assessment of TBI in this population.

Clinically Inconsequential Alerts: The Characteristics of Opioid Drug Alerts and Their Utility in Preventing Adverse Drug Events in the Emergency Department

STUDY OBJECTIVE We examine the characteristics of clinical decision support alerts triggered when opioids are prescribed, including alert type, override rates, adverse drug events associated with opioids, and preventable adverse drug events. METHODS This was a retrospective chart review study assessing adverse drug event occurrences for emergency department (ED) visits in a large urban academic medical center using a commercial electronic health record system with clinical decision support. Participants include those aged 18 to 89 years who arrived to the ED every fifth day between September 2012 and January 2013. The main outcome was characteristics of opioid drug alerts, including alert type, override rates, opioid-related adverse drug events, and adverse drug event preventability by clinical decision support. RESULTS Opioid drug alerts were more likely to be overridden than nonopioid alerts (relative risk 1.35; 95% confidence interval [CI] 1.21 to 1.50). Opioid drug-allergy alerts were twice as likely to be overridden (relative risk 2.24; 95% CI 1.74 to 2.89). Opioid duplicate therapy alerts were 1.57 times as likely to be overridden (95% CI 1.30 to 1.89). Fourteen of 4,581 patients experienced an adverse drug event (0.31%; 95% CI 0.15% to 0.47%), and 8 were due to opioids (57.1%). None of the adverse drug events were preventable by clinical decision support. However, 46 alerts were accepted for 38 patients that averted a potential adverse drug event. Overall, 98.9% of opioid alerts did not result in an actual or averted adverse drug event, and 96.3% of opioid alerts were overridden. CONCLUSION Overridden opioid alerts did not result in adverse drug events. Clinical decision support successfully prevented adverse drug events at the expense of generating a large volume of inconsequential alerts. To prevent 1 adverse drug event, providers dealt with more than 123 unnecessary alerts. It is essential to refine clinical decision support alerting systems to eliminate inconsequential alerts to prevent alert fatigue and maintain patient safety.