Correction: Correction to 'Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients Presenting to the Emergency Department With Seizures' [Annals of Emergency Medicine 63 (2014) 437-447.e15].

Due to a miscommunication during the process of transferring this manuscript from our editorial team to Production, the Members of the American College of Emergency Physicians Clinical Policies Committee (Oversight Committee) were not properly indexed in PubMed. This has now been corrected online. The publisher would like to apologize for any inconvenience caused.

Increased prognostic accuracy of TBI when a brain electrical activity biomarker is added to loss of consciousness (LOC).

BACKGROUND: Extremely high accuracy for predicting CT+ traumatic brain injury (TBI) using a quantitative EEG (QEEG) based multivariate classification algorithm was demonstrated in an independent validation trial, in Emergency Department (ED) patients, using an easy to use handheld device. This study compares the predictive power using that algorithm (which includes LOC and amnesia), to the predictive power of LOC alone or LOC plus traumatic amnesia. PARTICIPANTS: ED patients 18-85years presenting within 72h of closed head injury, with GSC 12-15, were study candidates. 680 patients with known absence or presence of LOC were enrolled (145 CT+ and 535 CT- patients). METHODS: 5-10min of eyes closed EEG was acquired using the Ahead 300 handheld device, from frontal and frontotemporal regions. The same classification algorithm methodology was used for both the EEG based and the LOC based algorithms. Predictive power was evaluated using area under the ROC curve (AUC) and odds ratios. RESULTS: The QEEG based classification algorithm demonstrated significant improvement in predictive power compared with LOC alone, both in improved AUC (83% improvement) and odds ratio (increase from 4.65 to 16.22). Adding RGA and/or PTA to LOC was not improved over LOC alone. CONCLUSIONS: Rapid triage of TBI relies on strong initial predictors. Addition of an electrophysiological based marker was shown to outperform report of LOC alone or LOC plus amnesia, in determining risk of an intracranial bleed. In addition, ease of use at point-of-care, non-invasive, and rapid result using such technology suggests significant value added to standard clinical prediction.

Bardoxolone methyl and kidney function in CKD with type 2 diabetes.

BACKGROUND: Chronic kidney disease (CKD) associated with type 2 diabetes is the leading cause of kidney failure, with both inflammation and oxidative stress contributing to disease progression. Bardoxolone methyl, an oral antioxidant inflammation modulator, has shown efficacy in patients with CKD and type 2 diabetes in short-term studies, but longer-term effects and dose response have not been determined. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assigned 227 adults with CKD (defined as an estimated glomerular filtration rate [GFR] of 20 to 45 ml per minute per 1.73 m(2) of body-surface area) in a 1:1:1:1 ratio to receive placebo or bardoxolone methyl at a target dose of 25, 75, or 150 mg once daily. The primary outcome was the change from baseline in the estimated GFR with bardoxolone methyl, as compared with placebo, at 24 weeks; a secondary outcome was the change at 52 weeks. RESULTS: Patients receiving bardoxolone methyl had significant increases in the mean (±SD) estimated GFR, as compared with placebo, at 24 weeks (with between-group differences per minute per 1.73 m(2) of 8.2±1.5 ml in the 25-mg group, 11.4±1.5 ml in the 75-mg group, and 10.4±1.5 ml in the 150-mg group; P<0.001). The increases were maintained through week 52, with significant differences per minute per 1.73 m(2) of 5.8±1.8 ml, 10.5±1.8 ml, and 9.3±1.9 ml, respectively. Muscle spasms, the most frequent adverse event in the bardoxolone methyl groups, were generally mild and dose-related. Hypomagnesemia, mild increases in alanine aminotransferase levels, and gastrointestinal effects were more common among patients receiving bardoxolone methyl. CONCLUSIONS: Bardoxolone methyl was associated with improvement in the estimated GFR in patients with advanced CKD and type 2 diabetes at 24 weeks. The improvement persisted at 52 weeks, suggesting that bardoxolone methyl may have promise for the treatment of CKD. (Funded by Reata Pharmaceuticals; BEAM ClinicalTrials.gov number, NCT00811889.).

Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with seizures.

This clinical policy from the American College of Emergency Physicians is the revision of a 2004 policy on critical issues in the evaluation and management of adult patients with seizures in the emergency department. A writing subcommittee reviewed the literature to derive evidence-based recommendations to help clinicians answer the following critical questions: (1) In patients with a first generalized convulsive seizure who have returned to their baseline clinical status, should antiepileptic therapy be initiated in the emergency department to prevent additional seizures? (2) In patients with a first unprovoked seizure who have returned to their baseline clinical status in the emergency department, should the patient be admitted to the hospital to prevent adverse events? (3) In patients with a known seizure disorder in which resuming their antiepileptic medication in the emergency department is deemed appropriate, does the route of administration impact recurrence of seizures? (4) In emergency department patients with generalized convulsive status epilepticus who continue to have seizures despite receiving optimal dosing of a benzodiazepine, which agent or agents should be administered next to terminate seizures? A literature search was performed, the evidence was graded, and recommendations were given based on the strength of the available data in the medical literature.

Differences in interpretation of cranial computed tomography in ED traumatic brain injury patients by expert neuroradiologists.

Cranial computed tomography (CT) is generally regarded as the standard for evaluation of structural brain injury in patients with traumatic brain injury (TBI) presenting to the emergency department (ED). However, the subjective nature of the visual interpretations of CT scans and the qualitative nature of reporting may lead to poor interrater reliability. This is significant because CT positive scans include a continuum of structural injury with differences in treatment. The purpose of the present study was to evaluate the consistency of readings of head CT scans obtained within 24 hours after mild TBI in the ED, as assessed by an independent adjudication panel of 3 experienced neuroradiologists. In 80.1% of the cases, all 3 adjudicators agreed with the determination of the presence of structural injury. However, when interrater agreement was assessed with respect to the specific classification of the injury, agreement was poor, with a κ of 0.3 (0.29-0.316; confidence interval [CI] 95%). When classification was collapsed, considering only the presence or absence of hematomas, agreement among all 3 adjudicators improved to 55%, but the κ of 0.355, (0.332-0.78; CI 95%) was still only fair. The data suggest the need for improved recognition and quantification of specific structural injuries in the TBI population for better identification of patients requiring clinical intervention.

Nonurgent commercial air travel after nonhemorrhagic cerebrovascular accident.

Nonurgent commercial air travel in patients who have experienced a nonhemorrhagic cerebrovascular accident (CVA) may occur, particularly in the elderly traveling population. A recent CVA, particularly occurring during a person's travel, presents a significant challenge to the patient, companions, family, and health care team. Specific medical recommendation, based on accumulated scientific data and interpreted by medical experts, is needed so that travel health care professionals can appropriately guide the patient. Unfortunately, such recommendations are almost entirely lacking despite the relative frequency of CVA and air travel. This article reviews the existing recommendations with conclusions based on both these limited data and rationale conjecture.

Air travel of patients with abdominal aortic aneurysm: urgent air medical evacuation and nonurgent commercial air repatriation.

Abdominal aortic aneurysm (AAA) presents across a spectrum of severity. Although some resources suggest a theoretic risk for rupture related to air travel, this claim remains unproven. In fact, there are little data from which to make evidence-based recommendations. Air medical evacuation of a patient with either an AAA at risk of imminent rupture or status post recent rupture can be performed, assuming that local surgical care is not available and that transfer is taking the patient to a higher level of medical intervention. Furthermore, medical opinion suggests that patients with asymptomatic and/or surgically corrected AAA can safely travel by commercial aircraft for nonurgent reasons, assuming that other issues including postoperative needs are appropriately addressed. In this discussion, answers to the following issues are sought: flight safety for urgent evacuation and nonurgent repatriation scenarios, waiting time to fly nonurgently after AAA diagnosis, and the need for medical accompaniment.

High-sensitivity electronic Stark spectrometer featuring a laser-driven light source.

We report developmental details of a high-sensitivity Stark absorption spectrometer featuring a laser-driven light source. The light source exhibits intensity fluctuations of ∼0.3% over timescales ranging from 1 min to 12 h, minimal drift (≤0.1%/h), and very little 1/f noise at frequencies greater than 200 Hz, which are comparable to or better than an arc-driven light source. Additional features of the spectrometer include balanced detection with multiplex sampling, which yielded lower noise in A, and constant wavelength or wavenumber (energy) spectral bandpass modes. We achieve noise amplitudes of ∼7 × 10-4 and ∼6 × 10-6 in measurements of single A and ΔA spectra (with 92 data points) taking ∼7 and ∼19 min, respectively.

Emergency neurological life support: approach to the patient with coma.

Coma is an acute failure of neuronal systems governing arousal and awareness and represents a neurological emergency. When encountering a comatose patient, the clinician must have an organized approach to detect easily remedial causes, prevent ongoing neurologic injury, and determine a hierarchy of diagnostic tests, treatments, and neuromonitoring. Coma was chosen as an Emergency Neurological Life Support (ENLS) protocol because timely medical and surgical interventions can be life-saving, and the initial work-up of such patients is critical to establishing a correct diagnosis.

Emergency neurological life support: intracranial hypertension and herniation.

Sustained intracranial hypertension and acute brain herniation are "brain codes," signifying catastrophic neurological events that require immediate recognition and treatment to prevent irreversible injury and death. As in cardiac arrest, evidence supports the organized implementation of a stepwise management algorithm. Because there are multiple etiologies and many treatments that can potentially reverse cerebral herniation, intracranial hypertension and herniation was chosen as an Emergency Neurological Life Support (ENLS) protocol.

Effect of bardoxolone methyl on kidney function in patients with T2D and Stage 3b-4 CKD.

BACKGROUND/AIMS: Bardoxolone methyl, a novel synthetic triterpenoid, induces Nrf2, a transcription factor known to play a key role in decreasing oxidative stress and the production of pro-inflammatory molecules. METHODS: This exploratory multi-center, open-label study assessed the clinical activity and safety of bardoxolone methyl in 20 patients with moderate to severe chronic kidney disease and type 2 diabetes. Patients received 25 mg of bardoxolone methyl daily for 28 days, followed by 75 mg daily for another 28 days. RESULTS: The study achieved its primary efficacy endpoint, as demonstrated by a significant increase from baseline in estimated glomerular filtration rate (eGFR) of 7.2 ml/min/1.73 m2 (p < 0.001). Improvements were seen in approximately 90% of patients and showed a dose- and time-dependent increase in eGFR. The eGFR change paralleled a significant reduction in serum creatinine (-0.3 mg/dl) and blood urea nitrogen (-4.9 mg/dl), along with an increase in creatinine clearance (+14.6 ml/min/1.73 m2), without a change in the 24-hour creatinine excretion rate. Markers of vascular injury and inflammation were improved by treatment with bardoxolone. No life-threatening adverse events or drug-related serious adverse events were reported. CONCLUSIONS: The results describe an apparent increase in kidney function following relatively short-term treatment with bardoxolone methyl, a promising new agent that warrants placebo-controlled studies to define its long-term effects on renal function.

A peptide-doxorubicin 'prodrug' activated by prostate-specific antigen selectively kills prostate tumor cells positive for prostate-specific antigen in vivo.

We covalently linked doxorubicin with a peptide that is hydrolyzable by prostate-specific antigen. In the presence of prostate tumor cells secreting prostate-specific antigen, the peptide moiety of this conjugate, L-377,202, was hydrolyzed, resulting in the release of leucine-doxorubicin and doxorubicin, which are both very cytotoxic to cancer cells. However, L-377,202 was much less cytotoxic than conventional doxorubicin to cells in culture that do not secrete prostate-specific antigen. L-377,202 was approximately 15 times more effective than was conventional doxorubicin at inhibiting the growth of human prostate cancer tumors in nude mice when both drugs were used at their maximally tolerated doses. Nude mice inoculated with human prostate tumor cells secreting prostate-specific antigen showed considerable reductions in tumor burden with minimal total body weight loss when treated with L-377, 202. This improvement in therapeutic index correlated with the selective localization of leucine-doxorubicin and free doxorubicin in tissues secreting prostate-specific antigen after exposure to L-377,202.

Insights into native epitopes of proliferating cell nuclear antigen using recombinant DNA protein products.

A cDNA clone encoding full-length human proliferating cell nuclear antigen (PCNA) was used to generate a panel of in vitro translated labeled protein products with COOH-terminal deletions and to construct a set of fusion proteins with COOH- and NH2-terminal deletions. A rabbit antiserum raised against an NH2-terminal peptide, a well-characterized murine monoclonal antibody (mAb), and 14 human lupus sera with autoantibody to PCNA were analyzed for their reactivity with the constructs using both immunoprecipitation and immunoblotting techniques. The rabbit antiserum reacted in immunoprecipitation and immunoblotting with constructs containing the appropriate NH2-terminal sequence and mAb reacted with a sequence from the midregion of PCNA. These experimentally induced antibodies also reacted with 15-mer synthetic peptides in enzyme-linked immunosorbent assay (ELISA). In contrast, none of the lupus sera reacted with synthetic peptides in ELISA. 9 of the 14 lupus sera also failed to react in Western immunoblotting with any recombinant fusion protein, although they all immunoprecipitated in vitro translated full-length protein. Four of the nine had variable patterns of immunoprecipitation with shorter constructs. The remaining five lupus sera were able to immunoprecipitate translation products as well as Western blot recombinant fusion proteins. From analysis of the patterns of reactivity of human lupus sera, it was deduced that the apparent heterogeneity of human autoantibodies to PCNA could be explained by immune response to highly conformational epitopes. These observations demonstrate that there might be special features in "native" epitopes of intranuclear antigens that are recognized by autoantibodies, and that these special features of native epitopes might not be present in prepared antigen used for experimental immunization. These features may be related to protein folding or to association of the antigen with other intranuclear proteins or nucleic acids, as might occur with antigens that are components of subcellular particles.

A methodology for investigating the impact of medical countermeasures on the risk of exposure induced death.

The space radiation environment is composed of ionizing particles that may pose health risks to crew members during Low Earth Orbit (LEO) and deep space missions. NASA has established astronaut career radiation limits for cancer of 3% Risk of Exposure Induced Death (REID) at the 95% confidence level. The REID is the increased lifetime risk of death from cancer due to radiation exposure in comparison to an unexposed background population and has been traditionally mitigated by passive shielding design concepts and limiting safe days in space. Additional reduction in radiation exposure risk may be achieved with Medical Countermeasures (MCM). Recent meta-analyses have demonstrated the efficacy of aspirin in the reduction of the background colorectal cancer incidence and mortality rates for specific cohorts. Additional studies of warfarin in patients greater than 50 years of age have indicated statistically significant decreases in stomach, bladder, brain, prostate, and lung cancer incidence as compared to control groups. While ultimate selection of suitable countermeasures will be the responsibility of flight surgeons, this paper presents a general methodology for incorporating MCM into the NASA Space Radiation Cancer Risk model and includes modifications of the background mortality rates (hazard rates) and the radiation risk coefficients to numerically quantify the benefits of MCM. As examples of the method, aspirin and warfarin will be employed as MCM in a sensitivity analysis to compute the REID for astronauts embarking on a one-year deep space mission scenario.

Multiple organ carcinogenicity of 1,3-butadiene in B6C3F1 mice after 60 weeks of inhalation exposure.

Groups of 50 male and 50 female B6C3F1 mice were exposed 6 hours per day, 5 days per week, for 60 to 61 weeks to air containing 0, 625, or 1250 parts per million 1,3-butadiene. These concentrations are somewhat below and slightly above the Occupational Safety and Health Administration standard of 1000 parts per million for butadiene. The study was designed for 104-week exposures but had to be ended early due to cancer-related mortality in both sexes at both exposure concentrations. There were early induction and significantly increased incidences of hemangiosarcomas of the heart, malignant lymphomas, alveolar-bronchiolar neoplasms, squamous cell neoplasms of the forestomach in males and females and acinar cell carcinomas of the mammary gland, granulosa cell neoplasms of the ovary, and hepatocellular neoplasms in females. Current workplace standards for exposure to butadiene should be reexamined in view of these findings.

Electrocardiographic ST-segment elevation: Takotsubo cardiomyopathy versus ST-segment elevation myocardial infarction--a case series.

Takotsubo cardiomyopathy, or left ventricular apical ballooning syndrome, is a newly described disorder in which patients develop anginal symptoms, often times with acute congestive heart failure, during periods of stress. The electrocardiogram demonstrates ST-segment and/or T-wave abnormalities similar to those findings seen in acute coronary events; on occasion, serum markers can be abnormal. As an extreme, acute pulmonary edema with or without cardiogenic shock can also be encountered. At cardiac catheterization, these patients are found to have abnormal left ventricular function yet normal coronary arteries. We compared 2 populations encountered in the emergency department (ED) population--Takotsubo cardiomyopathy and ST-segment elevation myocardial infarction. In the ED, features of the presentation and management were similar between the 2 groups with the exception of the presence of female sex and abnormal QT interval occurring more often in Takotsubo cardiomyopathy subgroup. These 2 cardiovascular maladies present in very similar fashion in the ED; distinction in the ED may not be possible.

Triage of Mild Head-Injured Intoxicated Patients Could Be Aided by Use of an Electroencephalogram-Based Biomarker.

OBJECTIVE: Drug and alcohol (DA)-related emergency department (ED) visits represent an increasing fraction the head-injured population seen in the ED. Such patients present a challenge to the evaluation of head injury and determination of need for computed tomographic (CT) scan and further clinical path. This effort examined whether an electroencephalogram (EEG)-based biomarker could aid in reducing unnecessary CT scans in the intoxicated ED population. METHOD: This is a retrospective secondary study of an independent prospective US Food and Drug Administration validation trial that demonstrated the efficacy of (1) an automatic Structural Injury Classifier for the likelihood of injury visible on a CT (CT+) and (2) an EEG-based Brain Function Index to assess functional impairment in minimally impaired, head-injured adults presenting within 3 days of injury. Impact on the biomarker performance in patients who presented with or without DA was studied. RESULTS: Structural Injury Classifier sensitivity was not significantly impacted by the presence of DA. Although specificity decreased, it remained several times higher than obtained using standard CT decision rules. Furthermore, the potential to reduce the number of unnecessary scans by approximately 30% was demonstrated when the Structural Injury Classifier was integrated into CT clinical triage. The Brain Function Index was demonstrated to be independent of the presence of DA. CONCLUSION: This EEG-based assessment technology used to identify the likelihood of structural or functional brain injury in mildly head-injured patients represents an objective way to aid in triage patients with DA on presentation, with the potential to decrease overscanning while not sacrificing sensitivity to injuries visible on CT.

Emergency Department Time Course for Mild Traumatic Brain Injury Workup.

INTRODUCTION: Mild traumatic brain injury (mTBI) is a common cause for visits to the emergency department (ED). The actual time required for an ED workup of a patient with mTBI in the United States is not well known. National emergency medicine organizations have recommended reducing unnecessary testing, including head computed tomography (CT) for these patients.10. METHODS: To examine this issue, we developed a care map that included each step of evaluation of mTBI (Glasgow Coma Scale Score 13-15) - from initial presentation to the ED to discharge. Time spent at each step was estimated by a panel of United States emergency physicians and nurses. We subsequently validated time estimates using retrospectively collected, real-time data at two EDs. Length of stay (LOS) time differences between admission and discharged patients were calculated for patients being evaluated for mTBI. RESULTS: Evaluation for mTBI was estimated at 401 minutes (6.6 hours) in EDs. Time related to head CT comprised about one-half of the total LOS. Real-time data from two sites corroborated the estimate of median time difference between ED admission and discharge, at 6.3 hours for mTBI. CONCLUSION: Limiting use of head CT as part of the workup of mTBI to more serious cases may reduce time spent in the ED and potentially improve overall ED throughput.