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Pharmacogenetic dosing improves the accuracy of warfarin dosing, but current pharmacogenetic dosing algorithms are less accurate in populations of African ancestry. The cytochrome P450 2C9*5 (CYP2C9*5) allele is found almost exclusively in populations of African ancestry, and in vitro studies suggest CYP2C9*5 is associated with reduced clearance of warfarin. The clinical relevance of this single‐nucleotide variation (SNV) (formerly SNP) is uncertain. In this multicentered study of 2,298 patients (49% female, 35% Black) taking warfarin, we quantified the association between the CYP2C9*5 allele and warfarin requirements. The CYP2C9*5 SNV was present in 2.3% of Black and 0.07% of White patients. Without taking CYP2C9*5 into account, pharmacogenetic algorithms that include other SNVs overestimated the warfarin dose by 30% (95% confidence interval (19–40%), P < 0.001), an average of 1.87 mg/day (SD 1.64) in heterozygotes (P < 0.001). Noncarriers required a slightly (0.23 mg/day, SD 2.09) higher than predicted dose. Genotyping for CYP2C9*5 corrected the potential overdose and halved overall dosing error in heterozygotes. Patients carrying CYP2C9*5 require a clinically relevant reduction in warfarin dose. Given the potential to improve the accuracy and safety of warfarin dosing in populations of African ancestry, we have incorporated this SNV into a nonprofit website to assist warfarin initiation (www.WarfarinDosing.org). [ABSTRACT FROM AUTHOR]

Background: The accuracy and speed by which acute myocardial infarction (AMI) is excluded are an important determinant of emergency department (ED) length of stay and resource utilization. While high‐sensitivity troponin I (hsTnI) >99th percentile (upper reference level [URL]) represents a "rule‐in" cutpoint, our purpose was to evaluate the ability of the Beckman Coulter hsTnI assay, using various level‐of‐quantification (LoQ) cutpoints, to rule out AMI within 3 hours of ED presentation in suspected acute coronary syndrome (ACS) patients. Methods: This multicenter evaluation enrolled adults with >5 minutes of ACS symptoms and an electrocardiogram obtained per standard care. Exclusions were ST‐segment elevation or chronic hemodialysis. After informed consent was obtained, blood samples were collected in heparin at ED admission (baseline), ≥1 to 3, ≥3 to 6, and ≥6 to 9 hours postadmission. Samples were processed and stored at –20°C within 1 hour and were tested at three independent clinical laboratories on an immunoassay system (DxI 800, Beckman Coulter). Analytic cutpoints were the URL of 17.9 ng/L and two LoQ cutpoints, defined as the 10 and 20% coefficient of variation (5.6 and 2.3 ng/L, respectively). A criterion standard MI diagnosis was adjudicated by an independent endpoint committee, blinded to hsTnI, and using the universal definition of MI. Results: Of 1,049 patients meeting the entry criteria, and with baseline and 1‐ to 3‐hour hsTnI results, 117 (11.2%) had an adjudicated final diagnosis of AMI. AMI patients were typically older, with more cardiovascular risk factors. Median (IQR) presentation time was 4 (1.6–16.0) hours after symptom onset, although AMI patients presented ~0.5 hour earlier than non‐AMI. Enrollment and first blood draw occurred at a mean of ~1 hour after arrival. To evaluate the assay's rule‐out performance, patients with any hsTnI > URL were considered high risk and were excluded. The remaining population (n = 829) was divided into four LoQ relative categories: both hsTnI < LoQ (Lo‐Lo cohort); first hsTnI < LoQ and 2nd > LoQ (Lo‐Hi cohort); first > LoQ and second < LoQ (Hi‐Lo cohort); or both > LoQ (Hi‐Hi cohort). In patients with any hsTnI result <20% CV LoQ (Groups 1–3), n = 231 (23.9% ruled out), AMI negative predictive value (NPV) was 100% (95% confidence interval [CI] = 98.9% to 100%). In patients with any hsTnI below the 10% LoQ, n = 611 (58% rule out), AMI NPV was 100% (95% CI = 99.5% to 100%). Of the Hi‐Hi cohort (i.e., no hsTnI below the 10% LoQ, but both < URL), there were four AMI patients, NPV was 98.2% (95% CI = 95.4% to 99.3%), and sensitivity was 96.6. Conclusions: Patients presenting >3 hours after the onset of suspected ACS symptoms, with at least two Beckman Coulter Access hsTnI < URL and at least one of which is below either the 10 or the 20% LoQ, had a 100% NPV for AMI. Two hsTnI values 1 to 3 hours apart with both < URL, but also >LoQ had inadequate sensitivity and NPV. [ABSTRACT FROM AUTHOR]

Key Clinical Message Susceptibility to quinoline antimalarial intoxication may reflect individual genetic and drug-induced variation in neuropharmacokinetics. In this report, we describe a case of chloroquine intoxication that appeared to be prolonged by subsequent use of multiple psychotropic medications. This case highlights important new considerations for the management of quinoline antimalarial intoxication. [ABSTRACT FROM AUTHOR]

Objectives Chest pain is a common complaint to emergency departments ( EDs) and clinical risk factors are used to predict which patients are at risk for worse outcomes and mortality. The goal was to assess the novel biomarker midregional proadrenomedullin ( MR-pro ADM) in prediction of mortality and major adverse cardiac events ( MACE). Methods This was a subanalysis of the CHOPIN study, a 16-center prospective trial that enrolled 2,071 patients presenting with chest pain within 6 hours of onset. The primary endpoint was 6-month all-cause mortality and the secondary endpoint was 30-day and 6-month MACE: ED visits or hospitalization for acute myocardial infarction, unstable angina, reinfarction, revascularization, and heart failure. Results MR-pro ADM performed similarly to troponin ( cTnI; c-statistic = 0.845 and 0.794, respectively) for mortality prediction in all subjects and had similar results in those with noncardiac diagnoses. MR-pro ADM concentrations were stratified by decile, and the cohort in the top decile had a 9.8% 6-month mortality risk versus 0.9% risk for those in the bottom nine deciles (p < 0.0001). MR-pro ADM, history of coronary artery disease ( CAD), and hypertension were predictors of short-term MACE, while history of CAD, hypertension, cTnI, and MR-pro ADM were predictors of long-term MACE. Conclusions In patients with chest pain, MR-pro ADM predicts mortality and MACE in all-comers with chest pain and has similar prediction in those with a noncardiac diagnosis. This exploratory analysis is primarily hypotheses-generating and future prospective studies to identify its utility in risk stratification should be considered. [ABSTRACT FROM AUTHOR]

Fentanyl deaths have increased with availability of transdermal patches. Interpretation of postmortem fentanyl levels may be complicated by postmortem redistribution and absorption of fentanyl from a patch. We applied an unused 100-μg/h fentanyl patch onto the lower abdomen of a decedent with no premortem fentanyl exposure. Ocular fluid, blood, and urine were collected prior to placement, and the decedent was refrigerated for 23 h. Prior to the autopsy, urine, subcutaneous tissue under the patch, and samples from the same anatomic sites were obtained. We observed no fentanyl in any postpatch placement samples ( LOD: 0.1 ng/mL for blood and vitreous fluid, 1.0 ng/mL urine, 2.0 ng/g for tissues). Although we observed no postmortem absorption of fentanyl, this was only a single case; therefore, we recommend that patches be removed after receipt of a cadaver before initiation of an autopsy, with the location of removed patch documented. [ABSTRACT FROM AUTHOR]

ACADEMIC EMERGENCY MEDICINE 2011; 18:947-958 © 2011 by the Society for Academic Emergency Medicine Abstract Objectives: Few tools exist that provide objective accurate prediction of short-term mortality risk in patients presenting with acute heart failure (AHF). The purpose was to describe the accuracy of several biomarkers for predicting short-term death rates in patients diagnosed with AHF in the emergency department (ED). Methods: The Biomarkers in ACute Heart failure (BACH) trial was a prospective, 15-center, international study of patients presenting to the ED with nontraumatic dyspnea. Clinicians were blinded to all investigational markers, except troponin and natriuretic peptides, which used the local hospital reference range. For this secondary analysis, a core lab was used for all markers except troponin. This study evaluated patients diagnosed with AHF by the on-site emergency physician (EP). Results: In the 1,641 BACH patients, 466 (28.4%) had an ED diagnosis of AHF, of whom 411 (88.2%) had a final diagnosis of AHF. In the ED-diagnosed HF patients, 59% were male, 69% had a HF history, and 19 (4.1%) died within 14 days of their ED visit. The area under the curve (AUC) for the 14-day mortality receiver operating characteristic (ROC) curve was 0.484 for brain natriuretic peptide (BNP), 0.586 for N-terminal pro-B-type natriuretic peptide (NT-proBNP), 0.755 for troponin (I or T), 0.742 for adrenomedullin (MR-proADM), and 0.803 for copeptin. In combination, MR-proADM and copeptin had the best 14-day mortality prediction (AUC = 0.818), versus all other markers. Conclusions: MR-proADM and copeptin, alone or in combination, may provide superior short-term mortality prediction compared to natriuretic peptides and troponin. Presented results are explorative due to the limited number of events, but validation in larger trials seems promising. [ABSTRACT FROM AUTHOR]

We employed physiogenomic analyses to investigate the relationship between myalgia and selected polymorphisms in serotonergic genes, based on their involvement with pain perception and transduction of nociceptive stimuli. We screened 195 hypercholesterolemic, statin-treated patients, all of whom received either atorvastatin, simvastatin, or pravastatin. Patients were classified as having no myalgia, probable myalgia, or definite myalgia, and assigned a myalgia score of 0, 0.5, or 1, respectively. Fourteen single nucleotide polymorphisms (SNPs) were selected from candidates within the 5-HT receptor gene families [5a-hydroxytryptamine receptor genes ( HTR) 1D, 2A, 2C, 3A, 3B, 5A, 6, 7] and the serotonin transporter gene ( SLC6A4). SNPs in the HTR3B and HTR7 genes, rs2276307 and rs1935349, respectively, were significantly associated with the myalgia score. Individual differences in pain perception and nociception related to specific serotonergic gene variants may affect the development of myalgia in statin-treated patients. Muscle Nerve, 2007 [ABSTRACT FROM AUTHOR]

This study compares endogenous serum growth hormone concentrations over a 24-hour period in patients with chronic heart failure (CHF) and matched controls. Design: Prospective, 24-hour, endogenous concentration comparison. Setting: Hospital research center. Patients: Eight evaluable patients with nonischemic dilated cardiomyopathy and 10 healthy control subjects, matched for age and sex. Intervention: Over a 24-hour period, blood was drawn from the study participants every 20 minutes for determination of growth hormone. Measurements and Main Results: For each patient, the area under the concentration-time curve from time 0-24 hours (AUC[sub0-24]), maximum concentration (C[submax]), and minimum concentration (C[subnadir]) of growth hormone were determined. The AUC[sub0-24] and C[submax] were 74% (p<0.05) and 62% (p<0.05) lower in patients with CHF than in controls, respectively. The C[subnadir] for all participants was 0 μg/L. Variability in growth hormone concentrations over the 24 hours was considerable for all study participants. Conclusions: Growth hormone concentrations are suppressed over a 24-hour period in patients with CHF versus healthy controls. Variability in levels throughout the day suggests that a single point evaluation cannot be used to determine deficiency or abundance of growth hormone. [ABSTRACT FROM AUTHOR]

Reimbursement policies for health care services are greatly diminishing in the U.S. and Western Europe. Hence, there is an increasing need for doctors and other care givers to reduce costs without compromising the quality of the care being delivered. The clinical laboratory is viewed as an area of high costs where significant reductions have been targeted. Efficient utilization of laboratory services can be achieved by elimination of the general health panel, removal of old tests or those that provide redundant information, a reduction in the use of standing orders, more judicious use of drug assays, acceptance of clinical practice guidelines, and use of reflex testing algorithms. New technologies such as DNA probes can substantially improve diagnostic efficiency. Point-of-care testing devices which have higher costs than incremental central laboratory expenses should only be used if they reduce overall operating expenses. Implementation of expert systems can make remaining tests more effective. Doctors and laboratorians must collaborate to achieve more efficient utilization practices. [ABSTRACT FROM AUTHOR]

A case is presented of a 39-year-old woman who suffered severe debilitation because of a hemorrhagic stroke in the context of substance abuse. The patient presented to the emergency room with rapidly diminishing mental status, hypertension, and vasoconstriction; her friends provided a history of ingestion of cocaine, 3,4-methylenedioxymethamphetamine (MDMA), and 2C-I, a novel designer amine. A multi-targeted LC-MS/MS method for sympathomimetic amines and related drugs in urine detected and quantified 2C-I and MDA, while ruling out MDMA. The cause of the stroke was determined to be an underlying cerebrovascular abnormality called Moyamoya, secondary to substance abuse. In clinical laboratories, gas chromatography–mass spectrometry or liquid chromatography–tandem mass spectrometry (LC-MS/MS) confirmation of a positive amphetamine immunoassay is usually directed only towards amphetamine, methamphetamine, MDMA and MDA. This report demonstrates the utility of testing for a wider menu of compounds using LC-MS/MS in order to better characterize the prevalence and toxicities of novel amines such as 2C-I. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented entitled "Transfusion-related acute lung injury and transfusion-associated circulatory overload: Mutually exclusive or coexisting entities?" published within the issue.

Background: Brain-type natriuretic peptide (BNP) and the amino-terminal fragment of its prohormone (NT-proBNP) are known predictors of cardiovascular outcomes in patients with coronary heart disease; however, the relative prognostic value of these 2 biomarkers for secondary events remains unclear., Methods and Results: In 983 participants with stable coronary heart disease, we evaluated the association of BNP and NT-proBNP with time to hospitalization for heart failure, nonfatal myocardial infarction, stroke or transient ischemic attack, cardiovascular death, and combined major adverse cardiovascular events (MACE). During an average follow-up of 6.5±3.3 years, both BNP and NT-proBNP were associated with increased risk of MACE in a multivariable-adjusted model (hazard ratio per standard deviation of log BNP: 1.58; 95% CI: 1.32 to 1.89; hazard ratio per standard deviation of log NT-proBNP: 1.84; 95% CI: 1.52 to 2.24). When added to traditional risk factors, NT-proBNP predicted MACE better than BNP (C statistic: 0.76 versus 0.72, P<0.001). Similarly, the addition of NT-proBNP resulted in a greater net reclassification improvement for predicting MACE than the addition of BNP (65% for NT-proBNP, 56% for BNP)., Conclusions: Both BNP and NT-proBNP were significant predictors of MACE in stable coronary heart disease; however, NT-proBNP was superior to BNP for net risk reclassification for MACE., (© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

While anemia is a significant risk factor for poor outcomes in patients with heart failure (HF), it is not in defined guidelines for HF assessment. B-type natriuretic peptide (BNP) is a marker for diagnosis and management of patients with HF. We determined the incidence of anemia in patients with HF and the relationship between BNP and hemoglobin (Hgb) levels in patients with and without HF. Results from the Breathing Not Properly Multinational Trial consisted of 1,586 patients presenting to the emergency department (ED) with dyspnea. Because renal insufficiency is a confounding variable for BNP, patients with a creatinine of >or=2.0 mg/dL were excluded. The remaining data were evaluated from 620 non-HF patients (337 M, 283 F) and 547 HF patients (299 M, 248 F). The New York Heart Association (NYHA) HF classification and ejection fraction by echocardiography were assessed for HF patients. Blood was tested for Hgb, BNP, and creatinine. Using World Health Organization criteria for anemia, we observed that HF patients in NYHA class III or IV had lower mean Hgb levels (12.5 g/dL, P < 0.05) and a higher incidence of anemia (48.2%, P < 0.05) than did HF patients in class I or II (13.4 g/dL and 33.9%, respectively). There was no correlation between Hgb and log BNP for females without HF or the aggregate of all HF patients. In contrast, a significant inverse correlation was observed for males without HF (P < 0.001). Although there were differences in the BMI, age, and estimated glomerular filtration rate (eGFR) versus Hgb observed in this group, the log BNP correlation remained significant after multivariate analysis. A significant inverse correlation for log BNP and Hgb were also observed for diastolic (EF >or= 50) HF (P < 0.05) that was also not accounted for by the BMI, age, or eGFR. The presence of anemia is associated with worsening HF at ED presentation. For males without HF and diastolic HF patients of both genders, a low Hgb may be a confounding variable toward increasing BNP. Among systolic HF patients, the presence of a low hemoglobin concentration is not a factor in the interpretation of BNP results.