Ambient air pollution and consumer spending: Evidence from Spain.

Research on the economic burden of air pollution has focused primarily on its macroeconomic impact. However, as some studies have found that air pollution can lead to avoidance behavior-for example, reducing the time spent outdoors-we hypothesize that it can also influence consumer spending activity. We combine high frequency data on ozone and fine particulate pollution with daily consumer spending in brick-and-mortar retail in 129 postal codes in Spain during 2014 to estimate the association between the two. Using a linear fixed effects model, we find that a 1-standard deviation increase in ozone concentration (20.97 µg/m3) is associated with 3.9 percent decrease in consumer spending (95% CI: -0.066, -0.012; p<0.01). The association of fine particulate matter with consumer spending is, however, not statistically significant (ß: 0.005; 95% CI: -0.009, 0.018; p>0.10). Further, we do not observe a sufficiently strong bounce-back in consumer spending in the day-or even the week-following higher ozone concentration. Also, we find that the relationship between ozone concentration and consumer spending is heterogeneous, with those aged below 25 and those aged 45 or above exhibiting stronger negative association. This research informs policymakers about a plausibly unaccounted cost of ambient air pollution, even at concentrations lower than the WHO air quality guideline for short-term exposure.

Glomerular Disease in Temporal Association with SARS-CoV-2 Vaccination: A Series of 29 Cases.

Background: Immune responses to vaccination are a known trigger for a new onset of glomerular disease or disease flare in susceptible individuals. Mass immunization against SARS-CoV-2 in the COVID-19 pandemic provides a unique opportunity to study vaccination-associated autoimmune kidney diseases. In the recent literature, there are several patient reports demonstrating a temporal association of SARS-CoV-2 immunization and kidney diseases. Methods: Here, we present a series of 29 cases of biopsy-proven glomerular disease in patients recently vaccinated against SARS-CoV-2 and identified patients who developed a new onset of IgA nephropathy, minimal change disease, membranous nephropathy, ANCA-associated GN, collapsing glomerulopathy, or diffuse lupus nephritis diagnosed on kidney biopsies postimmunization, as well as recurrent ANCA-associated GN. This included 28 cases of de novo GN within native kidney biopsies and one disease flare in an allograft. Results: The patients with collapsing glomerulopathy were of Black descent and had two APOL1 genomic risk alleles. A brief literature review of patient reports and small series is also provided to include all reported cases to date (n=52). The incidence of induction of glomerular disease in response to SARS-CoV-2 immunization is unknown; however, there was no overall increase in incidence of glomerular disease when compared with the 2 years prior to the COVID-19 pandemic diagnosed on kidney biopsies in our practice. Conclusions: Glomerular disease to vaccination is rare, although it should be monitored as a potential adverse event.

Neutrophilic dermatosis of the dorsal hands in an elderly man.

recently diagnosed with stage II lung adenocarcinoma, who presented to the clinic with a 14-day history of painful macules that progressed to bullae on the dorsal surface of his hands; decreased range of motion was noted. Examination revealed bilateral small, tender violaceous vesicopustules admixed with larger tense hemorrhagic pus-filled bullae on the dorsal aspect of his hands. Biopsy demonstrated changes consistent with neutrophilic dermatosis of the dorsal hands. The patient had been diagnosed with ulcerative colitis in the 1970s, although the condition was asymptomatic at the time of presentation. Treatment with prednisone 60 mg daily resulted in significant improvement by the next day. This regimen was continued for two weeks and was followed by a 6-week steroid taper. After a review of the approximate 75 cases currently reported, we also discuss the recurrence rate of NDDH of approximately 10%.

Melanoma-derived factors alter the maturation and activation of differentiated tissue-resident dendritic cells.

Dendritic cells (DCs) are key regulators of host immunity that are capable of inducing either immune tolerance or activation. In addition to their well-characterized role in shaping immune responses to foreign pathogens, DCs are also known to be critical for the induction and maintenance of anti-tumor immune responses. Therefore, it is important to understand how tumors influence the function of DCs and the quality of immune responses they elicit. Although the majority of studies in this field to date have utilized either immortalized DC lines or DC populations that have been generated under artificial conditions from hematopoietic precursors in vitro, we wished to investigate how tumors impact the function of already differentiated, tissue-resident DCs. Therefore, we used both an ex vivo and in vivo model system to assess the influence of melanoma-derived factors on DC maturation and activation. In ex vivo studies with freshly isolated splenic DCs, we demonstrate that the extent to which DC maturation and activation are altered by these factors correlates with melanoma tumorigenicity, and we identify partial roles for tumor-derived transforming growth factor (TGF)ß1 and vascular endothelial growth factor (VEGF)-A in the altered functionality of DCs. In vivo studies using a lung metastasis model of melanoma also demonstrate tumorigenicity-dependent alterations to the function of lung-resident DCs, and skewed production of proinflammatory cytokines and chemokines by these tumor-altered cells is associated with recruitment of an immune infiltrate that may ultimately favor tumor immune escape and outgrowth.

Diagnostic yield of routine noninvasive cardiovascular testing in low-risk acute chest pain patients.

Contemporary professional society recommendations for patients presenting to the emergency department with acute chest pain and low clinical risk encourage noninvasive testing for coronary artery disease (CAD) before, or shortly after, discharge from the emergency department. Recent reports indicate that a strategy of universal testing has a low diagnostic yield and may not be necessary. We examined data from a prospective cohort of patients who underwent evaluation of acute chest pain in our chest pain evaluation center (CPEC). Patients presenting with normal initial electrocardiogram and cardiac injury markers were eligible for observation and noninvasive testing for CAD in our CPEC. All patients were asked to participate in the prospective registry. The 213 subjects who consented were young, obese, and predominantly women (mean age 43.8 ± 12.5, mean body mass index of 30.8 ± 7, 64.8% women). Prevalence of diabetes was 10.3% (hypertension 37.1%, hyperlipidemia 17.8%, and current tobacco use 23.5%) Exercise treadmill testing was the primary method of evaluation (n = 104, 49%) followed by computed tomography coronary angiography (n = 58, 27%) and myocardial perfusion imaging (n = 20, 9%). Of 203 patients who underwent testing, 11 had abnormal test results, 4 of whom had obstructive CAD based on invasive coronary angiography. The positive predictive value for obstructive CAD after an abnormal test was 45.5%, and the overall diagnostic yield for obstructive CAD was 2.5%. In conclusion, in patients with acute chest pain evaluated in a CPEC, the yield of routine use of noninvasive testing for CAD was minimal and the positive predictive value of an abnormal test was low.

An unusual case of nonsustained ventricular tachycardia.

A 54-year-old woman with advanced cirrhosis secondary to hepatitis C, end-stage kidney failure on hemodialysis, and nonischemic cardiomyopathy was admitted to the medical intensive care unit for treatment of a superior vena cava (SVC) thrombus involving a recently implanted cardioverter-defibrillator (ICD). During her hospitalization, the patient abruptly developed frequent ventricular ectopy with up to 20 beat runs of hemodynamically significant nonsustained ventricular tachycardia. Because ventricular ectopy was not previously seen in the patient, the sudden onset prompted a thorough evaluation. After other causes were excluded, a recently placed scopolamine patch was removed; the ventricular ectopy completely resolved within 24 hours and did not recur for the remainder of the patient's extended hospitalization. While anticholinergic syndrome is associated with a vagally mediated sinus tachycardia, ventricular arrhythmias have not previously been reported with scopolamine, to the best of the authors' knowledge. The observed cardiac side effects of scopolamine rarely occur at therapeutic doses. Scopolamine is metabolized primarily in the liver and excreted by the kidneys, so renal and hepatic impairment should be considered when initiating and dosing this medication. Because anticholinergic medications including scopolamine are commonly used in various clinical settings, we believe that clinicians should be aware of this significant but completely reversible adverse effect.

Metrics of quality care in veterans: correlation between primary-care performance measures and inappropriate myocardial perfusion imaging.

BACKGROUND: Approximately 10% to 20% of myocardial perfusion imaging (MPI) tests are inappropriate based on professional-society recommendations. The correlation between inappropriate MPI and quality care metrics is not known. HYPOTHESIS: Inappropriate MPI will be associated with low achievement of quality care metrics. METHODS: We conducted a retrospective cross-sectional investigation at a single Veterans Affairs medical center. Myocardial perfusion imaging tests ordered by primary-care clinicians between December 2010 and July 2011 were assessed for appropriateness (by 2009 criteria). Using documentation of the clinical encounter where MPI was ordered, we determined how often quality care metrics were achieved. RESULTS: Among 516 MPI patients, 52 (10.1%) were inappropriate and 464 (89.9%) were not inappropriate (either appropriate or uncertain). Hypertension (82.2%), diabetes mellitus (41.3%), and coronary artery disease (41.1%) were common. Glycated hemoglobin levels were lower in the inappropriate MPI cohort (6.6% vs 7.5%; P = 0.04). No difference was observed in the proportion with goal hemoglobin (62.5% vs 46.3% for appropriate/uncertain; P = 0.258). Systolic blood pressure was not different (132 mm Hg vs 135 mm Hg; P = 0.34). Achievement of several other categorical quality metrics was low in both cohorts and no differences were observed. More than 90% of clinicians documented a plan to achieve most metrics. CONCLUSIONS: Inappropriate MPI is not associated with performance on metrics of quality care. If an association exists, it may be between inappropriate MPI and overly aggressive care. Most clinicians document a plan of care to address failure of quality metrics, suggesting awareness of the problem.

An update to returning genetic research results to individuals: perspectives of the industry pharmacogenomics working group.

The ease with which genotyping technologies generate tremendous amounts of data on research participants has been well chronicled, a feat that continues to become both faster and cheaper to perform. In parallel to these advances come additional ethical considerations and debates, one of which centers on providing individual research results and incidental findings back to research participants taking part in genetic research efforts. In 2006 the Industry Pharmacogenomics Working Group (I-PWG) offered some 'Points-to-Consider' on this topic within the context of the drug development process from those who are affiliated to pharmaceutical companies. Today many of these points remain applicable to the discussion but will be expanded upon in this updated viewpoint from the I-PWG. The exploratory nature of pharmacogenomic work in the pharmaceutical industry is discussed to provide context for why these results typically are not best suited for return. Operational challenges unique to this industry which cause barriers to returning this information are also explained.

D-dimer: simple test, tough problems.

CONTEXT: D-dimer is widely used for exclusion, or as an aid in diagnosis, of venous thromboembolism (VTE); however, the D-dimer assay methods available from manufacturers and the laboratory application of those methods vary widely. OBJECTIVES: To describe the current laboratory practice regarding the assay and reporting of D-dimer. DESIGN: Laboratories' D-dimer proficiency testing data were analyzed and laboratory practices regarding the performance and reporting of D-dimer were surveyed. RESULTS: Initial grading of D-dimer proficiency testing demonstrated high variability within and among methods. This variability continued to be present for several years after attempts to intervene. The number of laboratories using D-dimer to exclude VTE grew from 1500 in 2004 to more than 3500 in 2012. Survey and proficiency testing data demonstrated that 33% of laboratories changed the type or magnitude of units from that recommended by the manufacturer, a practice associated with as much as a 20-fold increase in the failure of proficiency testing. Many laboratories used a threshold for the exclusion of VTE that is higher than that recommended by the manufacturer. Many laboratories continue to use qualitative assays with insufficient sensitivity for exclusion of VTE. CONCLUSIONS: There is considerable variability both within and among quantitative methods used to assay D-dimer by laboratories. Laboratory practice continues to vary widely regarding the type and magnitude of units reported and the setting of the threshold for the exclusion of VTE. Although improved, the variability continues despite initial efforts to intervene.

Safety and pharmacokinetics of the antisense oligonucleotide (ASO) LY2181308 as a single-agent or in combination with idarubicin and cytarabine in patients with refractory or relapsed acute myeloid leukemia (AML).

Survivin is expressed in tumor cells, including acute myeloid leukemia (AML), regulates mitosis, and prevents tumor cell death. The antisense oligonucleotide sodium LY2181308 (LY2181308) inhibits survivin expression and may cause cell cycle arrest and restore apoptosis in AML. In this study, the safety, pharmacokinetics, and pharmacodynamics/efficacy of LY2181308 was examined in AML patients, first in a cohort with monotherapy (n = 8) and then post-amendment in a cohort with the combination of cytarabine and idarubicin treatment (n = 16). LY2181308 was administered with a loading dosage of three consecutive daily infusions of 750 mg followed by weekly intravenous (IV) maintenance doses of 750 mg. Cytarabine 1.5 g/m(2) was administered as a 4-hour IV infusion on Days 3, 4, and 5 of Cycle 1, and idarubicin 12 mg/m(2) was administered as a 30-minute IV infusion on Days 3, 4, and 5 of Cycle 1. Cytarabine and idarubicin were administered on Days 1, 2, and 3 of each subsequent 28-day cycle. Reduction of survivin was evaluated in peripheral blasts and bone marrow. Single-agent LY2181308 was well tolerated and survivin was reduced only in patients with a high survivin expression. In combination with chemotherapy, 4/16 patients had complete responses, 1/16 patients had incomplete responses, and 4/16 patients had cytoreduction. Nine patients died on study: 6 (monotherapy), 3 (combination). LY2181308 alone is well tolerated in patients with AML. In combination with cytarabine and idarubicin, LY2181308 does not appear to cause additional toxicity, and has shown some clinical benefit needing confirmation in future clinical trials.

Biomarkers of the Hedgehog/Smoothened pathway in healthy volunteers.

The Hedgehog (Hh) pathway is involved in oncogenic transformation and tumor maintenance. The primary objective of this study was to select surrogate tissue to measure messenger ribonucleic acid (mRNA) levels of Hh pathway genes for measurement of pharmacodynamic effect. Expression of Hh pathway specific genes was measured by quantitative real time polymerase chain reaction (qRT-PCR) and global gene expression using Affymetrix U133 microarrays. Correlations were made between the expression of specific genes determined by qRT-PCR and normalized microarray data. Gene ontology analysis using microarray data for a broader set of Hh pathway genes was performed to identify additional Hh pathway-related markers in the surrogate tissue. RNA extracted from blood, hair follicle, and skin obtained from healthy subjects was analyzed by qRT-PCR for 31 genes, whereas 8 samples were analyzed for a 7-gene subset. Twelve sample sets, each with ≤500 ng total RNA derived from hair, skin, and blood, were analyzed using Affymetrix U133 microarrays. Transcripts for several Hh pathway genes were undetectable in blood using qRT-PCR. Skin was the most desirable matrix, followed by hair follicle. Whether processed by robust multiarray average or microarray suite 5 (MAS5), expression patterns of individual samples showed co-clustered signals; both normalization methods were equally effective for unsupervised analysis. The MAS5- normalized probe sets appeared better suited for supervised analysis. This work provides the basis for selection of a surrogate tissue and an expression analysis-based approach to evaluate pathway-related genes as markers of pharmacodynamic effect with novel inhibitors of the Hh pathway.

Quantitative measurement of cell-free plasma DNA and applications for detecting tumor genetic variation and promoter methylation in a clinical setting.

An elevated cell-free DNA (cfDNA) level is often reported in patients with advanced cancer and is thought to represent nuclear material from a distant inaccessible tumor. cfDNA can become a valuable source to monitor tumor dynamics and evaluate genetic markers for predictive, prognostic, and diagnostic testing. DNA extraction and quantification were optimized with plasma collected from 20 patients with advanced cancer and 16 healthy controls. Plasma cfDNA from patients with advanced cancer was evaluated for TP53 genetic variation and methylation status of CpG islands in several promoters of known disease-related genes. Tumor biopsy and corresponding plasma specimens were collected from study participants to determine whether the same genetic variations were present in both samples. The cfDNA isolation method provided a lower DNA detection limit of 144 pg, equivalent to DNA from approximately 24 cells. Normal pooled human plasma cfDNA averaged 110 copies/mL of the ACTB gene. Extracted cfDNA was suitable for gene-specific variant detection, sequencing, and promoter methylation analysis. DNA extracted from tumor biopsy and corresponding plasma specimens from two patients with advanced cancer revealed an identical, nonsynonymous variant present in both samples. Immunohistochemical analysis confirmed the TP53 mutant phenotype in the tumor specimens. Quantitative measurement of cfDNA represents a useful biomarker to follow treatment outcome and is a valuable tool with which to characterize specific genetic alterations for both patient selection and personalized treatment.

Risk factors for the hemolytic uremic syndrome in children infected with Escherichia coli O157:H7: a multivariable analysis.

BACKGROUND: Escherichia coli O157:H7 is the leading cause of hemolytic uremic syndrome (HUS). Risk factors for development of this complication warrant identification. METHODS: We enrolled children infected with E. coli O157:H7 within 1 week of the onset of diarrhea in this prospective cohort study. The study was conducted in 5 states over 9.5 years . The primary and secondary outcomes were HUS (hematocrit <30% with smear evidence of hemolysis, platelet count <150 × 10(3)/µL, and serum creatinine concentration > upper limit of normal for age) and oligoanuric HUS. Univariate and multivariable and ordinal multinomial regression analyses were used to test associations between factors apparent during the first week of illness and outcomes. RESULTS: Of the 259 children analyzed, 36 (14%) developed HUS. Univariate analysis demonstrated that children who received antibiotics during the diarrhea phase more frequently developed HUS than those who did not (36% vs 12%; P = .001). The higher rate of HUS was observed across all antibiotic classes used. In multivariable analysis, a higher leukocyte count (adjusted odds ratios [aOR] 1.10; 95% CI, 1.03-1.19), vomiting (aOR 3.05; 95% CI, 1.23-7.56), and exposure to antibiotics (aOR 3.62; 95% CI, 1.23-10.6) during the first week of onset of illness were each independently associated with development of HUS. Multinomial ordinal logistic regression confirmed that initial leukocyte count and antibiotic use were independently associated with HUS and, additionally, these variables were each associated with the development of oligoanuric HUS. CONCLUSIONS: Antibiotic use during E. coli O157:H7 infections is associated with a higher rate of subsequent HUS and should be avoided.

Association of long-term administration of the survivin mRNA-targeted antisense oligonucleotide LY2181308 with reversible kidney injury in a patient with metastatic melanoma.

A 57-year-old man with metastatic melanoma was treated with the survivin inhibitor and antisense oligonucleotide LY2181308 as part of a First-in-Human Dose trial. After 18 months of treatment, he developed kidney injury and the treatment was discontinued. At 9 months and before the development of kidney injury, LY2181308 concentrations were 8- to 10-fold higher relative to median predicted values, but within the targeted exposure considered to be safe. However, at 17 months, 28 days after stopping LY2181308 therapy, LY2181308 concentration exceeded the predicted range by 38-fold. His decreased kidney function was slow to improve after stopping treatment. A kidney biopsy showed signs of acute tubular injury with regeneration. Complete recovery of kidney function occurred 6 months after treatment was stopped. The relationship between high exposures and slow LY2181308 clearance with the gradual improvement in kidney function after stopping the antisense treatment suggests that the oligonucleotide was related to the kidney injury. Based on this case report, kidney function should be monitored frequently in patients receiving long-term treatment with antisense oligonucleotides that specifically target survivin, particularly when they receive concomitant angiotensin-converting enzyme inhibitors or nonsteroidal anti-inflammatory drugs.

Validation of the revised Schwartz estimating equation in a predominantly non-CKD population.

Recently, Schwartz et al. (J Am Soc Nephrol 20:629-637, 2009) used data from the National Institutes of Health-funded Chronic Kidney Disease in Children (CKiD) study to generate new equations for estimating the glomerular filtration rate (eGFR), including an update of the commonly used bedside equation. However, it is unclear if the equation can be generalized to a broader pediatric population. We have used the updated equation on a sample of pediatric patients with less impaired renal function to evaluate the correlation between the new Schwartz equation and measured GFR by iothalamate clearance. We retrospectively analyzed 738 iothalamate clearance tests from 503 patients with a mean serum creatinine of 0.50 mg/dl whose ages ranged from 1 to 16 years. We measured bias, precision, and accuracy and performed a Bland-Altman plot to determine the measure of agreement between the two methods. The mean GFR by iothalamate clearance was 110.6 ml/min/1.73 m(2) and by the new Schwartz estimation 104.7 ml/min/1.73 m(2). The mean difference was 5.84 ml/min/1.73 m(2) (95% CI 4.00-7.67). The newly purposed bedside Schwartz equation therefore demonstrated good agreement with the iothalamate renal clearances in our patient population and appears to be a valid bedside estimating equation for GFR in this sample of children.

Orthostatic proteinuria and the spectrum of diurnal variability of urinary protein excretion in healthy children.

The aim of this study was to characterize the 24-h and diurnal variability of urinary protein excretion and identify the prevalence of orthostatic proteinuria (OP) in healthy children. Upright, supine, and 24-h total urinary protein (UrTP) and creatinine clearance (CrCl) were measured in 91 healthy children ages 6-19 years. Urinary protein and creatinine excretions were calculated and examined by gender, age, Tanner stage, and body mass index (BMI). Orthostatic proteinuria (OP) was defined as a 24-h UrTP >100 mg/m(2) with a normal supine UrTP (<4 mg/m(2)/h). There exists a marked diurnal variability in UrTP. The upright UrTP rate was three to four-times greater than the supine rate. UrTP, adjusted for body surface area, is higher in boys than girls and increases with age and BMI. There is a similar increase in upright CrCl compared with supine. Urinary protein to creatinine ratio (UPcr) is strongly correlated with UrTP. OP is common, being found in 20% of children in this cohort, and is more common in boys and associated with age >10 years and BMI >85%. In children with OP, a first morning UPcr shows a value in the normal range, whereas a random daytime UPcr is elevated. There exists a diurnal variability in urinary protein excretion that is exaggerated in participants with OP. UPcr reliably estimates 24-h UrTP. Using current pediatric criteria, OP is very common, particularly in boys. A normal first morning UPcr ratio indicates that a child with elevated random urinary protein has OP.

Inhibition of platelet aggregation with prasugrel and clopidogrel: an integrated analysis in 846 subjects.

This integrated analysis compared speed of onset, level of platelet inhibition, and response variability to prasugrel and clopidogrel in healthy subjects and in patients with stable coronary artery disease with data pooled from 24 clinical pharmacology studies. Data from subjects (N = 846) were categorized into the following treatment groups: prasugrel 60 mg loading dose (LD)/10 mg maintenance dose (MD), clopidogrel 300 mg LD/75 mg MD, or clopidogrel 600 mg LD/75 mg MDs. Maximum platelet aggregation (MPA) and inhibition of platelet aggregation (IPA) to 5 and 20 muM ADP were assessed by turbidimetric aggregometry. A linear mixed-effect model compared the MPA and IPA between treatments over time points evaluated in the integrated database, and covariates affecting platelet inhibition were identified. Prasugrel 60 mg LD resulted in faster onset, greater magnitude, and more consistent levels of inhibition of platelet function compared to either clopidogrel 300 mg or 600 mg LDs. Greater and more consistent levels of platelet inhibition were observed with the prasugrel 10 mg MD compared to the clopidogrel 75 mg MD. This integrated analysis confirms the findings of earlier individual studies, that prasugrel achieves faster onset of greater extent and more consistent platelet inhibition compared to the approved and higher loading doses of clopidogrel. Gender, race, body weight, and age were identified as statistically significant covariates impacting platelet inhibition.

Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes.

BACKGROUND: Both clopidogrel and prasugrel require biotransformation to active metabolites by cytochrome P450 (CYP) enzymes. Among persons treated with clopidogrel, carriers of reduced-function CYP2C19 alleles have significantly lower levels of active metabolite, diminished platelet inhibition, and higher rates of adverse cardiovascular events. The effect of CYP polymorphisms on the clinical outcomes in patients treated with prasugrel remains unknown. METHODS AND RESULTS: The associations between functional variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to prasugrel were tested in 238 healthy subjects. We then examined the association of these genetic variants with cardiovascular outcomes in a cohort of 1466 patients with acute coronary syndromes allocated to treatment with prasugrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38 trial. Among the healthy subjects, no significant attenuation of the pharmacokinetic or the pharmacodynamic response to prasugrel was observed in carriers versus noncarriers of at least 1 reduced-function allele for any of the CYP genes tested (CYP2C19, CYP2C9, CYP2B6, CYP3A5, and CYP1A2). Consistent with these findings, in subjects with acute coronary syndromes treated with prasugrel, no significant associations were found between any of the tested CYP genotypes and risk of cardiovascular death, myocardial infarction, or stroke. CONCLUSIONS: Common functional CYP genetic variants do not affect active drug metabolite levels, inhibition of platelet aggregation, or clinical cardiovascular event rates in persons treated with prasugrel. These pharmacogenetic findings are in contrast to observations with clopidogrel, which may explain, in part, the different pharmacological and clinical responses to the 2 medications.