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1.  Proatherogenic Oxidized Low-Density Lipoprotein/β2-Glycoprotein I Complexes in Arterial and Venous Disease 
Journal of Immunology Research  2014;2014:234316.
OxLDL/β2GPI complexes have been implicated in the initiation and progression of atherosclerosis and associated with disease severity and adverse outcomes. We investigate the significance of anti-oxLDL/β2GPI antibodies and oxLDL/β2GPI complexes in patients with arterial and idiopathic venous disease. A cohort of 61 arterial disease patients, 32 idiopathic venous disease patients, and 53 healthy controls was studied. Because statins influence oxLDL/β2GPI, these complexes were analyzed on subjects not taking statins. Arterial and venous groups expressed higher levels of IgG anti-oxLDL/β2GPI antibodies than controls without any other significant clinical association. OxLDL/β2GPI complexes were significantly elevated in arterial (0.69 U/mL, P = 0.004) and venous disease (0.54 U/mL, P = 0.025) than controls (0.39 U/mL). Among arterial diseases, oxLDL/β2GPI was 0.85 U/mL for carotid artery disease, 0.72 U/mL for peripheral artery disease, and 0.52 U/mL for abdominal aortic aneurysm. There was a significant association with male gender, age, hypertension, and history of thrombosis. Subjects with oxLDL/β2GPI above the median (0.25 U/mL) were more likely to have arterial (OR 4.5, P = 0.004) or venous disease (OR 4.1, P = 0.008). Multivariate regression indicated that males (P = 0.021), high cholesterol (P = 0.011), and carotid disease (P = 0.023) were significant predictors of oxLDL/β2GPI. The coexistence of oxLDL/β2GPI in arterial and venous disease may suggest a common oxidative mechanism that independently predicts carotid artery disease.
doi:10.1155/2014/234316
PMCID: PMC4227323  PMID: 25405208
3.  Prognostic Value of Stress Cardiac Magnetic Resonance Imaging in Patients With Known or Suspected Coronary Artery Disease 
Journal of the American College of Cardiology  2013;62(9):10.1016/j.jacc.2013.03.080.
Objectives
This study sought to perform a systematic review and meta-analysis to understand the role of stress cardiac magnetic resonance imaging (CMR) in assessing cardiovascular prognosis in patients with known or suspected coronary artery disease (CAD).
Background
Although stress CMR is excellent for the diagnosis of obstructive CAD, the prognostic value of stress CMR has been less well described.
Methods
PubMed, Cochrane CENTRAL, and metaRegister of Controlled Trials were searched for stress CMR studies with >6 months of prognostic data. Primary endpoints were cardiovascular death, myocardial infarction (MI), and a composite outcome of cardiovascular death or MI during follow-up. Summary effect estimates were generated with random-effects modeling, and annualized event rates were assessed.
Results
Nineteen studies (14 vasodilator, 4 dobutamine, and 1 that used both) involved a total of 11,636 patients with a mean follow-up of 32 months. Patients had a mean age of 63 ± 12 years, 63% were male, and 26% had previous MI; mean left ventricular ejection fraction was 61 ± 12%; and late gadolinium enhancement was present in 29% and ischemia in 32%. Patients with ischemia had a higher incidence of MI (odds ratio [OR]: 7.7; p < 0.0001), cardiovascular death (OR: 7.0; p < 0.0001), and the combined endpoint (OR: 6.5; p < 0.0001) compared with those with a negative study. The combined outcome annualized events rates were 4.9% for a positive versus 0.8% for a negative stress CMR (p < 0.0001), 2.8% versus 0.3% for cardiovascular death (p < 0.0001), and 2.6% versus 0.4% for MI (p < 0.0005). The presence of late gadolinium enhancement was also significantly associated with a worse prognosis.
Conclusions
A negative stress CMR study is associated with very low risk of cardiovascular death and MI. Stress CMR has excellent prognostic characteristics and may help guide risk stratification of patients with known or suspected CAD.
doi:10.1016/j.jacc.2013.03.080
PMCID: PMC3863376  PMID: 23727209
late gadolinium enhancement; myocardial perfusion; prognosis; stress cardiac MRI
4.  Aspirin Attenuates Platelet Activation and Immune Activation in HIV-1-Infected Subjects on Antiretroviral Therapy: A Pilot Study 
Background
Mechanisms for increased cardiovascular risk in HIV-1-infected adults are incompletely understood, but platelet activation and immune activation leading to a prothrombotic state have been proposed as significant contributors. Aspirin has antiplatelet and immunomodulatory properties. We explored whether 1 week of low-dose aspirin attenuates platelet activation and immune activation in HIV-1-infected and virologically suppressed adults on antiretroviral therapy.
Methods
Platelet activation and immune activation were measured in HIV-1-infected subjects virologically suppressed on antiretroviral therapy and controls before and after 1 week of low-dose aspirin.
Results
Compared with control subjects, HIV-1-infected subjects had increased platelet activation, as measured by spontaneous platelet aggregation and aggregation in response to adenosine diphosphate, collagen, and arachidonic acid. After aspirin therapy, percent aggregation decreased similarly in both HIV-1-infected and control subjects to all platelet agonists tested except aggregation in response to arachidonic acid, which remained elevated in the HIV-1-infected group. HIV-1-infected subjects exhibited increased markers of T-cell activation (CD38 and HLA-DR) and monocyte activation (sCD14), which decreased after 1 week of aspirin therapy. Moreover, leukocyte responses to Toll-like receptor stimulation were enhanced after 1 week of aspirin therapy. In vitro studies showed that HIV-1 plasma could activate healthy platelets, which in turn activated monocytes, implicating a direct role for activated platelets in immune activation.
Conclusions
Our data demonstrate that heightened platelet activation and immune activation in treated HIV-1 disease are attenuated by 1 week of aspirin therapy. Aspirin should be further studied for its antithrombotic and immunomodulatory benefits in treated HIV-1 disease.
doi:10.1097/QAI.0b013e31828a292c
PMCID: PMC3756489  PMID: 23406976
platelets; HIV-1; aspirin; immune activation; aggregation
5.  Mean platelet volume reproducibility and association with platelet activity and anti-platelet therapy 
Platelets  2013;25(3):188-192.
Some studies suggest that mean platelet volume (MPV) correlates with increased risk for cardiovascular morbidity and mortality. In this study, we aim to assess reproducibility, need for standardized measurements, effect of aspirin, and association with other established markers of platelet activity. Following an overnight fast, 48 healthy volunteers had weekly assessment of platelet activity and were administered aspirin 81 mg daily for 7 d between weeks 3 and 4. We investigated the influence of time between phlebotomy and MPV measurement (n=10). Reproducibility was assessed by coefficient of variation (CV) and intraclass correlation coefficient (ICC). MPV measurements were reproducible (Week 1: 10.6 fL [9.9–11], Week 2: 10.6 fL [10.0–10.9], Week 3: 10.6 fL [9.8–11]). CV was ≤4% and ICC>0.85 (p<0.001) for each comparison, indicating excellent reproducibility. There was no effect of aspirin on MPV (10.6 fL [9.8–11] versus 10.5 fL [9.9–11]; p=0.81). MPV significantly increased as time between phlebotomy and MPV measurement increased (Spearman’s rho=0.94, p=0.001). Increasing MPV tertiles was associated with collagen- and thrombin receptor-activated peptide-induced platelet aggregation but not with ADP- or arachidonic acid-induced or spontaneous platelet aggregation. In conclusion, when standardized, MPV is a reproducible marker of platelet size and not affected by low-dose aspirin. MPV is modestly associated with some, but not all, markers of platelet activity.
doi:10.3109/09537104.2013.793794
PMCID: PMC3809021  PMID: 23786366
Aspirin; mean platelet volume; platelet aggregation
6.  Thrombotic and Bleeding Complications Following Orthopedic Surgery 
American heart journal  2013;165(3):427-433.e1.
Background
Thrombotic and bleeding complications are major concerns during orthopedic surgery. Given the frequency of orthopedic surgical procedures and the limited data in the literature, we sought to investigate the incidence and risk factors for thrombotic (myocardial necrosis and infarction) and bleeding events in patients undergoing orthopedic surgery.
Methods and Results
We performed a retrospective cohort analysis of 3,082 consecutive subjects ≥ 21 years of age undergoing hip, knee, or spine surgery between November 1, 2008, and December 31, 2009. Patient characteristics were ascertained using ICD-9 diagnosis coding and retrospective review of medical records, and laboratory/blood bank databases. In-hospital outcomes included myocardial necrosis (elevated troponin), major bleeding, coded myocardial infarction (MI), and coded hemorrhage as defined by ICD-9 coding. Of the 3,082 subjects, mean age was 60.8 ± 13.3 years and 59% were female. Myocardial necrosis, coded MI, major bleeding, and coded hemorrhage occurred in 179 (5.8%), 20 (0.7%), 165 (5.4%), and 26 (0.8%) subjects, respectively. Increasing age (P<0.001), CAD (P<0.001), cancer (P=0.004), and chronic kidney disease (P=0.01) were independent predictors of myocardial necrosis, while procedure type (P<0.001), cancer (P<0.001), female sex (P<0.001), CAD (P<0.001), and COPD (P=0.01) were independent predictors of major bleeding.
Conclusion
There is a delicate balance between thrombotic and bleeding events in the perioperative period following orthopedic surgery. Perioperative risk of both thrombosis and bleeding deserve careful attention in preoperative evaluation and future prospective studies aimed at attenuating this risk are warranted.
doi:10.1016/j.ahj.2012.11.005
PMCID: PMC3595114  PMID: 23453114
arterial thrombosis; major bleeding; perioperative management
7.  Mean Platelet Volume and Long-Term Mortality in Patients Undergoing Percutaneous Coronary Intervention 
The American journal of cardiology  2012;111(2):185-189.
Increased platelet activity is associated with adverse cardiovascular events. Mean platelet volume (MPV) correlates with platelet activity but the relationship between MPV and long-term mortalityin patients undergoing percutaneous coronary intervention(PCI) is not well established. Furthermore, the role of change in MPV over time has not been previously evaluated. We evaluatedMPV at baseline, 30 days, 60 days, 90 days, 1 year, 2 years, and 3 years post-procedure in 1,512 patients who underwent PCI. The speed of change in MPV was estimated using slope of linear regression. Mortality was determined by query of social security death index. Over a median of 8.7 years, mortality was 49.3% post-PCI. There was no significant difference in mortality when stratified by MPV quartiles (1stquartile 50.1%, 2nd quartile 47.7%, 3rd quartile 51.3%, 4thquartile 48.3%, p=0.74). In patients with available data to determine a change in MPV over time post-PCI (n=839), mortality was 49.1% and significantly higher in patients with an increase (52.9%) compared to those with a decrease (44.2%) or no change (49.1%) in MPV over time (p<0.0001). In conclusion, there was no association between baseline MPV and long-term mortality in patients undergoing PCI. However, there was increased mortality when MPV increasedover time post-PCI. Monitoring MPV after coronary revascularization may play a role in risk stratification.
doi:10.1016/j.amjcard.2012.09.014
PMCID: PMC3538911  PMID: 23102880
Mean platelet volume; percutaneous coronary intervention; long-term mortality
8.  Hyperreactive platelet phenotypes: Relationship to altered serotonin transporter number, transport kinetics and intrinsic response to adrenergic co-stimulation 
Thrombosis and haemostasis  2012;109(1):85-92.
Summary
The mechanism underlying a hyperreactive platelet phenotype remains unknown. Since serotonin has been shown to influence platelet biology and atherothrombosis, we sought to investigate the association of platelet serotonin transporter number, binding affinity, and uptake kinetics to platelet aggregation. A total of 542 healthy volunteers had light transmittance platelet aggregometry measured in response to varying concentrations of epinephrine, serotonin, epinephrine plus serotonin, ADP and collagen. Transporter-dependent serotonin uptake rate was determined (Vmax), as were serotonin transporter number (Bmax) and binding affinity (Kd) using 3H paroxetine binding in a homologous displacement assay, nonlinear regression and validated algorithms for kinetic modeling. Stimulation with submaximal (2 μM) epinephrine concentration elicited a distinct, bimodal pattern of platelet aggregation in this population. In contrast, subjects exhibited minimal aggregation in response to serotonin alone. Co-stimulation with submaximal epinephrine and serotonin induced platelet aggregation to a level beyond that observed with either agonist alone and maintained a bimodal response distribution. Subjects with heightened (>60%) platelet aggregation to both epinephrine alone and epinephrine plus serotonin exhibited increased platelet serotonin uptake, and transporter number and affinity. In a population of healthy subjects, co-stimulation with submaximal concentrations of epinephrine and serotonin identifies a subset of individuals with a hyperreactive platelet aggregation profile that is associated with changes in platelet serotonin function.
doi:10.1160/TH12-03-0202
PMCID: PMC3582386  PMID: 23223800
Platelets; platelet activity; serotonin; epinephrine; transporter
9.  Peripheral artery disease, biomarkers, and darapladib 
American heart journal  2011;161(5):972-978.
Objective
Subjects with peripheral artery disease (PAD) are at increased risk of cardiovascular morbidity and mortality, perhaps in part, related to increased levels of inflammation, platelet activity, and lipids. We therefore sought to investigate the relationship between PAD and levels of inflammatory, platelet, and lipid biomarkers and the treatment effect of darapladib, a novel lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor.
Methods
This is a post hoc analysis of the 959 patients with coronary disease or their risk equivalent receiving atorvastatin who were randomized to receive darapladib or placebo to examine the effects of an Lp-PLA2 inhibitor on the biomarkers of cardiovascular risk. We conducted an exploratory analysis evaluating the levels of biomarkers in subjects with PAD (n = 172) compared with those without PAD (n = 787).
Results
After adjustment for age, sex, smoking, body mass index, and diabetes, subjects with PAD had greater levels of matrix metalloproteinase-9 (between group comparisons 22%, 95% confidence interval [10–31], P < .01), myeloperoxidase (12% [2–20], P = .01), interleukin-6 (13% [4–21], P = .01), adiponectin (17% [7–26], P < .01), intercellular adhesion molecule-1 (7% [2–11], P < .01), osteoprotegrin (6% [1–10], P = .02), CD40 ligand (15% [1–28], P = .04), high-sensitivity C-reactive protein (17% [1–31], P = .04), and triglycerides (11% [0.2–21], P = .05). No significant difference was detected for Lp-PLA2 activity, P-selectin, urinary 11-dehydrothroboxane B2, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol between subjects with and without PAD. Darapladib produced highly significant inhibition of Lp-PLA2 activity when compared with placebo at weeks 4 and 12 (P < .01) in patients with and without PAD.
Conclusions
Subjects with PAD had elevated levels of matrix metalloproteinase-9, myeloperoxidase, interleukin-6, adiponectin, intercellular adhesion molecule-1, osteoprotegrin, CD40 ligand, high-sensitivity C-reactive protein, and triglycerides compared with those without PAD. Darapladib, a novel Lp-PLA2 inhibitor, was equally effective in reducing Lp-PLA2 activity levels in subjects with and without PAD.
doi:10.1016/j.ahj.2011.01.017
PMCID: PMC3750980  PMID: 21570531
10.  Mean platelet volume and prevalence of peripheral artery disease, the National Health and Nutrition Examination Survey, 1999–2004 
Atherosclerosis  2010;213(2):586-591.
Objectives
We sought to determine whether mean platelet volume (MPV) is associated with the prevalence of peripheral artery disease (PAD).
Background
Platelets play a pivotal role in the pathogenesis of atherosclerosis and PAD. MPV, a measure of platelet size available in every blood count, is increasingly recognized as an important marker of platelet activity.
Methods
We analyzed data from 6354 participants aged 40 years and older from the 1999 to 2004 National Health and Nutrition Examination Survey (NHANES), a nationally representative sample of the US population. PAD was defined as an ankle brachial index ≤0.90 in either leg. Odds ratios and 95% confidence intervals were estimated by logistic regression.
Results
The prevalence of PAD in the cohort was 5.7%. MPV was significantly associated with PAD prevalence (tertile 1 – 4.4%, tertile 2 – 6.1%, tertile 3 – 7.0%, P for trend = 0.003). After adjustment for age, sex, and race, the odds ratio of PAD comparing the highest tertile to the lowest tertile was 1.57 (95% confidence interval 1.15–2.13). After further adjustment for smoking status, hypertension, hypercholesterolemia, diabetes, glomerular filtration rate, body mass index, and platelet count the corresponding odds ratio was 1.58 (95% confidence interval 1.14–2.19). The addition of triglycerides, hemoglobin A1c, and C-reactive protein did not affect the results. The significant association between MPV and PAD was unchanged when MPV was used as a continuous variable.
Conclusions
Mean platelet volume is independently associated with PAD. These findings support the hypothesis that platelet size is an independent predictor of increased risk for PAD.
doi:10.1016/j.atherosclerosis.2010.09.010
PMCID: PMC3739454  PMID: 20940069
Mean platelet volume; Platelets; Peripheral artery disease; Epidemiology
11.  The Relationship Between Diabetes, Metabolic Syndrome, and Platelet Activity as Measured by Mean Platelet Volume 
Diabetes Care  2012;35(5):1074-1078.
OBJECTIVE
The association between platelet activity, diabetes, and glucometabolic control is uncertain. We aim to investigate mean platelet volume (MPV), a marker of platelet size and platelet activity, with the prevalence of diabetes, metabolic syndrome, and degree of glycemic control.
RESEARCH DESIGN AND METHODS
This is a retrospective analysis of 13,021 participants in the National Health and Nutrition Examination Survey from 1999 to 2004. Prevalence of diabetes was defined as nonfasting glucose >200 mg/dL, fasting glucose ≥126 mg/dL, or treatment with hypoglycemic agents. Presence of metabolic syndrome was determined by the National Cholesterol Education Program Adult Treatment Panel III definition. Odds ratios and 95% CIs were estimated by logistic regression.
RESULTS
MPV was significantly higher in subjects with diabetes (8.20 vs. 8.06 femtoliter [fL], P < 0.01) but not in subjects with metabolic syndrome (8.09 vs. 8.07 fL, P = 0.24). For the metabolic syndrome components, MPV was significantly higher in abdominal obesity (P = 0.03) and low HDL (P = 0.04), and not different in high blood pressure (P = 0.07), abnormal glucose metabolism (P = 0.71), or hypertriglyceridemia (P = 0.46). There was a significant correlation between MPV and glucose (P < 0.0001) and between MPV and hemoglobin A1c (P < 0.0001) in subjects with diabetes. These correlations were no longer significant in those without diabetes. The adjusted odds of diabetes rose with increasing MPV levels and were most pronounced in subjects with MPV levels exceeding the 90th percentile (≥9.31 fL). The association between MPV and diabetes was most apparent in those with the poorest glucose control.
CONCLUSIONS
Mean platelet volume is strongly and independently associated with the presence and severity of diabetes.
doi:10.2337/dc11-1724
PMCID: PMC3329806  PMID: 22410814
12.  Lipid and Lipoprotein Biomarkers and the Risk of Ischemic Stroke in Postmenopausal Women 
Background
Few studies simultaneously investigated lipids and lipoprotein biomarkers as predictors of ischemic stroke. The value of these biomarkers as independent predictors of ischemic stroke remains controversial.
Methods
We conducted a prospective nested case-control study among postmenopausal women from the Women’s Health Initiative Observational Study to assess the relationship between fasting lipids (total cholesterol, LDL-C, HDL-C, and triglycerides), lipoproteins (LDL, HDL and VLDL particle number and size, IDL particle number, and lipoprotein [a]) and risk of ischemic stroke. Among women free of stroke at baseline, 774 ischemic stroke patients were matched according to age and race to controls using a 1:1 ratio.
Results
In bivariate analysis, baseline triglycerides (P<0.001), IDL particles (P<0.01), LDL particles (P<0.01), VLDL triglyceride (P<0.001), VLDL particles (P<0.01), VLDL size (P<0.001), LDL size (P=0.03), and total/HDL cholesterol ratio (P<0.01) were significantly higher among women with incident ischemic stroke, while levels of HDL-C (P<0.01) and HDL size (P<0.01) were lower. No significant baseline difference for total cholesterol (P=0.15), LDL-C (P=0.47), and lipoprotein (a) (P=0.11) was observed. In multivariable analysis, triglycerides, (OR for the highest vs lowest quartile, 1.56; 95% CI, 1.13-2.17, P for trend =0.02), VLDL size (OR 1.59, 95% CI, 1.10-2.28, P for trend =0.03) and IDL particle number (OR 1.46, 95% CI, 1.04-2.04, P for trend =0.02) were significantly associated with ischemic stroke.
Conclusion
Among a panel of lipid and lipoprotein biomarkers, baseline triglycerides, VLDL size and IDL particle number were significantly associated with incident ischemic stroke in postmenopausal women.
doi:10.1161/STROKEAHA.111.641324
PMCID: PMC3547588  PMID: 22308251
Lipids; Lipoproteins; Ischemic Stroke; Women; Triglycerides
13.  Centrifugation Speed Affects Light Transmission Aggregometry 
BACKGROUND
Light transmission aggregometry (LTA) is considered the gold-standard for investigating platelet activity ex vivo. However, LTA protocols are not standardized and differences in LTA procedure are a potential source of variance in results. Centrifugation speed is an essential component of platelet preparation in LTA, has yet to be standardized, and may affect platelet aggregation results. We sought to investigate the effect of relative centrifugal force (RCF) intensity on LTA results.
METHODS
Ten healthy controls had venous blood drawn and centrifuged at 150g, 200g, 300g, and 500g for 10 minutes. Cell counts in whole blood and PRP were measured using a hematology analyzer. LTA was performed using 1.0uM ADP and 0.4uM epinephrine as an agonist. Aggregation (%) was compared at 60, 120, 180, and 300 seconds (s) and at maximum aggregation.
RESULTS
Centrifugation speed was associated with decreasing platelet count (P<0.001) and decreasing MPV (P<0.001) in platelet rich plasma. Maximum aggregation decreased with increasing speeds for ADP 1.0uM (150g-89%, 200g-93%, 300g-71%, 500g-17%; P<0.001). Similar findings were noted at 120s (150g-69%, 200g-50%, 300g-35%, 500g-12%; P<0.001), 180s (150g-82%, 200g-74%, 300g-44%, 500g-13%; P<0.001), and 300s (150g-85%, 200g-88%, 300g-55%, 500g-14%; P<0.001). Consistently, platelet aggregation in response to epinephrine 0.4uM decreased significantly with increasing centrifuge RCF at 60s, 120s, 180s, 300s, and at maximum aggregation (P<0.05 for each comparison).
CONCLUSIONS
Our data demonstrate the importance of centrifugation speed in the interpretation of LTA results, supporting the need for standardization of centrifugation RCF in LTA protocols.
doi:10.1111/j.1751-553X.2011.01360.x
PMCID: PMC3209490  PMID: 21794095
Light transmission aggregometry; Methodology; Centrifuge; Platelets
14.  Relationship Express: A Pilot Program to Teach Anesthesiology Residents Communication Skills 
Background
The Accreditation Council for Graduate Medical Education requires residency programs to teach 6 core competencies and to provide evidence of effective standardized training through objective measures. George Washington University's Department of Anesthesiology and Critical Care Medicine implemented a pilot program to address the interpersonal and communication skill competency. In this program, we aimed to pilot the Relationship Express model, a series of exercises in experiential learning to teach anesthesiology residents to build effective relationships with patients in time-limited circumstances. The purpose of this paper is to describe the application of this model for anesthesiology training.
Methods
A total of 7 first-year clinical anesthesiology residents participated in this pilot study, and 4 residents completed the entire program for analysis purposes. Relationship Express was presented in three 1.5-hour sessions: (1) introduction followed by 2-case, standardized patient pretest with feedback to residents from faculty observers; (2) interpersonal and communication skills didactic workshop with video behavior modeling; and (3) review discussion followed by 2-case, standardized patient posttest and evaluation.
Results
Modified Brookfield comments revealed the following themes: (1) time constraints were realistic compared with clinical practice; (2) admitting errors with patients was difficult; (3) patients were more aware of body language than anticipated; (4) residents liked the group discussions and the video interview; (5) standardized patients were convincing; and (6) residents found the feedback from faculty and standardized patients helpful.
Conclusions
Resident retrospective self-assessment and learning comments confirm the potential value of the Relationship Express model. This program will require further assessment and refinement with a larger number of residents.
doi:10.4300/JGME-D-10-00012.1
PMCID: PMC3010947  PMID: 22132285
15.  Smoking, Clopidogrel, and Mortality in Patients with Established Cardiovascular Disease 
Circulation  2009;120(23):2337.
Background
Smoking increases platelet aggregability, and the degree of platelet inhibition by clopidogrel on ex vivo platelet function tests. Whether smoking status affects the relationship between clopidogrel and clinical outcomes is unknown.
Methods and Results
We evaluated the relationship between smoking status (current smoker (CS), former smoker (FS), and never smoker (NS)) and treatment with clopidogrel on the risk of all-cause, cardiovascular, and cancer mortality among the 12,152 participants from the CHARISMA trial with established cardiovascular disease. Current smoking was associated with an increase in all-cause (adjusted hazard ratio [HR] 2.58, [1.85–3.60]), cardiovascular (HR 2.26, [1.48–3.45]), and cancer mortality (HR 4.16, [2.46–7.03]) compared to NS. The impact of clopidogrel and mortality differed by smoking status (P for interaction = 0.018 for current smokers). Among CS, clopidogrel was associated with a reduction in all-cause mortality (HR 0.68, [0.49–0.94]); clopidogrel did not reduce all cause mortality among FS (HR 0.95, [0.75–1.19]) or NS (HR 1.14, [0.83–1.58]). A similar pattern was noted for cardiovascular mortality. As expected, no relationship was observed between clopidogrel and cancer mortality by smoking status. The risk of bleeding seemed to differ according to smoking status; randomized clopidogrel was associated with a significantly increased hazard of severe or moderate bleeding (HR 1.62, P=0.04) among CS, but a smaller and nonsignificant increase among NS (HR 1.31, P=0.15).
Conclusion
Clopidogrel therapy may be more effective, but with a greater bleeding risk in CS than in patients who are not smokers. Further studies are needed to investigate this possibility.
doi:10.1161/CIRCULATIONAHA.109.866533
PMCID: PMC2814172  PMID: 19933933
Smoking; Clopidogrel; Mortality; Cardiovascular disease
16.  Sex Differences in Mortality Following Acute Coronary Syndromes 
Context
There is conflicting information about whether sex-differences modulate short-term mortality following acute coronary syndromes (ACS).
Objective
To investigate the relationship between sex and 30-day mortality in ACS, and determine whether this relationship is modified by clinical syndrome or coronary anatomy using a large database across the spectrum of ACS and adjusting for potentially confounding clinical covariates.
Design Setting and Participants
Data from 11 ACS trials from 1993 to 2006 were pooled. Of 136,247 patients, 38,048 (28%) were women; 102,004 (26% women) STEMI, 14,466 (29% women) NSTEMI and 19,777 (40% women) unstable angina (UA).
Main Outcome Measure
Thirty-day mortality following ACS.
Results
Mortality at 30 days was 9.6% in women and 5.3% in men (odds ratio [OR] 1.91, 95% confidence interval [CI] 1.83–2.00). After multivariable adjustment, mortality was not significantly different between women and men (adjusted OR 1.06, 95% CI 0.99–1.15). Importantly, a significant sex by type of ACS interaction was demonstrated (P<0.001). In STEMI, 30-day mortality was higher among women (adjusted OR 1.15, 95% CI 1.06–1.24), whereas NSTEMI (adjusted OR 0.77, 95% CI 0.63–0.95), and UA mortality was lower among women (adjusted OR 0.55, 95% CI 0.43–0.70). In a cohort of 35,128 patients with angiographic data, women more often had non-obstructive (15% vs. 8%,) and less often had 2-vessel (25% vs. 28%) and 3-vessel (23% vs. 26%) coronary disease regardless of ACS type. After additional adjustment for angiographic disease severity, 30-day mortality among women was not significantly different than men, regardless of ACS type. The relationship between sex and 30-day mortality was similar across the levels of angiographic disease severity (p-value for interaction =0.70),
Conclusions
Sex-based differences exist in 30-day mortality among ACS patients and vary depending on clinical presentation. However, these differences are markedly attenuated following adjustment for clinical differences and angiographic data.
doi:10.1001/jama.2009.1227
PMCID: PMC2778841  PMID: 19706861
17.  Aspirin Use, Dose, and Clinical Outcomes in Postmenopausal Women with Stable Cardiovascular Disease: The Women’s Health Initiative Observational Study 
Background
Despite compelling evidence that aspirin reduces fatal and non-fatal vascular events among the overall population in various settings, women have frequently been underrepresented and their data underreported. We sought to evaluate the relationship between aspirin use, dose (81 or 325mg) and clinical outcomes among postmenopausal women with stable cardiovascular disease.
Methods
Women with cardiovascular disease (n=8928) enrolled in the Women’s Health Initiative Observational Study were used for this analysis. The primary outcome was the incidence of all-cause mortality and cardiovascular events (myocardial infarction, stroke and cardiovascular death).
Results
Among 8928 women with stable cardiovascular disease, 4101 (46%) reported taking aspirin, of whom 30% were on 81 and 70% were on 325mg. At 6.5 years of follow-up, no significant association was noted for aspirin use and all-cause mortality or cardiovascular events. However, after multivariate adjustment, aspirin use was associated with a significantly lower all-cause (adjusted HR 0.86, [0.75-0.99], P=0.04) and cardiovascular related mortality (adjusted HR 0.75, [0.60-0.95], P=0.01) compared with no aspirin. Aspirin use was associated with a lower risk of cardiovascular events (adjusted HR 0.90, [0.78-1.04], P=0.14) which did not meet statistical significance. Compared with 325mg, use of 81mg was not significantly different for all-cause mortality, cardiovascular events or any individual endpoint.
Conclusions
After multivariate adjustment, aspirin use was associated with significantly lower risk of all-cause mortality, specifically cardiovascular mortality, among postmenopausal women with stable cardiovascular disease. No significant difference was noted between 81 and 325mg of aspirin. Overall, aspirin use was low in this cohort of women with stable cardiovascular disease.
doi:10.1161/CIRCOUTCOMES.108.791269
PMCID: PMC2801891  PMID: 20031819
Aspirin; Dose; Women; Cardiovascular Disease; Observational Study
18.  Competency in Chest Radiography 
BACKGROUND
Accurate interpretation of chest radiographs (CXR) is essential as clinical decisions depend on readings.
OBJECTIVE
We sought to evaluate CXR interpretation ability at different levels of training and to determine factors associated with successful interpretation.
DESIGN
Ten CXR were selected from the teaching file of the internal medicine (IM) department. Participants were asked to record the most important diagnosis, their certainty in that diagnosis, interest in a pulmonary career and adequacy of CXR training. Two investigators independently scored each CXR on a scale of 0 to 2.
PARTICIPANTS
Participants (n = 145) from a single teaching hospital were third year medical students (MS) (n = 25), IM interns (n = 44), IM residents (n = 45), fellows from the divisions of cardiology and pulmonary/critical care (n = 16), and radiology residents (n = 15).
RESULTS
The median overall score was 11 of 20. An increased level of training was associated with overall score (MS 8, intern 10, IM resident 13, fellow 15, radiology resident 18, P<.001). Overall certainty was significantly correlated with overall score (r = .613, P<.001). Internal medicine interns and residents interested in a pulmonary career scored 14 of 20 while those not interested scored 11 (P = .027). Pneumothorax, misplaced central line, and pneumoperitoneum were diagnosed correctly 9%, 26%, and 46% of the time, respectively. Only 20 of 131 (15%) participants felt their CXR training sufficient.
CONCLUSION
We identified factors associated with successful CXR interpretation, including level of training, field of training, interest in a pulmonary career and overall certainty. Although interpretation improved with training, important diagnoses were missed.
doi:10.1111/j.1525-1497.2006.00427.x
PMCID: PMC1484801  PMID: 16704388
education; medical; radiography; thoracic; clinical competence; educational measurement
19.  Ethics of Practicing Medical Procedures on Newly Dead and Nearly Dead Patients 
OBJECTIVE
To examine the ethical issues raised by physicians performing, for skill development, medically nonindicated invasive medical procedures on newly dead and dying patients.
DESIGN
Literature review; issue analysis employing current normative ethical obligations, and evaluation against moral rules and utilitarian assessments manifest in other common perimortem practices.
RESULTS
Practicing medical procedures for training purposes is not uncommon among physicians in training. However, empiric information is limited or absent evaluating the effects of this practice on physician competence and ethics, assessing public attitudes toward practicing medical procedures and requirements for consent, and discerning the effects of a consent requirement on physicians' clinical competence. Despite these informational gaps, there is an obligation to secure consent for training activities on newly and nearly dead patients based on contemporary norms for informed consent and family respect. Paradigms of consent-dependent societal benefits elsewhere in health care support our determination that the benefits from physicians practicing procedures does not justify setting aside the informed consent requirement.
CONCLUSION
Current ethical norms do not support the practice of using newly and nearly dead patients for training in invasive medical procedures absent prior consent by the patient or contemporaneous surrogate consent. Performing an appropriately consented training procedure is ethically acceptable when done under competent supervision and with appropriate professional decorum. The ethics of training on the newly and nearly dead remains an insufficiently examined area of medical training.
doi:10.1046/j.1525-1497.2002.11139.x
PMCID: PMC1495118  PMID: 12390553
medical education; invasive procedures; medical ethics

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