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1.  Vein Graft Preservation Solutions, Patency, and Outcomes After Coronary Artery Bypass Graft Surgery 
JAMA surgery  2014;149(8):798-805.
IMPORTANCE
In vitro and animal model data suggest that intraoperative preservation solutions may influence endothelial function and vein graft failure (VGF) after coronary artery bypass graft (CABG) surgery. Clinical studies to validate these findings are lacking.
OBJECTIVE
To evaluate the effect of vein graft preservation solutions on VGF and clinical outcomes in patients undergoing CABG surgery.
DESIGN, SETTING, AND PARTICIPANTS
Data from the Project of Ex-Vivo Vein Graft Engineering via Transfection IV (PREVENT IV) study, a phase 3, multicenter, randomized, double-blind, placebo-controlled trial that enrolled 3014 patients at 107 US sites from August 1, 2002, through October 22, 2003, were used. Eligibility criteria for the trial included CABG surgery for coronary artery disease with at least 2 planned vein grafts.
INTERVENTIONS
Preservation of vein grafts in saline, blood, or buffered saline solutions.
MAIN OUTCOMES AND MEASURES
One-year angiographic VGF and 5-year rates of death, myocardial infarction, and subsequent revascularization.
RESULTS
Most patients had grafts preserved in saline (1339 [44.4%]), followed by blood (971 [32.2%]) and buffered saline (507 [16.8%]). Baseline characteristics were similar among groups. One-year VGF rates were much lower in the buffered saline group than in the saline group (patient-level odds ratio [OR], 0.59 [95% CI, 0.45-0.78; P < .001]; graft-level OR, 0.63 [95% CI, 0.49-0.79; P < .001]) or the blood group (patient-level OR, 0.62 [95% CI, 0.46-0.83; P = .001]; graft-level OR, 0.63 [95% CI, 0.48-0.81; P < .001]). Use of buffered saline solution also tended to be associated with a lower 5-year risk for death, myocardial infarction, or subsequent revascularization compared with saline (hazard ratio, 0.81 [95% CI, 0.64-1.02; P = .08]) and blood (0.81 [0.63-1.03; P = .09]) solutions.
CONCLUSIONS AND RELEVANCE
Patients undergoing CABG whose vein grafts were preserved in a buffered saline solution had lower VGF rates and trends toward better long-term clinical outcomes compared with patients whose grafts were preserved in saline- or blood-based solutions.
doi:10.1001/jamasurg.2014.87
PMCID: PMC4332522  PMID: 25073921
2.  Relationship between postoperative clopidogrel use and subsequent angiographic and clinical outcomes following coronary artery bypass grafting 
Dual antiplatelet therapy with both aspirin and clopidogrel is increasingly used after coronary artery bypass grafting (CABG); however, little is known about the safety or efficacy. We sought to determine the relationship between postoperative clopidogrel and clinical and angiographic outcomes following CABG. We evaluated 3,014 patients from PREVENT IV who underwent CABG at 107 US sites. Postoperative antiplatelet therapy was left to physician discretion. Risk-adjusted angiographic and clinical outcomes were compared in patients taking and not taking clopidogrel 30 days post-CABG. At 30 days, 633 (21 %) patients were taking clopidogrel. Clopidogrel users were more likely to have peripheral vascular (15 vs. 11 %) and cerebrovascular disease (17 vs. 11 %), prior myocardial infarction (MI) (46 vs. 41 %), and off-pump surgery (33 vs. 18 %). Clopidogrel use was associated with statistically insignificant higher graft failure (adjusted odds ratio 1.3; 95 % confidence interval [CI] [1.0, 1.7]; P = 0.05). At 5-year follow-up, clopidogrel use was associated with similar composite rates of death, MI, or revascularization (27 vs. 24 %; adjusted hazard ratio 1.1; 95 % CI [0.9, 1.4]; P = 0.38) compared with those not using clopidogrel. There was an interaction between use of cardiopulmonary bypass and clopidogrel with a trend toward lower 5-year clinical events with clopidogrel in patients undergoing off-pump CABG. In this observational analysis, clopidogrel use was not associated with better 5-year outcomes following CABG. There may be better outcomes with clopidogrel among patients having off-pump surgery. Adequately powered randomized clinical trials are needed to determine the role of dual antiplatelet therapy after CABG.
doi:10.1007/s11239-013-0904-1
PMCID: PMC4322756  PMID: 23543398
Clopidogrel; CABG; Dual antiplatelet therapy; Coronary artery bypass surgery; Outcomes
3.  Anesthesia-Based Evaluation of Outcomes of Lower-Extremity Vascular Bypass Procedures 
Annals of vascular surgery  2012;27(2):199-207.
Background
This report examines the effects of regional versus general anesthesia for infrainguinal bypass procedures performed in the treatment of critical limb ischemia (CLI).
Methods
Nonemergent infrainguinal bypass procedures for CLI (defined as rest pain or tissue loss) were identified using the 2005 to 2008 American College of Surgeons National Surgical Quality Improvement Program database using International Classification of Disease, ninth edition, and Current Procedure Terminology codes. Patients were classified according to National Surgical Quality Improvement Program data as receiving either general anesthesia or regional anesthesia. The regional anesthesia group included those specified as having regional, spinal, or epidural anesthesia. Demographic, medical, risk factor, operative, and outcomes data were abstracted for the study sample. Individual outcomes were evaluated according to the following morbidity categories: wound, pulmonary, venous thromboembolic, genitourinary, cardiovascular, and operative. Length of stay, total morbidity, and mortality were also evaluated. Associations between anesthesia types and outcomes were evaluated using linear or logistic regression.
Results
A total of 5,462 inpatient hospital visits involving infrainguinal bypasses for CLI were identified. Mean patient age was 69 ± 12 years; 69% were Caucasian; and 39% were female. In all, 4,768 procedures were performed using general anesthesia and 694 with regional anes­thesia. Patients receiving general anesthesia were younger and significantly more likely to have a history of smoking, previous lower-extremity bypass, previous amputation, previous stroke, and a history of a bleeding diathesis including the use of warfarin. Patients receiving regional anesthesia had a higher prevalence of chronic obstructive pulmonary disease.
Tibial-level bypasses were performed in 51% of procedures, whereas 49% of procedures were popliteal-level bypasses. Cases performed using general anesthesia demonstrated a higher rate of resident involvement, need for blood transfusion, and operative time. There was no difference in the rate of popliteal-level and infrapopliteal-level bypasses between groups. Infrapopliteal bypass procedures performed using general anesthesia were more likely to involve prosthetic grafts and composite vein. Mortality occurred in 157 patients (3%). The overall morbidity rate was 37%. Mean and median lengths of stay were 7.5 days (±8.1) and 6.0 days (Q1: 4.0, Q3: 8.0), respectively. Multivariate analyses demonstrated no significant differences by anesthesia type in the incidence of morbidity, mortality, or length of stay.
Conclusion
These results provide no evidence to support the systematic avoidance of general anesthesia for lower-extremity bypass procedures. These data suggest that anesthetic choice should be governed by local expertise and practice patterns.
doi:10.1016/j.avsg.2012.04.006
PMCID: PMC4279240  PMID: 22944010
4.  Are Central Institutional Review Boards the Solution? The National Heart, Lung, and Blood Institute Working Group's Report on Optimizing the IRB Process 
The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) convened a working group in June 2011 to examine alternative institutional review board (IRB) models. The working group was held in response to proposed changes in the regulations for government-supported research and the proliferation of multicenter clinical trials where multiple individual reviews may be inefficient. Group members included experts in heart, lung, and blood research, research oversight, bioethics, health economics, regulations, and information technology (IT). The group discussed alternative IRB models, ethical concerns, metrics for evaluating IRBs, IT needs, and economic considerations. Participants noted research gaps in IRB best practices and in metrics. The group arrived at recommendations for process changes, such as defining specific IRB performance requirements in funding announcements, requiring funded researchers to use more efficient alternative IRB models, and developing IT systems to facilitate information sharing and collaboration among IRBs. Despite the success of the National Cancer Institute's central IRB (CIRB), the working group, concerned about the creation costs and unknown cost efficiency of a new CIRB, and about the risk of shifting the burden of dealing with multiple IRBs from sponsors to research institutions, did not recommend the creation of an NHLBI-funded CIRB.
doi:10.1097/ACM.0b013e3182720859
PMCID: PMC4267852  PMID: 23095928
5.  EPC mobilization after erythropoietin treatment in acute ST-elevation myocardial infarction: the REVEAL EPC substudy 
Erythropoietin (EPO) was hypothesized to mitigate reperfusion injury, in part via mobilization of endothelial progenitor cells (EPCs). The REVEAL trial found no reduction in infarct size with a single dose of EPO (60,000 U) in patients with ST-segment elevation myocardial infarction. In a substudy, we aimed to determine the feasibility of cryopreserving and centrally analyzing EPC levels to assess the relationship between EPC numbers, EPO administration, and infarct size. As a prespecified substudy, mononuclear cells were locally cryopreserved before as well as 24 and 48–72 h after primary percutaneous coronary intervention. EPC samples were collected in 163 of 222 enrolled patients. At least one sample was obtained from 125 patients, and all three time points were available in 83 patients. There were no significant differences in the absolute EPC numbers over time or between EPO- and placebo-treated patients; however, there was a trend toward a greater increase in EPC levels from 24 to 48–72 h postintervention in patients receiving ≥30,000 U of EPO (P = 0.099 for CD133+ cells, 0.049 for CD34+ cells, 0.099 for ALDHbr cells). EPC numbers at baseline were inversely related to infarct size (P = 0.03 for CD133+ cells, 0.006 for CD34+ cells). Local whole cell cryopreservation and central EPC analysis in the context of a multicenter randomized trial is feasible but challenging. High-dose (≥30,000 U) EPO may mobilize EPCs at 48–72 h, and baseline EPC levels may be inversely associated with infarct size.
doi:10.1007/s11239-013-0944-6
PMCID: PMC4008147  PMID: 23700090
Erythropoietin; Endothelial progenitor cells; Myocardial infarction; Cryopreservation
6.  Evidence for the Long-Term Stability of HIV Transmission-Associated Sexual Behavior Following HIV Diagnosis 
Sexually transmitted diseases  2013;40(1):41-45.
Background
Most persons diagnosed with HIV alter their sexual behavior in a way that reduces the risk of HIV transmission, but the durability of such behavior change is unknown.
Methods
We conducted annual anonymous cross-sectional surveys in randomly selected patients with appointments at a large, public hospital HIV Clinic in Seattle, Washington from 2005 to 2009. We used logistic regression to assess the association between time since HIV diagnosis and self-report of unprotected anal or vaginal intercourse (UAVI) with partners of negative or unknown HIV status (nonconcordant UAVI), and quantile regression to evaluate the association between time since HIV diagnosis and number of anal or vaginal sex partners.
Results
We analyzed 845 surveys collected over 5 years. MSM had been diagnosed with HIV a mean of 12 (SD 7) years and non-MSM a mean of 11 (SD 6) years. Among 597 MSM, longer time since HIV diagnosis was associated with lower age-adjusted odds of reporting nonconcordant UAVI [(OR 0.96 (95% CI: 0.92 – 0.99)] and a lower age-adjusted number of sex partners (β coefficient −0.03, p=0.007). Among 248 women and heterosexual men, time since HIV diagnosis was not significantly associated with age-adjusted odds of nonconcordant UAVI [OR 0.99 (95% CI: 0.93 – 1.04)] or number of sex partners (β coefficient −0.01, p=0.48).
Conclusions
These results indicate that HIV transmission-associated behavior is relatively stable following the first year after HIV diagnosis. Our findings suggest that behavior change in the first year after HIV diagnosis, reported in other studies, is durable.
doi:10.1097/OLQ.0b013e3182753327
PMCID: PMC4150917  PMID: 23254116
Sexual Behavior; HIV Infections/psychology; Homosexuality, male; Substance-Related Disorders/complications
7.  Careers in Clinical Cardiovascular Research 
Circulation  2009;119(22):2945-2950.
doi:10.1161/CIRCULATIONAHA.107.752717
PMCID: PMC4145852  PMID: 19506126
8.  Non-Occupational Post-Exposure Prophylaxis for HIV: 10-Year Retrospective Analysis in Seattle, Washington 
PLoS ONE  2014;9(8):e105030.
Despite treatment guidelines in place since 2005, non-occupational post-exposure HIV prophylaxis (nPEP) remains an underutilized prevention strategy. We conducted a retrospective chart review of patients presenting to a publicly-funded HIV clinic in Seattle, Washington for nPEP between 2000 and 2010 (N = 360). nPEP prescriptions were provided for 324 (90%) patients; 83% of prescription decisions were appropriate according to Centers for Disease Control and Prevention guidelines, but only 31% (N = 111/360) of patients were considered “high risk.” In order to use limited resources most efficiently, public health agencies should target messaging for this high-cost intervention to individuals with high-risk HIV exposures.
doi:10.1371/journal.pone.0105030
PMCID: PMC4139302  PMID: 25140868
9.  d-Dimer elevation and adverse outcomes 
d-Dimer is a biomarker of fibrin formation and degradation. While a d-dimer within normal limits is used to rule out the diagnosis of deep venous thrombosis and pulmonary embolism among patients with a low clinical probability of venous thromboembolism (VTE), the prognostic association of an elevated d-dimer with adverse outcomes has received far less emphasis. An elevated d-dimer is independently associated with an increased risk for incident VTE, recurrent VTE, and mortality. An elevated d-dimer is an independent correlate of increased mortality and subsequent VTE across a broad variety of disease states. Therefore, medically ill subjects in whom the d-dimer is elevated constitute a high risk subgroup in which the prospective evaluation of the efficacy and safety of antithrombotic therapy is warranted.
doi:10.1007/s11239-014-1101-6
PMCID: PMC4300425  PMID: 25006010
d-Dimer; Deep vein thrombosis; Mortality; Prognosis; Pulmonary embolism
10.  Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial 
European Heart Journal  2014;35(31):2083-2093.
Aims
The optimal platelet inhibition strategy for ACS patients managed without revascularization is unknown.
We aimed to evaluate efficacy and safety of ticagrelor vs. clopidogrel in the non-ST-elevation acute coronary syndrome (NSTE-ACS) subgroup of the PLATO trial, in the total cohort, and in the subgroups managed with and without revascularization within 10 days of randomization.
Methods and results
We performed a retrospective analysis of the primary endpoint of cardiovascular death/myocardial infarction/stroke. Among 18 624 PLATO patients, 11 080 (59%) were categorized as NSTE-ACS at randomization. During the initial 10 days, 74% had angiography, 46% PCI, and 5% CABG. In NSTE-ACS patients, the primary endpoint was reduced with ticagrelor vs. clopidogrel [10.0 vs. 12.3%; hazard ratio (HR) 0.83; 95% confidence interval (CI) = 0.74–0.93], as was myocardial infarction (6.6 vs. 7.7%; HR 0.86; 95% CI = 0.74–0.99), cardiovascular death (3.7 vs. 4.9%; HR 0.77; 95% CI = 0.64–0.93), and all-cause death (4.3 vs. 5.8%; HR 0.76; 95% CI = 0.64–0.90). Major bleeding rate was similar between treatment groups (13.4 vs. 12.6%; HR 1.07; 95% CI = 0.95–1.19), but ticagrelor was associated with an increase in non-CABG major bleeding (4.8 vs. 3.8%; HR 1.28; 95% CI = 1.05–1.56). Within the first 10 days, 5366 (48.4%) patients were managed without revascularization. Regardless of revascularization or not, ticagrelor consistently reduced the primary outcome (HR 0.86 vs. 0.85, interaction P = 0.93), and all-cause death (HR 0.75 vs. 0.73, interaction P = 0.89) with no significant increase in overall major bleeding.
Conclusion
In patients with NSTE-ACS, benefit of ticagrelor over clopidogrel in reducing ischaemic events and total mortality was consistent with the overall PLATO trial, independent of actually performed revascularization during the initial 10 days.
doi:10.1093/eurheartj/ehu160
PMCID: PMC4132637  PMID: 24727884
Platelet inhibition; Acute coronary syndrome
11.  Outcomes among non-ST-segment elevation acute coronary syndromes patients with no angiographically obstructive coronary artery disease: observations from 37,101 patients 
Aims:
Limited data exist concerning outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) with no angiographically obstructive coronary artery disease (non-obstructive CAD). We assessed the frequency of clinical outcomes among patients with non-obstructive CAD compared with obstructive CAD.
Methods and results:
We pooled data from eight NSTE ACS randomized clinical trials from 1994 to 2008, including 37,101 patients who underwent coronary angiography. The primary outcome was 30-day death or myocardial infarction (MI). Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for 30-day death or MI for non-obstructive versus obstructive CAD were generated for each trial. Summary ORs (95% CIs) across trials were generated using random effects models. Overall, 3550 patients (9.6%) had non-obstructive CAD. They were younger, more were female, and fewer had diabetes mellitus, previous MI or prior percutaneous coronary intervention than patients with obstructive CAD. Thirty-day death or MI was less frequent among patients with non-obstructive CAD (2.2%) versus obstructive CAD (13.3%) (ORadj 0.15; 95% CI, 0.11–0.20); 30-day death or spontaneous MI and six-month mortality were also less frequent among patients with non-obstructive CAD (ORadj 0.19 (0.14–0.25) and 0.37 (0.28–0.49), respectively).
Conclusion:
Among patients with NSTE ACS, one in 10 had non-obstructive CAD. Death or MI occurred in 2.2% of these patients by 30 days. Compared with patients with obstructive CAD, the rate of major cardiac events was lower in patients with non-obstructive CAD but was not negligible, prompting the need to better understand management strategies for this group.
doi:10.1177/2048872613489315
PMCID: PMC3932771  PMID: 24562802
Acute coronary syndromes; angiography; atherosclerosis; coronary disease; infarction
12.  Edifoligide and Long-Term Outcomes After Coronary Artery Bypass Grafting: PREVENT IV 5-Year Results 
American heart journal  2012;164(3):379-386.e1.
Background
Edifoligide, an E2F transcription factor decoy, does not prevent vein graft failure or adverse clinical outcomes at 1-year in patients undergoing coronary artery bypass grafting (CABG). We compared the 5-year clinical outcomes of patients in PREVENT IV treated with edifoligide and placebo and to identify predictors of long-term clinical outcomes.
Methods
A total of 3014 patients undergoing CABG with at least 2 planned vein grafts were enrolled. Kaplan-Meier curves were generated to compare the long-term effects of edifoligide and placebo. A Cox proportional hazards model was constructed to identify factors associated with 5-year post-CABG outcomes. The main outcome measure was death, myocardial infarction (MI), repeat revascularization, and rehospitalization through 5 years.
Results
Five-year follow-up was complete in 2865 (95.1%) patients. At 5 years, patients randomized to edifoligide and placebo had similar rates of death (11.7% and 10.7%), MI (2.3% and 3.2%), revascularization (14.1% and 13.9%), and rehospitalization (61.6% and 62.5%). The 5-year composite outcome of death, MI, or revascularization occurred at similar frequency in patients assigned to edifoligide and placebo (26.3% and 25.5%; hazard ratio 1.03 [95% confidence interval 0.89–1.18]; P=0.721). Factors associated with death, MI, or revascularization at 5 years included diabetes, sex, worst graft quality, peri-index CABG MI, and ejection fraction.
Conclusions
Up to a quarter of patients undergoing CABG will have a major cardiac event or repeat revascularization procedure within 5 years of surgery. Edifoligide does not affect outcomes following CABG; however, common identifiable baseline and procedural risk factors are associated with long-term outcomes following CABG.
doi:10.1016/j.ahj.2012.05.019
PMCID: PMC3677726  PMID: 22980305
vein graft failure; coronary artery bypass graft surgery; transcription factor decoy; outcomes
13.  Duration of eptifibatide infusion after percutaneous coronary intervention and outcomes among high-risk patients with non-ST-segment elevation acute coronary syndrome: insights from EARLY ACS 
Background and Objectives:
Eptifibatide is indicated during percutaneous coronary intervention (PCI) with continuation for 18–24 hours post procedure but is associated with bleeding. We examined the efficacy and safety of shorter post-PCI eptifibatide infusions in high-risk non-ST-segment elevation acute coronary syndrome (NSTE ACS) patients.
Methods:
EARLY ACS patients treated with PCI and eptifibatide were grouped by post-procedure infusion duration: <10, 10–13, 13–17, and 17–25 (per protocol) hours. Adjusted estimated event rates for 96-hour death/myocardial infarction (MI)/recurrent ischaemia requiring urgent revascularization (RIUR), 30-day death/MI, post-PCI packed red blood cell (PRBC) transfusion, and GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) moderate/severe bleeding were obtained using inverse-propensity weighting to account for informative censoring of infusions.
Results:
Among 3271 eptifibatide-treated PCI patients, there were 66 96-hour death/MI/RIUR events, 94 30-day death/MI events, 127 PRBC transfusions, and 115 GUSTO moderate/severe bleeds. Compared with per protocol, patients receiving post-PCI infusions <10 hours had similar adjusted estimated rates of 96-hour death/MI/RIUR (absolute difference 0.021 higher; 0.040 vs. 0.019, 95% CI −0.023 to 0.064; p=0.35) and 30-day death/MI (0.020 higher; 0.046 vs. 0.026, 95% CI −0.021 to 0.062; p=0.34). There were also no differences in ischaemic outcomes between infusions of 10–17 hours and per-protocol infusions. Adjusted estimated rates of PRBC transfusion were higher for the <10-hour infusion group compared with per protocol (0.048 higher; 0.079 vs. 0.031, 95% CI 0.005 to 0.091, p=0.03) but were similar for other groups. Adjusted GUSTO moderate/severe bleeding rates were similar to per-protocol rates for all groups.
Conclusions:
In high-risk NSTE ACS patients, post-PCI eptifibatide infusions <18 hours were not associated with worse ischaemic outcomes. Shorter eptifibatide infusions in this population may be feasible.
doi:10.1177/2048872612474922
PMCID: PMC3821813  PMID: 24222836
Acute coronary syndrome; glycoprotein IIb/IIIa inhibitor; percutaneous coronary intervention
14.  Relationship Between Vein Graft Failure and Subsequent Clinical Outcomes After Coronary Artery Bypass Surgery 
Circulation  2012;125(6):749-756.
Background
Vein graft failure (VGF) is common after coronary artery bypass graft surgery, but its relationship with long-term clinical outcomes is unknown. In this retrospective analysis, we examined the relationship between VGF, assessed by coronary angiography 12 to 18 months after coronary artery bypass graft surgery, and subsequent clinical outcomes.
Methods and Results
Using the Project of Ex Vivo Vein Graft Engineering via Transfection IV (PREVENT IV) trial database, we studied data from 1829 patients who underwent coronary artery bypass graft surgery and had an angiogram performed up to 18 months after surgery. The main outcome measure was death, myocardial infarction, and repeat revascularization through 4 years after angiography. VGF occurred in 787 of 1829 patients (43%). Clinical follow-up was completed in 97% of patients with angiographic follow-up. The composite of death, myocardial infarction, or revascularization occurred more frequently among patients who had any VGF compared with those who had none (adjusted hazard ratio, 1.58; 95% confidence interval, 1.21–2.06; P=0.008). This was due mainly to more frequent revascularization with no differences in death (adjusted hazard ratio, 1.04; 95% confidence interval, 0.71–1.52; P=0.85) or death or myocardial infarction (adjusted hazard ratio, 1.08; 95% confidence interval, 0.77–1.53; P=0.65).
Conclusions
VGF is common after coronary artery bypass graft surgery and is associated with repeat revascularization but not with death and/or myocardial infarction. Further investigations are needed to evaluate therapies and strategies for decreasing VGF to improve outcomes in patients undergoing coronary artery bypass graft surgery.
doi:10.1161/CIRCULATIONAHA.111.040311
PMCID: PMC3699199  PMID: 22238227
angiography; coronary artery bypass; graft survival; outcome assessment; veins
15.  Paradoxical Immune Reconstitution Inflammatory Syndrome in HIV-Infected Patients Treated With Combination Antiretroviral Therapy After AIDS-Defining Opportunistic Infection 
Paradoxical immune reconstitution inflammatory syndrome (IRIS) was uncommon in patients with AIDS-defining Candida esophagitis or Pneumocystis pneumonia, whereas over 10% of those with Kaposi sarcoma (KS), tuberculosis, or Cryptococcus experienced this syndrome. Visceral KS-IRIS led to considerable morbidity and mortality.
Background. The incidence of immune reconstitution inflammatory syndrome (IRIS) when antiretroviral therapy (ART) is initiated after an AIDS-defining opportunistic infection (OI) is uncertain and understudied for the most common OIs.
Methods. We examined patients in the University of Washington Human Immunodeficiency Virus Cohort initiating potent ART subsequent to an AIDS-defining OI. IRIS was determined through retrospective medical record review and adjudication using a standardized data collection process and clinical case definition. We compared demographic and clinical characteristics, and immunologic changes in patients with and without IRIS.
Results. Among 196 patients with 260 OIs, 21 (11%; 95% confidence interval, 7%–16%) developed paradoxical IRIS in the first year on ART. The 3 most common OIs among study patients were Pneumocystis pneumonia (PCP, 28%), Candida esophagitis (23%), and Kaposi sarcoma (KS, 16%). Cumulative 1-year incidence of IRIS was 29% (12/41) for KS, 16% (4/25) for tuberculosis, 14% (1/7) for Cryptococcus, 10% (1/10) for Mycobacterium avium complex, and 4% (3/72) for PCP. Morbidity and mortality were highest in those with visceral KS-IRIS compared with other types of IRIS (100% [6/6] vs 7% [1/15], P < .01). Patients with mucocutaneous KS and tuberculosis-IRIS experienced greater median increase in CD4+ cell count during the first 6 months of ART compared with those without IRIS (+158 vs +53 cells/μL, P = .04, mucocutaneous KS; +261 vs +113, P = .04, tuberculosis).
Conclusions. Cumulative incidence and features of IRIS varied depending on the OI. IRIS occurred in >10% of patients with KS, tuberculosis, or Cryptococcus. Visceral KS-IRIS led to considerable morbidity and mortality.
doi:10.1093/cid/cir802
PMCID: PMC3258272  PMID: 22095568
16.  Somatic Symptoms and the Association between Hepatitis C Infection and Depression in HIV-infected Patients 
AIDS care  2011;23(10):1208-1218.
Studies of depression and hepatitis C virus (HCV) infection in HIV-infected patients have been contradictory and often not addressed key differences between HCV-infected and uninfected individuals including substance use. This cross-sectional observational study from the University of Washington HIV Cohort examined associations between HCV, symptoms, and depression in HIV-infected patients in routine clinical care. Patients completed instruments measuring depression, symptoms, and substance use. We generated depression severity scores and used linear regression to examine the relationship with HCV accounting for demographic and clinical characteristics. We conducted sensitivity analyses in which we removed depression somatic items (e.g. fatigue) from depression scores, and sensitivity analyses in which we also adjusted for non-depression somatic symptom items to examine the role of somatic and non-somatic symptoms in the association between depression and HCV. Of 764 HIV-infected patients, 160 (21%) were HCV-infected. In adjusted analysis, HCV-infected patients had worse depression severity (p=0.01) even after adjusting for differences in substance use. HCV remained associated with depression severity in secondary analyses that omitted the depression somatic PHQ-9 items (p = 0.01). However, when non-depression somatic symptoms were included as covariates in multivariate analyses, HCV was no longer associated with depression (p = 0.09).
Conclusions
We found a high prevalence and severity of depression among HIV-infected patients in routine care, particularly among those with HCV. The association between HCV and depression persisted even when depression somatic PHQ-9 items were omitted suggesting the association was not due to misclassification of HCV-related somatic symptoms like fatigue as depression. However, in models that also adjusted for non-depression somatic symptoms, the association disappeared highlighting the strong relationship between symptom burden and depression. Longitudinal studies are needed to assess the degree symptoms mediate the association between HCV and depression, and whether increased symptom burden is due in part to depression.
doi:10.1080/09540121.2011.555739
PMCID: PMC3534977  PMID: 21562994
hepatitis C virus; depression; HIV; somatic symptoms; antidepressant medications
17.  Offering an American Graduate Medical HIV Course to Health Care Workers in Resource-Limited Settings via the Internet 
PLoS ONE  2012;7(12):e52663.
Background
Western accredited medical universities can offer graduate-level academic courses to health care workers (HCWs) in resource-limited settings through the internet. It is not known whether HCWs are interested in these online courses, whether they can perform as well as matriculated students, or whether such courses are educationally or practically relevant.
Methods and Findings
In 2011, the University of Washington (UW) Schools of Medicine and Nursing offered the graduate course, “Clinical Management of HIV”, to HCWs that included a demographic survey, knowledge assessment, and course evaluation. UW faculty delivered HIV clinical topics through ten 2-hour weekly sessions from the perspectives of practicing HIV medicine in developed and developing settings. HCWs viewed lectures through Adobe Acrobat Connect Pro (Adobe Systems, San Jose, CA), and completed online homework on HIV Web Study (http://depts.washington.edu/hivaids/) and online quizzes. HCWs, who met the same passing requirements as UW students by attending 80% lectures, completing ≥90% homework, and achieving a cumulative ≥70% grade on quizzes, were awarded a certificate. 369 HCWs at 33 sites in 21 countries joined the course in 2011, a >15-fold increase since the course was first offered in 2007. The majority of HCWs came from Africa (72%), and most were physicians (41%), nurses (22%), or midlevel practitioners (20%). 298 HCWs (81%) passed all requirements and earned a certificate. In a paired analysis of pre- and post-course HIV knowledge assessments, 56% of HCWs improved their post-course score (p<0.0001) with 27% improving by at least 30%. In the course evaluation, most HCWs rated the course as excellent (53%) or very good (39%).
Conclusions
This online HIV course demonstrated that opening a Western graduate medical and nursing curriculum to HCWs in resource-limited settings is feasible, popular, and valuable, and may address logistic and economic barriers to the provision of high quality education in these settings.
doi:10.1371/journal.pone.0052663
PMCID: PMC3527561  PMID: 23285139
18.  Intravenous Erythropoietin in Patients with ST-Segment Elevation Myocardial Infarction 
Context
Acute ST-segment elevation myocardial infarction (STEMI) is a leading cause of morbidity and mortality. In experimental models of MI, erythropoietin reduces infarct size and improves left ventricular (LV) function.
Objective
To evaluate the safety and efficacy of a single intravenous bolus of epoetin alfa in patients with STEMI.
Design, Setting, and Patients
Prospective, randomized, double-blind, placebo-controlled trial with a dose-escalation safety phase and a single-dose (60,000 units of epoetin alfa) efficacy phase involving 222 patients with STEMI who underwent successful percutaneous coronary intervention (PCI) as a primary or rescue reperfusion strategy.
Intervention
Participants were randomly assigned to treatment with intravenous epoetin alfa or matching saline placebo administered within 4 hours of reperfusion.
Main Outcome Measure
Infarct size, expressed as a percentage of LV mass, assessed by cardiac magnetic resonance (CMR) imaging 2–6 days after study medication administration.
Results
In the efficacy cohort (n=138), infarct size did not differ between groups at either 2–6 days (15.8±10.3 vs. 15.0±10.0, P=.666) or 12±2 weeks (10.6±8.6 vs. 10.4±7.6, P=.886). Left ventricular ejection fraction also did not differ between groups at either the early (48.2±9.1 vs. 48.9±8.7, P=.671) or late (52.5±9.3 vs. 52.0±8.8, P=.760) timepoints. In pre-specified analyses of patients aged ≥70 years (n=21), mean infarct size within the first week was larger in the epoetin alfa arm than in the placebo group (19.9±9.9 vs.11.7±7.2, P=.026). Patients who received epoetin alfa had a higher incidence of the composite endpoint of death, myocardial infarction, stroke, or stent thrombosis (4.0% vs. 0.0%, P=.042), and a higher incidence of serious adverse events (20.0% vs. 10.3%, P=.052).
Conclusions
In STEMI patients successfully reperfused with primary or rescue PCI, a single intravenous bolus of epoetin alfa did not reduce infarct size and was associated with higher rates of adverse cardiovascular events. Furthermore, it may be associated with increased infarct size in older patients.
Trial Registration
clinicaltrials.gov identifier NCT00378352.
doi:10.1001/jama.2011.592
PMCID: PMC3486644  PMID: 21558517
Myocardial infarction; MRI; Randomized controlled trial; Erythropoietin; Recombinant
19.  Comparative Effectiveness and Toxicity of Statins Among HIV-Infected Patients 
This study compared the effectiveness and toxicity of different statins among 700 HIV-infected patients in routine clinical care. Findings suggest that atorvastatin and rosuvastatin are preferable to pravastatin leading to greater declines in lipid levels with similar low rates of toxicity.
Background. Dyslipidemia is common and is often treated with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins). Little is known about the comparative effectiveness of statins among human immunodeficiency virus (HIV)–infected patients. This study compared the effectiveness and toxicity of statins among HIV-infected patients in clinical care.
Methods. We conducted a retrospective cohort study of patients starting their initial statin medications at 2 large HIV clinics (N = 700). The primary observation was change in lipid levels during statin therapy. Secondary observations included whether individualized National Cholesterol Education Program (NCEP) goals for low density lipoprotein cholesterol (LDL-C) and non–high density lipoprotein cholesterol (non-HDL-C) levels were reached, and toxicity rates. We used linear regression to examine change in lipid levels, controlling for baseline lipid values and demographic and clinical characteristics. We conducted secondary analyses using propensity scores to address confounding by indication.
Results. The most commonly prescribed statins were atorvastatin (N = 303), pravastatin (N = 280), and rosuvastatin (N = 95). One year after starting a statin therapy, patients who received atorvastatin or rosuvastatin had significantly greater decreases in total cholesterol, LDL-C, and non-HDL-C than patients on pravastatin. The likelihood of reaching NCEP goals for LDL-C levels was higher with the use of rosuvastatin (OR 2.1; P = .03) and atorvastatin (odds ratio [OR], 2.1; P = .001) compared with that of pravastatin. The likelihood of reaching NCEP goals for non-HDL-C levels was higher for rosuvastatin (OR 2.3; P = .045) but not atorvastatin (OR, 1.5; P = .1) compared with pravastatin. Toxicity rates were similar for all 3 statins: 7.3% for atorvastatin, 6.1% for pravastatin, and 5.3% for rosuvastatin.
Conclusions. Our findings suggest that atorvastatin and rosuvastatin are preferable to pravastatin for treatment of HIV-infected patients with dyslipidemia, due to greater declines in total cholesterol, LDL-C, and non-HDL-C, with similar lower toxicity rates.
doi:10.1093/cid/ciq111
PMCID: PMC3106249  PMID: 21189273
21.  Design and rationale of the Reduction of Infarct Expansion and Ventricular Remodeling with Erythropoietin After Large Myocardial Infarction (REVEAL) trial 
American heart journal  2010;160(5):795-803.e2.
Background
Acute myocardial infarction (MI) remains a leading cause of death despite advances in pharmacologic and percutaneous therapies. Animal models of ischemia/reperfusion have demonstrated that single-dose erythropoietin (EPO) may reduce infarct size, decrease apoptosis, and increase neovascularization, possibly through mobilization of endothelial progenitor cells (EPCs).
Study Design
REVEAL is a randomized, double-blind, placebo-controlled, multicenter trial evaluating the effects of epoetin alfa on infarct size and left ventricular (LV) remodeling in patients with large MIs. The trial comprises a dose-escalation safety phase and a single-dose efficacy phase using the highest acceptable epoetin alfa dose up to 60,000 units. Up to 250 STEMI patients undergoing primary or rescue percutaneous coronary intervention (PCI) will be randomized to intravenous epoetin alfa or placebo within 4 hours of successful reperfusion. The primary study endpoint is infarct size expressed as a percentage of LV mass, as measured by cardiac magnetic resonance imaging 2–6 days post study medication administration. Secondary endpoints will assess changes in EPC numbers and changes in indices of ventricular remodeling.
Conclusion
The REVEAL trial will evaluate the safety and efficacy of the highest tolerated single dose of epoetin alfa in patients who have undergone successful rescue or primary PCI for acute STEMI.
doi:10.1016/j.ahj.2010.09.007
PMCID: PMC3018783  PMID: 21095264
22.  Intramyocardial, Autologous CD34+ Cell Therapy for Refractory Angina 
Circulation research  2011;109(4):428-436.
Rationale
A growing number of patients with coronary disease have refractory angina. Preclinical and early-phase clinical data suggest that intramyocardial injection of autologous CD34+ cells can improve myocardial perfusion and function.
Objective
Evaluate the safety and bioactivity of intramyocardial injections of autologous CD34+ cells in patients with refractory angina who have exhausted all other treatment options.
Methods and Results
In this prospective, double-blind, randomized, phase II study (ClinicalTrials.gov identifier: NCT00300053), 167 patients with refractory angina received 1 of 2 doses (1×105 or 5×105 cells/kg) of mobilized autologous CD34+ cells or an equal volume of diluent (placebo). Treatment was distributed into 10 sites of ischemic, viable myocardium with a NOGA mapping injection catheter. The primary outcome measure was weekly angina frequency 6 months after treatment. Weekly angina frequency was significantly lower in the low-dose group than in placebo-treated patients at both 6 months (6.8±1.1 versus 10.9±1.2, P=0.020) and 12 months (6.3±1.2 versus 11.0±1.2, P=0.035); measurements in the high-dose group were also lower, but not significantly. Similarly, improvement in exercise tolerance was significantly greater in low-dose patients than in placebo-treated patients (6 months: 139±151 versus 69±122 seconds, P=0.014; 12 months: 140±171 versus 58±146 seconds, P=0.017) and greater, but not significantly, in the high-dose group. During cell mobilization and collection, 4.6% of patients had cardiac enzyme elevations consistent with non-ST segment elevation myocardial infarction. Mortality at 12 months was 5.4% in the placebo-treatment group with no deaths among cell-treated patients.
Conclusions
Patients with refractory angina who received intramyocardial injections of autologous CD34+ cells (105 cells/kg) experienced significant improvements in angina frequency and exercise tolerance. The cell-mobilization and -collection procedures were associated with cardiac enzyme elevations, which will be addressed in future studies.
doi:10.1161/CIRCRESAHA.111.245993
PMCID: PMC3190575  PMID: 21737787
angiogenesis; endothelial progenitor cells (EPC) myocardial ischemia; myocardial regeneration; stem cells
23.  Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial 
Objective To evaluate efficacy and safety outcomes in patients in the PLATelet inhibition and patient Outcomes (PLATO) trial who at randomisation were planned for a non-invasive treatment strategy.
Design Pre-specified analysis of pre-randomisation defined subgroup of prospective randomised clinical trial.
Setting 862 centres in 43 countries.
Participants 5216 (28%) of 18 624 patients admitted to hospital for acute coronary syndrome who were specified as planned for non-invasive management.
Interventions Randomised treatment with ticagrelor (n=2601) versus clopidogrel (2615).
Main outcome measurements Primary composite end point of cardiovascular death, myocardial infarction, and stroke; their individual components; and PLATO defined major bleeding during one year.
Results 2183 (41.9%) patients had coronary angiography during their initial hospital admission, 1065 (20.4%) had percutaneous coronary intervention, and 208 (4.0%) had coronary artery bypass surgery. Cumulatively, 3143 (60.3%) patients had been managed non-invasively by the end of follow-up. The incidence of the primary end point was lower with ticagrelor than with clopidogrel (12.0% (n=295) v 14.3% (346); hazard ratio 0.85, 95% confidence interval 0.73 to 1.00; P=0.04). Overall mortality was also lower (6.1% (147) v 8.2% (195); 0.75, 0.61 to 0.93; P=0.01). The incidence of total major bleeding (11.9% (272) v 10.3% (238); 1.17, 0.98 to 1.39; P=0.08) and non-coronary artery bypass grafting related major bleeding (4.0% (90) v 3.1% (71); 1.30, 0.95 to 1.77; P=0.10) was numerically higher with ticagrelor than with clopidogrel.
Conclusions In patients with acute coronary syndrome initially intended for non-invasive management, the benefits of ticagrelor over clopidogrel were consistent with those from the overall PLATO results, indicating the broad benefits of P2Y12 inhibition with ticagrelor regardless of intended management strategy.
Trial registration Clinical trials NCT00391872.
doi:10.1136/bmj.d3527
PMCID: PMC3117310  PMID: 21685437
24.  Pandemic (H1N1) 2009 and HIV Infection 
Emerging Infectious Diseases  2011;17(6):1140-1143.
doi:10.3201/eid1706.102018
PMCID: PMC3358220  PMID: 21749797
H1N1; influenza; HIV; co-infection; viruses; letter
25.  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

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