Edward Hulten

Analysis of Antibiotic Resistance Genes in Multidrug-Resistant Acinetobacter sp. Isolates from Military and Civilian Patients Treated at the Walter Reed Army Medical Center

ABSTRACT Military medical facilities treating patients injured in Iraq and Afghanistan have identified a large number of multidrug-resistant (MDR) Acinetobacter baumannii isolates. In order to anticipate the impact of these pathogens on patient care, we analyzed the antibiotic resistance genes responsible for the MDR phenotype in Acinetobacter sp. isolates collected from patients at the Walter Reed Army Medical Center (WRAMC). Susceptibility testing, PCR amplification of the genetic determinants of resistance, and clonality were determined. Seventy-five unique patient isolates were included in this study: 53% were from bloodstream infections, 89% were resistant to at least three classes of antibiotics, and 15% were resistant to all nine antibiotics tested. Thirty-seven percent of the isolates were recovered from patients nosocomially infected or colonized at the WRAMC. Sixteen unique resistance genes or gene families and four mobile genetic elements were detected. In addition, this is the first report of blaOXA-58-like and blaPER-like genes in the U.S. MDR A. baumannii isolates with at least eight identified resistance determinants were recovered from 49 of the 75 patients. Molecular typing revealed multiple clones, with eight major clonal types being nosocomially acquired and with more than 60% of the isolates being related to three pan-European types. This report gives a “snapshot” of the complex genetic background responsible for antimicrobial resistance in Acinetobacter spp. from the WRAMC. Identifying genes associated with the MDR phenotype and defining patterns of transmission serve as a starting point for devising strategies to limit the clinical impact of these serious infections.

Prognostic value of cardiac computed tomography angiography: a systematic review and meta-analysis.

OBJECTIVES The purpose of this study was to systematically review and perform a meta-analysis of the ability of cardiac computed tomography angiography (CCTA) to predict future cardiovascular events and death. BACKGROUND The diagnostic accuracy of CCTA is well reported. The prognostic value of CCTA has been described in several studies, but many were underpowered. Pooling outcomes increases the power to predict rare events. METHODS We searched multiple databases for longitudinal studies of CCTA with at least 3 months follow-up of symptomatic patients with suspected coronary artery disease (CAD) reporting major adverse cardiovascular events (MACE), consisting of death, myocardial infarction (MI), and revascularization. Annualized event rates were pooled using a bivariate mixed-effects binomial regression model to calculate summary likelihood ratios and receiver-operating characteristic curves. RESULTS Eighteen studies evaluated 9,592 patients with a median follow-up of 20 months. The pooled annualized event rate for obstructive (any vessel with >50% luminal stenosis) versus normal CCTA was 8.8% versus 0.17% per year for MACE (p < 0.05) and 3.2% versus 0.15% for death or MI (p < 0.05). The pooled negative likelihood ratio for MACE after normal CCTA findings was 0.008 (95% confidence interval [CI]: 0.0004 to 0.17, p < 0.001), the positive likelihood ratio was 1.70 (95% CI: 1.42 to 2.02, p < 0.001), sensitivity was 0.99 (95% CI: 0.93 to 1.00, p < 0.001), and specificity was 0.41 (95% CI: 0.31 to 0.52, p < 0.001). Stratifying by no CAD, nonobstructive CAD (worst stenosis <50%), or obstructive CAD, there were incrementally increasing adverse events. CONCLUSIONS Adverse cardiovascular events among patients with normal findings on CCTA are rare. There are incrementally increasing future MACE with increasing CAD by CCTA.

Prevalence and Severity of Coronary Artery Disease and Adverse Events Among Symptomatic Patients With Coronary Artery Calcification Scores of Zero Undergoing Coronary Computed Tomography Angiography Results From the CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter) Registry

OBJECTIVES The purpose of this study was to describe the prevalence and severity of coronary artery disease (CAD) in relation to prognosis in symptomatic patients without coronary artery calcification (CAC) undergoing coronary computed tomography angiography (CCTA). BACKGROUND The frequency and clinical relevance of CAD in patients without CAC are unclear. METHODS We identified 10,037 symptomatic patients without CAD who underwent concomitant CCTA and CAC scoring. CAD was assessed as <50%, ≥50%, and ≥70% stenosis. All-cause mortality and the composite endpoint of mortality, myocardial infarction, or late coronary revascularization (≥90 days after CCTA) were assessed. RESULTS Mean age was 57 years, 56% were men, and 51% had a CAC score of 0. Among patients with a CAC score of 0, 84% had no CAD, 13% had nonobstructive stenosis, and 3.5% had ≥50% stenosis (1.4% had ≥70% stenosis) on CCTA. A CAC score >0 had a sensitivity, specificity, and negative and positive predictive values for stenosis ≥50% of 89%, 59%, 96%, and 29%, respectively. During a median of 2.1 years, there was no difference in mortality among patients with a CAC score of 0 irrespective of obstructive CAD. Among 8,907 patients with follow-up for the composite endpoint, 3.9% with a CAC score of 0 and ≥50% stenosis experienced an event (hazard ratio: 5.7; 95% confidence interval: 2.5 to 13.1; p < 0.001) compared with 0.8% of patients with a CAC score of 0 and no obstructive CAD. Receiver-operator characteristic curve analysis demonstrated that the CAC score did not add incremental prognostic information compared with CAD extent on CCTA for the composite endpoint (CCTA area under the curve = 0.825; CAC + CCTA area under the curve = 0.826; p = 0.84). CONCLUSIONS In symptomatic patients with a CAC score of 0, obstructive CAD is possible and is associated with increased cardiovascular events. CAC scoring did not add incremental prognostic information to CCTA.

Prognostic Value of Nonobstructive and Obstructive Coronary Artery Disease Detected by Coronary Computed Tomography Angiography to Identify Cardiovascular Events

Background—The contribution of plaque extent to predict cardiovascular events among patients with nonobstructive and obstructive coronary artery disease (CAD) is not well defined. Our objective was to evaluate the prognostic value of plaque extent detected by coronary computed tomography angiography. Methods and Results—All consecutive patients without prior CAD referred for coronary computed tomography angiography to evaluate for CAD were included. Examination findings were classified as normal, nonobstructive (<50% stenosis), or obstructive (≥50%). Based on the number of segments with disease, extent of CAD was classified as nonextensive (⩽4 segments) or extensive (>4 segments). The cohort included 3242 patients followed for the primary outcome of cardiovascular death or myocardial infarction for a median of 3.6 (2.1–5.0) years. In a multivariable analysis, the presence of extensive nonobstructive CAD (hazard ratio, 3.1; 95% confidence interval, 1.5–6.4), nonextensive obstructive (hazard ratio, 3.0; 95% confidence interval, 1.3–6.9), and extensive obstructive CAD (hazard ratio, 3.9; 95% confidence interval, 2.2–7.2) were associated with an increased rate of events, whereas nonextensive, nonobstructive CAD was not. The addition of plaque extent to a model that included clinical probability as well as the presence and severity of CAD improved risk prediction. Conclusions—Among patients with nonobstructive CAD, those with extensive plaque experienced a higher rate of cardiovascular death or myocardial infarction, comparable with those who have nonextensive disease. Even among patients with obstructive CAD, greater extent of nonobstructive plaque was associated with higher event rate. Our findings suggest that regardless of whether obstructive or nonobstructive disease is present, the extent of plaque detected by coronary computed tomography angiography enhances risk assessment.

Outcomes After Coronary Computed Tomography Angiography in the Emergency Department: A Systematic Review and Meta-Analysis of Randomized, Controlled Trials

OBJECTIVES The aim of the study was to systematically review and perform a meta-analysis of randomized, controlled trials of coronary computed tomography angiography (CCTA) versus usual care (UC) triage of acute chest pain in the emergency department (ED). BACKGROUND CCTA allows rapid evaluation of patients presenting to the ED with acute chest pain syndromes; however, the impact of such testing on patient management and downstream testing has emerged as a concern. METHODS We systematically searched for randomized, controlled trials of CCTA in the ED and performed a meta-analysis of clinical outcomes. RESULTS Four randomized, controlled trials were included, with 1,869 patients undergoing CCTA and 1,397 undergoing UC. There were no deaths and no difference in the incidence of myocardial infarction, post-discharge ED visits, or rehospitalizations. Four studies reported decreased length of stay with CCTA and 3 reported cost savings; 8.4% of patients undergoing CCTA versus 6.3% of those receiving UC underwent invasive coronary angiography (ICA), whereas 4.6% of patients undergoing CCTA versus 2.6% of those receiving UC underwent coronary revascularization. The odds ratio of ICA for CCTA patients versus UC patients was 1.36 (95% confidence interval [CI]: 1.03 to 1.80, p = 0.030), and for revascularization, it was 1.81 (95% CI: 1.20 to 2.72, p = 0.004). The absolute increase in ICA after CCTA was 21 per 1,000 CCTA patients (95% CI: 1.8 to 44.9), and the number needed to scan was 48. The absolute increase in revascularization after CCTA was 20 per 1,000 patients (95% CI: 5.0 to 41.4); the number needed to scan was 50. Both percutaneous coronary intervention and coronary artery bypass graft surgery independently contributed to the significant increase in revascularization. CONCLUSIONS Compared with UC, the use of CCTA in the ED is associated with decreased ED cost and length of stay but increased ICA and revascularization.

HIV positivity, protease inhibitor exposure, and subclinical atherosclerosis: A systematic review and meta-analysis of observational studies

Context: Patients with HIV may have increased risk of atherosclerotic cardiovascular disease owing to multiple biological mechanisms. Objective: To evaluate the evidence for subclinical atherosclerosis among patients with HIV. Design: Systematic review of observational studies. Data sources: We searched Medline, Cochrane DSR, ACP Journal Club, DARE, CMR, HTA, NHSEED, Embase and the Cochrane Controlled Trials Register for studies published before November 2008. Study selection: Eligible studies were cross-sectional, cohort, or case–control studies reporting carotid ultrasound intima-media thickness (CIMT), focal plaque incidence, or coronary artery calcium (CAC), as determined by HIV positivity or protease inhibitor (PI) exposure. Data extraction: Two independent reviewers abstracted data using a standardised form. The primary outcome was weighted mean difference (WMD) for CIMT comparing HIV positive versus negative patients. Other outcomes included WMD by PI exposure and the odds ratio (OR) for a focal carotid plaque or CAC. Data from six cross-sectional, seven case–control and 13 cohort studies were included, involving 5456 HIV positive and 3600 HIV negative patients. Results: The weighted mean CIMT was 0.04 mm thicker among patients with HIV than among non-HIV patients (95% CI 0.02 to 0.06; p<0.001). HIV positivity was not associated with carotid plaque or CAC. PI exposure did not significantly affect CIMT, carotid plaque, or CAC. There was evidence of publication bias and stratified analysis and meta-regression showed outcomes were influenced by study design, age, gender and smoking. However, HIV positivity slightly increased CIMT even after sensitivity analyses. Conclusions: HIV infection and PI exposure are not strong independent risk factors for subclinical atherosclerosis. Confounding may contribute to overestimation of the risk associated with HIV and PI exposure.

Coronary Artery Disease Detected by Coronary Computed Tomographic Angiography Is Associated With Intensification of Preventive Medical Therapy and Lower Low-Density Lipoprotein Cholesterol

Background—Coronary computed tomographic angiography (CCTA) is an accurate test for the identification of coronary artery disease (CAD), yet the impact of CCTA results on subsequent medical therapy and risk factors has not been widely reported. Methods and Results—We identified consecutive patients aged >18 years without prior CAD who underwent CCTA from 2004 to 2011 and had complete data on medications before and after CCTA. CCTA results were categorized as no CAD, <50% stenosis, and ≥50% stenosis. Based on the number of involved segments, extent of disease was categorized as nonextensive (⩽4 segments) or extensive CAD (>4 segments). Electronic medical records and patient interviews were reviewed blinded to CCTA findings to assess initiation of aspirin and intensification of lipid-lowering therapies. Survival analysis was performed to evaluate intensification of lipid therapy as a predictor of cardiovascular death or nonfatal myocardial infarction. Among 2839 patients with mean follow-up of 3.6 years, the odds of physician intensification of lipid-lowering therapy significantly increased for those with nonobstructive CAD (odds ratio, 3.6; 95% confidence interval, 2.9–4.9; P<0.001) and obstructive CAD (odds ratio, 5.6; 95% confidence interval, 4.3–7.3; P<0.001). Low-density lipoprotein cholesterol levels declined significantly in association with intensification of lipid-lowering therapy after CCTA in all patient subgroups. In a hypothesis-generating analysis, among patients with nonobstructive but extensive CAD, statin use after CCTA was associated with a reduction in cardiovascular death or myocardial infarction (hazards ratio, 0.18; 95% confidence interval, 0.05–0.66; P=0.01). Conclusions—Abnormal CCTA findings are associated with downstream intensification in statin and aspirin therapy. In particular, CCTA may lead to increased use of prognostically beneficial therapies in patients identified as having extensive, nonobstructive CAD.

Coronary CT angiography versus intravascular ultrasound for estimation of coronary stenosis and atherosclerotic plaque burden: a meta-analysis.

BACKGROUND Numerous studies have compared coronary CT angiography (CTA) with quantitative coronary angiography. However, the ability of coronary CTA to identify atherosclerosis and to accurately measure plaque and coronary area and volume measurements as compared with intravascular ultrasound (IVUS) has not been fully defined. OBJECTIVE We sought to assess the ability of coronary CTA to quantify coronary and plaque measurements commonly performed with IVUS. METHODS We searched multiple databases for diagnostic studies that directly compared coronary CTA and IVUS for coronary plaque detection, vessel luminal area, percentage of area stenosis, plaque area, and plaque volume. We used a bivariate mixed-effects binomial regression model to pool test sensitivity and specificity for detection of any coronary plaque. RESULTS Forty-two studies that evaluated 1360 patients (75% men; mean age, 59 years) were identified. No significant difference was found between coronary CTA and IVUS measurements of vessel lumen cross-sectional area, plaque area, percentage of area stenosis, or plaque volume within the overall cohort and no difference for the measurement of cross-sectional area (n = 5 studies) and plaque volume (n = 8 studies) among a subgroup that used automated or semiautomated measurement techniques. Sensitivity and specificity of coronary CTA to detect any plaque compared with IVUS were 93% and 92%, respectively, with an area under the receiver-operating curve of 0.97. CONCLUSIONS Compared with IVUS, coronary CTA appears to be highly accurate for estimation of luminal area, percentage of area stenosis, plaque volume, and plaque area and for detection of plaque. The use of automated vessel and stenosis measurements appears promising in limited studies to date.

Marathon Running as a Cause of Troponin Elevation: A Systematic Review and Meta-Analysis

BACKGROUND Cardiac troponin (cTn) has high sensitivity and specificity for myocardial injury in acute coronary syndrome. Our objective was to review the published literature regarding the incidence of cTn elevations in marathon runners. METHODS Systematic review and meta-analysis of observational studies published before September 2009. We included studies of patients who had completed a marathon and had serum cTn levels within 24 hours. The primary outcome was the odds ratio for conversion of a normal pre-marathon cTn to an elevated post-marathon cTn. Secondary outcomes included the pooled prevalence of cTn elevation and comparison of the odds ratio for post-marathon elevation of cTnI versus cTnT. RESULTS Sixteen studies of 939 participants met criteria for inclusion. The mean age was 39 ± 4 years and patients were 74 ± 14% male. There were 6 pre-marathon cTn elevations and 579 post-race elevations. The pooled odds ratio for converting from a normal pre-race to an elevated post-race cTn was 51.84 (95% CI 16-168, I² = 66%, P < 0.001). The pooled incidence of a post-marathon cTn elevation was 51% (95% CI 33-69, I² = 98%, P < 0.001) of all runners. For the primary outcome there was no significant publication bias. Age and gender were not associated, but publication date and assay sensitivity was associated with cTn elevation. cTnI was less commonly elevated versus cTnT. CONCLUSIONS The available data demonstrate that cTn levels are frequently elevated after a marathon with unclear cardiovascular significance. This elevation of cTn appears to be consistent among a diverse patient population.

Changes in Preventive Medical Therapies and CV Risk Factors After CT Angiography

OBJECTIVES The aim of the study was to determine the association of coronary computed tomographic angiography (CTA)-identified coronary artery disease (CAD) with post-test aspirin, statin, and antihypertensive medication use and changes in cholesterol and blood pressure (BP). BACKGROUND The relationship of CTA findings to subsequent changes in preventive cardiovascular medication prescribing patterns and risk factors is largely unknown. METHODS We studied 1,125 consecutive patients without known CAD referred for coronary CTA. CAD was defined as none, nonobstructive (<50%), or obstructive (≥50%). Prescriptions were queried in the 6 months pre- and post-CTA for comparison of aspirin, statin, and BP treatment. Medication intensification was defined as initiation, dose increase, or, for statins, change to a more potent formulation. Lipid and BP values were obtained at 12 months pre- and post-CTA. RESULTS Patients were 50 ± 12 years of age (59% men), with 34%, 47%, and 33% on baseline statin, BP medication(s), and aspirin, respectively. Relative to patients without CAD (n = 617), patients with nonobstructive (n = 411) and obstructive CAD (n = 97) demonstrated significant intensification in unadjusted rates of statin (26%, 46%, and 46% of patients; p < 0.001), BP (11%, 21%, and 24%; p < 0.001), and aspirin therapies (9%, 29%, and 40%; p < 0.001), and significant improvements in total cholesterol (-6.7, -14.7, and -24.7 mg/dl; p = 0.008), low-density lipoprotein cholesterol (-5.6, -14.1, and -24.6 mg/dl; p = 0.001), systolic (+0.1, -1.4, and -4.9 mm Hg; p = 0.002), and diastolic BP (-0.6, -1.0, and -3.4 mm Hg; p = 0.012), respectively. Adjusted for baseline risk factors and medications, CAD was independently associated with increased aspirin, statin, and BP medication use rates in CTA-identified nonobstructive CAD (odds ratio [OR]: 6.9, 95% confidence interval [CI]: 4.7 to 10.2; OR: 6.6, 95% CI: 3.0 to 14.3; OR: 1.6, 95% CI: 1.1 to 2.2, respectively; p < 0.05), and aspirin and statin use in obstructive CAD (OR: 42.4, 95% CI: 15.8 to 113.9; OR: 30.3, 95% CI: 3.2 to 289.2, respectively; p < 0.05). CONCLUSIONS CAD presence and severity on CTA are associated with increased use of preventive cardiovascular medications and improvements in cholesterol and BP.