CAGm: a repository of germline microsatellite variations in the 1000 genomes project.

The human genome harbors an abundance of repetitive DNA; however, its function continues to be debated. Microsatellites-a class of short tandem repeat-are established as an important source of genetic variation. Array length variants are common among microsatellites and affect gene expression; but, efforts to understand the role and diversity of microsatellite variation has been hampered by several challenges. Without adequate depth, both long-read and short-read sequencing may not detect the variants present in a sample; additionally, large sample sizes are needed to reveal the degree of population-level polymorphism. To address these challenges we present the Comparative Analysis of Germline Microsatellites (CAGm): a database of germline microsatellites from 2529 individuals in the 1000 genomes project. A key novelty of CAGm is the ability to aggregate microsatellite variation by population, ethnicity (super population) and gender. The database provides advanced searching for microsatellites embedded in genes and functional elements. All data can be downloaded as Microsoft Excel spreadsheets. Two use-case scenarios are presented to demonstrate its utility: a mononucleotide (A) microsatellite at the BAT-26 locus and a dinucleotide (CA) microsatellite in the coding region of FGFRL1. CAGm is freely available at http://www.cagmdb.org/.

Estimating the number of genetic mutations (hits) required for carcinogenesis based on the distribution of somatic mutations.

Individual instances of cancer are primarily a result of a combination of a small number of genetic mutations (hits). Knowing the number of such mutations is a prerequisite for identifying specific combinations of carcinogenic mutations and understanding the etiology of cancer. We present a mathematical model for estimating the number of hits based on the distribution of somatic mutations. The model is fundamentally different from previous approaches, which are based on cancer incidence by age. Our somatic mutation based model is likely to be more robust than age-based models since it does not require knowing or accounting for the highly variable mutation rate, which can vary by over three orders of magnitude. In fact, we find that the number of somatic mutations at diagnosis is weakly correlated with age at cancer diagnosis, most likely due to the extreme variability in mutation rates between individuals. Comparing the distribution of somatic mutations predicted by our model to the actual distribution from 6904 tumor samples we estimate the number of hits required for carcinogenesis for 17 cancer types. We find that different cancer types exhibit distinct somatic mutational profiles corresponding to different numbers of hits. Why might different cancer types require different numbers of hits for carcinogenesis? The answer may provide insight into the unique etiology of different cancer types.

DNA sequencing of anatomy lab cadavers to provide hands-on precision medicine introduction to medical students.

BACKGROUND: Medical treatment informed by Precision Medicine is becoming a standard practice for many diseases, and patients are curious about the consequences of genomic variants in their genome. However, most medical students' understanding of Precision Medicine derives from classroom lectures. This format does little to foster an understanding for the potential and limitations of Precision Medicine. To close this gap, we implemented a hands-on Precision Medicine training program utilizing exome sequencing to prepare a clinical genetic report of cadavers studied in the anatomy lab. The program reinforces Precision Medicine related learning objectives for the Genetics curriculum. METHODS: Pre-embalmed blood samples and embalmed tissue were obtained from cadavers (donors) used in the anatomy lab. DNA was isolated and sequenced and illustrative genetic reports provided to the students. The reports were used to facilitate discussion with students on the implications of pathogenic genomic variants and the potential correlation of these variants in each "donor" with any anatomical anomalies identified during cadaver dissection. RESULTS: In 75% of cases, analysis of whole exome sequencing data identified a variant associated with increased risk for a disease/abnormal condition noted in the donor's cause of death or in the students' anatomical findings. This provided students with real-world examples of the potential relationship between genomic variants and disease risk. Our students also noted that diseases associated with 92% of the pathogenic variants identified were not related to the anatomical findings, demonstrating the limitations of Precision Medicine. CONCLUSION: With this study, we have established protocols and classroom procedures incorporating hands-on Precision Medicine training in the medical student curriculum and a template for other medical educators interested in enhancing their Precision Medicine training program. The program engaged students in discovering variants that were associated with the pathophysiology of the cadaver they were studying, which led to more exposure and understanding of the potential risks and benefits of genomic medicine.

Intermittent upper and lower body perfusion during circulatory arrest is safe for aortic repair.

INTRODUCTION: We report our initial surgical experience of intermittent upper and lower body retrograde perfusion during aortic repair under circulatory arrest. METHODS: Between 2007 and 2015, 148 consecutive patients underwent surgical aortic repair using moderate hypothermic circulatory arrest with intermittent upper and lower body retrograde perfusion. RESULTS: All patients underwent ascending aorta replacement; eight had hemiarch replacement (5.4%) and 92 had aortic root surgery (62.2%). Twenty-nine patients (19.6%) had re-operations and 60 patients (40.5%) had concomitant procedures. The mean duration of circulatory arrest was 23.2 ± 5.4 minutes (range 13-48 minutes). Hospital length of stay was 11.3 ± 16.9 days (median 7.0 days; interquartile range [IQR] 6 days). Complications included death in 0.7%, stroke in 3.4%, respiratory failure in 12.8%, renal replacement therapy in 2.0% and re-exploration for bleeding in 0.7%. Peak renal and hepatic biomarkers were: creatinine 1.2 ± 0.3 mg/dL, aspartate aminotransferase (AST) 291 ± 1112 U/L (IQR 91.8 U/L), alanine aminotransferase (ALT) 212 ± 924 U/L (IQR 43.0 U/L) and total bilirubin 1.2 ± 0.9 mg/dL. Peak lactate was 5.0 ± 3.3 mmol/L (IQR 3.3 mmol/L) and the mean time to normalization (<2 mmol/L) was 14.3 ± 14.0 hours. CONCLUSIONS: Intermittent upper and lower body retrograde perfusion during circulatory arrest is safe for aortic repair, resulting in low morbidity and mortality. There were only modest rises in hepatic and renal injury biomarkers as well as the rapid clearance of lactate. These findings support the continued study of this technique to reduce end-organ dysfunction during circulatory arrest, including expansion to patients with longer circulatory arrest duration and a direct comparison with conventional circulatory arrest without retrograde upper and lower body perfusion.

Surgical ablation of atrial fibrillation during mitral-valve surgery.

BACKGROUND: Among patients undergoing mitral-valve surgery, 30 to 50% present with atrial fibrillation, which is associated with reduced survival and increased risk of stroke. Surgical ablation of atrial fibrillation has been widely adopted, but evidence regarding its safety and effectiveness is limited. METHODS: We randomly assigned 260 patients with persistent or long-standing persistent atrial fibrillation who required mitral-valve surgery to undergo either surgical ablation (ablation group) or no ablation (control group) during the mitral-valve operation. Patients in the ablation group underwent further randomization to pulmonary-vein isolation or a biatrial maze procedure. All patients underwent closure of the left atrial appendage. The primary end point was freedom from atrial fibrillation at both 6 months and 12 months (as assessed by means of 3-day Holter monitoring). RESULTS: More patients in the ablation group than in the control group were free from atrial fibrillation at both 6 and 12 months (63.2% vs. 29.4%, P<0.001). There was no significant difference in the rate of freedom from atrial fibrillation between patients who underwent pulmonary-vein isolation and those who underwent the biatrial maze procedure (61.0% and 66.0%, respectively; P=0.60). One-year mortality was 6.8% in the ablation group and 8.7% in the control group (hazard ratio with ablation, 0.76; 95% confidence interval, 0.32 to 1.84; P=0.55). Ablation was associated with more implantations of a permanent pacemaker than was no ablation (21.5 vs. 8.1 per 100 patient-years, P=0.01). There were no significant between-group differences in major cardiac or cerebrovascular adverse events, overall serious adverse events, or hospital readmissions. CONCLUSIONS: The addition of atrial fibrillation ablation to mitral-valve surgery significantly increased the rate of freedom from atrial fibrillation at 1 year among patients with persistent or long-standing persistent atrial fibrillation, but the risk of implantation of a permanent pacemaker was also increased. (Funded by the National Institutes of Health and the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00903370.).

Ross Procedure Following a Dislodged Transcatheter Aortic Valve Replacement.

A 36-year-old pregnant woman with a history of rheumatic heart disease and prior aortic valve replacement and mitral valve repair presented to an outside hospital with severe aortic stenosis. The patient had a cardiac arrest upon labor induction and underwent a transcatheter aortic valve replacement (TAVR), which dislodged two days later. Five months later, the patient underwent removal of the dislodged TAVR and a Ross procedure at the authors' institution. The patient was stable upon discharge, with minimal aortic and pulmonary regurgitation. To the authors' knowledge, the present report is the first of the Ross procedure being used under such circumstances. It is suggested that caution be taken when using bioprosthetic and transcatheter aortic valves in young patients, and primary use of the Ross procedure is encouraged at experienced centers.

A Survey of Presbyopic Contact Lens Wearers in a University Setting.

PURPOSE: To determine why presbyopic patients discontinue contact lens wear and describe their opinions of comfort and visual quality with contact lenses. METHODS: A survey assessing current age, gender, contact lens material/design, and opinions of contact lens comfort and visual quality was mailed to 2400 presbyopic patients (age 40 years and older) that have had eye exams in the Ohio State University College of Optometry's Contact Lens Services over the last 4 years. RESULTS: A total of 496 surveys were analyzed. The mean age of survey respondents was 57 ± 9 years, and 68% of the sample was female. Permanent discontinuation of contact lens wear was reported by 15%. No association was found between contact lens discontinuation and age (p = 0.7), gender (p = 0.2), age of beginning contact lens wear (p = 0.1), or contact lens material (p = 0.1). Poor vision (38%), discomfort (34%), convenience (20%), and cost (6%) were the primary reported reasons for discontinuation. There was no difference between the proportion of subjects reporting "poor vision" as their primary discontinuation reason and those reporting "discomfort" (p = 0.7). Discontinued wearers had a worse overall opinion of their distance (p = 0.03), intermediate (p = 0.01), and near vision (p = 0.002) compared to subjects who were still wearing their contact lenses. CONCLUSIONS: Discomfort has been reported as the primary reason for contact lens discontinuation. In this presbyopic population, dissatisfaction with vision and discomfort were reported equally as often as primary reasons for discontinuation. As well, subjects who ceased contact lens wear had worse overall opinions of their vision at all distances than current contact lens wearers. The results of this survey suggest that presbyopes have unique demands and opinions related to contact lens wear.

Perioperative Management of Novel Pharmacotherapies for Heart Failure and Pulmonary Hypertension.

Heart failure (HF) and pulmonary hypertension (PH) are increasingly prevalent comorbidities in patients presenting for noncardiac surgery. The unique pathophysiology and pharmacotherapies associated with these syndromes have important perioperative implications. As new medications for HF and PH emerge, it is imperative that anesthesiologists and other perioperative providers understand their mechanisms of action, pharmacokinetics, and potential adverse effects. We present an overview of the novel HF and PH pharmacotherapies and strategies for their perioperative management.

Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.

Autism spectrum disorders (ASDs) are a heterogeneous group of neuro-developmental disorders. While significant progress has been made in the identification of genes and copy number variants associated with syndromic autism, little is known to date about the etiology of idiopathic non-syndromic autism. Sanger sequencing of 21 known autism susceptibility genes in 339 individuals with high-functioning, idiopathic ASD revealed de novo mutations in at least one of these genes in 6 of 339 probands (1.8%). Additionally, multiple events of oligogenic heterozygosity were seen, affecting 23 of 339 probands (6.8%). Screening of a control population for novel coding variants in CACNA1C, CDKL5, HOXA1, SHANK3, TSC1, TSC2 and UBE3A by the same sequencing technology revealed that controls were carriers of oligogenic heterozygous events at significantly (P < 0.01) lower rate, suggesting oligogenic heterozygosity as a new potential mechanism in the pathogenesis of ASDs.

Operative mortality and morbidity after the Ross procedure: a 26- year learning curve.

BACKGROUND AND AIM OF THE STUDY: The role of the Ross procedure in adults is controversial. In comparison with prosthetic aortic valve replacement (AVR), its greater technical complexity has been associated with increased operative mortality. The aim of the present study was to evaluate the impact of surgeon experience on early outcomes after the Ross procedure. METHODS: Using multivariate analysis, the details of 530 consecutive patients who had undergone the Ross operation between 1987 and 2013 were analyzed according to whether they had surgery during the early, middle, or later phases of a single-surgeon experience. RESULTS: Cumulative sum analysis revealed an initial learning curve of around 100 cases. There was no operative mortality in the later phase of 305 cases, compared to 3% (3/100) in the early phase and 2.4% (3/125) in the middle phase (p = 0.04). The mean EuroSCORE did not change significantly across the series (2.3-3.2%, p = 0.4), whereas the patient mix did change. A decreasing incidence of comorbidities, such as acute endocarditis (from 10% to 1.3%, p = 0.02), congestive heart failure (from 8% to 2.3%, p = 0.03) and coronary artery disease (from 11% to 2.3%, p = 0.001), occurred in parallel with increasing case complexity. Isolated Ross procedures were performed less frequently later in the series (42%, n = 130) compared to the early stage (68%, n = 68; p < 0.001), and concomitant ascending aortic or arch replacement were significantly more likely to be performed in later patients (33.8%, n = 103) compared to early-stage patients (1%, n = 1; p <0.001). Independent predictors of operative mortality and major morbidity included endocarditis (odds ratio (OR) 5.2, 95% confidence interval (CI) 1.3-21.5), diabetes (OR 4.3, 95% CI 1.2-15.5), and concomitant coronary artery bypass (OR 3.2, 95% CI 1.2-8.4). Residents or junior faculty performed the surgery in 26 cases, under direct supervision and without patient mortality. CONCLUSION: The Ross procedure can be performed with early outcomes comparable to that of isolated AVR in adults. The impact of the learning curve on patient outcomes may be mitigated by careful patient selection and experienced supervision.

Failure to Rescue: A Quality Metric for Cardiac Surgery and Cardiovascular Critical Care.

Failure to rescue, defined as mortality after a surgical complication, is a widely accepted quality metric across many specialties and is becoming an important metric in cardiac surgery. The failure to rescue metric provides a target for improvements in patient outcomes after complications occur. To be used appropriately, the failure to rescue metric must be defined using a prespecified set of life-threatening and rescuable complications. Successful patient rescue requires a systematic approach of complication recognition, timely escalation of care, effective medical management, and mitigation of additional complications. This process requires contributions from cardiac surgeons, intensivists, and other specialists including cardiologists, neurologists, and anaesthesiologists. Factors that affect failure to rescue rates in cardiac surgery and cardiovascular critical care include nurse staffing ratios, intensivist coverage, advanced specialist support, hospital and surgical volume, the presence of trainees, and patient comorbidities. Strategies to improve patient rescue include working to understand the mechanisms of failure to rescue, anticipating postoperative complications, prioritizing microsystem factors, enhancing early escalation of care, and educating and empowering junior clinicians. When used appropriately, the failure to rescue quality metric can help institutions focus on improving processes of care that minimize morbidity and mortality from rescuable complications after cardiac surgery.

Propensity-Matched Comparison of the Ross Procedure and Prosthetic Aortic Valve Replacement in Adults.

BACKGROUND: There has recently been renewed interest in the Ross procedure in adults. OBJECTIVES: The goal of this study was to compare long-term outcomes after the Ross procedure vs biological and mechanical aortic valve replacement (AVR) in adults (aged 18-50 years) undergoing aortic valve surgery. METHODS: Mandatory California and New York databases were queried between 1997 and 2014. Exclusion criteria included: ≥1 concomitant procedure, reoperations, infective endocarditis, intravenous drug use, hemodialysis, and out-of-state residency. Propensity matching (1:1:1) was used, resulting in 434 patients per group. The primary endpoint was all-cause mortality. Secondary endpoints were stroke, major bleeding, reoperation, and endocarditis. Median follow-up was 12.5 years (IQR: 9.3-15.7 years). RESULTS: At 15 years, actuarial survival after the Ross procedure was 93.1% (95% CI: 89.1%-95.7%), similar to that of the age-, sex-, and race-matched U.S. general population. It was significantly lower after biological AVR (HR: 0.42; 95% CI: 0.23-0.075; P = 0.003) and mechanical AVR (HR: 0.45; 95% CI: 0.26-0.79; P = 0.006). At 15 years, the Ross procedure was associated with a lower cumulative risk of reintervention (P = 0.008) and endocarditis (P = 0.01) than biological AVR. In contrast, at 15 years, the Ross procedure was associated with a higher cumulative incidence of reoperation (P < 0.001) but lower risks of stroke (P = 0.03) and major bleeding (P = 0.016) than mechanical AVR. Thirty-day mortality after valve-related complications was lowest after a reintervention. CONCLUSIONS: In young adults, the Ross procedure is associated with better long-term survival and freedom from valve-related complications compared with prosthetic AVR. This confirms the notion that a living valve substitute in the aortic position translates into improved clinically relevant outcomes.

Connexin 43 confers chemoresistance through activating PI3K.

Circumventing chemoresistance is crucial for effectively treating cancer including glioblastoma, a lethal brain cancer. The gap junction protein connexin 43 (Cx43) renders glioblastoma resistant to chemotherapy; however, targeting Cx43 is difficult because mechanisms underlying Cx43-mediated chemoresistance remain elusive. Here we report that Cx43, but not other connexins, is highly expressed in a subpopulation of glioblastoma and Cx43 mRNA levels strongly correlate with poor prognosis and chemoresistance in this population, making Cx43 the prime therapeutic target among all connexins. Depleting Cx43 or treating cells with αCT1-a Cx43 peptide inhibitor that sensitizes glioblastoma to the chemotherapy temozolomide-inactivates phosphatidylinositol-3 kinase (PI3K), whereas overexpression of Cx43 activates this signaling. Moreover, αCT1-induced chemo-sensitization is counteracted by a PI3K active mutant. Further research reveals that αCT1 inactivates PI3K without blocking the release of PI3K-activating molecules from membrane channels and that Cx43 selectively binds to the PI3K catalytic subunit ß (PIK3CB, also called PI3Kß or p110ß), suggesting that Cx43 activates PIK3CB/p110ß independent of its channel functions. To explore the therapeutic potential of simultaneously targeting Cx43 and PIK3CB/p110ß, αCT1 is combined with TGX-221 or GSK2636771, two PIK3CB/p110ß-selective inhibitors. These two different treatments synergistically inactivate PI3K and sensitize glioblastoma cells to temozolomide in vitro and in vivo. Our study has revealed novel mechanistic insights into Cx43/PI3K-mediated temozolomide resistance in glioblastoma and demonstrated that targeting Cx43 and PIK3CB/p110ß together is an effective therapeutic approach for overcoming chemoresistance.

Operative risks of the Ross procedure.

BACKGROUND: The risk of the Ross procedure continues to be debated. We sought to determine the immediate outcomes of the Ross procedure in a large consecutive cohort that included patients undergoing reoperative cardiac surgery and/or concomitant cardiac procedures. METHODS: Between March 1987 and September 2019, 702 patients underwent a full root Ross procedure. There were 530 male patients and 172 female patients, with a mean age of 41.6 years. One hundred and one patients had at least one previous sternotomy; 323 patients had concomitant procedures. Patients were stratified into 2 groups: simple and complex. Simple Ross patients were those who had no previous sternotomy and had only minor concomitant procedures performed at the time of their Ross, such as aortoplasty or closure of patent foramen ovale. The complex Ross group included patients with at least one previous sternotomy and/or additional procedures that we deemed complex, such as ascending aortic replacement and mitral valve repair. Complexity and group outcomes were evaluated in consecutive terciles of time. RESULTS: There were 7 (1%) operative deaths. Morbidity affected 46 other patients (6.6%). The simple Ross group comprised 419 patients (59.7%), with mortality in 3 (0.7%) and morbidity in 20 (4.8%). The complex Ross comprised 283 patients (40.3%), with mortality in 4 (1.4%) and morbidity in 26 (9.2%). Simple Ross cases decreased in volume over time, with complex cases increasing from 34% to 48%. CONCLUSIONS: Excellent results can be achieved with the Ross procedure despite broader indications that include patients with previous sternotomy and with the need for concomitant procedures.

An integrated approach to biomarker discovery reveals gene signatures highly predictive of cancer progression.

Current cancer biomarkers present variability in their predictive power and demonstrate limited clinical efficacy, possibly due to the lack of functional relevance of biomarker genes to cancer progression. To address this challenge, a biomarker discovery pipeline was developed to integrate gene expression profiles from The Cancer Genome Atlas and essential survival gene datasets from The Cancer Dependency Map, the latter of which catalogs genes driving cancer progression. By applying this pipeline to lung adenocarcinoma, lung squamous cell carcinoma, and glioblastoma, genes highly associated with cancer progression were identified and designated as progression gene signatures (PGSs). Analysis of area under the receiver operating characteristics curve revealed that PGSs predicted patient survival more accurately than previously identified cancer biomarkers. Moreover, PGSs stratified patients with high risk for progressive disease indicated by worse prognostic outcomes, increased frequency of cancer progression, and poor responses to chemotherapy. The robust performance of these PGSs were recapitulated in four independent microarray datasets from Gene Expression Omnibus and were further verified in six freshly dissected tumors from glioblastoma patients. Our results demonstrate the power of an integrated approach to cancer biomarker discovery and the possibility of implementing PGSs into clinical biomarker tests.

Abundance of ethnically biased microsatellites in human gene regions.

Microsatellites-a type of short tandem repeat (STR)-have been used for decades as putatively neutral markers to study the genetic structure of diverse human populations. However, recent studies have demonstrated that some microsatellites contribute to gene expression, cis heritability, and phenotype. As a corollary, some microsatellites may contribute to differential gene expression and RNA/protein structure stability in distinct human populations. To test this hypothesis, we investigate genotype frequencies, functional relevance, and adaptive potential of microsatellites in five super-populations (ethnicities) drawn from the 1000 Genomes Project. We discover 3,984 ethnically-biased microsatellite loci (EBML); for each EBML at least one ethnicity has genotype frequencies statistically different from the remaining four. South Asian, East Asian, European, and American EBML show significant overlap; on the contrary, the set of African EBML is mostly unique. We cross-reference the 3,984 EBML with 2,060 previously identified expression STRs (eSTRs); repeats known to affect gene expression (64 total) are over-represented. The most significant pathway enrichments are those associated with the matrisome: a broad collection of genes encoding the extracellular matrix and its associated proteins. At least 14 of the EBML have established links to human disease. Analysis of the 3,984 EBML with respect to known selective sweep regions in the genome shows that allelic variation in some of them is likely associated with adaptive evolution.

Author Correction: Differentiating between cancer and normal tissue samples using multi-hit combinations of genetic mutations.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Differentiating between cancer and normal tissue samples using multi-hit combinations of genetic mutations.

Cancer is known to result from a combination of a small number of genetic defects. However, the specific combinations of mutations responsible for the vast majority of cancers have not been identified. Current computational approaches focus on identifying driver genes and mutations. Although individually these mutations can increase the risk of cancer they do not result in cancer without additional mutations. We present a fundamentally different approach for identifying the cause of individual instances of cancer: we search for combinations of genes with carcinogenic mutations (multi-hit combinations) instead of individual driver genes or mutations. We developed an algorithm that identified a set of multi-hit combinations that differentiate between tumor and normal tissue samples with 91% sensitivity (95% Confidence Interval (CI) = 89-92%) and 93% specificity (95% CI = 91-94%) on average for seventeen cancer types. We then present an approach based on mutational profile that can be used to distinguish between driver and passenger mutations within these genes. These combinations, with experimental validation, can aid in better diagnosis, provide insights into the etiology of cancer, and provide a rational basis for designing targeted combination therapies.

Systematic review: the comparative effectiveness of percutaneous coronary interventions and coronary artery bypass graft surgery.

BACKGROUND: The comparative effectiveness of coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI) for patients in whom both procedures are feasible remains poorly understood. PURPOSE: To compare the effectiveness of PCI and CABG in patients for whom coronary revascularization is clinically indicated. DATA SOURCES: MEDLINE, EMBASE, and Cochrane databases (1966-2006); conference proceedings; and bibliographies of retrieved articles. STUDY SELECTION: Randomized, controlled trials (RCTs) reported in any language that compared clinical outcomes of PCI with those of CABG, and selected observational studies. DATA EXTRACTION: Information was extracted on study design, sample characteristics, interventions, and clinical outcomes. DATA SYNTHESIS: The authors identified 23 RCTs in which 5019 patients were randomly assigned to PCI and 4944 patients were randomly assigned to CABG. The difference in survival after PCI or CABG was less than 1% over 10 years of follow-up. Survival did not differ between PCI and CABG for patients with diabetes in the 6 trials that reported on this subgroup. Procedure-related strokes were more common after CABG than after PCI (1.2% vs. 0.6%; risk difference, 0.6%; P = 0.002). Angina relief was greater after CABG than after PCI, with risk differences ranging from 5% to 8% at 1 to 5 years (P < 0.001). The absolute rates of angina relief at 5 years were 79% after PCI and 84% after CABG. Repeated revascularization was more common after PCI than after CABG (risk difference, 24% at 1 year and 33% at 5 years; P < 0.001); the absolute rates at 5 years were 46.1% after balloon angioplasty, 40.1% after PCI with stents, and 9.8% after CABG. In the observational studies, the CABG-PCI hazard ratio for death favored PCI among patients with the least severe disease and CABG among those with the most severe disease. LIMITATIONS: The RCTs were conducted in leading centers in selected patients. The authors could not assess whether comparative outcomes vary according to clinical factors, such as extent of coronary disease, ejection fraction, or previous procedures. Only 1 small trial used drug-eluting stents. CONCLUSION: Compared with PCI, CABG was more effective in relieving angina and led to fewer repeated revascularizations but had a higher risk for procedural stroke. Survival to 10 years was similar for both procedures.