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The authors regret that the first name and last name of the author Sandro Sponga was published incorrectly in the original version and this has now been corrected.

Background: The prognostic impact of cross-clamp time (XCT) in patients undergoing isolated coronary artery bypass grafting (CABG) has not been thoroughly investigated. Material and Methods: 2957 patients who underwent on-pump isolated CABG from the prospective multicentre E-CABG study were the subjects of this analysis. Results: The mean XCT in this series was 58 ± 25 minutes Cross-clamp time was >60 minutes in 1134 patients (38.3%), >75 minutes in 619 patients (20.9%) and >90 minutes in 296 patients (10.0%). Multivariate analysis showed that XCT was an independent predictor of 30-day mortality (p < 0.0001, OR 1.027, 95%CI 1.015–1.039) along with age (p < 0.0001), female gender (p = 0.001), pulmonary disease (p = 0.001), poor mobility (p = 0.002), urgency status (p = 0.007), critical preoperative status (p = 0.002) and participating centres (p = 0.015). Adjusted risk of 30-day mortality was highest for XCT >75 minutes (2.9% vs. 1.7%, p = 0.002, OR 3.479, 95%CI 1.609–7.520). Analysis of 428 propensity score matched pairs showed that XCT >75 minutes was associated with significantly increased risk of early mortality, prolonged use of inotropes, postoperative use of intra-aortic balloon pump, use of extracorporeal membrane oxygenation, atrial fibrillation, prolonged stay in the intensive care unit and of composite major adverse events. Conclusions: Isolated CABG is currently performed with prolonged XCT in a significant number of patients and this seems to be a determinant of poor early outcome.

Background: Bilateral internal mammary artery (BIMA) grafting is increasingly used in elderly patients without evidence of its risks or benefits compared with single internal mammary artery (SIMA) grafting. Methods: In all, 2,899 patients aged 70 years or older (855 [29.5%] underwent BIMA grafting) operated on from January 2015 to December 2016 and included in the prospective multicenter Outcome After Coronary Artery Bypass Grafting (E-CABG) study were considered in this analysis. Results: One-to-one propensity matching resulted in 804 pairs with similar preoperative risk profile. Propensity score matched analysis showed that BIMA grafting was associated with a nonstatistically significant increased risk of inhospital death (2.7% versus 1.6%, p = 0.117). The BIMA grafting cohort had a significantly increased risk of any sternal wound infection (7.7% versus 5.1%, p = 0.031) as well as higher risk of deep sternal wound infection/mediastinitis (4.0% versus 2.2%, p = 0.048). The BIMA grafting cohort required more frequently extracorporeal membrane oxygenation (1.0% versus 0.1%, p = 0.02), and the intensive care unit stay (mean 3.6 versus 2.6 days, p < 0.001) and inhospital stay (mean 11.3 versus 10.0 days, p < 0.001) were significantly longer compared with the SIMA grafting cohort. Test for interaction showed that urgent operation in patients undergoing BIMA grafting was associated with higher risk of inhospital death (5.6% versus 1.3%, p = 0.009). Conclusions: Bilateral internal mammary artery grafting in elderly patients seems to be associated with a worse early outcome compared with SIMA grafting, particularly in patients undergoing urgent operation. Until more conclusive results are gathered, BIMA grafting should be reserved only for elderly patients with stable coronary artery disease, without significant baseline comorbidities and with long life expectancy.

Background: The clinical impact of prior percutaneous coronary intervention (PCI) in patients requiring coronary artery bypass grafting (CABG) remains unsettled. We sought to determine whether prior PCI is associated with adverse outcome after CABG. Methods and Results: Data from the prospective E-CABG (European Multicenter Study on Coronary Artery Bypass Grafting) conducted between January 2015 and March 2016 at 16 European centres were analyzed using propensity weighted methodology to adjust for confounding. A parallel systematic review/meta-analysis (MEDLINE, Embase, SCOPUS, and Cochrane Library) through September 2017 was accomplished. Of a total of 3641 adult patients included in the E-CABG study, 685 (19%) patients had a history of PCI. At multivariable level, prior PCI was not associated with an increased hospital mortality in both unweighted and weighted patient groups (odds ratio, 0.73; 95% confidence interval, 0.29–1.38; P=0.33 and odds ratio, 0.90; 95% confidence interval, 0.39–2.08; P=0.81, respectively). Subgroup analyses confirmed that prior PCI had no impact on hospital mortality and morbidity, including reexploration for bleeding, blood transfusion, hospital resource use, and neurological, renal, and cardiac complications. The systematic review provided a total of 71 366 individuals and showed a trend toward higher in-hospital/30-day mortality (adjusted odds ratio, 1.30; 95% confidence interval, 0.99–1.70; I²=43.1%) in patients with prior PCI. Conclusions: Our prospective multicenter study showed that prior PCI was not associated with an increased risk of mortality or other adverse outcomes in patients undergoing CABG. In light of a trend toward increased mortality observed in the meta-analysis, further studies are needed to ascertain the prognostic impact of prior PCI in the outcome after CABG.

Objectives: The aim of this study was to evaluate the prognostic impact of untreated asymptomatic carotid artery stenosis (CS) in patients undergoing isolated coronary artery bypass grafting (CABG). Methods: This was a post hoc analysis of data from a prospective multicentre observational study. Patients without history of stroke or transient ischaemic attack from the multicentre E-CABG registry who were screened for CS before isolated CABG were included. Results: Among 2813 patients screened by duplex ultrasound and who did not undergo carotid intervention for asymptomatic CS, 11.1% had a stenosis of 50–59%, 6.0% of 60–69%, 3.1% of 70–79%, 1.4% of 80–89%, 0.5% of 90–99%, and 1.1% had carotid occlusion. In the screened population post-operative stroke occurred in 25 patients (0.9%), with an incidence of 1.5% among patients with CS ≥ 50% (n = 649). Pre-operative screening had not found a relevant CS in 15 of 25 patients suffering stroke after CABG. Brain imaging identified cerebral ischaemic injury in 20 patients, which was bilateral in five patients (25%), ipsilateral to a CS ≥ 50% in six (30%), and ipsilateral to a CS ≥ 70% in three (15%). In univariable analysis, the severity of CS was associated with a significantly increased risk of stroke (CS < 50%, 0.7%; 50–59%, 1.0%; 60–69%, 0.6%; 70–79%, 1.2%; 80–89%, 5.1%; 90–99%, 7.7%; occluded, 6.7%, p < .001). In multivariable analysis, a CS of 90–99% (OR 12.03, 95% CI 1.34–108.23) and the presence of an occluded internal carotid artery (OR 8.783, 95% CI 1.820–42.40) were independent predictors of stroke along with urgency of the procedure, severe massive bleeding according to the E-CABG classification, and the presence of a porcelain ascending aorta. Conclusions: Among screened patients with untreated asymptomatic patients, CS ≥ 90% was an independent predictor of post-operative stroke. As this condition has a low prevalence and when left untreated is associated with a relatively low rate of stroke, pre-o

Objectives: The aim of this study was to assess the impact of frailty on the outcome after coronary artery bypass grafting (CABG) and whether it may improve the predictive ability of European System for Cardiac Operative Risk Evaluation (EuroSCORE II). Methods: The Clinical Frailty Scale (CFS) was assessed preoperatively in patients undergoing isolated CABG from the multicentre E-CABG registry, and patients were stratified into 3 classes: scores 1–2, scores 3–4 and scores 5–7. Results: Of the 6156 patients enrolled, 39.2% had CFS scores 1–2, 57.6% scores 3–4, and 3.2% scores 5–7. Logistic regression adjusted for multiple covariates showed that the CFS was an independent predictor of hospital/30-day mortality [CFS scores 3–4, odds ratio (OR) 3.95, 95% confidence interval (CI) 2.19–7.14; CFS scores 5–7, OR 5.90, 95% CI 2.67–13.05] and resulted in an Integrated Improvement Index of 1.3 (P < 0.001) and a Net Reclassification Index of 55.6 (P < 0.001) for prediction of hospital/30-day mortality. Adding the CFS classes to EuroSCORE II resulted in an Integrated Improvement Index of 0.9 (P < 0.001) and Net Reclassification Index of 59.6 (P < 0.001) for prediction of hospital/30-day mortality with a significantly larger area under the receiver operating characteristics curve (0.809 vs 0.781, P = 0.028). The CFS was an independent predictor of mid-term mortality [CFS scores 3–4, hazard ratio (HR) 2.05, 95% CI 1.43–2.85; CFS scores 5–7, HR 3.05, 95% CI 1.83–5.06]. Conclusions: The CFS predicted early- and mid-term mortality in patients undergoing isolated CABG. Further studies are needed to evaluate whether frailty may improve the estimation of the operative risk of patients undergoing adult cardiac surgery.

Background: Multiple percutaneous coronary interventions (PCIs) are considered determinant of poor outcome in patients undergoing coronary artery bypass grafting (CABG), but scarce data exist to substantiate this. Methods and results: Patients who underwent CABG without history of prior PCI or with PCI performed >30 days before surgery were selected for the present analysis from the prospective, multicenter E‐CABG (European Multicenter Study on Coronary Artery Bypass Grafting) registry. Out of 6563 patients with data on preoperative SYNTAX (Synergy between PCI With Taxus and Cardiac Surgery) score, 1181 patients (18.0%) had undergone PCI >30 days before CABG. Of these, 11.6% underwent a single PCI, 4.4% 2 PCIs, and 2.1% ≥3 PCIs. PCI of a single main coronary vessel was performed in 11.3%, of 2 main vessels in 4.9%, and of 3 main vessels in 1.6% of patients. Multivariable analysis showed that differences in early mortality and other outcomes were not significantly different in the study cohorts. The adjusted hospital/30‐day mortality rate was 1.8% in patients without history of prior PCI, 1.9% in those with a history of 1 PCI, 1.4% after 2 PCIs, and 2.5% after ≥3 PCIs (adjusted P=0.8). The adjusted hospital/30‐day mortality rate was 2.0% in those who had undergone PCI of 1 main coronary vessel, 1.3% after PCI of 2 main vessels, and 3.1% after PCI of 3 main coronary vessels (adjusted P=0.6). Conclusions: Multiple prior PCIs are not associated with increased risk of early adverse events in patients undergoing isolated CABG. The present results are conditional to survival after PCI and should not be viewed as a support for a policy of multiple PCI as opposed to earlier CABG. Clinical trial registration: URL: http://www.Clinicaltrials.gov. Unique identifier: NCT02319083. ( J Am Heart Assoc. 2018;7: e010089. DOI: 10.1161/JAHA.118.010089.)

Ponatinib has potent activity against native and mutant BCR-ABL1, including BCR-ABL1T315I. The pivotal phase 2 Ponatinib Ph1 ALL and CML Evaluation (PACE) trial evaluated efficacy and safety of ponatinib at a starting dose of 45 mg once daily in 449 patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL) resistant/intolerant to dasatinib or nilotinib, or with BCR-ABL1T315I. This analysis focuses on chronic-phase CML (CP-CML) patients (n 5 270) with 56.8-month median follow-up. Among 267 evaluable patients, 60%, 40%, and 24% achieved major cytogenetic response (MCyR), major molecular response (MMR), and 4.5-log molecular response, respectively. The probability of maintaining MCyR for 5 years was 82% among responders. Dose reductions were implemented in October 2013 to decrease the risk of arterial occlusive events (AOEs); ‡90% of CP-CML patients who had achieved MCyR or MMR maintained response 40 months after elective dose reductions. Estimated 5-year overall survival was 73%. In CP-CML patients, the most common treatment-emergent adverse events were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%). The cumulative incidence of AOEs in CP-CML patients increased over time to 31%, while the exposure-adjusted incidence of new AOEs (15.8 and 4.9 per 100 patient-years in years 1 and 5, respectively) did not increase over time. These final PACE results demonstrate ponatinib provides durable and clinically meaningful responses, irrespective of dose reductions, in this population of heavily pretreated CP-CML patients. This trial was registered at www.clinicaltrials.gov as #NCT01207440

Severe perioperative bleeding after coronary artery bypass grafting (CABG) is associated with poor outcome. An additive score for prediction of severe bleeding was derived (n=2494) and validated (n=1250) in patients from the E-CABG registry. Severe bleeding was defined as E-CABG bleeding grades 2–3 (transfusion of >4 units of red blood cells or reoperation for bleeding). The overall incidence of severe bleeding was 6.4 %. Preoperative anaemia (3 points), female gender (2 points), eGFR <45 ml/min/1.73 m² (3 points), potent antiplatelet drugs discontinued less than five days (2 points), critical preoperative state (5 points), acute coronary syndrome (2 points), use of low-molecular-weight heparin/fondaparinux/unfractionated heparin (1 point) were independent predictors of severe bleeding. The WILL-BLEED score was associated with increasing rates of severe bleeding in both the derivation and validation cohorts (scores 0–3: 2.9 % vs 3.4 %; scores 4–6: 6.8 % vs 7.5 %; scores>6: 24.6 % vs 24.2 %, both p<0.0001). The WILL-BLEED score had a better discriminatory ability (AUC 0.725) for prediction of severe bleeding compared to the ACTION (AUC 0.671), CRUSADE (AUC 0.642), Papworth (AUC 0.605), TRUST (AUC 0.660) and TRACK (AUC 0.640) bleeding scores. The net reclassification index and integrated discrimination improvement using the WILL-BLEED score as opposed to the other bleeding scores were significant (p<0.0001). The decision curve analysis demonstrated a net benefit with the WILL-BLEED score compared to the other bleeding scores. In conclusion, the WILL-BLEED risk score is a simple risk stratification method which allows the identification of patients at high risk of severe bleeding after CABG.

Perioperative bleeding is a determinant of poor outcome in patients undergoing coronary artery bypass grafting (CABG), but there is a lack of adequate stratification of its severity. The ability of the European registry of Coronary Artery Bypass Grafting (E-CABG), Universal Definition of Perioperative Bleeding (UDPB), Study of Platelet Inhibition and Patient Outcomes (PLATO), Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events−Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENT-OASIS 7), Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events (ESSENCE), and SafeTy and Efficacy of Enoxaparin in Percutaneous coronary intervention patients, an internationaL randomized Evaluation (STEEPLE) bleeding classifications to predict early mortality, stroke, acute kidney injury (AKI) stage 3, and deep sternal wound infection/mediastinitis was investigated in 3,730 patients from the prospective, multicentre E-CABG registry. Increasing grades of the E-CABG, UDPB, PLATO, and CURRENT-OASIS 7 classifications were associated with increasing risks of early mortality, had similar receiver-operating characteristic area under the curves (>0.7), and were predictive also when adjusted for EuroSCORE II. The E-CABG and UDPB classifications had satisfactory area under the curves (>0.6) in predicting stroke, AKI stage 3, and deep sternal wound infection/mediastinitis even when adjusted for EuroSCORE II. The PLATO and CURRENT-OASIS 7 classifications had similar predictive ability for stroke and AKI stage 3 as confirmed by multivariate analysis adjusted for EuroSCORE II but showed inferior ability in predicting severe wound infection compared to the E-CABG and UDPB classifications. The STEEPLE and ESSENCE classifications had a poor ability of predicting all these adverse events. Decision curve analysis showed a benefit of the E-CABG bleeding classification over the other classifications in predicting all adverse events. In concl

The functions of polycomb products extend beyond their well-known activity as transcriptional regulators to include genome duplication processes. Polycomb activities during DNA replication and DNA damage repair are unclear, particularly without induced replicative stress.We have used a cellularmodel of conditionally inactive polycomb E3 ligases (RING1A and RING1B), which monoubiquitylate lysine 119 of histone H2A (H2AK119Ub), to examine DNA replication in unperturbed cells. We identify slow elongation and fork stalling during DNA replication that is associated with the accumulation of mid and late S-phase cells. Signs of replicative stress and colocalisation of double-strand breaks with chromocenters, the sites of coalesced pericentromeric heterocromatic (PCH) domains, were enriched in cells at mid S-phase, the stage at which PCH is replicated. Altered replication was rescued by targeted monoubiquitylation of PCH through methyl- CpG binding domain protein 1. The acute senescence associated with the depletion of RING1 proteins, which is mediated by p21 (also known as CDKN1A) upregulation, could be uncoupled from a response to DNA damage. These findings link cell proliferation and the polycomb proteins RING1A and RING1B to S-phase progression through a specific function in PCH replication.