Unrepaired base excision repair intermediates in template DNA strands trigger replication fork collapse and PARP inhibitor sensitivity.

DNA single-strand breaks (SSBs) disrupt DNA replication and induce chromosome breakage. However, whether SSBs induce chromosome breakage when present behind replication forks or ahead of replication forks is unclear. To address this question, we exploited an exquisite sensitivity of SSB repair-defective human cells lacking PARP activity or XRCC1 to the thymidine analogue 5-chloro-2'-deoxyuridine (CldU). We show that incubation with CldU in these cells results in chromosome breakage, sister chromatid exchange, and cytotoxicity by a mechanism that depends on the S phase activity of uracil DNA glycosylase (UNG). Importantly, we show that CldU incorporation in one cell cycle is cytotoxic only during the following cell cycle, when it is present in template DNA. In agreement with this, while UNG induces SSBs both in nascent strands behind replication forks and in template strands ahead of replication forks, only the latter trigger fork collapse and chromosome breakage. Finally, we show that BRCA-defective cells are hypersensitive to CldU, either alone and/or in combination with PARP inhibitor, suggesting that CldU may have clinical utility.

The role of resilience and spirituality in recovery following cardiac surgery.

Higher levels of resilience and spirituality are independently linked to better physical and mental health outcomes, within both general and cardiac populations. We investigated the long-term associations of such psychological factors following cardiac surgery. A total of 402 patients undergoing routine cardiac surgery at two large urban hospitals in the Dallas, Texas, area were prospectively enrolled in this study, with completed follow-up data for 364 (90.5%). Data were collected from August 2013 to January 2017. Resilience, spirituality, and secondary measures were assessed at baseline, 1 month, and 1 year via the Connor-Davidson Resilience Scale-10 and Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale. Linear regression and correlational analyses assessed associations between resilience and spirituality, as well as other demographic and psychosocial factors. Resilience was significantly associated with every construct except posttraumatic growth. Spirituality was associated with increasing resilience over the ensuing year, whereas never being married was associated with a decrease in resilience. Our findings identify a population that is vulnerable to a decrease in resilience following cardiac surgery, as well as an avenue (i.e., spirituality) for potentially bolstering resilience. Improving resilience via spirituality postoperatively may foster better overall recovery and better mental and physical health outcomes.

Comparison of outcomes after transcatheter aortic valve implantation following home versus non-home discharge.

As more patients undergo transcatheter aortic valve implantation (TAVI), knowledge of 1-year mortality and associated factors becomes increasingly important. After other cardiac procedures, discharge location has been shown to be associated with 1-year mortality. We examined outcomes of TAVI patients discharged home vs an extended care facility (ECF). All TAVI patients from January 1, 2012, to December 31, 2017, were evaluated. Cox proportional hazard regression models with cubic splines were used to estimate the adjusted effect of discharge to ECF on 1-year mortality. A total of 957 (85.6%) patients discharged home were compared to 160 (14.3%) discharged to ECF. On univariate analysis, patients discharged home were younger and had a lower Society of Thoracic Surgeons Predicted Risk of Mortality, higher albumin, and fewer vascular complications and strokes. Patients discharged to ECF had a higher 30-day mortality (3.8% vs. 0.5%, P = 0.001) and 1-year mortality (25.7% vs. 8.3%, P < 0.001). Cox proportional hazard regression models showed increased risk of 1-year mortality for patients discharged to ECF. In conclusion, patients discharged to ECF had a higher 30-day and 1-year mortality. The strongest predictor of 1-year mortality was discharge to ECF. Society of Thoracic Surgeons Predicted Risk of Mortality score was not a predictor of 1-year mortality.

Current Penetration, Completeness, and Representativeness of The Society of Thoracic Surgeons Adult Cardiac Surgery Database.

BACKGROUND: The Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database (ACSD) is the largest cardiac surgical database in the world. Linked data from STS ACSD and the Centers for Medicare and Medicaid Services (CMS) database were used to determine contemporary completeness, penetration, and representativeness of STS ACSD. METHODS: Variables common to both STS and CMS databases were used to link STS procedures to CMS data for all CMS coronary artery bypass grafting surgery (CABG) discharges between 2000 and 2018, inclusive. For each CMS CABG hospitalization, it was determined whether a matching STS record existed. RESULTS: Center-level penetration (number of CMS sites with at least 1 matched STS participant divided by total number of CMS CABG sites) increased from 45% in 2000 to 95% in 2018. In 2018, 949 of 1004 CMS CABG sites (95%) were linked to an STS site. Patient-level penetration (number of CMS CABG hospitalizations at STS sites divided by total number of CMS CABG hospitalizations) increased from 51% in 2000 to 97% in 2018. In 2018, 68,584 of 70,818 CMS CABG hospitalizations (97%) occurred at an STS site. Completeness of case inclusion at STS sites (number of CMS CABG cases at STS sites linked to STS records divided by total number of CMS CABG cases at STS sites) increased from 88% in 2000 to 98% in 2018. In 2018, 66,673 of 68,108 CMS CABG hospitalizations at STS sites (98%) were linked to an STS record. CONCLUSIONS: Linkage of the STS and CMS databases demonstrates high and increasing penetration and completeness of STS ACSD. STS ACSD now includes 97% of CABG in the United States.

The Society of Thoracic Surgeons Coronary Artery Bypass Graft Composite Measure: 2021 Methodology Update.

BACKGROUND: The Society of Thoracic Surgeons (STS) original coronary artery bypass graft surgery (CABG) composite measure uses a 1-year analytic cohort and 98% credible intervals (CrI) to classify better than expected (3-star) performance or worse than expected (1-star) performance. As CABG volumes per STS participant (eg, hospital or practice group) have decreased, it has become more challenging to classify performance categories using this approach, especially for lower volume programs, and alternative approaches have been explored. METHODS: Among 990 STS Adult Cardiac Surgery Database participants, performance classifications for the CABG composite were studied using various analytic cohorts: 1 year (current approach, 2017); 3 years (2015 to 2017); last 450 cases within 3 years; and most recent year (2017) plus additional cases to 450 total. We also compared 98% CrI with 95% CrI (used in other STS composite measures). RESULTS: Using 3 years of data and 95% CrIs, 113 of 990 participants (11.4%) were classified 1-star and 198 (20%) 3-star. Compared with 1-year analytic cohorts and 98% CrI, the absolute and relative increases in the proportion of 3-star participants were 14 percentage points and 233% (n = 198 [20%] vs n = 59 [6%]). Corresponding changes for 1-star participants were 6.5 percentage points and 133% (n = 113 [11.4%] vs n = 48 [4.9%]). These changes were particularly notable among lower volume (fewer than 199 CABG per year) participants. Measure reliability with the 3-year, 95% CrI modification is 0.78. CONCLUSIONS: Compared with current STS CABG composite methodology, a 3-year analytic cohort and 95% CrI increases the number and proportion of better or worse than expected outliers, especially among lower-volume Adult Cardiac Surgery Database participants. This revised methodology is also now consistent with other STS procedure composites.

Failure to Rescue: A New Society of Thoracic Surgeons Quality Metric for Cardiac Surgery.

BACKGROUND: Failure to rescue (FTR) focuses on the ability to prevent death among patients who have postoperative complications. The Society of Thoracic Surgeons (STS) Quality Measurement Task Force has developed a new, risk-adjusted FTR quality metric for adult cardiac surgery. METHODS: The study population was taken from 1118 STS Adult Cardiac Surgery Database participants including patients who underwent isolated CABG, aortic valve replacement with or without CABG, or mitral valve repair or replacement with or without CABG between January 2015 and June 2019. The FTR analysis was derived from patients who had one or more of the following complications: prolonged ventilation, stroke, reoperation, and renal failure. Data were randomly split into 70% training samples (n = 89,059) and 30% validation samples (n = 38,242). Risk variables included STS predicted risk of mortality, operative procedures, and intraoperative variables (cardiopulmonary bypass and cross-clamp times, unplanned procedures, need for circulatory support, and massive transfusion). RESULTS: Overall mortality for patients undergoing any of the index operations during the study period was 2.6% (27,045 of 1,058,138), with mortality of 0.9% (8316 of 930,837), 8% (7618 of 94,918), 30.6% (8247 of 26,934), 51.9% (2661 of 5123), and 62.3% (203 of 326), respectively, among patients having none, one, two, three, or four complications. The FTR risk model calibration was excellent, as were model discrimination (c-statistic 0.806) and the Brier score (0.102). Using 95% Bayesian credible intervals, 62 participants (5.6%) performed worse and 53 (4.7%) performed better than expected. CONCLUSIONS: A new risk-adjusted FTR metric has been developed that complements existing STS performance measures. The metric specifically assesses institutional effectiveness of postoperative care, allowing hospitals to target quality improvement efforts.

Quality of Life Is Improved 1 Year After Cardiac Surgery.

BACKGROUND: Quality of life (QoL) is increasingly important in the era of patient-centered outcomes and value-based reimbursement. However most follow-up is limited to 30 days, and long-term data on QoL improvement associated with symptom relief are lacking. Therefore we sought to analyze QoL after cardiac surgery in a nonemergent, all-comers population. METHODS: Four hundred two patients undergoing routine cardiac surgery at 2 large urban hospitals in the Dallas, Texas area were enrolled. Follow-up was complete for 364 patients. Data were collected from August 2013 to January 2017. The Kansas City Cardiomyopathy Questionnaire was administered at baseline, 1 month, and 1 year after surgery. Repeated-measures analysis was used for each domain of the questionnaire for all procedures and stratified by procedure. If time was found to be a significant factor, pairwise analysis was performed with P values adjusted using the Tukey-Kramer method. RESULTS: There was a significant increase across all domains of Kansas City Cardiomyopathy Questionnaire scores for all procedures and for most domains when stratifying by procedure. This increase in QoL was most marked after 1 month. All domain scores increased through 1 year except symptom stability, which peaked at 1 month postsurgery and then regressed at 1 year, suggesting an overall improvement and stabilization of symptoms. The occurrence of complications did not alter this trajectory. CONCLUSIONS: QoL and other patient-centered outcomes are improved at 1 month and continue to improve throughout the year. Knowledge of these data is important for patient selection, fully informed consent, and shared decision-making.

Volume-Outcome Association of Mitral Valve Surgery in the United States.

Importance: Early surgery for severe primary degenerative mitral regurgitation is recommended, provided optimal outcomes are achievable. Contemporary national data defining mitral valve surgery volume and outcomes are lacking. Objective: To assess national 30-day and 1-year outcomes of mitral valve surgery and define the hospital- and surgeon-level volume-outcome association with mitral valve repair or replacement (MVRR) in patients with primary mitral regurgitation. Design, Setting, and Participants: This multicenter cross-sectional observational study used the Society of Thoracic Surgeons Adult Cardiac Surgery Database to identify patients undergoing isolated MVRR for primary mitral regurgitation in the United States. Operative data were collected from July 1, 2011, to December 31, 2016, and analyzed from March 1 to July 1, 2019, with data linked to the Centers for Medicare and Medicaid Services. Main Outcomes and Measures: The primary outcome was 30-day in-hospital operative mortality after isolated MVRR for primary mitral regurgitation. Secondary outcomes were 30-day composite mortality plus morbidity (any occurrence of bleeding, stroke, prolonged ventilation, renal failure, or deep wound infection), rate of successful mitral valve repair of primary mitral regurgitation (residual mitral regurgitation of mild [1+] or better), and 1-year mortality, reoperation, and rehospitalization for heart failure. Results: A total of 55 311 patients, 1094 hospitals, and 2410 surgeons were identified. Increasing hospital and surgeon volumes were associated with lower risk-adjusted 30-day mortality, lower 30-day composite mortality plus morbidity, and higher rate of successful repair. The lowest vs highest hospital volume quartile had higher 1-year risk-adjusted mortality (hazard ratio [HR], 1.61, 95% CI, 1.31-1.98), but not mitral reoperation (odds ratio [OR], 1.51; 95% CI, 0.81-2.78) or hospitalization for heart failure (HR, 1.25; 95% CI, 0.96-1.64). The surgeon-level 1-year volume-outcome associations were similar for mortality (HR, 1.60; 95% CI, 1.32-1.94) but not significant for mitral reoperation (HR, 1.14; 95% CI, 0.60-2.18) or hospitalization for heart failure (HR, 1.17; 95% CI, 0.91-1.50). Conclusions and Relevance: National hospital- and surgeon-level inverse volume-outcome associations were observed for 30-day and 1-year mortality after mitral valve surgery for primary mitral regurgitation. These findings may help to define access to experienced centers and surgeons for the management of primary mitral regurgitation.

Current State of Surgical Left Atrial Appendage Exclusion: How and When.

Left atrial appendage exclusion is efficacious for stroke prophylaxis in patients with atrial fibrillation. Surgical excision provides reliable left atrial appendage exclusion, whereas surgical occlusion does not. Specifically, 2-layer internal suture ligation has a high failure rate. Left atrial appendage exclusion concomitant to another cardiac surgical procedure is indicated in patients with atrial fibrillation but not in patients without baseline atrial fibrillation. Studies currently underway will further define the role of concomitant surgical left atrial appendage exclusion, especially for the population without baseline atrial fibrillation but at high risk of developing postoperative atrial fibrillation.

Preoperative ß-Blockers as a Coronary Surgery Quality Metric: The Lack of Evidence of Efficacy.

BACKGROUND: Two quality measures used in public reporting and value-based payment programs require ß-blockers be administered less than 24 hours before isolated coronary artery bypass graft surgery to prevent atrial fibrillation and mortality. Questions have arisen about continued use of these measures. METHODS: We conducted a systematic search for randomized controlled trials (RCTs) examining the impact of preoperative ß-blockers on atrial fibrillation or mortality after isolated coronary artery bypass graft surgery to determine what evidence of efficacy supports the measures. RESULTS: We identified 11 RCTs. All continued ß-blockers postoperatively, making it unfeasible to separate the benefits of preoperative vs postoperative administration. Meta-analysis was precluded by methodologic variation in ß-blocker utilized, timing and dosage, and supplemental and comparison treatments. Of the eight comparisons of ß-blockers/ß-blocker plus digoxin versus placebo (n = 826 patients), six showed significant reductions in atrial fibrillation/supraventricular arrhythmias. Of the three comparisons (n = 444) of ß-blockers versus amiodarone, two found no significant difference in atrial fibrillation; the third showed significantly lower incidence with amiodarone. One RCT compared ß-blocker plus amiodarone versus each of those drugs separately; the combination reduced atrial fibrillation significantly better than the ß-blocker alone, but not amiodarone alone. Seven RCTs reported short-term mortality, but this outcome was too rare and the sample sizes too small to provide any meaningful comparisons. CONCLUSIONS: Existing RCT evidence does not support the structure of quality measures that require ß-blocker administration specifically within 24 hours before coronary artery bypass graft surgery to prevent postoperative atrial fibrillation or short-term mortality. Quality measures should be revised to align with the evidence, and further studies conducted to determine optimal timing and method of prophylaxis.

Postcoronary Artery Bypass Graft Atrial Fibrillation Event Count and Survival: Differences by Sex.

BACKGROUND: New-onset atrial fibrillation (AF) after coronary artery bypass graft surgery (CABG) is associated with poor outcomes, but data on the effects of its characteristics are lacking and conflicting. We examined the effect number of post-CABG AF events has on long-term mortality risk, and whether this is sex dependent. METHODS: Routinely collected Society of Thoracic Surgeons (STS) data were supplemented with details on new-onset post-CABG AF (detected in-hospital by continuous electrocardiogram/telemetry monitoring) and long-term survival for 9203 consecutive patients with isolated-CABG (2002-2010). With the use of Cox regression, we determined the propensity-adjusted (STS-recognized risk factors) effect of number of AF events on survival, testing for effect modification by sex and controlling for AF duration. RESULTS: AF occurred in 739 women (29.4%) and 2157 men (32.3%) (P < .001). Adjusted results showed 2 or more AF events significantly (P < .001) increased 5-year mortality risk, independently of total AF duration. However, mortality risk differed between the sexes (P < .001): women with 2 AF episodes had the greatest increase (hazard ratio [HR] = 2.98; 95% confidence interval [CI], 1.43-4.83; versus women without AF), followed by women and men with 4 or more AF events (HR = 2.76 [95% CI, 1.27-4.55] and HR = 2.73 [95% CI, 2.30-3.19], respectively). A single post-CABG AF episode was not associated with increased mortality risk. CONCLUSIONS: Both men and women who experienced 2 or more post-CABG AF episodes showed increased risk of 5-year mortality, independent of total AF duration. Although men's risk increased as the number of AF events increased, women's risk peaked at 2 AF events. Future research needs to determine whether this divergence stems from differences in treatment/management or underlying biology.

Prospective Evaluation of a Blood Transfusion Protocol for Patients Undergoing Cardiac Operations.

BACKGROUND: The Society of Thoracic Surgeons clinical practice guidelines recommend the creation of an interdisciplinary blood management team to implement protocols for improved blood transfusion practices. We report our center's prospective evaluation of a blood transfusion protocol. METHODS: An interdisciplinary blood management team developed protocols for transfusion of packed red blood cells, fresh frozen plasma, platelets, and cryoprecipitate. The protocols were prospectively evaluated by tracking transfusions administered to consecutive patients undergoing cardiac operations, and the primary outcome of interest was the mean number of adjusted units of blood product transfused per patient. Protocol implementation phases were separated by washout phases to control for a potential Hawthorne effect associated with protocol implementation. Protocol compliance was also assessed. RESULTS: A total of 1441 patients underwent cardiac operations during the 16-month study period. Although there was no statistically significant reduction in transfusions with an unadjusted analysis, there was a significant trend toward a reduction of the mean adjusted total units transfused per patient over the course of the study period (P < .001). The mean adjusted total units transfused per patient were significantly less during the second washout phase (2.8 units; 95% confidence interval [CI], 2.3-3.3) and second protocol phase (2.8 units; 95% CI, 2.32-3.27) compared with the initial baseline survey phase (3.6 units, 95% CI, 3.1-4.1; P < .05 for both comparisons). Only 55.2% of all units were transfused in compliance to the implemented protocols: platelets, 46.8%; cryoprecipitate, 32.1%; packed red blood cells, 60.7%; and fresh frozen plasma, 53.6%. CONCLUSIONS: During a prospective evaluation of blood transfusion protocols, a risk-adjusted analysis demonstrated a reduction in transfusions despite poor protocol compliance.

Temporal relationships between esophageal injury type and progression in patients undergoing atrial fibrillation catheter ablation.

BACKGROUND: Currently, little is known about the onset, natural progression, and management of esophageal injuries after atrial fibrillation (AF) ablation. OBJECTIVES: We sought to provide a systematic review on esophageal injury after AF ablation and identify temporal relationships between various types of esophageal lesions, their progression, and clinical outcomes. METHODS: A comprehensive search of PubMed and Web of Science was conducted until September 21, 2017. All AF ablation patients who underwent upper gastrointestinal endoscopy within 1 week of the procedure were included. Patients with esophageal lesions were classified into 3 types by using our novel Kansas City classification: type 1: erythema; type 2a: superficial ulcers; type 2b: deep ulcers; type 3a: perforation without communication with the atria; and type 3b: perforation with atrioesophageal fistula. RESULTS: Thirty studies met our inclusion criteria. Of the 4473 patients, 3921 underwent upper gastrointestinal evaluation. The overall incidence of esophageal injuries was 15% (570). There were 206 type 1 lesions (36%), 222 type 2a lesions (39%), and 142 type 2b lesions (25%). Six of 142 type 2b lesions (4.2%) progressed further to type 3, of which, 5 were type 3a and 1 was type 3b. All type 1 and type 2a and most type 2b lesions resolved with conservative management. One type 3a and 1 type 3b lesions were fatal. CONCLUSION: Based on our classification, all type 1 and most type 2 lesions resolved with conservative management. A small percentage (4.2% [6 of 142]) of type 2b lesions progressed to perforation and/or fistula formation, and these patients need to be followed closely.

Totally Thoracoscopic Closure of the Left Atrial Appendage.

The left atrial appendage (LAA) is a major site of clot formation in atrial fibrillation. Stand-alone thoracoscopic LAA complete closure can decrease stroke risk and may be an alternative to life-long oral anticoagulation. This report describes a technique for totally thoracoscopic LAA exclusion with an epicardial clip device. This approach provides a safe and likely more effective alternative to LAA management than other endocardial devices.