Preoperative Treatment of Obstructive Sleep Apnea With Positive Airway Pressure is Associated With Decreased Incidence of Atrial Fibrillation After Cardiac Surgery.

OBJECTIVE: Based on clinical studies in the nonsurgical population that positive airway pressure (PAP) therapy for patients with obstructive sleep apnea (OSA) provides benefits for those with atrial fibrillation, the authors tested the hypothesis that PAP in patients with OSA reduces the incidence of postoperative atrial fibrillation (POAF) after cardiac surgery. DESIGN: Retrospective analysis. SETTING: Single-center university hospital. PARTICIPANTS: The study comprised 192 patients in sinus rhythm preoperatively who were undergoing nontransplantation or ventricular assist device implantation cardiac surgery requiring cardiopulmonary bypass but not requiring systemic circulatory arrest, with documented PAP adherence from January 2008 to October 2015. INTERVENTIONS: Retrospective review of medical records. MEASUREMENTS AND MAIN RESULTS: POAF was defined as atrial fibrillation requiring therapeutic intervention. Of the 192 patients with OSA, 104 (54%) were documented to be PAP-adherent and 88 (46%) were reported to be PAP-nonadherent. Among PAP users, 49 (47%) developed POAF; among PAP nonusers, 59 (66%) developed POAF. The adjusted hazard ratio was 0.59 (95% confidence interval 0.40-0.86, p<0.01). No differences were observed in intensive care unit length of stay (4.0±3.4 days for PAP-adherent group v 5.0±6.2 days for PAP-nonadherent group; p = 0.22) or hospital length of stay (10.7±6.6 days for PAP-adherent group v 10.9±7.3 days for PAP nonadherent group; p = 0.56). A lower median postoperative creatinine rise was observed in PAP-adherent patients (18.2% [8.3%-37.5%) v 31.3% [13.3%-50%]; p< 0.01). CONCLUSION: Preoperative PAP use in patients with OSA was associated with a decreased rate of POAF after cardiac surgery.

Obstructive Sleep Apnea Is an Independent Predictor of Postoperative Atrial Fibrillation in Cardiac Surgery.

OBJECTIVE: To test the hypothesis that obstructive sleep apnea (OSA) is a risk factor for development of postoperative atrial fibrillation (POAF) after cardiac surgery. DESIGN: Retrospective analysis. SETTING: Single-center university hospital. PARTICIPANTS: Five hundred forty-five patients in sinus rhythm preoperatively undergoing coronary artery bypass grafting (CABG), aortic valve replacement, mitral valve replacement/repair, or combined valve/CABG surgery from January 2008 to April 2011. INTERVENTIONS: Retrospective review of medical records. MEASUREMENTS AND MAIN RESULTS: Postoperative atrial fibrillation was defined as atrial fibrillation requiring therapeutic intervention. Of 545 cardiac surgical patients, 226 (41%) patients developed POAF. The risk was higher in 72 OSA patients than 473 patients without OSA (67% v 38%, adjusted hazard ratio 1.83 [95% CI: 1.30-2.58], p<0.001). Of the 32 OSA patients who used home positive airway pressure (PAP) therapy, 18 (56%) developed POAF compared with 29 of 38 (76%) patients who did not use PAP at home (unadjusted hazard ratio 0.63 [95% CI: 0.35-1.15], p = 0.13). CONCLUSION: OSA is significantly associated with POAF in cardiac surgery patients. Further investigation is needed to determine whether or not use of positive airway pressure in OSA patients reduces the risk of POAF.

P-wave characteristics on routine preoperative electrocardiogram improve prediction of new-onset postoperative atrial fibrillation in cardiac surgery.

OBJECTIVE: To test the hypothesis that including preoperative electrocardiogram (ECG) characteristics with clinical variables significantly improves the new-onset postoperative atrial fibrillation prediction model. DESIGN: Retrospective analysis. SETTING: Single-center university hospital. PARTICIPANTS: Five hundred twenty-six patients, ≥ 18 years of age, who underwent coronary artery bypass grafting, aortic valve replacement, mitral valve replacement/repair, or a combination of valve surgery and coronary artery bypass grafting requiring cardiopulmonary bypass. INTERVENTIONS: Retrospective review of medical records. MEASUREMENTS AND MAIN RESULTS: Baseline characteristics and cardiopulmonary bypass times were collected. Digitally-measured timing and voltages from preoperative electrocardiograms were extracted. Postoperative atrial fibrillation was defined as atrial fibrillation requiring therapeutic intervention. Two hundred eight (39.5%) patients developed postoperative atrial fibrillation. Clinical predictors were age, ejection fraction<55%, history of atrial fibrillation, history of cerebral vascular event, and valvular surgery. Three ECG parameters associated with postoperative atrial fibrillation were observed: Premature atrial contraction, p-wave index, and p-frontal axis. Adding electrocardiogram variables to the prediction model with only clinical predictors significantly improved the area under the receiver operating characteristic curve, from 0.71 to 0.78 (p<0.01). Overall net reclassification improvement was 0.059 (p = 0.09). Among those who developed postoperative atrial fibrillation, the net reclassification improvement was 0.063 (p = 0.03). CONCLUSION: Several p-wave characteristics are independently associated with postoperative atrial fibrillation. Addition of these parameters improves the postoperative atrial fibrillation prediction model.

Discovery of Potent and Selective Covalent Inhibitors of HER2WT and HER2YVMA.

HER2 overexpression and amplification have been identified as oncogenic drivers, and the development of therapies to treat tumors harboring these markers has received considerable attention. Activation of HER2 signaling and subsequent cell growth can also be induced by HER2 mutations, including the common YVMA insertion in exon 20 within the kinase domain. Enhertu is currently the only approved treatment for HER2 mutant tumors in NSCLC. TKIs tested in this space have suffered from off-target activity, primarily due to EGFRWT inhibition or attenuated activity against HER2 mutants. The goal of this work was to identify a TKI that would provide robust inhibition of oncogenic HER2WT and HER2 mutants while sparing EGFRWT activity. Herein, we describe the development of a potent, covalent inhibitor of HER2WT and the YVMA insertion mutant while providing oral bioavailability and avoiding the inhibition of EGFRWT.

A next-generation BRAF inhibitor overcomes resistance to BRAF inhibition in patients with BRAF-mutant cancers using pharmacokinetics-informed dose escalation.

RAF inhibitors have transformed treatment for BRAF V600-mutant cancer patients, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAF V600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer inhibitors are limited by narrow therapeutic index. PF-07799933 (ARRY-440) is a brain-penetrant, selective, pan-mutant BRAF inhibitor. PF-07799933 inhibited signaling in vitro, disrupted endogenous mutant-BRAF:wild-type-CRAF dimers, and spared wild-type ERK signaling. PF-07799933 ± binimetinib inhibited growth of mouse xenograft tumors driven by mutant BRAF that functions as dimers and by BRAF V600E with acquired resistance to current RAF inhibitors. We treated patients with treatment-refractory BRAF-mutant solid tumors in a first-in-human clinical trial (NCT05355701) that utilized a novel, flexible, pharmacokinetics-informed dose escalation design that allowed rapid achievement of PF-07799933 efficacious concentrations. PF-07799933 ± binimetinib was well-tolerated and resulted in multiple confirmed responses, systemically and in the brain, in BRAF-mutant cancer patients refractory to approved RAF inhibitors.

Perioperative outcomes of major noncardiac surgery in adults with congenital heart disease.

BACKGROUND: An increasing number of patients with congenital heart disease are surviving to adulthood. Consensus guidelines and expert opinion suggest that noncardiac surgery is a high-risk event, but few data describe perioperative outcomes in this population. METHODS: By using the Nationwide Inpatient Sample database (years 2002 through 2009), the authors compared patients with adult congenital heart disease (ACHD) who underwent noncardiac surgery with a non-ACHD comparison cohort matched on age, sex, race, year, elective or urgent or emergency procedure, van Walraven comborbidity score, and primary procedure code. Mortality and morbidity were compared between the two cohorts. RESULTS: A study cohort consisting of 10,004 ACHD patients was compared with a matched comparison cohort of 37,581 patients. Inpatient mortality was greater in the ACHD cohort (407 of 10,004 [4.1%] vs. 1,355 of 37,581 [3.6%]; unadjusted odds ratio, 1.13; P = 0.031; adjusted odds ratio, 1.29; P < 0.001). The composite endpoint of perioperative morbidity was also more commonly observed in the ACHD cohort (2,145 of 10.004 [21.4%] vs. 6,003 of 37,581 [16.0%]; odds ratio, 1.44; P < 0.001). ACHD patients comprised an increasing proportion of all noncardiac surgical admissions over the study period (P value for trend is <0.001), and noncardiac surgery represented an increasing proportion of all ACHD admissions (P value for trend is <0.001). CONCLUSIONS: Compared with a matched control cohort, ACHD patients undergoing noncardiac surgery experienced increased perioperative morbidity and mortality. Within the limitations of a retrospective analysis of a large administrative dataset, this finding demonstrates that this is a vulnerable population and suggests that better efforts are needed to understand and improve the perioperative care they receive.

HURP controls spindle dynamics to promote proper interkinetochore tension and efficient kinetochore capture.

Through a functional genomic screen for mitotic regulators, we identified hepatoma up-regulated protein (HURP) as a protein that is required for chromosome congression and alignment. In HURP-depleted cells, the persistence of unaligned chromosomes and the reduction of tension across sister kinetochores on aligned chromosomes resulted in the activation of the spindle checkpoint. Although these defects transiently delayed mitotic progression, HeLa cells initiated anaphase without resolution of these deficiencies. This bypass of the checkpoint arrest provides a tumor-specific mechanism for chromosome missegregation and genomic instability. Mechanistically, HURP colocalized with the mitotic spindle in a concentration gradient increasing toward the chromosomes. HURP binds directly to microtubules in vitro and enhances their polymerization. In vivo, HURP stabilizes mitotic microtubules, promotes microtubule polymerization and bipolar spindle formation, and decreases the turnover rate of the mitotic spindle. Thus, HURP controls spindle stability and dynamics to achieve efficient kinetochore capture at prometaphase, timely chromosome congression to the metaphase plate, and proper interkinetochore tension for anaphase initiation.

Gene expression profiling: classification of mice with left ventricle systolic dysfunction using microarray analysis.

OBJECTIVE: We tested the hypothesis that a set of differentially expressed genes could be used to classify mice according to cardiovascular phenotype after prolonged catecholamine stress. DESIGN: Prospective, randomized study. SETTING: University-based research laboratory. SUBJECTS: One hundred seventy-three male mice were studied: wild-type (WT) C57, WT FVB, WT B6129SF2/J, and beta2 adrenergic receptor knockout. INTERVENTIONS: Mice of each genotype were randomly assigned to 14-day infusions of isoproterenol (120 microg/g/day) or no treatment. Approximately half of the animals underwent left ventricle pressure volume loop analysis. The remaining animals were killed for extraction of messenger RNA from whole heart preparations for microarray analysis. MEASUREMENTS AND MAIN RESULTS: We observed that WT FVB and beta2 adrenergic receptor knockout mice developed systolic dysfunction in response to continuous catecholamine infusion, whereas WT C57 mice developed diastolic dysfunction. Using these mice as the derivation cohort, we identified a set of 83 genes whose differential expression correlated with left ventricle systolic dysfunction. The gene set was then used to accurately classify mice from a separate group (WT B6129SF2/J) into the cohort that developed left ventricle systolic dysfunction after catecholamine stress. CONCLUSIONS: The differential expression pattern of 83 genes can be used to accurately classify mice according to physiological phenotype after catecholamine stress.

Case report: a thrombus in the venous reservoir while using bivalirudin in a patient with heparin-induced thrombocytopenia undergoing heart transplantation.

Direct thrombin inhibitors are heparin alternatives for anticoagulation during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia. We report a case of a large thrombus forming in the venous reservoir while using bivalirudin. We suggest that blood stasis associated with the full venous reservoir maintained in this case led to formation of a large thrombus at the top of the venous canister. Furthermore, activated clotting times may not accurately reflect the magnitude of anticoagulation when using direct thrombin inhibitors.

Mutation position is an important determinant for predicting cancer neoantigens.

Tumor-specific mutations can generate neoantigens that drive CD8 T cell responses against cancer. Next-generation sequencing and computational methods have been successfully applied to identify mutations and predict neoantigens. However, only a small fraction of predicted neoantigens are immunogenic. Currently, predicted peptide binding affinity for MHC-I is often the major criterion for prioritizing neoantigens, although little progress has been made toward understanding the precise functional relationship between affinity and immunogenicity. We therefore systematically assessed the immunogenicity of peptides containing single amino acid mutations in mouse tumor models and divided them into two classes of immunogenic mutations. The first comprises mutations at a nonanchor residue, for which we find that the predicted absolute binding affinity is predictive of immunogenicity. The second involves mutations at an anchor residue; here, predicted relative affinity (compared with the WT counterpart) is a better predictor. Incorporating these features into an immunogenicity model significantly improves neoantigen ranking. Importantly, these properties of neoantigens are also predictive in human datasets, suggesting that they can be used to prioritize neoantigens for individualized neoantigen-specific immunotherapies.

The checkpoint protein Chfr is a ligase that ubiquitinates Plk1 and inhibits Cdc2 at the G2 to M transition.

The checkpoint protein Chfr delays entry into mitosis, in the presence of mitotic stress (Scolnick, D.M., and T.D. Halazonetis. 2000. Nature. 406:430-435). We show here that Chfr is a ubiquitin ligase, both in vitro and in vivo. When transfected into HEK293T cells, Myc-Chfr promotes the formation of high molecular weight ubiquitin conjugates. The ring finger domain in Chfr is required for the ligase activity; this domain auto-ubiquitinates, and mutations of conserved residues in this domain abolish the ligase activity. Using Xenopus cell-free extracts, we demonstrated that Chfr delays the entry into mitosis by negatively regulating the activation of the Cdc2 kinase at the G2-M transition. Specifically, the Chfr pathway prolongs the phosphorylated state of tyrosine 15 in Cdc2. The Chfr-mediated cell cycle delay requires ubiquitin-dependent protein degradation, because inactivating mutations in Chfr, interference with poly-ubiquitination, and inhibition of proteasomes all abolish this delay in mitotic entry. The direct target of the Chfr pathway is Polo-like kinase 1 (Plk1). Ubiquitination of Plk1 by Chfr delays the activation of the Cdc25C phosphatase and the inactivation of the Wee1 kinase, leading to a delay in Cdc2 activation. Thus, the Chfr pathway represents a novel checkpoint pathway that regulates the entry into mitosis by ubiquitin-dependent proteolysis.

Factors contributing to adverse perioperative events in adults with congenital heart disease: a structured analysis of cases from the closed claims project.

OBJECTIVE: Prior investigations have suggested that the rapidly growing population of adults with congenital heart disease is at increased risk of perioperative morbidity and mortality, but information is limited on the nature of those perioperative factors that may relate to adverse outcomes. We sought to use a national claims database to describe the contribution of perioperative factors to adverse outcomes and compare contributing factors in cardiac vs. noncardiac operations. DESIGN: The study is a retrospective in-depth structured analysis of cases from the Anesthesia Closed Claims Project database. SETTING: We examined the largest national anesthesia malpractice claims database. PATIENTS: We included all claims cases involving adult patients with congenital heart disease (CHD). INTERVENTIONS: Patients in this retrospective analysis were classified by type of surgery (cardiac or noncardiac). OUTCOME MEASURES: Perioperative factors contributing to an adverse event were assessed by an expert panel of cardiac anesthesiologists. RESULTS: Of 21 confirmed cases, 11 (52%) involved cardiac procedures and 10 (48%) noncardiac procedures. The most common factors contributing to the adverse event in cardiac cases were surgical technique (73% of cases) and intraoperative anesthetic care (55%), whereas in noncardiac cases, postoperative monitoring/care (50%), CHD (50%) and preoperative assessment or optimization (40%) were most common. The factors contributing to the patient injury differed similarly: in cardiac cases, the most common factors were intraoperative anesthetic care (55%) and surgical technique (45%) compared with postoperative monitoring/care (50%) and CHD (50%) in noncardiac cases. CONCLUSIONS: Within the limitations of a small number of events in a claims-based database, this study offers advantages of being a national, structured analysis of real cases to provide detailed information on phenomena that are otherwise abstract and hypothesized by expert opinion. These results should help affirm the role of anesthesiologists in acquiring and executing expertise as consultants in perioperative medicine for adults with congenital heart disease patients.

A Xenopus cell-free system for analysis of the Chfr ubiquitin ligase involved in control of mitotic entry.

The checkpoint protein Chfr delays entry into mitosis in the presence of mitotic stress. We have analyzed the Chfr checkpoint pathway in the Xenopus cell-free system. We showed that Chfr is a ubiquitin ligase that targets polo-like kinase (Plk1) for degradation, leading to delayed activation of the Cdc25C phosphatase and prolonged inhibitory phosphorylation of Cdc2 at the G2/M transition. In this chapter, we will describe biochemical methods we developed to analyze the Chfr auto-ubiquitination activity and the ubiquitination of its substrate Plk1, as well as functional assays to investigate the Chfr pathway in Xenopus extracts.

Decentralization of care for adults with congenital heart disease in the United States: a geographic analysis of outpatient surgery.

BACKGROUND: Guidelines recommend that adults with congenital heart disease (CHD) undergo noncardiac surgery in regionalized centers of expertise, but no studies have assessed whether this occurs in the United States. We hypothesized that adults with CHD are less likely than children to receive care at specialized CHD centers. METHODS: Using a comprehensive state ambulatory surgical registry (California Ambulatory Surgery Database, 2005-2011), we calculated the proportion of adult and pediatric patients with CHD who had surgery at a CHD center, distance to the nearest CHD center, and distance to the facility where surgery was performed. RESULTS: Patients with CHD accounted for a larger proportion of the pediatric population (n = 11,254, 1.0%) than the adult population (n = 10,547, 0.07%). Only 2,741 (26.0%) adults with CHD had surgery in a CHD center compared to 6,403 (56.9%) children (p<0.0001). Adult CHD patients who had surgery at a non-specialty center (11.9 ± 15.4 miles away) lived farther from the nearest CHD center (37.9 ± 43.0 miles) than adult CHD patients who had surgery at a CHD center (23.2 ± 28.4 miles; p<0.0001). Pediatric CHD patients who had surgery at a non-specialty center (18.0 ± 20.7 miles away) lived farther from the nearest CHD center (35.7 ± 45.2 miles) than pediatric CHD patients who had surgery at a CHD center (22.4 ± 26.0 miles; p<0.0001). CONCLUSIONS: Unlike children with CHD, most adults with CHD (74%) do not have outpatient surgery at a CHD center. For both adults and children with CHD, greater distance from a CHD center is associated with having surgery at a non-specialty center. These results have significant public health implications in that they suggest a failing to achieve adequate regional access to specialized ACHD care. Further studies will be required to evaluate potential strategies to more reliably direct this vulnerable population to centers of expertise.

Perioperative morbidity and mortality after noncardiac surgery in young adults with congenital or early acquired heart disease: a retrospective cohort analysis of the National Surgical Quality Improvement Program database.

An increasing number of patients with congenital heart disease survive to adulthood. Expert opinion suggests that noncardiac surgery is a high-risk event, but few data describe perioperative outcomes in this population. Using the National Surgical Quality Improvement Program database, we identified a cohort of patients aged 18 to 39 years with prior heart surgery who underwent noncardiac surgery between 2005 and 2010. A comparison cohort with no prior cardiovascular surgery was matched on age, sex, race/ethnicity, operation year, American Society of Anesthesiologists physical status, and Current Procedural Terminology code. A study cohort consisting of 1191 patients was compared with a cohort of 5127 patients. Baseline dyspnea, inpatient status at the time of surgery, and a prior operation within 30 days were more common in the study cohort. Postoperative outcomes were less favorable in the study cohort. Observed rates of death, perioperative cardiac arrest, myocardial infarction, stroke, respiratory complications, renal failure, sepsis, venous thromboembolism, perioperative transfusion, and reoperation were significantly higher in the study cohort (P < 0.01 for all). Mean postoperative length of stay was greater in the study cohort (5.8 vs 3.6 days, P < 0.01). Compared with a matched control cohort, young adult patients with a history of prior cardiac surgery experienced significantly greater perioperative morbidity and mortality after noncardiac surgery. A history of prior cardiac surgery represents a marker of substantial perioperative risk in this young population that is not accounted for by the matched variables. These results suggest that adult patients with congenital heart disease are at risk for adverse outcomes and support the need for further registry-based investigations.

Perioperative morbidity and mortality of cardiothoracic surgery in patients with a do-not-resuscitate order.

Background. Do-not-resuscitate (DNR) orders are often active in patients with multiple comorbidities and a short natural life expectancy, but limited information exists as to how often these patients undergo high-risk operations and of the perioperative outcomes in this population. Methods. Using comprehensive inpatient administrative data from the Public Discharge Data file (years 2005 through 2010) of the California Office of Statewide Health Planning and Development, which includes a dedicated variable recording DNR status, we identified cohorts of DNR patients who underwent major cardiac or thoracic operations and compared themto age- and procedure-matched comparison cohorts. The primary study outcome was in-hospital mortality. Results. DNR status was not uncommon in cardiac (n = 2,678, 1.1% of all admissions for cardiac surgery, age 71.6 ± 15.9 years) and thoracic (n = 3,129, 3.7% of all admissions for thoracic surgery, age 73.8 ± 13.6 years) surgical patient populations. Relative to controls, patients who were DNR experienced significantly greater inhospital mortality after cardiac (37.5% vs. 11.2%, p < 0.0001 and thoracic (25.4% vs. 6.4%) operations. DNR status remained an independent predictor of in-hospital mortality onmultivariate analysis after adjustment for baseline and comorbid conditions in both the cardiac (OR 4.78, 95% confidence interval 4.21-5.41, p < 0.0001) and thoracic (OR 6.11, 95% confidence interval 5.37-6.94, p < 0.0001) cohorts. Conclusions. DNR status is associated with worse outcomes of cardiothoracic surgery even when controlling for age, race, insurance status, and serious comorbid disease. DNR status appears to be a marker of substantial perioperative risk, and may warrant substantial consideration when framing discussions of surgical risk and benefit, resource utilization, and biomedical ethics surrounding end-of-life care.

Heart transplantation with or without prior mechanical circulatory support in adults with congenital heart disease.

OBJECTIVES: Recent analyses establish that heart transplantation is increasing among adults with congenital heart disease (ACHD), but the effects of pretransplant mechanical circulatory support (MCS) on perioperative and post-transplant outcomes have not been examined in the ACHD population. METHODS: Scientific Registry of Transplant Recipients data on all adult heart transplants from September 1987 to September 2012 (n = 47 160) were classified based on primary diagnosis codes as CHD or non-CHD and MCS or non-MCS. Demographic, procedural, outcome and survival variables were compared between MCS and non-MCS ACHD patient groups. RESULTS: MCS was used in 83 (6.8%) ACHD patients compared with 8625 (18.8%) patients without CHD (P < 0.001). MCS as a fraction of ACHD transplants increased over time (P = 0.002). MCS patients spent more time on the wait list, had a higher baseline serum creatinine and were more likely to be male, status 1A, hospitalized, in the ICU and/or on a ventilator prior to transplant. However, MCS patients experienced equivalent short-term survival (30-day mortality = 10.8% in MCS vs 13.5% in non-MCS, P = 0.62) and overall survival by Kaplan-Meier analysis (P = 0.57). MCS patients had a longer post-transplant length of stay and were more likely to be transfused, but otherwise had no significant differences in adverse outcomes. CONCLUSIONS: MCS is less commonly used in adult CHD patients compared with all patients undergoing heart transplant, but has been increasing over time. Within the ACHD population, patients with MCS have a higher risk profile, but except for increased transfusion rate and longer length of stay, do not experience less favourable post-transplant outcomes.

Temporal changes in survival after cardiac surgery are associated with the thirty-day mortality benchmark.

OBJECTIVE: To assess the hypothesis that postoperative survival exhibits heterogeneity associated with the timing of quality metrics. DATA SOURCES: Retrospective observational study using the Nationwide Inpatient Sample from 2005 through 2009. STUDY DESIGN: Survival analysis was performed on all admission records with a procedure code for major cardiac surgery (n = 595,089). The day-by-day hazard function for all-cause in-hospital mortality at 1-day intervals was analyzed using joinpoint regression (a data-driven method of testing for changes in hazard). DATA EXTRACTION METHODS: A comprehensive analysis of a publicly available national administrative database was performed. PRINCIPAL FINDINGS: Statistically significant shifts in the pattern of postoperative mortality occurred at day 6 (95 percent CI = day 5-8) and day 30 (95 percent CI = day 20-35). CONCLUSIONS: While the shift at day 6 plausibly can be attributed to the separation between routine recovery and a complicated postoperative course, the abrupt increase in mortality at day 30 has no clear organic etiology. This analysis raises the possibility that this observed shift may be related to clinician behavior because of the use of 30-day mortality as a quality metric, but further studies will be required to establish causality.