New Approach Methodologies for the Endocrine Activity Toolbox: Environmental Assessment for Fish and Amphibians.

Multiple in vivo test guidelines focusing on the estrogen, androgen, thyroid, and steroidogenesis pathways have been developed and validated for mammals, amphibians, or fish. However, these tests are resource-intensive and often use a large number of laboratory animals. Developing alternatives for in vivo tests is consistent with the replacement, reduction, and refinement principles for animal welfare considerations, which are supported by increasing mandates to move toward an "animal-free" testing paradigm worldwide. New approach methodologies (NAMs) hold great promise to identify molecular, cellular, and tissue changes that can be used to predict effects reliably and more efficiently at the individual level (and potentially on populations) while reducing the number of animals used in (eco)toxicological testing for endocrine disruption. In a collaborative effort, experts from government, academia, and industry met in 2020 to discuss the current challenges of testing for endocrine activity assessment for fish and amphibians. Continuing this cross-sector initiative, our review focuses on the current state of the science regarding the use of NAMs to identify chemical-induced endocrine effects. The present study highlights the challenges of using NAMs for safety assessment and what work is needed to reduce their uncertainties and increase their acceptance in regulatory processes. We have reviewed the current NAMs available for endocrine activity assessment including in silico, in vitro, and eleutheroembryo models. New approach methodologies can be integrated as part of a weight-of-evidence approach for hazard or risk assessment using the adverse outcome pathway framework. The development and utilization of NAMs not only allows for replacement, reduction, and refinement of animal testing but can also provide robust and fit-for-purpose methods to identify chemicals acting via endocrine mechanisms. Environ Toxicol Chem 2023;42:757-777. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Rigid Plate Fixation Versus Wire Cerclage: Patient-Reported and Economic Outcomes From a Randomized Trial.

BACKGROUND: In a multicenter randomized trial, sternal closure after cardiac operations using rigid plate fixation (RPF) compared with wire cerclage (WC) resulted in improved sternal healing, reduced sternal complications, and was cost neutral at 6 months. Additional secondary end points are presented from this trial. METHODS: Twelve United States centers randomized 236 patients to RPF (n = 116) or WC (n = 120). Patient-reported outcomes measures, including pain, function, and quality of life scores, were assessed through 6 months and correlated to computed tomography-derived sternal healing scores using logistic regression. Cost analysis through 90 days was performed to mimic bundled care models. RESULTS: All patient-reported outcomes measures were numerically better in RPF patients than in WC patients at all assessments. RPF resulted in more patients reporting no sternal pain after coughing at 3 weeks (41.1% vs 19.6%; p = 0.001) and 6 weeks (54.5% vs 35.1%; p = 0.005) and at rest at 6 weeks (74.1% vs 58.8%; p = 0.02) and 3 months (87.6% vs 75.9%; p = 0.03) compared with WC. Better sternal healing scores correlated to having no sternal pain at rest (odds ratio, 1.6; 95% confidence interval, 1.2 to 2.2; p = 0.002) and after coughing (odds ratio, 1.6; 95% confidence interval, 1.2 to 2.2; p = 0.0007). RPF resulted in improvements in the 36-Item Short Form Health Survey quality of life scores at 3 weeks (53.5 ± 8.7 vs 50.5 ± 10.4; p = 0.03), 6 weeks (45.3 ± 8.4 vs 42.7 ± 8.4; p = 0.03), and 6 months (56.4 ± 6.8 vs 53.9 ± 9.0; p = 0.04) compared with WC. Through 90 days, RPF compared with WC was $1,888 less (95% confidence interval, -$8,889 to $4,273; p = 0.52). CONCLUSIONS: In patients undergoing sternal closure after median sternotomy, RPF compared with WC resulted in reduced sternal pain, improved upper extremity function, and similar total 90-day costs.

Randomized, multicenter trial comparing sternotomy closure with rigid plate fixation to wire cerclage.

OBJECTIVE: To evaluate sternal healing, complications, and costs after sternotomy closure with rigid plate fixation or wire cerclage. METHODS: This prospective, single-blinded, multicenter trial randomized 236 patients at 12 US centers at the time of sternal closure to either rigid plate fixation (n = 116) or wire cerclage (n = 120). The primary endpoint, sternal healing at 6 months, was evaluated by a core laboratory using computed tomography and a 6-point scale (greater scores represent greater healing). Secondary endpoints included sternal complications and costs from the time of sternal closure through 6 months. RESULTS: Rigid plate fixation resulted in better sternal healing scores at 3 (2.6 ± 1.1 vs 1.8 ± 1.0; P < .0001) and 6 months (3.8 ± 1.0 vs 3.3 ± 1.1; P = .0007) and greater sternal union rates at 3 (41% [42/103] vs 16% [16/102]; P < .0001) and 6 months (80% [81/101] vs 67% [67/100]; P = .03) compared with wire cerclage. There were fewer sternal complications through 6 months with rigid plate fixation (0% [0/116] vs 5% [6/120]; P = .03) and a trend towards fewer sternal wound infections (0% [0/116] vs 4.2% [5/120]; P = .06) compared with wire cerclage. Although rigid plate fixation was associated with a trend toward greater index hospitalization costs ($23,437 vs $20,574; P = .11), 6-month follow-up costs tended to be lower ($9002 vs $13,511; P = .14). As a result, total costs from randomization through 6 months were similar between groups ($32,439 vs $34,085; P = .61). CONCLUSIONS: Sternotomy closure with rigid plate fixation resulted in significantly better sternal healing, fewer sternal complications, and no additional cost compared with wire cerclage at 6 months after surgery.

Effects of Blood Transfusion on Cause-Specific Late Mortality After Coronary Artery Bypass Grafting-Less Is More.

BACKGROUND: Red blood cell transfusion after coronary artery bypass graft surgery has been associated with increased late all-cause death. Yet, whether this association is, first, independent of the packed red blood cells and perioperative morbidity association, and second, of a cardiac versus noncardiac etiology remains unknown. METHODS: We analyzed patients undergoing coronary artery bypass graft surgery at two Ohio hospitals (n = 6,947) from 1994 to 2007. Salvage operations and patients with preoperative renal failure were excluded. Long-term outcomes and leading cause of death (cardiac, noncardiac, all cause) were derived from the US Social Security Death Index and later from Ohio Department of Health Death Index. Fifteen-year mortality cumulative incidence functions were compared for transfusion groups (yes, n = 2,540; no, n = 4,806) overall, and then stratified based on perioperative complications status (yes, n = 2,638; no, n = 4,708). Comprehensive, 32 covariates, risk-adjusted transfusion effects were estimated by competing risk regression. Results were confirmed by propensity score adjusted analysis. RESULTS: Perioperative transfusions and complications occurred in 33.9% and 35.2% of patients, respectively. In all, 3,108 deaths (48.1%) have been documented (median time to death, 7.43 years). Both transfusion rates (25.6% versus 49.1%, p < 0.001) and deaths (58.2% versus 38.5%, p < 0.001) were more frequent among complications patients. Red blood cells transfusion increased intermediate to late mortality risk overall (15-year adjusted hazard ratio [AHR] 1.21, 95% confidence interval [CI]: 1.11 to 1.31), and for complications (AHR 1.24, 95% CI: 1.11 to 1.39) and no complications (AHR 1.16, 95% CI: 1.03 to 1.31). The increased mortality was true for cardiac and noncardiac etiologies (AHR 1.19, 95% CI: 1.03 to 1.36, and AHR 1.14, 95% CI: 1.01 to 1.29, respectively). Red blood cell transfusion increased mostly cardiac deaths (AHR 1.38, 95% CI: 1.14 to 1.66) among the complications group, and noncardiac mortality (AHR 1.24, 95% CI: 1.05 to 1.47) for the no complications group. A parallel propensity matched sensitivity analysis confirmed these findings. CONCLUSIONS: Perioperative red blood cells transfusion is associated with significant adverse late death effects among both complicated patients and noncomplicated patients, principally seen between 0 and 5 years postoperatively, and is driven by both increased cardiovascular and noncardiovascular mortality. Further studies are needed to elucidate the mechanisms behind these findings, including their potential dose dependence.

Equipoise between radial artery and right internal thoracic artery as the second arterial conduit in left internal thoracic artery-based coronary artery bypass graft surgery: a multi-institutional study†.

OBJECTIVES: Multiple arterial coronary artery grafting (MABG) improves long-term survival compared with single arterial CABG (SABG), yet the best second arterial conduit to be used with the left internal thoracic artery (LITA) remains undefined. Outcomes in patients grafted with radial artery (RA-MABG) versus right internal thoracic artery (RITA-MABG) as the second arterial graft were compared with SABG. METHODS: Multi-institutional, retrospective analysis of non-emergent isolated LITA to left anterior descending coronary artery CABG patients was performed using institutional Society of Thoracic Surgeon National Adult Cardiac Surgery Databases. 4484 (54.5%) SABG [LITA ± saphenous vein grafts (SVG)], 3095 (37.6%) RA-MABG (RA ± SVG) and 641 (7.9%) RITA-MABG (RITA ± SVG) patients were included. The RITA was used as a free (68%) or in situ (32%) graft. RA grafts were principally anastomosed to the ascending aorta. Long-term survival was ascertained from US Social Security Death Index and institutional follow-up. Triplet propensity matching and covariate-adjusted multivariate logistic regression were used to adjust for baseline differences between study cohorts. RESULTS: Compared with the SABG cohort, the RITA-MABG cohort was younger (58.6 ± 10.2vs65.9 ± 10.4, P < 0.001), had a higher prevalence of males (87% vs 65%, P < 0.001) and was generally healthier (MI: 36.7% vs 56.7%, P < 0.001, smoking: 56.8% vs 61.1%, IDDM: 3.0% vs 14.4%, CVA: 2.6% vs 10.0%). The RA-MABG cohort was generally characterized by a risk profile intermediate to that of SABG and RlTA-MABG. Unadjusted 5-, 10- and 15-year survival rates were best in RITA-MABG (95.2%, 89% and 82%), intermediate in RA-MABG (89%, 74%, 57%) and worst in SABG (82%, 61% and 44%) cohorts (all P < 0.001). Propensity matching yielded 551 RA-MABG, RITA-MABG and SABG triplets, which showed similar 30-day mortality. Late survival (16 years) was equivalent in the RA-MABG and RITA-MABG cohorts [68.2% vs 66.7%, P = 0.127, hazard ratio (HR) = 1.28 (0.96-1.71)] and both significantly better than SABG (61.1%). The corresponding SABG versus RITA-MABG and SABG versus RA-MABG HRs (95% confidence interval) were 1.52 (1.18-1.96) and 1.31 (1.01-1.69) with P < 0.002 and P = 0.038, respectively. CONCLUSIONS: RA-MABG or RITA-MABG equally improve long-term survival compared with SABG and thus should be embraced by the Heart Team as the therapy of choice in LITA-based coronary artery bypass surgery.

Bioaccumulation assessment using predictive approaches.

Mandated efforts to assess chemicals for their potential to bioaccumulate within the environment are increasingly moving into the realm of data inadequacy. Consequently, there is an increasing reliance on predictive tools to complete regulatory requirements in a timely and cost-effective manner. The kinetic processes of absorption, distribution, metabolism, and elimination (ADME) determine the extent to which chemicals accumulate in fish and other biota. Current mathematical models of bioaccumulation implicitly or explicitly consider these ADME processes, but there is a lack of data needed to specify critical model input parameters. This is particularly true for compounds that are metabolized, exhibit restricted diffusion across biological membranes, or do not partition simply to tissue lipid. Here we discuss the potential of in vitro test systems to provide needed data for bioaccumulation modeling efforts. Recent studies demonstrate the utility of these systems and provide a "proof of concept" for the prediction models. Computational methods that predict ADME processes from an evaluation of chemical structure are also described. Most regulatory agencies perform bioaccumulation assessments using a weight-of-evidence approach. A strategy is presented for incorporating predictive methods into this approach. To implement this strategy it is important to understand the "domain of applicability" of both in vitro and structure-based approaches, and the context in which they are applied.