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Background: Liver resection increases venous thromboembolism (VTE) risk due to malignancy-related hyper-coagulopathy and surgical inflammation. Current guidelines recommend early post-operative and extended pharmacologic prophylaxis for all patients but lack stratification by patient or surgical factors. Despite these guidelines, surgeon preferences influence prophylaxis practices. This study aimed to identify clinical factors associated with VTE following liver resection., Methods: Using data from the Hemorrhage During Liver Resection (HeLiX) trial, a randomized clinical trial of patients undergoing liver resection for cancer, univariate comparisons and logistic regression were performed., Results: Study cohort VTE incidence was 4.1 %. Multivariable analysis identified major liver resection (odds ratio (OR) 2.59, 95 % confidence interval (CI) 1.38-5.03) and higher estimated blood loss (EBL) (OR 1.14 per 500 mL increase, 95 % CI 1.03-1.26) as associated with increased risk. Surgical duration (OR 1.14 per hour increase, 95 % CI 0.95-1.34) and use of tranexamic acid (OR 1.77, 95 % CI 0.98-3.27) did not reach statistical significance. VTE rate was highly dependent on extent of resection (1-2 segments, 1.7 %; 3-4 segments, 5.4 %; >4 segments, 6.7 %)., Conclusion: Major resection and increased EBL are associated with higher risk of VTE. These patients may warrant more intensive prophylax compared to those having minor resections with minimal blood loss., Competing Interests: Conflicts of interest None declared., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: We previously published the protocol and statistical analysis plan for a randomized controlled trial of Proportional Assist Ventilation for Minimizing the Duration of Mechanical Ventilation: the PROMIZING study in Trials ( https://doi.org/10.1186/s13063-023-07163-w ). This update summarizes changes made to the statistical analysis plan for the trial since the publication of the original protocol and statistical analysis plan., Methods/design: The Proportional Assist Ventilation for Minimizing the Duration of Mechanical Ventilation (PROMIZING) study is a multi-center, open-label, randomized controlled trial designed to determine if ventilation with proportional assist ventilation with load-adjustable gain factors will result in a shorter duration of time spent on mechanical ventilation compared to ventilation with pressure support ventilation for patients with acute respiratory failure. The statistical analysis plan for the trial was incorporated into the original publication of the protocol in Trials ( https://doi.org/10.1186/s13063-023-07163-w ) and was based on version 5.0 of the study protocol and version 1.0 of the statistical analysis plan (SAP), which included plans for both frequentist and Bayesian analyses. We have since updated the SAP to refine the Bayesian analysis plan, update the multistate model diagram, and include plans for a cluster analysis to determine if there is heterogeneity of treatment effect. This update summarizes the changes made and their rationale and provides a refined SAP for the PROMIZING trial with additional background information, in adherence with guidelines for the prospective reporting of SAPs for randomized controlled trials., Trial Registration: ClinicalTrials.gov Identifier: NCT02447692 prospectively registered May 19, 2015., Competing Interests: Declarations. Ethics approval and consent to participate: Ethics approval was granted from the Western University Research Ethics Board through Clinical Trials Ontario (CTO #0733) for the PROMIZING study. Written, informed consent to participate will be obtained from all participants or their Substitute Decision Maker (SDM). All centers participating in the study get their own ethics committee approval. Consent for publication: Not applicable. Competing interests: The authors declare they have no direct competing interests in the study. The study received partial industry funding through the first grant which was a CIHR-industry partnership, with the industry partner at arm’s length. The industry partner, Medtronic, has no role in the study design, data collection, analysis, interpretation, or publication of manuscript. No author received personal financial remuneration for the study. The authors declare no other competing interests in the study., (© 2024. The Author(s).)

Importance: The optimal screening frequency and spontaneous breathing trial (SBT) technique to liberate adults from ventilators are unknown., Objective: To compare the effects of screening frequency (once-daily screening vs more frequent screening) and SBT technique (pressure-supported SBT with a pressure support level that was >0-≤8 cm H2O and a positive end-expiratory pressure [PEEP] level that was >0-≤5 cm H2O vs T-piece SBT) on the time to successful extubation., Design, Setting, and Participants: Randomized clinical trial with a 2 × 2 factorial design including critically ill adults who were receiving invasive mechanical ventilation for at least 24 hours, who were capable of initiating spontaneous breaths or triggering ventilators, and who were receiving a fractional concentration of inspired oxygen that was 70% or less and a PEEP level of 12 cm H2O or less. Recruitment was between January 2018 and February 2022 at 23 intensive care units in North America; last follow-up occurred October 18, 2022., Interventions: Participants were enrolled early to enable protocolized screening (more frequent vs once daily) to identify the earliest that patients met criteria to undergo pressure-supported or T-piece SBT lasting 30 to 120 minutes., Main Outcome and Measures: Time to successful extubation (time when unsupported, spontaneous breathing began and was sustained for ≥48 hours after extubation)., Results: Of 797 patients (198 in the once-daily screening and pressure-supported SBT group, 204 in once-daily screening and T-piece SBT, 195 in more frequent screening and pressure-supported SBT, and 200 in more frequent screening and T-piece SBT), the mean age was 62.4 (SD, 18.4) years and 472 (59.2%) were men. There were no statistically significant differences by screening frequency (hazard ratio [HR], 0.88 [95% CI, 0.76-1.03]; P = .12) or by SBT technique (HR, 1.06 [95% CI, 0.91-1.23]; P = .45). The median time to successful extubation was 2.0 days (95% CI, 1.7-2.7) for once-daily screening and pressure-supported SBT, 3.1 days (95% CI, 2.7-4.8) for once-daily screening and T-piece SBT, 3.9 days (95% CI, 2.9-4.7) for more frequent screening and pressure-supported SBT, and 2.9 days (95% CI, 2.0-3.1) for more frequent screening and T-piece SBT. An unexpected interaction between screening frequency and SBT technique required pairwise contrasts that revealed more frequent screening (vs once-daily screening) and pressure-supported SBT increased the time to successful extubation (HR, 0.70 [95% CI, 0.50-0.96]; P = .02). Once-daily screening and pressure-supported SBT (vs T-piece SBT) did not reduce the time to successful extubation (HR, 1.30 [95% CI, 0.98-1.70]; P = .08)., Conclusions and Relevance: Among critically ill adults who received invasive mechanical ventilation for more than 24 hours, screening frequency (once-daily vs more frequent screening) and SBT technique (pressure-supported vs T-piece SBT) did not change the time to successful extubation. However, an unexpected and statistically significant interaction was identified; protocolized more frequent screening combined with pressure-supported SBTs increased the time to first successful extubation., Trial Registration: ClinicalTrials.gov Identifiers: NCT02399267 and NCT02969226.

Objectives: To examine the late outcomes of valve-sparing root replacement and concomitant mitral valve repair in patients who have been followed prospectively for more than 2 decades., Methods: From 1992 to 2020, 54 consecutive patients (mean age, 47 ± 16 years; 80% men) underwent valve-sparing root replacement (45 reimplantation and 9 remodeling) with concomitant repair of the mitral valve. Patients were followed prospectively for a median of 9 years (IQR, 3-14 years)., Results: No patient experienced perioperative death or stroke. There were 3 late deaths and the 15-year overall survival was 96.0% (95% CI, 74.8%-99.4%), similar to the age- and sex-matched population. Over the follow-up period, 6 patients had reoperation of the aortic valve and 3 on the mitral valve. Of those, 2 had reoperation on both aortic and mitral valves for a total of 7 reoperations in this cohort. The cumulative proportion of reoperation at 10 years of either or both valves were as follows: aortic valve 11.4% (95% CI, 3.9%-33.3%), mitral valve 4.2% (95% CI, 0.6%-28.4%), and both valves 11.4% (95% CI, 3.9%-33.3%). The estimated probability of developing moderate/severe aortic insufficiency at 15 years was 18.5% (95% CI, 9.0%-34.2%). On final echocardiographic follow-up, none of the patients had developed moderate/severe mitral regurgitation., Conclusions: In this single-center series of concomitant valve-sparing root replacement and mitral valve repair, we observed excellent clinical outcomes with a low risk of death or valve-related complications. Continued surveillance of late valve function is necessary., Competing Interests: Conflict of Interest Statement Dr Ouzounian has consulting agreements with Terumo, Cryolife, Edwards, and Medtronic. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2024 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Importance: Tranexamic acid reduces bleeding and blood transfusion in many types of surgery, but its effect in patients undergoing liver resection for a cancer-related indication remains unclear., Objective: To determine whether tranexamic acid reduces red blood cell transfusion within 7 days of liver resection., Design, Setting, and Participants: Multicenter randomized clinical trial of tranexamic acid vs placebo conducted from December 1, 2014, to November 8, 2022, at 10 hepatopancreaticobiliary sites in Canada and 1 site in the United States, with 90-day follow-up. Participants, clinicians, and data collectors were blinded to allocation. A volunteer sample of 1384 patients undergoing liver resection for a cancer-related indication met eligibility criteria and consented to randomization., Interventions: Tranexamic acid (1-g bolus followed by 1-g infusion over 8 hours; n = 619) or matching placebo (n = 626) beginning at induction of anesthesia., Main Outcomes and Measures: The primary outcome was receipt of red blood cell transfusion within 7 days of surgery., Results: The primary analysis included 1245 participants (mean age, 63.2 years; 39.8% female; 56.1% with a diagnosis of colorectal liver metastases). Perioperative characteristics were similar between groups. Red blood cell transfusion occurred in 16.3% of participants (n = 101) in the tranexamic acid group and 14.5% (n = 91) in the placebo group (odds ratio, 1.15 [95% CI, 0.84-1.56]; P = .38; absolute difference, 2% [95% CI, -2% to 6%]). Measured intraoperative blood loss (tranexamic acid, 817.3 mL; placebo, 836.7 mL; P = .75) and total estimated blood loss over 7 days (tranexamic acid, 1504.0 mL; placebo, 1551.2 mL; P = .38) were similar between groups. Participants receiving tranexamic acid experienced significantly more complications compared with placebo (odds ratio, 1.28 [95% CI, 1.02-1.60]; P = .03), with no significant difference in venous thromboembolism (odds ratio, 1.68 [95% CI, 0.95-3.07]; P = .08)., Conclusions and Relevance: Among patients undergoing liver resection for a cancer-related indication, tranexamic acid did not reduce bleeding or blood transfusion but increased perioperative complications., Trial Registration: ClinicalTrials.gov Identifier: NCT02261415.

Background: Minimally invasive extracorporeal circulation (MiECC) is employed as a strategy to attenuate the physiologic disturbance caused by cardiopulmonary bypass. The aim of this study was to compare the coagulation profile of MiECC to an optimized conventional extracorporeal circuit (OpECC) with regards to platelet function, rotational thromboelastometry and blood product usage., Methods: A retrospective analysis of coronary artery bypass grafting operations using either MiECC or OpECC was performed at a single institution., Results: A total of 112 patients were included, with 61 receiving MiECC and 51 OpECC patients. OpECC patients had a significantly larger BSA (1.95+/- 0.22m2 vs 1.88 +/- 0.18m2, p = 0.034), than those who received MiECC. No difference between groups was observed regarding red blood cell, plasma, and platelet transfusions. Functional platelet count during the warming phase of cardiopulmonary bypass was found to be higher in the MiECC group ((136 (102-171) x10 9 /L vs 109 (94-136) x10 9 /L), p = 0.027), as were functional platelets as a percent of total platelet count ((86 (77-91)% vs 76 (63-82)%), p = 0.003). There were no significant differences between other outcomes such as operative mortality, incidence of stroke, and intensive care unit length of stay., Conclusion: While we did not see a difference in blood transfusions, MiECC resulted in a statistically significant advantage over OpECC with regards to preservation of functional platelets., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The number of effective evidence-based treatment options for patients with Tourette syndrome (TS) is limited. Emerging evidence shows cannabinoids as promising for the treatment of tics. Objectives: To compare the efficacy and tolerability of single doses of three vaporized medical cannabis products and placebo in reducing tics in adults with TS. Methods: In a randomized, double-blind, crossover design, each participant received a vaporized single 0.25 g dose of Δ 9 -tetrahydrocannabinol (THC) 10%, THC/cannabidiol (CBD) 9%/9%, CBD 13%, and placebo at 2-week intervals. Our primary outcome was the Modified Rush Video-Based Tic Rating Scale (MRVTRS), taken at baseline and at 0.5, 1, 2, 3, and 5 h after dose administration. Secondary measures included the Premonitory Urge for Tics Scale (PUTS), Subjective Units of Distress Scale (SUDS), and Clinical Global Impression-Improvement (CGI-I). Correlations between outcomes and cannabinoid plasma levels were calculated. Tolerability measures included open-ended and specific questions about adverse events (AEs). Results: Twelve adult patients with TS were randomized, with nine completing the study. There was no statistically significant effect of product on the MRVTRS. However, there was a significant effect of THC 10%, and to a lesser extent THC/CBD 9%9%, versus placebo on the PUTS, SUDS, and CGI-I. As well, there were significant correlations between plasma levels of THC and its metabolites, but not CBD, with MRVTRS, PUTS, and SUDS measures. There were more AEs from all cannabis products relative to placebo, and more AEs from THC 10% versus other cannabis products, particularly cognitive and psychomotor effects. Most participants correctly identified whether they had received cannabis or placebo. Conclusions: In this pilot randomized controlled trial of cannabis for tics in TS, there was no statistically significant difference on the MRVTRS for any of the cannabis products, although the THC 10% product was significantly better than placebo on the secondary outcome measures. Also, THC and metabolite plasma levels correlated with improvement on all measures. The THC 10% product resulted in the most AEs. ClinicalTrials.gov ID: NCT03247244.

Background: Genetic defects in the RAS/mitogen-activated protein kinase pathway are an important cause of hypertrophic cardiomyopathy (RAS-HCM). Unlike primary HCM (P-HCM), the risk of sudden cardiac death (SCD) and long-term survival in RAS-HCM are poorly understood., Objectives: The study's objective was to compare transplant-free survival, incidence of SCD, and implantable cardioverter-defibrillator (ICD) use between RAS-HCM and P-HCM patients., Methods: In an international, 21-center cohort study, we analyzed phenotype-positive pediatric RAS-HCM (n = 188) and P-HCM (n = 567) patients. The between-group differences in cumulative incidence of all outcomes from first evaluation were compared using Gray's tests, and age-related hazard of all-cause mortality was determined., Results: RAS-HCM patients had a lower median age at diagnosis compared to P-HCM (0.9 years [IQR: 0.2-5.0 years] vs 9.8 years [IQR: 2.0-13.9 years], respectively) (P < 0.001). The 10-year cumulative incidence of SCD from first evaluation was not different between RAS-HCM and P-HCM (4.7% vs 4.2%, respectively; P = 0.59). The 10-year cumulative incidence of nonarrhythmic deaths or transplant was higher in RAS-HCM compared with P-HCM (11.0% vs 5.4%, respectively; P = 0.011). The 10-year cumulative incidence of ICD insertions, however, was 5-fold lower in RAS-HCM compared with P-HCM (6.9% vs 36.6%; P < 0.001). Nonarrhythmic deaths occurred primarily in infancy and SCD primarily in adolescence., Conclusions: RAS-HCM was associated with a higher incidence of nonarrhythmic death or transplant but similar incidence of SCD as P-HCM. However, ICDs were used less frequently in RAS-HCM compared to P-HCM. In addition to monitoring for heart failure and timely consideration of advanced heart failure therapies, better risk stratification is needed to guide ICD practices in RAS-HCM., Competing Interests: Funding Support and Author Disclosures The project was supported through funding from the Ted Rogers Centre for Heart Research, the Heart and Stroke Foundation/Robert M Freedom Chair, and the Canadian Institutes of Health Research to Dr Mital. Dr Lynch is supported by a Heart Failure Research Fellowship from Bristol Myers Squibb, Mitacs, and Myant. Dr Mital has served as a consultant for Bristol Myers Squibb and Tenaya Therapeutics; and has received unrestricted education funding from Bristol Myers Squibb. Dr Conway has served as a medical monitor for the PumpKIN trial; and has received unrestricted education funding from Abbott. Dr Rossano has served as a consultant for Merck, Bayer, Myokardia, and Cytokinetics. Dr Kantor has served as a consultant for Novartis and AstraZeneca. Dr Balaji has served as a consultant for Milestone Pharmaceuticals and Janssen Pharmaceuticals; and has received a research support grant from the Medtronic External Research Program. Dr Godown has served as a consultant for Daiichi-Sankyo. Dr Aziz has served on the Medical Advisory Board for Medtronic. Dr Jeewa has served as a medical monitor for the PumpKIN trial; and has served as a consultant for Abbott. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Valve-sparing root replacement (VSRR) has excellent outcomes when performed in experienced centers in well-selected patients. It is suggested that reimplantation of the aortic valve may have better durability than remodeling in patients with Marfan syndrome (MFS), although long-term comparative data are limited., Methods: Between 1988 and 2018, 194 patients with MFS underwent VSRR at our institution. From these, we derived a propensity-matched cohort of 68 patients (44 who underwent reimplantation and 24 who had remodeling). Early outcomes included death and perioperative complications. Late outcomes were survival, probability of aortic insufficiency, and reintervention up to 20 years of follow-up. Median follow-up was 17.8 years (interquartile range, 12.0-20.6 years) for the entire matched cohort., Results: Baseline variables were similar between reimplantation and remodeling patients after matching: age (39 ± 12 vs 40 ± 13 years, P = .75) and male sex (28 [64%] vs 15 [63%], P = 1.0). Similar 20-year survival was observed after reimplantation compared with remodeling (82% vs 72%, P = .20), whereas the probability of developing greater than mild aortic insufficiency at 20 years was increased after remodeling (5.8% vs 13%, P = .013). More patients underwent reoperation on the aortic valve after a remodeling procedure than after reimplantation of the aortic valve (18% vs 0%, P = .018)., Conclusions: VSRR provides excellent long-term survival and freedom from valve-related complications outcomes in patients with MFS. Reimplantation of the aortic valve was associated with a lower risk of aortic valve reoperation and aortic insufficiency than the remodeling procedure after 2 decades of follow-up., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Sodium-glucose cotransporter 2 inhibitors have been demonstrated to promote reverse cardiac remodeling in people with diabetes or heart failure. Although it has been theorized that sodium-glucose cotransporter 2 inhibitors might afford similar benefits in people without diabetes or prevalent heart failure, this has not been evaluated. We sought to determine whether sodium-glucose cotransporter 2 inhibition with empagliflozin leads to a decrease in left ventricular (LV) mass in people without type 2 diabetes or significant heart failure., Methods: Between April 2021 and January 2022, 169 individuals, 40 to 80 years of age, without diabetes but with risk factors for adverse cardiac remodeling were randomly assigned to empagliflozin (10 mg/d; n=85) or placebo (n=84) for 6 months. The primary outcome was the 6-month change in LV mass indexed (LVMi) to baseline body surface area as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and LV end-systolic volumes indexed to baseline body surface area and LV ejection fraction., Results: Among the 169 participants (141 men [83%]; mean age, 59.3±10.5 years), baseline LVMi was 63.2±17.9 g/m 2 and 63.8±14.0 g/m 2 for the empagliflozin- and placebo-assigned groups, respectively. The difference (95% CI) in LVMi at 6 months in the empagliflozin group versus placebo group adjusted for baseline LVMi was -0.30 g/m 2 (-2.1 to 1.5 g/m 2 ; P =0.74). Median baseline (interquartile range) NT-proBNP (N-terminal-pro B-type natriuretic peptide) was 51 pg/mL (20-105 pg/mL) and 55 pg/mL (21-132 pg/mL) for the empagliflozin- and placebo-assigned groups, respectively. The 6-month treatment effect of empagliflozin versus placebo (95% CI) on blood pressure and NT-proBNP (adjusted for baseline values) were -1.3 mm Hg (-5.2 to 2.6 mm Hg; P =0.52), 0.69 mm Hg (-1.9 to 3.3 mm Hg; P =0.60), and -6.1 pg/mL (-37.0 to 24.8 pg/mL; P =0.70) for systolic blood pressure, diastolic blood pressure, and NT-proBNP, respectively. No clinically meaningful between-group differences in LV volumes (diastolic and systolic indexed to baseline body surface area) or ejection fraction were observed. No difference in adverse events was noted between the groups., Conclusions: Among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, sodium-glucose cotransporter 2 inhibition with empagliflozin did not result in a meaningful reduction in LVMi after 6 months., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT04461041.

Background: Limited data are available concerning comparative outcomes of redo aortic valve interventions, including surgery after aortic valve replacement (AVR) with either stented or stentless bioprostheses. We investigated the comparative outcomes of redo aortic valve interventions, including surgery after AVR with either stented or stentless bioprostheses., Methods: The cohort consisted of 112 patients who underwent aortic valve intervention for infective endocarditis or structural valve deterioration between 2001 and 2020. One hundred patients received a stented valve (stented group) and 12 patients received a stentless valve (stentless group) during the initial surgery. Early and late outcomes were evaluated., Results: The mean [IQR] ages during the current interventions were 66 [54, 77] years in the stented group and 74 [67, 79] years in the stentless group (P = 0.13). In the stented group, aortic valve interventions included redo AVRs with stented valves (n = 54), mechanical valves (n = 26), stentless valves (n = 16), and transcatheter aortic valve implantations (n = 4). In the stentless group, redo AVRs were performed with stented valves (n = 4), mechanical valves (n = 2), stentless valves (n = 1), and transcatheter valve implantations (n = 5). Hospital mortality was observed in 2 (2%) patients in the stented group and 1 (8%) patients in the stentless group (P = 0.29). The 5-year survival was 80.8% [66.8, 88.5] in the stented group and 91.7% [53.9, 98.8] in stentless group. Statistically significant differences in thromboembolisms were observed between the groups., Conclusions: No significant differences in early and mid-term outcomes (except thromboembolism) after aortic valve interventions were detected between patients with stented and stentless AVRs., (© 2023. The Author(s).)

Background: Aortic cusp fenestrations are common in patients with aortic root aneurysm, and their management during aortic valve repair remains controversial. We believe that fenestrations in the area of the commissures may rupture after reimplantation of the aortic valve because this operation increases the mechanical stress on the cusps. For this reason we have reinforced the free margin of the aortic cusp with fenestration with fine Gore-Tex sutures (WL Gore). This study examines the outcomes of reimplantation of the aortic valve in patients who had cusp fenestration reinforced with Gore-Tex sutures., Methods: A review of all patients who had reimplantation of the aortic valve for aortic root aneurysm disclosed 111 patients who had at least 1 cusp fenestration reinforced with a double layer of a fine Gore-Tex suture. The outcomes of these patients were examined and compared with a group of patients without fenestration using propensity score analysis. All patients were followed prospectively with images of the heart., Results: The median follow-up was 8.3 years. Overall the cumulative incidence of aortic valve reintervention at 15 years was 4.8% and the cumulative incidence of aortic insufficiency of moderate or severe degree was 9.2%. Comparison of outcomes of patients with and without fenestrations showed similar results up to 15 years of follow-up., Conclusions: Reinforcement of the free margins of cusps with fenestrations using Gore-Tex sutures is safe and does not seem to adversely affect the durability of reimplantation of the aortic valve., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: The objectives of this study were to examine operative and long-term results of combined aortic and mitral valve replacement when reconstruction of the fibrous skeleton of the heart is needed because of calcification, abscess, previous operations, or patient-prosthesis mismatch., Methods: From 1985 to 2020, 182 consecutive patients underwent combined aortic and mitral valve replacement with reconstruction of the intervalvular fibrous skeleton in all cases and also the posterior mitral annulus in 63 patients. Bovine pericardium or Dacron grafts were used for the reconstructions. Median follow-up was 7.5 (interquartile range, 2.1-12.6) years and 98% complete., Results: Patient mean age was 62 years; 69% had 1 or more previous valve operations, and 92% were functional class III or IV. The indications for reconstruction were extensive calcification of the fibrous skeleton in 34%, abscess in 13%, tissue damage secondary to previous operations in 39%, and patient-prosthesis mismatch of the mitral valve in 13%. Bovine pericardium was used in two-thirds of cases and Dacron grafts in one-third. Operative mortality was 13.2% and postoperative complications were common. Survival at 1, 10, and 20 years was 81.8%, 51.1%, and 23.7%, respectively. Fourteen patients required reoperation and 3 transcatheter interventions. The cumulative probability of reinterventions at 1, 10, and 20 years were 3.3%, 5.8%, and 9.1%, respectively. Most patients experienced symptomatic improvement postoperatively., Conclusions: Reconstructions of the fibrous skeleton of the heart are associated with high operative mortality but the long-term results are satisfactory because most patients would not have survived without surgical intervention., (Copyright © 2021 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Liberating patients from mechanical ventilation (MV) requires a systematic approach. In the context of a clinical trial, we developed a simple algorithm to identify patients who tolerate assisted ventilation but still require ongoing MV to be randomized. We report on the use of this algorithm to screen potential trial participants for enrollment and subsequent randomization in the Proportional Assist Ventilation for Minimizing the Duration of MV (PROMIZING) study., Methods: The algorithm included five steps: enrollment criteria, pressure support ventilation (PSV) tolerance trial, weaning criteria, continuous positive airway pressure (CPAP) tolerance trial (0 cmH 2 O during 2 min) and spontaneous breathing trial (SBT): on fraction of inspired oxygen (F i O 2 ) 40% for 30-120 min. Patients who failed the weaning criteria, CPAP Zero trial, or SBT were randomized. We describe the characteristics of patients who were initially enrolled, but passed all steps in the algorithm and consequently were not randomized., Results: Among the 374 enrolled patients, 93 (25%) patients passed all five steps. At time of enrollment, most patients were on PSV (87%) with a mean (± standard deviation) F i O 2 of 34 (± 6) %, PSV of 8.7 (± 2.9) cmH 2 O, and positive end-expiratory pressure of 6.1 (± 1.6) cmH 2 O. Minute ventilation was 9.0 (± 3.1) L/min with a respiratory rate of 17.4 (± 4.4) breaths/min. Patients were liberated from MV with a median [interquartile range] delay between initial screening and extubation of 5 [1-49] hours. Only 7 (8%) patients required reintubation., Conclusion: The trial algorithm permitted identification of 93 (25%) patients who were ready to extubate, while their clinicians predicted a duration of ventilation higher than 24 h., (© 2022. The Author(s).)

Background: The ideal aortic valve substitute for young and middle-aged adults remains elusive., Objectives: This study sought to compare the long-term outcomes of patients undergoing the Ross procedure and those receiving bioprosthetic aortic valve replacements (AVRs)., Methods: Consecutive patients aged 16-60 years who underwent a Ross procedure or surgical bioprosthetic AVR at the Toronto General Hospital between 1990 and 2014 were identified. Propensity score matching was used to account for differences in baseline characteristics. The primary outcome was all-cause mortality. Secondary outcomes included valve reintervention, valve deterioration, endocarditis, thromboembolic events, and permanent pacemaker implantation., Results: Propensity score matching yielded 108 pairs of patients. The median age was 41 years (IQR: 34-47 years). Baseline characteristics were similar between the matched groups. There was no operative mortality in either group. Mean follow-up was 14.5 ± 7.2 years. All-cause mortality was lower following the Ross procedure (HR: 0.35; 95% CI: 0.14-0.90; P = 0.028). Using death as a competing risk, the Ross procedure was associated with lower rates of reintervention (HR: 0.21; 95% CI: 0.10-0.41; P < 0.001), valve deterioration (HR: 0.25; 95% CI: 0.14-0.45; P < 0.001), thromboembolic events (HR: 0.15; 95% CI: 0.05-0.50; P = 0.002), and permanent pacemaker implantation (HR: 0.22; 95% CI: 0.07-0.64; P = 0.006)., Conclusions: In this propensity-matched study, the Ross procedure was associated with better long-term survival and freedom from adverse valve-related events compared with bioprosthetic AVR. In specialized centers with sufficient expertise, the Ross procedure should be considered the primary option for young and middle-aged adults undergoing AVR., Competing Interests: Funding Support and Author Disclosures Dr Ouzounian is partially supported by the Antonio & Helga DeGasperis Chair in Clinical Trials and Outcomes Research at University Health Network; and has consulting agreements with Cryolife, Terumo Aortic, Medtronic, and Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Aortic valve stenosis is the most common type of congenital left ventricular (LV) outflow tract obstruction. Balloon aortic valvuloplasty (BAV) has become the first-line treatment pathway in many centers. Our aim was to assess the trajectory of LV remodeling following BAV in children and its relationship to residual aortic stenosis (AS) and insufficiency (AI)., Methods: Children <18 years of age who underwent BAV for isolated aortic stenosis from 2004 to 2012 were eligible for inclusion. Those with AI before BAV, other complex congenital heart lesions, or <2 accessible follow-up echocardiograms were excluded. Baseline and serial echocardiographic data pertaining to aortic valve and LV size and function were retrospectively collected through December 2017 or the first reintervention. Longitudinal data was assessed using per-patient time profiles with superimposed trend lines using locally estimated scatterplot smoothing. Associations with reintervention or death were also evaluated., Results: Among the 98 enrolled children, the median (interquartile range) age at BAV was 2.8 months (0.2-75). The median (interquartile range) follow-up was 6.8 years (1.9-9.0). Children with predominantly residual AI (n=11) demonstrated progressive increases in their LV end-diastolic dimension Z score within the first 3 years after the BAV, followed by a plateau ( P <0.001). Their mean LV circumferential and longitudinal strain values remained within the normal range but lower than in the non-AI group ( P <0.001 and P =0.001, respectively). Children with predominantly residual aortic stenosis (n=44) had no changes in LV dimensions but had a rapid early increase in mean LV circumferential and longitudinal strain. The cumulative proportion (95% CI) of reintervention at 5 years following BAV was 33.7% (23.6%-42.4%)., Conclusions: Our study demonstrates that LV remodeling occurs mainly during the first 3 years in children with predominantly residual AI after BAV, with no subsequent significant functional changes over the medium term. These data improve our understanding of expected patient trajectories and thus may inform decisions on the timing of reintervention.

Objectives: We sought to evaluate the early outcomes of patients undergoing a Bentall procedure after previous cardiac surgery., Methods: From 1990 to 2014, 473 patients underwent a Bentall procedure after previous cardiac surgery with a composite valve graft at a single institution: composite valve graft with a mechanical prosthesis (n = 256) or composite valve graft with a bioprosthesis (n = 217). Patients were excluded if their index operation was less than 30 days before the reoperation. The primary outcome was 30-day mortality. The secondary outcome was a composite of major morbidity and operative mortality: stroke, renal failure, prolonged mechanical ventilation, deep sternal infection, or reoperation during the same admission. Multivariable logistic regression was used to identify risk factors associated with the primary and secondary outcomes of interest., Results: Median age was 57 (interquartile range, 44-67) years, and 349 patients (74%) were male. Median time between index surgery and reoperation was 13 (interquartile range, 8-21) years. A total of 178 patients (38%) underwent urgent or emergency intervention, 61 patients (13%) had active endocarditis/abscess, 87 patients (19%) had left ventricular ejection fraction less than 40%, and 262 patients (55%) had undergone more than 1 previous operation. Previous operations (not mutually exclusive) included coronary artery bypass grafting (n = 58, 12%), aortic valve/root replacement (n = 376, 80%) or repair (n = 36, 8%), and other surgical interventions (n = 245, 52%). Ninety-six patients (20%) had undergone coronary reimplantation during the previous operation, which consisted of a Bentall procedure in 81 patients, a Ross operation in 8 patients, a valve-sparing root replacement in 4 patients, and an arterial switch in 3 patients. At the time of the reoperative Bentall, both coronary arteries were reimplanted directly in 357 patients (77%), whereas 79 patients (17%) received at least 1 interposition graft. In 26 patients (5%), at least 1 of the native coronary arteries was oversewn and a vein graft bypass was performed. Thirty-day mortality occurred in 37 patients (7.8%), and 152 patients (32%) had major morbidity and operative mortality. On multivariable analysis, risk factors associated with increased 30-day mortality included older age and coronary reimplantation by a technique other than direct anastomosis. Indirect coronary reimplantation was also associated with a higher incidence of major morbidity and operative mortality, as were more than 1 previous cardiac operation and preoperative New York Heart Association functional class III/IV or greater., Conclusions: In the largest reported cohort of aortic root replacement after previous cardiac surgery, the reoperative Bentall procedure was associated with a significant operative risk. The need for complex coronary reimplantation techniques was an important factor associated with adverse perioperative events., (Copyright © 2020. Published by Elsevier Inc.)

Objective: To examine the late outcomes of reimplantation of the aortic valve (RAV) in patients followed prospectively since surgery., Methods: All 465 patients who had RAV from 1989 to 2018 were followed prospectively with periodic clinical and echocardiographic assessments. Mean follow-up was 10 ± 6 years and 98% complete., Results: Patients' mean age was 47 ± 5.1 years, and 78% were men. The aortic root aneurysm was associated with Marfan syndrome in 164 patients, Loeys-Dietz syndrome in 13, bicuspid aortic valve (BAV) in 67, and type A aortic dissection in 33. Aortic insufficiency (AI) was greater than mild in 298 patients. Concomitant procedures were performed in 105 patients. There were 5 operative and 51 late deaths. At 20 years, 69.1% of patients were alive and free from aortic valve reoperation, and the cumulative probability of aortic valve reoperation with death as a competing risk was 6.0%, and the cumulative probability of developing moderate or severe AI was 10.2%. Only time per 1-year interval was associated with the development of postoperative AI by multivariable analysis (hazard ratio, 1.06; 95% confidence interval, >1.02-1.10; P = .006). Gradients across preserved BAV increased in 5 patients, and 1 required reoperation for aortic stenosis. Distal aortic dissections occurred in 22 patients, primarily in those with associated genetic syndromes., Conclusions: RAV provides excellent long-term results, but there is a progressive rate of AI over time, and patients with BAV may develop aortic stenosis. Patients with genetic syndromes have a risk of distal aortic dissections. Continued surveillance after RAV is necessary., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Despite known clinical risk factors, predicting anthracycline cardiotoxicity remains challenging., Objectives: This study sought to develop a clinical and genetic risk prediction model for anthracycline cardiotoxicity in childhood cancer survivors., Methods: We performed exome sequencing in 289 childhood cancer survivors at least 3 years from anthracycline exposure. In a nested case-control design, 183 case patients with reduced left ventricular ejection fraction despite low-dose doxorubicin (≤250 mg/m 2 ), and 106 control patients with preserved left ventricular ejection fraction despite doxorubicin >250 mg/m 2 were selected as extreme phenotypes. Rare/low-frequency variants were collapsed to identify genes differentially enriched for variants between case patients and control patients. The expression levels of 5 top-ranked genes were evaluated in human induced pluripotent stem cell-derived cardiomyocytes, and variant enrichment was confirmed in a replication cohort. Using random forest, a risk prediction model that included genetic and clinical predictors was developed., Results: Thirty-one genes were differentially enriched for variants between case patients and control patients (p < 0.001). Only 42.6% case patients harbored a variant in these genes compared to 89.6% control patients (odds ratio: 0.09; 95% confidence interval: 0.04 to 0.17; p = 3.98 × 10 -15 ). A risk prediction model for cardiotoxicity that included clinical and genetic factors had a higher prediction accuracy and lower misclassification rate compared to the clinical-only model. In vitro inhibition of gene-associated pathways ( PI3KR2 , ZNF827 ) provided protection from cardiotoxicity in cardiomyocytes., Conclusions: Our study identified variants in cardiac injury pathway genes that protect against cardiotoxicity and informed the development of a prediction model for delayed anthracycline cardiotoxicity, and it also provided new targets in autophagy genes for the development of cardio-protective drugs. (Preventing Cardiac Sequelae in Pediatric Cancer Survivors [PCS2]; NCT01805778)., Competing Interests: The study was supported by the Canadian Cancer Society, Toronto, Canada; Canadian Institutes of Health Research, Toronto, Canada; the Pediatric Oncology Group of Ontario, Toronto, Canada; the Ontario Institute for Cancer Research, Toronto, Canada; Children’s Cancer and Blood disorders, Toronto, Canada; Ted Rogers Centre for Heart Research, Toronto, Canada; and the Labatt Family Heart Center at the Hospital for Sick Children, Toronto, Canada. Dr. Sender is Senior Vice President, Medical Affairs for Pediatric, Adolescent and Young Adult Oncology at NantKwest. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2020 The Authors.)

Background: The interactive relationship between left ventricular (LV) ejection fraction (LVEF) and LV size in predicting perioperative outcomes after cardiac surgery has not been clarified., Methods: This study reviewed all patients who underwent cardiac surgery between 2010 and 2016 with either preserved LVEF (>60%; n = 5685) or severely reduced LVEF (<20%; n = 143). LV size was categorized by using either LV end-diastolic or end-systolic diameter or a qualitative assessment, as follows: normal, smaller than 4 cm; mildly enlarged, 4.1 to 5.4 cm moderately enlarged, 5.5 to 6.5 cm; and severely enlarged, larger than 6.5 cm. Using propensity-score analysis, we matched patients with LVEF less than 20% (n = 143) in a 3:1 ratio with patients with LVEF greater than 60% (n = 429)., Results: There were significant differences in mortality, major morbidity, and operative mortality and prolonged length of stay between patients with LVEF less than 20% and LVEF greater than 60%. In patients with LVEF less than 20%, there were no significant differences in outcomes between those with an LV size of 5.4 cm or smaller and an LV size of 5.5 cm or larger. In patients undergoing isolated coronary artery bypass grafting (CABG), LV size predicted mortality, major morbidity, and operative mortality (odds ratio, 5.5 [95% confidence interval, 2.0 to 15.7]; P < .001) and prolonged length of stay (odds ratio, 3.4 [95% confidence interval, 1.2 to 10.3]; P = .026), respectively., Conclusions: LVEF is more important than LV size in predicting outcomes after cardiac surgery. However, in patients undergoing isolated CABG, LV size has an interactive effect with LVEF and can potentially aid the decision-making process. Risk adjustment models using only LVEF may be inaccurate, particularly with respect to isolated CABG procedures., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The number of transplantations performed for adult congenital heart disease (ACHD) patients is increasing. We sought to compare survival and post-transplantation complications, including graft failure, rejection, dialysis, and use of a right ventricular assist device, between ACHD and a cohort of dilated (DCM) and ischemic (ICM) cardiomyopathy patients matched by age and year of transplantation., Methods: We retrospectively reviewed our single-institution heart transplantation database and selected all patients who had surgery from 1988 to 2017. In our primary analysis, we looked at survival and post-transplantation complications across cardiomyopathy groups. Our secondary analysis was matched to mitigate era effects as well as differences in age at transplant., Results: We analyzed a cohort consisting of 303 heart transplant patients with cardiomyopathy due to either 1) ACHD (n = 38), 2) ICM (n = 110), or 3) DCM (n = 155). Kaplan-Meier analysis and a multivariable Cox proportional hazard regression model were used for all-cause mortality, and cause-specific hazard regression for cause-specific mortality and morbidity. There was no statistically significant survival difference across groups. The 1-year survival was 68.5% for ACHD, 85.4% for ICM, and 85.5% for DCM. In multivariable analysis, ICM and DCM patients showed a 66% lower risk of death relative to the ACHD group. The matched analysis showed no significant difference in survival across groups., Conclusions: ACHD patients represent a growing high-risk patient cohort referred for transplantation. To improve survival outcomes we need to address modifiable risk factors., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objectives: This study examines the durability of mitral valve (MV) repair for mitral regurgitation using chordal replacement with expanded polytetrafluoroethylene sutures to correct leaflet prolapse., Methods: Isolated chordal replacement was used to correct prolapse in 186 (24.9%) patients and combined with leaflet resection in 560 (75.1%). Patients were followed prospectively with periodical clinical and echocardiographic assessments for a median follow-up of 11 years (range, 7-16 years)., Results: Patients' median age was 58 years (range, 48-67 years) and 516 (69.2%) were men. Bileaflet prolapse was present in 63% of patients and advanced myxomatous degeneration was present in 32%. The number of neochords per repaired valve increased over time and was not associated with MV reoperation or recurrent mitral regurgitation. The cumulative incidence of MV reoperation with death as a competing risk was 4.2% (95% confidence interval [CI], 2.4-6.0) at 20 years. Multivariable analysis revealed that previous cardiac operations (hazard ratio, 5.70; 95% CI, 1.96-16.53; P = .001), and isolated anterior leaflet prolapse (hazard ratio, 3.92; 95% CI, 1.106-13.91; P = .034) were associated with increased hazard of MV reoperation. The probability of recurrent moderate or severe mitral regurgitation using repeated measures regression models was 14.1% (95% CI, 10.3-19.0) at 20 years. Variables associated with recurrent MR in multivariable regression analysis were left ventricular ejection <40% (hazard ratio, 3.57; 95% CI, 1.37-9.32; P = .009) and preoperative complete heart block (hazard ratio, 5.90; 95% CI, 2.47-14.09; P < .001)., Conclusions: Chordal replacement with expanded polytetrafluoroethylene sutures provides stable MV function in most patients during the first 2 decades of follow-up., (Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Hypertrophic cardiomyopathy is the leading cause of sudden cardiac death (SCD) in children and young adults. Our objective was to develop and validate a SCD risk prediction model in pediatric hypertrophic cardiomyopathy to guide SCD prevention strategies., Methods: In an international multicenter observational cohort study, phenotype-positive patients with isolated hypertrophic cardiomyopathy <18 years of age at diagnosis were eligible. The primary outcome variable was the time from diagnosis to a composite of SCD events at 5-year follow-up: SCD, resuscitated sudden cardiac arrest, and aborted SCD, that is, appropriate shock following primary prevention implantable cardioverter defibrillators. Competing risk models with cause-specific hazard regression were used to identify and quantify clinical and genetic factors associated with SCD. The cause-specific regression model was implemented using boosting, and tuned with 10 repeated 4-fold cross-validations. The final model was fitted using all data with the tuned hyperparameter value that maximizes the c-statistic, and its performance was characterized by using the c-statistic for competing risk models. The final model was validated in an independent external cohort (SHaRe [Sarcomeric Human Cardiomyopathy Registry], n=285)., Results: Overall, 572 patients met eligibility criteria with 2855 patient-years of follow-up. The 5-year cumulative proportion of SCD events was 9.1% (14 SCD, 25 resuscitated sudden cardiac arrests, and 14 aborted SCD). Risk predictors included age at diagnosis, documented nonsustained ventricular tachycardia, unexplained syncope, septal diameter z -score, left ventricular posterior wall diameter z score, left atrial diameter z score, peak left ventricular outflow tract gradient, and presence of a pathogenic variant. Unlike in adults, left ventricular outflow tract gradient had an inverse association, and family history of SCD had no association with SCD. Clinical and clinical/genetic models were developed to predict 5-year freedom from SCD. Both models adequately discriminated between patients with and without SCD events with a c-statistic of 0.75 and 0.76, respectively, and demonstrated good agreement between predicted and observed events in the primary and validation cohorts (validation c-statistic 0.71 and 0.72, respectively)., Conclusion: Our study provides a validated SCD risk prediction model with >70% prediction accuracy and incorporates risk factors that are unique to pediatric hypertrophic cardiomyopathy. An individualized risk prediction model has the potential to improve the application of clinical practice guidelines and shared decision making for implantable cardioverter defibrillator insertion. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT0403679.

Aims: Current guidelines recommend initiating family screening for hypertrophic cardiomyopathy (HCM) after age 10 or 12 years unless early screening criteria are met. The aim was to evaluate if current screening guidelines miss early onset disease., Methods and Results: Children who underwent family screening for HCM before age 18 years were analysed. Major cardiac events (MaCEs) were defined as death, sudden cardiac death (SCD), or need for major cardiac interventions (myectomy, implantable cardioverter-defibrillator insertion, transplantation). Of 524 children screened, 331 were under 10 years of age, 9.9% had echocardiographic evidence of HCM, and 1.1% were symptomatic at first screening. The median (interquartile range) age at HCM onset was 8.9 (4.7-13.4) years, and at MaCE was 10.9 (8.5-14.3) years with a median time to MaCE from HCM onset of 1.5 (0.5-4.1) years. About 52.5% phenotype-positive children and 41% with MaCEs were <10 years old. Only 69% children with early HCM met early screening criteria. Cox regression identified male gender, family history of SCD, and pathogenic variants in MYH7/MYBPC3 as a predictor of early onset HCM and MaCEs., Conclusion: A third of children not eligible for early screening by current guidelines had phenotype-positive HCM. MYH7 and MYBC3 mutation-positive patients were at highest risk for developing early HCM and experiencing an event or requiring a major intervention. Our findings suggest that younger family members should be considered for early clinical and genetic screening to identify the subset in need of closer monitoring and interventions., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Mitral valve (MV) repair has become the standard therapy for mitral regurgitation (MR) due to degenerative diseases, but information on late outcomes is limited., Objectives: The purpose of this study was to examine the late results of MV repair for MR in a large cohort of patients., Methods: A total of 1,234 consecutive patients (median age 59 years; 70.4% men) had MV repair for MR due to leaflet prolapse and were followed prospectively for a median of 13 years (interquartile range: 8 to 34 years) with periodical echocardiographic studies. There were 163 patients still at risk at 20 years. Cumulative incidences of adverse events and associated factors were examined with death as a competing outcome., Results: At 20 years, reoperation-free survival was 60.4% (95% confidence interval: 56.2% to 64.2%) and the cumulative incidence of cardiac and valve-related deaths was 12%, noncardiac deaths 21.3%, reoperation on the MV 4.6%, infective endocarditis 1.1%, thromboembolism 10.3%, and bleeding 6.4%. The probability of recurrent moderate or severe MR was 12.5%, persistent or new moderate or severe tricuspid regurgitation (TR) 20.8%, and new atrial fibrillation (AF) 32.4%. Multivariable analysis identified older age, complete heart block, MV repair without annuloplasty ring, and the degree of myxomatous degeneration of the MV to be associated with recurrent MR. The development of AF and TR was unrelated to recurrent MR., Conclusions: MV reoperation was uncommon after MV repair, but there was an increasing incidence of recurrent MR, TR, and new AF over time., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: The study objective was to examine the long-term results of the Ross procedure in a cohort of patients followed prospectively for more than 2 decades., Methods: From 1990 to 2004, 212 consecutive patients with a median age (interquartile range) of 34 years (28-41) underwent the Ross procedure; 82% had congenital aortic valve disease. The technique of aortic root replacement was used in one half of the patients. Patients have been followed prospectively for a median (interquartile range) of 18.0 (14.6-21.2) years. Valve function was assessed by echocardiography., Results: Cumulative mortality at 20 years was 10.8% (95% confidence interval, 6.5-17.8). Thirty patients required Ross-related reoperations and 3 for coronary artery disease. The cumulative probability of Ross-related reoperations at 20 years was 16.8% (95% confidence interval, 11.3-24.5), on the pulmonary autograft was 11.5% (95% confidence interval, 7.2-18.0), and on the pulmonary homograft was 8.2% (4.6-14.7). The implantation technique was not associated with the cumulative incidence of reoperations on the pulmonary autograft. The development of moderate or severe aortic insufficiency and pulmonary homograft dysfunction increased with time. At 20 years, the probability of aortic insufficiency was 13% (95% confidence interval, 8.0-20.3) and of pulmonary homograft dysfunction was 19.7% (95% confidence interval, 13.9-27.2). Preoperative aortic insufficiency was associated with increased odds of postoperative aortic insufficiency., Conclusions: The long-term results of the Ross procedure are excellent regardless of the implantation technique, but there is a progressive deterioration of function of both semilunar valves., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Tacrolimus pharmacokinetics are influenced by age and CYP3A5 genotype with CYP3A5 expressors (CYP3A5*1/*1 or *1/*3) being fast metabolizers. However, the benefit of genotype-guided dosing in pediatric solid organ transplantation has been understudied., Objective: To determine whether age and CYP3A5 genotype-guided starting dose of tacrolimus result in earlier attainment of therapeutic drug concentrations., Setting: Single hospital-based transplant center., Methods: This was a randomized, semi-blinded, 30-day pilot trial. Between 2012 and 2016, pediatric patients listed for solid organ transplant were consented and enrolled into the study. Participants were categorized as expressors, CYP3A5*1/*1 or CYP3A5*1/*3, and nonexpressors, CYP3A5*3/*3. Patients were stratified by age (≤ or > 6 years) and randomized (2:1) after transplant to receive genotype-guided (n = 35) or standard (n = 18) starting dose of tacrolimus for 36-48 hours and were followed for 30 days., Results: Median age at transplant in the randomized cohort was 2.1 (0.75-8.0) years; 24 (45%) were male. Participants in the genotype-guided arm achieved therapeutic concentrations earlier at a median (IQR) of 3.4 (2.5-6.6) days compared to those in the standard dosing arm of 4.7 (3.5-8.6) days (P = 0.049), and had fewer out-of-range concentrations [OR (95% CI) = 0.60 (0.44, 0.83), P = 0.002] compared to standard dosing, with no difference in frequency of adverse events between the two groups., Conclusions: CYP3A5 genotype-guided dosing stratified by age resulted in earlier attainment of therapeutic tacrolimus concentrations and fewer out-of-range concentrations., (© 2018 The Authors. Pediatric Transplantation Published by Wiley Periodicals, Inc.)

Objectives: Adrenergic receptor (ADR) genotypes have been associated with adverse outcomes in heart failure. Our objective was to evaluate the association of ADR genotypes with post-Norwood outcomes in infants with hypoplastic left heart syndrome (HLHS)., Methods: Infants with HLHS participating in the Pediatric Heart Network Single-Ventricle Reconstruction Trial underwent genotyping for 4 single-nucleotide polymorphisms in 3 ADR genes: ADRB1&#95;231A/G, ADRB1&#95;1165G/C, ADRB2&#95;5318C/G, and ADRA2A&#95;2790C/T. The association of genotype with freedom from serious adverse events (SAEs) (death, transplant, extracorporeal membrane oxygenation, cardiopulmonary resuscitation, acute shunt failure, unplanned reoperations, or necrotizing enterocolitis) during 14 months' follow-up was assessed with Cox regression and the association with post-Norwood complications was assessed with Poisson regression. Models were adjusted for clinical and surgical factors., Results: The study included 351 eligible patients (62% male; 83% white). The mean age at Norwood procedure was 5.6 ± 3.6 days. A total of 152 patients had SAEs during 14-month follow-up including 84 deaths and 10 transplants. ADRA2A&#95;2790CC genotype had lower SAE-free survival compared with CT/TT genotypes during follow-up (Log rank test, P = .02), and this association was independent of clinical and surgical risk factors (adjusted Cox regression, hazard ratio 1.54 [95% confidence interval 1.04, 2.30] P = .033). Post-Norwood complication rate did not differ by genotype., Conclusions: Infants with HLHS harboring ADR genotypes that are associated with greater catecholamine release or sensitivity had lower event-free survival after staged palliation. Excess catecholamine activation may adversely affect cardiovascular adaptation after the Norwood procedure. Future studies should explore whether targeting adrenergic activation in those harboring risk genotypes can improve outcomes. (ClinicalTrials.gov number NCT00115934)., (Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Deep brain stimulation of the basal ganglia and other brain regions has been used successfully to treat a variety of neurological disorders. However, the mechanisms by which it works, remain unclear. In a previous study, we showed that locally delivered single current pulses delivered from a nearby microelectrode are sufficient to inhibit firing in the internal globus pallidus for tens of milliseconds. The GPi and the substantia nigra pars reticulata are the output nuclei of the basal ganglia and share many anatomical and physiological features. The goal of the current study was to examine the after-effects of trains of high-frequency microstimulation on neuronal firing in the GPi of Parkinson's disease and dystonia patients as well as in the SNr of PD patients. Microelectrode recordings and microstimulation were performed in a total of 57 patients during stereotactic surgery. We found that firing in the GPi and SNr is inhibited for several hundreds of milliseconds following the end of a short, 200 Hz high-frequency train delivered through the recording electrode (e.g., on average 618 ms when stimulating in the SNr with a 0.5 s train of 4 microA pulses at 200 Hz). Inhibition duration usually increased with increasing current intensity, train frequency and generally peaked for trains of 1-2 s, while it decreased with increasing train durations. Statistical analysis with general linear models revealed a significant linear relationship between current intensity and inhibition duration in all nuclei and patient groups. There was also a significant relationship between train frequency and inhibition duration in the SNr and GPi of PD patients and between train duration and inhibition duration in the GPi of PD patients. There was no significant difference in inhibition duration across patient groups but the current threshold for inhibition was significantly different in the SNr compared to the GPi. The characteristics of the inhibition observed are consistent with stimulation-induced GABA release following activation of the GABAergic afferents in the SNr and GPi. The findings suggest that high-frequency microstimulation of the GPi and SNr depresses local neuronal activity and synaptic transmission, and such mechanisms may contribute to the therapeutic effects of DBS.

Object: The aim of the current study was to examine and compare the aftereffects of local high-frequency microstimulation through the recording electrode on the firing of neurons in the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr) in patients undergoing surgery for deep brain stimulation. Deep brain stimulation has been playing an increasing role in the treatment of Parkinson disease, with the subthalamic nucleus (STN) being the preferred implantation target. Changes in cellular activity indicative of the borders of the STN are typically used during surgery to determine the extent of the STN and locate the optimal target, but in some cases borders may be difficult to identify. In this study the authors compared the effects of microstimulation in the SNr and STN. In previous studies they have shown that microstimulation in the internal globus pallidus, which is functionally similar to the SNr, inhibits firing, whereas similar microstimulation in the STN has minimal effect. The presence of inhibition in the SNr but not in the STN could be used as an additional criterion to help identify the location of the border between the STN and SNr., Methods: Dual microelectrode recordings were performed during stereotactic surgery in 4 patients. Well-isolated high-amplitude units were stimulated extracellularly through the recording microelectrode with 0.5-second trains of high frequency (200 Hz) and low current (

The mammalian spinal cord contains a locomotor central pattern generator (CPG) that can produce alternating rhythmic activity of flexor and extensor motoneurones in the absence of rhythmic input and proprioceptive feedback. During such fictive locomotor activity in decerebrate cats, spontaneous omissions of activity occur simultaneously in multiple agonist motoneurone pools for a number of cycles. During these 'deletions', antagonist motoneurone pools usually become tonically active but may also continue to be rhythmic. The rhythmic activity that re-emerges following a deletion is often not phase shifted. This suggests that some neuronal mechanism can maintain the locomotor period when motoneurone activity fails. To account for these observations, a simplified computational model of the spinal circuitry has been developed in which the locomotor CPG consists of two levels: a half-centre rhythm generator (RG) and a pattern formation (PF) network, with reciprocal inhibitory interactions between antagonist neural populations at each level. The model represents a network of interacting neural populations with single interneurones and motoneurones described in the Hodgkin-Huxley style. The model reproduces the range of locomotor periods and phase durations observed during real locomotion in adult cats and permits independent control of the level of motoneurone activity and of step cycle timing. By altering the excitability of neural populations within the PF network, the model can reproduce deletions in which motoneurone activity fails but the phase of locomotor oscillations is maintained. The model also suggests criteria for the functional identification of spinal interneurones involved in the mammalian locomotor pattern generation.

We examined the features of spontaneous deletions of bursts of motoneuron activity that can occur within otherwise rhythmic alternating flexor and extensor activity during fictive locomotion and scratch in adult decerebrate cats. Deletions of activity were observed both in hindlimb flexor and extensor motoneuron pools during brain stem-stimulation-evoked fictive locomotion but only in extensors during fictive scratch. Paired intracellular motoneuron recordings showed that deletions reduced the depolarization of homonymous motoneurons in qualitatively similar ways. Differences occurred in the extent to which activity in synergist motoneuron pools operating at other joints within the limb was reduced during deletions. The timing of the rhythmic activity that followed a deletion was often at an integer multiple of the preexisting locomotor or scratch cycle period. This maintenance of cycle period was also seen during deletions in which there was a complete failure of motoneuron depolarization. The activity of antagonist motoneurons was usually sustained during deletions with some rhythmic modulation at intervals of the preexisting cycle period. We discuss an organization of the central pattern generator for locomotion and scratch that functions as a single rhythm generator with separate and multiple pattern formation modules for controlling the hyper- and depolarization of subsets of motoneurons within the limb.