The cone repair allows right ventricle rehabilitation with excellent tricuspid valve function following the Starnes procedure.

BACKGROUND: We present a case series of right ventricle (RV) rehabilitation after the Starnes procedure in patients with Ebstein anomaly (EA), applying the Cone repair of the tricuspid valve (TV) to achieve 2-ventricle or 1.5-ventricle physiology. METHODS: This is a retrospective database analysis from 2 institutions in North America. We included all consecutive cases of Cone repair after the Starnes procedure. The data are expressed as median and interquartile range (IQR). RESULTS: Eleven patients underwent RV rehabilitation between 2019 and 2023 after initial Starnes palliation at a median age of 27 months (IQR, 20.5 months). All patients were critically ill before their Starnes procedure, and 4 were on extracorporeal membrane oxygenation. Before the Cone repair, the median preoperative regurgitant velocity at the Starnes patch was 1.65 m/s (IQR, 1.3 m/s). During the Cone procedure, 9 patients required a concomitant pulmonary valve repair, of whom 3 needed a transannular monocusp patch. Four patients were successfully rerouted to a 2-ventricle repair, and 7 patients with a previous Glenn achieved 1.5-ventricle circulation. There were no cases of heart block and no deaths. Seven patients had trivial, 3 patients had mild, and 1 patient had moderate tricuspid regurgitation (TR) at a median follow-up of 11 months (IQR, 21.5 months). There was no significant TV stenosis; all patients had good functional status at the last follow-up despite severe RV dysfunction in 1 patient. CONCLUSIONS: After the Starnes procedure, the Cone repair allowed RV rehabilitation, resulting in trivial or mild TR at a midterm follow-up. The Starnes procedure is a reproducible technique that no longer commits patients to lifetime single-ventricle physiology.

Midterm Outcomes After Aortic Valve Neocuspidization (Ozaki Procedure) in Adults.

BACKGROUND: Trileaflet aortic valve neocuspidization (AVN) using autologous pericardium (Ozaki procedure) is an emerging surgical treatment option for aortic valve diseases. Although excellent results have been reported from Japan, data pertaining to its use in the United States are sparse. METHODS: All adult patients who underwent AVN (AVN group) or surgical aortic valve replacement (SAVR) with a bioprosthetic valve (SAVR group) between 2015 and 2022 were identified. Propensity score matching was used to adjust the baseline characteristics between the 2 groups. RESULTS: A total of 101 patients underwent AVN, and 1816 patients underwent SAVR with a bioprosthetic valve. None in the AVN group required conversion to SAVR. Before matching, mean age in the AVN group was 68.5 ± 8.8 years, and 56 patients (55.4%) underwent concomitant procedures. Preoperatively, 3 (3%) had endocarditis. Bicuspid valve was observed in 38 (38.4%). None died at 30 days in the AVN group. The median follow-up duration was 3.2 years. After propensity score matching, the expected survival and freedom from at least moderate aortic regurgitation at 5 years was 91.7% ± 3.1% and 97.6% ± 1.7%, respectively. Propensity score matching yielded 77 patients in each group. The Kaplan-Meier curve demonstrated equivalent survival at 5 years between the 2 groups (P = .95). Additionally, freedom from at least moderate aortic regurgitation was comparable at 5 years (P = .23). CONCLUSIONS: AVN can be safely performed for a variety of aortic valve diseases, with or without concomitant operations. AVN demonstrated similar midterm outcomes compared with SAVR with a bioprosthetic valve in the United States adult population.

Optimizing Surgical Selection for Transposition With Left Ventricular Outflow Tract Obstruction.

BACKGROUND: Studies that have assessed the Rastelli and Nikaidoh operations for transposition of the great arteries (TGA) with obstructed left ventricular outflow tract obstruction (LVOTO) have not fully evaluated the anatomic drivers that may contribute to surgical selection. We present our procedural selection process for optimizing outcomes of complex TGA in the modern era. METHODS: This is a single-center, retrospective study that included pediatric patients who underwent either a Nikaidoh or Rastelli operation for the treatment of TGA-LVOTO, congenitally corrected TGA-LVOTO, or double-outlet right ventricle TGA type-LVOTO from June 2004 to June 2021. RESULTS: There were 34 patients stratified by Nikaidoh (n = 16) or Rastelli (n = 18) operation. The incidence of all postoperative complications and mortality was low, and the incidence of complications between the groups was similar. Patients were more likely to have undergone a Nikaidoh than a Rastelli if they had a pulmonary annulus >5 mm (87.5% vs 11.1%), anteriorly/posteriorly oriented great vessels (88% vs 8%), remote (80% vs 11%) or restrictive (75% vs 6%) ventricular septal defect, and right ventricular hypoplasia (50% vs 0%; all, P < .05). The resulting rates of reoperation were similar between the groups (44.0% vs 37.5%; P = .24) and largely composed of conduit replacements in the Rastelli patients and valvular repairs or replacements in the Nikaidoh group. Rates of catheter-based interventions were also similar. CONCLUSIONS: These findings suggest that for the optimal treatment of conotruncal anomalies with discordant ventriculoarterial connections, procedural selection should be based on pathoanatomic criteria that can ensure patients undergo the operation most suited to their anatomy.

Congenital Heart Surgery Training Experiences and Perceptions Among Cardiothoracic Surgery Residents.

Interest and core training in congenital heart surgery (CHS) has not been characterized among current cardiothoracic surgical trainees. This study aimed to evaluate perceptions, interest, exposure, and experience among current trainees. A 22 question survey was distributed to all cardiothoracic surgical trainees in ACGME-accredited thoracic surgery residencies. Questions included demographics, exposure to CHS during, perceptions of, participation in and quality assessment of CHS training. There were 106 responses (20.1% response rate) of which 31 (29.0%) were female and 87 (81.3%) were cardiothoracic track. While 69 (64.5%) reported having an interest in CHS at some point during training, only 24 (22.4%) were actively pursuing CHS. All but 7 (6.5%) residents reported having easy access to congenital mentorship, with 35 (32.7%) actively participating in CHS research. Three months was the median duration of congenital rotations. Residents reported less operative participation on CHS compared to adult cardiac surgery. Several residents noted the need for earlier exposure and increased technical/operative experience as areas in need of improvement. The most cited primary influences to pursue CHS included: mentorship, breadth of pathology, and technical nature of the specialty. Lack of consistent job availability and length of additional training were reported as negative influences. Cardiothoracic residents report adequate exposure to obtain case requirements and knowledge for board examinations in CHS but highly variable operative involvement. Mentorship and early exposure remain important for those interested in CHS, while additional training time and limited job availability remain hurdles to CHS.

Predictors of Mediastinal Exploration While on Extracorporeal Membrane Oxygenation After Pediatric Cardiac Surgery.

Cardiac surgical patients requiring extracorporeal membrane oxygenation (ECMO) are at increased risk for hemorrhage due to necessary anticoagulation, in-situ cannulas, and disturbed hemostasis. We performed a retrospective, cross-sectional study of patients 0-18 years old in our cardiac intensive care unit (CICU) cannulated to ECMO within 48 h of cardiopulmonary bypass. The 69 patients included in the study were divided into three analysis groups based on serial chest tube output per hour: no bleeding (NB) on admission to the CICU (21/69, 30%), bleeding stopped (BS) with medical management (26/69, 38%), bleeding requiring emergent mediastinal exploration (BME) (22/69, 32%). The NB group had a more favorable coagulation profile upon admission to the CICU (PTT 53 s NB, 105 s BS, 83 s BME p < 0.001, ACT 169 s NB, 225 s BS, 211 s BME, p =0.013). Only chest tube output during the first three postcannulation hours remained associated with the need for mediastinal exploration by multivariable analysis. An average chest-tube output of 11.6 mL/kg/h during the first three hours had the highest percentage of patients classified correctly (84%) for requiring mediastinal exploration during their ECMO run (sensitivity 91%, specificity 81%).

The effect of receiving an award from the American Association for Thoracic Surgery Foundation.

Objective: This study's objective was to evaluate the scholastic and career effects of receiving either the American Association for Thoracic Surgery (AATS) Foundation research scholarship or surgical investigator program. Methods: AATS annual reports and recipient listings were used to generate the awardees. MEDLINE and SCOPUS were used to assess publications, citations, and H-Index for awardees. The National Institutes of Health (NIH) RePorter was used to collate NIH grant awarding to awardees. Publicly available institutional profiles were used to assess promotion status and leadership positions. Results: Awardees of the research scholarship had a median of 4733 citations and a median H-Index of 33. The surgical investigator program recipients had a median of 1346 citations with a median H-Index of 17. Across both funding mechanisms, 45% secured subsequent NIH funding. Most awardees received an academic promotion, with 62% of the research scholarship awardees promoted to full professor and 37% of the surgical investigator program to associate professor. Approximately half (48%) of all awardees hold leadership positions, with most being a clinical director or division chief. Conclusions: Receiving the AATS Foundation research scholarship or surgical investigator program positions early-career cardiothoracic surgeons for a promising future in academic surgery.

Standardized Aortic Valve Neocuspidization for Treatment of Aortic Valve Diseases.

BACKGROUND: Aortic valve replacement is the traditional surgical treatment for aortic valve diseases, yet standardized aortic valve neocuspidization (AVNeo) is a promising alternative that is gaining popularity. The purpose of this article is to review the available published literature of AVNeo using glutaraldehyde-treated autologous pericardium, also known as the Ozaki procedure, including indications, outcomes, potential benefits, and modes of failure for the reconstructed valve. METHODS: A comprehensive literature search was performed using keywords related to aortic valve repair, AVNeo, or Ozaki procedure. All articles describing performance of AVNeo were reviewed. RESULTS: Reported early mortality after AVNeo varies from 0% to 5.88%. The largest cohort of patients in the literature includes 850 patients with an inhospital mortality rate of 1.88%. Cumulative incidence of aortic valve reoperation was 4.2% in the largest series. Reoperation was uncommon and mainly due to infective endocarditis or degeneration of the reconstructed valve (most commonly due to aortic valve regurgitation, rather than stenosis). CONCLUSIONS: Aortic valve neocuspidization is a versatile and standardized alternative to aortic valve replacement with a biological prosthesis. Early to midterm outcomes from a number of centers are excellent and demonstrate the safety and durability of the procedure. Long-term outcomes and clinical trial data are necessary to determine which patients benefit the most from this procedure.

Aortic Root Replacement With Autologous Pericardium Valved Conduit.

Available aortic prosthesis replacement options present a challenge to achieving low perioperative morbidity, low pressure gradients, and prolonged durability. Trileaflet aortic valve reconstruction using autologous pericardium offers an alternative treatment option with excellent postoperative gradients, large effective orifice areas, and the avoidance of long-term anticoagulation. The modified Bentall procedure with either tissue xenograft valved conduit or mechanical valved conduit is considered the gold standard for patients with aortic root pathology requiring surgical replacement. We report a novel adaptation of the modified Bentall procedure with a self-fabricated valved conduit with trileaflet aortic valve neocuspidization using autologous pericardium.

High Risk Status for Stage I Palliation Increases Mortality After Stage II But Not Stage III.

BACKGROUND: High risk (HR) factors have been shown to have increased rates of mortality after stage 1 palliation (S1P) for single ventricle physiology. It remains unclear how initial HR status affects longitudinal outcomes after subsequent stage 2 palliation (S2P) and stage 3 palliation (S3P). METHODS: Single ventricle patients undergoing S1P between July 2004 and October 2018 at a single institution were included. Patients having one or more HR factors were considered to have HR status, with all others classified as low risk (LR). Longitudinal survival stratified by risk status was compared after each palliative stage, in addition to readmission and length of stay. Proportional hazards modeling was used to determine risk factors for longitudinal mortality. RESULTS: Of 132 patients presenting during the study for S1P, 57 (43.2%) were classified as HR. Overall 10-year survival was decreased in the HR cohort (P = .001). The HR patients were at significantly increased risk of death during interstage I (P = .01) and interstage II (P = .01), but survival was similar to that of LR patients after S3P (P = .31). Readmission rates after S2P were higher among HR patients (41.9% vs 22.5%, P = .029), but were similar after S3P. Length of stay was increased in the HR cohort after S2P (median 11 vs 9 days, P = .024) but similar to the LR group after S3P. Prematurity was the risk factor most consistently associated with increased mortality after all stages. CONCLUSIONS: A high risk status of patients undergoing S1P portends a higher risk of mortality, length of stay, and readmission after S2P. High-risk patients have survival similar to that of low-risk patients after S3P.

Utilization and Outcomes of the Nikaidoh, Rastelli, and REV Procedures: An Analysis of The Society of Thoracic Surgeons Congenital Heart Surgery Database.

BACKGROUND: Aortic root translocation (Nikaidoh), Rastelli, and réparation à l'etage ventriculaire (REV) are repair options for transposition of the great arteries (TGA) with ventricular septal defects and left ventricular outflow tract obstruction (VSD-LVOTO) or double outlet right ventricle TGA type (DORV-TGA). METHODS: This retrospective study using The Society of Thoracic Surgeons Congenital Heart Surgery Database evaluates surgical procedure utilization and outcomes of patients undergoing repair of TGA-VSD-LVOTO and DORV-TGA with a Nikaidoh, Rastelli, or REV procedure. RESULTS: A total of 293 patients underwent repair at 82 centers (January 2010 to June 2019). Most patients underwent a Rastelli (n = 165, 56.3%) or a Nikaidoh (n = 119, 40.6%) operation; only 3.1% (n = 9) underwent a REV. High-volume centers performed the majority of the repairs. Fewer Nikaidoh than Rastelli patients had prior cardiac operations (n = 57 [48.7%] vs n = 102 [63.0%]; P = .004). Nikaidohs had longer median cardiopulmonary bypass time (227 [interquartile range (IQR), 167-299] minutes vs 175 [IQR, 133-225] minutes; P < .001) and median aortic cross-clamp times (131 [IQR, 91-175] minutes vs 105 [IQR, 82-141] minutes; P = .0015). Operative mortality was 3.1% (95% confidence interval [CI], 1.0%-7.0%; n = 5) for Rastelli, 4.4% (95% CI, 1.4%-9.9%; n = 5) for Nikaidoh, and 11.1% (95% CI, 0.3%-48.3%, n = 1) for REV. The rates of cardiac arrest, unplanned reoperation, mechanical circulatory support, prolonged ventilation, and permanent pacemaker placement were higher in the Nikaidoh population but with 95% CIs overlapping those of the other procedures. CONCLUSIONS: Rastelli and Nikaidoh procedures are the prevalent repair strategies for patients with DORV-TGA and TGA-VSD-LVOTO. Most are performed at high-volume institutions, and early outcomes are similar.

The impact of coronavirus 2019 on general surgery residency: A national survey of program directors.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has had a widespread impact on graduate medical education. This survey aims to assess how general surgery residency programs adapted to the initial wave of the COVID-19 pandemic in the United States (US). MATERIALS AND METHODS: General surgery program directors (PDs) in the US were invited to partake in a 16-question survey between April 17 and May 1, 2020. The survey included questions about basic program information, clinical practice changes, changes to education structure, surgery resident clinical duties, and perceived impact on resident operative experience and future career choices. RESULTS: Forty-eight PDs completed the survey in the designated two-week period. Almost all (44/48, 91.7%) programs changed their didactic education to an online video conference-based format. Thirteen programs (27.1%) decreased the amount/frequency of formal education, and 13 (27.1%) reported canceling didactic education for some period of time. The majority of PDs (26/48, 54.2%) felt these changes had no impact on resident didactic participation, 14 (29.2%) reported an increase in participation, and 8 (16.7%) reported decreased participation. Ten programs (20.8%) redeployed residents to non-surgical services at the time of this survey, 30 (62.5%) have not redeployed residents but plan to if needed, and 8 (16.7%) did not have any plans to redeploy residents. CONCLUSIONS: The outbreak of COVID-19 has required general surgery residency PDs to change numerous aspects of resident education and clinical roles. Future inquiry is needed to assess if these changes lead to appreciable differences in resident preparedness and career selection.

Polytetrafluoroethylene Tricuspid Valved Conduit for Right Ventricular Outflow Tract Reconstruction.

The ideal conduit for reconstruction of the right ventricular outflow tract in pediatric patients remains a topic of discussion. We present a technique for construction of a handmade tricuspid valved polytetrafluoroethylene conduit for use in patients of all ages requiring right ventricular outflow tract reconstruction at the time of congenital cardiac surgery. This conduit provides an economically advantageous and readily available option globally when compared with homograft, without sacrificing surgical results.

A Risk Score for Adults With Congenital Heart Disease Undergoing Heart Transplantation.

BACKGROUND: This study derived and validated a risk score for 1-year mortality in patients with adult congenital heart disease (ACHD) undergoing orthotopic heart transplantation (OHT). METHODS: The United Network for Organ Sharing registry identified patients with ACHD (≥18 years of age) who underwent OHT between 1987 and 2018. The primary outcome was 1-year mortality. Associated covariates (univariate P < .2) were entered into a multivariable logistic regression model. Variable inclusion in the model was assessed by improvement in the McFadden pseudo-R2, likelihood ratio test, and C-index. A risk score was created using the absolute magnitude of the odds ratios from the derivation cohort, and its ability to predict 1-year mortality was tested in the validation cohort. RESULTS: A total of 1388 recipients were randomly divided into derivation (66.7%, n = 950) and validation (33.3%, n = 438) cohorts. A 13-point risk score incorporating 4 pretransplant variables (age, dialysis dependence, serum bilirubin level, and mechanical ventilation) was created. The predicted 1-year mortality ranged from 14.6% (0 points) to 49.9% (13 points) (P < .001). In weighted regression analysis, there was a strong correlation between predicted 1-year mortality and observed 1-year mortality in the validation cohort (r = 0.85, P < .001). Logistic regression also demonstrated a significant association (odds ratio, 1.18; 95% confidence interval, 1.1-1.3; P = .004). The Brier score of the composite score in the validation cohort was 0.14. Kaplan-Meier analysis demonstrated that risk scores of 4 points or higher portended worse survival at 1-year posttransplant (P < .001). CONCLUSIONS: This 13-point risk score for ACHD is predictive of mortality within 1 year after OHT and has potential utilization in improving recipient selection for OHT in adult patients with CHD.

The impact of COVID-19 on thoracic surgery residency programs in the US: A program director survey.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) has altered how the current generation of thoracic surgery residents are being trained. The aim of this survey was to determine how thoracic surgery program directors (PDs) are adapting to educating residents during the COVID-19 pandemic. METHODS: Thoracic surgery PDs of integrated, traditional (2 or 3 year), and combined 4 + 3 general/thoracic surgery training programs in the United States were surveyed between 17th April and 1st May 2020 during the peak of the COVID-19 pandemic in much of the United States. The 15-question electronic survey queried program status, changes to the baseline surgical practice, changes to didactic education, deployment/scheduling of residents, and effect of the pandemic on case logs and preparedness for resident graduation. RESULTS: All 23 institutions responding had ceased elective procedures, and most had switched to telemedicine clinic visits. Online virtual didactic sessions were implemented by 91% of programs, with most (69.6%) observing same or increased attendance. PDs reported that 82.7% of residents were on a non-standard schedule, with most being deployed in a 1 to 2 week on, 1 to 2 week off block schedule. Case volumes were affected for both junior and graduating trainees, but a majority of PDs report that graduating residents will graduate on time without perceived negative effect on first career/fellowship position. CONCLUSIONS: The COVID-19 pandemic has radically changed the educational approach of thoracic surgery programs. PDs are adapting educational delivery to optimize training and safety during the pandemic. Long-term effects remain uncertain and require additional study.

Bidirectional Glenn Procedure in Patients Less Than 3 Months of Age: A 14-Year Experience.

BACKGROUND: Contradictory data exist regarding timing of stage 2 palliation (S2P). Prolonged interstage hospitalizations and home surveillance programs have contributed to a more rapid progression to S2P. Our goal is to describe the S2P population and explore the relationships of clinical outcomes and S2P timing at our institution over the last 14 years. METHODS: S2P procedures from 2004 to 2018 at a single institution were included in a retrospective analysis. The analysis was stratified by S2P timing and clinical variables. The primary outcome was Fontan completion, and secondary outcomes included mortality and orthotopic heart transplantation rate, as well as perioperative clinical variables. RESULTS: A total of 114 patients who underwent S2P were included. The median age and weight at S2P were 100 days (interquartile range [IQR], 87-119) and 5.1 (IQR, 4.6-5.5) kg, respectively. The median age in the early group was 79 (IQR, 73-87) days and in the nonearly group was 107 (IQR, 100-124) days. Ninety percent of cavopulmonary anastomoses were augmented with an ePTFE (expanded polytetrafluoroethylene) patch. The overall Fontan completion rate was 76%, without differences in Kaplan-Meier estimates. There were no operative mortalities and no differences in late mortality rate (P = .30). CONCLUSIONS: The interstage period continues to be high risk for those undergoing single-ventricle palliation. In our experience, S2P performed at less than 90 days seems to be a viable and safe procedure when indicated, resulting in comparable Fontan completion rates.

The Fate of Homograft Versus Polytetrafluoroethylene Conduits After Neonatal Truncus Arteriosus Repair.

BACKGROUND: Despite significant improvement in outcomes with truncus arteriosus (TA) repair, right ventricular outflow tract (RVOT) reconstruction with a right ventricular to pulmonary artery (RV-to-PA) conduit remains a source of long-term reintervention and reoperation. This study evaluated our experience with reintervention in homograft and polytetrafluoroethylene (PTFE) RV-to-PA conduits in neonates. METHODS: Primary TA repairs from 2004 to 2016 at a single institution were included. Stratification was based on RVOT reconstruction with PTFE or homograft conduit. Primary outcome was operative conduit replacement. Secondary outcomes included the rates and types of catheter-based conduit interventions. RESULTS: Twenty-eight patients underwent primary TA repair and 89.3% (n = 25) of them had RVOT reconstruction with a homograft (28.0%, n = 7) or PTFE (72.0%, n = 18) conduit. Rates of reoperation for conduit replacement and catheter-based interventions were similar between those with PTFE and homograft conduits (85.7% vs 72.2%, P = .49 and 57.1% vs 83.3%, P = .11, respectively). Additionally, the median time to conduit replacement and catheter-based conduit interventions were comparable. In multivariable analysis, conduit size, but not conduit type, was a predictor of conduit revision (hazard ratio: 1.66, 95% confidence interval: 1.11-2.49, P = .02). At five-year and ten-year follow-up, patients with PTFE conduits had better survival than those with homograft conduits (100.0% vs 71.4%, P = .02); however, no mortalities were associated with conduit reoperations or catheter-based reinterventions. CONCLUSIONS: Polytetrafluoroethylene and homograft RVOT reconstruction in neonatal TA repair demonstrate similar durability as defined by reoperation and reintervention rates. The validation of the durability of PTFE conduits in neonatal TA repair requires confirmatory studies in larger cohorts.

A Novel Restorative Pulmonary Valve Conduit: Early Outcomes of Two Clinical Trials.

Objectives: We report the first use of a biorestorative valved conduit (Xeltis pulmonary valve-XPV) in children. Based on early follow-up data the valve design was modified; we report on the comparative performance of the two designs at 12 months post-implantation. Methods: Twelve children (six male) median age 5 (2 to 12) years and weight 17 (10 to 43) kg, had implantation of the first XPV valve design (XPV-1, group 1; 16 mm (n = 5), and 18 mm (n = 7). All had had previous surgery. Based on XPV performance at 12 months, the leaflet design was modified and an additional six children (five male) with complex malformations, median age 5 (3 to 9) years, and weight 21 (14 to 29) kg underwent implantation of the new XPV (XPV-2, group 2; 18 mm in all). For both subgroups, the 12 month clinical and echocardiographic outcomes were compared. Results: All patients in both groups have completed 12 months of follow-up. All are in NYHA functional class I. Seventeen of the 18 conduits have shown no evidence of progressive stenosis, dilation or aneurysm formation. Residual gradients of >40 mm Hg were observed in three patients in group 1 due to kinking of the conduit (n = 1), and peripheral stenosis of the branch pulmonary arteries (n = 2). In group 2, one patient developed rapidly progressive stenosis of the proximal conduit anastomosis, requiring conduit replacement. Five patients in group 1 developed severe pulmonary valve regurgitation (PI) due to prolapse of valve leaflet. In contrast, only one patient in group 2 developed more than mild PI at 12 months, which was not related to leaflet prolapse. Conclusions: The XPV, a biorestorative valved conduit, demonstrated promising early clinical outcomes in humans with 17 of 18 patients being free of reintervention at 1 year. Early onset PI seen in the XPV-1 version seems to have been corrected in the XPV-2, which has led to the approval of an FDA clinical trial. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02700100 and NCT03022708.