Histopathological Spectrum and Molecular Characterization of Liver Tumors in the Setting of Fontan-Associated Liver Disease.

PURPOSE: Univentricular heart is corrected with the Fontan procedure (FP). In the long term, so-called Fontan-associated liver diseases (FALDs) can develop. The aim of this study is to analyze the molecular profile of FALDs. METHODS: FALDs between January 1990 and December 2022 were reviewed for histology and immunohistochemistry, laboratory data, and images. Targeted next generation sequencing (NGS), performed on the DNA and RNA of both neoplastic and non-lesional liver tissue, was applied. RESULTS: A total of 31/208 nodules > 1 cm in diameter were identified on imaging, but a liver biopsy was available for five patient demonstrating the following: one hepatocellular adenoma (HA), two hepatocellular carcinomas (HCCs), one fibrolamellar carcinoma (FLC), and one intrahepatic cholangiocarcinoma (ICC). Molecular analysis showed a copy number alteration involving FGFR3 in three cases (two HCCs and one ICC) as well as one HCC with a hotspot mutation on the CTNNB1 and NRAS genes. Tumor mutational burden ranged from low to intermediate. A variant of uncertain significance in GNAS was present in two HCCs and in one ICC. The same molecular profile was observed in a non-lesional liver. A DNAJB1-PRKACA fusion was detected only in one FLC. CONCLUSIONS: Neoplastic FALDs show some unusual molecular profiles compared with non-Fontan ones. The presence of the same alterations in non-lesional cardiac cirrhosis could contribute to the development of FALD.

New Onset Cardiac Murmur and Exertional Dyspnea in an Apparently Healthy Child: A Rare Localization of Obstructive Myxoma in the Right Ventricle Outflow Tract without Pulmonary Embolization-A Case Report and Literature Review.

Myxomas are slowly growing benign neoplasms which are rare in children. Up to 80% can be located in the left atrium and generate symptoms such as embolism, cardiac failure, fever and weight loss. Rarely, myxomas can be detected in the right ventricle outflow tract, causing arrhythmias, pulmonary emboli and sudden death. We report the case of a 13-year-old healthy child brought to the Emergency Department (ED) of the Children's Hospital Bambino Gesù, Rome, for recent dyspnea, chest pain on exertion and new onset cardiac murmur. Patient underwent medical examination and echocardiogram with the finding of a rounded and lobulated voluminous mass in the right ventricle outflow tract (RVOT) which caused severe obstruction. The contrast computed tomography (CT) scan confirmed the presence of a heterogeneously enhancing soft-tissue mass occupying the RVOT with no evidence of pulmonary embolization. The mass was surgically excised, and the pathologic examination confirmed our suspicion of myxoma. Our experience suggests that myxoma can have mild clinical symptoms, the presentation may be non-specific, and diagnosis can be a challenge Careful examination and a diagnostic imaging workup, primarily with the transthoracic echocardiogram, are needful to make a rapid differential diagnosis and to better manage surgical treatment and follow-up.

Incidence and predictors of pericardial effusion following surgical closure of atrial septal defect in children: A single center experience.

Objectives: To evaluate the incidence of pericardial effusion (PE) after surgical atrial septal defect (ASD) closure and to investigate the presence of predictive risk factors for its development. Methods: We collected data from 203 patients followed at Bambino Gesù Children's Hospital of Rome who underwent cardiac surgery for ASD repair between January 2015 and September 2019. Results: A total of 200/203 patients with different types of ASD were included. Patients were divided into two groups: Group 1) 38 (19%) who developed PE and Group 2) 162 (81%) without PE. No differences were noted between the two groups with regard to gender or age at the surgery. Fever in the 48 h after surgery was significantly more frequent in group 1 than in group 2 (23.7 vs. 2.5%; p < 0.0001). ECG at discharge showed significant ST-segment elevation in children who developed PE, 24.3 vs. 2.0% in those who did not (p < 0.0001). Group 1 patients were divided into two subgroups on the basis of the severity of PE, namely, 31 (81.6%) with mild and 7 (18.4%) with moderate/severe PE. Patients with moderate/severe PE had a significantly higher BMI value (median 19.1 Kg/m2) (range 15.9-23.4, p = 0.004). Conclusion: The presence of fever and ST-segment elevation after surgery predicts subsequent development of PE suggesting a closer follow-up for these categories of patients. A higher BMI appears to be associated with a higher risk of moderate/severe PE.

Late outcome of extracardiac Fontan patients: 32 years of follow-up.

OBJECTIVES: We sought to evaluate the long-term survival and risk factors for morbidity and mortality in our cohort of patients after extracardiac (EC) Fontan. METHODS: We collected and analysed follow-up data until September 2020 for all patients who underwent EC Fontan operation at our institution from November 1988 to November 2015. RESULTS: Out of 406 patients treated with EC Fontan at a mean age of 5.4 ± 4.5 years, 372 (91.6%) were discharged home; 15% were lost to follow-up. The median follow-up was 14.6 years (interquartile range 8.7-20.3). Two hundred patients (54%) had a good long-term outcome, with an event-free long-term survival, but late adverse events of any kind needing interventional or surgical reoperations were reported in 128 patients (34%). Forty-four patients (12%) developed late Fontan failure. Thirty-seven survivors (10%) had late arrhythmias, with the need for pacemaker implantation. Obstruction of the cavopulmonary pathway occurred in 49 patients (13%), but just 8 patients needed conduit surgical replacement. At 32 years, the survival probability was 84%. The risk of orthotopic heart transplant, considering death as a competing event (showed as cumulative incidence), was 12.5%. A preoperative diagnosis of hypoplastic left heart syndrome was an independent risk factor for the need for heart transplant. CONCLUSIONS: The EC Fontan shows satisfactory long-term survival and low incidence of adverse events and late failure. Conduit replacement is rare, and its longevity may not represent a substantial issue in these patients. However, as with other technical variants, the need for reoperations during long-term follow-up is a significant challenge.

Predictors of survival in paediatric mitral valve surgery: the impact of age at operation at late follow-up.

OBJECTIVES: The aim of this study was to elucidate predictors of death and reintervention after mitral valve (MV) surgery in children. METHODS: A single-centre retrospective study was performed enrolling 142 patients younger than 18 years who underwent primary index surgical mitral repair or replacement at Bambino Gesù Children's Hospital in Rome from July 1982 to April 2020. Patients with complete, transitional or partial atrioventricular septal defect and patients with single ventricle physiology were excluded. Patients were stratified according to the age group: group 1 (<1 year old), group 2 (1-5 years old) and group 3 (>5 years old). The composite primary outcome was freedom from death or transplant. The secondary outcome was freedom from redo MV surgery. RESULTS: Transplant-free survival was 89% at 5 years and 88% at 10 years. Stratified by age, group 1 had poorer outcome in comparison with other groups (log-rank test P = 0.105). Both univariate and multivariate analyses showed that age <1 year was a significant risk factor for death or transplant (P = 0.044). Age <1 year was associated with increased risk of reoperation (aHR = 3.38, P = 0.009), while the presence of genetic syndrome (aHR = 0.22) and preoperative EF% (aHR = 0.97) were protective factors for reoperation. CONCLUSIONS: The overall survival and freedom from reoperation in children undergoing MV surgery still need improvements. Younger age was a significant risk factor for death and reintervention both after repair and replacement of the MV. In particular, infants and neonates have a three-fold risk for death compared to children.

Ascending aortic extension to increase aortopulmonary space after comprehensive stage II palliation.

Aortic reconstruction at the time of the comprehensive stage II (CSII) procedure can be complicated by compression within the aortopulmonary space resulting in airway or pulmonary artery narrowing. We describe our experience with 2 patients with hypoplastic left heart syndrome and pulmonary artery stenosis after the CSII procedure. Both patients underwent an aortic extension with a Hemashield interposition graft to open up the aortopulmonary space. The patients were discharged from the hospital. In all cases the aortopulmonary space was enlarged, and the pulmonary arteries and airway were free from compression. Aortic extension is an option to be considered in children with pulmonary artery compression who previously had a CSII procedure.

Use of Transcarotid IMPELLA 2.5 Axial-Flow Pump Device for Left Ventricle Unloading During VA-ECMO Support in Pediatric Acute Heart Failure.

An alternative strategy for left ventricular (LV) venting during short-term mechanical circulatory support is use of Impella axial-flow pump. We present our transcarotid Impella 2.5 implantation technique using a polytetrafluoroethylene graft, in two children with acute heart failure treated primarily with venoarterial ECMO. The venoarterial extracorporeal membrane oxygenator and Impella support were maintained for 5 and 17 days, respectively. Transcarotid Impella implantation might be an alternative and feasible option in pediatrics patients affected by severe LV failure, as a bridge to decision or bridge to candidacy. Potentially, the Impella 2.5 device provides less invasive support for children with heart failure.

Use of carotid artery cannulation during redo sternotomy in congenital cardiac surgery: a single-centre experience.

OBJECTIVES: Management of resternotomy is often a difficult challenge in patients with congenital diseases who have undergone multiple sternotomies. Our goal was to report our single-centre experience with carotid cannulation using a graft interposed during redo sternotomy in complex cardiac reintervention procedures. METHODS: We performed a retrospective review of all patients who had undergone complex redo sternotomies between January 2019 and May 2020 utilizing a cervical cannulation technique with a Gore-Tex graft interposed on the carotid artery. We classified our population study on the basis of the primary diagnosis and the type of surgery. The primary outcomes of our analysis were the evaluation of the safety of the procedure in terms of survival and freedom from neurological events. RESULTS: We analysed 22 patients who had undergone previous complex operations. The median age and weight at the time of reintervention were 130.35 (range 0.46-435) months and 31.5 (range 2.2-85) kg, respectively. Composite graft carotid cannulation provided adequate arterial flow in all patients with a median arterial flow of 3.5 l/min/m2 (range 0.6-6). One major cardiac injury occurred during sternotomy when emergency cardiopulmonary bypass (CPB) was initiated. Moreover, during their hospital stays, all patients had an uneventful recovery without neurological or vascular complications and no cervical wound infections. CONCLUSIONS: Carotid cannulation using interposition of a side graft on the common carotid artery for arterial inflow is a reliable and safe method for initiation of CPB in complex redo surgeries in patients with congenital disease. Complications directly associated with this type of cannulation are uncommon and allow surgical re-entry with overall low risks.

Predictors of survival in paediatric mitral valve replacement.

OBJECTIVES: The aim of this study was to identify the predictors of death and of reintervention after mitral valve replacement (MVR) in children. METHODS: A single-centre retrospective study was performed including 115 patients under the age of 18 undergoing MVR between 1982 and 2019. For all patients, the ratio of prosthetic valve size (diameter in mm) to weight (kg) at surgery was calculated and long-term result was assessed. The primary outcome was freedom from mitral valve (MV) re-replacement. The composite secondary outcome was freedom from death or transplant. RESULTS: Fifty-four patients had a previous surgical attempt to MV repair. The median age at surgery was 5.5 years (interquartile range 1.21-9.87). Death/transplant-free survival was 77 ± 4% at 5 years and 72 ± 5% at 10 years. Univariate analysis showed a size/weight ratio higher than 2 and age <2 years as significant risk factors for death or transplant. Freedom from MV re-replacement at 5 and 10 years was 90 ± 3% and 72 ± 6%, respectively. Biological prosthesis implanted at first replacement (P = 0.007) and size/weight ratio higher than 2 (P = 0.048) were predictors of reoperation. Significant upsizing (P < 0.0001) of mitral prosthesis was observed at re-replacement. CONCLUSIONS: MVR is a viable strategy in children with unrepairable MV disease. Mortality can be predicted based on size/weight ratio and age <2 years. MV re-replacement can be performed with low morbidity and mortality and a larger-size prosthesis can often be placed at the time of redo.

Long-term veno-arterial extracorporeal membrane oxygenation as a bridge to heart-lung transplant.

En bloc heart-lung transplantation still represents definitive therapy for end-stage cardiopulmonary failure. However, patients may critically decompensate while awaiting suitable donor organs and necessitate veno-arterial extracorporeal membrane oxygenation. In this article, we describe the combined use of central cannulation with the Berlin Heart EXCOR ventricular assist device cannulae and the CentriMag centrifugal pump as an extended bridge to heart-lung transplantation in three pediatric patients.

Outcome for Conservative Surgery for the Correction of Severe Mitral Valve Regurgitation in Children: A Single-Center Experience.

Evolving reconstructive techniques have progressively become the preferred approach for treatment of pediatric mitral valve regurgitation. We present our experience in a cohort of patients undergoing surgical correction for severe mitral regurgitation. Fifty-five patients (age 1 month-18 years; median 5 years) were included in the present analysis. Different surgical techniques were used (posterior leaflet augmentation in 25, isolated cleft closure in 12, Alfieri-type procedure in 10, annuloplasty in 5, with artificial chordae in 2, and quadrangular resection with chordal transposition in 1). Follow-up time ranged from 1 to 192 months (median 38[IQR 12-54] months). Operative and follow-up mortality was 0%. Reintervention in the whole population occurred in 31% of patients. However, when first surgery was performed under 2 years of age (no = 17), reintervention reached nearly 50%. The degree of residual mitral regurgitation at follow-up remained stable after surgery, while a significant increase in mean transmitral gradient was observed over time (paired t test = 0.03). In multivariable Cox-regression analysis, post-surgical transmitral gradient was the only independent predictor for reintervention (p = 0.017; HR 2.4; 95%CI 1.2-5.1), after correcting for differences in age at surgery, type of reintervention, mitral annulus dimension, and BSA at the first surgery. ROC curve demonstrated that a post-surgical transmitral mean gradient value > 5 mmHg, was predictive for reintervention (AUC = 0.89; Youden index = 0.44). Our study suggests that the use of conservative technique strategy achieves satisfactory functional results in infants and children with severe MR, although the rate of reoperation in younger patients remains substantial. Post-operative moderate mitral stenosis was the strongest predictor for reoperation.

Impact of complex congenital heart disease on the prevalence of arterial hypertension after aortic coarctation repair.

OBJECTIVES: This study was designed to evaluate the difference in the prevalence of long-term arterial hypertension among patients with corrected aortic coarctation according to the existence of associated cardiac congenital lesions. METHODS: We identified 235 patients who had undergone surgery for aortic coarctation and classified them into 2 groups: patients with isolated coarctation of the aorta (CoA) and patients with aortic coarctation associated with complex congenital heart disease. Data were retrospectively analysed. RESULTS: There were 148 subjects with isolated CoA and 87 with complex CoA (CoA-c). Patients were defined as hypertensive if they required antihypertensive treatment and/or when blood pressure was above 95th percentile. Patients with isolated aortic coarctation were significantly younger than patients with CoA-c (P < 0.001) and a markedly higher prevalence of arterial hypertension (44% vs 24%) was documented in the isolated coarctation group. The difference in the prevalence of hypertension in the 2 groups was still significant after correcting for differences in age (P < 0.001), confirming that the prevalence of arterial hypertension in patients with CoA-c was half of that of patients with isolated CoA. CONCLUSIONS: We conclude that complex congenital heart disease in patients who have undergone surgical correction for aortic coarctation results in a significantly lower prevalence of late-onset hypertension. Reduced systemic flow and pressure before surgery in patients with CoA-c might be associated with a lower rate of arterial hypertension.

Midterm Echocardiographic Assessment of Right Ventricular Function After Midline Unifocalization.

BACKGROUND: Patients with an open ventricular septal defect (VSD) after repair of pulmonary atresia (PA), VSD, and major aortopulmonary collaterals (MAPCAs) are the most vulnerable subgroup. We analyzed the impact of concomitant versus delayed VSD closure on survival and intermediate-term right ventricular (RV) function. METHODS: Between October 1996 and February 2017, 96 patients underwent a pulmonary flow study-aided repair of PA/VSD/MAPCAs. For patients who underwent either concomitant or delayed intracardiac repair, echocardiographic RV systolic function was retrospectively calculated to assess (1) RV fractional area change (RVFAC) and (2) two-dimensional RV longitudinal strain (RVLS) of the free wall of the right ventricle. QLAB cardiac analysis software version 10.3 (Philips Medical Systems, Andover, MA) was used for analysis. RESULTS: A total of 64 patients underwent concomitant VSD closure at the time of unifocalization, and 16 patients underwent delayed VSD closure at a median of 2.3 years (range: 3 days to 7.4 years). At a median follow-up of 8.1 years (range: 0.1 to 19.5 years) for the concomitant repair group versus 7.4 years (range: 0.01 to 15.3 years) for the delayed repair group, no differences in RVFAC and RVLS were observed (RVFAC: 41.0% ± 6.2% versus 41.2% ± 7.6%, p = 0.91; RVLS: -18.7 ± 4.3 versus -18.9 ± 4.0, p = 0.87). CONCLUSIONS: Patients (83%) with PA/VSD/MAPCAs underwent complete repair at intermediate-term follow-up with preserved RV function. Delayed VSD closure was accomplished in 50% of the patients initially deemed unsuitable for repair. Delayed VSD closure did not affect survival and did not portend impaired RV systolic function.

Bradyarrhythmias in Repaired Atrioventricular Septal Defects: Single-Center Experience Based on 34 Years of Follow-Up of 522 Patients.

Atrioventricular Septal Defect (AVSD) is a rare congenital heart defect (CHD) often associated with genetic syndromes, most commonly Down syndrome (DS). Over the last four decades, surgical repair has increased survival and improved quality of life in these patients. The prevalence of bradyarrhythmias namely, atrioventricular block (AVB) and sinus node dysfunction (SND) in AVSD is partially known. 522 cases with both partial and complete AVSD (38.7% with DS), undergoing intracardiac repair from 1982 to 2016 at our institution, were reviewed from our system database. 38 (7.3%) patients received permanent PM implantation for AVB (early or late) or SND. On one hand, AVB requiring PM was found in 26 (4.98%). This was further subdivided into early-onset 14 (2.6%) and late-onset AVB 12 (2.2%) (median 4 [IQR 1-7] years). On the other hand, 12 (2.3%) experienced late SND requiring PM (median 11 [IQR 3.5-15.2] years). Early and late AVB were independent from the type of AVSD (partial or complete), whereas the late SND was remarkably observed in complete AVSD compared to partial AVSD (p = 0.017). We classified the cohort into two main categories: DS (202, 38.7%) and non-DS (320, 61.3%). At Kaplan-Meier survival analysis, DS was significantly associated with late-onset bradyarrhythmias (p = 0.024). At Cox regression analysis, we identified DS as an independent predictor of PM implantation (HR 2.17). In conclusion, about 7% of repaired AVSD patients need PM implantation during follow-up. There are no differences in early and late AVB occurrence according to the type of AVSD. There is a higher incidence of late SND in repaired complete AVSD, with a later timing onset in patients with associated DS. Moreover, DS seems to be an independent predictor of PM implantation.

Mechanically Assisted Total Cavopulmonary Connection With an Axial Flow Pump: Computational and In Vivo Study.

A relevant number of patients undergoing total cavopulmonary connection (TCPC) experience heart failure (HF). Heart transplant is then the final option when all other treatments fail. The axial flow blood pumps are now the state of the art; however, there is little experience in low-pressure circuits, such as support of the right ventricle or even a TCPC circulation. A new T-shaped model of mechanically assisted TCPC using the "Jarvik Child 2000" axial pump, (flow rates between 1 and 3 L/m in a range of 5000-9000 rpm) was designed, simulated numerically, and then tested in animals. Eight sheep (42-45 kg) were studied: two pilot studies, four pump-supported (PS) TCPC for 3 h, and two not pump-supported (NPS) TCPC. In the PS, the axial pump was set to maintain the baseline cardiac output (CO). Pressures, CO, systemic and pulmonary vascular resistance, lactate levels, and blood gases were recorded for 3 h. Computational fluid dynamics (CFD) study allows us to set the feasible operating condition and the safety margins to minimize the venous collapse risk. In the NPS animals, a circulatory deterioration, with increasing lactate level, occurred rapidly. In the PS animals, there was a stable cardiac index of 2.7 ± 1.4 L/min/m(2), central venous pressure of 12.3 ± 1 mm Hg, and a mean pulmonary artery pressure (PAP) of 18.1 ± 6 after 3 h of support up to 9000 rpm. systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), blood gasses, and arterial lactate levels remained stable to baseline values. No caval collapse occurred. A new pediatric axial flow pump provides normal CO and physiologic stability in a new T-shaped model of TCPC in sheep, in vivo. CFD and in vivo data showed that this experimental arrangement will allow us to evaluate the potential for mechanical support in patients with Fontan failure avoiding major adverse events.

Vacuum-assisted closure system in newborns after cardiac surgery.

OBJECTIVE: To analyze the effectiveness and the results of the use of a vacuum-assisted closure (VAC) system for the treatment of complex sternal wounds in newborns after cardiac surgery. METHODS: From May 2008 until December 2012, six patients developed post-sternotomy wound problems (large defects of epithelialization or mediastinitis), which were treated with a VAC system. Median age at the time of institution of VAC was 24.5 days (range 16 to 65 days). Median time of treatment was 14 days (range 3 to 42 days). RESULTS: All patients were newborns and all underwent delayed sternal closure after cardiac surgery. The indications for using the VAC system were: mediastinitis in two patients (33.3%) and impairment of healing without signs of infection in four (66.7%). All children after VAC therapy achieved healing of the sternal wound. VAC therapy was started with high negative pressures (-125 mmHg) continuously then switched to an intermittent modality in all patients. CONCLUSION: VAC system with high negative pressure is safe, effective, and is a well-tolerated therapy in newborns with complex sternal wounds.

Two decades of experience with the Ross operation in neonates, infants and children from the Italian Paediatric Ross Registry.

OBJECTIVE: Children undergoing Ross operation were expected to have longer autograft, but shorter homograft durability compared with adults. In order to define the outcome in the second decade after Ross operation in children, a nationwide review of 23 years of experience was undertaken. METHODS: 305 children underwent Ross operation in 11 paediatric units between 1990 and 2012. Age at surgery was 9.4±5.7 years, indication aortic stenosis in 103 patients, regurgitation in 109 and mixed lesion in 93. 116 (38%) patients had prior procedures. Root replacement was performed in 201 patients, inclusion cylinder in 14, subcoronary grafting in 17 and Ross-Konno in 73. RESULTS: There were 10 (3.3%) hospital and 12 late deaths (median follow-up 8.7 years). Survival was 93±2% and 89±3% and freedom from any reoperation was 76±3% and 67±6% at 10 and 15 years. 34 children had autograft 37 reoperations (25 replacement, 12 repair): three required transplantation after reoperation. Freedom from autograft reoperation was 86±3% and 75±6% at 10 and 15 years. 32 children had right heart redo procedures, and only 25 (78%) conduit replacements (15-year freedom from replacement, 89±4%). Prior operation (p=0.031), subcoronary implant (p=0.025) and concomitant surgical procedure (p=0.004) were risk factors for left heart reoperation, while infant age (p=0.015) was for right heart. The majority (87%) of late survivors were in NYHA class I, 68% free from medication and six women had pregnancies. CONCLUSIONS: Despite low hospital risk and satisfactory late survival, paediatric Ross operation bears substantial valve-related morbidity in the first two decades. Contrary to expectation, autograft reoperation is more common than homograft.

The Ross procedure in patients aged less than 18 years: the midterm results.

OBJECTIVE: This study reviews a single-center experience with the Ross procedure in infants and young children. METHODS: From November 1993 to March 2012, 55 children aged less than 17 years underwent a Ross procedure. The patients ranged in age from 2 days to 17 years (median, 5.9 years). Thirteen patients were infants, and 18 patients were preschool children. The predominant indication for the Ross procedure was aortic stenosis. Twenty-seven patients (49%) with left ventricular outflow tract obstruction underwent a modified Ross-Konno procedure. Twenty-five patients (45%) had undergone 40 previous cardiac procedures. Preoperatively, 3 patients showed severe left ventricular dysfunction, with 2 of the patients requiring intubation and inotropic support. Concomitant procedures were performed in 11 patients (20%). Nine patients underwent mitral valve surgery, and 2 patients underwent subaortic membrane resection. RESULTS: Patients were followed up for a median of 66 months (range, 3 months to 17 years). Overall survival at 1, 2, 5, and 10 years was 84.9%. Hospital mortality rate was 13% (7/55 patients). All deaths occurred in neonates or infants, except 1 who was aged less than 4 years. Freedom from reoperation for autograft failure was 100% at 1 year, 96.7% at 5 years, and 73.7% at 10 years. During follow-up, 7 patients required a reoperation on the autograft for dilatation and severe aortic insufficiency. Freedom from reoperation for the right ventricular outflow tract replacement was 56.1% at 10 years. CONCLUSIONS: The low rate of autograft failure demonstrates that the Ross procedure is an attractive option for the management of aortic valve disease and complex left ventricular outflow tract obstruction in the pediatric population. However, alternative options must be considered in adolescents and young adults.