Infant Heart Transplant Recipients Research Articles

Risk Factors for Severe Primary Graft Dysfunction in Infants Following Heart Transplant

BackgroundPrevious studies suggest that infant heart transplant (HT) recipients are at higher risk of developing severe primary graft dysfunction (PGD) than older children. We sought to identify risk factors for developing severe PGD in infant HT recipients.Methods and ResultsWe identified all HT recipients aged <1 year in the United States during 1996 to 2015 using the Organ Procurement and Transplant Network database. We linked their data to ELSO (Extracorporeal Life Support Organization) registry data to identify those with severe PGD, defined by initiation of extracorporeal membrane oxygenation support for PGD within 2 days following HT. We used multivariable logistic regression to assess risk factors for developing severe PGD. Of 1718 infants analyzed, 600 (35%) were <90 days old and 1079 (63%) had congenital heart disease. Overall, 134 (7.8%) developed severe PGD; 95 (71%) were initiated on extracorporeal membrane oxygenation support on the day of HT, 34 (25%) the next day, and 5 (4%) the following day. In adjusted analysis, recipient congenital heart disease, extracorporeal membrane oxygenation, or biventricular assist device support at transplant, recipient blood type AB, donor‐recipient weight ratio <0.9, and graft ischemic time ≥4 hours were independently associated with developing severe PGD whereas left ventricular assist device support at HT was not. One‐year graft survival was 48% in infants with severe PGD versus 87% without severe PGD.ConclusionsInfant HT recipients with severe PGD have poor graft survival. Although some recipient‐level risk factors are nonmodifiable, avoiding modifiable risk factors may mitigate further risk in infants at high risk of developing severe PGD.

Outcomes From Three Decades of Infant and Pediatric Heart Transplantation.

Infants are a unique transplant population due to a suspected immunologic advantage, in addition to differences in size and physiology. Consequently, we expect infants to have significantly different diagnoses, comorbidities, and outcomes than pediatric transplant recipients. In this study, we compare patterns and trends in pediatric and infant heart transplantation during three decades. The United Network for Organ Sharing (UNOS) database was queried for transplants occurring between January 1990 and December 2018. Patients were categorized as pediatric (1-17) or infant (0-1). Congenital heart disease (CHD) primary diagnoses have increased from 37% to 42% in pediatric patients (p = 0.001) and decreased from 80% to 61% in infants during the 1990s and 2010s (p < 0.001). Those with CHD had worse outcomes in both age groups (p < 0.001). Infants who underwent ABO-incompatible transplants had similar survival as compared to those with compatible transplants (p = 0.18). Overall, infants had better long-term survival and long-term graft survival than pediatric patients; however, they had worse short-term survival (p < 0.001). Death due to rejection or graft failure was less likely in infants (p = 0.034). However, death from infection was over twice as common (p < 0.001). In summary, pediatric and infant heart transplant recipients differ in diagnoses, comorbidities, and outcomes, necessitating different care for these populations.

Donor-specific anti-HLA antibody production following pediatric ABO-incompatible heart transplantation.

ABO-i heart transplantation can be performed in infants with end-stage heart failure to increase organ availability. The development of newly detected DSAs is associated with decreased cardiac graft survival, and the effect of ABO-i transplantation on DSA production is unknown. We examined DSA production and rejection frequency in infant recipients of ABO-i and ABO-c heart transplants via a retrospective cohort study of infant heart transplant recipients transplanted at a single pediatric center between January 2004 and November 2014. Patients were included if they were less than 1year of age at transplant and had a minimum of 6months follow-up. DSA positivity was examined under two categories, either the lowest level detectable (MFI>500) or a level presumed to have clinical relevance in our immunogenetics laboratory (MFI > 5000). Of 52 patients, 36 received ABO-c transplants and 16 received ABO-i transplants. Compared to ABO-c recipients, the ABO-i group showed a consistent but statistically non-significant finding of less frequent ndDSA positivity (69.4% ABO-c vs 43.8% ABO-i with MFI >500, P=0.122; 41.7% ABO-c vs 25% ABO-i with MFI >5000, P=0.353). Additionally, ABO-i patients were less likely to have any form of rejection (12.5% vs 47.2%, P=0.027) or acute cellular rejection (6.3% vs 38.9%, P=0.021). Our data suggest that infants receiving ABO-i heart transplants may be less likely to develop ndDSAs or have rejection compared to same age ABO-c recipients. Larger multicenter studies are needed to confirm results from this single center study.

Status on Heart Transplantation in China.

Status on Heart Transplantation in China.

(896) - Single Drug Immunosuppression for Infant Heart Transplant Recipients

Infant heart transplant (HT) recipients may have increased immune tolerance of their grafts. Thus, they may tolerate single-drug immunosuppression (SD). This study compared graft failure and mortality of patients transitioned to SD to those maintained on multi-drug immunosuppression (MD).

Abstract 17246: Predictors for Listing for Transplant in Infants with Hypoplastic Left Heart Syndrome : an analysis of the Single Ventricle Reconstruction Trial

Background: Infants with Hypoplastic Left Heart Syndrome (HLHS) following the Norwood procedure have the worst survival among infant heart transplant (HT) recipients. The Single Ventricle Reconstruction (SVR) trial collected vital status and HT data in 920 eligible patients (pts) and prospective preoperative, operative and post-operative data in 554 randomized pts. This trial provides a unique opportunity to evaluate predictors of the need for HT in HLHS infants. Methods: The public use SVR database was used to analyze factors associated with listing for HT and mortality on the wait list and in HT pts. Pts listed for HT were compared with those who survived without listing. Results: Among 920 eligible pts, 41 were listed for HT and follow up data was available in 33/554 pts. 25 pts underwent HT. The median age at listing was 135 days (6 [[Unable to Display Character: &amp;#8211;]] 713 days). All pts listed were status 1A, except for 2 at status 7 and 1 at status 2. Mean RV fractional area change at birth was significantly lower in the listed group (29±8% vs.35±9, p&lt;0.05). ECMO/ CPR, and need for pacemaker were also more common in listed pts compared to the unlisted group. Gestational age, anatomic diagnosis of aortic atresia, AV valve insufficiency and the number of catheterization interventions were not risk factors for HT listing. The median time from listing to HT was 47 days (2 - 340 days). ECMO or VAD support was used in 10 pts prior to HT. Wait list mortality was 29% with a median time to death of 134 days (10 [[Unable to Display Character: &amp;#8211;]] 707 days). Causes of death on the wait list included cardiac (8 pts), renal (1 pt), surgical (1 pt) and other (2pts). Mortality after HT was 36% with a median time to death of 197 days (48-658 days). Overall mortality after listing, including after HT, was 51%; younger age at listing was associated with increased mortality (292 vs 149 days, p&lt;0.04). Conclusion: HT as a rescue procedure for HLHS in the first year of life carries a significant risk of mortality.

Failure of Neonatal B-Cell Tolerance Induction by ABO-Incompatible Kidney Grafts in Piglets

ABO-incompatible (ABOi) infant heart transplantation results in B-cell tolerance to graft A/B antigens, confirming human susceptibility to acquired immunologic or "neonatal" tolerance as described originally in murine models. Starting with this clinical observation, we sought to model neonatal ABOi organ transplantation to allow mechanistic studies of tolerance. Plasma anti-A/B antibodies were measured over time in piglets to establish developmental antibody kinetics. Blood group O piglets received kidney allografts from group A (AO-incompatible) or group O (AO-compatible) donors under cyclosporine immunosuppression. Anti-A antibodies were measured serially after transplantation; A/H antigen expression and allograft rejection were assessed in graft biopsies. Anti-A antibodies developed in naïve piglets in a kinetic pattern analogous to human infants; anti-B remained low. After transplantation, anti-A antibodies developed similarly in AO-incompatible and AO-compatible groups and were not suppressed by cyclosporine. A/H antigen expression was persistent in all graft biopsies; however, A/H antigens were not detected in vascular endothelium. Cellular and antibody-mediated rejection was absent or minimal in early and late biopsies in both groups, with one exception. Naturally delayed isohemagglutinin production in piglets is analogous to the developmental kinetics in human infants. However, in contrast to deficient anti-A antibody production as seen long-term after "A-into-O" infant heart transplant recipients, normal anti-A antibody production after "A-into-O" piglet kidney transplantation indicates that tolerance did not develop despite graft A antigen persistence. These findings suggest that the impact on the host immune system of exposure to nonself ABH antigens during early life in human heart versus porcine kidney grafts may depend on expression in vascular endothelium.

Pediatric Thymic Tissue as a Source of Regulatory T Cells for Cellular Therapy

Purpose Infant heart transplant (HTx) recipients have better graft survival than older recipients. Nonetheless, due to need for lifelong therapy, infants carry a heavier immunosuppressive burden. Cellular therapy using regulatory T cells (Tregs) to suppress graft-directed immune responses would greatly benefit these infants. A major challenge is generating a large quantity of stable, suppressive Tregs. During infant cardiac surgery, thymectomy is usually performed to gain exposure of the retrosternal operative field. We studied the potential of thymic tissue as a source of CD25+FOXP3+ Tregs. Methods and Materials Thymuses (n=8) were obtained during pediatric cardiac surgery; thymocytes were recovered through mechanical dissociation. FOXP3+ cells were sorted by automated magnetic cell separation of CD25+ cells and expanded with αCD3, IL-2, rapamycin and CD32+ L-cells; CD25- cells were used as controls. FOXP3 and intracellular cytokine staining were done to define characteristics. Suppressive capacity was determined by co-culturing expanded cells with αCD3/CD28-stimulated peripheral blood mononuclear cells (PBMC) and analyzing proliferative responses by Cell Proliferation ELISA. Results FOXP3+ cell frequency within total thymocytes ranged from 2.2 to 3.2%. Isolated CD25+ cells were 72% positive for FOXP3 (median, range: 60-81%). After two weeks of culture, we observed a 4 to 48-fold expansion of CD25+ cells with >95% viability; 0.4 to 25-fold expansion was observed for control cells with 49–88% viability. Expanded CD25+ cells were >90% FOXP3+ and produced no IL-2 or IFN-γ, whereas control cells were 50% at a 1:10 ratio of Tregs:PBMC. Conclusions Highly suppressive FOXP3+ Tregs can be expanded from CD25+ thymocytes isolated from pediatric thymic tissue, indicating that explanted thymuses may be a source of Tregs for cellular therapy for infant HTx recipients.

Expansion of Highly Suppressive FOXP3+ Regulatory T Cells from Pediatric Thymic Tissue

Introduction: Infant heart transplant (HTx) recipients have better graft survival than patients transplanted at older ages. Nonetheless, due to lifelong need for therapy, infant HTx recipients can expect to carry an immunosuppressive heavier burden, resulting in substantial morbidities from adverse drug effects. Development of a cellular therapy using regulatory T cells (Tregs) to suppress graft-directed immune responses would greatly benefit these infants. A major challenge for such a therapy, however, is generating a large quantity of stable, highly suppressive Tregs. Infants undergoing HTx usually have thymectomy in order to gain adequate exposure of the retrosternal operative field. We investigated the potential of explanted thymic tissue as a source for isolation and expansion of highly suppressive CD4+CD25+CD127lowFOXP3+ Tregs. Methodology: Thymic tissue (n=3) was obtained from thymectomy during pediatric cardiac surgery and thymocytes were recovered through mechanical dissociation. FOXP3+ cells were isolated by automated magnetic cell separation of CD4+CD127lowCD25+ thymocytes. CD4+CD127low-depleted cells were used as controls. Cells were expanded for two weeks by stimulation with anti-CD3, IL-2, rapamycin and CD32+ L cells. FOXP3 and intracellular cytokine staining was performed to define characteristics of expanded cells. The suppressive capacity after expansion was determined by co-culturing the expanded cells with PKH-labeled anti-CD3/CD28-stimulated peripheral blood mononuclear cells (PBMC) and analyzing proliferative responses by flow cytometry. Results: CD4+CD25+CD127lowFOXP3+ cell frequency within the total thymocyte population ranged from 2.8 to 7.9%. Isolated CD4+CD25+CD127low cell populations were 65-84% positive for FOXP3. After two weeks of culture, we observed a 4 to 40-fold expansion of CD4+CD25+CD127low cells with >95% viability; 0.4 to 25-fold expansion was observed for control cells with 49-88% viability. The expanded CD4+CD25+CD127low cells were >95% FOXP3+ and produced no IL-2 or IFN-γ, whereas control cells were < 14% FOXP3+ and 58-65% produced IFN-γ. Moreover, in contrast to control cells, expanded CD4+CD25+CD127lowFOXP3+ cells were highly potent suppressors, efficiently suppressing the frequency of proliferating PBMC >80% even at a 1:20 ratio of Tregs:PBMC. Conclusion: In this preliminary study, we showed that highly suppressive FOXP3+ Tregs can be expanded from CD4+CD25+CD127low T cells isolated from pediatric thymic tissue, indicating that explanted thymuses may be a potential source for isolation and expansion of Tregs for cellular therapy. Future work includes defining the stability of expanded Tregs and their suppressive capacity of alloantigen immune responses.

602 Increased Risk of Autoimmune and Severe Atopic Disease in Infant Heart Transplant Recipients

602 Increased Risk of Autoimmune and Severe Atopic Disease in Infant Heart Transplant Recipients

Early survival after heart transplant in young infants is lowest after failed single-ventricle palliation: A multi-institutional study

Infant heart transplant (HT) recipients have the best long-term survival of any age group, but the small donor pool and high early mortality limit the therapeutic effectiveness. We sought to determine the relationship between pre-HT diagnosis and early HT outcome to better define the mortality risk associated with a diagnosis of congenital heart disease (CHD) and to examine differences between early and current HT eras. The Pediatric Heart Transplant Study (PHTS) database was used to identify 739 infant HT recipients at age ≤ 6 months between 1993 and 2008 divided into the following etiologic groups: cardiomyopathy (CM), 18%; hypoplastic left heart syndrome (HLHS) without surgery, 41%; HLHS with surgery, 9%; other CHD without surgery, 16%; and other CHD with surgery, 15%. Severity of illness at HT, post-HT survival, and era effects were compared. At 1 year after HT, survival was 89% for the CM group, which was the best, 79% for CHD without surgery, 82% for CHD with surgery, 79% for HLHS without surgery, and 70% for HLHS with surgery, which was the worst outcome. Hazard function analysis demonstrated the difference occurred within the first 3 months after HT. After adjusting for illness severity, differences in mortality risk persisted across etiologic groups. HT survival was similar in the current surgical era for HLHS with surgery, 71% (1993-1998) vs 70% (1999-2008). Infant HT recipients with different pre-HT diagnoses have significantly different post-HT outcomes. HLHS infants with surgery have the lowest survival and their outcome is unchanged in the current era.

Abstract 16940: Heart Transplant After Failed Single Ventricle Palliation in Young Infants Carries Excess Mortality Risk: A Multi-Institutional Study

BACKGROUND: Infant heart transplant (HT) recipients have the best long term survival of any age group, but small donor pool and high early mortality limit the therapeutic efficacy. We aimed to determine the relationship between pre-HT diagnosis and early HT outcome to identify infants most likely to benefit from HT. METHODS: The Pediatric Heart Transplant Study (PHTS) database was used to identify 739 infants s/p HT at age ≤6 mths between 1993-2008 divided into the following etiologic groups: cardiomyopathy (CM: 132, 18%); hypoplastic left heart syndrome without prior surgery (HLHS_WOS: 303, 41%); HLHS with surgery (HLHS_WS: 69, 9%); other congenital heart disease without surgery (CHD_WOS: 121, 16%; and other congenital heart disease with surgery (CHD_WS: 114, 15%). Severity of illness at HT, post HT survival, and era effects were compared among the 4 groups. RESULTS: The 1 yr survival for HLHS_WOS (79%) was similar to CHD_WOS (79%) and CHD_WS (82%) but worse than CM (89%). HLHS_WS had the highest mortality w 1 yr survival of 70%, p=0.03. Hazard function analysis showed the difference occurred within the 1st 6 mths after HT. Survival remained poor in the current surgical era for HLHS_WS, 71% (1993-1998) v 70% (1999-2008). Risk factors at HT associated w mortality included age &lt;1 mth (OR 2.5; CI 1.3-4.7, p=0.01), ECMO (OR 3.7; CI 2-6.8, p&lt;0.01), ventilator use (OR 1.8; CI 1-3.2, p=0.04), and HLHS_WS (OR 2.3; CI 1.3-4.1, p&lt;0.01). After adjusting for illness severity, differences in mortality risk persisted across etiologic groups. HLHS_WS (HR 2.3, CI 1.3-4, P&lt;0.01), CHD_WOS (HR 1.8, 1.1-3.1, P= 0.03), and HLHS_WOS (HR 1.7, 1.1-2.8, P=0.02) had significantly higher risk for mortality compared to CM. CONCLUSIONS: Infant HT recipients with different pre-HT diagnoses have strikingly different outcomes after HT that are unchanged over time and seem unrelated to clinical acuity at HT. CM infants have excellent survival, but HLHS_WS represent a high risk group for early mortality after HT.

Psychosocial implications during adolescence for infant heart transplant recipients.

Background & Objectives:As more heart transplant recipients survive into late adolescence, research addressing long-term psychosocial and neurodevelopmental outcomes is imperative. The limited literature available suggests risk for psychosocial difficulties and lower cognitive, academic, and neuropsychological functioning. This paper reviews topic-related literature and provides preliminary data examining psychosocial and neuropsychological functioning of adolescents who received their heart transplant during infancy. Method:This paper offers a literature review AND presents preliminary data from studies conducted through Loma Linda University Children’s Hospital (LLUCH). Study one examined psychosocial functioning and quality of life of adolescent infant heart transplant recipients. In study two, cognitive, academic, and neuropsychological data were analyzed. Results: Study 1: Overall psychosocial functioning fell in the Average range, however, a significant percentage of participants presented with difficulties on one or more of the psychosocial domains. Quality of life was also within normal limits, though concerns with general health and bodily discomfort were noted. Study 2: Cognitive functioning was assessed to be Below Average, with 43-62% of the participants demonstrating significant impairments. Neuropsychological functioning yielded significant weakness on language functioning, and mild weakness on visual-motor integration and executive functioning. Conclusion:While the majority of the participants demonstrate psychosocial resiliency, a subgroup present with difficulties suggesting the need for intervention. Cognitive/neuropsychological functioning suggests poorer functioning with patterns similar to other high-risk pediatric populations. These results are preliminary and further research on long-term psychosocial and neuropsychological development of pediatric heart transplant recipients is needed to better understand and ameliorate developmental trajectories.

Pediatric cardiac retransplant: Differing patterns of primary graft failure by age at first transplant

This study compared graft failure leading to retransplant in infants versus older children at initial heart transplant. Twenty-six retransplant recipients were compared by age at first transplant: infant group (<1 year) and pediatric group (≥1 year). Early retransplant survival was 92%. Retransplant survivals at 1, 3, and 5 years were 83%, 74%, and 67%. There were 15 infant and 11 pediatric patients. First transplant ages were 0.4 ± 0.3 vs. 8.5 ± 5.7 years in infant and pediatric groups, respectively (P < .01). First graft rejection episodes were more common in pediatric group (4.8 ± 2.5 vs 3.1 ± 2.1, P = .032), and rejection rate was higher (1.5 ± 1.1 vs 0.4 ± 0.4, P = .0024). Median first graft survival was longer in infant group (10.7 years vs 3.9 years, P < .001). Recurrent cellular rejection was retransplant indication in 40% of infant group versus 91% of pediatric group (P < .05). Cardiac allograft vasculopathy was more prevalent in infant group (73% vs 20% in pediatric group, P = .032). Infant heart transplant recipients had longer primary graft survival, fewer cellular rejection episodes, and higher incidence of cardiac allograft vasculopathy relative to older graft recipients requiring retransplant. Advantages in adaptive immunity in infant heart recipients confer improved primary graft survival, but longer graft life in these patients is limited by cardiac allograft vasculopathy. Older recipient first graft failure was rejection related, and shorter graft life probably limited development of cardiac allograft vasculopathy.

Cause of Death in Pediatric and Infant Heart Transplant Recipients: Review of a 20-year, Single-institution Cohort

Cause of Death in Pediatric and Infant Heart Transplant Recipients: Review of a 20-year, Single-institution Cohort

Cause of Death in Pediatric and Infant Heart Transplant Recipients: Review of a 20-year, Single-institution Cohort

As infant and pediatric heart transplantation becomes more common, there is a growing need to better understand the causes of failure or death, if we are to continue to improve the outcome in these children. A multidisciplinary team reviewed all deaths occurring in the cohort of infants and children transplanted during the first 20 years of the Loma Linda Pediatric Heart Transplant program, with 2 additional years of follow-up beyond the 20-year accrual period, and classified them as to cause. There were 169 deaths among 421 recipients, with a median follow-up of 9.7 years. Autopsy was performed in 128 cases. The causes of death, in decreasing order of frequency, included acute rejection (26.0%), infection (16.0%), cardiac allograft vasculopathy (CAV) (14.2%), technical issues (8.3%), acute graft dysfunction (6.5%), neoplasm (7.1%), chronic graft dysfunction (4.7%) and miscellaneous factors (10.1%), and in twelve deaths (7.1%) the cause was unclassified. Acute graft dysfunction and technical issues accounted for nearly two-thirds of the deaths in the first 30 days after transplant, while acute rejection resulted in the largest number of deaths after the first year (30.4%), with CAV a close second (23.5%). Acute graft dysfunction and technical issues were the most frequent cause of early death. Late deaths were most often due to acute rejection and CAV, which differs somewhat from the experience reported in adults. Acute rejection was the single most important cause of late mortality, and resulted in a significant number of late sudden and unexpected deaths.

Infant Heart Transplantation Ten Years Later—Where Are They Now?

Many uncertainties regarding the fate of children undergoing heart transplantation as infants were present when we and others embarked on this program. Although no truly long-term results are available, a significant cohort of children has now reached preteen and early teenage status. We reviewed our group of infants transplanted more than 10 years ago to assess survival and quality of life as they approach their teenage years. We retrospectively reviewed the medical records of all infant (younger than 6 months of age) heart transplant recipients, transplanted between 1988 and 1995, to ascertain survival statistics, incidence of complications, and current health status. A total of 42 patients were identified. The majority of these underwent transplantation for hypoplastic left heart syndrome. Eleven patients have died, 4 early and 7 late. The actual survival at 10 years is 76%. Twenty-seven of the 31 long-term survivors attend regular school; 4 are in special education classes owing to developmental delay. Five patients take medication for attention-deficit disorder. Malignancies have been discovered in 5, and 1 died secondary to this. Six patients have significant renal insufficiency, 1 of whom has undergone renal transplantation. One patient has undergone retransplantation for coronary artery disease. One patient required reoperation for supravalvar aortic stenosis. Other general medical problems that are being treated include sleep apnea (n = 1), hypertension (n = 5), and recurrent pneumonias (n = 1). Although these children require ongoing medical attention, including daily medications and regular follow-up visits, most have a satisfactory quality of life and behave much like normal children.

22: Infant heart transplant recipients as children and adolescents: A study of long-term medical morbidities

Previous long-term follow-up studies of pediatric heart transplant recipients have included few infant recipients and emphasized the importance of coronary artery disease and rejection as major causes of morbidity and mortality >5 years after transplant. The lower rates of rejection and coronary disease in infant recipients suggest their long-term morbidities may differ from older pediatric recipients.

21: Cognitive and emotional development in infant heart transplant recipients

As survival rates of infant heart transplant recipients have increased and the oldest of these children are now becoming adolescents, it has become imperative to assess their quality of life and cognitive development. This study examined the cognitive, academic, and behavioral/emotional development of infant heart transplant recipients through adolescence.

Neuropsychological outcome of infant heart transplant recipients

To assess long-term neuropsychological outcomes of infant heart transplant recipients. Fifty-five children (mean age, 6.4 years) with a primary diagnosis of hypoplastic left heart syndrome or other cardiac disorders participated in the study. Six areas of risk were assessed (birth; preoperative, intraoperative, and postoperative status; long-term medical complications; and socioeconomic factors). Neuropsychological evaluations included the following: Wechsler Scales of Intelligence, Wechsler Individual Achievement Test, Berry Visual Motor Integration Scale, Comprehensive Evaluation of Language Function, and Achenbach Child Behavioral Checklist. Intellectual functioning scores revealed a mean full-scale IQ of 81 +/- 19. Intraoperative and postoperative variables (bypass time, hospital course, and lowest posttransplant pH), long-term medical complications (serious infections and posttransplant surgical procedures), and socioeconomic factors were associated with cognitive functioning. Visual-motor functioning was also related to bypass and total support time. Long-term outcomes reveal low-average neuropsychological functioning and are related to intrasurgical-postsurgical, long-term medical, and socioeconomic factors. The neuropsychological and psychosocial functioning of infant heart transplant recipients will be important to address as they mature during adolescence and adulthood.