Measurement of lung oxygenation by near-infrared spectroscopy in preterm infants with bronchopulmonary dysplasia.

INTRODUCTION: It has recently been reported that it is possible to monitor lung oxygenation (rSO2L) by near-infrared spectroscopy (NIRS) in preterm infants with respiratory distress syndrome (RDS). Thus, our aim was to assess the possibility of monitoring rSO2L in infants with evolving and established bronchopulmonary dysplasia (BPD) and to evaluate if rSO2L correlates with BPD severity and other oxygenation indices. METHODS: We studied 40 preterm infants with gestational age ≤30 weeks at risk for BPD. Patients were continuously studied for 2 h by NIRS at 28 ± 7 days of life and 36 weeks ± 7 days of postmenstrual age. RESULTS: rSO2L was similar at the first and second NIRS recordings (71.8 ± 7.2 vs. 71.4 ± 4.2%) in the overall population, but it was higher in infants with mild than in those with moderate-to-severe BPD at both the first (73.3 ± 3.1 vs. 71.2 ± 3.2%, p = .042) and second (72.3 ± 2.8 vs. 70.5 ± 2.8, p = .049) NIRS recording. A rSO2L cutoff value of 71.6% in the first recording was associated with a risk for moderate-to-severe BPD with a sensitivity of 66% and a specificity of 60%. Linear regression analysis demonstrated a significant positive relationship between rSO2L and SpO2/FiO2 ratio (p = .013) and a/APO2 (p = .004). CONCLUSIONS: Monitoring of rSO2L by NIRS in preterm infants with evolving and established BPD is feasible and safe. rSO2L was found to be higher in infants with mild BPD, and predicts the risk for developing moderate-to-severe BPD and correlates with other indices of oxygenation.

The emerging role of extracellular vesicles in bronchopulmonary dysplasia.

Extracellular vesicle (EV) biology in neonatal lung development and disease is a rapidly growing area of investigation. Although EV research in the neonatal population lags behind EV research in adult lung diseases, recent discoveries demonstrate promise in furthering our understanding of the pathophysiology of bronchopulmonary dysplasia and the potential use of EVs in the clinical setting, as both biomarkers and therapeutic agents. This review article explores some of the recent advances in this field and our evolving knowledge of the role of EVs in bronchopulmonary dysplasia.

Relationships of Severity of Bronchopulmonary Dysplasia with Adverse Neurodevelopmental Outcomes and Poor Respiratory Function at 7-8 Years of Age.

OBJECTIVE: To clarify the relationships of 3 definitions of severity of bronchopulmonary dysplasia (BPD) with adverse neurodevelopmental and respiratory outcomes at early school-age. STUDY DESIGN: Participants comprised 218 consecutive survivors to 7-8 years of age born either <28 weeks' gestation or weighing <1000 g in Victoria, Australia, in 2005. BPD was classified as none, grade 1 (mild), grade 2 (moderate), or grade 3 (severe), using 2 commonly accepted definitions: 1) Jobe2001, and 2) Higgins2018, and our own 3) Victorian Infant Collaborative Study (VICS) 2005, adapted from Jensen2019. Outcomes included major neurodevelopmental disability, low IQ and academic achievement, poor motor function, and poor respiratory function as assessed by spirometry. Outcomes for children with each grade of BPD were compared with children with no BPD. RESULTS: Of the 218 survivors, 132 (61%) had BPD on Jobe2001 criteria, and 113 (52%) had BPD on both Higgins2018 and VICS2005 criteria. Grade 1 on any criteria was not associated with any adverse neurodevelopmental outcomes. Grade 1 on both Higgins2018 and VICS2005 was associated with reduced spirometry, grade 2 on both Higgins2018 and VICS2005, and grade 3 on all criteria were associated with increased risk for both adverse neurodevelopmental and respiratory outcomes. CONCLUSIONS: Compared with no BPD, receiving additional oxygen up to 29% but no positive pressure support at 36 weeks' postmenstrual age increased the risk of abnormal respiratory function but not adverse neurodevelopment. Receiving ≥30% oxygen or any positive pressure support at 36 weeks increased the risk of both adverse outcomes.

Flow-resistive loading and diaphragmatic muscle function in term and preterm infants.

PURPOSE: We aimed to assess diaphragmatic function in term and preterm infants with and without history of bronchopulmonary dysplasia (BPD), before and after the application of inspiratory flow resistive loading. METHODS: Forty infants of a median (range) gestational age of 34 (25-40) weeks were studied. BPD was defined as supplemental oxygen requirement for >28 days of life. Seventeen infants were term, 17 preterm without history of BPD, and six preterm with a history of BPD. The diaphragmatic pressure-time index (PTIdi) was calculated as the mean to maximum trans-diaphragmatic pressure ratio times the inspiratory duty cycle. The PTIdi was calculated before and after the application of an inspiratory-flow resistance for 120 s. Airflow was measured by a pneumotachograph and the transdiaphragmatic pressure by a dual pressure catheter. RESULTS: The median (interquartile range [IQR]) pre-resistance PTIdi was higher in preterm infants without BPD (0.064 [0.050-0.077]) compared with term infants (0.052 [0.044-0.062], p = .029) and was higher in preterm infants with BPD (0.119 [0.086-0.132]) compared with a subgroup of preterm infants without BPD (0.062 [0.056-0.072], p = .004). The median (IQR) postresistance PTIdi was higher in preterm infants without BPD (0.101 [0.084-0.132]) compared with term infants (0.067 [0.055-0.083], p < .001) and was higher in preterm infants with BPD [0.201(0.172-0.272)] compared with the preterm subgroup without BPD (0.091 [0.081-0.108],p = .004). The median (IQR) percentage change of the PTIdi after the application of the resistance was higher in preterm infants without BPD (65 [51-92] %) compared with term infants (34 [20-39] %, p < .001). CONCLUSIONS: Preterm infants, especially those recovering from BPD, are at increased risk of diaphragmatic muscle fatigue under conditions of increased inspiratory loading.

Retrospective study of serial polysomnograms of bronchopulmonary dysplasia patients with oxygen dependence.

INTRODUCTION: This retrospective study describes characteristics of serial polysomnograms (PSGs) of BPD patients on home oxygen therapy and describes PSG parameters associated with discontinuation of supplemental oxygen. METHODS: A single-center study was performed at Children's Hospital Los Angeles, where serial PSGs for 44 patients with BPD infants discharged on home oxygen therapy were extracted for maximum of five PSGs or until oxygen discontinuation. Clinical and polysomnography data was collected. Characteristics of PSG1 were compared amongst the patients who were weaned from oxygen after PSG2 and PSG3. RESULTS: Of 44 patients, 68.2% of patients were males with median birth gestational age of 26 weeks (IQR: 24.6-28.1), median birthweight of 777.5 g (IQR: 632.5-1054 g) and 77.3% of the cohort had severe BPD. A total of 138 PSGs were studied between all 44 patients serially. When comparing PSG1 and PSG2 parameters, statistically significant improvement was noted in multiple parameters. Median baseline SpO2, peak RR, and average PETCO2 were found to be potential predictors of prolonged oxygen use. Gestational age and birth weight were not associated with prolonged oxygen use after PSG3. The median age of oxygen discontinuation was calculated to be about 2 years of age. CONCLUSIONS: The severity of hypoxia and tachypnea on initial infant PSG are associated with prolonged oxygen therapy past 2 years of age. Growth and development of lungs with maturation of control of breathing help improve these parameters over time regardless of BPD severity. The study may inform discussions between providers and parents for patients discharged home on oxygen therapy.

Postnatal diuretics, weight gain and home oxygen requirement in extremely preterm infants.

OBJECTIVES: Diuretics are often given to infants with evolving/established bronchopulmonary dysplasia (BPD) with the hope of improving their pulmonary outcomes. We aimed to determine if diuretic use in preterm infants was associated with improved pulmonary outcomes, but poorer weight gain. METHODS: An observational study over a 5 year period was undertaken of all infants born at less than 29 weeks of gestation and alive at discharge in all neonatal units in England who received consecutive diuretic use for at least 7 days. Postnatal weight gain and home supplementary oxygen requirement were the outcomes. A literature review of randomised controlled trials (RCTs) and crossover studies was undertaken to determine if diuretic usage was associated with changes in lung mechanics and oxygenation, duration of supplementary oxygen and requirement for home supplementary oxygen. RESULTS: In the observational study, 9,457 infants survived to discharge, 44.6% received diuretics for at least 7 days. Diuretic use was associated with an increased probability of supplementary home oxygen of 0.14 and an increase in weight gain of 2.5 g/week. In the review, seven of the 10 studies reported improvements only in short term lung mechanics. There was conflicting evidence regarding whether diuretics resulted in short term improvements in oxygenation. CONCLUSIONS: Diuretic use was not associated with a reduction in requirement for supplemental oxygen on discharge. The literature review highlighted a lack of RCTs assessing meaningful long-term clinical outcomes. Randomised trials are needed to determine the long-term risk benefit ratio of chronic diuretic use.

Función pulmonar: función pulmonar en pacientes con displasia broncopulmonar / Pulmonary function: pulmonary function in patients with bronchopulmonary dysplasia

La displasia broncopulmonar (DBP) es una complicación frecuente en los prematuros extremos. La detención de la alveolarización determina menor volumen pulmonar total, el cual se recupera al menos parcialmente en el trayecto de la vida. La vía aérea se ve afectada en su crecimiento en mayor proporción que los alvéolos, y en los pacientes con displasia severa va a existir hasta la etapa adulta una limitación al flujo aéreo debido a su menor calibre. En este artículo, se describirá el origen, hallazgos característicos y evolución de las alteraciones en la función pulmonar, especialmente, en los pacientes con la nueva DBP.

Bronchopulmonary dysplasia (BPD) is a frequent complication in extremely premature infants. The arrest of alveolarization determines a lower total lung volume, which recovers at least partially during life. The airway is affected in its growth to a greater extent than the alveoli, and in patients with severe dysplasia there will be airflow limitation until adulthood due to its smaller caliber. In this article, the origin, characteristic findings, and evolution of changes in lung function will be described, especially in patients with the new BPD.

Definición de displasia broncopulmonar propuesta por la Comisión Neo SOCHINEP / Definition of bronchopulmonary dysplasia proposed by the Neo SOCHINEP Commission

La displasia broncopulmonar (DBP) es la enfermedad crónica más frecuente del recién nacido prematuro. Los avances en su prevención y tratamiento han permitido una mayor sobrevida de prematuros más pequeños, pero su incidencia se ha mantenido estable en el tiempo, con una fisiopatología y presentación clínica que abarca un amplio espectro y que difiere de la DBP descrita originalmente hace más de 50 años. Aún existen controversias en su definición, la que se ha establecido en base al tratamiento, específicamente al requerimiento de soporte respiratorio. Las definiciones más utilizadas son el requerimiento de oxígeno por 28 días y a las 36 semanas de edad gestacional corregida (EGC). Recientemente se ha propuesto definirla en base al requerimiento de ventilación mecánica a las 36 semanas de EGC, lo que identificaría a los prematuros con DBP más grave y mayor probabilidad de complicaciones respiratorias y neurológicas en los 2 primeros años de vida. Nuestro objetivo en la comisión de Neo-SOCHINEP es el de recomendar la definición y clasificación que nos parece más adecuada para identificar a los prematuros portadores de DBP, considerando los aspectos fisiopatológicos, del compromiso de la función pulmonar y consecuencias prácticas de la definición en nuestro medio. También proponemos la definición del requerimiento de oxígeno en el prematuro cuando esta en neonatología, las condiciones e interpretación de la saturometría contínua cuando está pronto al alta y el seguimiento de la oxigenoterapia posterior al alta.

Bronchopulmonary dysplasia (BPD) is the most frequent chronic disease of the premature newborn. Advances in its prevention and treatment have allowed a greater survival of smaller preterm infants, but its incidence has remained stable over time, with a pathophysiology and clinical presentation that covers a wide spectrum and differs from the BPD originally described more than 50 years ago. There are still controversies in its definition, which has been established based on the treatment, specifically the requirement of respiratory support. The most used definitions are the oxygen requirement for 28 days and at 36 weeks of postmenstrual age (PMA). It has recently been proposed a definition based on the requirement of mechanical ventilation at 36 weeks of PMA, which would identify premature infants with more severe BPD and a greater probability of respiratory and neurological complications in the first 2 years of life. Our objective in the Neo-SOCHINEP commission is to recommend the definition and classification that we believe is most appropriate to identify premature infants with BPD, considering the pathophysiological aspects, the compromised lung function, and practical consequences of the definition in our medium. We also propose the definition of the oxygen requirement in premature infants when they are in neonatology, the conditions and interpretation of continuous saturation when they are soon discharged, and the follow-up of post-discharge oxygen therapy.

Impact of the definition of bronchopulmonary dysplasia on neurodevelopmental outcomes.

Understanding the short and long-term pulmonary and neurologic outcomes of neonates with bronchopulmonary dysplasia (BPD) is important in neonatal care for low-birth-weight infants. Different criteria for BPD may have different associations with long-term outcomes. Currently, two criteria for diagnosing BPD have been proposed by the NIH (2001) and NRN (2019) for preterm infants at a postmenstrual age (PMA) of 36 weeks. We investigated which BPD definition best predicts long-term outcomes. Korean nationwide data for preterm infants born between 24+0 and < 32+0 weeks gestation from January 2013 to December 2015 were collected. For long-term outcomes, severity based on the NRN criteria was significantly related to neurodevelopmental impairment (NDI) in a univariate analysis after other risk factors were controlled. For the admission rate for respiratory disorder, grade 3 BPD of the NRN criteria had the highest specificity (96%), negative predictive value (86%), and accuracy (83%). For predicting NDI at the 18-24 month follow-up, grade 3 BPD of the NRN criteria had the best specificity (98%), positive (64%) and negative (79%) predictive values, and accuracy (78%) while NIH severe BPD had the highest sensitivity (60%). The NRN definition was more strongly associated with poor 2-year developmental outcomes. BPD diagnosed by NRN definitions might better identify infants at high risk for NDI.

Right ventricular function and vasoactive peptides for early prediction of bronchopulmonary dysplasia.

BACKGROUND: To assess the prognostic value of early echocardiographic indices of right ventricular function and vasoactive peptides for prediction of bronchopulmonary dysplasia (BPD) or death in very preterm infants. METHODS: Prospective study involving 294 very preterm infants (median [IQR] gestational age 28.4 [26.4-30.4] weeks, birth weight 1065 [800-1380] g), of whom 57 developed BPD (oxygen supplementation at 36 weeks postmenstrual age) and 10 died. Tricuspid annular plane systolic excursion (TAPSE), right ventricular index of myocardial performance (RIMP), plasma concentrations of mid-regional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET1) were measured on day 7 of life. RESULTS: RIMP was significantly increased (median [IQR] 0.3 [0.23-0.38] vs 0.22 [0.15-0.29]), TAPSE decreased (median [IQR] 5.0 [5.0-6.0] vs 6.0 [5.4-7.0] mm), MR-proANP increased (median [IQR] 784 [540-936] vs 353 [247-625] pmol/L), and CT-proET1 increased (median [IQR] 249 [190-345] vs 199 [158-284] pmol/L) in infants who developed BPD or died, as compared to controls. All variables showed significant but weak correlations with each other (rS -0.182 to 0.359) and predicted BPD/death with similar accuracy (areas under receiver operator characteristic curves 0.62 to 0.77). Multiple regression revealed only RIMP and birth weight as independent predictors of BPD or death. CONCLUSIONS: Vasoactive peptide concentrations and echocardiographic assessment employing standardized measures, notably RIMP, on day 7 of life are useful to identify preterm infants at increased risk for BPD or death.

Association between Intermittent Hypoxemia and Severe Bronchopulmonary Dysplasia in Preterm Infants.

Rationale: Bronchopulmonary dysplasia increases the risk of disability in extremely preterm infants. Although the pathophysiology remains uncertain, prior exposure to intermittent hypoxemia may play a role in this relationship. Objectives: To determine the association between prolonged episodes of intermittent hypoxemia and severe bronchopulmonary dysplasia. Methods: A post hoc analysis of extremely preterm infants in the Canadian Oxygen Trial who survived to 36 weeks' postmenstrual age was performed. Oxygen saturations <80% for ⩾1 minute and the proportion of time per day with hypoxemia were quantified using continuous pulse oximetry data that had been sampled every 10 seconds from within 24 hours of birth until 36 weeks' postmenstrual age. The study outcome was severe bronchopulmonary dysplasia as defined in the 2001 NIH Workshop Summary. Measurements and Main Results: Of 1,018 infants, 332 (32.6%) developed severe bronchopulmonary dysplasia. The median number of hypoxemic episodes ranged from 0.8/day (interquartile range, 0.2-1.1) to 60.2/day (interquartile range, 51.4-70.3) among the least and most affected 10% of infants. Compared with the lowest decile of exposure to hypoxemic episodes, the adjusted relative risk of severe bronchopulmonary dysplasia increased progressively from 1.72 (95% confidence interval, 1.55-1.90) at the 2nd decile to 20.40 (95% confidence interval, 12.88-32.32) at the 10th decile. Similar risk gradients were observed for time in hypoxemia. Significant differences in the rates of hypoxemia between infants with and without severe bronchopulmonary dysplasia emerged within the first week after birth. Conclusions: Prolonged intermittent hypoxemia beginning in the first week after birth was associated with an increased risk of developing severe bronchopulmonary dysplasia among extremely preterm infants. Clinical trial registered with www.isrctn.com (ISRCTN62491227) and www.clinicaltrials.gov (NCT00637169).

Air quality, Environment and Respiratory Outcomes in Bronchopulmonary Dysplasia, the AERO-BPD cohort study: design and adaptation during the SARS-CoV-2 pandemic.

INTRODUCTION: Almost half of all school-age children with bronchopulmonary dysplasia (BPD) have asthma-like symptoms and more suffer from lung function deficits. While air pollution and indoor respiratory irritants are known to affect high-risk populations of children, few studies have objectively evaluated environmental contributions to long-term respiratory morbidity in this population. This study aimed to examine the role of indoor environmental exposures on respiratory morbidity in children with BPD. METHODS AND ANALYSIS: The Air quality, Environment and Respiratory Ouctomes in BPD (AERO-BPD) study is a prospective, single-centre observational study that will enrol a unique cohort of 240 children with BPD and carefully characterise participants and their indoor home environmental exposures. Measures of indoor air quality constituents will assess the relationship of nitrogen dioxide (NO2), particulate matter (PM2.5), nitric oxide (NO), temperature and humidity, as well as dust concentrations of allergens, with concurrently measured respiratory symptoms and lung function.Adaptations to the research protocol due to the SARS-CoV-2 pandemic included remote home environment and participant assessments. ETHICS AND DISSEMINATION: Study protocol was approved by the Boston Children's Hospital Committee on Clinical Investigation. Dissemination will be in the form of peer-reviewed publications and participant information products. TRIAL REGISTRATION NUMBER: NCT04107701.

VIP/PACAP signaling as an alternative target during hyperoxic exposure in preterm newborns.

The use of oxygen therapy (high doses of oxygen - hyperoxia) in the treatment of premature infants results in their survival. However, it also results in a high incidence of chronic lung disease known as bronchopulmonary dysplasia, a disease in which airway hyper-responsiveness and pulmonary hypertension are well known as consequences. In our previous studies, we have shown that hyperoxia causes airway hyper-reactivity, characterized by an increased constrictive and impaired airway smooth muscle relaxation due to a reduced release of relaxant molecules such as nitric oxide, measured under in vivo and in vitro conditions (extra- and intrapulmonary) airways. In addition, the relaxation pathway of the vasoactive intestinal peptide (VIP) and/or pituitary adenylate cyclase activating peptide (PACAP) is another part of this system that plays an important role in the airway caliber. Peptide, which activates VIP cyclase and pituitary adenylate cyclase, has prolonged airway smooth muscle activity. It has long been known that VIP inhibits airway smooth muscle cell proliferation in a mouse model of asthma, but there is no data about its role in the regulation of airway and tracheal smooth muscle contractility during hyperoxic exposure of preterm newborns.

Established severe BPD: is there a way out? Change of ventilatory paradigms.

Improved survival of extremely preterm newborn infants has increased the number of infants at risk for developing bronchopulmonary dysplasia (BPD). Despite efforts to prevent BPD, many of these infants still develop severe BPD (sBPD) and require long-term invasive mechanical ventilation. The focus of research and clinical management has been on the prevention of BPD, which has had only modest success. On the other hand, research on the management of the established sBPD patient has received minimal attention even though this condition poses large economic and health problems with extensive morbidities and late mortality. Patients with sBPD, however, have been shown to respond to treatments focused not only on ventilatory strategies but also on multidisciplinary approaches where neurodevelopmental support, growth promoting strategies, and aggressive treatment of pulmonary hypertension improve their long-term outcomes. In this review we will try to present a physiology-based ventilatory strategy for established sBPD, emphasizing a possible paradigm shift from acute efforts to wean infants at all costs to a more chronic approach of stabilizing the infant. This chronic approach, herein referred to as chronic phase ventilation, aims at allowing active patient engagement, reducing air trapping, and improving ventilation-perfusion matching, while providing sufficient support to optimize late outcomes. IMPACT: Based on pathophysiological aspects of evolving and established severe BPD in premature infants, this review presents some lung mechanical properties of the most severe phenotype and proposes a chronic phase ventilatory strategy that aims at reducing air trapping, improving ventilation-perfusion matching and optimizing late outcomes.

Surfactant protein D and bronchopulmonary dysplasia: a new way to approach an old problem.

Surfactant protein D (SP-D) is a collectin protein synthesized by alveolar type II cells in the lungs. SP-D participates in the innate immune defense of the lungs by helping to clear infectious pathogens and modulating the immune response. SP-D has shown an anti-inflammatory role by down-regulating the release of pro-inflammatory mediators in different signaling pathways such as the TLR4, decreasing the recruitment of inflammatory cells to the lung, and modulating the oxidative metabolism in the lungs. Recombinant human SP-D (rhSP-D) has been successfully produced mimicking the structure and functions of native SP-D. Several in vitro and in vivo experiments using different animal models have shown that treatment with rhSP-D reduces the lung inflammation originated by different insults, and that rhSP-D could be a potential treatment for bronchopulmonary dysplasia (BPD), a rare disease for which there is no effective therapy up to date. BPD is a complex disease in preterm infants whose incidence increases with decreasing gestational age at birth. Lung inflammation, which is caused by different prenatal and postnatal factors like infections, lung hyperoxia and mechanical ventilation, among others, is the key player in BPD. Exacerbated inflammation causes lung tissue injury that results in a deficient gas exchange in the lungs of preterm infants and frequently leads to long-term chronic lung dysfunction during childhood and adulthood. In addition, low SP-D levels and activity in the first days of life in preterm infants have been correlated with a worse pulmonary outcome in BPD. Thus, SP-D mediated functions in the innate immune response could be critical aspects of the pathogenesis in BPD and SP-D could inhibit lung tissue injury in this preterm population. Therefore, administration of rhSP-D has been proposed as promising therapy that could prevent BPD.

Lung function trajectories in children with post-prematurity respiratory disease: identifying risk factors for abnormal growth.

BACKGROUND: Survivors of prematurity are at risk for abnormal childhood lung function. Few studies have addressed trajectories of lung function and risk factors for abnormal growth in childhood. This study aims to describe changes in lung function in a contemporary cohort of children born preterm followed longitudinally in pulmonary clinic for post-prematurity respiratory disease and to assess maternal and neonatal risk factors associated with decreased lung function trajectories. METHODS: Observational cohort of 164 children born preterm ≤ 32 weeks gestation followed in pulmonary clinic at Boston Children's Hospital with pulmonary function testing. We collected demographics and neonatal history. We used multivariable linear regression to identify the impact of neonatal and maternal risk factors on lung function trajectories in childhood. RESULTS: We identified 264 studies from 82 subjects with acceptable longitudinal FEV1 data and 138 studies from 47 subjects with acceptable longitudinal FVC and FEV1/FVC data. FEV1% predicted and FEV1/FVC were reduced compared to childhood norms. Growth in FVC outpaced FEV1, resulting in an FEV1/FVC that declined over time. In multivariable analyses, longer duration of mechanical ventilation was associated with a lower rate of rise in FEV1% predicted and greater decline in FEV1/FVC, and postnatal steroid exposure in the NICU was associated with a lower rate of rise in FEV1 and FVC % predicted. Maternal atopy and asthma were associated with a lower rate of rise in FEV1% predicted. CONCLUSIONS: Children with post-prematurity respiratory disease demonstrate worsening obstruction in lung function throughout childhood. Neonatal risk factors including exposure to mechanical ventilation and postnatal steroids, as well as maternal atopy and asthma, were associated with diminished rate of rise in lung function. These results may have implications for lung function trajectories into adulthood.