Modulatory effects of fMRI acquisition time of day, week and year on adolescent functional connectomes across spatial scales: Implications for inference.

Metabolic, hormonal, autonomic and physiological rhythms may have a significant impact on cerebral hemodynamics and intrinsic brain synchronization measured with fMRI (the resting-state connectome). The impact of their characteristic time scales (hourly, circadian, seasonal), and consequently scan timing effects, on brain topology in inherently heterogeneous developing connectomes remains elusive. In a cohort of 4102 early adolescents with resting-state fMRI (median age = 120.0 months; 53.1 % females) from the Adolescent Brain Cognitive Development Study, this study investigated associations between scan time-of-day, time-of-week (school day vs weekend) and time-of-year (school year vs summer vacation) and topological properties of resting-state connectomes at multiple spatial scales. On average, participants were scanned around 2 pm, primarily during school days (60.9 %), and during the school year (74.6 %). Scan time-of-day was negatively correlated with multiple whole-brain, network-specific and regional topological properties (with the exception of a positive correlation with modularity), primarily of visual, dorsal attention, salience, frontoparietal control networks, and the basal ganglia. Being scanned during the weekend (vs a school day) was correlated with topological differences in the hippocampus and temporoparietal networks. Being scanned during the summer vacation (vs the school year) was consistently positively associated with multiple topological properties of bilateral visual, and to a lesser extent somatomotor, dorsal attention and temporoparietal networks. Time parameter interactions suggested that being scanned during the weekend and summer vacation enhanced the positive effects of being scanned in the morning. Time-of-day effects were overall small but spatially extensive, and time-of-week and time-of-year effects varied from small to large (Cohen's f ≤ 0.1, Cohen's d<0.82, p < 0.05). Together, these parameters were also positively correlated with temporal fMRI signal variability but only in the left hemisphere. Finally, confounding effects of scan time parameters on relationships between connectome properties and cognitive task performance were assessed using the ABCD neurocognitive battery. Although most relationships were unaffected by scan time parameters, their combined inclusion eliminated associations between properties of visual and somatomotor networks and performance in the Matrix Reasoning and Pattern Comparison Processing Speed tasks. Thus, scan time of day, week and year may impact measurements of adolescent brain's functional circuits, and should be accounted for in studies on their associations with cognitive performance, in order to reduce the probability of incorrect inference.

Catathrenia in children: clinical presentation, polysomnographic features, natural history, and response to therapy.

STUDY OBJECTIVES: To determine the clinical presentation, polysomnographic appearance, and the response to therapy of catathrenia in children. METHODS: A retrospective analysis was performed in children referred or evaluated at the Boston Children's Hospital Sleep Center between 1998 and 2021 who were documented to have catathrenia either as a chief complaint or an incidental finding. RESULTS: Catathrenia was identified in 21 children. The age of onset by parent report was 6.4 ± 4.4 years (range: birth-14 years), but the diagnosis was at 8.3 ± 3.8 years (range: 1.5-14 years). Catathrenia was the chief complaint for 24% of patients and was incidentally identified in 76% referred for breathing concerns. Bruxism was observed in 62% of patients. Catathrenia events most often occur following an electrocortical arousal (79%) and are most common in the second half of the night (73%). Catathrenia was observed exclusively in rapid eye movement (REM) sleep (16%), exclusively in non-REM sleep (32%), and in both sleep states (52%). Treatment of obstructive sleep apnea resulted in resolution or improvement in the obstructive sleep apnea in all patients, but the catathrenia persisted at a reduced level. CONCLUSIONS: Most catathrenia in children is diagnosed incidentally during evaluation for sleep-disordered breathing, although the groaning often started many years earlier. Catathrenia events decreased considerably after treatment of obstructive sleep apnea, but persisted in all patients. Catathrenia was also observed in children without signs or symptoms of sleep-disordered breathing, indicating that these are distinct conditions. The majority of children with catathrenia had no sleepiness or behavioral concerns. CITATION: Katz ES, D'Ambrosio C. Catathrenia in children: clinical presentation, polysomnographic features, natural history, and response to therapy. J Clin Sleep Med. 2023;19(8):1505-1511.

Sleep from Infancy Through Adolescence.

This article describes the changes in normal sleep regulation, structure, and organization and sleep-related changes in respiration from infancy to adolescence. The first 2 years of age are striking, with more time asleep than awake. With development, the electroencephalogram architecture has a marked reduction in rapid eye movement sleep and the acquisition of K-complexes, sleep spindles, and slow-wave sleep. During adolescence there is a reduction in slow-wave sleep and a delay in the circadian phase. Infants have a more collapsible upper airway and lower lung volumes than older children, which predisposes them to obstructive sleep apnea and sleep-related hypoxemia.

Twenty-year follow-up of children with obstructive sleep apnea.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) in children is associated with acute metabolic, cardiovascular, and neurocognitive abnormalities. The long-term outcomes of childhood OSA into adulthood have not been established. We performed a 20-year follow-up of patients with polysomnography-documented OSA in childhood compared to a healthy control group to evaluate the long-term anthropometric, sleep, cognitive, and cardiovascular outcomes. METHODS: Children diagnosed with severe OSA between ages 1 and 17 years (mean, 4.87 ± 2.77) were prospectively contacted by telephone as young adults after approximately 20 years. Data collected included reported anthropometric information, educational level, health history, and Berlin questionnaire scores. RESULTS: Young adults with confirmed severe OSA in childhood had significantly higher adulthood body mass index (P = .038), fewer academic degrees (P < .001), and more snoring (P = .045) compared to control patients. The apnea-hypopnea index during childhood trended toward predicting cardiovascular outcomes and the results of the Berlin questionnaire in adulthood. CONCLUSIONS: Adults with a history of severe childhood OSA have a high risk of snoring, elevated body mass index, and lower academic achievement in adulthood. Thus, children with severe OSA may be at increased risk of chronic diseases later in life. The intervening coronavirus disease 2019 (COVID-19) pandemic has introduced considerable additional neurobehavioral morbidity complicating the identification of the full long-term consequences of childhood OSA. CITATION: Nosetti L, Zaffanello M, Katz ES, et al. Twenty-year follow-up of children with obstructive sleep apnea. J Clin Sleep Med. 2022;18(6):1573-1581.

Shorter Duration and Lower Quality Sleep Have Widespread Detrimental Effects on Developing Functional Brain Networks in Early Adolescence.

Sleep is critical for cognitive health, especially during complex developmental periods such as adolescence. However, its effects on maturating brain networks that support cognitive function are only partially understood. We investigated the impact of shorter duration and reduced quality sleep, common stressors during development, on functional network properties in early adolescence-a period of significant neural maturation, using resting-state functional magnetic resonance imaging from 5566 children (median age = 120.0 months; 52.1% females) in the Adolescent Brain Cognitive Development cohort. Decreased sleep duration, increased sleep latency, frequent waking up at night, and sleep-disordered breathing symptoms were associated with lower topological efficiency, flexibility, and robustness of visual, sensorimotor, attention, fronto-parietal control, default-mode and/or limbic networks, and with aberrant changes in the thalamus, basal ganglia, hippocampus, and cerebellum (P < 0.05). These widespread effects, many of which were body mass index-independent, suggest that unhealthy sleep in early adolescence may impair neural information processing and integration across incompletely developed networks, potentially leading to deficits in their cognitive correlates, including attention, reward, emotion processing and regulation, memory, and executive control. Shorter sleep duration, frequent snoring, difficulty waking up, and daytime sleepiness had additional detrimental network effects in nonwhite participants, indicating racial disparities in the influence of sleep metrics.

American Thoracic Society 2019 Pediatric Core Curriculum.

The American Thoracic Society Pediatric Core Curriculum updates clinicians annually in pediatric pulmonary disease in a 3 to 4 year recurring cycle of topics. The 2019 course was presented in May during the Annual International Conference. An American Board of Pediatrics Maintenance of Certification module and a continuing medical education exercise covering the contents of the Core Curriculum can be accessed online at www.thoracic.org.

A Framework for Evaluation of the Higher-Risk Infant After a Brief Resolved Unexplained Event.

In 2016, the American Academy of Pediatrics published a clinical practice guideline that more specifically defined apparent life-threatening events as brief resolved unexplained events (BRUEs) and provided evidence-based recommendations for the evaluation of infants who meet lower-risk criteria for a subsequent event or serious underlying disorder. The clinical practice guideline did not provide recommendations for infants meeting higher-risk criteria, an important and common population of patients. Therefore, we propose a tiered approach for clinical evaluation and management of higher-risk infants who have experienced a BRUE. Because of a vast array of potential causes, the initial evaluation prioritizes the diagnosis of time-sensitive conditions for which delayed diagnosis or treatment could impact outcomes, such as child maltreatment, feeding problems, cardiac arrhythmias, infections, and congenital abnormalities. The secondary evaluation addresses problems that are less sensitive to delayed diagnosis or treatment, such as dysphagia, intermittent partial airway obstruction, and epilepsy. The authors recommend a tailored, family-centered, multidisciplinary approach to evaluation and management of all higher-risk infants with a BRUE, whether accomplished during hospital admission or through coordinated outpatient care. The proposed framework was developed by using available evidence and expert consensus.

Delayed Sleep Phase Syndrome: A common sleep disorder in adolescents, with important quality of life repercussions / Síndrome de fase de sueño retrasada: un trastorno del sueño frecuente en adolescentes, con importante repercusión en su calidad de vida

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Brief resolved unexplained events: Retrospective validation of diagnostic criteria and risk stratification.

BACKGROUND AND OBJECTIVES: This study retrospectively evaluated the AAP guidelines for diagnosis and risk stratification of Brief Resolved Unexplained Events (BRUE) in a well-characterized cohort of infants admitted with an Apparent Life Threatening Event (ALTE). Further, using prospective follow-up, we endeavored to determine the safety of implementing ambulatory care for the lower risk BRUE population (LR-BRUE) and estimate the cost-savings of this practice. METHODS: Retrospective application of the BRUE criteria on infants younger than 12 months of age who had been admitted with an ALTE from 2006 to 2016 at a single tertiary care center in Lombardy, Italy. ALTE patients were classified into three groups; (1) Not a BRUE; (2) Lower-risk (LR)-BRUE; and (3) Higher-risk (HR)-BRUE. Patients were contacted prospectively to obtain long-term follow-up outcomes and medical records and billing databases were reviewed. RESULTS: Among the 84 infants admitted for an ALTE, 35 (42%) were not a BRUE, 16 (19%) were a LR-BRUE, and 33 (39%) were a HR-BRUE. Only one of the LR-BRUE patients had a subsequent LR-BRUE event, and was later diagnosed with a seizure disorder. Two HR-BRUE babies had also previously presented with a LR-BRUE. Application of the LR-BRUE guidelines would have decreased health expenditure by 20%. There were no deaths or significant morbidities in either BRUE group. CONCLUSIONS: Applying the recent AAP BRUE guidelines and risk stratification to a well-characterized cohort of admitted ALTE patients is a safe and cost-effective approach. Careful out-patient follow-up is recommended as one of our patients with a LR-BRUE had a recurrence, and was subsequently diagnosed with a seizure disorder.

Depressive symptomatology in school-aged children with obstructive sleep apnea syndrome: incidence, demographic factors, and changes following a randomized controlled trial of adenotonsillectomy.

Study Objectives: Depressive symptoms following adenotonsillectomy (AT) relative to controls were examined in children with obstructive sleep apnea syndrome (OSAS). Methods: The Childhood Adenotonsillectomy Trial (CHAT) multisite study examined the impact of AT in 453 children aged 5 to 9.9 years with polysomnographic evidence of OSAS without prolonged desaturation, randomized to early adenotonsillectomy (eAT) or watchful waiting with supportive care (WWSC). One hundred seventy-six children (eAT n = 83; WWSC n = 93) with complete evaluations for depressive symptomatology between baseline and after a 7-month intervention period were included in this secondary analysis. Results: Exact binomial test assessed proportion of depressive symptomatology relative to norms, while effects of AT and OSAS resolution were assessed through linear quantile mixed-models. Treatment group assignment did not significantly impact depression symptoms, although self-reported depression symptoms improved over time (p < 0.001). Resolution of OSAS symptoms demonstrated a small interaction effect in an unexpected direction, with more improvement in parent ratings of anxious/depressed symptoms for children without resolution (p = 0.030). Black children reported more severe depressive symptoms (p = 0.026) and parents of overweight/obese children reported more withdrawn/depressed symptoms (p = 0.004). Desaturation nadir during sleep was associated with self-report depressed (r = -0.17, p = 0.028), parent-reported anxious/depressed (r = -0.15, p = 0.049), and withdrawn/depressed (r = -0.24, p = 0.002) symptoms. Conclusions: Increased risk for depressed and withdrawn/depressed symptoms was detected among children with OSAS, and different demographic variables contributed to risk in self-reported and parent-reported depression symptoms. Arterial oxygen desaturation nadir during sleep was strongly associated with depressed symptoms. However, despite improvements in child-reported depressed symptoms over time, changes were unrelated to either treatment group or OSAS resolution status. Trials Registration: Childhood Adenotonsillectomy Study for Children with OSAS (CHAT), https://clinicaltrials.gov/show/NCT00560859, NCT00560859.

Impaired memory consolidation in children with obstructive sleep disordered breathing.

Memory consolidation is stabilized and even enhanced by sleep (and particularly by 12-15 Hz sleep spindles in NREM stage 2 sleep) in healthy children but it is unclear what happens to these processes when sleep is disturbed by obstructive sleep disordered breathing. This cross-sectional study investigates differences in declarative memory consolidation among children with primary snoring (PS) and obstructive sleep apnea (OSA) compared to controls. We further investigate whether memory consolidation group differences are associated with NREM stage 2 (N2) sigma (12-15 Hz) or NREM slow oscillation (0.5-1 Hz) spectral power bands. In this study, we trained and tested participants on a spatial declarative memory task with cued recall. Retest occurred after a period of daytime wake (Wake) or a night of sleep (Sleep) with in-lab polysomnography. 36 participants ages 5-9 years completed the protocol: 14 with OSA as defined by respiratory disturbance index (RDI) > 1/hour, 12 with primary snoring (PS) and 10 controls. OSA participants had poorer overall memory consolidation than controls across Wake and Sleep conditions [OSA: mean = -18.7% (5.8), controls: mean = 1.9% (7.2), t = -2.20, P = 0.04]. In contrast, PS participants and controls had comparable memory consolidation across conditions (t = 0.41; P = 0.38). We did not detect a main effect for condition (Sleep, Wake) or group x condition interaction on memory consolidation. OSA participants had lower N2 sigma power than PS (P = 0.03) and controls (P = 0.004) and N2 sigma power inversely correlated with percentage of time snoring on the study night (r = -0.33, P<0.05). Across all participants, N2 sigma power modestly correlated with memory consolidation in both Sleep (r = 0.37, P = 0.03) and Wake conditions (r = 0.44, P = 0.009). Further observed variable path analysis showed that N2 sigma power mediated the relationship between group and mean memory consolidation across Sleep and Wake states [Bindirect = 6.76(3.5), z = 2.03, P = 0.04]. NREM slow oscillation power did not correlate with memory consolidation. All results retained significance after controlling for age and BMI. In sum, participants with mild OSA had impaired memory consolidation and results were mediated by N2 sigma power. These results suggest that N2 sigma power could serve as biomarker of risk for cognitive dysfunction in children with sleep disordered breathing.

Airflow Shape Is Associated With the Pharyngeal Structure Causing OSA.

BACKGROUND: OSA results from the collapse of different pharyngeal structures (soft palate, tongue, lateral walls, and epiglottis). The structure involved in collapse has been shown to impact non-CPAP OSA treatment. Different inspiratory airflow shapes are also observed among patients with OSA. We hypothesized that inspiratory flow shape reflects the underlying pharyngeal structure involved in airway collapse. METHODS: Subjects with OSA were studied with a pediatric endoscope and simultaneous nasal flow and pharyngeal pressure recordings during natural sleep. The mechanism causing collapse was classified as tongue-related, isolated palatal, lateral walls, or epiglottis. Flow shape was classified according to the degree of negative effort dependence (NED), defined as the percent reduction in inspiratory flow from peak to plateau. RESULTS: Thirty-one subjects with OSA (mean apnea-hypopnea index score ± SD, 54 ± 27 events/h) who were 50 ± 9 years of age were studied. NED was associated with the structure causing collapse (P < .001). Tongue-related obstruction (n = 13) was associated with a small amount of NED (median, 19; interquartile range [IQR], 14%-25%). Moderate NED was found among subjects with isolated palatal collapse (median, 45; IQR, 39%-52%; n = 8) and lateral wall collapse (median, 50; IQR, 44%-64%; n = 8). The epiglottis was associated with severe NED (median, 89; IQR, 78%-91%) and abrupt discontinuities in inspiratory flow (n = 9). CONCLUSIONS: Inspiratory flow shape is influenced by the pharyngeal structure causing collapse. Flow shape analysis may be used as a noninvasive tool to help determine the pharyngeal structure causing collapse.

Effects of Adenotonsillectomy on Parent-Reported Behavior in Children With Obstructive Sleep Apnea.

Objectives: The childhood obstructive sleep apnea syndrome (OSAS) is associated with behavioral abnormalities. Studies on the effects of OSAS treatment on behavior are conflicting, with few studies using a randomized design. Further, studies may be confounded by the inclusion of behavioral outcome measures directly related to sleep. The objective of this study was to determine the effect of adenotonsillectomy on behavior in children with OSAS. We hypothesized that surgery would improve behavioral ratings, even when sleep symptom items were excluded from the analysis. Methods: This was a secondary analysis of Child Behavior Checklist (CBCL) data, with and without exclusion of sleep-specific items, from the Childhood Adenotonsillectomy Trial (CHAT). CBCL was completed by caregivers of 380 children (7.0+1.4 [range 5-9] years) with OSAS randomized to early adenotonsillectomy (eAT) versus 7 months of watchful waiting with supportive care (WWSC). Results: There was a high prevalence of behavioral problems at baseline; 16.6% of children had a Total Problems score in the clinically abnormal range. At follow-up, there were significant improvements in Total Problems (p < .001), Internalizing Behaviors (p = .04), Somatic Complaints (p = .01), and Thought Problems (p = .01) in eAT vs. WWSC participants. When specific sleep-related question items were removed from the analysis, eAT showed an overall improvement in Total (p = .02) and Other (p = .01) problems. Black children had less improvement in behavior following eAT than white children, but this difference attenuated when sleep-related items were excluded. Conclusions: This large, randomized trial showed that adenotonsillectomy for OSAS improved parent-rated behavioral problems, even when sleep-specific behavioral issues were excluded from the analysis.

Are three-dimensional airway evaluations obtained through computed and cone-beam computed tomography scans predictable from lateral cephalograms? A systematic review of evidence.

OBJECTIVE: To systematically review the literature correlating upper airway parameters between lateral cephalograms (LC) and cone-beam computed tomography (CBCT) or computed tomography (CT) scans to determine the utility of using LC to predict three-dimensional airway parameters. MATERIALS AND METHODS: Both electronic and manual searches of the included studies were performed by two reviewers, and the quality of the studies that met selection criteria were assessed. RESULTS: A total of 11 studies from the literature met the selection criteria. Assessed outcome variables showed correlation r < .7 between the LC and CT scans. The correlation between the LC and CBCT ranged from weak to strong with -.78 ≤ r and r ≤ .93 reported in the nasopharyngeal segment. In the oropharyngeal segment, a weak to strong correlation was reported with a range of -37 ≤ r and r ≤ .83 between the CBCT and LC. All associations in the hypopharyngeal segment showed a weak correlation. Four of studies were of weak quality, five were of moderate quality, and two were rated to be of strong quality. CONCLUSION: No strong correlations were reported between the LC and CT scans. However, the LC-derived adenoid-nasopharyngeal ratio and the linear measurement (posterior nasal spine, PNS, to posterior pharyngeal wall) had a strong correlation with upright nasopharyngeal area and volume in the CBCTs. The area measurement in conventional LC can be also used as an initial screening tool to predict the upright three-dimensional oropharyngeal volumetric data. The variability of the hypopharyngeal segment cannot be predicted by LCs. However, more well-designed studies are needed to determine the clinical utility of using LC to predict airway size.

Effect of Adenotonsillectomy on Parent-Reported Sleepiness in Children with Obstructive Sleep Apnea.

STUDY OBJECTIVES: To describe parental reports of sleepiness and sleep duration in children with polysomnography (PSG)-confirmed obstructive sleep apnea (OSA) randomized to early adenotonsillectomy (eAT) or watchful waiting with supportive care (WWSC) in the ChildHood Adenotonsillectomy Trial (CHAT). We hypothesized children with OSA would have a larger improvement in sleepiness 6 mo following eAT compared to WWSC. METHODS: Parents of children aged 5.0-9.9 y completed the Epworth Sleepiness Scale modified for children (mESS) and the Pediatric Sleep Questionnaire-Sleepiness Subscale (PSQ-SS). PSG was performed at baseline and at 7-mo endpoint. Children underwent early adenotonsillectomy or WWSC. RESULTS: The mESS and PSQ-SS classified 24% and 53% of the sample as excessively sleepy, respectively. At baseline, mean mESS score was 7.4 ± 5.0 (SD) and mean PSQ-SS score was 0.44 ± 0.30. Sleepiness scores were higher in African American children; children with shorter sleep duration; older children; and overweight children. At endpoint, mean mESS score decreased by 2.0 ± 4.2 in the eAT group versus 0.3 ± 4.0 in the WWSC group (P < 0.0001); mean PSQ-SS score decreased 0.29 ± 0.40 in eAT versus 0.08 ± 0.40 in the WWSC group (P < 0.0001). Despite higher baseline sleepiness, African American children experienced similar improvement with adenotonsillectomy than other children. Improvement in sleepiness was weakly associated with improved apnea-hypopnea index or oxygen desaturation indices, but not with change in other polysomnographic measures. CONCLUSIONS: Sleepiness assessed by parent report was prevalent; improved more after eAT than after WWSC; and was not strongly predicted by sleep disturbances identified by PSG. CLINICAL TRIAL REGISTRATION: Childhood Adenotonsillectomy Study for Children with OSA (CHAT). ClinicalTrials.gov Identifier #NCT00560859.

Cognitive Effects of Adenotonsillectomy for Obstructive Sleep Apnea.

OBJECTIVE: Research reveals mixed evidence for the effects of adenotonsillectomy (AT) on cognitive tests in children with obstructive sleep apnea syndrome (OSAS). The primary aim of the study was to investigate effects of AT on cognitive test scores in the randomized Childhood Adenotonsillectomy Trial. METHODS: Children ages 5 to 9 years with OSAS without prolonged oxyhemoglobin desaturation were randomly assigned to watchful waiting with supportive care (n = 227) or early AT (eAT, n = 226). Neuropsychological tests were administered before the intervention and 7 months after the intervention. Mixed model analysis compared the groups on changes in test scores across follow-up, and regression analysis examined associations of these changes in the eAT group with changes in sleep measures. RESULTS: Mean test scores were within the average range for both groups. Scores improved significantly (P < .05) more across follow-up for the eAT group than for the watchful waiting group. These differences were found only on measures of nonverbal reasoning, fine motor skills, and selective attention and had small effects sizes (Cohen's d, 0.20-0.24). As additional evidence for AT-related effects on scores, gains in test scores for the eAT group were associated with improvements in sleep measures. CONCLUSIONS: Small and selective effects of AT were observed on cognitive tests in children with OSAS without prolonged desaturation. Relative to evidence from Childhood Adenotonsillectomy Trial for larger effects of surgery on sleep, behavior, and quality of life, AT may have limited benefits in reversing any cognitive effects of OSAS, or these benefits may require more extended follow-up to become manifest.

Brief Resolved Unexplained Events (Formerly Apparent Life-Threatening Events) and Evaluation of Lower-Risk Infants.

This is the first clinical practice guideline from the American Academy of Pediatrics that specifically applies to patients who have experienced an apparent life-threatening event (ALTE). This clinical practice guideline has 3 objectives. First, it recommends the replacement of the term ALTE with a new term, brief resolved unexplained event (BRUE). Second, it provides an approach to patient evaluation that is based on the risk that the infant will have a repeat event or has a serious underlying disorder. Finally, it provides management recommendations, or key action statements, for lower-risk infants. The term BRUE is defined as an event occurring in an infant younger than 1 year when the observer reports a sudden, brief, and now resolved episode of ≥1 of the following: (1) cyanosis or pallor; (2) absent, decreased, or irregular breathing; (3) marked change in tone (hyper- or hypotonia); and (4) altered level of responsiveness. A BRUE is diagnosed only when there is no explanation for a qualifying event after conducting an appropriate history and physical examination. By using this definition and framework, infants younger than 1 year who present with a BRUE are categorized either as (1) a lower-risk patient on the basis of history and physical examination for whom evidence-based recommendations for evaluation and management are offered or (2) a higher-risk patient whose history and physical examination suggest the need for further investigation and treatment but for whom recommendations are not offered. This clinical practice guideline is intended to foster a patient- and family-centered approach to care, reduce unnecessary and costly medical interventions, improve patient outcomes, support implementation, and provide direction for future research. Each key action statement indicates a level of evidence, the benefit-harm relationship, and the strength of recommendation.