A stellar stream remnant of a globular cluster below the metallicity floor.

Stellar ejecta gradually enrich the gas out of which subsequent stars form, making the least chemically enriched stellar systems direct fossils of structures formed in the early Universe1. Although a few hundred stars with metal content below 1,000th of the solar iron content are known in the Galaxy2-4, none of them inhabit globular clusters, some of the oldest known stellar structures. These show metal content of at least approximately 0.2% of the solar metallicity [Formula: see text]. This metallicity floor appears universal5,6, and it has been proposed that protogalaxies that merged into the galaxies we observe today were simply not massive enough to form clusters that survived to the present day7. Here we report observations of a stellar stream, C-19, whose metallicity is less than 0.05% of the solar metallicity [Formula: see text]. The low metallicity dispersion and the chemical abundances of the C-19 stars show that this stream is the tidal remnant of the most metal-poor globular cluster ever discovered, and is significantly below the purported metallicity floor: clusters with significantly lower metallicities than observed today existed in the past and contributed their stars to the Milky Way halo.

A bidirectional relationship between sleep and oxidative stress in Drosophila.

Although sleep appears to be broadly conserved in animals, the physiological functions of sleep remain unclear. In this study, we sought to identify a physiological defect common to a diverse group of short-sleeping Drosophila mutants, which might provide insight into the function and regulation of sleep. We found that these short-sleeping mutants share a common phenotype of sensitivity to acute oxidative stress, exhibiting shorter survival times than controls. We further showed that increasing sleep in wild-type flies using genetic or pharmacological approaches increases survival after oxidative challenge. Moreover, reducing oxidative stress in the neurons of wild-type flies by overexpression of antioxidant genes reduces the amount of sleep. Together, these results support the hypothesis that a key function of sleep is to defend against oxidative stress and also point to a reciprocal role for reactive oxygen species (ROS) in neurons in the regulation of sleep.

Tired and stressed: Examining the need for sleep.

A key feature of circadian rhythms is the sleep/wake cycle. Sleep causes reduced responsiveness to the environment, which puts animals in a particularly vulnerable state; yet sleep has been conserved throughout evolution, indicating that it fulfils a vital purpose. A core function of sleep across species has not been identified, but substantial advances in sleep research have been made in recent years using the genetically tractable model organism, Drosophila melanogaster. This review describes the universality of sleep, the regulation of sleep, and current theories on the function of sleep, highlighting a historical and often overlooked theory called the Free Radical Flux Theory of Sleep. Additionally, we summarize our recent work with short-sleeping Drosophila mutants and other genetic and pharmacological tools for manipulating sleep which supports an antioxidant theory of sleep and demonstrates a bi-directional relationship between sleep and oxidative stress.

Criteria for Critical Care Infants and Children: PICU Admission, Discharge, and Triage Practice Statement and Levels of Care Guidance.

OBJECTIVES: To update the American Academy of Pediatrics and Society of Critical Care Medicine's 2004 Guidelines and levels of care for PICU. DESIGN: A task force was appointed by the American College of Critical Care Medicine to follow a standardized and systematic review of the literature using an evidence-based approach. The 2004 Admission, Discharge and Triage Guidelines served as the starting point, and searches in Medline (Ovid), Embase (Ovid), and PubMed resulted in 329 articles published from 2004 to 2016. Only 21 pediatric studies evaluating outcomes related to pediatric level of care, specialized PICU, patient volume, or personnel. Of these, 13 studies were large retrospective registry data analyses, six small single-center studies, and two multicenter survey analyses. Limited high-quality evidence was found, and therefore, a modified Delphi process was used. Liaisons from the American Academy of Pediatrics were included in the panel representing critical care, surgical, and hospital medicine expertise for the development of this practice guidance. The title was amended to "practice statement" and "guidance" because Grading of Recommendations, Assessment, Development, and Evaluation methodology was not possible in this administrative work and to align with requirements put forth by the American Academy of Pediatrics. METHODS: The panel consisted of two groups: a voting group and a writing group. The panel used an iterative collaborative approach to formulate statements on the basis of the literature review and common practice of the pediatric critical care bedside experts and administrators on the task force. Statements were then formulated and presented via an online anonymous voting tool to a voting group using a three-cycle interactive forecasting Delphi method. With each cycle of voting, statements were refined on the basis of votes received and on comments. Voting was conducted between the months of January 2017 and March 2017. The consensus was deemed achieved once 80% or higher scores from the voting group were recorded on any given statement or where there was consensus upon review of comments provided by voters. The Voting Panel was required to vote in all three forecasting events for the final evaluation of the data and inclusion in this work. The writing panel developed admission recommendations by level of care on the basis of voting results. RESULTS: The panel voted on 30 statements, five of which were multicomponent statements addressing characteristics specific to PICU level of care including team structure, technology, education and training, academic pursuits, and indications for transfer to tertiary or quaternary PICU. Of the remaining 25 statements, 17 reached consensus cutoff score. Following a review of the Delphi results and consensus, the recommendations were written. CONCLUSIONS: This practice statement and level of care guidance manuscript addresses important specifications for each PICU level of care, including the team structure and resources, technology and equipment, education and training, quality metrics, admission and discharge criteria, and indications for transfer to a higher level of care. The sparse high-quality evidence led the panel to use a modified Delphi process to seek expert opinion to develop consensus-based recommendations where gaps in the evidence exist. Despite this limitation, the members of the Task Force believe that these recommendations will provide guidance to practitioners in making informed decisions regarding pediatric admission or transfer to the appropriate level of care to achieve best outcomes.

Multi-Stakeholder Informed Guidelines for Direct Admission of Children to Hospital.

OBJECTIVES: To develop pediatric direct admission guidelines and prioritize outcomes to evaluate the safety and effectiveness of hospital admission processes. STUDY DESIGN: We conducted deliberative discussions at 1 children's hospital and 2 community hospitals, engaging parents of hospitalized children and inpatient, outpatient, and emergency department physicians and nurses to identify shared and dissenting perspectives regarding direct admission processes and outcomes. Discussions were audio-recorded, professionally transcribed, and analyzed using a general inductive approach. We then convened a national panel to prioritize guideline components and outcome measures using a RAND/UCLA Modified Delphi approach. RESULTS: Forty-eight stakeholders participated in 6 deliberative discussions. Emergent themes related to effective multistakeholder communication, resources needed for high quality direct admissions, written direct admission guidelines, including criteria to identify children appropriate for and inappropriate for direct admission, and families' needs. Building on these themes, Delphi panelists endorsed 71 guideline components as both appropriate and necessary at children's hospitals and community hospitals and 13 outcomes to evaluate hospital admission systems. Guideline components include (1) pre-admission communication, (2) written guidelines, (3) hospital resources to optimize direct admission processes, (4) special considerations for pediatric populations that may be at particular risk of nosocomial infection and/or stress in emergency departments, (5) communication with families referred for direct admission, and (6) quality reviews to evaluate admission systems. CONCLUSIONS: These direct admission guidelines can be adapted by hospitals and health systems to inform hospital admission policies and protocols. Multistakeholder engagement in evaluation of hospital admission processes may improve transitions of care and health system integration.

Antibiotic Prescribing Patterns Across the Continuum of Care for Children Hospitalized With Community-Acquired Pneumonia.

OBJECTIVES: The aim of this study was to describe the variation in antibiotic prescribing practices for uncomplicated community-acquired pneumonia across the continuum of care for hospitalized pediatric patients to better inform future efforts at standardizing antibiotic therapy throughout a single hospitalization. METHODS: This is a retrospective cohort study involving 4 hospitals caring for children aged 3 months to 18 years, hospitalized between January 1, 2011, and December 31, 2012, with diagnosis of uncomplicated pneumonia and without complex chronic medical conditions.Data collected include antibiotics prescribed before hospitalization, at the emergency department (ED) encounter, during hospitalization, and at hospital discharge. RESULTS: Six hundred nine children met inclusion criteria, with a mean age of 5.3 years and median length of stay of 2 days. Emergency department providers prescribed narrow-spectrum therapy 27% of the time, whereas discharging providers prescribed narrow-spectrum therapy 56% of the time. Third- and fourth-generation cephalosporins were less often prescribed in the preadmission setting and at discharge but were more often prescribed in the ED and inpatient setting. There was an association between inpatient prescription of broad-spectrum antibiotics when a blood culture was obtained, when broad-spectrum antibiotics were prescribed in the ED, and with increasing length of stay. CONCLUSION: Broad-spectrum antibiotic therapy for community-acquired pneumonia, especially third- and fourth-generation cephalosporins, often originates in the ED. When initiated in this setting, it is likely to be continued in the inpatient setting.

An extremely primitive star in the Galactic halo.

The early Universe had a chemical composition consisting of hydrogen, helium and traces of lithium; almost all other elements were subsequently created in stars and supernovae. The mass fraction of elements more massive than helium, Z, is known as 'metallicity'. A number of very metal-poor stars has been found, some of which have a low iron abundance but are rich in carbon, nitrogen and oxygen. For theoretical reasons and because of an observed absence of stars with Z < 1.5 × 10(-5), it has been suggested that low-mass stars cannot form from the primitive interstellar medium until it has been enriched above a critical value of Z, estimated to lie in the range 1.5 × 10(-8) to 1.5 × 10(-6) (ref. 8), although competing theories claiming the contrary do exist. (We use 'low-mass' here to mean a stellar mass of less than 0.8 solar masses, the stars that survive to the present day.) Here we report the chemical composition of a star in the Galactic halo with a very low Z (≤ 6.9 × 10(-7), which is 4.5 × 10(-5) times that of the Sun) and a chemical pattern typical of classical extremely metal-poor stars--that is, without enrichment of carbon, nitrogen and oxygen. This shows that low-mass stars can be formed at very low metallicity, that is, below the critical value of Z. Lithium is not detected, suggesting a low-metallicity extension of the previously observed trend in lithium depletion. Such lithium depletion implies that the stellar material must have experienced temperatures above two million kelvin in its history, given that this is necessary to destroy lithium.

Early cerebral small vessel disease and brain volume, cognition, and gait.

OBJECTIVE: Decline in cognitive function begins by the 40s, and may be related to future dementia risk. We used data from a community-representative study to determine whether there are age-related differences in simple cognitive and gait tests by the 40s, and whether these differences were associated with covert cerebrovascular disease on magnetic resonance imaging (MRI). METHODS: Between 2010 and 2012, 803 participants aged 40 to 75 years in the Prospective Urban Rural Epidemiological (PURE) study, recruited from prespecified postal code regions centered on 4 Canadian cities, underwent brain MRI and simple tests of cognition and gait as part of a substudy (PURE-MIND). RESULTS: Mean age was 58 ± 8 years. Linear decreases in performance on the Montreal Cognitive Assessment, Digit Symbol Substitution Test (DSST), and Timed Up and Go test of gait were seen with each age decade from the 40s to the 70s. Silent brain infarcts were observed in 3% of 40- to 49-year-olds, with increasing prevalence up to 18.9% in 70-year-olds. Silent brain infarcts were associated with slower timed gait and lower volume of supratentorial white matter. Higher volume of supratentorial MRI white matter hyperintensity was associated with slower timed gait and worse performance on DSST, and lower volumes of the supratentorial cortex and white matter, and cerebellum. INTERPRETATION: Covert cerebrovascular disease and its consequences on cognitive and gait performance and brain atrophy are manifest in some clinically asymptomatic persons as early as the 5th decade of life.

Hypotonic versus isotonic fluids in hospitalized children: a systematic review and meta-analysis.

OBJECTIVE: To determine whether the use of hypotonic vs isotonic maintenance fluids confers an increased risk of hyponatremia in hospitalized children. STUDY DESIGN: A search of MEDLINE (1946 to January 2013), the Cochrane Central Registry (1991 to December 2012), Cumulative Index for Nursing and Allied Health Literature (1990 to December 2012), and Pediatric Academic Societies (2000-2012) abstracts was conducted using the terms "hypotonic fluids/saline/solutions" and "isotonic fluids/saline/solutions," and citations were reviewed using a predefined protocol. Data on the primary and secondary outcomes were extracted from original articles by 2 authors independently. Meta-analyses of the primary and secondary outcomes were performed when possible. RESULTS: A total of 1634 citations were screened. Ten studies (n = 893) identified as independent randomized controlled trials were included. Five studies examined subjects in the intensive care unit setting, including 4 on regular wards and 1 in a mixed setting. In hospitalized children receiving maintenance intravenous fluids, hyponatremia was seen more often in those receiving hypotonic fluids than in those receiving isotonic fluids, with an overall relative risk of 2.37 (95% CI, 1.72-3.26). Receipt of hypotonic fluids was associated with a relative risk of moderate hyponatremia (<130 mmol/L) of 6.1 (95% CI, 2.2-17.3). A subgroup analysis of hypotonic fluids with half-normal saline found a relative risk of hyponatremia of 2.42 (95% CI, 1.32-4.45). CONCLUSION: In hospitalized children in intensive care and postoperative settings, the administration of hypotonic maintenance fluids increases the risk of hyponatremia when compared with administration of isotonic fluids. For patients on general wards, insufficient data are available based on the reviewed studies, and individual risk factors must be assessed.

'It's satisfying but destructive': A qualitative study on the experience of bedtime procrastination in new career starters.

BACKGROUND: Bedtime procrastination, the volitional delay of going to bed without any external circumstances causing the delay, is linked to multiple indicators of inadequate sleep. Intervening to reduce bedtime procrastination may be an important avenue to improve sleep outcomes, yet the phenomenon remains poorly understood in populations at risk for bedtime procrastination. New career starters, those who have graduated from tertiary education and started a new full-time job within the past 12 months, may be susceptible to problematic bedtime procrastination and are at an opportune time for a 'fresh start' to change behaviour. AIMS: The objectives of this study were to understand how bedtime procrastination is experienced and perceived by new career starters, to identify the enablers and barriers to behaviour change in new career starters and to explore themes for future interventions. MATERIALS & METHODS: Data were collected through in-depth semi-structured interviews with 28 participants. RESULTS: Inductive thematic analysis was used to find seven themes: (1) negative feelings before and during bedtime procrastination; (2) wanting to versus knowing I shouldn't; (3) difficulty falling asleep; (4) influence of automatic processes; (5) consequences of bedtime procrastination; (6) lack of self-control and (7) technology captures late-night attention. Participants emphasised the need for me-time, self-negotiation to continue procrastinating and knowledge of the value of sleep. DISCUSSION & CONCLUSION: Findings suggest that bedtime procrastination involves both reflective and automatic cognitive processes. Future interventions would benefit from a dual-process approach, using cognitive and behavioural techniques to reduce bedtime procrastination.

Assessing proxy reports: agreement between children with asthma and their caregivers on quality of life.

BACKGROUND: Health-related quality of life (HRQOL) questionnaires are important tools to evaluate health status in children with asthma; however, children with asthma and their caregivers have shown only low to moderate agreement in their responses. OBJECTIVE: To analyze the agreement between children with asthma and their caregivers on HRQOL, specifically in the domains of activity limitation, emotional function, and overall quality of life (QOL). METHODS: We enrolled 79 pediatric patients (ages 5-17 years) with asthma (53 with acute asthma and 26 with refractory asthma) and their caregivers. Children completed the Pediatric Asthma Quality of Life Questionnaire, and caregivers completed the Pediatric Asthma Caregiver's Quality of Life Questionnaire (potential score, 1-7; higher scores indicate better QOL). We used paired t test to examine differences in child and caregiver responses, Pearson correlation to describe patterns of agreement, and multivariate analysis to evaluate the effect of sex, age, and ethnicity on differences in child and caregiver responses. RESULTS: Children with asthma and their caregivers reported similar scores and demonstrated moderate correlation in emotional function and overall QOL. Children reported a significantly better QOL than their caregivers in response to questions about activity limitation (mean score, 4.62 vs 3.49; P < .001). Male children were more likely to differ from their caregivers than females, especially in regard to activity limitation. CONCLUSION: Although caregivers of children with asthma can provide useful proxy information about QOL, their responses cannot be substituted for their children's reports regarding activity limitation. Clinicians and researchers should ask both children and their caregivers about asthma-specific QOL.

Mycoplasma pneumoniae in children with acute and refractory asthma.

BACKGROUND: The presence of Mycoplasma pneumoniae has been associated with worsening asthma in children. Sensitive assays have been developed to detect M pneumoniae-derived community-acquired respiratory distress syndrome (CARDS) toxin. OBJECTIVES: To identify the frequency and persistence of M pneumoniae detection in respiratory secretions of children with and without asthma and to evaluate antibody responses to M pneumoniae and the impact of M pneumoniae on biological markers, asthma control, and quality of life. METHODS: We enrolled 143 pediatric patients (53 patients with acute asthma, 26 patients with refractory asthma, and 64 healthy controls; age range, 5-17 years) during a 20-month period with 2 to 5 follow-up visits. We detected M pneumoniae using CARDS toxin antigen capture and polymerase chain reaction and P1 adhesin polymerase chain reaction. Immune responses to M pneumoniae were determined by IgG and IgM levels directed against CARDS toxin and P1 adhesin. pH was measured in exhaled breath condensates, and asthma control and quality of life were assessed using the Asthma Control Test and Pediatric Asthma Quality of Life Questionnaire. RESULTS: M pneumoniae was detected in 64% of patients with acute asthma, 65% with refractory asthma, and 56% of healthy controls. Children with asthma had lower antibody levels to M pneumoniae compared with healthy controls. Exhaled breath condensate pHs and asthma control and quality of life scores were lower in M pneumoniae-positive patients with asthma. CONCLUSION: The results suggest that M pneumoniae detection is common in children, M pneumoniae detection is associated with worsening asthma, and children with asthma may have poor humoral immune responses to M pneumoniae.

Direct Admission to Hospital for Children in the United States.

One in four unscheduled hospital admissions for children and adolescents in the United States occurs via direct admission, defined as hospital admission without first receiving care in the hospital's emergency department. The purpose of this policy statement is to present recommendations to optimize the quality and safety of this hospital admission approach for children. Recommendations included in this policy statement provide guidance related to: (i) direct admission written guidelines, (ii) clear systems of communication between members of the health care team and with families of children requiring admission, (iii) triage systems to identify patient acuity and disease severity, (iv) identification of hospital resources needed to support direct admission systems of care, (v) consideration of patient populations that may be at increased risk of adverse outcomes during the hospital admission process, (vi) addressing the relevance of local factors and resources, and (vii) ongoing evaluation of direct admission processes and outcomes. The recommendations included in this policy statement are intended to support the implementation of safe direct admission processes and to foster awareness of outcomes associated with this common portal of hospital admission.

Go to bed! A systematic review and meta-analysis of bedtime procrastination correlates and sleep outcomes.

Bedtime procrastination is defined as the volitional delay of going to bed, without any external circumstances causing the delay, and is associated with inadequate sleep. Alleviating bedtime procrastination is an important target for interventions promoting adequate sleep, yet the correlates of bedtime procrastination are poorly understood. This study examined (1) correlates of bedtime procrastination, and (2) strength and direction of the association between bedtime procrastination and sleep outcomes. Six databases (CINAHL, EMBASE, PsychINFO, PubMed, Scopus, Web of Science) were searched from inception to September 2021 against pre-determined eligibility criteria. Forty-three studies were included (GRADE = low). Meta-analysis revealed that bedtime procrastination had a moderate negative association with self-control (z = -0.39; CI: -0.45, -0.29) and a moderate positive association with evening chronotype (z = 0.43; CI: 0.32, 0.48). Furthermore, bedtime procrastination was moderately negatively associated with sleep duration (z = -0.31; CI: -0.37, -0.24), sleep quality (z = -0.35; CI: -0.42, -0.27) and moderately positively associated with daytime fatigue (z = 0.32; CI: 0.25, 0.38). Further high-quality studies are needed to identify causal relationships between bedtime procrastination and correlates, as well as bedtime procrastination and sleep. Future work will guide the development of interventions targeting bedtime procrastination for improved sleep outcomes. STUDY REGISTRATION: PROSPERO registration number CRD42021248891.

Major Adverse Cardiac Events With Immune Checkpoint Inhibitors: A Pooled Analysis of Trials Sponsored by the National Cancer Institute-Cancer Therapy Evaluation Program.

PURPOSE: Major adverse cardiac events (MACEs) because of immune checkpoint inhibitors (ICIs) are infrequent immune-related adverse events (irAEs) that comprise a spectrum of cardiac toxicities with variable manifestations. ICI-related MACEs can lead to significant morbidity and mortality, hence the need to better define presentations of MACEs and their association with noncardiac irAEs in ICI-treated patients. METHODS: We conducted a retrospective pooled analysis of MACE captured in the serious adverse events reporting database of the National Cancer Institute-Cancer Therapy Evaluation Program for National Cancer Institute-sponsored investigational clinical trials between June 2015 and December 2019. Patients were eligible if they had been treated with anti-programmed cell death protein-1 (anti-PD-1)/programmed cell death-ligand 1 (anti-PD-L1) alone or with additional anticancer therapies. RESULTS: A total of 6,925 participants received anti-PD-(L)1-based therapies; 48% (n = 3,354) were treated with single-agent anti-PD-(L)1 therapy. Of 6,925 patients, 0.6% (n = 40) qualified as ICI-related MACE, with 77.5% (n = 31 of 40) being ≥ grade 3. Myocarditis accounted for 45% (n = 18 of 40) of total ICI-MACEs. Concurrent multisystem involvement with other noncardiac irAEs was seen in 65% (n = 26 of 40). Most patients with myocarditis (83%, n = 15 of 18) had one or more noncardiac irAEs associated. Incidence of MACE was higher with anti-PD-(L)1 + targeted therapies compared with anti-PD-(L)1 + anti-cytotoxic T-cell lymphocyte-4 combinations (2.1% v 0.9%, P = .08). There was a higher incidence of myocarditis with anti-PD-(L)1-based combination therapies versus single-agent anti-PD-(L)1 therapies (0.36%, n = 13 of 3,571 v 0.15%, n = 5 of 3,354, P = .08). Deaths related to myocarditis were identified in 22.5% (n = 4 of 18). All four patients who died had concurrent myositis. CONCLUSION: Increasing patient and prescriber awareness in understanding patterns of ICI-MACE and associated noncardiac irAEs should be emphasized. Better characterization of the risk of MACE with the concurrent use of non-ICI-based anticancer therapies with anti-PD-(L)1 treatments is needed.

Guidance for Structuring a Pediatric Intermediate Care Unit.

The purpose of this policy statement is to update the 2004 American Academy of Pediatrics clinical report and provide enhanced guidance for institutions, administrators, and providers in the development and operation of a pediatric intermediate care unit (IMCU). Since 2004, there have been significant advances in pediatric medical, surgical, and critical care that have resulted in an evolution in the acuity and complexity of children potentially requiring IMCU admission. A group of 9 clinical experts in pediatric critical care, hospital medicine, intermediate care, and surgery developed a consensus on priority topics requiring updates, reviewed the relevant evidence, and, through a series of virtual meetings, developed the document. The intended audience of this policy statement is broad and includes pediatric critical care professionals, pediatric hospitalists, pediatric surgeons, other pediatric medical and surgical subspecialists, general pediatricians, nurses, social workers, care coordinators, hospital administrators, health care funders, and policymakers, primarily in resource-rich settings. Key priority topics were delineation of core principles for an IMCU, clarification of target populations, staffing recommendations, and payment.

Incidence of apnea in infants hospitalized with respiratory syncytial virus bronchiolitis: a systematic review.

OBJECTIVE: To determine the incidence of apnea in infants hospitalized with respiratory syncytial virus (RSV) bronchiolitis and identify relevant risk factors from the available literature. STUDY DESIGN: A systematic search of available databases for studies reporting the rate of apnea in a consecutive cohort of infants hospitalized with RSV infection was performed. The overall incidence of apnea was extracted and analyzed in relation to preterm birth, age, and potentially confounding illnesses. RESULTS: The incidence of apnea in the study population of 5575 hospitalized patients with RSV ranged from a high of 23.8% to a low of 1.2%. Comparison of the cohort by term and preterm birth revealed an expected excess in apnea incidence in preterms, even in the absence of information about chronologic age. Many studies appeared to be confounded by the inclusion of impaired infants with neuromuscular disorders. CONCLUSIONS: Based on the available data, precisely quantifying the risk of apnea attributable to RSV infection is not possible. Factors intrinsic to the individual infants may account for a significant percentage of the apnea attributed to RSV. Recent studies have found a < 1% incidence of apnea with RSV in previously healthy term infants.

Practical management of asthma.

OBJECTIVES: After completing this article, readers should be able to: 1. Identify the major environmental factors and comorbid conditions that affect asthma. 2. Describe the role of a written asthma action plan in the management of asthma. 3. Know how to assess asthma control and adjust therapy appropriately. 4. Discuss the evaluation and management of the child who has an acute exacerbation of asthma.

Asthma epidemiology, pathophysiology, and initial evaluation.

The prevalence of asthma and the burden of disease remain high, despite efforts to improve public awareness about and medical management of asthma. Asthma is a disease of airway inflammation that has a variable natural history. Atopy is the most important risk factor for the development of asthma.