ATS core curriculum 2023. Pediatric pulmonary medicine: Respiratory disorders in infants.

The American Thoracic Society Core Curriculum updates clinicians annually in pediatric pulmonary disease. This is a summary of the Pediatric Pulmonary Medicine Core Curriculum presented at the 2023 American Thoracic Society International Conference. The respiratory disorders of infancy discussed in this year's review include: the care of the patient with bronchopulmonary dysplasia in the neonatal intensive care unit, clinical phenotypes and comorbidities; diffuse lung disease; pulmonary hypertension; central and obstructive sleep apnea. The care of infants with respiratory disorders often poses significant challenges to the general pediatric pulmonologist, sleep clinician, and neonatologist. This review aims to highlight the most clinically relevant aspects of the evaluation, management, and outcomes of infants with these key respiratory disorders, while emphasizing the importance of multidisciplinary care. Furthermore, this document summarizes essential aspects of genetic testing, novel imaging and treatment modalities, and includes multiple resources for clinical practice.

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.

Assessing the role of tracheostomy placement in bronchopulmonary dysplasia with pulmonary hypertension.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth and is associated with abnormal vasculature that contributes to pulmonary hypertension (PH). We evaluated how a tracheostomy may alter PH in these patients. METHODS: A retrospective chart review over 15-years identified 17 patients with BPD and PH who underwent tracheostomy. Each patient had four echocardiograms re-reviewed and scored for tricuspid valve regurgitation velocity (TR), tricuspid annular plane systolic excursion (TAPSE), right atrial cross-sectional area (RACA), and left ventricle eccentricity indices (EI). RESULT: There was improvement in TR, TAPSE, RACA, and left ventricle EI indicating reduction in PH after tracheostomy. CONCLUSION: PH improves over time though role of tracheostomy in PH needs to be further defined. The EI may be a sensitive marker to follow over time in these patients.

Role of miRNAs to control the progression of Chronic Myeloid Leukemia by their expression levels.

Chronic Myeloid Leukemia (CML) is a myeloproliferative disorder distinguished by a specific genetic anomaly known as a reciprocal translocation between chromosomes 9 and 22. This translocation causes fusion between the BCR and ABL regions. Consequently, BCR::ABL oncoprotein is formed, which plays a significant role in driving CML progression. Imatinib, a tyrosine kinase inhibitor (TKI), became the first line of drugs against CML. However, with continuous treatment, patients developed resistance against it. Indeed, to address this challenge, microRNA-based therapy emerges as a promising approach. miRNAs are 20-25 nucleotides long and hold great significance in various cellular processes, including cell differentiation, proliferation, migration, and apoptosis. In several malignancies, it has been reported that miRNAs might help to promote or prevent tumourigenesis and abnormal expression because they could act as both oncogenes/tumor suppressors. Recently, because of their vital regulatory function in maintaining cell homeostasis, miRNAs might be used to control CML progression and in developing new therapies for TKI-resistant patients. They might also act as potential prognostic, diagnostic, and therapeutic biomarkers based on their expression profiles. Various annotation tools and microarray-based expression profiles can be used to predict dysregulated miRNAs and their target genes. The main purpose of this review is to provide brief insights into the role of dysregulated miRNAs in CML pathogenesis and to emphasize their clinical relevance, such as their significant potential as therapeutics against CML. Utilizing these miRNAs as a therapeutic approach by inhibition or amplification of their activity could unlock new doors for the therapy of CML.

Number of children in the household influences respiratory morbidities in children with bronchopulmonary dysplasia in the outpatient setting.

BACKGROUND: Bronchopulmonary dysplasia (BPD), a common complication of prematurity, is associated with outpatient morbidities, including respiratory exacerbations. Daycare attendance is associated with increased rates of acute and chronic morbidities in children with BPD. We sought to determine if additional children in the household conferred similar risks for children with BPD. METHODS: The number of children in the household and clinical outcomes were obtained via validated instruments for 933 subjects recruited from 13 BPD specialty clinics in the United States. Clustered logistic regression models were used to test for associations. RESULTS: The mean gestational age of the study population was 26.5 ± 2.2 weeks and most subjects (69.1%) had severe BPD. The mean number of children in households (including the subject) was 2.1 ± 1.3 children. Each additional child in the household was associated with a 13% increased risk for hospital admission, 13% increased risk for antibiotic use for respiratory illnesses, 10% increased risk for coughing/wheezing/shortness of breath, 14% increased risk for nighttime symptoms, and 18% increased risk for rescue medication use. Additional analyses found that the increased risks were most prominent when there were three or more other children in the household. CONCLUSIONS: We observed that additional children in the household were a risk factor for adverse respiratory outcomes. We speculate that secondary person-to-person transmission of respiratory viral infections drives this finding. While this risk factor is not easily modified, measures do exist to mitigate this disease burden. Further studies are needed to define best practices for mitigating this risk associated with household viral transmission.

The US national registry for childhood interstitial and diffuse lung disease: Report of study design and initial enrollment cohort.

INTRODUCTION: Childhood interstitial and diffuse lung disease (chILD) encompasses a broad spectrum of rare disorders. The Children's Interstitial and Diffuse Lung Disease Research Network (chILDRN) established a prospective registry to advance knowledge regarding etiology, phenotype, natural history, and management of these disorders. METHODS: This longitudinal, observational, multicenter registry utilizes single-IRB reliance agreements, with participation from 25 chILDRN centers across the U.S. Clinical data are collected and managed using the Research Electronic Data Capture (REDCap) electronic data platform. RESULTS: We report the study design and selected elements of the initial Registry enrollment cohort, which includes 683 subjects with a broad range of chILD diagnoses. The most common diagnosis reported was neuroendocrine cell hyperplasia of infancy, with 155 (23%) subjects. Components of underlying disease biology were identified by enrolling sites, with cohorts of interstitial fibrosis, immune dysregulation, and airway disease being most commonly reported. Prominent morbidities affecting enrolled children included home supplemental oxygen use (63%) and failure to thrive (46%). CONCLUSION: This Registry is the largest longitudinal chILD cohort in the United States to date, providing a powerful framework for collaborating centers committed to improving the understanding and treatment of these rare disorders.

When to panic about a panic attack: A challenging case of hypersensitivity pneumonitis.

The COVID-19 pandemic has created diagnostic difficulties with the increase in mental health illnesses that often present with nonspecific symptoms, like hypersensitivity pneumonitis. Hypersensitivity pneumonitis is a complex syndrome of varying triggers, onset, severity, and clinical manifestations that can be challenging to diagnose in many cases. Typical symptoms are nonspecific and can be attributed to other entities. There are no pediatric guidelines, which contributes to diagnostic difficulties and delays in treatment. It is particularly important to avoid diagnostic biases, have an index of suspicion for hypersensitivity pneumonitis, and to develop pediatric guidelines as outcomes are excellent when diagnosed and treated promptly. This article discusses hypersensitivity pneumonitis with a focus on the causes, pathogenesis, diagnostic approach, outcomes, and prognosis while using a case to illustrate the diagnostic difficulties worsened by the COVID-19 pandemic.

Respiratory Outcomes for Ventilator-Dependent Children With Bronchopulmonary Dysplasia.

OBJECTIVES: To describe outpatient respiratory outcomes and center-level variability among children with severe bronchopulmonary dysplasia (BPD) who require tracheostomy and long-term mechanical ventilation. METHODS: Retrospective cohort of subjects with severe BPD, born between 2016 and 2021, who received tracheostomy and were discharged on home ventilator support from 12 tertiary care centers participating in the BPD Collaborative Outpatient Registry. Timing of key respiratory events including time to tracheostomy placement, initial hospital discharge, first outpatient clinic visit, liberation from the ventilator, and decannulation were assessed using Kaplan-Meier analysis. Differences between centers for the timing of events were assessed via log-rank tests. RESULTS: There were 155 patients who met inclusion criteria. Median age at the time of the study was 32 months. The median age of tracheostomy placement was 5 months (48 weeks' postmenstrual age). The median ages of hospital discharge and first respiratory clinic visit were 10 months and 11 months of age, respectively. During the study period, 64% of the subjects were liberated from the ventilator at a median age of 27 months and 32% were decannulated at a median age of 49 months. The median ages for all key events differed significantly by center (P ≤ .001 for all events). CONCLUSIONS: There is wide variability in the outpatient respiratory outcomes of ventilator-dependent infants and children with severe BPD. Further studies are needed to identify the factors that contribute to variability in practice among the different BPD outpatient centers, which may include inpatient practices.

Validation of an outpatient questionnaire for bronchopulmonary dysplasia control.

INTRODUCTION: Despite bronchopulmonary dysplasia (BPD) being a common morbidity of preterm birth, there is no validated objective tool to assess outpatient respiratory symptom control for clinical and research purposes. METHODS: Data were obtained from 1049 preterm infants and children seen in outpatient BPD clinics of 13 US tertiary care centers from 2018 to 2022. A new standardized instrument was modified from an asthma control test questionnaire and administered at the time of clinic visits. External measures of acute care use were also collected. The questionnaire for BPD control was validated in the entire population and selected subgroups using standard methodology for internal reliability, construct validity, and discriminative properties. RESULTS: Based on the scores from BPD control questionnaire, the majority of caregivers (86.2%) felt their child's symptoms were under control, which did not differ by BPD severity (p = 0.30) or a history of pulmonary hypertension (p = 0.42). Across the entire population and selected subgroups, the BPD control questionnaire was internally reliable, suggestive of construct validity (albeit correlation coefficients were -0.2 to -0.4.), and discriminated control well. Control categories (controlled, partially controlled, and uncontrolled) were also predictive of sick visits, emergency department visits, and hospital readmissions. CONCLUSION: Our study provides a tool for assessing respiratory control in children with BPD for clinical care and research studies. Further work is needed to identify modifiable predictors of disease control and link scores from the BPD control questionnaire to other measures of respiratory health such as lung function testing.

Identifying Posterior Fossa Abnormality in Pediatric Aerodigestive Patients, a Case Series.

OBJECTIVES: Multidisciplinary clinics like Aerodigestive programs focus on issues associated with airway, pulmonary, and gastrointestinal issues. Rarely, significant neurological issues like posterior fossa abnormality are identified as the primary etiology. We describe 3 such patients and compare their clinical presentation to the other patients seen in Aerodigestive clinic. METHODS: A retrospective chart review was conducted to review the 3 posterior fossa patients and the remainder of children that were referred to the Aerodigestive Clinic at Children's Hospital Los Angeles from June 2016 to August 2018. Clinical characteristics including triple endoscopies and sleep studies were recorded. RESULTS: Of the 110 patients included for review, 3 patients (3%) had an underlying posterior fossa abnormality; all of whom had symptoms of sleep disordered breathing along with dysphagia compared with 30% incidence of this symptom profile in the remaining Aerodigestive population. CONCLUSION: Presence of sleep disordered breathing and dysphagia, with underlying vomiting history, warrants considering evaluation for posterior fossa abnormalities in addition to traditional workup for aerodigestive disorders. Due to the rarity of this presentation and small sample size, future studies with multicenter collaboration may help better describe identifiers to delineate this population with similar aerodigestive symptoms and clarify diagnostic algorithms.

Daycare Attendance is Linked to Increased Risk of Respiratory Morbidities in Children Born Preterm with Bronchopulmonary Dysplasia.

OBJECTIVES: To test the hypothesis that daycare attendance among children with bronchopulmonary dysplasia (BPD) is associated with increased chronic respiratory symptoms and/or greater health care use for respiratory illnesses during the first 3 years of life. STUDY DESIGN: Daycare attendance and clinical outcomes were obtained via standardized instruments for 341 subjects recruited from 9 BPD specialty clinics in the US. All subjects were former infants born preterm (<34 weeks) with BPD (71% severe) requiring outpatient follow-up between 0 and 3 years of age. Mixed logistic regression models were used to test for associations. RESULTS: Children with BPD attending daycare were more likely to have emergency department visits and systemic steroid usage. Children in daycare up to 3 years of age also were more likely to report trouble breathing, having activity limitations, and using rescue medications when compared with children not in daycare. More severe manifestations were found in children attending daycare between 6 and 12 months of chronological age. CONCLUSIONS: In this study, children born preterm with BPD who attend daycare were more likely to visit the emergency department, use systemic steroids, and have chronic respiratory symptoms compared with children not in daycare, indicating that daycare may be a potential modifiable risk factor to minimize respiratory morbidities in children with BPD during the preschool years.

Insurance coverage and respiratory morbidities in bronchopulmonary dysplasia.

INTRODUCTION: Preterm infants and young children with bronchopulmonary dysplasia (BPD) are at increased risk for acute care utilization and chronic respiratory symptoms during early life. Identifying risk factors for respiratory morbidities in the outpatient setting could decrease the burden of care. We hypothesized that public insurance coverage was associated with higher acute care usage and respiratory symptoms in preterm infants and children with BPD after initial neonatal intensive care unit (NICU) discharge. METHODS: Subjects were recruited from BPD clinics at 10 tertiary care centers in the United States between 2018 and 2021. Demographics and clinical characteristics were obtained through chart review. Surveys for clinical outcomes were administered to caregivers. RESULTS: Of the 470 subjects included in this study, 249 (53.0%) received employer-based insurance coverage and 221 (47.0%) received Medicaid as sole coverage at least once between 0 and 3 years of age. The Medicaid group was twice as likely to have sick visits (adjusted odd ratio [OR]: 2.06; p = 0.009) and emergency department visits (aOR: 2.09; p = 0.028), and three times more likely to be admitted for respiratory reasons (aOR: 3.04; p = 0.001) than those in the employer-based group. Additionally, those in the Medicaid group were more likely to have nighttime respiratory symptoms (aOR: 2.62; p = 0.004). CONCLUSIONS: Children with BPD who received Medicaid coverage were more likely to utilize acute care and have nighttime respiratory symptoms during the first 3 years of life. More comprehensive studies are needed to determine whether the use of Medicaid represents a barrier to accessing care, lower socioeconomic status, and/or a proxy for detrimental environmental exposures.

Perioperative respiratory adverse events in children undergoing triple endoscopy.

OBJECTIVES: Children with aerodigestive disorders often have many of the reported risk factors for development of perioperative respiratory adverse events. This study sought to evaluate the incidence of such events in this group of patients undergoing general anesthesia for "triple endoscopy" (flexible bronchoscopy with bronchoalveolar lavage, rigid laryngoscopy and bronchoscopy, and esophagogastroduodenoscopy) and to identify any patient-specific or procedure-specific risk factors associated with higher incidence of perioperative respiratory adverse events. METHODS: We performed a retrospective chart review of children 18 years or younger who underwent triple endoscopy as part of an aerodigestive evaluation. Data collected from medical records included: preoperative polysomnography, symptoms of acute respiratory illness, medical comorbidities, demographics, postoperative hospital or intensive care unit admission, and all respiratory events and interventions in the perioperative period. Patient-specific and procedure-specific factors were investigated via univariate analysis for any correlations with perioperative respiratory adverse events. RESULTS: Of the 122 patients undergoing triple endoscopy, 69 (57%) experienced a perioperative respiratory adverse event. We found no difference in the incidence of perioperative respiratory adverse events among children with documented lung disease compared with those with no lung disease (OR: 0.89, p = .8 95% CI: 0.43, 1.8), and no significant difference between those children who had a respiratory illness at the time of surgery, 1-2 weeks prior, 3-4 weeks prior, and those with no preceding respiratory illness. A higher percentage of males had a perioperative respiratory adverse event, compared with females (OR: 2.7, p = .01 95% CI: 1.3, 5.09). CONCLUSION: Patients undergoing triple endoscopy for evaluation of aerodigestive disorders at our institution experienced perioperative respiratory adverse events at a rate of 57%.

Bronchiectasis and Bronchiolectasis With Severe Herniating Pattern Associated With STAT1 Gain-of-Function Mutation: Detailed Clinicopathological Findings.

STAT1 gain-of-function (GOF) mutations are associated with a rare autosomal dominant immunodeficiency disorder with main clinical manifestations including chronic mucocutaneous candidiasis (CMC) and bronchiectasis. In addition, these patients show higher incidences of cerebral and extracerebral aneurysm, malignancies and various autoimmune conditions compared to the general population. Although previous publications have reported clinical findings in patients with STAT1 GOF mutation, they did not include histopathologic features. Herein, we describe the first case with detailed histologic findings in the lung of a 5-year-old patient with a de novo STAT1 GOF mutation, who presented with CMC and bronchiectasis. The biopsy showed severe bronchiolectasis with extensive airway dilatation and occasional disruptions. Peribronchiolar inflammation was not always present and evident mainly in areas of airway disruption; inflammation may have not been a main driver of the airway damage in this case. The airway dilatation often showed an interesting herniating pattern, possibly implying a connective tissue etiology. This case also demonstrates the diagnostic utility of whole exome sequencing as STAT1 GOF mutations are not detected by routine workup. The definitive diagnosis will lead to more specific treatments and increased surveillance for serious conditions, such as cerebral aneurysms and malignancies.

Retrospective analysis of inpatient polysomnogram characteristics and discharge outcomes in infants with bronchopulmonary dysplasia requiring home oxygen therapy.

RATIONALE: Little is known about the polysomnogram (PSG) characteristics in infants with bronchopulmonary dysplasia (BPD), especially severe BPD, who do not need home ventilatory support but are at increased risk for chronic hypoxia and are vulnerable to its effects. OBJECTIVE: This study aims to assess PSG characteristics and change in discharge outcomes in premature infants with BPD who required oxygen therapy at discharge. METHODS: This is a retrospective chart review of premature infants with BPD who were admitted to a quaternary newborn and infant intensive care unit from January 1, 2012 to December 31, 2015 and who underwent polysomnography before discharge. MEASUREMENTS AND MAIN RESULTS: Data from 127 patients were analyzed. The median gestational age of our patients was 26 weeks and 1 day (interquartile range [IQR]: 24.71, 28.86). The majority of the patients had moderate-to-severe BPD. The median obstructive apnea-hypopnea index was 5.3 events/h (IQR: 2.2, 10.1). The median oxygen desaturation index was 15.7 events/h (IQR: 4.7, 35). Nadir oxygen saturation measured by pulse oximeter was 81% (IQR: 76-86) and the arousal/awakening index was 21.9 (IQR: 13.3-30.9). No statistically significant difference was noted between severe and nonsevere BPD groups for PSG characteristics. However, average end-tidal CO2 was significantly higher in the severe BPD group (p = .0438). Infants in the severe BPD group were intubated longer than infants with nonsevere BPD (p = .0082). The corrected gestational age (CGA) at the time of discharge (CGA-PSG) and PSG (CGA-DC) was higher in severe BPD patients but not statistically different. The majority of premature infants who underwent a PSG were discharged home with oxygen, and 69% required a titration of their level of support based on results from the PSG. CONCLUSION: Our results highlight the presence of abnormal PSG characteristics in BPD patients, as early as 43 weeks CGA. These findings have not been previously described in this patient population prior to initial discharge from the hospital. A severe BPD phenotype tends to be associated with higher respiratory morbidity compared with a nonsevere BPD phenotype for the comparable CGA. PSG, when available, may be helpful for individualizing and streamlining treatment in preparation for discharge home and mitigating the effects of intermittent hypoxic episodes.

Successful Induction Treatment With Rituximab of Isolated Pauci-Immune Pulmonary Capillaritis Presenting as Diffuse Alveolar Hemorrhage in a Pediatric Patient.

Diffuse alveolar hemorrhage often presents as dyspnea, cough, or hemoptysis, and it is mediated by both immune and nonimmune processes. Isolated pauci-immune capillaritis (IPPC) is a rare diagnosis in which capillaritis, small-vessel vasculitis of the lung, is found on biopsy in the absence of an underlying systemic disorder. Traditionally, IPPC has been treated similarly to anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis with cyclophosphamide and glucocorticoids. However, few cases describing management options are available in the literature, especially among pediatric patients. Our report of successful induction of remission in an adolescent girl suggests that the combination of IV rituximab and pulse methylprednisolone may be a viable option for disease control in pediatric patients with IPPC.

Factors impacting participation in flexible endoscopic evaluation of swallowing in children.

OBJECTIVES: Flexible endoscopic evaluation of swallowing (FEES) is a common and useful tool for assessment of dysphagia and swallowing safety in children, however an important problem is limited participation in some children. We examine the factors associated with adequate participation in children undergoing FEES, including the completion rate, whether a clear diagnosis or feeding plan was made, and the incidence of adverse events (AEs). METHODS: We conducted a retrospective review of children undergoing FEES at an urban children's hospital. Data collected included age, gender, race, comorbidities, AEs and outcomes of FEES. RESULTS: Of the 130 patients, 46 (35%) were female with a median age of 2.6 years. 113 (87%) patients cooperated and obtained a result, while 15 (12%) patients did not cooperate and no result was obtained; there was no significant difference in gender, comorbidities, or race between those groups. The age distribution of FEES subjects in this study was skewed with nearly 75% below age 5. Patients who cooperated had a higher median age (3 years) than those who did not (1.2 years) and 47% of non-cooperators were less than 1 year of age. There were no significant AEs, the most common mild AE was excessive crying (34 subjects, 26%). In a multivariate model controlling for age and gender, excessive crying was associated with a decreased odds of cooperation (OR: 0.16, p = 0.004, 95% CI: 0.04, 0.54). CONCLUSION: Children who undergo FEES have an overall favorable completion rate and no serious adverse events, however its utility is limited in cases where children refuse to participate. Understanding the factors associated with failure to cooperate with FEES is important in developing strategies to improve participation. Excessive crying is identified as such a factor in this study.

Pulmonary manifestations of rheumatologic diseases.

PURPOSE OF REVIEW: The present review intends to provide an overview of the diversity and complexity of pulmonary manifestations of rheumatologic diseases and gaps in knowledge to effectively manage them. RECENT FINDINGS: Diffuse lung disease in children with rheumatologic diseases represents a heterogeneous group of autoimmune disorders. Despite their significant morbidity and mortality, we have limited understanding about their pathogenesis. Here, we provide an overview of the pathophysiology and current management approach of these disorders, highlighting tools which assist with diagnosis, risk stratification and therapy. In this context, we address the need to develop a standardized approach to diagnose at-risk patients with rheumatologic disease and to predict their progression and the need to develop robust studies which evaluate the factors and interventions that influence pulmonary disease outcome. SUMMARY: Diffuse lung disease in children with rheumatologic diseases represents a heterogeneous group of severe autoimmune disorders. By adopting a collaborative research approach among multicenters to help diagnose, risk stratify, and understand disease progression, effective management decisions can be optimized to improve clinical outcome.

Anti-coagulant therapy with dabigatran for cystic fibrosis patients.

Patients with cystic fibrosis (CF) are at increased risk of venous thromboembolism, especially in association with central venous catheter use. Coumarin drugs and low molecular weight heparin are frequently used for anti-coagulant therapy, but are more challenging to administer in CF patients. Dabigatran, an oral thrombin antagonist, is an alternative anti-coagulant medication, but its use in CF has not been reported. We describe our experience in successfully using dabigatran for long-term anti-coagulation therapy in two CF patients. Our experience suggests that dabigatran can serve as an option for anticoagulation therapy in CF. Pediatr Pulmonol. 2016;51:E29-E30. © 2016 Wiley Periodicals, Inc.