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Abstract-Pulmonary hypertension is associated with diverse cardiac, pulmonary, and systemic diseases in neonates, infants, and older children and contributes to significant morbidity and mortality. However, current approaches to caring for pediatric patients with pulmonary hypertension have been limited by the lack of consensus guidelines from experts in the field. In a joint effort from the American Heart Association and American Thoracic Society, a panel of experienced clinicians and clinician-scientists was assembled to review the current literature and to make recommendations on the diagnosis, evaluation, and treatment of pediatric pulmonary hypertension. This publication presents the results of extensive literature reviews, discussions, and formal scoring of recommendations for the care of children with pulmonary hypertension. Key Words: AHA Scientific Statements ◼ bronchopulmonary dysplasia ◼ congenital diaphragmatic hernia ◼ congenital heart disease ◼ genetics ◼ persistent pulmonary hypertension of the newborn ◼ sickle cell disease © 2015 by the American Heart Association, Inc., and the American Thoracic Society.Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIR.0000000000000329 †Deceased. The American Heart Association and the American Thoracic Society make every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.This document was approved by the American Heart Association Science Advisory and Coordinating Committee on May 12, 2015, the American Heart Association Executive Committee on July 22, 2015, and the American Thoracic Society on July 24, 2015.The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIR.0000000000000329/-/DC1. The American Heart Association requests that this document be cited as follows: Abman SH, Hansmann G, Archer SL, Ivy DD, Adatia I, Chung WK, Hanna BD, Rosenzweig EB, Raj JU, Cornfield D, Stenmark KR, Steinhorn R, Thébaud B, Fineman JR, Kuehne T, Feinstein JA, Friedberg MK, Earing M, Barst RJ, Keller RL, Kinsella JP, Mullen M, Deterding R, Kulik T, Mallory G, Humpl T, Wessel DL; on behalf of the American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation, Council on Clinical Cardiology, Council on Cardiovascular Disease in the Young, Council on Cardiovascular Radiology and Intervention, Council on Cardiovascular Surgery and Anesthesia, and the American Thoracic Society. Pediatric pulmonary hypertension: guidelines from the American Heart Association and American Thoracic Society. Circulation. 2015;132:2037-2099 Copies: This document is available on the World Wide Web site of the American Heart Associat...

Culture of bronchoalveolar lavage fluid (BALF) is the gold standard for detection of pathogens in the lower airways in cystic fibrosis (CF). However, current culture results do not explain all clinical observations in CF, including negative culture results during pulmonary exacerbation and inflammation in the absence of pathogens. We hypothesize that organisms not routinely identified by culture occur in the CF airway and may contribute to disease. To test this hypothesis we used a culture-independent molecular approach, based on use of rRNA sequence analysis, to assess the bacterial composition of BALF from children with CF and disease controls (DC). Specimens from 42 subjects (28 CF) were examined, and Ϸ6,600 total clones were screened to identify 121 species of bacteria. In general, a single rRNA type dominated clone libraries from CF specimens, but not DC. Thirteen CF subjects contained bacteria that are not routinely assessed by culture. In four CF subjects, candidate pathogens were identified and include the anaerobe Prevotella denticola, a Lysobacter sp., and members of the Rickettsiales. The presumptive pathogens Tropheryma whipplei and Granulicatella elegans were identified in cases from the DC group. The presence of unexpected bacteria in CF may explain inflammation without documented pathogens and consequent failure to respond to standard treatment. These results show that molecular techniques provide a broader perspective on airway bacteria than do routine clinical cultures and thus can identify targets for further clinical evaluation. pulmonary microbiology ͉ ribosomal RNA C ystic fibrosis (CF), the most common autosomal lethal disease in Caucasians, is caused by mutation in the CF transmembrane conductance regulator gene, which results in a generalized exocrinopathy (1). Thickened secretions caused by improper regulation of airway surface liquid contribute to the accumulation of mucus in the airway and defective mucociliary clearance (2). Retained mucus plugs provide a niche for bacterial colonization and persistence. Most morbidity and mortality associated with CF is attributed to microbial infections in the airway and the persistent inflammatory response (3).A small number of pathogens are recognized traditionally in CF airway disease. These include Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, and the Burkholderia cepacia complex (4-7). Other bacteria, including Stenotrophomonas maltophilia and Achromobacter xylosoxidans, also are associated with CF, but there is controversy as to their roles as pathogens (8)(9)(10). This view of bacteria associated with CF is based on culture, however, which may not recover or identify all bacteria present in a specimen. Although known pathogens clearly are important in airway disease, a more comprehensive picture of the bacterial community in the CF airway potentially could lead to improved insight about the disease and thus better treatment. For instance, ''normal'' microbiota that are commonly present, but not considered pathogenic, ...

We sought to determine the clinical course and histologic findings in lung biopsies from a group of children who presented with signs and symptoms of interstitial lung disease (ILD) without identified etiology. Patients were identified from the pathology files at the Texas Children's Hospital who presented below age 2 years with persistent tachypnea, hypoxia, retractions, or respiratory crackles, and with nonspecific and nondiagnostic lung biopsy findings. Age-matched lung biopsy controls were also identified. Their clinical courses were retrospectively reviewed. Biopsies were reviewed, and immunostaining with antibodies to neuroendocrine cells was done. Fifteen pediatric ILD patients and four control patients were identified for inclusion in the study. Clinically, the mean onset of symptoms was 3.8 months (range, 0-11 months). Radiographs demonstrated hyperinflation, interstitial markings, and ground-glass densities. Oxygen was initially required for prolonged periods, and medication trials did not eliminate symptoms. After a mean of 5 years, no deaths had occurred, and patients had improved. On review of the lung biopsies, all had a similar appearance, with few abnormalities noted. Immunostaining with antibodies to neuroendocrine cell products showed consistently increased bombesin staining. Subsequent morphometric analysis showed that immunoreactivity for bombesin and serotonin was significantly increased over age-matched controls. In conclusion, we believe this may represent a distinct group of pediatric patients defined by the absence of known lung diseases, clinical signs and symptoms of ILD, and idiopathic neuroendocrine cell hyperplasia of infancy. These findings may be important for the evaluation of ILD in young children.

Differentiation of functional thyroid epithelia from pluripotent stem cells (PSCs) holds the potential for application in regenerative medicine. However, progress toward this goal is hampered by incomplete understanding of the signaling pathways needed for directed differentiation without forced over-expression of exogenous transgenes. Here we use mouse PSCs to identify key conserved roles for BMP and FGF signaling in regulating thyroid lineage specification from foregut endoderm in mouse and Xenopus. Thyroid progenitors derived from mouse PSCs can be matured into thyroid follicular organoids that provide functional secretion of thyroid hormones in vivo and rescue hypothyroid mice after transplantation. Moreover, by stimulating the same pathways we were also able to derive human thyroid progenitors from normal and disease-specific iPSCs generated from patients with hypothyroidism resulting from NKX2-1 haploinsufficiency. Our studies have therefore uncovered the regulatory mechanisms that underlie early thyroid organogenesis and provide a significant step toward cell-based regenerative therapy for hypothyroidism.