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The management of acute hypoxemic respiratory failure (AHRF) in newborns continues to be a clinical challenge with elevated risk for significant morbidities and mortality, especially when accompanied with persistent pulmonary hypertension of the newborn (PPHN). PPHN is a syndrome characterized by marked hypoxemia secondary to extrapulmonary right-to-left shunting across the ductus arteriosus and/or foramen ovale with high pulmonary artery pressure and increased pulmonary vascular resistance (PVR). After optimizing respiratory support, cardiac performance and systemic hemodynamics, targeting persistent elevations in PVR with inhaled nitric oxide (iNO) therapy has improved outcomes of neonates with PPHN physiology. Despite aggressive cardiopulmonary management, a significant proportion of patients have an inadequate response to iNO therapy, prompting consideration for additional pulmonary vasodilator therapy. This article reviews the pathophysiology and management of PPHN in term newborns with AHRF while highlighting both animal and human data to inform a physiologic approach to the use of PH-targeted therapies.

The purpose of this report is to make what is “invisible” visible and to suggest three evidence-based strategies that have the capacity to enable educators, in collaboration with the families and the communities they serve, to create learning environments where students living in deep poverty are supported and successful. The report begins by documenting the human cost of deep poverty and how past policy decisions have contributed to the persistence of deep poverty. Based on this background, the report focuses on three promising strategies for meeting the learning and social-emotional needs of all children, including those living in deep poverty: (1) begin with funding adequacy and equity, (2) develop community schools and partnerships, and (3) develop a whole child teaching and learning culture.

OBJECTIVES: Recent evidence suggests that measuring the procalcitonin level may improve identification of low-risk febrile infants who may not need intervention. We describe outcomes after the implementation of a febrile infant clinical pathway recommending measurement of the procalcitonin level for risk stratification. METHODS: In this single-center retrospective pre-post intervention study of febrile infants aged 29 to 60 days, we used interrupted time series analyses to evaluate outcomes of lumbar puncture (LP), antibiotic administration, hospital admission, and emergency department (ED) length of stay (LOS). A multivariable logistic regression was used to evaluate the odds of LP. RESULTS: Data were analyzed between January 2017 and December 2019 and included 740 participants. Procalcitonin use increased post–pathway implementation (PI). The proportion of low-risk infants receiving an LP decreased significantly post-PI (P = .001). In the adjusted interrupted time series analysis, there was no immediate level change (shift) post-PI for LP (0.98 [95% confidence interval (CI): 0.49–1.97]), antibiotics (1.17 [95% CI: 0.56–2.43]), admission (1.07 [95% CI: 0.59–1.96]), or ED LOS (1.08 [95% CI: 0.92–1.28]), and there was no slope change post-PI versus pre-PI for any measure (LP: 1.01 [95% CI: 0.94–1.08]; antibiotics: 1.00 [95% CI: 0.93–1.08]; admission: 1.03 [95% CI: 0.97–1.09]; ED LOS: 1.01 [95% CI: 0.99–1.02]). More patients were considered high risk, and fewer had incomplete laboratory test results post-PI (P < .001). There were no missed serious bacterial infections. A normal procalcitonin level significantly decreased the odds of LP (P < .001). CONCLUSIONS: Clinicians quickly adopted procalcitonin testing. Resource use for low-risk infants decreased; however, there was no change to resource use for the overall population because more infants underwent laboratory evaluation and were classified as high risk post-PI.

Introduction There is limited evidence regarding the optimal number of sampling sites and specimen dimension in histological diagnosis of malignant pleural mesothelioma (MPM). Previously we have validated 2-tier nuclear grade as an independent predictor of survival in epithelioid MPM. This study evaluates the association between sampling parameters and the performance of 2-tier nuclear grade and growth pattern as survival predictors using a biopsy-heavy cohort. Methods Clinicopathological information including the number of sampling sites, tissue dimension, 2-tier nuclear grade, predominant growth pattern and overall survival (OS) were retrieved from an institutional mesothelioma database comprising 614 consecutive cases of epithelioid MPM over a 15 year period. Survival analysis was performed using Kaplan-Meier method. Association between categorical variables was analysed using Fisher exact test, and was assessed in relation to biopsy size and number. Statistical significance was defined as p Results The mean age was 69.1 years, with male preponderance (75.6%). 87.0% (534/614) received biopsy only. The median number of sites sampled was 1 (range 1–20). The median maximum tissue dimension was 18 mm for biopsies (range 2–140 mm) and 145 mm for resections (range 40–350 mm). 17.7% of all biopsies (95/534) were taken from a single site with a maximum dimension of ≤10 mm (median: 8 mm). Low grade tumours showed significantly prolonged OS compared with high grade (19.3 months vs. 8.9 months, p Conclusions We propose an optimal sampling standard of 3 sites or a maximum tissue dimension of ≥20 mm from a single site. This then allows a 2-tier nuclear grading system to provide prognostic stratification for clinical care and research of epithelioid MPM.

Introduction Two quality of life instruments are widely used in bronchiectasis clinical trials, the Quality of Life bronchiectasis questionnaire and the St Georges Respiratory Questionnaire with few large scale multi-centre direct comparisons. Convergent validity represents an assessment of the instrument against other measures that are considered to represent severity of disease, since a valid instrument should agree with clinical assessments of severity of disease and disease burden. We evaluated the convergent validity in the BRONCH-UK dataset. Methods Prospective registry of adults with bronchiectasis from 13 secondary care centres across the UK, embedded within the EMBARC European platform. Patients completed baseline QOL-B and SGRQ and comprehensive clinical assessment. Linear regression and Spearman correlation evaluated the relationship between QOL scores and clinical variables. Results 1403 patients were recruited. We report data on the first 813 with complete core datasets; 504 were female (62%), 309 male (38%). The mean age 65 years SD 12.6. The mean QOL-B RSS was 61 points (SD 22) and mean SGRQ was 42.2 (SD 22) indicating a population with moderate to severe impairment of quality of life There was a strong inverse relationship between the QOL-B respiratory symptom score and the SGRQ (r=-0.74, p The QOL-B RSS correlated with FEV1% predicted (r=0.31, p High risk populations e.g. chronic P. aeruginosa infection and frequent exacerbators (3 or more per year) had higher SGRQ and lower QOL-B RSS scores (p Conclusion Both the QOL-B RSS and the St Georges Respiratory Questionnaire show acceptable convergent validity in large representative population of patients with bronchiectasis in the UK. Acknowledgements MRC Funding grant MR/L011263/1, Recruiting sites and patients

Bronchiectasis is increasingly recognised but poorly described. There is variability in aetiology, management and outcomes. We have adapted the EMBARC platform and created a multisite UK based registry with affiliated biobank. The BronchUK partnership (www.bronch.ac.uk) aimed to recruit 1500 adult patients with annual follow up over 3–5 years. We report our demographic data. Methods Multicentre recruitment (13 secondary care sites) with databasing of patient demographics. Data is quality assured on a routine basis. We followed the EMBARC protocol for data collection including Quality of Life Bronchiectasis (QOL-B) and SGRQ questionnaires. Results 1403 patients have been recruited. We report data on the first 813 with complete core datasets; 504 were female (62%), 309 male (38%). The mean age 65 years SD 12.6 (median is 67 IQR 61–73). Patients were predominantly Caucasian (93%). The majority were never smokers 478 (58.8%) or ex-smokers 304 (37.4%) with only 31 (3.8%) self-reporting current smoking. Morbidity was high; Cardiovascular disease was present in 234 (28.8%). 147 (18.1%) were hospitalised in the last year due to respiratory disease, 666 (81.9%) were not. Exacerbations were common with one – 144 (17.7%), Two – 144 (17.7%) three or more- 319 (39.3%). Only 206 (25.3%) reported no exacerbations in prior 12 months. Haemophilus influenzae was the most frequent organism isolated (19.1% of all patients/29.3% of patients producing baseline sputum). Pseudomonas was cultured in most recent sputum in 98 (12.1%) rising to 223 (27.4%) isolating Pseudomonas in the last 2 years. The mean BMI was 26.5 (22.3–29.3) and median, FEV1% predicted median 76.9 (59.1–95.1). The Bronchiectasis severity index (BSI) was - mild= 233 (29%), moderate= 391 (48%), severe= 189 (23%). Common aetiologies were idiopathic (40%) and post infectious (34%). COPD and Asthma were either common comorbidities or suspected aetiologies (16–21% and 3–39%) respectively. Conclusions The BronchUK registry has a broadly representative cohort of patients in terms of simple demographics (female predominant, Haemophilus infections, idiopathic/post infectious aetiologies) but the morbidity levels and hospitalisation rates are noteworthy. Long term follow up will help us ascertain which patients are at highest risk of poor outcomes. Acknowledgements MRC Funding grant MR/L011263/1, Recruiting sites and patients.

Background and aims Between July 2016 and September 2018, NHS Genomic Medicine Centres (GMCs) recruited families with specified rare diseases to the 100,000 Genomes Project for whole genome sequencing (WGS), and linkage to phenotypic information from NHS Health Records. Methods Genomics England protocols were followed for disease nominations, data model generation based on human phenotype ontology (HPO) terms,1 and development/review of PanelApp gene panels.2 Genomics England performed all WGS, data alignments, and initial variant tiering. This incorporated appropriate familial segregation patterns for variants in genes known to cause the patient‘s disease (Tier 1: clear loss of function variants, Tier2: other variants), and clear loss of function or de novo variants in other genes (Tier 3). The Respiratory GeCIP (Clinical Interpretation Partnership) was established to analyse full WGS/phenotypic datasets. Results Six respiratory diseases were nominated and passed through 100K pipelines: primary ciliary dyskinesia (PCD), familial pulmonary fibrosis (FPF), aggressive non-CF bronchiectasis, pulmonary arteriovenous malformations (PAVMs), hereditary haemorrhagic telangiectasia (HHT) and familial pneumothorax. National and international networks were established for each, including a focus on patient/public engagement. Patient results were returned to UK GMCs from August 2017. Recruited participants with recessive and dominant diseases each had 0–2 Tier 1 variants, 0–2 Tier 2 variants and up to 536 Tier 3 variants. Genomic diagnoses have been fed back to 57 respiratory families for 15 different genes in PCD, FPF, non-CF bronchiectasis, and PAVMs/HHT, already modifying PanelApp, with validations in two potentially new ciliopathy genes in progress. Full WGS results have been released quarterly to the Research Data Embassy at steadily increasing numbers. HPO term capture identifies further patients; for example, there are data on 269 families recruited with bronchiectasis plus another 27 with relevant HPO terms. Respiratory GeCIP Data Embassy access and Projects were secured through 2018–2019. New analytic resources available through the Data Embassy (particularly LabKey and IVA 2.0) enable >90 Domain members to identify annotated variants through indexed systems. Custom scripts are being used to access variant information from the whole genome. Conclusions The Respiratory GeCIP has established a collaborative resource for the advancement of NHS Respiratory Genomics. References http://human-phenotype-ontology.github.io/ https://bioinfo.extge.co.uk/crowdsourcing/PanelApp

Background Chorioamnionitis (CA) is associated with a high risk for the development of bronchopulmonary dysplasia (BPD) after preterm birth, but mechanisms that increase susceptibility for BPD and strategies to prevent BPD are uncertain. As a model of CA, antenatal intra-amniotic (IA) endotoxin (ETX) exposure alters placental structure, causes fetal growth restriction, increases perinatal mortality, and causes sustained cardiorespiratory abnormalities throughout infancy. Vitamin D (Vit D) has been shown to have both anti-inflammatory and proangiogenic properties. Antenatal IA treatment with Vit D (1,25-(OH)2D3) during IA ETX exposure improves survival and increases vascular and alveolar growth in infant rats. Whether IA ETX causes decreased placental vascular development and if the protective effects of prenatal Vit D treatment are due to direct effects on the fetus or to improved placental vascular development remain unknown. Objective The objective of this study was to determine if IA ETX impairs placental vascular development and Vit D metabolism, and whether 1,25-(OH)2D3 treatment improves placental vascularity after IA ETX exposure during late gestation in pregnant rats. Design/Methods Fetal rats were exposed to ETX (10 mg), ETX + 1,25-(OH)2D3 (1 ng/mL), 1,25-(OH)2D3 (1 ng/mL), or saline (control) via IA injection at E20 and delivered 2 days later. To assess placental vascular development, histologic sections from the placenta were stained for CD31 and vessel density per high power field (HPF) was determined and analyzed using Matlab software. To determine the effects of ETX on placental Vit D metabolism, Vit D receptor (VDR) and activity of the Vit D conversion enzyme, CYP27B1, were assayed from placental homogenates. Angiogenic mediators were measured by reverse transcription polymerase chain reaction by RNA extracted from placental tissue. Results IA ETX reduced placenta and newborn birth weights by 22 and 20%, respectively, when compared with controls (placental weight: 0.60 vs. 0.47 g; p Conclusion IA ETX decreases placental growth and vessel density and decreases placental VDR and CYP27B1 protein expression, and that antenatal 1,25-(OH)2D3 restores placental weight and vessel density, as well as birth weight. We speculate that 1,25-(OH)2D3 treatment preserves placental function in experimental CA and that these effects may be mediated by increased vascular growth.

If we want to build authentic evidence-based policy, we need a strong descriptive foundation of evidence on the everyday experience of poverty. The National Poverty Study (NPS), which is currently in development, provides this foundation with a new “qualitative census” of the everyday conditions of poverty in rural, suburban, and urban sites. The NPS will allow us to build new evidence-based theories of poverty, evaluate and improve existing place-based antipoverty policies, validate official poverty measures, and assist local communities in improving the safety net for vulnerable populations.

The respiratory tract surface is protected from inhaled pathogens by a secreted layer of mucus that is rich in mucin glycoproteins. Disrupted mucus production is a cardinal feature of chronic respiratory diseases but how this alteration affect interactions between mucins and pathogens is complex and poorly understood. Here, we identify a central and unexpected role for the major airway mucin MUC5AC in pathogenesis of virus-induced exacerbations of chronic obstructive pulmonary disease (COPD). Virus induction of MUC5AC is augmented in COPD compared to healthy subjects, is enhanced in frequent exacerbators and correlates with inflammation, symptom severity and secondary bacterial infection during exacerbation. MUC5AC is functionally related to inflammation as MUC5AC-deficient (Muc5ac-/-) mice had attenuated rhinovirus-induced airway inflammation whilst exogenous MUC5AC glycoprotein administration augmented virus-induced inflammatory responses and bacterial load. Mechanistically, MUC5AC-augmentation of rhinovirus-induced inflammation occurred through release of extracellular adenosine triphosphate (ATP). Therapeutic suppression of virus-induced MUC5AC release using an epidermal growth factor receptor (EGFR) inhibitor ameliorated exaggerated pro-inflammatory responses in a mouse COPD exacerbation model. Collectively, these studies demonstrate previously unrecognised pro-inflammatory effects of MUC5AC during infection and thus highlight a key unforeseen role in driving COPD exacerbation severity.

Chronic obstructive pulmonary disease (COPD) is a smoking-related illness affecting 64 million people worldwide. Airway infection drives recurrent exacerbations and lung function decline. Prophylactic antibiotics may prevent exacerbations but their use is a significant cause of population antimicrobial resistance.We characterised the sputum microbiome by 16S rRNA gene analysis using 138 samples collected during a randomised controlled trial of prophylactic antibiotics in 71 patients with stable COPD. On comparing the profile of the microbiome obtained by sequencing to the isolates grown from samples using standard culture, there were similarities overall, although with a much narrower spectrum of genera on culture with under-representation of certain genera including Veillonella and Prevotella. There was concordance in the most abundant genera within samples and the number of isolates cultured reflected the measured bacterial diversity.We found that at baseline the microbiota of 17 (24%) patients were dominated by Haemophilus influenzae, accompanied by narrowed microbial diversity and higher levels of sputum inflammatory cytokines. Different H. influenzae strains co-existed within individuals. Opportunistic whole genome sequencing of six H. influenzae isolates obtained during the study revealed that all were non-typeable H. influenzae (NTHI), with a range of different antibiotic resistance gene profiles, but an identical complement of virulence genes.Administration of 13 weeks prophylaxis with moxifloxacin, azithromycin or doxycycline revealed distinctive changes in microbial communities for each group. Haemophilus numbers reduced by 90% compared to placebo only after moxifloxacin, and significant reduction in sputum cytokines occurred in patients dominated by Haemophilus at baseline. Haemophilus influenzae dominance defines COPD patients with active disease who may particularly benefit from antibiotics or vaccination.

BACKGROUND: Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions. OBJECTIVE: To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals. METHODS: In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWA data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. RESULTS: We report associations between several DENND1B variants (P = 2.2 × 10(-7) for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2691 asthmatic children (screening data). The top DENND1B single nucleotide polymorphisms (SNPs) were next evaluated in seven independent replication data sets comprising 2014 asthmatics, and rs4915551 was nominally replicated (P > 0.05) in two of the seven studies and of borderline significance in one (P = 0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, P = 0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m(2) (P = 0.01 for combined screening and replication data sets, N = 4705) per additional G allele of this DENND1B SNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status. CONCLUSIONS AND CLINICAL RELEVANCE: DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here, we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.

This article is a revision of the previous edition article by M. Hallinan, volume 20, pp. 13563–13567, © 2001, Elsevier Ltd.

Background: Repetitive alveolar damage and aberrant repair may be important in the development of the fatal condition Idiopathic Pulmonary Fibrosis (IPF). The role played by microorganisms in this cycle is unknown. Methods: We consecutively enrolled patients diagnosed with IPF according to international criteria together with healthy smokers, non-smokers and subjects with moderate Chronic Obstructive Pulmonary Disease (COPD) as controls. Subjects underwent bronchoalveolar lavage (BAL) from which genomic DNA was isolated. The V3-V5 region of the bacterial 16S rRNA gene was amplified, allowing quantification of bacterial load and identification of communities by 16S rRNA qPCR and pyrosequencing. Results: Our 65 IPF patients had 3.9x109 copies of the 16S rRNA gene per ml of BAL, two-fold more than the 1.8x109 copies in 44 sex- and smoking-matched controls (P