Noninvasive Ventilatory Support of COVID-19 Patients Outside the Intensive Care Units (WARd-COVID).

Ann Am Thorac Soc. 2021 Jan 04;:

Authors: Bellani G, Grasselli G, Cecconi M, Antolini L, Borelli M, De Giacomi F, Bosio G, Latronico N, Filippini M, Gemma M, Giannotti C, Antonini B, Petrucci N, Zerbi SM, Maniglia P, Castelli GP, Marino G, Subert M, Citerio G, Radrizzani D, Mediani TS, Lorini FL, Russo FM, Faletti A, Beindorf A, Covello RD, Greco S, Bizzarri MM, Ristagno G, Mojoli F, Pradella A, Severgnini P, Da Macallè M, Albertin A, Ranieri VM, Rezoagli E, Vitale G, Magliocca A, Cappelleri G, Docci M, Aliberti S, Serra F, Rossi E, Valsecchi MG, Pesenti A, Foti G, COVID-19 Lombardy ICU Network

Abstract
RATIONALE: Treatment with non-invasive ventilation (NIV) in COVID-19 is frequent. Shortage of Intensive care unit (ICU) beds led clinicians to deliver NIV also outside intensive care units (ICUs). Data about the use of NIV in COVID-19 is limited.
OBJECTIVE: To describe the prevalence and clinical characteristics of patients with COVID-19 treated with NIV outside the ICUs. To investigate the factors associated with NIV failure (need for intubation or death).
METHODS: In this prospective single day observational study, we enrolled adult COVID-19 patients, treated with NIV outside the ICU from thirty-one hospitals in Lombardy, Italy.
RESULTS: We collected data on demographic, clinical characteristics, ventilatory management and patients' outcome. Of 8753 COVID-19 patients present in the hospitals on the study day, 909 (10%) were receiving NIV outside the ICU. 778/909 (85%) patients were treated with Continuous Positive Airway Pressure (CPAP), delivered by helmet in 617 (68%). NIV failed in 300 patients (37.6%), while 498 (62.4%) were discharged alive without intubation. Overall mortality was 25%. NIV failure occurred in 152/284 (53%) patients with a PaO2/FiO2 ratio < 150 mmHg. Higher C-reactive protein, lower PaO2/FiO2, and platelet counts were independently associated with increased risk of NIV failure.
CONCLUSIONS: The use of NIV outside the ICUs, in COVID-19 was common, with a predominant use of helmet CPAP, with a rate of success greater than 60% and close to 75% in full treatment patients. C-reactive protein, PaO2/FiO2, platelet counts were independently associated with increased risk of NIV failure. Clinical trial registered with ClinicalTrials.gov (NCT04382235).

PMID: 33395553 [PubMed - as supplied by publisher]

Erratum to: Epidemiology of Nontuberculous Mycobacteria Infection in Children and Young People With Cystic Fibrosis: Analysis of UK Cystic Fibrosis Registry.

Clin Infect Dis. 2021 Jan 04;:

Authors:

PMID: 33395460 [PubMed - as supplied by publisher]

Obstructive lung diseases and allergic bronchopulmonary aspergillosis.

Curr Opin Pulm Med. 2020 Dec 24;Publish Ahead of Print:

Authors: Muthu V, Prasad KT, Sehgal IS, Dhooria S, Aggarwal AN, Agarwal R

Abstract
PURPOSE OF REVIEW: Allergic bronchopulmonary aspergillosis (ABPA) is a disease frequently complicating asthma and cystic fibrosis. ABPA is increasingly recognized in other obstructive lung diseases (OLDs), including chronic obstructive pulmonary disease (COPD) and noncystic fibrosis bronchiectasis. Herein, we summarize the recent developments in ABPA complicating OLDs.
RECENT FINDINGS: Recent research has described the clinical features and natural history of ABPA complicating asthma in children and the elderly. We have gained insights into the pathophysiology of ABPA, especially the role of eosinophil extracellular trap cell death and mucus plugs. The utility of recombinant fungal antigens in the diagnosis of ABPA has been established. Newer, more sensitive criteria for the diagnosis of ABPA have been proposed. Although ABPA is uncommon in COPD and noncystic fibrosis bronchiectasis, aspergillus sensitization is more common and is associated with a higher exacerbation rate.
SUMMARY: Several advances have occurred in the diagnosis and treatment of ABPA in recent years. However, there is an unmet need for research into the genetic predisposition, pathophysiology, and treatment of ABPA. Apart from asthma and cystic fibrosis, patients with other OLDs also require evaluation for Aspergillus sensitization and ABPA.

PMID: 33394749 [PubMed - as supplied by publisher]

Influence of Acid Blockade on the Aerodigestive Tract Microbiome in Children With Cystic Fibrosis.

J Pediatr Gastroenterol Nutr. 2020 Dec 02;:

Authors: Khalaf RT, Furuta GT, Wagner BD, Robertson CE, Andrews R, Stevens MJ, Fillon SA, Zemanick ET, Harris JK

Abstract
BACKGROUND: Acid blockade is commonly prescribed in patients with cystic fibrosis (CF). Growing concerns, however, exist about its possible role in the pathophysiology of pulmonary infections. We aimed to investigate if acid blockade alters esophageal and respiratory microbiota leading to dysbiosis and inflammation.
METHODS: We performed a cross sectional study of children with CF who were either prescribed acid blockade or not. Samples from the gastrointestinal and respiratory tracts were obtained and microbiome analyzed. Mixed effect models were used to compare outcomes between cohorts and across sampling sites. A random subject intercept was included to account for the multiple sampling sites per individual.
RESULTS: A cohort of 25 individuals, 44% girls with median age of 13.8 years [IQR 11.2--14.8] were enrolled. Alpha diversity, total bacterial load, and beta diversity were similar across anatomic compartments, across the upper gastrointestinal tract, and in respiratory samples. Similar alpha diversity, total bacterial load, and beta diversity results were also observed when comparing individuals on versus those off acid blockade. IL-8 was elevated in the distal versus proximal esophagus in the whole cohort (P < 0.01). IL-8 concentrations were similar in the distal esophagus in patients on and off acid blockade, but significantly greater in the proximal esophagus of subjects on treatment (P < 0.01).
CONCLUSIONS: On the basis of these data, acid blockade use does not appear to influence the microbiome of the aerodigestive tract in children with cystic fibrosis suggesting a complex interplay between these medications and the bacterial composition of the esophagus and lung.

PMID: 33394582 [PubMed - as supplied by publisher]

Distinctive metabolic profiles between Cystic Fibrosis mutational subclasses and lung function.

Metabolomics. 2021 Jan 04;17(1):4

Authors: Masood A, Jacob M, Gu X, Abdel Jabar M, Benabdelkamel H, Nizami I, Li L, Dasouki M, Abdel Rahman AM

Abstract
INTRODUCTION: Cystic fibrosis (CF) is a lethal multisystemic disease of a monogenic origin with numerous mutations. Functional defects in the cystic fibrosis transmembrane conductance receptor (CFTR) protein based on these mutations are categorised into distinct classes having different clinical presentations and disease severity.
OBJECTIVES: The present study aimed to create a comprehensive metabolomic profile of altered metabolites in patients with CF, among different classes and in relation to lung function.
METHODS: A chemical isotope labeling liquid chromatography-mass spectrometry metabolomics was used to study the serum metabolic profiles of young and adult CF (n = 39) patients and healthy controls (n = 30). Comparisons were made at three levels, CF vs. controls, among mutational classes of CF, between CF class III and IV, and correlated the lung function findings.
RESULTS: A distinctive metabolic profile was observed in the three analyses. 78, 20, and 13 significantly differentially dysregulated metabolites were identified in the patients with CF, among the different classes and between class III and IV, respectively. The significantly identified metabolites included amino acids, di-, and tri-peptides, glutathione, glutamine, glutamate, and arginine metabolism. The top significant metabolites include 1-Aminopropan-2-ol, ophthalmate, serotonin, cystathionine, and gamma-glutamylglutamic acid. Lung function represented by an above-average FEV1% level was associated with decreased glutamic acid and increased guanosine levels.
CONCLUSION: Metabolomic profiling identified alterations in different amino acids and dipeptides, involved in regulating glutathione metabolism. Two metabolites, 3,4-dihydroxymandelate-3-O-sulfate and 5-Aminopentanoic acid, were identified in common between the three anlayses and may represent as highly sensitive biomarkers for CF.

PMID: 33394183 [PubMed - as supplied by publisher]

Cystic fibrosis or not? Familial occurrence of a rare mutation in the CFTR gene.

Adv Respir Med. 2020;88(6):612-614

Authors: Zapolnik P, Zapolnik B

Abstract
Cystic fibrosis is a monogenic disease caused by a mutation in the CFTR gene. The classic presentation of the disease includes chronic bronchopulmonary symptoms. However, abnormalities in this gene may also be manifested by other phenotypes, so-called CFTR-related disorders. This is a group of entities including disseminated bronchiectasis, congenital bilateral absence of vas deferens, and chronic pancreatitis. In this article, we present a family with a rare F1052V mutation and a polymorphic variant of IVS-5T+11TG. No classical form of the disease was observed in any of the persons affected by the above changes. Results of special investigations are also not typical, which hinders unequivocal diagnosis.

PMID: 33393655 [PubMed - in process]

In vivo Evaluation of Mucociliary Clearance in Mice.

J Vis Exp. 2020 Dec 18;(166):

Authors: Feldman KS, Zahid M

Abstract
Respiratory motile cilia, specialized organelles of the cell, line the apical surface of epithelial cells lining the respiratory tract. By beating in a metachronal, synchronal fashion, these multiple, motile, actin-based organelles generate a cephalad fluid flow clearing the respiratory tract of inhaled pollutants and pathogens. With increasing environmental pollution, novel viral pathogens and emerging multi-drug resistant bacteria, cilia generated mucociliary clearance (MCC) is essential for maintaining lung health. MCC is also depressed in multiple congenital disorders like primary ciliary dyskinesia, cystic fibrosis as well as acquired disorders like chronic obstructive pulmonary disease. All these disorders have established, in some case multiple, mouse models. In this publication, we detail a method using a small amount of radioactivity and dual-modality SPECT/CT imaging to accurately and reproducibly measure MCC in mice in vivo. The method allows for recovery of mice after imaging, making serial measurements possible, and testing potential therapeutics longitudinally over time. The data in wild-type mice demonstrates the reproducibility of the MCC measurement as long as adequate attention to detail is paid, and the protocol strictly adhered to.

PMID: 33393517 [PubMed - in process]

A Case of Scedosporium aurantiacum Infection in the United States.

Mycopathologia. 2021 Jan 03;:

Authors: Mizusawa M, Totten M, Zhang SX

Abstract
Scedosporium aurantiacum is one of the emergent opportunistic fungal pathogens among immunocompromised hosts. Colonization of S. aurantiacum can also occur in patients with underlying lung diseases such as cystic fibrosis. S. aurantiacum is highly resistant to multiple antifungal agents, and management of the infected patients can be very challenging compared to those infected with other species of Scedosporium. Clinical cases have been geographically restricted mostly in Australia with a small number of cases identified in Europe and Japan. Although clinical isolates of S. aurantiacum from the USA have been included in several research studies, no clinical case of S. aurantiacum infection from the USA has been described. We report a case of S. aurantiacum infection acquired in the SA. Awareness of S. aurantiacum among healthcare providers and the species-level identification for Scedosporium are critically important for appropriate selection of antifungal agents and improvement of treatment outcomes.

PMID: 33392858 [PubMed - as supplied by publisher]

Altered Degranulation and pH of Neutrophil Phagosomes Impacts Antimicrobial Efficiency in Cystic Fibrosis.

Front Immunol. 2020;11:600033

Authors: Hayes E, Murphy MP, Pohl K, Browne N, McQuillan K, Saw LE, Foley C, Gargoum F, McElvaney OJ, Hawkins P, Gunaratnam C, McElvaney NG, Reeves EP

Abstract
Studies have endeavored to understand the cause for impaired antimicrobial killing by neutrophils of people with cystic fibrosis (PWCF). The aim of this study was to focus on the bacterial phagosome. Possible alterations in degranulation of cytoplasmic granules and changes in pH were assessed. Circulating neutrophils were purified from PWCF (n = 28), PWCF receiving ivacaftor therapy (n = 10), and healthy controls (n = 28). Degranulation was assessed by Western blot analysis and flow cytometry. The pH of phagosomes was determined by use of BCECF-AM-labelled Staphylococcus aureus or SNARF labelled Candida albicans. The antibacterial effect of all treatments tested was determined by colony forming units enumeration. Bacterial killing by CF and healthy control neutrophils were found to differ (p = 0.0006). By use of flow cytometry and subcellular fractionation the kinetics of intraphagosomal degranulation were found to be significantly altered in CF phagosomes, as demonstrated by increased primary granule CD63 (p = 0.0001) and myeloperoxidase (MPO) content (p = 0.03). In contrast, decreased secondary and tertiary granule CD66b (p = 0.002) and decreased hCAP-18 and MMP-9 (p = 0.02), were observed. After 8 min phagocytosis the pH in phagosomes of neutrophils of PWCF was significantly elevated (p = 0.0001), and the percentage of viable bacteria was significantly increased compared to HC (p = 0.002). Results demonstrate that the recorded alterations in phagosomal pH generate suboptimal conditions for MPO related peroxidase, and α-defensin and azurocidine enzymatic killing of Staphylococcus aureus and Pseudomonas aeruginosa. The pattern of dysregulated MPO degranulation (p = 0.02) and prolonged phagosomal alkalinization in CF neutrophils were normalized in vivo following treatment with the ion channel potentiator ivacaftor (p = 0.04). Our results confirm that alterations of circulating neutrophils from PWCF are corrected by CFTR modulator therapy, and raise a question related to possible delayed proton channel activity in CF.

PMID: 33391268 [PubMed - in process]

Oxygen uptake kinetics during treadmill walking in adolescents with clinically stable cystic fibrosis.

Physiother Theory Pract. 2021 Jan 04;:1-9

Authors: Combret Y, Medrinal C, Prieur G, Robledo Quesada A, Gillot T, Gravier FE, Bonnevie T, Lamia B, Le Roux P, Reychler G

Abstract
Background: Oxygen uptake (V̇O2) kinetics have been shown to be slowed in adolescents with cystic fibrosis (CF) during heavy-intensity cycling and maximal exercise testing. Objectives: This study investigated V̇O2 kinetics in adolescents with CF compared to control adolescents (CON) during a treadmill-walking exercise. Methods: Eight adolescents with CF and mild-to-moderate pulmonary obstruction (5 girls; 13.1 ± 2.5 years; FEV1 67.8 ± 21.4%) and 18 CON adolescents (10 girls; 13.8 ± 1.8 years) were recruited. Pulmonary gas exchange and ventilation were measured during a single transition of 10 min of treadmill walking and a 5 min seated recovery period. Participant's walking speed was determined during a one-minute self-paced walking task along a 50-m corridor. A six-parameter, non-linear regression model was used to describe the changes in V̇O2 function during the treadmill walking and recovery, with monoexponential curve fitting used to describe the mean response time (MRT1) at the onset of exercise, and the half-life (T1/2V̇O2) at the offset of exercise. V̇O2 baseline and amplitude, minute ventilation and respiratory equivalents were recorded. Results: V̇O2 kinetics were slower in CF group compared to CON group during the treadmill walking with a greater MRT1 (32 ± 14 s vs 21 ± 16 s; p = .04, effect size = 0.75). The T1/2V̇O2 was prolonged during recovery in CF group compared to CON group (86 ± 24 s vs 56 ± 22 s; p = .04, effect size = 1.31). The mean VE/V̇CO2 during exercise was the only parameter significantly greater in CF group compared to CON group (32.9 ± 2.3 vs 29.0 ± 2.4; p < .01, effect size = 1.66). Conclusion: V̇O2 kinetics were found to be slowed in adolescents with CF during treadmill walking.

PMID: 33390080 [PubMed - as supplied by publisher]

Increasing dosages of low-molecular-weight heparin in hospitalized patients with Covid-19.

Intern Emerg Med. 2021 Jan 03;:

Authors: Martinelli I, Ciavarella A, Abbattista M, Aliberti S, De Zan V, Folli C, Panigada M, Gori A, Artoni A, Ierardi AM, Carrafiello G, Monzani V, Grasselli G, Blasi F, Peyvandi F

Abstract
We conducted an observational cohort study in adult patients consecutively admitted for the respiratory illness Covid-19 to our hub hospital from March 9 to April 7, 2020. The high observed rate of venous thromboembolism prompted us to increase the prophylactic doses of enoxaparin from 40 mg daily up to 1 mg/kg twice daily in patients admitted to intensive care units (ICU), 0.7 mg/kg twice daily in high-intensity of care wards and 1 mg/kg daily in low-intensity of care wards. Patients on high enoxaparin doses were compared to those who received prophylaxis with the standard dosage. Efficacy endpoints were mortality, clinical deterioration, and the occurrence of venous thromboembolism, safety endpoint was the occurrence of major bleeding. Of 278 patients with Covid-19, 127 received prophylaxis with high enoxaparin doses and 151 with standard dosage. At 21 days, the incidence rate of death and clinical deterioration were lower in patients on higher doses than in those on the standard dosage (hazard ratio 0.39, 95% confidence interval 0.23-0.62), and the incidence of venous thromboembolism was also lower (hazard ratio 0.52, 95% confidence interval 0.26-1.05). Major bleeding occurred in four of 127 patients (3.1%) on the high enoxaparin dosage. In conclusion, in the cohort of patients with Covid-19 treated with high enoxaparin dosages we observed a 60% reduction of mortality and clinical deterioration and a 50% reduction of venous thromboembolism compared to standard dosage prophylaxis. However, 3% of patients on high enoxaparin dosages had non-fatal major bleeding.

PMID: 33389568 [PubMed - as supplied by publisher]

Predicting Substance Use from Religiosity/Spirituality in Individuals with Cystic Fibrosis.

J Relig Health. 2021 Jan 03;:

Authors: Burgess BE, Mrug S, Bray LA, Leon KJ, Troxler RB

Abstract
Religiosity and spirituality predict lower alcohol and other substance use in community samples of adolescents and adults. However, the roles of religiosity and spirituality in substance use have not been examined in individuals with cystic fibrosis (CF). Adults with CF (n = 123) completed measures of spirituality, religiosity, and substance use. Clinical measures of illness severity (e.g., BMI and  %FEV1) were obtained from participants' medical records. Substance use rates for alcohol, tobacco, and marijuana were lower in this sample than those seen in the general population. Of the measured BMMRS subscales, spiritual experiences and religious commitment were significant predictors of lower alcohol use. These results suggest that personal factors of religiosity and spirituality are more important for substance use in adults with CF than participation in religious service and events or adoption of religious practices.

PMID: 33389481 [PubMed - as supplied by publisher]

Abnormal Lung Clearance Index in Cystic Fibrosis Children with Normal FEV1 and Single-Breath Nitrogen Washout Test.

Lung. 2021 Jan 03;:

Authors: Kasi AS, Wee CP, Keens TG, Salinas DB

Abstract
Single- and multiple-breath washout tests (SBW and MBW) measure ventilation inhomogeneity, but the relationship between them is unclear. Forty-three subjects with cystic fibrosis (CF) and healthy controls (HC) 8-21 years of age were recruited (CF = 30 and HC = 13) and performed nitrogen MBW, vital capacity SBW, spirometry, and plethysmography. Mean phase III slope from SBW (SIII) and lung clearance index (LCI) were significantly different between CF and HC (p = 0.017 and p < 0.0001, respectively). Based on Pearson correlation, SIII and LCI showed strong correlation (ρ = 0.81, p < 0.0001). Both SIII and LCI significantly correlated with spirometry (all p < 0.05). Among CF subjects with normal FEV1 (≥ 80%; n = 17), 76% (n = 13) had normal SIII but abnormal LCI. We conclude that LCI can be abnormal despite normal SIII and FEV1 in CF children. Although LCI and SIII showed strong correlation, our results suggest that LCI is a better test to detect ventilation inhomogeneity in CF children with normal FEV1.

PMID: 33389068 [PubMed - as supplied by publisher]

VITAMIND AND ITS THERAPEUTIC RELEVANCE IN PULMONARY DISEASES.

J Nutr Biochem. 2020 Dec 31;:108571

Authors: Ahmad S, Arora S, Khan S, Mohsin M, Mohan A, Syed KMMA

Abstract
Vitamin D is customarily involved in maintaining bone and calcium homeostasis. However, contemporary studies have identified the implication of Vitamin D in several cellular processes including cellular proliferation, differentiation, wound healing, repair and regulatory systems inclusive of host defence, immunity and inflammation. Multiple studies have indicated co-relations between low serum levels of Vitamin D, perturbed pulmonary functions and enhanced incidences of inflammatory diseases. Almost all of the pulmonary diseases including Acute lung injury, cystic fibrosis, asthma, COPD, Pneumonia and Tuberculosis, all are inflammatory in nature. Studies have displayed strong inter-relations with Vitamin D deficiency and progression of lung disorders; however, the underlying mechanism is still unknown. Vitamin D has emerged to possess inhibiting effects on pulmonary inflammation while exaggerating innate immune defences by strongly influencing functions of inflammatory cells including dendritic cells, monocyte/macrophages, T cells and B cells along with structural epithelial cells. This review dissects the effects of Vitamin D on the inflammatory cells and their therapeutic relevance in pulmonary diseases. Although, the data obtained is very limited and needs further corroboration but presents an exciting area of further research. This is because of its ease of supplementation and development of personalized medicine which could lead us to an effective adjunct and cost-effective method of therapeutic modality for highly fatal pulmonary diseases.

PMID: 33388351 [PubMed - as supplied by publisher]

Impact of COVID-19 pandemic on the management of paediatric inflammatory bowel disease: An Italian multicentre study on behalf of the SIGENP IBD Group.

Dig Liver Dis. 2020 Dec 26;:

Authors: Arrigo S, Alvisi P, Banzato C, Bramuzzo M, Celano R, Civitelli F, D'Arcangelo G, Dilillo A, Dipasquale V, Felici E, Fuoti M, Gatti S, Knafelz D, Lionetti P, Mario F, Marseglia A, Martelossi S, Moretti C, Norsa L, Panceri R, Renzo S, Romano C, Romeo E, Strisciuglio C, Martinelli M

Abstract
BACKGROUND: IBD management has been significantly affected during the COVID-19 lockdown with potential clinical issues.
AIMS: The aim of this study was to analyse the impact of COVID-19 pandemic on the Italian paediatric IBD cohort.
METHODS: This was a multicentre, retrospective, cohort investigation including 21 different Italian IBD referral centres. An electronic data collection was performed among the participating centres including: clinical characteristics of IBD patients, number of COVID-19 cases and clinical outcomes, disease management during the lockdown and the previous 9 weeks.
RESULTS: 2291 children affected by IBD were enrolled. We experienced a significant reduction of the hospital admissions [604/2291 (26.3%) vs 1281/2291 (55.9%); p < 0.001]. More specifically, we observed a reduction of hospitalizations for new diagnosis (from n = 44 to n = 27) and endoscopic re-evaluations (from n = 46 to n = 8). Hospitalization for relapses and surgical procedures remained substantially unchanged. Biologic infusions did not significantly vary [393/2291 (17.1%) vs 368/2291 (16%); p = 0.3]. Telemedicine services for children with IBD were activated in 52.3% of the centres. In 42/2291(1.8%) children immunosuppressive therapies were adapted due to the concurrent COVID-19 pandemic.
CONCLUSION: Due to the several limitations of the lockdown, cares for children with IBD have been kept to minimal standards, giving priorities to the urgencies and to biologics' infusions and implementing telemedicine services.

PMID: 33388247 [PubMed - as supplied by publisher]

Vitamin E supplementation in people with cystic fibrosis: Summary of a Cochrane review.

Explore (NY). 2020 Dec 26;:

Authors: Barker B

PMID: 33388246 [PubMed - as supplied by publisher]

OTX2 regulates CFTR expression during endoderm differentiation and occupies 3' cis-regulatory elements.

Dev Dyn. 2021 Jan 01;:

Authors: Kerschner JL, Paranjapye A, NandyMazumdar M, Yin S, Leir SH, Harris A

Abstract
BACKGROUND: Cell-specific and developmental mechanisms contribute to expression of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, however, its developmental regulation is poorly understood. Here we use human induced pluripotent stem cells (hiPSCs) differentiated into pseudostratified airway epithelial cells to study these mechanisms.
RESULTS: Changes in gene expression and open chromatin profiles were investigated by RNA-seq and ATAC-seq, and revealed that alterations in CFTR expression are associated with differences in stage-specific open chromatin. Additionally, 2 novel open chromatin regions, at +19.6kb and +22.6kb 3' to the CFTR translational stop signal, were observed in definitive endoderm (DE) cells, prior to an increase in CFTR expression in anterior foregut endoderm (AFE) cells. Chromatin studies in DE and AFE cells revealed enrichment of active enhancer marks and occupancy of OTX2 at these sites in DE cells. Loss of OTX2 in DE cells alters histone modifications across the CFTR locus and results in a 2.5-fold to 5-fold increase in CFTR expression. However, deletion of the +22.6kb site alone does not affect CFTR expression in DE or AFE cells.
CONCLUSIONS: These results suggest that a network of interacting cis-regulatory elements recruit OTX2 to the locus to impact CFTR expression during early endoderm differentiation. This article is protected by copyright. All rights reserved.

PMID: 33386644 [PubMed - as supplied by publisher]

Bridging the survival gap in cystic fibrosis: An investigation of lung transplant outcomes in Canada and the United States.

J Heart Lung Transplant. 2020 Dec 07;:

Authors: Stephenson AL, Ramos KJ, Sykes J, Ma X, Stanojevic S, Quon BS, Marshall BC, Petren K, Ostrenga JS, Fink AK, Faro A, Elbert A, Chaparro C, Goss CH

Abstract
BACKGROUND: Previous literature in cystic fibrosis (CF) has shown a 10-year survival gap between Canada and the United States (US). We hypothesized that differential access to and survival after lung transplantation may contribute to the observed gap. The objectives of this study were to compare CF transplant outcomes between Canada and the US and estimate the potential contribution of transplantation to the survival gap.
METHODS: Data from the Canadian CF Registry and the US Cystic Fibrosis Foundation Patient Registry supplemented with data from United Network for Organ Sharing were used. The probability of surviving after transplantation between 2005 and 2016 was calculated using the Kaplan‒Meier method. Survival by insurance status at the time of transplantation and transplant center volume in the US were compared with those in Canada using Cox proportional hazard models. Simulations were used to estimate the contribution of transplantation to the survival gap.
RESULTS: Between 2005 and 2016, there were 2,653 patients in the US and 470 in Canada who underwent lung transplantation for CF. The 1-, 3-, and 5-year survival rates were 88.3%, 71.8%, and 60.3%, respectively, in the US compared with 90.5%, 79.9%, and 69.7%, respectively, in Canada. Patients in the US were also more likely to die on the waitlist (p < 0.01) than patients in Canada. If the proportion of who underwent transplantation and post-transplant survival in the US were to increase to those observed in Canada, we estimate that the survival gap would decrease from 10.8 years to 7.5 years.
CONCLUSIONS: Differences in waitlist mortality and post-transplant survival can explain up to a third of the survival gap observed between the US and Canada.

PMID: 33386232 [PubMed - as supplied by publisher]

Age at Lung Transplant Impacts Post-Transplant Survival in Cystic Fibrosis; Why?

Ann Am Thorac Soc. 2021 Jan;18(1):28-29

Authors: Clausen ES, Hadjiliadis D

PMID: 33385231 [PubMed - as supplied by publisher]

Genetic information from discordant sibling pairs points to ESRP2 as a candidate trans-acting regulator of the CF modifier gene SCNN1B.

Sci Rep. 2020 Dec 31;10(1):22447

Authors: Becker T, Pich A, Tamm S, Hedtfeld S, Ibrahim M, Altmüller J, Dalibor N, Toliat MR, Janciauskiene S, Tümmler B, Stanke F

Abstract
SCNN1B encodes the beta subunit of the epithelial sodium channel ENaC. Previously, we reported an association between SNP markers of SCNN1B gene and disease severity in cystic fibrosis-affected sibling pairs. We hypothesized that factors interacting with the SCNN1B genomic sequence are responsible for intrapair discordance. Concordant and discordant pairs differed at six SCNN1B markers (Praw = 0.0075, Pcorr = 0.0397 corrected for multiple testing). To identify the factors binding to these six SCNN1B SNPs, we performed an electrophoretic mobility shift assay and captured the DNA-protein complexes. Based on protein mass spectrometry data, the epithelial splicing regulatory protein ESRP2 was identified when using SCNN1B-derived probes and the ESRP2-SCNN1B interaction was independently confirmed by coimmunoprecipitation assays. We observed an alternative SCNN1B transcript and demonstrated in 16HBE14o- cells that levels of this transcript are decreased upon ESRP2 silencing by siRNA. Furthermore, we confirmed that mildly and severely affected siblings have different ESPR2 genetic backgrounds and that ESRP2 markers are linked to the response of CF patients' nasal epithelium to amiloride, indicating ENaC involvement (Pbest = 0.0131, Pcorr = 0.068 for multiple testing). Our findings demonstrate that sibling pairs clinically discordant for CF can be used to identify meaningful DNA regulatory elements and interacting factors.

PMID: 33384439 [PubMed - in process]