MiR-146a is over-expressed and controls IL-6 production in cystic fibrosis macrophages.

Sci Rep. 2019 Nov 07;9(1):16259

Authors: Luly FR, Lévêque M, Licursi V, Cimino G, Martin-Chouly C, Théret N, Negri R, Cavinato L, Ascenzioni F, Del Porto P

Abstract
Cystic fibrosis (CF) is an inherited disease that is characterised by susceptibility to bacterial infections and chronic lung inflammation. Recently, it was suggested that macrophages contribute to impaired host defence and excessive inflammatory responses in CF. Indeed, dysfunction attributed to CF macrophages includes decreased bacterial killing and exaggerated inflammatory responses. However, the mechanisms behind such defects have only been partially defined. MicroRNAs (miRNAs) have emerged as key regulators of several macrophage functions, including their activation, differentiation and polarisation. The goal of this study was to investigate whether miRNA dysregulation underlies the functional abnormalities of CF macrophages. MiRNA profiling of macrophages was performed, with 22 miRNAs identified as differentially expressed between CF and non-CF individuals. Among these, miR-146a was associated with significant enrichment of validated target genes involved in responses to microorganisms and inflammation. As miR-146a dysregulation has been reported in several human inflammatory diseases, we analysed the impact of increased miR-146a expression on inflammatory responses of CF macrophages. These data show that inhibition of miR-146a in lipopolysaccharide-stimulated CF macrophages results in increased interleukin-6 production, which suggests that miR-146a overexpression in CF is functional, to restrict inflammatory responses.

PMID: 31700158 [PubMed - in process]

ERS/TSANZ Task Force Statement on the Management of Reproduction and Pregnancy in Women with Airways Diseases.

Eur Respir J. 2019 Nov 07;:

Authors: Middleton PG, Gade EJ, Aguilera C, MacKillop L, Button BM, Coleman C, Johnson B, Albrechtsen C, Edenborough F, Rigau D, Gibson PG, Backer V

Abstract
This Statement outlines a review of the literature and expert opinion concerning management of reproduction and pregnancy in women with airways diseases. The Statement represents the first collaboration of the European Respiratory Society (ERS) and the Thoracic Society of Australia and New Zealand (TSANZ) to develop such documents. This Statement covers airways diseases - namely Asthma, Cystic Fibrosis (CF) and non-CF Bronchiectasis. Many women with these diseases are now living into reproductive age with some developing moderate to severe impairment of lung function in early adulthood. The Statement covers aspects of fertility, management during pregnancy, effects of drugs and issues during delivery. The Statement summarises current knowledge but does not make recommendations. This Statement will not discuss the physiological changes occurring in pregnancy, such as the changes in airway physiology, resting ventilation and sleep nor other forms of lung disease such as pulmonary fibrosis, pulmonary hypertension, gastro-oesophageal reflux-related lung disease or issues with nicotine consumption.

PMID: 31699837 [PubMed - as supplied by publisher]

Insights into the variability of nasal potential difference, a biomarker of CFTR activity.

J Cyst Fibros. 2019 Nov 04;:

Authors: Kyrilli S, Henry T, Wilschanski M, Fajac I, Davies JC, Jais JP, Sermet-Gaudelus I

Abstract
BACKGROUND: Nasal potential difference (NPD) is used to evaluate CFTR function in vivo. We aimed to evaluate the intrasubject and intersubject variability of NPD measurements.
METHODS: We reviewed NPD tracings of 116 patients with CF enrolled in the placebo arm of a multicenter study. Patients carried at least one nonsense mutation and underwent repeated NPD tests every 16 weeks. NPD parameters included basal potential difference (basal PD), inhibition of sodium absorption by amiloride (Δ Amiloride), chloride (Cl-) transport in response to a Cl--free solution (Δ Low Cl-), isoproterenol (Δ Isoproterenol), the sum of Δ Low Cl- and Δ Isoproterenol (Δ Low Cl--Isoproterenol) and ATP (Δ ATP).
RESULTS: Basal PD and Δ Amiloride displayed the highest variabilities, mainly stemming from intercenter and intrasubject effect. Δ Low Cl-, Δ Isoproterenol and Δ Low Cl--Isoproterenol demonstrated a large intrasubject variability but a smaller intersubject variability. The intrasubject measurement variability for Δ Low Cl--Isoproterenol, was within ± 7.2 mV with 95% probability. It was greater in patients reporting ongoing pulmonary exacerbations.
CONCLUSIONS: The large intercenter variability of basal PD and Δ Amiloride highlights the operator-dependent aspect of these measurements. A difference greater than 7.2 mV in Δ Low Cl--Isoproterenol in a given patient on CFTR modulator can be attributed, with 95% probability, to a treatment effect rather than to the variability inherent in the measurement.

PMID: 31699569 [PubMed - as supplied by publisher]

An Intriguing Involvement of Mitochondria in Cystic Fibrosis.

J Clin Med. 2019 Nov 06;8(11):

Authors: Favia M, de Bari L, Bobba A, Atlante A

Abstract
Cystic fibrosis (CF) occurs when the cystic fibrosis transmembrane conductance regulator (CFTR) protein is not synthetized and folded correctly. The CFTR protein helps to maintain the balance of salt and water on many body surfaces, such as the lung surface. When the protein is not working correctly, chloride becomes trapped in cells, then water cannot hydrate the cellular surface and the mucus covering the cells becomes thick and sticky. Furthermore, a defective CFTR appears to produce a redox imbalance in epithelial cells and extracellular fluids and to cause an abnormal generation of reactive oxygen species: as a consequence, oxidative stress has been implicated as a causative factor in the aetiology of the process. Moreover, massive evidences show that defective CFTR gives rise to extracellular GSH level decrease and elevated glucose concentrations in airway surface liquid (ASL), thus encouraging lung infection by pathogens in the CF advancement. Recent research in progress aims to rediscover a possible role of mitochondria in CF. Here the latest new and recent studies on mitochondrial bioenergetics are collected. Surprisingly, they have enabled us to ascertain that mitochondria have a leading role in opposing the high ASL glucose level as well as oxidative stress in CF.

PMID: 31698802 [PubMed]

A combination of LCPUFAs regulates the expression of miRNA-146a-5p in a murine asthma model and human alveolar cells.

Prostaglandins Other Lipid Mediat. 2019 Nov 04;:106378

Authors: Fussbroich D, Kohnle C, Schwenger T, Driessler C, Dücker RP, Eickmeier O, Gottwald G, Jerkic SP, Zielen S, Kreyenberg H, Beermann C, Chiocchetti AG, Schubert R

Abstract
BACKGROUND: LCPUFAs are suggestive of having beneficial effects on inflammatory diseases such as asthma. However, little is known about the modulative capacity of omega-(n)-3 and n-6 LCPUFAs within the epigenetic regulation of inflammatory processes.
OBJECTIVE: The aim of this study was to investigate whether a specific combined LCPUFA supplementation restores disease-dysregulated miRNA-profiles in asthmatic mice. In addition, we determined the effect of the LCPUFA supplementation on the interaction of the most regulated miRNA expression and oxygenase activityin vitro.
METHODS: Sequencing of miRNA was performed by NGS from lung tissue of asthmatic and control mice with normal diet, as well as of LCPUFA supplemented asthmatic mice. Network analysis and evaluation of the biological targets of the miRNAs were performed by DIANA- miRPath v.3 webserver software, TargetScanMouse 7.2, and tool String v.10, respectively. Expression of hsa-miRNA-146a-5p and activity of COX-2 and 5-LO in LCPUFA-treated A549 cells were assessed by qPCR and flow cytometry, respectively.
RESULTS: In total, 62 miRNAs were dysregulated significantly in murine allergic asthma. The LCPUFA combination restored 21 of these dysregulated miRNAs, of which eight (mmu-miR-146a-5p, -30a-3p, -139-5p, -669p-5p, -145a-5p, -669a-5p, -342-3p and -15b-5p) were even normalized compared to the control levels. Interestingly, six of the eight rescued miRNAs are functionally implicated in TGF-β signaling, ECM-receptor interaction and fatty acid biosynthesis. Furthermore, in vitro experiments demonstrated that upregulation of hsa-miRNA-146a-5p is accompanied by a reduction of COX-2 and 5-LO activity. Moreover, transfection experiments revealed that LCPUFAs inhibit 5-LO activity in the presence and absence of anti-miR-146a-5p.
CONCLUSION: Our results demonstrate the modulative capacity of LCPUFAs on dysregulated miRNA expression in asthma. In addition, we pointed out the high regulative potential of LCPUFAs on 5-LO regulation and provided evidence that miR-146a partly controls the regulation of 5-LO.

PMID: 31698144 [PubMed - as supplied by publisher]

Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele.

N Engl J Med. 2019 Nov 07;381(19):1809-1819

Authors: Middleton PG, Mall MA, Dřevínek P, Lands LC, McKone EF, Polineni D, Ramsey BW, Taylor-Cousar JL, Tullis E, Vermeulen F, Marigowda G, McKee CM, Moskowitz SM, Nair N, Savage J, Simard C, Tian S, Waltz D, Xuan F, Rowe SM, Jain R, VX17-445-102 Study Group

Abstract
BACKGROUND: Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes.
METHODS: We conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes. Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV1) at week 4.
RESULTS: A total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor-tezacaftor-ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor-tezacaftor-ivacaftor group.
CONCLUSIONS: Elexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.).

PMID: 31697873 [PubMed - in process]

Genetic modifiers of cystic fibrosis-related diabetes have extensive overlap with type 2 diabetes and related traits.

J Clin Endocrinol Metab. 2019 Oct 19;:

Authors: Aksit MA, Pace RG, Vecchio-Pagan B, Ling H, Rommens JM, Boelle PY, Guillot L, Raraigh KS, Pugh E, Zhang P, Strug LJ, Drumm ML, Knowles MR, Cutting GR, Corvol H, Blackman SM

Abstract
CONTEXT: Individuals with cystic fibrosis (CF) develop a distinct form of diabetes characterized by β-cell dysfunction and islet amyloid accumulation similar to type 2 diabetes (T2D) but generally normal insulin sensitivity. CF-related diabetes (CFRD) risk is determined by both CFTR, the gene responsible for CF, and other genetic variants.
OBJECTIVE: To identify genetic modifiers of CFRD and determine the genetic overlap with other types of diabetes.
DESIGN AND PATIENTS: A genome-wide association study was conducted for CFRD onset on 5740 individuals with CF. Weighted polygenic risk scores (PRSs) for T1D, T2D and diabetes endophenotypes were tested for association with CFRD.
RESULTS: Genome-wide significance was obtained for variants at a novel locus (PTMA) and two known CFRD genetic modifiers (TCF7L2 and SLC26A9). PTMA and SLC26A9 variants were CF-specific; TCF7L2 variants also associated with T2D. CFRD was strongly associated with PRSs for T2D, insulin secretion, post-challenge glucose concentration and fasting plasma glucose, and less strongly with T1D PRSs. CFRD was inconsistently associated with PRSs for insulin sensitivity and was not associated with a PRS for islet autoimmunity. A CFRD PRS comprised of variants selected from these PRSs (with FDR p-value<0.1) and the genome-wide significant variants was associated with CFRD in a replication population.
CONCLUSIONS: CFRD and T2D have more etiologic and mechanistic overlap than previously known, aligning along pathways involving β-cell function rather than insulin sensitivity. Two CFRD risk loci are unrelated to T2D and may affect multiple aspects of CF. An 18-variant PRS stratifies risk of CFRD in an independent population.

PMID: 31697830 [PubMed - as supplied by publisher]

Whole body periodic acceleration in normal and reduced mucociliary clearance of conscious sheep.

PLoS One. 2019;14(11):e0224764

Authors: Sabater JR, Sackner MA, Adams JA, Abraham WM

Abstract
The purpose of this investigation was to ascertain whether nitric oxide (NO) released into the circulation by a noninvasive technology called whole body periodic acceleration (WBPA) could increase mucociliary clearance (MCC). It was based on observations by others that nitric oxide donor drugs increase ciliary beat frequency of nasal epithelium without increasing mucociliary clearance. Tracheal mucous velocity (TMV), a reflection of MCC, was measured in sheep after 1-hour treatment of WBPA and repeated after pretreatment with the NO synthase inhibitor, L-NAME to demonstrated action of NO. Aerosolized human neutrophil elastase (HNE) was administered to sheep to suppress TMV as might occur in cystic fibrosis and other inflammatory lung diseases. WBPA increased TMV to a peak of 136% of baseline 1h after intervention, an effect blocked by L-NAME. HNE reduced TMV to 55% of baseline but slowing was reversed by WBPA, protection lost in the presence of L-NAME. NO released into the circulation from eNOS by WBPA can acutely access airway epithelium for improving MCC slowed in cystic fibrosis and other inflammatory lung diseases as a means of enhancing host defense against pathogens.

PMID: 31697733 [PubMed - in process]

Pre-Clinical Modeling for Therapeutic Development in Cystic Fibrosis.

Am J Respir Crit Care Med. 2019 Nov 07;:

Authors: Bonfield TL

PMID: 31697560 [PubMed - as supplied by publisher]

Computational Analysis of Energy Landscapes Reveals Dynamic Features that Contribute to Binding of Inhibitors to CFTR-Associated Ligand.

J Phys Chem B. 2019 Nov 07;:

Authors: Holt GT, Jou JD, Gill NP, Lowegard AU, Martin JW, Madden DR, Donald BR

Abstract
The CFTR-associated ligand PDZ domain (CALP) binds to the cystic fibrosis transmembrane conductance regulator (CFTR) and mediates lysosomal degradation of mature CFTR. Inhibition of this interaction has been explored as a therapeutic avenue for cystic fibrosis. Previously, we reported the ensemble-based computational design of a novel peptide inhibitor of CALP, which resulted in the most binding-efficient inhibitor to date. This inhibitor, kCAL01, was designed using OSPREY and evinced significant biological activity in in vitro cell-based assays. Here, we report a crystal structure of kCAL01 bound to CALP and compare structural features against iCAL36, a previously developed inhibitor of CALP. We compute side-chain energy landscapes for each structure to not only enable approximation of binding thermodynamics, but also reveal ensemble features that contribute to the comparatively efficient binding of kCAL01. Finally, we compare the previously reported design ensemble for kCAL01 vs. the new crystal structure and show that, despite small differences between the design model and crystal structure, significant biophysical features that enhance inhibitor binding are captured in the design ensemble. This suggests not only that ensemble-based design captured thermodynamically significant features observed in vitro, but also that a design eschewing ensembles would miss the kCAL01 sequence entirely.

PMID: 31697075 [PubMed - as supplied by publisher]

Development of a library of thiophene-based drug-like LEGO molecules: evaluation of their anion binding, transport properties and cytotoxicity.

Chemistry. 2019 Nov 07;:

Authors: Vieira P, Miranda MQ, Marques I, Carvalho S, Chen LJ, Howe ENW, Zhen C, Leung CY, Spooner MJ, Morgado B, Cruz E Silva OAB, Moiteiro C, Gale PA, Félix V

Abstract
The anion binding and transport properties of an extensive library of thiophene-based molecules are reported. Seventeen bis-urea positional isomers, with different binding conformations and lipophilicities, were synthetized by the appendage of α-, β-thiophene or α-, β-, γ-benzo[ b ]thiophene motifs to the ortho -phenylenediamine central core, yielding six subsets of positional isomers. Through 1 H NMR, X-ray crystallography, molecular modelling and anion efflux studies, it was demonstrated that most active transporters display a pre-organised binding conformation able to promote the recognition of chloride using urea and C-H binding groups in a cooperative fashion. Additional LUV based assays, carried out under electroneutral and electrogenic conditions, together with NMDG-Cl assays, indicate that anion efflux occurs mainly through H + /Cl - symport mechanism. On the other hand, the most efficient anion transporter displays cytotoxicity against tumour cell lines while having no effects on a cystic fibrosis cell line.

PMID: 31696989 [PubMed - as supplied by publisher]

Erratum: Profile Of Tezacaftor/Ivacaftor Combination And Its Potential In The Treatment Of Cystic Fibrosis [Erratum].

Ther Clin Risk Manag. 2019;15:1207

Authors:

Abstract
[This corrects the article DOI: 10.2147/TCRM.S165027.].

PMID: 31696867 [PubMed - in process]

Aquagenic wrinkling of the palms.

G Ital Dermatol Venereol. 2019 Jun;154(3):364-366

Authors: Donnarumma M, Megna M, Napolitano M, Patruno C

PMID: 29368852 [PubMed - indexed for MEDLINE]

32 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

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52 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

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54 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Cystic Fibrosis"

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PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Immune and Cytokine Dysfunction in Cystic Fibrosis.

Am J Respir Cell Mol Biol. 2019 Nov;61(5):656-658

Authors: Leung ST, Khoury O, Barrios C, Ortega VE, Atala A, Murphy SV

PMID: 31674827 [PubMed - in process]

The CYSMA web server: an example of integrative tool for in silico analysis of missense variants identified in Mendelian disorders.

Hum Mutat. 2019 Nov 01;:

Authors: Sasorith S, Baux D, Bergougnoux A, Paulet D, Lahure A, Bareil C, Taulan-Cadars M, Roux AF, Koenig M, Claustres M, Raynal C

Abstract
Exome sequencing used for molecular diagnosis of Mendelian disorders considerably increases the number of missense variants of unclear significance, whose pathogenicity can be assessed by a variety of prediction tools. As performance of algorithms may vary according to the datasets, complementary specific resources are needed to improve variants interpretation. As a model, we were interested in the Cystic Fibrosis Transmembrane conductance Regulator gene (CFTR) causing cystic fibrosis, in which at least 40% of missense variants are reported. CYSMA (CYStic fibrosis Missense Analysis) is a new web server designed for online estimation of pathological relevance of CFTR missense variants. CYSMA generates a set of computationally derived data, ranging from evolutionary conservation to functional observations from three-dimensional structures, provides all available allelic frequencies, clinical observations and references for functional studies. Compared to software classically used in analysis pipelines on a dataset of 141 well-characterized missense variants, CYSMA was the most efficient tool to discriminate benign missense variants, with a specificity of 85%, and a very good sensitivity of 89%. These results suggest that such integrative tools could be adapted to numbers of genes involved in Mendelian disorders to improve the interpretation of missense variants identified in the context of diagnosis. This article is protected by copyright. All rights reserved.

PMID: 31674704 [PubMed - as supplied by publisher]

Excess mucus viscosity and airway dehydration impact COPD airway clearance.

Eur Respir J. 2019 Oct 31;:

Authors: Lin VY, Kaza N, Birket SE, Kim H, Edwards LJ, LaFontaine J, Liu L, Mazur M, Byzek SA, Hanes J, Tearney GJ, Raju SV, Rowe SM

Abstract
The mechanisms by which cigarette smoking impairs airway mucus clearance are not well understood. We recently established a ferret model of cigarette smoke-induced chronic obstructive pulmonary disease (COPD) exhibiting chronic bronchitis. We investigated the effects of cigarette smoke on mucociliary transport (MCT).Adult ferrets were exposed to cigarette smoke for 6 months, with in vivo mucociliary clearance (MCC) measured by Tc-labeled DTPA (Tc-DTPA) retention. Excised tracheae were imaged with micro-optical coherence tomography. Mucus changes in primary human airway epithelial cells and ex vivo ferret airways were assessed by histology and particle tracking microrheology. Linear mixed models for repeated measures identified key determinants of MCT.Compared to air controls, cigarette smoke-exposed ferrets exhibited mucus hypersecretion, delayed MCC (-89.0%, p<0.01), and impaired tracheal MCT (-29.4%, p<0.05). Cholinergic stimulus augmented airway surface liquid (ASL) depth (5.8±0.3 to 7.3±0.6 µm, p<0.0001) and restored MCT (6.8±0.8 to 12.9±1.2 mm·min-1, p<0.0001). Mixed model analysis controlling for covariates indicated smoking exposure, mucus hydration (ASL) and CBF were important predictors of MCT. Ferret mucus was hyperviscous following smoke exposure in vivo or in vitro and contributed to diminished MCT. Primary cells from smokers with and without COPD recapitulated these findings, which persisted despite the absence of continued smoke exposure.Cigarette smoke impairs MCT by inducing airway dehydration and increased mucus viscosity, and can be partially abrogated by cholinergic secretion of fluid secretion. These data elucidate the detrimental effects of cigarette smoke exposure on mucus clearance and suggest additional avenues for therapeutic intervention.

PMID: 31672759 [PubMed - as supplied by publisher]

Differences in clinical outcomes of paediatric cystic fibrosis patients with and without meconium ileus.

J Cyst Fibros. 2019 Oct 28;:

Authors: Tan SMJ, Coffey MJ, Ooi CY

Abstract
BACKGROUND: Meconium ileus (MI) affects up to 20% of newborns with cystic fibrosis (CF). We compared clinical outcomes between Australian paediatric CF patients with and without meconium ileus (non-MI).
METHODS: This was a retrospective case-control study of MI and non-MI patients in New South Wales, Australia, from 1988 to 2010. MI patients were matched 1:1 with pancreatic insufficient non-MI patients for age, sex and CF clinic. Clinical measurements, nutrition and gastrointestinal outcomes over this period were compared between groups using linear mixed models for continuous variables to account for age.
RESULTS: There were 162 matched pairs (N=324, 52% female) with mean (SD) age of 15.3 (8.2) and 14.9 (7.9) years for MI and non-MI patients respectively (P=0.6). MI patients aged 5-23 had poorer FEV1% compared to non-MI patients (estimate -0.070 SE [0.02], P=0.003). There were no significant differences in P. aeruginosa isolation rates; however S. aureus isolation rates were lower in MI patients (72%) compared to non-MI (82%) (OR 0.6 [0.3-1.0], P=0.03). Chronic colonisation rates for P. aeruginosa and S. aureus were not significantly different between groups. MI patients aged 2-20 had significantly lower BMI Z-scores over time (estimate -0.25 SE [0.1], P=0.02). MI patients were more likely to receive oral feed supplements (OR 2.8 [1.4-6.1], P=0.003) and gastrostomy formation (OR 4.4 [1.1-24.6], P=0.02).
CONCLUSIONS: CF patients with MI may have worse lung function, growth and nutrition than non-MI patients over time. Meconium ileus may be an early poor prognostic factor for CF.

PMID: 31672555 [PubMed - as supplied by publisher]