Transparency and diversity in cystic fibrosis research.

Lancet. 2020 Aug 29;396(10251):601

Authors: McGarry M

PMID: 32861304 [PubMed - in process]

Transparency and diversity in cystic fibrosis research.

Lancet. 2020 Aug 29;396(10251):601-602

Authors: Holman B, DeVito NJ, Vassar M

PMID: 32861303 [PubMed - in process]

Three-dimensional magnetic resonance imaging ultrashort echo-time cones for assessing lung density in pediatric patients.

Pediatr Radiol. 2020 Aug 29;:

Authors: Zeimpekis KG, Geiger J, Wiesinger F, Delso G, Kellenberger CJ

Abstract
BACKGROUND: MRI of lung parenchyma is challenging because of the rapid decay of signal by susceptibility effects of aerated lung on routine fast spin-echo sequences.
OBJECTIVE: To assess lung signal intensity in children on ultrashort echo-time sequences in comparison to a fast spin-echo technique.
MATERIALS AND METHODS: We conducted a retrospective study of lung MRI obtained in 30 patients (median age 5 years, range 2 months to 18 years) including 15 with normal lungs and 15 with cystic fibrosis. On a fast spin-echo sequence with radial readout and an ultrashort echo-time sequence, both lungs were segmented and signal intensities were extracted. We compared lung-to-background signal ratios and histogram analysis between the two patient cohorts using non-parametric tests and correlation analysis.
RESULTS: On ultrashort echo-time the lung-to-background ratio was age-dependent, ranging from 3.15 to 1.33 with high negative correlation (Rs = -0.86). Signal in posterior dependent portions of the lung was 18% and 11% higher than that of the anterior lung for age groups 0-2 and 2-18 years, respectively. The fast spin-echo sequence showed no variation of signal ratios by age or location, with a median of 0.99 (0.98-1.02). Histograms of ultrashort echo-time slices between controls and children with aggravated cystic fibrosis with mucus plugging and wall thickening exhibited significant discrepancies that differentiated between normal and pathological lungs.
CONCLUSION: Signal intensity of lung on ultrashort echo-time is higher than that on fast spin-echo sequences, is age-dependent and shows a gravity-dependent anterior to posterior gradient. This signal variation appears similar to lung density described on CT.

PMID: 32860525 [PubMed - as supplied by publisher]

The role of biochemical testing in cystic fibrosis.

Malays J Pathol. 2020 Aug;42(2):297-300

Authors: Abdul Rahim FH, Thambiah CS, Samsudin IN, Mohamed Mokhtar N

Abstract
INTRODUCTION: Cystic fibrosis (CF) is a life-limiting autosomal recessive disorder as a result of CF transmembrane conductance regulator gene mutation. It has a wide range of disease severity in patients with the same genotype.
CASE REPORT: A 5-year-old Malay boy with a history of recurrent pneumonia, presented with productive cough, fever and worsening tachypnoea. Physical examination revealed coarse crepitations, reduced breath sounds and clubbing. Biochemical investigations showed that he had respiratory type 2 failure as a result of bronchiectasis. Sweat conductivity done twice was raised supporting a diagnosis of CF. Other investigations such as bronchoscopy to look for congenital anomaly of the lung, infectious disease screening and tuberculosis, fungal and viral culture and sensitivity were negative. Further cascade screening revealed high sweat conductivity results in his siblings.
DISCUSSION: Although CF prevalence is low in Malaysia, it is nevertheless an important diagnosis to be recognised as it is associated with increased morbidity.

PMID: 32860386 [PubMed - as supplied by publisher]

Crushing pancreatic enzymes with enteral feeds in an extremely premature infant with cystic fibrosis-a novel and effective technique.

Eur J Clin Nutr. 2020 Aug 28;:

Authors: Grunert J, Tai A

PMID: 32859988 [PubMed - as supplied by publisher]

Cyst growth in ADPKD is prevented by pharmacological and genetic inhibition of TMEM16A in vivo.

Nat Commun. 2020 Aug 28;11(1):4320

Authors: Cabrita I, Kraus A, Scholz JK, Skoczynski K, Schreiber R, Kunzelmann K, Buchholz B

Abstract
In autosomal dominant polycystic kidney disease (ADPKD) multiple bilateral renal cysts gradually enlarge, leading to a decline in renal function. Transepithelial chloride secretion through cystic fibrosis transmembrane conductance regulator (CFTR) and TMEM16A (anoctamin 1) are known to drive cyst enlargement. Here we demonstrate that loss of Pkd1 increased expression of TMEM16A and CFTR and Cl- secretion in murine kidneys, with TMEM16A essentially contributing to cyst growth. Upregulated TMEM16A enhanced intracellular Ca2+ signaling and proliferation of Pkd1-deficient renal epithelial cells. In contrast, increase in Ca2+ signaling, cell proliferation and CFTR expression was not observed in Pkd1/Tmem16a double knockout mice. Knockout of Tmem16a or inhibition of TMEM16A in vivo by the FDA-approved drugs niclosamide and benzbromarone, as well as the TMEM16A-specific inhibitor Ani9 largely reduced cyst enlargement and abnormal cyst cell proliferation. The present data establish a therapeutic concept for the treatment of ADPKD.

PMID: 32859916 [PubMed - as supplied by publisher]

Cystic fibrosis newborn screening: the importance of bloodspot sample quality.

Arch Dis Child. 2020 Aug 28;:

Authors: Doull I, Course CW, Hanks RE, Southern KW, Forton JT, Thia LP, Moat SJ

Abstract
OBJECTIVE: Wales has an immunoreactive trypsin (IRT)-DNA cystic fibrosis (CF) newborn screening (NBS) programme. Most CF NBS false negative cases are due to an IRT concentration below the screening threshold. The accuracy of IRT results is dependent on the quality of the dried bloodspot (DBS) sample. The aim of this study was to determine the cause of false negative cases in CF NBS and their relationship to DBS quality.
DESIGN: Longitudinal birth cohort.
SETTING: Wales 1996-2016.
PATIENTS: Children with CF.
INTERVENTIONS: Identification of all CF patients with triangulation of multiple data sources to detect false negative cases.
MAIN OUTCOME MEASURES: False negative cases.
RESULTS: Over 20 years, 673 952 infants were screened and 239 were diagnosed with CF (incidence 1:2819). The sensitivity of the programme was 0.958, and positive predictive value was 0.476. Eighteen potential false negatives were identified, of whom eight were excluded: four screened outside Wales, two had complex comorbidities, no identified cystic fibrosis transmembrane conductance regulator (CFTR) variants on extended analysis and thus not considered to have CF and two were diagnosed after their 16th birthday. Of the 10 false negatives, 9 had a low DBS IRT and at least one common CFTR variant and thus should have received a sweat test under the programme. DBS cards were available for inspection for five of the nine false negative cases-all were classified as small/insufficient or poor quality.
CONCLUSIONS: The majority of false negatives had a low bloodspot IRT, and this was associated with poor quality DBS. The optimal means to improve the sensitivity of our CF NBS programme would be to improve DBS sample quality.

PMID: 32859613 [PubMed - as supplied by publisher]

From Mouse to Man and Back: Closing the Correlation Gap between Imaging and Histopathology for Lung Diseases.

Diagnostics (Basel). 2020 Aug 26;10(9):

Authors: Tielemans B, Dekoster K, Verleden SE, Sawall S, Leszczyński B, Laperre K, Vanstapel A, Verschakelen J, Kachelriess M, Verbeken E, Swoger J, Vande Velde G

Abstract
Lung diseases such as fibrosis, asthma, cystic fibrosis, infection and cancer are life-threatening conditions that slowly deteriorate quality of life and for which our diagnostic power is high, but our knowledge on etiology and/or effective treatment options still contains important gaps. In the context of day-to-day practice, clinical and preclinical studies, clinicians and basic researchers team up and continuously strive to increase insights into lung disease progression, diagnostic and treatment options. To unravel disease processes and to test novel therapeutic approaches, investigators typically rely on end-stage procedures such as serum analysis, cyto-/chemokine profiles and selective tissue histology from animal models. These techniques are useful but provide only a snapshot of disease processes that are essentially dynamic in time and space. Technology allowing evaluation of live animals repeatedly is indispensable to gain a better insight into the dynamics of lung disease progression and treatment effects. Computed tomography (CT) is a clinical diagnostic imaging technique that can have enormous benefits in a research context too. Yet, the implementation of imaging techniques in laboratories lags behind. In this review we want to showcase the integrated approaches and novel developments in imaging, lung functional testing and pathological techniques that are used to assess, diagnose, quantify and treat lung disease and that may be employed in research on patients and animals. Imaging approaches result in often novel anatomical and functional biomarkers, resulting in many advantages, such as better insight in disease progression and a reduction in the numbers of animals necessary. We here showcase integrated assessment of lung disease with imaging and histopathological technologies, applied to the example of lung fibrosis. Better integration of clinical and preclinical imaging technologies with pathology will ultimately result in improved clinical translation of (therapy) study results.

PMID: 32859103 [PubMed - as supplied by publisher]

Short-Chain Fatty Acids Promote Mycobacterium avium subsp. hominissuis Growth in Nutrient-Limited Environments and Influence Susceptibility to Antibiotics.

Pathogens. 2020 Aug 26;9(9):

Authors: Silva CAME, Rojony R, Bermudez LE, Danelishvili L

Abstract
Mycobacterium avium subsp. hominissuis (MAH) is a common intracellular pathogen that infects immunocompromised individuals and patients with pre-existing chronic lung diseases, such as cystic fibrosis, who develop chronic and persistent pulmonary infections. The metabolic remodeling of MAH in response to host environmental stresses or within biofilms formed in bronchial airways plays an important role in development of the persistence phenotype contributing to the pathogen's tolerance to antibiotic treatment. Recent studies suggest a direct relationship between bacterial metabolic state and antimicrobial susceptibility, and improved antibiotic efficacy has been associated with the enhanced metabolism in bacteria. In the current study, we tested approximately 200 exogenous carbon source-dependent metabolites and identified short-chain fatty acid (SCFA) substrates (propionic, butyric and caproic acids) that MAH can utilize in different physiological states. Selected SCFA enhanced MAH metabolic activity in planktonic and sessile states as well as in the static and established biofilms during nutrient-limited condition. The increased bacterial growth was observed in all conditions except in established biofilms. We also evaluated the influence of SCFA on MAH susceptibility to clinically used antibiotics in established biofilms and during infection of macrophages and found significant reduction in viable bacterial counts in vitro and in cultured macrophages, suggesting improved antibiotic effectiveness against persistent forms of MAH.

PMID: 32859077 [PubMed - as supplied by publisher]

Sleep disorders are distinctively associated with exercise intolerance and sedentary behavior in children with cystic fibrosis.

Sleep Med. 2020 Jul 18;74:145-151

Authors: Barbosa RRB, Coelho PF, Liberato FMG, Vidal PDR, Couto Olimpio de Carvalho RB, Melotti RCNC, Donadio MVF

Abstract
OBJECTIVE: To evaluate the presence of sleep disorders and its associations with exercise capacity and daily physical activity levels among children and adolescents with CF.
METHODS: Children age 6-18 years with a diagnosis of CF were recruited. Information regarding sociodemographic profile, pulmonary function and nutritional status were collected. Sleep disorders (polysomnography), exercise capacity (modified shuttle test - MST) and daily physical activity levels (questionnaire and five days accelerometer use) were evaluated.
RESULTS: Thirty-one patients, median age of 9.6 years and forced expiratory volume in 1 s (FEV1) of 68.1 ± 24.4%, were included. Obstructive sleep apnea syndrome (OSAS) was present in 32.3% and nocturnal hypoxemia in 29%. The MST distance correlated with the mean peripheral oxyhemoglobin saturation (SpO2) during sleep (r = 0.40) and the percent of total sleep time with SpO2<90% (r = -0.49). The final MST SpO2 correlated with the occurrence of OSAS (r = -0.48) and mean nocturnal SpO2 (r = 0.45). Sedentary activities, as measured by accelerometry, correlated with sleep architecture, including the percent of stage II (r = 0.60) and rapid eye movement (REM) stage sleep (r = -0.37). Patients with OSAS and nocturnal hypoxemia presented lower values (p < 0.05) of distance and final SpO2 in the MST. Nocturnal hypoxemia was the main variable to influence exercise capacity (r2 = 0.521).
CONCLUSION: Sleep disorders are distinctively related with exercise capacity and daily physical activity levels, as nocturnal hypoxemia is associated with exercise intolerance and sleep architecture disorders are associated with sedentary physical activity levels.

PMID: 32858275 [PubMed - as supplied by publisher]

Activity of airway antimicrobial peptides against cystic fibrosis pathogens.

Pathog Dis. 2020 Aug 28;:

Authors: Cabak A, Hovold G, Petersson AC, Ramstedt M, Påhlman LI

Abstract
Antimicrobial peptides are important players of the innate host defence against invading microorganisms. The aim of this study was to evaluate the activity of airway antimicrobial peptides against the common cystic fibrosis (CF) pathogen Pseudomonas aeruginosa, and to compare it to the emerging multi-drug resistant CF pathogens Achromobacter xylosoxidans and Stenotrophomonas maltophilia. Clinical bacterial isolates from CF patients were used, and the antimicrobial activity of human beta-defensin 2 and 3, LL37 and lysozyme was evaluated using radial diffusion assay and viable counts. The cell surface zeta potential was analysed to estimate the net charge at the bacterial surface. Of the bacterial species included in the study, A. xylosoxidans was the most resistant to antimicrobial peptides, whereas P. aeruginosa was the most susceptible. The net charge of the bacterial surface was significantly more negative for P. aeruginosa compared to A. xylosoxidans, which may in part explain the differences in susceptibility.

PMID: 32857857 [PubMed - as supplied by publisher]

O-Methylation of the glycopeptidolipid acyl chain defines surface hydrophobicity of Mycobacterium abscessus and macrophage invasion.

ACS Infect Dis. 2020 Aug 28;:

Authors: Daher W, Leclercq LD, Viljoen A, Karam J, Dufrêne YF, Guerardel Y, Kremer L

Abstract
Mycobacterium abscessus, an emerging pathogen responsible for severe lung infections in cystic fibrosis patients, displays either smooth (S) or rough (R) morphotypes. The S-to-R transition is associated with reduced levels of glycopeptidolipid (GPL) production and is correlated with increased pathogenicity in animal and human hosts. While the structure of GPL is well established, its biosynthetic pathway is incomplete. In addition, the biological functions of the distinct structural parts of this complex lipid remain elusive. Herein, the fmt gene encoding a putative O-methyltransferase was deleted in the M. abscessus S variant. Subsequent biochemical and structural analyses demonstrated that methoxylation of the fatty acyl chain of GPL was abrogated in the Δfmt mutant and this defect was rescued upon complementation with a functional fmt gene. In contrast, introduction of fmt derivatives mutated at residues essential for methyltransferase activity failed to restore GPL defects, indicating that fmt encodes an O-methyltransferase. Unexpectedly, phenotypic analyses showed that Δfmt was more hydrophilic than its parental progenitor, as demonstrated by hexadecane-aqueous buffer partitioning and atomic force microscopy experiments with hydrophobic probes. Importantly, the invasion rate of THP-1 macrophages by Δfmt was reduced by 50% when compared to the wild-type strain. Together, these results indicate that Fmt O-methylates the lipid moiety of GPL and plays a substantial role in conditioning the surface hydrophobicity of M. abscessus as well as in the early steps of interaction between the bacilli and macrophages.

PMID: 32857488 [PubMed - as supplied by publisher]

Correction to: Physiologically Based Pharmacokinetic Modeling of CFTR Modulation in People with Cystic Fibrosis Transitioning from Mono or Dual Regimens to Triple-Combination Elexacaftor/Tezacaftor/Ivacaftor.

Pulm Ther. 2020 Aug 27;:

Authors: Tsai A, Wu SP, Haseltine E, Kumar S, Moskowitz SM, Panorchan P, Shah K

Abstract
The original version of this article unfortunately contained a mistake.

PMID: 32856286 [PubMed - as supplied by publisher]

Efficacy and safety of TOBI Podhaler® in Pseudomonas aeruginosa-infected bronchiectasis patients: iBEST study.

Eur Respir J. 2020 Aug 27;:

Authors: Loebinger MR, Polverino E, Chalmers JD, Tiddens HAWM, Goossens H, Tunney M, Ringhausen FC, Hill AT, Pathan R, Angyalosi G, Blasi F, Elborn SJ, Haworth CS, iBEST-1 Trial Team

Abstract
INTRODUCTION: The study aimed to determine the efficacy of a safe and well-tolerated dose and regimen of tobramycin inhalation powder (TIP) on Pseudomonas aeruginosa (Pa) sputum density in patients with bronchiectasis (BE).
METHODS: This is a phase II, double-blind, randomised study in BE patients aged ≥18 years with chronic Pa infection. Patients were randomised 1:1:1 to either Cohort A: 3 capsules of TIP O.D. (84 mg); Cohort B: 5 capsules O.D. (140 mg) or Cohort C: 4 capsules B.I.D. (224 mg). Within each cohort, patients were further randomised 2:2:1 either to TIP continuously, TIP cyclically (alternating 28 days of TIP and placebo) or placebo for 16 weeks, respectively, and were followed up for 8 weeks.
RESULTS: Overall, 107 patients were randomised to Cohorts A (n=34), B (n=36) and C (n=37). All three TIP doses significantly reduced the Pa sputum density from baseline to Day 29 versus placebo in a dose-dependent manner (p≤0.0001, each). A smaller proportion of patients in the continuous-TIP (34.1%) and cyclical-TIP (35.7%) groups experienced pulmonary exacerbations versus placebo (47.6%) and also required fewer anti-pseudomonal antibiotics (38.6% on continuous-TIP and 42.9% on cyclical-TIP) versus placebo (57.1%) although not statistically significant. Pulmonary exacerbation of BE was the most frequent (37.4%) adverse event (AE). Overall, TIP was well tolerated, however, 23.4% of the patients discontinued the study drug due to AEs.
CONCLUSION: Continuous- and cyclical-TIP regimens with all three doses were safe and effective in reducing the Pa sputum density in patients with BE and chronic Pa infection.

PMID: 32855225 [PubMed - as supplied by publisher]

Ivacaftor Modifies Cystic Fibrosis Neutrophil Phenotype in Subjects with R117H Residual Function CFTR Mutations.

Eur Respir J. 2020 Aug 27;:

Authors: Hardisty GR, Law SM, Carter S, Grogan B, Singh PK, McKone EF, Gray RD

PMID: 32855222 [PubMed - as supplied by publisher]

Projecting the impact of delayed access to elexacaftor/tezacaftor/ivacaftor for people with Cystic Fibrosis.

J Cyst Fibros. 2020 Aug 05;:

Authors: Stanojevic S, Vukovojac K, Sykes J, Ratjen F, Tullis E, Stephenson AL

Abstract
BACKGROUND: Therapies that target the underlying defect in Cystic Fibrosis (CF) will likely impact the future characteristics of the CF population and healthcare utilization. The objectives of this study were to estimate the potential impact of elexacaftor/tezacaftor/ivacaftor on morbidity and mortality, and the impact of delayed access.
METHOD: A microsimulation transition model was applied to Canadian CF Registry data to forecast lung disease severity, pulmonary exacerbations, deaths and transplants to 2030 under three scenarios: 1) no availability of elexacaftor/tezacaftor/ivacaftor, 2) availability in 2021 ('early') or 3) availability in 2025 ('delayed'). Published Phase III data on treatment effects were used to estimate transition rates between disease severity states.
RESULTS: Under specific assumptions regarding disease state and treatment effect applied to the Canadian CF population it is projected that by 2030, early introduction of elexacaftor/tezacaftor/ivacaftor is expected to reduce the number of individuals with severe lung disease by 60% (95% CI 55.3; 63.9), increase the number of individuals with mild lung disease by 18% (95%CI 18.2; 19.0) and reduce the number of pulmonary exacerbations by 19% (95%CI 18.9; 19.5). Earlier introduction of elexacaftor/tezacaftor/ivacaftor could reduce deaths by 15% (95% 13.2; 18.4) and improve the median age of survival by 9.2 years (7.5; 10.8) over a 10-year period. The expected benefits of therapy are cumulative, therefore delayed access to elexacaftor/tezacaftor/ivacaftor will result in preventable health care utilization and deaths.
CONCLUSIONS: Delayed access to elexacaftor/tezacaftor/ivacaftor will have a negative impact on lung health and survival in the CF population.

PMID: 32855088 [PubMed - as supplied by publisher]

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

"Cystic Fibrosis"

These pubmed results were generated on 2020/08/28

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.

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

"Cystic Fibrosis"

These pubmed results were generated on 2020/08/28

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.

Explaining the sex effect on survival in cystic fibrosis: a joint modeling study of UK registry data.

Epidemiology. 2020 Aug 06;:

Authors: Taylor-Robinson D, Schlüter DK, Diggle PJ, Barrett JK

Abstract
BACKGROUND: Male sex is associated with better lung function and survival in people with cystic fibrosis but it is unclear whether the survival benefit is solely due to the sex-effect on lung function.
METHODS: This study analyzes data between 1996 and 2015 from the longitudinal registry study of the UK Cystic Fibrosis Registry. We jointly analyze repeated measurements and time-to-event outcomes to assess how much of the sex effect on lung function also explains survival. These novel methods allow examination of association between percent of forced expiratory volume (%FEV1) and covariates such as sex and genotype, and survival, in the same modeling framework. We estimate the probability of surviving one more year with a probit model.
RESULTS: The dataset includes 81,129 lung function measurements of %FEV1 on 9,741 patients seen between 1996 and 2015 and captures 1,543 deaths. Males compared to females experienced a more gradual decline in %FEV1 (difference 0.11 per year 95%CI 0.08 to 0.14). After adjusting for confounders, both overall level of %FEV1 and %FEV1 rate of change are associated with the concurrent hazard for death. There was evidence of a male survival advantage (probit coefficient 0.15; 95% CI 0.10, 0.19) which changed little after adjustment for %FEV1 using conventional approaches but was attenuated by 37% on adjustment for %FEV1 level and slope in the joint model (0.09; 95% CI 0.06, 0.12).
CONCLUSIONS: We estimate that about 37% of the association of sex on survival in cystic fibrosis is mediated through lung function.

PMID: 32841985 [PubMed - as supplied by publisher]

Sleep-disordered breathing in cystic fibrosis.

Sleep Med. 2020 Jun 05;74:57-65

Authors: Shakkottai A, Nasr SZ, Hassan F, Irani S, O'Brien LM, Chervin RD

Abstract
INTRODUCTION: Cystic fibrosis (CF) is a life-shortening, genetic disease that affects approximately 30,000 Americans. Although patients frequently report snoring, mouth breathing, and insomnia, the extent to which sleep-disordered breathing (SDB) may underlie these complaints remains unknown.
METHODS: Single-center retrospective review of polysomnography results from referred patients with and without CF individually-matched (1:2) for age, gender, race, and body mass index (BMI).
RESULTS: Mean ages were 8.0 ± 5.2 (sd) and 35.9 ± 12.9 years, among 29 children and 23 adults with CF respectively. The CF and non-CF groups were well-matched in age and BMI. Subjects with vs. without CF had three times greater odds of moderate-severe SDB (apnea-hypopnea index (AHI) ≥ 5 in children, ≥ 15 in adults) (p = 0.01). Nocturnal oxygen saturation nadir (Minimum SpO2) was lower among CF vs. non-CF groups (p = 0.002). For every 1-unit increase in AHI, the decline in Minimum SpO2 was larger for subjects with vs. without CF (p = 0.05). In subjects with CF, forced expiratory volume in 1 s percent predicted (FEV1 PPD) was associated with Minimum SpO2 (Pearson r = 0.68, p < 0.0001) but not AHI (r = -0.19, p = 0.27). For every 1-unit increase in AHI, magnitude of decline in Minimum SpO2 was larger for those with low vs. normal FEV1 PPD (p = 0.01).
CONCLUSION: Severity of SDB may be worse among referred patients with vs. without CF. The SDB may modify the relationship between CF lung disease and nocturnal hypoxemia. Markers of lung disease severity including lung function do not predict SDB severity, suggesting the need for routine polysomnography to screen for this sleep disorder.

PMID: 32841845 [PubMed - as supplied by publisher]